TWI382839B - Controlled release corticosteroid compositions and methods for the treatment of otic disorders - Google Patents

Description

Controlled release corticosteroid composition and method for treating ear disorders

Vertebrates have a pair of ears that are symmetrically located on opposite sides of the head. The ear acts as an organ that detects the sound receptor and maintains a balanced body position. The ear can be roughly divided into three parts: the outer ear, the middle ear (middle ear) and the inner ear (inside the ear).

The present invention discloses a controlled release composition, formulation, method of manufacture, method of treatment, use, kit, and delivery device for at least one corticosteroid to at least one structure or region of the ear. The present invention discloses a controlled release formulation for delivering corticosteroids to the ear. In some embodiments, the target portion of the ear is the middle ear or the middle of the ear. In some embodiments, the target portion of the ear is the inner ear, or the inside of the ear. In other embodiments, the target portion of the ear is both the middle ear and the inner ear. In certain embodiments, the controlled release formulation further comprises a fast or immediate release component for delivering a corticosteroid to the target ear structure. All formulations contain an acceptable carrier for the ear.

The present invention also discloses methods and compositions for treating ear disorders by administration of a controlled release formulation containing a corticosteroid. In certain embodiments, the ear disorder is Meniere's disease, Meniere's syndrome, or sensorineural hearing loss. In another embodiment, the ear disorder is an autoimmune inner ear disorder (AIED). The present invention also discloses local delivery of controlled release steroid compositions and formulations to suppress or ameliorate hearing and vestibular damage due to AIED, which may be triggered by other immune conditions, including ankylosing spondylitis, systemic lupus erythematosus ( SLE) system, Hugh's ( Syndrome, Cogan's disease, ulcerative colitis, Wegener's granulomatosis, rheumatoid arthritis, inflammatory bowel disease and cutaneous sclerosis and Behcet's disease Known as Bechet's disease-adamantiades). In other embodiments, the ear is dysfunctional to the middle ear. In other embodiments, the otic disorders of the vestibule are vestibular neuronitis, postural dizziness, Ramsay Hunt's Syndrome (herpes zoster infection), syphilis infection, drug-induced inner ear injury, auditory nerve tumor, Old age deafness, otosclerosis or ankle disease.

The present invention discloses a controlled release composition for treating an otic disorder comprising a therapeutically effective amount of one of a corticosteroid, a controlled release auris-acceptable excipient, and an auris-acceptable carrier. In one aspect, the controlled release auris-acceptable excipient is selected from the group consisting of an auris-acceptable polymer, an auris-acceptable viscosity enhancer, an auris-acceptable gel, an auris-acceptable hydrogen gel a gel or a combination thereof.

In certain embodiments, the pH of the composition and the actual osmotic pressure and/or volume osmolality are formulated to ensure that the body structure of the target ear structure is maintained constant. For example, the peripheral lymph has a volumetric osmotic concentration of between about 270 and 300 mOsm/L, and the compositions disclosed herein are optionally modulated to provide an actual volumetric osmotic concentration of from about 150 to about 1000 mOsm/L. In a particular embodiment, the formulations disclosed herein provide an actual volumetric osmolality at the target site of action (e.g., inner ear and/or peripheral lymph and/or endolymph) of from about 150 to about 500 mOsm/L. In a particular embodiment, the formulations disclosed herein provide an actual volumetric osmolality at the target location of action (e.g., inner ear and/or peripheral lymph and/or endolymph) of from about 200 to about 400 mOsm/L. In a particular embodiment, the formulations disclosed herein provide an actual volumetric osmolality at the target site of action (e.g., inner ear and/or peripheral lymph and/or endolymph) of from about 250 to about 350 mOsm/L. Similarly, the pH of the peripheral lymph is about 7.2-7.4, while the pH of the formulation of the invention (e.g., using a buffer) is between about 5.5 and about 9.0. In a particular embodiment, the pH of the formulation is between about 6.0 and about 7.6. In a particular embodiment, the pH of the endolymph is between about 7.2 and 7.9, and the pH of the formulation of the invention (e.g., using a buffer) is between about 5.5 and about 9.0, or between about 6.5 and about 8.0.

In certain aspects, the controlled release auris-acceptable excipient is biodegradable and/or bioremovable (eg, degraded and/or removed via urine, feces or other drainage routes). In another aspect, the controlled release composition further comprises an ear acceptable mucoadhesive, an acceptable penetration enhancer or an acceptable bioadhesive.

In one aspect, the controlled release composition is delivered using a drug delivery system which is a needle and syringe, pump, microinjection device, and in situ formed sponge material or combinations thereof. In certain embodiments, the corticosteroid controlling the release composition has a limit, or is a systemic release but is systemic, systemically toxic, has poor PK characteristics, or the like, when administered systemically. In still other aspects, the corticosteroid is methyl dehydrocorticosterol, shell cortisol, dehydrocortisol, methyl dehydrocortisol, deoxycorticosterone, 11-deoxycorticosterone, 18-hydroxyl -11-deoxycorticosterone, beclomethasone, tris-cortisol or a combination thereof. In another aspect, the corticosteroid is a phosphate ester or ester prodrug of a steroid. In another aspect, the corticosteroid is a salt of a steroid.

The present invention also discloses a method of treating an otic disorder comprising administering a composition and a formulation disclosed herein using the following schedule: every 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 days at least once, at least once a week, at least once every two weeks, at least once every three weeks, at least once every four weeks, at least once every five weeks, at least once every six weeks; or at least once a month, every two At least once a month, at least once every three months, at least once every four months, at least once every five months, at least once every six months, at least once every seven months, at least once every eight months, every nine At least once a month, at least once every ten months, at least once every eleven months, or at least once every twelve months. In a particular embodiment, the controlled release formulation disclosed herein provides a sustained dose of corticosteroid to the inner ear between subsequent doses of the controlled release formulation. That is, as exemplified by the exemplification, if a new dose of the corticosteroid controlled release formulation is injected into the round window membrane via the ear every 10 days, the controlled release formulation provides an effective dose of corticosteroid during the 10 day period to Inner ear (eg, throughout the round window film).

In another aspect, the composition is administered to bring the composition into contact with the round window film. In one aspect, the composition is administered via an in-ear injection.

The present invention provides a pharmaceutical composition for treating an ear disease or condition, which is formulated to provide a therapeutically effective amount of methyl dehydrocorticosteroid, methyl dehydrocortisol or dehydrocortisol, the composition comprising a substantially low degradation product of methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, the composition further comprising two or more properties selected from the group consisting of:

(i) between about 0.1% by weight and about 10% by weight of methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof;

(ii) between about 16% by weight and about 21% by weight of a polyoxyethylene-polyoxypropylene trimeric copolymer having the formula E106 P70 E106;

(iii) sterilized water, buffered in an amount to provide a pH between about 5.5 and about 8.0;

(iv) multiparticulate methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol;

(v) a gelation temperature between about 19 ° C and about 42 ° C;

(vi) less than about 50 colony forming units (cfu) per g of microbial formulation, and

(vii) A body weight of less than about 5 endotoxin units per kilogram of body weight.

In certain embodiments, the pharmaceutical compositions described herein comprise:

(i) between about 0.1% by weight and about 10% by weight of methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof;

(ii) between about 16% by weight and about 21% by weight of a polyoxyethylene-polyoxypropylene trimeric copolymer having the formula E106 P70 E106;

(iii) Multiparticulate methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol.

In certain embodiments, the pharmaceutical compositions described herein comprise:

(i) between about 0.1% by weight and about 10% by weight of methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof;

(ii) between about 16% by weight and about 21% by weight of a polyoxyethylene-polyoxypropylene trimeric copolymer having the formula E106 P70 E106;

(iii) multiparticulate methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol;

(iv) a gelation temperature between about 19 ° C and about 42 ° C.

In certain embodiments, the pharmaceutical compositions disclosed herein provide a delivery volume osmotic concentration of between about 250 and 320 mOsm/L.

In certain embodiments, the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the formulation over a period of at least 3 days. In certain embodiments, the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the formulation over a period of at least 5 days. This methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the formulation over a period of at least 10 days.

In certain embodiments, the pharmaceutical composition is an ear-acceptable thermoreversible gel. In certain embodiments, the polyoxyethylene-polyoxypropylene triblock copolymer is biodegradable and/or bioremovable (eg, the copolymer can be biodegraded by the body, such as in urine, feces) Or similar to remove and remove). In certain embodiments, the composition further comprises a mucoadhesive. In certain embodiments, the formulation further comprises a penetration enhancer. In certain embodiments, the formulation further comprises a thickening agent. In certain embodiments, the formulation further comprises a dye.

In yet another embodiment, the present invention provides a formulation further comprising a drug delivery device selected from the group consisting of a needle and a syringe, a pump, a microinjection device, a core, an in situ formation of a sponge material, or the like.

In certain embodiments, the compositions described herein are those wherein the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol or a pharmaceutically acceptable salt thereof has a limited or no systemic release, A composition of systemic toxicity, poor PK characteristics, or a combination thereof. In certain embodiments of the compositions described herein, the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is a free base, a free acid, a salt, a prodrug, or the like. The form of the combination. In certain embodiments of the compositions described herein, the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is administered as a phosphate or ester prodrug. In certain embodiments of the compositions described herein, such sterols are methyl dehydrocorticosteroids or methyldehydrocorticosterol acetate. In certain embodiments, the compositions described herein comprise methyl dehydrocorticosterol, methyl dehydrocortisol, dehydrocortisol, or a pharmaceutically acceptable salt thereof, a prodrug, or a combination thereof, Immediate release agent.

In certain embodiments, the compositions described herein are those wherein the methyl dehydrocorticosterol, methyl dehydrocortisol, or dehydrocortisol comprises multiple particles. In certain embodiments, the compositions described herein are those wherein the methyl dehydrocorticosterol, methyl dehydrocortisol, or dehydrocortisol is substantially in the form of micronized particles. In certain embodiments of the compositions described herein, the methyl dehydrocorticosterol is in the form of a micro-methyl dehydrocorticosterol powder.

In certain embodiments, the compositions described herein further comprise an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is a Na/K ATPase modulator, a chemotherapeutic agent, a collagen, a gamma-globulin, an interferon, an antimicrobial agent, an antibiotic, a topical effect An anesthetic, a platelet activating factor antagonist, an ear protectant, a nitric oxide synthase inhibitor, an anti-stun agent, a vasopressin antagonist, an antiviral agent, an anti-emetic, or a combination thereof.

In certain embodiments, the compositions described herein are those wherein the pH of the composition is between about 6.0 and about 7.6.

In certain embodiments of the compositions described herein, the ratio of polyoxyethylene-polyoxypropylene triblock copolymer having the formula E106 P70 E106 to a thickener is from about 40:1 to about 5: 1. In certain embodiments, the thickening agent is carboxymethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose.

In certain embodiments, the ear disease or condition is Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, aging-related hearing loss, autoimmune ear disease, or tinnitus.

The invention also provides a method of treating an ear disease or condition comprising administering to a subject in need of an in-ear composition comprising a therapeutically effective amount of methyl dehydrocorticosterol, methyl dehydrocortisol Or dehydrocortisol, the composition comprising a low degradation product of substantially methyl dehydrocorticosteroid, methyl dehydrocortisol or dehydrocortisol, the composition further comprising two or two selected from the following characteristics:

(i) between about 0.1% by weight and about 10% by weight of methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable prodrug or salt thereof;

(ii) between about 16% by weight and about 21% by weight of a polyoxyethylene-polyoxypropylene trimeric copolymer having the formula E106 P70 E106;

(iii) sterilized water, buffered in an amount to provide a pH between about 5.5 and about 8.0;

(iv) less than about 50 colony forming units (cfu) per microgram of microbial agent, and

(v) One body is less than about 5 endotoxin units per kilogram of body weight.

In certain embodiments of the methods of the present disclosure, the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the composition over a period of at least 3 days. In certain embodiments of the methods of the present disclosure, the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the composition by a period of at least 5 days. In certain embodiments of the methods of the present disclosure, the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the composition over a period of at least 10 days.

In certain embodiments of this method, the composition is administered throughout the inner ear round window. In certain embodiments of the method, the ear disease or condition is Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, aging-related hearing loss, autoimmune ear disease or tinnitus.

The present invention provides controlled release corticosteroid compositions and formulations for the treatment of ear diseases, including Meniere's disease and sensorineural hearing loss.

A few therapeutic products are available to treat otic disorders such as AIED; however, a systemic route via the oral, intravenous or intramuscular route is currently used to deliver such therapeutic agents. Systemic drug administration produces a potential inequality in drug concentration, with a higher circulating amount in serum and a lower amount in the middle ear and inner ear organ structures. Therefore, a large amount of drug is needed to overcome this unequality to deliver a sufficient, therapeutically effective amount of the drug to the inner ear. In addition, systemic drug administration increases the likelihood of systemic toxicity and adverse side effects because of the high blood volume required to perform adequate local delivery to the target site. Systemic toxicity may also occur as a result of liver breakdown and action of the therapeutic agent, which forms toxic metabolites that effectively eliminate any advantages obtained by administration.

In order to overcome the toxicity of delivery and accompanying side effects, the present invention discloses methods and compositions for the topical delivery of a therapeutic agent to a target ear structure. For example, access to the vestibule and cochlear organ will pass through the middle ear, which includes the inner ear round window membrane, the oval window/tibia panel, the annular ligament, and the ear cartilage sac/tibia.

Accordingly, the present invention provides controlled release corticosteroid formulations and compositions for topical treatment of the target ear structure, thereby avoiding the side effects of systemic administration of corticosteroid formulations and compositions. The topically applied corticosteroid formulation and composition are compatible with the target ear structure and can be administered directly to the intended target ear structure, such as the cochlear region, the ear canal or the outer ear, or administered to a structure that directly communicates with the inner ear region. Including but not limited to round window membranes, cochlear crowns or oval window membranes. By specifically aligning the ear structure, undesirable side effects from systemic treatment can be avoided. Furthermore, clinical trials have shown the advantages of prolonged exposure of the drug to the peripheral lymph of the cochlea, such as when the therapeutic agent is administered at multiple times, with improved clinical efficacy of transient hearing loss. Thus, by providing a controlled release corticosteroid formulation or composition to treat an otic disorder, a constant, variable and/or prolonged source of corticosteroids can be provided to an individual or patient suffering from an otic disorder to reduce or remove treatment variations. Sex. Accordingly, one embodiment of the present invention provides a formulation that provides for at least one release at a therapeutically effective dose at a variable or constant rate, thereby ensuring continuous release of at least one dose. In certain embodiments, the corticosteroids disclosed herein are administered as an immediate release formulation or composition. In other embodiments, the steroid and/or ATPase modulating agent is administered in a sustained release formulation that is released in a sustained, variable or in a pulsed manner or a variation thereof. In still another embodiment, the corticosteroid formulation is administered in an immediate release and controlled release formulation that is sustained, variable or pulsed or a modified release thereof. This release may optionally be dependent on environmental or physiological symptoms, for example, an external ionic environment (see, for example, Release system, Johnson & Johnson).

In addition, topical treatment of the subject's ear structure also provides the use of previously undesired therapeutic agents, including agents with poor PK profiles, poor absorption, low systemic release, and/or toxicity issues. Because of the local standard of the corticosteroid formulation and composition, as well as the biological blood barrier present in the inner ear, the risk of adverse effects due to previously unique or unproductive corticosteroids can be reduced. Accordingly, corticosteroids rejected by physicians for use in the treatment of otic disorders due to adverse or non-effective effects of corticosteroids are also contemplated in the context of the examples described herein.

One embodiment disclosed herein also includes the use of an additional ear-compatible compatibilizer in combination with the corticosteroid formulations and compositions disclosed herein. When used, the agent aids in the treatment of hearing or balance loss or dysfunction due to autoimmune disorders, including dizziness, tinnitus, hearing loss, balance disorders, infection, or the like. Accordingly, agents that improve or reduce dizziness, tinnitus, hearing loss, balance disorders, infection, inflammatory response, or the like may also be combined with corticosteroids, including anti-TNF agents, antiemetic agents, chemotherapy. Agents, including blood chemotherapeutic agents, azathiaprine or amine folate; collagen, gamma globulin, interferon, kepazon, central nervous system agents, local anesthetics, antibiotics, platelet-activating factor antagonists, Treatment of a combination of nitric oxide synthase inhibitors and the like.

In addition, the present invention describes an auris-acceptable controlled release corticosteroid formulation and treatment provided to the ear region of the subject in need thereof, which includes the inner ear and an additional oral dose of corticosteroid to the individual in need thereof. In certain embodiments, this oral dose of corticosteroid can be administered prior to administration of an acceptable controlled release corticosteroid formulation for the ear, such that the oral dose is reduced in time to provide an acceptable controlled release of the corticosteroid formulation. Alternatively, this oral dose of corticosteroid can be administered during the administration of an acceptable controlled release corticosteroid formulation for the ear, so the oral dose is reduced with the time available to provide an acceptable controlled release of the corticosteroid formulation. Alternatively, this oral dose of corticosteroid can be administered after administration of an acceptable controlled release corticosteroid formulation to the ear, so the oral dose is reduced in time to provide an acceptable controlled release of the corticosteroid formulation.

In addition, the corticosteroid pharmaceutical composition or formulation also includes carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, and salts and/or buffers for regulating osmotic pressure. The carrier, adjuvant and other excipients are compatible with the environment of the standard ear structure. Accordingly, carriers, adjuvants, and excipients that are non-toxic or minimally toxic are specifically contemplated to allow for effective treatment of the ear disorders contemplated by the present invention with minimal side effects in the target area or portion. To prevent ototoxicity, the corticosteroid pharmaceutical compositions or formulations disclosed herein may be directed to different regions of the ear structure, including but not limited to auricular, vestibular bone and membrane labyrinth, cochlear bone and membrane labyrinth and others. An anatomical or physiological structure located in the inner ear.

Specific definition

As used herein, the term "ear-acceptable" is used in relation to a formulation, composition or ingredient which does not have a continuing detrimental effect on the treated subject in the middle and inner ear. As used herein, "ear-medical acceptable" refers to a substance, such as a carrier or diluent, which does not abolish the biological activity or properties of the compound to the middle and inner ear, and is relatively or reducing the middle and inner ear. Toxicity, that is, administration of the substance to a body does not cause undesired utility or interacts with any of the components contained in the composition in a deleterious manner. .

The use of a particular compound or pharmaceutical composition for the purpose of ameliorating or ameliorating the reduction, delay, or delay of the syndrome, disorder, or symptom of a particular ear disease is due to or accompanied by administration of the compound or composition. The onset of symptoms, the development of a slow course of disease, or a shortened period, whether permanent or temporary, continuous or instantaneous.

"Antioxidants" are ear-medicinal acceptable antioxidants and include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite, and vitamin E. In a particular embodiment, the antioxidant promotes the desired chemical stability. Antioxidants are also useful for counteracting the ototoxic effects of certain therapeutic agents, including agents used in combination with the ear agents described herein.

"Inner ear" means the inner ear, including the cochlea and vestibular labyrinth, and the inner ear round window of the connected cochlea and middle ear.

"ear bioavailability" or "inner ear bioavailability" or "middle ear bioavailability" or "external ear bioavailability" means that the dosage of the compound disclosed in the present invention is available in the ear structure of the animal or human being studied, respectively. percentage.

"Middle ear" means the middle ear, which includes the tympanic, ossicular, and oval windows that connect the middle and inner ear.

"External ear" refers to the outer ear, including the ear flap, the ear tube, and the eardrum, which connects the outer ear to the middle ear.

"Blood plasma concentration" refers to the concentration of a compound provided by the present invention in the plasma component of a patient's plasma.

A "carrier material" is an excipient that is compatible with the release profile properties of corticosteroids, standard ear structures, and ear-acceptable pharmaceutical formulations. Such carrier materials include, for example, binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Aur-medical compatible carrier materials" include, but are not limited to, gum arabic, gelatin, colloidal cerium oxide, calcium glycerol phosphate, calcium lactate, maltodextrin, glycerin, magnesium citrate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol ester, sodium caseinate, soy lecithin, taurocholic acid, phospholipid choline, sodium chloride, calcium triphosphate, potassium diphosphate, cellulose and cellulose conjugate, sugar stearin Sodium citrate, staghorn, monoglyceride, diglyceride, pregelatinized starch and the like.

The term "diluent" refers to a chemical compound that is used for dilution prior to delivery of a corticosteroid and is compatible with the standard ear structure.

"Dispersant" and/or "viscous modifier" are substances that control the diffusion and homogeneity of corticosteroids via a liquid medium. Examples of diffusion promoters/dispersants include, but are not limited to, hydrophilic polymers, electrolytes, Tween 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone) And sugar-based dispersants such as hydroxypropyl cellulose (eg HPC, HPC-SL and HPC-L), hydroxypropyl methylcellulose (eg HPMC K100, HPMC K4M, HPMC K15M and HPMC K100M) , sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalic acid, hydroxypropyl methyl cellulose Acetate stearate (HPMCAS), amorphous cellulose, aluminum magnesium niobate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/ethylene acetate copolymer (S630), 4-(1,1 , 3,3-tetramethylbutyl)-phenol polymer and ethylene oxide with formaldehyde (also known as tetrabutyl phenolic), poloxamer (eg, Pluronic F127, Pluronics F68 , F88 And F108 , which is a block copolymer of ethylene oxide and propylene oxide; and Poloxamines (eg Tetronic 908) Also known as Poloxamine 908 , which is a tetrakid functional block copolymer derived from ethylene diamine by propylene oxide and ethylene oxide (BASF, Pasani, New Jersey, USA), polyvinylpyrrolidone K12, Polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/ethylene acetate copolymer (S-630), polyethylene glycol (for example having a molecular weight of about 300) To about 6000, or about 3350 to about 4000, or about 7000 to about 5400 polyethylene glycol), sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gum (eg , tragacanth and gum arabic), tannin extract, sanxian gum (including Sanxian gum), sugar, cellulose (such as sodium carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose), poly Sorbitol-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, pravone, carbomer, polyvinyl alcohol (PVA), A combination of alginate, polyglucamine, and the like. Plasticizers such as cellulose or triethyl cellulose can also be used as the dispersing agent. The dispersing agent for the liposome dispersion and the autoemulsion dispersion for the corticosteroid described herein is diterpenoid phospholipid choline phosphocholine (c8-c18), phospholipid ethanolamine (c8-c18), Phospholipid glycerol (c8-c18), natural phospholipid choline from egg or soybean, natural phospholipid glycerol from egg or soybean, cholesterol and isopropyl myristyl ester. .

"Pharmaceutical absorption" or "absorption" refers to the process by which a corticosteroid is moved from a localized site of administration, exemplified by a round window membrane of the inner ear and a barrier (a round window membrane, as described hereinafter) to the inner or inner ear structure. The term "co-administration" or its like as used herein is meant to encompass the administration of a corticosteroid to a patient and to include a treatment regimen of corticosteroids with the same or different routes of administration or at the same or different times.

The term "effective amount" or "therapeutically effective amount" as used herein refers to the administration of a full dose of a corticosteroid which is expected to slow down the symptomatic group of one or more treated diseases or conditions. For example, the administration of corticosteroids disclosed herein results in a reduction and/or alleviation of symptoms, syndromes or pathogens of AIED. For example, an "effective amount" for therapeutic use is the amount of corticosteroids that need to include a formulation as disclosed herein to provide a reduction or amelioration of disease syndrome without undue adverse side effects. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a corticosteroid composition as described herein is effective to achieve the desired pharmaceutical effect or therapeutic improvement without undue adverse side effects. In certain embodiments, it is to be understood that "an effective amount" or "a therapeutically effective amount" is different from one another by the metabolism of the compound administered, the age, the weight, the general symptoms of the individual, the symptoms being treated. The severity of the symptoms being treated and the judgment of the physician. It is also understood that "an effective amount" in an extended-release dosage form may differ from "an effective amount in an immediate-release dosage form" based on pharmacokinetic and pharmacodynamic considerations.

The term "enhance" or "enhancing" means the increase or prolongation of the potential or duration of action of a corticosteroid, or the reduction of any adverse symptoms, as a result of the administration of a therapeutic agent. pain. For example, with regard to enhancing the utility of the corticosteroids disclosed herein, the term "promoting" means increasing or prolonging the utility of the other therapeutic agents used in conjunction with the corticosteroids disclosed herein, whether in terms of potential or duration of action. As used herein, "promoting-effective amount" means an amount of a corticosteroid or other therapeutic agent that is suitable for enhancing the utility of other therapeutic agents or corticosteroids in an intended system. When used in a patient, the effective amount for such use depends on the severity and duration of the disease, disorder or condition, prior treatment, the patient's state of health and response to the drug, and the judgment of the treating physician.

The term "inhibition" includes preventing, slowing or reversing the development of symptoms, such as AIED, or the progression of symptoms in a patient in need of treatment.

The terms "kit" and "manufactured item" are used synonymously.

"Pharmacodynamic" means a factor of biological response in which the relative drug concentration observed is measured at a desired location within the target ear structure.

"Pharmacokinetics" means the factor at which the appropriate concentration of the drug is determined and maintained at the intended location within the target ear structure.

In prophylactic applications, a composition comprising a corticosteroid of the invention is administered to a patient susceptible to or at risk of a particular disease, disorder or symptom, such as Meniere's disease, or a patient suffering from an AIDD-related disease, including only Examples of ankylosing spondylitis, systemic lupus erythematosus (SLE), and Hugh's ( Syndrome, Cogan's disease, ulcerative colitis, Wegener's granulomatosis, inflammatory bowel disease, rheumatoid arthritis, cutaneous sclerosis and Behcet's disease. This amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount is also dependent on the patient's state of health, weight, and the like.

A "prodrug" refers to a corticosteroid that is converted to a parent drug in vivo. In a particular embodiment, a prodrug is enzymatically metabolized to a biological, pharmaceutical or therapeutically active form of the compound by at least one step or process. To produce a prodrug, a pharmaceutically active compound is modified to allow the active compound to be reconstituted in vivo. In one embodiment, the prodrug is designed to alter metabolic stability or drug delivery characteristics, mask side effects or toxicity, or alter other properties or properties of the drug. In certain embodiments, the compounds provided herein are derived into a convenient prodrug.

"Circular window film" covers the cochlear window in humans (also known as round windows, round windows (fenestrae rotunda), or round windows). In humans, the thickness of the round window film is about 70 microns.

"Solvent" refers to the ear - acceptable compounds such as triethylene glycerol, triethyl citrate, ethyl oleate, ethyl octanoate, sodium lauryl sulfate, sodium octyl sulfonate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol , n-butanol, isopropanol, cholesterol, bile salts, polyethylene glycol 200-600, tetrahydrofuran glycol ether, , propylene glycol and dimethyl isosorbide and similar.

"Stabilizer" means a compound that is compatible with the standard otic structure of the ear, such as any antioxidants, buffers, acids, preservatives, and the like. Stabilizers include, but are not limited to, any of the following: (1) improved compatibility of the excipient with a container or a delivery system, including a syringe or a glass vial, and (2) improved composition of the composition. Stability, or (3) improved formulation stability.

As used herein, a "steady state" is when the amount of drug administered to the subject's ear structure is equal to the amount of drug that is eliminated during the interval of administration to result in a flat or constant dose exposure within the target structure.

The term "individual" as used herein is used to refer to an animal, preferably a mammal, including human or non-human. Words such as patients and individuals can be used interchangeably.

"Surfactant" refers to an ear-acceptable compound such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triethylene glycol glycerol, vitamin E TPGS, phospholipids, lecithin, Phosphocholine (c8-c18), phospholipid ethanolamine (c8-c18), phospholipid glycerol (c8-c18), sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, Polaxomers , bile salts, glyceryl monostearate, ethylene oxide and propylene oxide copolymers, for example (BASF), and similar. Some other surfactants include polyoxyethylene fatty acid glycerin and vegetable oil, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ether and alkyl phenyl ether, such as octylphenol polyether 10, xin Polyphenol 40. In certain embodiments, a surfactant is included to enhance physical stability or for other purposes.

The words "treat", "treating" or "treatment" as used herein include reducing, attenuating or ameliorating a disease or symptom, a syndrome, preventing additional syndromes, improving or preventing syndromes, and inhibiting Potential metabolic causes of a disease or condition, such as stopping the progression of a disease or condition, slow-release disease or symptom, degenerative disease or condition, alleviating symptoms caused by a disease or symptom, or preventing or stopping treatment or stopping a disease or symptom. Syndrome.

Ear anatomy

As shown in the figure below, the outer ear is the outer part of the organ and the outer part of the ear wing (auricle), the ear canal (outer ear canal) and the tympanic membrane is also known as the tympanic membrane. This wing is the fleshy part of the outer ear and can be found on the first two sides, collecting sound waves and guiding them to the ear canal. Therefore, the outer ear function is to collect and direct the sound waves to the tympanic membrane and the middle ear.

The middle ear is a chamber filled with air after the tympanic membrane, called the tympanic chamber. The tympanic membrane, also known as the tympanic membrane, is a membrane that separates the outer ear by the ear. The middle ear is located in the tibia and includes the space in the three ear bones (the ossicle): the malleus, the anvil, and the tibia. The ossicles are joined together by tiny ligaments that form a bridge across the tympanic space. The malleus, one end of which is connected to the tympanic membrane, is connected at its front end to the anvil, which is sequentially connected to the tibia. The tibia is joined to the oval window and one of the two windows is located in the tympanic chamber. A fibrous tissue layer, known as an annular ligament, connects the tibia to the oval window. The tympanic membrane vibrates first by the sound waves of the outer ear. This vibration is transmitted through the cochlea through the ossicular and oval windows, which converts the fluid in the inner ear. Thus, the configured ossicle provides a mechanical connection between the tympanic membrane and the oval window in the liquid-filled inner ear, wherein the sound is transduced and transmitted to the inner ear for further processing. Loss of hardening, rigidity, or movement of the ossicle, tympanic membrane, or ovate window will result in hearing loss, such as otosclerosis, or sacral sclerosis.

The tympanic cavity is also connected to the larynx via the eustachian tube. The Eustachian tube provides the ability to have equal pressure between the external air and the middle ear cavity. The inner ear round window is part of the inner ear but can also be accessed in the tympanic cavity, which opens to the cochlea of the inner ear. The inner ear round window is covered by a membrane consisting of three layers: an outer or mucosal layer, an intermediate or fibrous layer, and an inner membrane that is in direct fluid communication with the cochlea. Therefore, the inner ear round window communicates directly with the inner ear via the inner membrane.

The movement of the oval and the inner ear round window is interconnected, that is, when the tibia is transported by the tympanic membrane to the oval window to move inwardly to grip the inner ear liquid, the inner ear round window (more correctly the round window membrane) corresponds to the outward Launch and move away from the cochlear fluid. Movement of the inner ear round window allows liquid movement in the cochlea, which in turn causes movement of hair cells in the cochlea, allowing for hearing signal conversion. The rigidity or movement of the inner ear round window causes hearing loss because the cochlear fluid lacks the ability to move. The current seminar has focused on implanting a mechanical transducer on the inner ear round window that bypasses the normal conduction path through the oval window and provides an amplified input to the cochlear chamber.

Auditory signal conduction occurs in the inner ear. The liquid-filled inner ear (inner ear) consists of two major components: the cochlea and the vestibular organ. The inside of the inner ear is located in the bone or bone labyrinth, which is a complex staggered series located in the tibia of the skull. The vestibular organ is a balanced organ and consists of a triad tube and a vestibule. The three semicircular canals are configured to each other so that they can be moved along the three orthogonal planes by the movement detection head of the liquid and subsequently processed by the sensor of the semicircular canal, which is called the auditory ridge. The auditory ridge contains hair cells and supporting cells and is covered by a semi-穹 gelatin substance called a top cap. The hair cells of this hair cell are buried in the top cap. This semi-regulator detects dynamic balance, rotation or angular movement balance.

When the head rotates rapidly, the semicircular canal moves with the head, but the endolymphatic fluid in the membranous semicircular canal remains stable. The endolymphatic fluid pushes against the top cap, which tends to one side. When the top cap is tilted, it bends over the hair on the hair cells of the ridge, which initiates a sensory pulse. Because each half gauge is located on a different half, the corresponding auditory ridge of each semicircular canal has a different response to the same movement of the head. This produces a burst of pulses that are transmitted to the central nervous system on the vestibular branch of the vestibular cochlear nerve. The central nervous system interprets these messages and initiates appropriate responses to maintain balance. The importance of the central nervous system is the cerebellum, the sense of balance and balance of the media.

The vestibule is the central portion of the inner ear and contains a mechanical receptor with hair cells that determines the static balance, or the position of the head relative to gravity. Static balance plays a role when the head does not move or moves in a straight line. The membrane diameter in the vestibule is divided into two capsule-like structures, an elliptical capsule and a balloon. Each structure sequentially contains a small structure called the macula, which responds to the maintenance of static equilibrium. This macula consists of sensory hair cells embedded in a gelatinous substance (similar to a top cap) that covers the macula. Calcium carbonate particles, called ossicles, are embedded in the surface of the gelatinous layer.

When the head is in the up position, the hair cells are straight along the macula. When the head is skewed, the gelatinous substance and the ossicle correspond to the skew, and the hair cells on the macula are partially bent. This bending action initiates a signal pulse to the central nervous system where the vestibular branch of the vestibular cochlear nerve travels, which in turn relays a motorized pulse to a suitable muscle to maintain balance.

The cochlea is the part of the inner ear that is related to hearing. The cochlea is a conical tube structure, and its coil is a snail-like component. The interior of the cochlea is divided into three regions, which are further defined by the vestibular membrane and the basement membrane. The part on the vestibular membrane is the vestibular step, which extends from the oval window to the cochlear apex and contains peripheral lymphoid fluid, which is a low potassium but high sodium content aqueous liquid. The basement membrane defines a tympanic region that extends from the top of the cochlea to the inner ear round window and also contains peripheral lymphatics. This brain base film contains thousands of hard fibers that extend gradually from the inner ear round window to the top of the cochlea. When activated by sound, the fibers of the bottom film vibrate. Between the vestibular step and the tympanic catheter is a cochlear catheter that terminates at the top of the cochlea as a closed capsule. The cochlear duct contains endolymph fluid, which is similar to the fluid in the cerebrospinal ridge and has a high potassium content.

The T-hearing sensory organ - the Coriolis spiral is located in the basement membrane and extends upward into the cochlear duct. Coriolis loudspeakers contain hair cells that have hair-like protrusions that extend from a free surface and are in contact with a gelled surface, which is referred to as a film. Although the hair cells do not have an axon, they are surrounded by sensory nerve fibers that form the vestibular cochlear nerve (brain nerve VIII) cochlear branches.

As discussed, the oval window is also known as an elliptical window that communicates with the tibia to convey the sound of vibrations by the tympanic membrane. The vibration transmitted to the oval window increases the pressure in the liquid-filled cochlea by the peripheral lymph and vestibular steps/drums, which in turn causes the membrane on the inner ear round window to expand in response. The inward compression of the uniform oval window/outward expansion of the inner ear circular window allows liquid movement within the cochlea without altering the inner cochlear pressure. However, when the vibration travels through the peripheral lymph in the vestibular diameter, it produces a corresponding resonance in the vestibular membrane. These corresponding resonances travel through the endolymph of the cochlear duct and are transmitted to the basement membrane of the brain. When the basement membrane oscillates, or moves up and down, the Coriolis spirals move along it. The hair cell receptor in the Coriolis spiral is then moved against the abdomen, causing mechanical deformation in the film. This mechanical deformation initiates a nerve impulse that travels through the vestibular cochlear nerve to the central nervous system, mechanically transmitting a sound wave as a signal, which is then processed by the central nervous system.

disease

Symptoms of ear disorders including dysregulation of the inner ear, middle ear, and outer ear include, but are not limited to, hearing loss, nystagmus, dizziness, tinnitus, inflammation, swelling, infection, and congestion. These disorders can have many causes, such as infection, trauma, inflammation, tumors, and adverse reactions to drugs or other chemotherapeutic agents. Many causes of impaired hearing and/or balance or inflammation can be attributed to autoimmune disorders and/or inflammatory responses to cytokine mediators. In one embodiment, the ear disorder is Meniere's disease. In one embodiment, the ear disorder is sensorineural hearing loss. In one embodiment, the ear disorder is autoimmune inner ear disorder (AIED). In one embodiment, the ear disorder is Meniere's disease. In still another embodiment, the ear disorder is Meniere's syndrome, vestibular neuronitis, postural dizziness, Ray's syndrome (herpes zoster infection), syphilis infection, drug-induced inner ear injury, auditory nerve tumor Excessive noise hearing loss, old age deafness, otosclerosis or ankle joint disease.

The diseases described herein, including those set forth hereinafter, are treated using the steroid medical compositions disclosed herein.

Meniere's disease

Meniere's disease is a spontaneous symptom characterized by a sudden onset of dizziness, nausea, and vomiting that can last for 3 to 24 hours and may gradually disappear. Progressive hearing loss, tinnitus, and pressure perception in the ear occur through the time of the disease. The cause of Meniere's disease may be related to a constant imbalance in the fluid in the inner ear, including an increase in fluid production in the inner ear or a decrease in fluid decomposition in the inner ear.

Surgery can be used to alleviate Meniere's symptoms, including disrupting vestibular function to alleviate dizziness syndrome. The purpose of these procedures is to relieve fluid pressure in the inner ear and/or disrupt inner ear balance. An endolymphatic drainage procedure that relieves fluid pressure and is performed in the inner ear to alleviate ventricular dysfunction. A vestibular nerve bypass can also be used, which can control dizziness while preserving hearing.

A standard care of Meniere's disease requires the patient to follow a low-salt diet. In a specific example, a low-salt diet is supplemented with an antibiotic. In a specific example, a low salt diet is supplemented with a pentamycin administration. In a specific example, the low salt diet is supplemented with an oral steroid administration. In a specific example, a low-salt diet is supplemented with a oral administration of Prysone (25-50 mg PO/IM/PR q4-6h).

In one set of embodiments, a patient treated with standard care as described above for the treatment of Meniere's disease is replaced with an auris-acceptable formulation and method for controlling the release of corticosteroids as described herein. In one set of embodiments, a patient treated with Meniere's disease using standard care as described above, but which is resistant or non-responsive to this treatment, is acceptable for the release of corticosteroids as described herein. Formula and method alternatives.

Meniere's syndrome

Meniere's syndrome, which presents similar symptoms to Meniere's disease, is the second cause of illness caused by other diseases, such as thyroid disease caused by syphilis or inflammation of the inner ear. Therefore, Meniere's syndrome is the second role of the pathogenesis of normal production or resorption of endolymph, including internal dissociation abnormalities, electrolyte imbalance, autoimmune dysfunction, drug preparations, infections (eg parasitic infections) or High lipidosis. Treatment with patients suffering from Meniere's syndrome is similar to Meniere's disease.

Sensorineural hearing loss

Sensorineural hearing loss is affected when the inner ear component or the accompanying nerve component is affected and may contain a nerve, that is, when the auditory or auditory nerve pathway of the brain is affected, or the component is sensed. Hearing loss is perceived as hereditary, or it may be caused by auditory trauma (ie, very loud noise), a viral infection, drug-induced or Meniere's disease. Neurological hearing loss can be caused by brain tumors, infections, or multiple brain and nerve disorders, such as stroke. Some hereditary diseases, such as Refsum's disease (defective accumulation of branched fatty acids), can also cause neurological disorders that affect hearing loss. The auditory nerve is destroyed by demyelinating diseases such as spontaneous inflammation, demyelinating diseases (including multiple sclerosis), transverse myelitis, Devic's disease, progressive progressive multiple leukoencephalopathy, Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy and anti-MAG peripheral neuropathy.

The incidence of transient deafness, or sensorineural hearing loss occurs in about 1 in 5,000 people and is caused by viral or bacterial infections such as mumps, measles, colds, varicella, cytomegalovirus, syphilis or infectious mononuclear leukocytes. Increased disease, or physical damage to the inner ear organs. In some cases, the cause was not identified. Tinnitus and dizziness may be accompanied by an instant deafness, which gradually subsides. Oral corticosteroids are often prescribed to treat sensorineural hearing loss. In some cases, surgery is required.

The formulations and methods described herein include the treatment of sensorineural hearing loss, including the treatment of transient sensorineural hearing loss, including spontaneous transient sensorineural hearing loss. For SSHL, current treatment options include high-dose oral steroids with methyl dehydrocorticosterol (4-10 mg/ml) or methyl-dehydrocortisol (40-62.5 mg/ml) for 2 weeks (4-7 Day treatment + 7-10 days reduction). As noted herein, high doses of oral steroids are associated with undesirable side effects and adverse conditions. Thus, it is contemplated that the formulations and methods described herein for sustained release of steroids, local delivery to the inner ear, result in significantly fewer side effects than oral/system steroid use. In one embodiment, the ISSHL characteristic is unilateral sensorineural hearing loss during a seizure of less than 72 hours, wherein HL is defined as >30 dB at a test frequency of at least 3 proximity.

A standard care for spontaneous transient sensorineural hearing loss (ISSHL) is treatment with high doses of oral steroids. In a particular example, one body is treated with a high dose of oral steroid for about two weeks. In a particular example, one body is treated with a high dose of oral steroid for about two weeks, followed by a gradual reduction in oral steroids from about 7 to about 10 days. In a particular example, the oral steroid is methyl dehydrocorticosterol (4-10 mg/ml). In a particular example, the oral steroid is methyl-dehydrocortisol (40-62.5 mg/ml).

In one set of embodiments, in one set of embodiments, a patient treated with the standard care treatment ISSHL described above is replaced with an auris-acceptable formulation and method for controlling the release of corticosteroids as described herein. In one set of embodiments, a patient who is treated with ISSHL using standard care as described above, but which is resistant or non-responsive to this treatment, is replaced by an auris-acceptable formulation and method for controlling the release of corticosteroids as described herein. .

Excessive noise causes hearing loss

Hearing loss can be caused by prolonged exposure to loud noises such as loud music, heavy instruments or implements, airplanes, gunshots or other human noise. This hearing loss occurs as a result of destruction of the inner ear hair cell receptor. This type of hearing loss is often accompanied by tinnitus. Permanent damage to hearing loss is usually diagnosed.

Although currently unable to treat noise-induced hearing loss, several treatments have been experimentally developed, including treatment with insulin-growth factor 1 (IGF-1). (Lee et al., Otol. Neurotol. (2007) 28: 976-981).

Elderly deafness

Deafness or aging - the hearing loss is part of normal aging and because of the Coriolis spiral in the inner ear (the Corti organ receptor cells degenerate). Other causes may also constitute a reduction in several nerve fibers in the vestibular cochlear nerve and loss of elasticity in the midbrain of the cochlea. The treatment of permanent hearing loss due to deafness or excessive noise is currently unknown.

Drug-induced inner ear damage

Damage caused by the administration of a drug, including specific antibiotics, diuretics (such as ethacrynic acid and furosemide), aspirin, and aspirin-like substances (such as salicylic acid) Salt) and quinine. Degeneration of the inner ear organ can be accelerated by the impaired renal function, which results in a reduced clearance of the drug and its metabolites. Medicine can affect hearing and balance, but it is unlikely to affect hearing to a large extent.

For example, neomycin, kenmycin, and amikacin have a greater utility in hearing ratio balance. The antibiotics ziosin, mycotoxin and tacromycin affect both hearing and balance. Streptomycin, another commonly administered antibiotic that causes hearing loss in addition to dizziness, and may cause Dandy's syndrome, which is difficult to walk in the dark and triggers the feeling of environmental movement at each step. Aspirin, when taken at high doses, may cause temporary hearing loss and tinnitus, which is a symptom of the sound when there is no external sound. Similarly, quinine, escicolic acid, and foximab can cause temporary or permanent hearing loss.

Autoimmune inner ear disease

Autoimmune inner ear disease (AIED) is one of the few reversible causes of sensorineural hearing loss. It is a disorder that occurs less frequently in both adults and children, and is usually a bilateral disorder of the inner ear and vestibular function. The AIED source may attack the inner ear structure with autoantibodies and/or immune cells, but with other autoimmune symptoms. In many cases, AIED occurs without systemic autoimmune symptoms, but up to one-third of patients also suffer from systemic autoimmune diseases such as inflammation, intestinal disease, rheumatoid arthritis, ankylosing spondylitis, systemic erythema Lupus (SLE), Hugh's syndrome, Kegang's disease, ulcerative colitis, Wegener's granulomatosis, and scleroderma. Besett's disease, multiple system diseases are also often heard, and there are also vestibular problems. There is some evidence that food-related allergies are the cause of autoimmunity in the cochlea and vestibule, but there is currently no recognition of its importance in disease etiology. A classification of AIED has been developed (Harris and Keithley, (2002) Autoimmune inner ear disease, in Otorhinolaryngology Head and Neck Surgery. 91, 18-32).

Treatment with corticosteroids relieves symptoms of AIED. Oral administration of the corticosteroid Prysson (60 mg/day for 4 weeks) showed an improvement in pure tone and speech hearing results. The regulation of corticosteroids occurs via corticosteroid receptors or mineralocorticoid receptors.

Inflammatory disorder

Inflammatory disorders of the ear include, but are not limited to, otitis media, otitis externa, mastoiditis, bullous tympanitis, Eustachian tubal catarrh, Eustachian salpingitis, vaginitis or the like. Examples include symptoms affecting otitis media (OM) in adults and children, including acute otitis media (AOM), otitis media with otitis (OME) and chronic otitis media. OM sensitivity is multifactorial and complex, including environment, microbes, and host factors. Increases in cytokine production have been observed in effluent mediators suffering from OM individuals, including interleukin and TNF. Treatment with anti-inflammatory steroids slows the symptoms of inflammatory disorders in the ear (eg, otitis media, Eustachian tubal catarrh or the like). In some instances, the inflammatory disorder is a bacterial infection (eg, OM). In some instances, a combination of an antibiotic and an anti-inflammatory corticosteroid can alleviate OM symptoms.

Pharmacy

The present invention provides a corticosteroid composition or formulation that ameliorates or reduces otic disorders, including Meniere's disease, sensorineural hearing loss and/or inflammatory disorders and concomitant symptoms including, but not limited to, hearing loss, nystagmus , dizziness, tinnitus, inflammation, swelling, infection and congestion. Ear disorders including AIED or Meniere's disease and/or inflammatory disorders have responses to the etiology and symptoms of the agents or other agents disclosed herein. Corticosteroids not described herein but useful for the amelioration or elimination of otave disorders are expressly included and are intended to be encompassed within the scope of embodiments of the invention.

Furthermore, agents which have been previously shown to be toxic, harmful or ineffective during systemic or topical application to other organ systems, such as toxic metabolites formed by liver action, drugs which are toxic to specific organs, tissues or systems, Agents that require high amounts to achieve utility, are not liberated via the system pathway, or are released via poor properties of pK can also be used in certain embodiments herein. For example, side effects of methyl dehydrocorticosteroids include: sodium retention, excess water retention, septic heart failure in susceptible patients, hypertension, muscle weakness, muscle wasting, osteoporosis, sputum rupture, gastric ulcer, ulcerative esophagus Inflammation, skin thinning, skin reaction, weakened wound healing, convulsions, dizziness, headache, psychological disorders, Cushing's syndrome, delayed growth of children, diabetes, hirsutism, cataracts, glaucoma, weight gain, Increase appetite and. nausea. Pharmaceutical agents having limited or no systemic release, systemic toxicity, poor pK properties, or the like, are desirably included in the scope of embodiments of the invention.

The corticosteroid formulations disclosed herein can be selectively aligned directly to the otic structure requiring treatment; for example, a contemplated embodiment is the direct administration of the corticosteroid formulation disclosed herein to the inner ear round window membrane or the cochlear cap crown, allowing direct Enter the inner or inner ear components and treatment. In other embodiments, the corticosteroid formulations disclosed herein are applied directly to a round window. In other embodiments, direct access can be achieved by direct microinjection into the inner ear, such as via a cochlear microperfusion. This embodiment can also optionally include a drug delivery device that delivers a corticosteroid formulation via a needle to a syringe, pump, microinjection device, an in situ formed sponge material, or the like, in any combination. In still other embodiments, the administration of the corticosteroid formulation is directed to the middle ear via perforation of the inner eardrum and the corticosteroid formulation is applied directly to the affected middle ear structure, including the tympanic wall or ossicular bone, to the middle ear. Thus, the corticosteroid formulations disclosed herein can be limited to the target middle ear structure and are not lost by diffusion or leakage, for example, through the tympanic membrane of the eustachian tube or perforation.

Corticosteroids/anti-inflammatory steroids

Corticosteroids are characterized by the effects of mineralocorticoids and glucocorticoids, depending on the pharmacology of the agent. The characteristic of mineralocorticoid is its similarity to aldosterone and its effect on the amount of electrolyte and water balance. Glucocorticoids, such as endogenous glucocorticoid cortisol, which control metabolism and have anti-inflammatory properties by preventing the release of cytokines. Many agents have the degree of mineralocorticoid and glucocorticoid activity. The relative potency and activity of several synthetic glucocorticoids are shown in the table below.

Systemic glucocorticoid therapy is currently used for the treatment of autoimmune hearing loss. The basic course of treatment is carried out for several months with side effects of substantial systemic treatment. Side effects for methyl dehydrocorticosteroids include: sodium retention, excess water retention, septic heart failure in susceptible patients, hypertension, muscle weakness, muscle wasting, osteoporosis, sputum rupture, gastric ulcer, ulcerative esophagitis Skin thinning, skin reaction, weakened wound healing, convulsions, dizziness, headache, psychological disorders, Cushing's syndrome, delayed growth of children, diabetes, hirsutism, cataract, glaucoma, weight gain, increase Appetite and nausea. One advantage of using the formulations described herein is the greatly reduced systemic exposure to anti-inflammatory glucocorticoid steroids.

Dehydrocortisol is a corticosteroid with a predominantly glucocorticoid and low mineralocorticoid activity. It has about 4-5 times the potency of endogenous cortisol. It is an active metabolite of oral administration of Prysone. Methyl dehydrocorticosteroid is a corticosteroid with glucocorticoid activity. It has about 25-30 times the potency of endogenous cortisol. Methyl dehydrocorticosterone sodium phosphate is a water-soluble phosphate prodrug of monomethyl dehydrocorticosterol. A method for determining the methyl dehydrocorticosteroid phosphate in the peripheral lymphatic fluid of the cochlea has been disclosed (Liu et al, J. of Chromatography B (2004), 805(2): 255-60). Tetancortisol is a synthetic glucocorticoid that can be administered orally, by injection, by inhalation, or as a topical cream or ointment. Teancortidol is a more potent analog. Teancortisol hexagram is a pivolyl ester of hexavolone. Beco Cortisol dipropionate is a very potent glucocorticoid drug, also known as beclometasone. Shell cortisol is a very potent corticosteroid when used in topical formulations. It has anti-inflammatory, antipruritic, tube contraction and immunomodulatory properties.

In one embodiment, the active pharmaceutical ingredient of the formulations described herein is dehydrocortisol. In another embodiment, in another embodiment, the active pharmaceutical ingredient of the formulation described herein is methyl dehydrocorticosterol. In another embodiment, the active pharmaceutical ingredient of the formulations described herein is methyl dehydrocorticosteroid phosphate. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is becocortisol. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is festibrol. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is steanocortisol. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is a spirulina ketal. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is clomipramine.

In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is a phosphate prodrug of a glucocorticoid steroid. In yet another embodiment, the active pharmaceutical ingredient of the formulations described herein is an ester prodrug of a glucocorticoid steroid. In yet another embodiment, the active pharmaceutical ingredient of the formulation described herein is selected from the group consisting of 21-acetoxypregnenolone, chlorocortisol, azestone, acinonide, Cortisol, belat Cortisol, buta cortisol, clprezin, clofibrate, lopabetasone, clocortolone, cloprednol, corticosterone, corticosterone , cortivazol, deflazacort, desonide, desoximetasone, methyl dehydrocorticosterol, diflupirone, difluorodeketide Diflucortolone), difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, acetone fluoride Fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluridolone, fluperolone acetate , fluprednidene acetate, fluorodehydrocortisol, fluranolidine Renolide), fluticacoretine propionate, formocortal, hacinionide, halobetasol propionate, halometasone, haloperidone acetate Halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, hydroxyprogesterone (medrysone), meipu Laisson, methyl dehydrocortisol, mometasone furoate, paramethasone, prednicarbate, dehydrocortisol, dehydrocortisol 25-diethylamino - acetate, dehydrocortisol sodium phosphate, predisin, prednival, prednylidene, rimexolone, tixocortol, triamian cortisol, Combination of albionol cortisol, Bennett cortisol (betanonide), hexaacetone tetanol and its phosphate prodrug or ester prodrug.

In certain embodiments, the formulations described herein have between about 0.01% and about 20% of the active ingredient of the formulation, between about 0.01% and about 10%, and between about 0.01% and about 8%. Between about 0.05-6%, between about 0.1-5%, between about 0.2-about 3%, or between about 0.1-about 2% active pharmaceutical ingredient concentration. In certain embodiments, the formulations described herein have a volume of from about 0.1 to about 70 mg/mL, between about 1 mg to about 70 mg/mL, and between about 1 mg to about 50 mg/mL, based on the volume of the formulation. , between about 1 mg/mL to about 20 mg/mL, between about 1 mg/mL to about 10 mg/mL, between about 1 mg/mL to about 5 mg/mL, or between about 0.5 mg/mL to about The concentration of active pharmaceutical ingredients between 5 mg/mL.

In certain embodiments, the formulations disclosed herein further comprise an antibiotic and are useful for treating an otic disease or condition described herein. Antibiotics include but are not limited to amikacin, mycotoxin, oxytetracycline, neomycin, typromycin, streptomycin, tyrosin, paromomycin, gelatin In addition to puromycin, loracarbif, ertapenem, doripenem, imipenem, imipenem, meropenem, cefazodime, cephalosporin, cefalotin, cephalexin , ceftazid, cefmenudene, cefoxitin, defprozil, cefotaxime, xifuxinmin, cefdinir, cefoperon, cefoperazone, ceftizoxime, cefpodoxime, cephalosporin Statins, ceftibuten, ceftizoxime, ceftriaxone sodium, cefepime, teicoplanin, vancomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, erythromycin , albinomycin, tylosin, spectinomycin, azalenol, amoxicillin, ampicillin, azlocillin, carbencillin, chlorthacillin, dichlorothiazide, fluorochlorothiazide Penicillin, mezlocillin, meticillin, phenoxypenicillin, acesulfame, penicillin, bepicillin, three Ticarcillan, cumin, colimycin, polymyxin B, capexazone, enofloxacin, gatifloxacin, lofloxacin, lomefloxacin, moxifloxacin Star, Norfossin, Ophelia, Trovfloxacin, Sulfamidon, Prontosil, Sulfonamide, Sulfamethoxazole, Sulfimimiimide , sulfsalazine, sulfsioxazole, trim ethoprim, demeclocycline, deoxytetracycline, menocycline, tetracycline, Oxtetracycline, arsenic arsenic, chloramphenicol, clindamycin, lincomycin, ethylenediamine dibutanol, foresporin, fusidic acid, Fulaiton , isonicotinic acid strontium, ranazolide, nitromethoxazole ethanol, mopirin, nitrofurantoin, plateau, pyrazine, quinolidine/dalofopine, ubiquitin , AL-15469A (Alcon Research), AL-38905 (Alcon Research) and combinations thereof.

General method of sterilization

The present invention provides an ear composition to ameliorate or alleviate the otic disorders described herein. The invention further provides a method of administering the otic composition. In certain embodiments, the composition is sterilized. The apparatus and method for sterilizing a pharmaceutical composition disclosed in the embodiments disclosed herein are for use in humans. The aim is to provide a safe pharmaceutical product with relatively no infection-causing microorganisms. The US Food and Drug Administration provides a published specification manual "Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing", which can be found at: http//www.fda.gov/cder/guidance/5882fnl.htm, which is As a reference.

Sterilization as used herein means a method of destroying or removing microorganisms present in a product or package. Any sterilizable method of the appropriate article and composition can be used. Methods of inactivating microorganisms that may be utilized include, but are not limited to, applications of superheat, lethal chemicals, or gamma radiation. In certain embodiments, a method of preparing an ear treatment formulation comprises subjecting the formulation to a sterilization process selected from the group consisting of heat sterilization, chemical sterilization, radiation sterilization, or filter sterilization. The method used will depend primarily on the nature of the device or composition being sterilized. A detailed description of many of the methods of sterilization can be found in Remington: The Science and Practice of Pharmacy published by Lippincott, Chapter 40, Williams & Wilkins, which is incorporated herein by reference.

Heat sterilization

Many methods are available for sterilization by extreme heat applications. One method is by using a saturated steam autoclave. In this method, a saturated vapor at a temperature of at least 121 ° C allows contact with the object to be sterilized. In the case where the article is sterilized, the heat is directly transferred to the microorganisms or indirectly to the microorganisms by heating the volume of the sterilized aqueous solution. This method is widely used because it allows for flexibility, safety, and economic considerations in the sterilization process.

Dry heat sterilization is used to increase the temperature to kill microorganisms and perform depyrogenation. The process is carried out in a device suitable for heating HEPA-filtered microbial free air to a temperature of at least 130-180 ° C for sterilization and for a temperature of at least 230-250 ° C for depyrogenation. Reconstituted concentrated or powdered formula water is also sterilized by autoclaving. In certain embodiments, the formulations described herein comprise a micronized agent (eg, a corticosteroid (eg, micro-methyl dehydrocorticosteroid)) that is dried by heat, such as at an internal powder temperature. It is heated at 130-140 ° C for about 7-11 hours, or sterilized by heating at an internal temperature of 150-180 ° C for about 1-2 hours.

Chemical sterilization

The chemical sterilization method is an alternative method for extreme conditions in which the product cannot withstand heat sterilization. In this method, various gases or vapors having bactericidal properties such as ethylene oxide, chlorine dioxide, formaldehyde or ozone are used as anti-apoptotic agents. The bactericidal activity of ethylene oxide, for example, from it can be used as a reactive alkylating agent. Therefore, sterilization requires ethylene oxide vapor to be in direct contact with the product being sterilized.

Radiation sterilization

One of the advantages of radiation sterilization is the ability to sterilize many forms of products without thermal degradation or other damage. The general radiation used is beta radiation or alternatively gamma radiation from a ⁶⁰ Co source. The penetrating power of gamma radiation allows for sterilization of many product types, including solutions, compositions, and heterogeneous mixtures. The bactericidal effect of radiation comes from the interaction of gamma radiation with biological macromolecules. This interaction produces charged species and free radicals. Subsequent chemical reactions, such as recombination and cross-linking, result in the loss of normal function of these biomacromolecules. Formulations described herein may also be selected for sterilization using beta radiation.

filter

Filtration sterilization is a method for removing from a solution without destroying the microorganism. A membrane filter was used to filter the heat sensitive solution. The screen is a thin, strong mixed fiber ester (MCE), polyfluorinated ethylene (PVF; also known as PVDF), or polytetrafluoroethylene (PTFE) having a pore size ranging from 0.1 to 0.22 μm. , homogeneous polymer. Different filtrations can be used to selectively filter different characteristic solutions. For example, PVF and PTFE membranes are known to be suitable for filtering organic solvents while aqueous solutions are filtered with PVF or MCE membranes. A range of screen devices for different scales can be obtained from a disposable filter attached to a single point on a syringe to a commercial scale for use in a manufacturing plant. The membrane screen can be sterilized by autoclaving or chemical sterilization. The effectiveness of the membrane filtration system is based on the following standard platforms (Microbiological Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3. Washington, DC: Health Industry Manufacturers Association, 1981) and is related to known amounts (about 10 ⁷ / The unusual small microbes of cm ² ) challenge membrane filters, such as Brevendomonas diminuta (ATCC 19146).

The pharmaceutical composition is optionally sterilized by passing through a membrane screen. A formulation containing nanoparticle (U.S. Patent No. 6,139,870) or a multilayered pore (Richard et al., International Journal of Pharmaceutics (2006), 312(1-2): 144-50) is suitable for filtration by a 0.22 μm filter. Without destroying the sterilization of its tissue structure.

In certain embodiments, the methods disclosed herein comprise sterilizing the formulation (or a component thereof) by filtration sterilization. In another embodiment, the ear-acceptable otic therapeutic formulation comprises a particle, wherein the particle formulation is suitable for filtration sterilization. In yet another embodiment, the particle formulation comprises particles having a particle size less than 300 nm, particles less than 200 nm in size, and particles less than 100 nm. In another embodiment, the ear-acceptable otic therapeutic formulation comprises a particle wherein the sterility of the particle is ensured by sterile filtration of a component solution of the precursor material. In another embodiment, the ear-acceptable formulation comprises a particle formulation wherein the sterility of the particles is ensured by cryogenic sterilization filtration. In still another embodiment, the low temperature sterilization filtration is performed at a temperature between 0 and 30 ° C, or between 0 and 20 ° C, or between 0 and 10 ° C, or between 10 and 20 ° C, or Between 20 and 30 ° C.

In another embodiment, a method of preparing an ear-acceptable particle formulation, comprising: filtering an aqueous solution containing a particle formulation via a sterile filter at a low temperature; lyophilizing the sterilization solution: and reconstituting the particle formulation with sterile water prior to administration In another embodiment. In certain embodiments, one of the formulations described herein is made from a suspension of active pharmaceutical ingredients in a single vial formulation containing micronization. A single vial formulation is prepared by mixing a sterile poloxamer solution with a sterile micronized active ingredient (e.g., methyl dehydrocorticosterol) and delivering the formulation to a sterile pharmaceutical container. In certain embodiments, a single vial containing a formulation described herein is resuspended prior to dispensing and/or administration.

In a particular embodiment, the filtering and/or filling step is performed at a gel temperature (T gel) of less than about 5 ° C below the formulation described herein, the gel formulation having a viscosity of less than the theoretical value of 100 cP to allow Use a peristaltic pump to filter at a reasonable time.

In still other embodiments, the ear-acceptable otic therapeutic formulation comprises a nanoparticle formulation wherein the nanoparticle formulation is suitable for filtration sterilization. In yet another embodiment, the nanoparticle formulation comprises a nanoparticle size of less than 300 nm, a size of less than 200 nm, or a size of less than 100 nm. In still other embodiments, the ear-acceptable formulation comprises a microsphere formulation wherein the sterility of the microspheres is ensured by sterile filtration of an organic solution of the precursor material and an aqueous solution. In still other embodiments, the ear-acceptable formulation comprises a thermoreversible gel formulation wherein the sterility of the gel formulation is ensured by cryogenic sterilization filtration. In still another embodiment, the low temperature sterilization filtration is performed at a temperature between 0 and 30 ° C, or between 0 and 20 ° C, or between 0 and 10 ° C, or between 10 and 20 ° C, or Between 20 and 30 ° C. In still other embodiments, a method of preparing an ear-acceptable thermoreversible gel formulation, comprising: filtering an aqueous solution containing a thermoreversible gel component via a sterile filter at a low temperature; lyophilizing the sterilization solution; Reconstitute the thermoreversible gel formulation with sterile water before administration.

In a particular embodiment, the active ingredient is dissolved in a convenient carrier (eg, a buffer) and separately sterilized (eg, by heat treatment, filtration, gamma irradiation); the remaining excipients (eg, liquid condensate in the presence of an ear formula) The gel component is sterilized in a separate step in a separate step (e.g., filtration and/or irradiation of the cooled mixture of excipients); the separately sterilized solutions are then aseptically mixed to provide a final ear formulation.

In some instances, conventional methods of sterilization (eg, heat treatment (eg, in an autoclave), gamma irradiation, filtration) result in a polymer component (eg, heat cure, gelatinization, or mucosa) in this formulation. Irreversible degradation of the adhesive polymer component) and/or activator. In some instances, sterilization of the ear formulation by membrane filtration (e.g., 0.2 [mu]m membrane) is not possible if the formulation contains a rocker visbreaking polymer that gels during filtration.

Accordingly, the present invention provides a method for sterilizing an ear formulation that prevents polymer components (eg, heat curing and/or gelling and/or mucoadhesive polymer components) and/or activators during sterilization Degradation. In certain embodiments, degradation of an activating agent (eg, any of the therapeutic ear agents described herein) can be utilized by the use of a particular range of pH components of the buffer component in the formulation and a particular ratio range of gelling agent. Reduce or remove. In certain embodiments, the selection of a suitable gelling agent and/or thermoset polymer may allow for the sterilization of the formulations described herein by filtration. In certain embodiments, a suitable thermoset polymer and a suitable copolymer (eg, a gelling agent) are used in combination with a particular pH range of the formulation to permit high temperature sterilization of the formulations described herein and substantially no therapeutic agent or polymer. Degradation of the agent. In a particular example, the sterilization method provided by the present invention is such that the formulation is subjected to final sterilization in an autoclave without any loss of activator and/or excipients and/or polymer components during the sterilization step and produces substantial absence. Microorganisms and / or pyrogens.

microorganism

The present invention provides an otic-acceptable composition for improving or alleviating the otic disorders described herein. A method of administration comprising the otic composition is further provided. In certain embodiments, the composition is substantially free of microorganisms. The acceptable amount of sterility is the application criteria for a defined therapeutically acceptable ear composition, including but not limited to the United States Pharmacopoeia Chapter 1111. For example, the acceptable amount of sterility includes 10 colony forming units (cfu) per gram of formulation, 50 cfu per gram of formulation, 100 cfu per gram of formulation, 500 cfu per gram of formulation or 1000 cfu per gram of formulation. In addition, acceptable amounts of sterility include the exclusion of specific undesired microbial agents. Exemplary specific dissatisfied microbial agents include, but are not limited to, Escherichia coli (E. coli), Salmonella sp., Pseudomonas aeruginosa (P. aeruginosa), and/or other specific microbial agents.

The sterility of the ear-acceptable otic formula formulation can be determined by the procedures of the United States Pharmacopoeia Nos. <61>, <62> and <71>. One of the requirements for aseptic quality control assurance, quality assurance and effective methods is the method of sterility testing. The exemplification of the sterility test is only an example of the two methods. The first was direct incubation in which a sample of the tested composition was added to the medium and incubated for a period of 21 days. The turbidity of the growth medium showed contamination. Disadvantages of this method include the small sample size reduction sensitivity of a large number of materials and the detection of microbial growth based on visual inspection. An alternative method is the membrane filtration sterility test. In this method, a volume of the product passes through a small membrane screen. This screen paper is then placed in the medium to promote the growth of microorganisms. This method has the advantage of greater sensitivity when sampling all quality products. A commercially available Millipore Steritest Aseptic Test System can be optionally used for the determination of membrane filtration sterility testing. For filtration testing of creams or ointments, use the Steritest Filtration System number TLHVSL210. For filtration testing of emulsions or viscous products, use Steritest Filtration System No. TLAREM210 or TDAREM210. For the filtration test of prefilled syringes, the Steritest filtration system number TTHASY210 was used. For filtration tests suspended in aerosol or foam materials, the Steritest Filtration System number TTHVA210 was used. For filtration testing of soluble powders in ampoules or vials, use the Steritest Filtration System number TTHADA210 or TTHADV210.

Tests for E. coli and Salmonella include incubation with lactose broth at 30-35 ° C for 24-72 hours, including incubation in MacConkey and/or EMB, 18-24 hours, and / Or use Rappaport medium. Testing for P. aeruginosa included the use of NAC agar. Chapter 62 of the United States Pharmacopoeia (USP) further identifies test procedures for specific unpleasant microorganisms.

In a particular embodiment, any of the controlled release formulations described herein have less than about 60 colony forming units (CFU) per gram of formulation, less than about 50 colony forming units, less than about 40 colony forming units, or less than about 30 Colony forming unit of microbial agent. In a particular embodiment, the formulated ear formula described herein is isotonic with endolymph and/or peripheral lymph nodes.

Endotoxin

The present invention provides an ear composition to ameliorate or alleviate the otic disorders described herein. A method of administering the composition of the ear is further provided. In certain embodiments, the composition is substantially free of endotoxin. An additional aspect of a sterilization process is the removal of by-products (hereinafter referred to as "products") derived from the killing microorganisms. The method of depyrogenation removes pyrogen from the sample. The pyrogen is an endotoxin or exotoxin that will elicit an immune response. An example of an endotoxin is a lipopolysaccharide (LPS) molecule found on the cell wall of a Gram-negative bacterium. When a sterilization process such as autoclaving or treatment with ethylene oxide to kill bacteria, the LPS residue induces a pre-inflammatory immune response, such as septic shock. Because the molecular size of endotoxin is very broad, the presence of endotoxin is expressed as "endotoxin unit" (EU). One EU is equivalent to 100 picograms of E. coli LPS. Humans can generate a response that is less than 5EU/kg of body weight. This sterility is expressed in any unit that is known in the art. In a particular embodiment, the otic compositions described herein contain a lower amount of endotoxin (eg, <4 EU/kg body weight) compared to a conventional acceptable amount of endotoxin (eg, 5 EU/kg body weight). In certain embodiments, in certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 5 EU/kg body weight of the individual. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 4 EU/kg body weight of the individual. In additional embodiments, the ear-acceptable otic therapeutic formulation has less than about 3 EU/kg body weight of the individual. In additional embodiments, the ear-acceptable otic therapeutic formulation has less than about 2 EU/kg body weight of the individual.

In certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 5 EU/kg of the formulation. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 4 EU/kg of the formulation. In additional embodiments, the ear-acceptable otic therapeutic formulation has less than about 3 EU/kg of the formulation. In certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 5 EU/kg of the product. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 1 EU/kg of the product. In additional embodiments, the ear-acceptable otic therapeutic formulation has less than about 0.2 EU/kg of product. In certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 5 EU/kg of the unit or product. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 4 EU/kg of the unit or product. In further embodiments, the ear-acceptable otic therapeutic formulation has less than about 3 EU/kg of the unit or product. In certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 5 EU/kg of the unit or product. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 4 EU/kg of the unit or product. In further embodiments, the ear-acceptable otic therapeutic formulation has less than about 3 EU/kg of the unit or product. In a particular embodiment, the presently disclosed ear compositions contain from about 1 to about 5 EU/mL of the formulation. In a particular embodiment, the disclosed ear compositions comprise from about 2 to about 5 EU/mL of the formulation, from about 3 to about 5 EU/mL of the formulation, or from about 4 to about 5 EU/mL of the formulation.

In a particular embodiment, the otic composition described herein contains a lower amount of endotoxin than a conventional acceptable amount of endotoxin (eg, 0.5 EU/mL of the formulation) (eg, <0 EU of formula 0) mL). In certain embodiments, the ear-acceptable otic therapeutic formulation has less than about 0.5 EU/mL of the formulation. In other embodiments, the ear-acceptable otic therapeutic formulation has less than about 0.4 EU/mL of the formulation. In additional embodiments, the ear-acceptable otic therapeutic formulation has less than about 0.2 EU/mL of the formulation.

As an example, pyrogen detection is performed by several methods. Suitable tests for sterility include those described in the United States Pharmacopoeia (USP) Chapter 71 Asperity Test (23rd Edition, 1995). The rabbit pyrogen test and the Limulus amebocyte lysate test are described in USP 23/151 (USP23/NF 18, Biological Tests, The United States Pharmacopeial Convention, Rockville, MD, 1995). . Alternative pyrogen detection has been developed based on single cell activation-cytokine detection. A suitable homogeneous cell line for quality control applications has been developed and demonstrated its ability to detect exothermicity in a sample that has passed the rabbit pyrogen test and the American cockroach test (Taktak et al. J. Pharm. Pharmacol. (1990), 43: 578-82). In yet another embodiment, the ear-acceptable otic therapeutic formulation is an independent depyrogen. In yet another embodiment, a method of making an ear-acceptable ear therapeutic formulation comprises testing the exothermicity of the formulation. In a particular embodiment, the formulations described herein are substantially pyrogen free.

pH and volume osmotic concentration

As used herein, "actual volume osmotic concentration" means the volumetric osmolality of a formulation by including an active agent with all excipients but excluding gelling and/or thickening agents (eg, polyoxyethylene-polyoxypropylene copolymerization). Measured with carboxymethylcellulose or the like. The actual volumetric osmolality of the formulations described herein can be measured by any convenient method, such as a freezing point drop method, as described in Viegas et al., Int. J. Pharm., 1998, 160, 157-162. The actual osmotic pressure of the ear formulations described herein is from about 100 mOsm/kg to about 1000 mOsm/kg, from about 200 mOsm/kg to about 800 mOsm/kg, from about 250 mOsm/kg to about 500 mOsm/kg, or from about 250 mOsm/kg to about 350 mOsm/ Kg or from about 280 mOsm/kg to about 320 mOsm/kg. In certain embodiments, the formulations described herein have an actual volumetric osmolality of from about 100 mOsm/L to about 1000 mOsm/L, from about 200 mOsm/L to about 800 mOsm/L, from about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm. /L to about 350 mOsm / L, or about 280 mOsm / L to about 320 mOsm / L.

In certain embodiments, the volumetric osmolality (eg, peripheral lymph) at the site of action is about the same as the deliverable volume osmotic concentration of any of the formulations described herein (ie, the material passes through or penetrates the round window membrane) Volume osmotic concentration). In certain embodiments, the formulations described herein have a deliverable volume osmotic concentration of from about 150 mOsm/L to about 500 mOsm/L, from about 250 mOsm/L to about 500 mOsm/L, from about 250 mOsm/L to about 350 mOsm/L, about From 280 mOsm/L to about 370 mOsm/L or from about 250 mOsm/L to about 320 mOsm/L.

The main cation present in the endolymph is potassium. In addition, the endolymph has a high concentration of a positive valency amino acid. The main cation present in the peripheral lymph is sodium. In a particular example, the ionic composition of the endolymph and peripheral lymphocytes regulates the electrochemical pulse of the hair cells. In a particular example, any change in the ionic balance of the endolymph or peripheral lymphocytes results in hearing loss due to conduction changes in chemical pulses along the ear hair cells. In certain embodiments, the compositions disclosed herein do not interfere with the ionic balance of the peripheral lymph. In certain embodiments, the compositions disclosed herein have the same or substantially the same ionic balance as the peripheral lymph. In certain embodiments, the compositions disclosed herein do not interfere with the ionic balance of the endolymph. In certain embodiments, the compositions disclosed herein have an ionic balance that is the same or substantially the same as the endolymph. In certain embodiments, the otic formulations described herein are formulated to provide an ionic balance that is compatible with the inner ear fluid (ie, the endolymph and/or peripheral lymph).

The Ph in the endolymph and the peripheral lymph is close to the physiological pH of the blood. The endolymph has a pH range of about 7.2-7.9; the peripheral lymph has a pH range of about 7.2-7.4. The in situ pH of the adjacent endolymph is about 7.4 and the pH away from the endolymph is about 7.9.

In certain embodiments, the pH of the compositions described herein is adjusted (eg, using a buffer) to an endolymph-compatible pH range of about 5.5 to 9.0. In a particular embodiment, the pH of the compositions described herein is adjusted to a pH range of about 5.5 to 8.0. In certain embodiments, the pH of the compositions described herein is adjusted to a pH range of about 6.0 to 7.6.

In certain embodiments, useful formulations also include one or more pH regimens or buffers. Suitable pH adjusting agents or buffers include, but are not limited to, acetates, bicarbonates, ammonium chlorides, citrates, phosphates, pharmaceutically acceptable salts thereof, combinations or mixtures thereof, in certain embodiments.

In one embodiment, when one or more buffering agents are used in the formulations disclosed herein, they are combined with, for example, a pharmaceutically acceptable carrier and are present in the final formulation, for example, from about 01% to about 20%. , about 0.5% to about 10%. In a particular embodiment of the present disclosure, the amount of buffer included in the gel formulation is such that the pH of the gel formulation does not interfere with the body's natural buffer system.

In one embodiment, the diluent is also used to stabilize the compound because the diluent provides a more stable environment. Salts dissolved in a buffer solution (which also provide pH control or maintenance) are utilized herein as diluents including, but not limited to, phosphate buffered physiological saline solutions.

In certain embodiments, any of the gel formulations described herein have a pH that facilitates sterilization of the gel formulation (eg, by filtration or aseptic mixing or heat treatment and/or autoclaving (eg, terminal sterilization)). No drug (eg, steroid) or degradation with a gel polymer. To reduce the hydrolysis and/or degradation of the otic agent and/or gel polymer during sterilization, the pH of the buffer is designed to maintain the pH of the formulation between 7 and 8 during sterilization (eg, autoclave) .

In a particular embodiment, any of the gel formulations described herein have a pH to allow for final sterilization of the gel formulation (eg, by heat treatment and/or autoclave) without degrading the gel-containing agent (eg, cortex) Steroids) or polymers. For example, to reduce hydrolysis and/or degradation of the otic agent and/or gel polymer during sterilization, the pH of the design buffer is maintained to maintain the pH of the formulation between 7-8 when warmed. Any suitable buffer is used depending on the ear used in this formulation. In some examples, as the temperature increases from about -0.03 / ℃ when the pK _a of TRIS decreases as temperature increases from about 0.003 / ℃ pK _a of increase of PBS at 250 ℉ (121 ℃) autoclave results in TRIS buffer Significant pH shifts in the liquid (i.e., more acidified), thus a relatively small upward shift in pH in the PBS buffer, thus increasing the more increased hydrolysis and/or degradation of the ear in TRIS than in PBS. Degradation of the otic agent is reduced by the use of a suitable buffer as described herein in combination with a polymeric additive (e.g., P407, CMC).

In certain embodiments, between about 5.0 and about 9.0, between about 5.5 and about 8.5, between about 6.0 and about 7.6, between about 7 and 7.8, between about 7.0 and about 7.6. Between about 7.2 and 7.6, a pH between about 7.2 and 7.4 is suitable for sterilization of the formulations described herein (e.g., by filtration or aseptic mixing or heat treatment and/or autoclaving (e.g., End sterilization ()). In a particular embodiment, the formulation pH of about 6.0, about 6.5, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6 is suitable for use in any of the compositions described herein. Sterilization (eg, by filtration or sterile mixing or heat treatment and/or high temperature pressure sterilization (eg, terminal sterilization)).

In certain embodiments, the formulation has a pH as described herein and includes a thickening agent (i.e., a viscous enhancer) that is non-limitingly exemplified by a cellulosic thickener as described herein. In certain instances, the addition of a second polymer (e.g., a thickener) and the pH of the formulation of the present invention allow for the sterilization of the formulations described herein without causing earrings in the ear formulation and/or Or substantial degradation of the polymer component. In certain embodiments, the ratio of thermally reversible poloxamer to thickener in a formulation having a pH as described herein is about 40:1, about 35:1, about 30:1, about 25: 1. About 20:1, about 15:1 or about 10:1. For example, in certain embodiments, the sustained and/or extended release formulations described herein comprise about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about 15: A combination of 1 or about 10:1 ratio of pluronic F127 and carboxymethylcellulose (CMC). In certain embodiments, the amount of thermoreversible polymer in any of the formulations described herein is about 10%, about 15%, about 20%, about 25%, about 30%, or about the total weight of the formulation. 5%. In certain embodiments, the amount of thermoreversible polymer in any of the formulations described herein is about 14%, about 15%, about 16%, about 17%, about 18%, about the total weight of the formulation. 19%, about 20%, about 21%, about 22%, about 23%, about 24% or about 25%. In certain embodiments, the amount of thickening agent (eg, gelling agent) in any of the formulations described herein is about 1%, 5%, about 10%, or about 15% of the total weight of the formulation. In certain embodiments, the amount of thickening agent (eg, gelling agent) in any of the formulations described herein is about 0.5%, about 1%, about 1.5%, about 2%, of the total weight of the formulation, About 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5%.

In certain embodiments, the medicament described herein is a stable formulation relative to pH over any of the following weeks: at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, At least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 1 Months, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months. In other embodiments, the formulations described herein are stable relative to at least about 1 week. Moreover, the formulations described herein are stable relative to at least about 1 month.

Tension agent

Usually, the endolymph has a higher osmotic pressure than the peripheral lymph. For example, the endolymph about 304mOsm / kg H ₂ O of the osmotic pressure, while the peripheral lymphoid about 294mOsm / kg H ₂ O an osmotic pressure. In certain embodiments, the ear compositions described herein are formulated to provide a volumetric osmotic concentration of from about 100 to about 1000 mOsm/kg, from about 200 to about 800 mOsm/kg, from about 250 to about 500 mOsm/kg osmotic pressure; about 250 To an osmotic pressure of about 350 mOsm/kg or about 280 to about 320 mOsm/kg. In certain embodiments, described herein has an actual volumetric osmotic concentration of from about 100 mOsm/L to about 1000 mOsm/L, from about 200 mOsm/L to about 800 mOsm/L, from about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm. /L to about 350 mOsm / L, or about 280 mOsm / L to about 320 mOsm / L.

In certain embodiments, the delivered volume osmotic concentration of any of the formulations described herein is designed to be isotonic with the target otic structure (eg, endolymph, peripheral lymph, or the like). In a particular embodiment, described herein is formulated to provide a composition of the ear target position osmolarity is used in transmission of from about 250 to about 320mOsm / L (of 320mOsm / kg H ₂ O an osmotic pressure of from about 250 to about) ; and preferably from about 270 to about 320mOsm / L (about 270 to about 320 mOsm / kg H ₂ O of osmotic pressure). In a particular embodiment, the delivery volume osmotic concentration/osmotic pressure of the formulation (ie, the volume osmotic concentration/osmotic pressure of the formulation without gelling or thickening agent (eg, thermoreversible gel polymer)) is utilized, for example, by Use an appropriate salt concentration (eg, potassium or sodium salt concentration) or use an isotonic agent to adjust for endolymph-compatible and/or peripheral lymph-compatible (ie, internal) when delivered to the target location Lymphatic and / or peripheral lymphatic isotonic). The volumetric osmolality of a formulation containing a thermoreversible gel polymer is an unreliable manner because of the amount of change in monomer units accompanying water and polymer. The actual volumetric osmolality of the formulation (i.e., the volumetric osmolality of the gel-free or thickener (e.g., thermoreversible gel polymer)) is a reliable measure and can be by any convenient method (e.g., , freezing point drop method) measurement. In certain instances, the formulations described herein provide a deliverable volume osmotic concentration that causes minimal disruption to the inner ear environment and causes minimal discomfort (eg, dizziness and/or nausea) in the mammal when administered (eg, to a target) Location (eg, peripheral lymph)).

In certain embodiments, any of the formulations described herein are isotonic with peripheral lymphoid and/or endolymphatic. An isotonic formulation is provided by the addition of an isotonic agent. Suitable isotonic agents include, but are not limited to, any pharmaceutically acceptable sugar, salt or combination or mixture thereof, such as, but not limited to, glucose, glycerol, mannitol, sorbitol, sodium chloride, and other electrolytes.

An effective ear composition includes one or more salts in an amount necessary to direct the osmotic pressure of the composition to an acceptable range. The salt includes a sodium, potassium or ammonium cation with a chloride, a citrate, an ascorbate, a borate, a phosphate, a hydrogencarbonate, a sulfate, a thiosulfate or a bisulfite anion; a suitable salt includes chlorine Sodium, potassium chloride, sodium carbonate, sodium hydrogen sulfate and ammonium sulfate.

In certain embodiments, the formulations described herein have a pH and volume osmotic concentration as described herein, and have between about 1 μM and about 10 μM, between about 1 mM and about 100 mM, and between about 0.1. The concentration of active pharmaceutical ingredient of mM and about 100 mM, between about 0.1 mM and about 100 nM. In certain embodiments, the formulations described herein have a pH and volume osmotic concentration as described herein and have an active pharmaceutical ingredient concentration of between about 0.1 and about 20% by weight of the formulation, between about 0.1 - between about 10%, between about 0.1 and about 7.5%, between about 0.1 and 5%, between about 0.2 and about 3%, and between about 0.1 and about 2% of the active ingredient. In certain embodiments, the formulations described herein have a pH and volume osmotic concentration as described herein and have an active pharmaceutical ingredient concentration between 0.1 and about 70 mg/mL of the formulation volume, between about 1 mg and about Between 70 mg/mL, between about 1 mg to about 50 mg/mL, between about 1 mg/mL and about 20 mg/mL, between about 1 mg/mL to about 10 mg/mL, between about 1 mg/mL to about An activator between 5 mg/mL, or between about 0.5 mg/mL to about 5 mg/mL.

Particle size

Use reduced size to increase surface area and/or modulate formulation dissolution properties. It is also used to maintain a consistent average particle size distribution (PSD) of any of the formulations described herein (eg, micron sized particles, nano-sized particles, or the like). In some instances, any of the formulations described herein comprise multiple particles, that is, a plurality of particle sizes (eg, microparticles, nano-sized particles, non-sized particles, colloidal particles); that is, the formulation is Multi-particle formula. In certain embodiments, any of the formulations described herein comprise one or more multiparticulate (eg, micron) therapeutic agents. Micron acts as a method of reducing the average diameter of particles of solid matter. The microparticles have a diameter ranging from about micrometers to a diameter of about nanometer-size. In certain embodiments, the micronized solid particles have an average diameter between about 0.5 [mu]m and about 500 [mu]m. In certain embodiments, the micronized solid particles have an average diameter between about 1 [mu]m and about 100 [mu]m. In certain embodiments, the micronized solid particles have an average diameter between about 2 [mu]m and about 100 [mu]m. In certain embodiments, the micronized solid particles have an average diameter between about 3 [mu]m and about 50 [mu]m. In certain embodiments, a micronized solid of a particle contains a particle size of less than about 5 microns, less than about 20 microns, and/or less than about 100 microns. In certain embodiments, particles of corticosteroids (eg, micronized particles) are extended with a corticosteroid that allows any of the formulations described herein relative to a formulation containing non-multiple particles (eg, no micronized) corticosteroids And / or sustained release. In some instances, formulations containing multiparticulate (eg, micron) corticosteroids are injected from a 1 mL syringe suitable for a 27G needle without any blockage or agglomeration.

In some examples, any of the particles of any of the formulations described herein are a coated particle (eg, a coated microparticle, a nanoparticle) and/or a microsphere and/or a liposome particle. Particle size reduction techniques include, for example, grinding, milling (eg, air abrading mills (spray mills), ball milling), colloidal agglomeration, high pressure homogenization, spray drying, and/or supercritical liquid crystallization. In some instances, particle size is accomplished by mechanical impact (eg, by a hammer mill, ball mill, and/or tip mill). In some examples, the particle size is via liquid energy (eg, by a spiral spray mill, a loop spray mill, and/or a fluidized bed spray mill). In certain embodiments, the formulations described herein comprise crystalline particles and/or isotropic particles. In certain embodiments, the formulations described herein comprise amorphous particles and/or non-isotropic particles. In certain embodiments, the formulations described herein comprise a therapeutic agent particle, wherein the therapeutic agent is a free base, or a salt or prodrug of a therapeutic agent, or any combination thereof.

In certain embodiments, the formulations described herein comprise one or more corticosteroids, wherein the corticosteroid comprises nanoparticle. In certain embodiments, the formulations described herein comprise a controlled release of excipient coated corticosteroid beads (eg, methyl dehydrocorticosteroid beads) as appropriate. In certain embodiments, the formulations described herein comprise a corticosteroid that is granulated and/or reduced in size and coated with a controlled release excipient; the particulate coated corticosteroid particles are then micronized as appropriate / or formulated with any of the compositions described herein.

In certain instances, a pulse release ear formulation is prepared according to the procedures described herein using a corticosteroid that is a free acid or a free base in combination with a corticosteroid salt. In certain formulations, a combination of a micronized corticosteroid (and/or a salt or prodrug thereof) and coated particles (eg, nanoparticles, lipid globules, microspheres) is prepared using any of the processes described herein. Pulse release ear formulation. Alternatively, a pulse release profile can be achieved by cyclodextrin, a surfactant (eg, poloxamer (407, 338, 188), Tween (80, 60, 20, 81), PEG-hydrogenated castor oil, total Solvents such as N-methyl-2-pyrrolidone or the like help dissolve up to 20% of the delivered dose of corticosteroids (eg, micronized corticosteroids, or their free alcohols, free acids or salts or prodrugs) A multiparticulate corticosteroid, or a free base thereof, or a free acid or salt or prodrug thereof, obtained using any of the processes described herein to prepare a pulsed release formulation.

In a particular embodiment, any of the ear compatible formulations described herein comprise one or more micronized agents (eg, steroids). In certain such embodiments, the one micronized agent comprises micronized particles, coated (e.g., to extend release coating) micronized particles, or combinations thereof. In certain such embodiments, a micronized agent comprising micronized particles, coated (eg, extended release coating) micronized particles, or combinations thereof, comprises a corticosteroid as a free acid, free Any combination of a base, a salt, a prodrug, or the like. In a particular embodiment, one of the pharmaceutical compositions described herein comprises methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, which are micronized powders. In a particular embodiment, one of the pharmaceutical compositions described herein comprises a methyl dehydrocorticosterol that is a micro-methyl dehydrocorticosterol powder.

The multiparticulate and/or micronized corticosteroids described herein are delivered to an ear structure (e.g., inner ear) by any type of matrix comprising a solid, liquid or gel matrix. In certain embodiments, the multiparticulate and/or micronized corticosteroids described herein are delivered to an ear structure (eg, inner ear) via an in-the-ear injection by any type of matrix comprising a solid, liquid or gel matrix. .

Pharmaceutical formula

The pharmaceutical compositions provided herein include at least one corticosteroid and a pharmaceutically acceptable diluent, excipient or carrier. In certain embodiments, the pharmaceutical composition includes other drugs or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution accelerators, and salts for regulating osmotic pressure, and/or Or buffer. In other embodiments, the pharmaceutical composition also contains other therapeutic substances.

In a specific embodiment of the auris-acceptable controlled release corticosteroid pharmaceutical formulation described herein, the corticosteroid is provided in a gel matrix and is also referred to herein as an "early acceptable gel formulation", "the inner ear is acceptable Gel Formulation, Middle Ear Acceptable Gel Formulation, Ear Acceptable Gel Formulation, Ear Gel Formula, or the like. All ingredients of this gel formulation must be compatible with the standard ear structure. Furthermore, the gel formulation provides controlled release of corticosteroids to the desired location within the target ear structure; in certain embodiments, the gel formulation also has an immediate or rapid release component to facilitate delivery of the corticosteroid to the intended location. . In other embodiments, the gel formulation has a sustained release component for the delivery of corticosteroids. In certain embodiments, the gel formulation comprises a multiparticulate (eg, micronized) corticosteroid. In certain embodiments, the otic gel formulation is biodegradable. In other embodiments, the ear gel formulation includes a mucoadhesive excipient to allow adhesion to the outer mucosal layer of the round window membrane. In still other embodiments, the ear gel formulation comprises a penetration enhancer excipient; in yet another embodiment, the ear gel formulation contains a viscosity enhancer sufficient to provide a viscosity Between 500 and 1,000,000 centipoise, between about 750 and 1,000,000 centipoise; between about 1000 and 400,000 centipoise; between about 2,000 and 100,000 centipoise; between about 3,000 and 50,000 centipoise; Between 4,000 and 25,000 centipoise; between about 5,000 and 20,000 centipoise; or between about 6,000 and 15,000 centipoise.

In an additional or alternative embodiment, the otic gel formulation can be administered intraocularly to the round window membrane or to the round window membrane. In other embodiments, the otic gel formulation is administered through the posterior ear incision and surgically to the round window membrane or to the round window membrane or coronal fossa crown region. Alternatively, the otic gel formulation is applied with a needle and a syringe, wherein the needle is inserted into the eardrum and guided to the area of the round window membrane or the crown of the cochlear socket. This ear gel formulation is then deposited on or near the round window membrane or the crown of the cochlear fossa to locally treat autoimmune ear disorders. In other embodiments, the otic gel formulation is administered by a catheter that is implanted into a patient, and in yet another embodiment, the formulation is applied to or near the round window membrane by a pump. In still the examples, the otic gel formulation is applied to or near the round window membrane by a microinjector device. In still other embodiments, the otic gel formulation is applied to the auricular acupoints. In still the examples, the ear gel formulation was applied to the eardrum. In still the examples, the otic gel formulation is applied to the ear canal or within the ear canal.

In yet another particular embodiment, any of the pharmaceutical compositions described herein comprise a multiparticulate corticosteroid in a liquid matrix (eg, a liquid composition for in-ear injection or ear drops). In a particular embodiment, any of the pharmaceutical compositions described herein comprise a multiparticulate corticosteroid in a solid matrix.

Control release formula

Typically, a controlled release drug formulation imparts a controlled release of the drug at a relative release site and release time within the body. As discussed herein, controlled release is a combination of delayed release, extended release, sustained release, and/or pulsed release (eg, a combination of extended release and immediate release), or the like. Many advantages are provided by controlled release. First, controlled release of the pharmaceutical agent allows for less dosing frequency and thus minimizes repeated treatment. Second, controlled release therapy results in more effective drug utilization and less compound residue. Third, controlled release provides the possibility of local drug delivery by placing a delivery device or formula at the disease site. Further, controlled release can provide for administration and release of at least two different drugs via a single dosage unit, each having a unique release profile, or releasing the same drug at different rates or during different periods.

Accordingly, one aspect of the embodiments described herein is to provide an auris-acceptable composition or formulation for controlled release corticosteroids for the treatment of autoimmune disorders and/or inflammatory disorders. Controlled release profiles of the compositions and/or formulations disclosed herein are provided via a variety of agents including, but not limited to, excipients, reagents or materials that are acceptable for use in or within the otic structure.

Ear-acceptable gel

Gels, sometimes referred to as gels, have been defined in a number of ways. For example, the United States Pharmacopoeia defines a gel as a semi-solid system that is a suspension of small inorganic particles or larger organic molecules that are penetrated by a liquid. The gel can be composed more of a single phase or a two phase system. A single-phase gel is uniformly dispersed organic molecules through a liquid, in this way there is no obvious boundary between the dispersed macromolecules and the liquid. Single-phase gels are usually made from synthetic macromolecules (for example, carbomers) Or prepared from natural gums (eg, yellow gum). In certain embodiments, the single phase gel is typically aqueous, but can also be made using alcohols and oils. The two-phase gel is formed from a network of small dispersed particles.

Gels can also be distinguished as hydrophobic or hydrophilic. In a particular embodiment, the matrix of the hydrophobic gel typically consists of a liquid petroleum wax containing polyethylene or a fatty oil and a fatty oil gelled with colloidal cerium oxide or aluminum or zinc soap. Conversely, the matrix of the hydrophobic gel is typically water, glycerin, or propylene glycol with a suitable gelling agent (eg, yellow gum, starch, cellulose derivatives, carboxyvinyl polymer, and/or aluminum magnesium silicate) Composition by gel. In a particular embodiment, the flow of the compositions disclosed herein becomes pseudoplastic, plastic, flow desorbing or expansive.

In one embodiment, the acne-accepting auris-acceptable formulations described herein are not liquid at room temperature. In a particular embodiment, the viscosity enhancing formulation is characterized by a phase transition between room temperature and body temperature (including a severely afflicted patient, such as up to about 42 °C). In some embodiments, the phase transition occurs at 1 ° C below body temperature, 2 ° C below body temperature, 3 ° C below body temperature, 4 ° C below body temperature, 6 ° C below body temperature, and below body temperature. Occurs at 8 ° C and occurs at a temperature below 10 ° C. In certain embodiments, this phase transition occurs at 15 ° C below body temperature, occurs at a temperature below 20 ° C, and occurs at a temperature below 25 ° C. In a particular embodiment, the formulation described herein has a gelation temperature (Tgel) of about 20 ° C, about 25 ° C, or about 30 ° C. In a particular embodiment, the formulation described herein has a gelation temperature (Tgel) of about 35 °C, or about 40 °C. In one embodiment, any of the formulations described herein reduce administration at about body temperature or inhibit the accompanying dizziness of the otic administration of the ear formulation. The definition of body temperature includes a healthy body or an unhealthy body temperature, the latter including a fever patient (up to ~42 ° C).

A polymer composed of polyoxypropylene and polyoxyethylene forms a thermoreversible gel when incorporated into an aqueous solution. Such polymers have the ability to change from a liquid state to a gel state at temperatures close to body temperature, thus allowing for an effective formulation for application to the target ear structure. This liquid-to-gel phase is converted to the polymer concentration and composition depending on the solution.

Poloxamer 407 (PF-127) is a nonionic surfactant composed of a polyoxyethylene-polyoxypropylene copolymer. Other poloxamers include 188 (F-68), 237 (F-87), and 338 (F-108). The poloxamer aqueous solution is stabilized in the presence of acids, bases and metal ions. PF-127 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer having the general formula E106 P70 E106 having an average molar mass of 13,000. This polymer can be further purified by a suitable method to promote gelling properties. It contains approximately 70% ethylene oxide, which is a hydrophilic source. It is one of a series of poloxamer ABA block copolymers whose members have the chemical formula shown below.

P-F127 is of particular relevance because the concentrated solution of the copolymer (>20% w/w) is converted from a low viscosity clear solution to a solid gel upon heating to body temperature. Therefore, this phenomenon suggests that when placed in contact with the body, the gel formulation will form a semi-solid structure and a controlled release reservoir. Furthermore, PF-127 has good solubility, low toxicity and is therefore considered a good drug delivery system medium.

In an alternate embodiment, the thermal gel is a PEG-PGLA-PEG triblock copolymer (Jeong et al, Nature (1997), 388: 860-2; Jeong et al, J. Control. Release (2000) 63: 155-63; Jeong et al, Adv. Drug Delivery Rev. (2002), 54: 37-51). The polymer exhibits peptid-gel properties at a concentration of from about 5% w/w to about 40% w/w. The lactose/ethyl lactone molar ratio in the PGLA copolymer can range from about 1:1 to about 20:1, depending on the desired properties. This resulting copolymer is soluble in water and forms a free-flowing liquid at room temperature, but forms a hydrogen gel at body temperature. A commercially available PEG-PGLA-PEG triblock copolymer is RESOMER RGP t50106 manufactured by Boehringer Ingelheim. This material consists of a 50:50 poly(DL-lactosyl-co-caprolactone) PGLA copolymer and 10% w/w PEG and has a molecular weight of about 6,000. This material consists of a 50:50 poly(DL-lactosyl-co-caprolactone) PGLA copolymer and is 10% w/w PEG and has a molecular weight of about 6000.

"Regel ^(TM) " is a trademark of Jude Company, which specifies a family of low molecular weight, biodegradable block copolymers having reversible thermogel properties, such as U.S. Patent Nos. 6,004,573, 6,117,949, 6,201,072 and 6,287,588. Also included are biodegradable polymeric drug carriers disclosed in U.S. Patent Application Serial Nos. 09/906,041, 09/559,799 and 10/919,603. The biodegradable drug carrier comprises an ABA-type or BAB-type triblock copolymer or a mixture thereof, wherein the A-block is relatively hydrophobic and comprises a biodegradable polyester or poly(orthoester) And the B-block is relatively hydrophilic and comprises polyethylene glycol (PEG) having a hydrophobic content of between 50.1 and 83 wt% and a hydrophilicity content of between 17 and 49.9 wt%, and The molecular weight of the total block copolymer is between 2,000 and 8,000 amps. The drug carrier exhibits water solubility at a temperature below the body temperature of a normal mammal and undergoes a reversible thermogel action to subsequently be present as a gel at a gel temperature equivalent to the physiological body temperature of the mammal. The biodegradable, hydrophobic A polymer block comprises a polyester or poly(orthoester), wherein the polyester is synthesized from monomers selected from the group consisting of between about 600 and 3000 amps. Average molecular weight: D, L-lactose, D-lactoside, L-lactoside, D, L-lactic acid, D-lactic acid, L-lactic acid, ethyl lactone, glycolic acid, ε-caprolactone, ε-hydroxyl Copolymers of caproic acid, γ-butyrolactone, γ-hydroxybutyric acid, δ-valerolactone, δ-hydroxyvaleric acid, hydroxybutyric acid, hydroxysuccinic acid, and the like. The hydrophilic B-block portion is preferably polyethylene glycol (PEG) having an average molecular weight of between about 500 and 2,200 amps.

Additional biodegradable thermoplastic polyesters include Atrigel ^TM (provided by Atrix Laboratories, Inc.) and / or are disclosed in, for example, U.S. Patent Nos. 5,324,519; 4,238763; 5,702,716; 5,744,153; and No. 5,990,194 in persons; disclosure of which may be suitable The biodegradable thermoplastic polyester is a thermoplastic polymer. Examples of suitable biodegradable thermoplastic polyesters include polylactoside, polyethyl lactone, polycaprolactone, copolymers thereof, tetrapolymers thereof, and combinations thereof. In such embodiments, suitable biodegradable thermoplastic polyesters are polyglycosides, polyethyl lactones, copolymers thereof, tetrapolymers thereof, or combinations thereof. In one embodiment, the biodegradable thermoplastic polyester is 50/50 poly(DL-lactosyl-co-lactone) having a carboxyl end group; and is present in an amount from about 30% to about 10% by weight of the composition. 40 wt%; and having an average molecular weight of from about 23,000 to about 45,000. Alternatively, in still other embodiments, the biodegradable thermoplastic polyester is 75/25 poly(DL-lactosyl-co-lactone) having no carboxyl end groups; and is present in an amount of about 40 wt% to about 50 wt%; and having an average molecular weight of from about 15,000 to about 24,000. In still another or alternative embodiment, the end group of the poly(DL-lactosyl-co-lactone) is a hydroxyl group, a carboxyl group, or an ester according to a polymerization method. The polycondensation of lactic acid or glycolic acid provides a polymer having a hydroxyl group and a carboxyl group. The ring-opening polymerization of a cyclic lactose or a lactone monomer with water, lactic acid, or glycolic acid provides a polymer having the same end groups. However, the ring monomer provides a polymer having a hydroxyl group and an ester end group by ring opening of a monofunctional alcohol such as methanol, ethanol or 1-dodecanol. The ring-opening polymerization of a ring monomer with a diol such as 1,6-hexanediol or polyethylene glycol provides a polymer having only hydroxyl end groups.

Because the polymer system of the thermoreversible gel dissolves more completely under cooling, the dissolution process involves adding the required amount of polymer to the amount of water used while cooling. Typically, after wetting the polymer by shaking, the mixture is capped and placed in a cold chamber or in a thermo-constant container at about 0-10 ° C to dissolve the polymer. The mixture is stirred or shaken to achieve an approximately faster thermal reversible gel polymer dissolution. Corticosteroids and various additives such as buffers, salts and preservatives are added and dissolved in sequence. In some instances, the corticosteroid and/or other pharmaceutically active agent is suspended in water if it is insoluble in water. This pH is modulated by the addition of a suitable buffer. The characteristics of the round window film mucoadhesive agent can be obtained by incorporating the round window film mucoadhesive carbomer, such as Kapomo. 934P (Carbopol 934P) to a composition imparts a thermoreversible gel (Majithiya et al., AAPS PharmSciTech (2006), 7(3), p. E1; EP0551626), both of which are incorporated herein by reference.

In one embodiment is an auris-acceptable pharmaceutical gel formulation that does not require the use of a viscosity enhancing agent. This gel formulation incorporates at least one pharmaceutically acceptable buffer. In one aspect, it is a gel formulation containing a corticosteroid and a pharmaceutically acceptable buffer. In another embodiment, the pharmaceutically acceptable excipient or carrier is a gelling agent.

In other embodiments, an effective corticosteroid acceptable pharmaceutical formulation also includes one or more pH adjusting or buffering agents to provide a suitable pH for endolymph or peripheral lymph. Suitable pH adjusting or buffering agents include, but are not limited to, acetates, hydrogencarbonates, ammonium chlorides, citrates, phosphates, pharmaceutically acceptable salts thereof, and the like, or combinations or mixtures thereof. The pH adjusting agent or buffer is used in an amount to maintain a pH of the composition between about 5 and about 9, in one embodiment, the pH is between about 6.5 and about 7.5, and in another embodiment The pH is about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5. In one embodiment, when one or more buffering agents are used in the formulations disclosed herein, they are combined with, for example, a pharmaceutically acceptable carrier and are present in the final formulation, for example, from about 01% to about 20%. , about 0.5% to about 10%. In a particular embodiment of the invention, the amount of buffer included in the gel formulation is such that the pH of the gel formulation does not interfere with the natural buffer system of the middle or inner ear, or does not interfere with the natural pH of the endolymph or peripheral lymph. : Depends on the target of the steroid formulation in the cochlea. In certain embodiments, a buffer of a concentration of from about 10 [mu]M to about 200 mM is present in the gel formulation. In a particular embodiment, a buffer is present at a concentration of from about 20 mM to about 100 mM. In one embodiment, a buffer is a slightly acidic pH such as acetate or citrate. In one embodiment, the buffer is a sodium acetate buffer having a pH of from about 4.5 to about 6.5. In one embodiment, the buffer is a sodium citrate buffer having a pH of from about 5.0 to about 8.0, or from about 5.5 to about 7.0.

In one embodiment, the buffer is a tris(hydroxymethyl)aminomethane, salt, carbonate or phosphate such as a slightly basic pH. In one embodiment, the buffer is a sodium bicarbonate buffer having a pH of from about 6.5 to about 8.5 or from about 7.0 to about 8.0. In one embodiment, the buffer is a disodium phosphate buffer having a pH of from about 6.0 to about 9.0.

Also described herein are controlled release formulations comprising a corticosteroid and a viscosity enhancing agent. Suitable viscosifying-initiating agents include gelling agents and suspending agents which are merely exemplary. In one embodiment, the viscosity enhancing formulation does not include a buffer. In other embodiments, the viscosity enhancing formulation comprises a pharmaceutically acceptable buffer. Sodium chloride or other tonicity agents are used to adjust the tonicity if needed.

For illustrative purposes only, ear-acceptable adhesives include hydroxypropyl methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium chondroitin, hyaluronic acid sodium. Other viscosities useful in the pharmaceutical compositions described herein include, but are not limited to, gum arabic, acacia, magnesium aluminum citrate, sodium alginate, sodium stearate, fucus, benton, Carbomer, Carrageenan, Carbomo, Capsule, Cellulose, Microcrystalline Cellulose (MCC), Carob, Sesame, Glucose, Fusselan Algin, gelatin, gum, tannin, bentonite (hectorite), lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, corn starch, potato starch, gelatin, sycamore gum , gums, polyethylene glycol (eg PEG 200-4500), tragacanth, ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose , hydroxyethyl methylcellulose, hydroxypropyl cellulose, poly(hydroxyethyl urethane), oxypoly gelatin, pectin, poly gelatin, pravone, propylene carbonate, methyl vinyl ether /maleic anhydride copolymer (PVM/MA), poly(methoxyethyl urethane), poly(methoxyethoxyethyl) Carbamate), hydroxypropylcellulose, hydroxypropylmethyl-cellulose (HPMC), sodium carboxymethyl-cellulose (CMC), cerium oxide, polyvinylpyrrolidone (PVP: Pivoxone) ), Splenda (Glucose maltodextrin and sucralose) or a combination thereof. In a particular embodiment, the viscous-promoting excipient is a combination of methylcellulose (MC) and CMC. In still other embodiments, the viscosity-promoter is combined with carboxymethylated polyglucamine, or chitin and alginate. The combination of chitin and alginate disclosed herein with the corticosteroids disclosed herein serves as a controlled release formulation that limits the diffusion of corticosteroids from this formulation. Furthermore, the combination of carboxymethylated polyglucosamine and alginate is optionally used to help increase the penetration of corticosteroids into the inner ear window membrane.

Some embodiments are a thickening formulation comprising from about 0.1 Mm to about 100 mM of a corticosteroid, a pharmaceutically acceptable viscous agent, and water for injection, the viscosity of the viscous agent being sufficient to provide a thickening formula The resulting viscous system is from about 100 to about 100,000 cP. In particular embodiments, the gel viscosity ranges from about 100 to about 50,000 cP, from about 100 to about 1,000 cP, from about 500 to about 1,500 cP, from about 1,000 to about 3,000 cP, and from about 2,000 to Between 8,000 cP, ranging from about 4,000 to about 50,000 cP, ranging from about 10,000 to about 500,000 cP, from about 15,000 cP to about 1,000,000 cP. In another embodiment, the biocompatible gel comprises at least about 35 wt%, at least about 45 wt%, at least about 55 wt%, at least about 65 wt%, at least about 70 wt%, at least when an even more viscous medium is desired. A corticosteroid of about 75 wt%, or at least about 80 wt%, and the like. In a highly concentrated sample, the biocompatible thickening formulation comprises at least about 25 wt%, at least about 35 wt%, at least about 45 wt%, at least about 55 wt%, at least about 65 wt%, at least about 75 wt%, at least about 85 wt%, At least about 90% by weight or at least about 95% by weight or more of the corticosteroid.

In certain embodiments, the viscosity of the gel formulations described herein is measured by any of the methods described herein. For example, in certain embodiments, the viscosity of the gel formulations described herein is calculated using an LVDV-II+CP Cone plate viscometer and Cone mandrel CPE-40. In other embodiments, a Brookfield (mandrel and cup) viscometer is used to calculate the viscosity of the gel formulations described herein. In certain embodiments, the viscosity range referred to herein is measured at room temperature. In other embodiments, the viscosity range referred to herein is measured at body temperature (eg, the average body temperature of a healthy human body).

In one embodiment, the pharmaceutically acceptable viscous auricular acceptable formulation comprises at least one corticosteroid and at least one gelling agent. Suitable gelling agents for preparing gel formulations include, but are not limited to, cellulose, cellulose derivatives, cellulose ethers (eg, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethyl) Cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose), tannin extract, Sanxian gum, locust bean gum, alginate (eg alginic acid), citrate, starch Any combination or mixture of yellow gum, carboxyvinyl polymer, cerulein, paraffin, petrolatum, and the like. In certain other embodiments, hydroxypropyl methylcellulose is utilized (Methocel ) is a gelling agent. In certain embodiments, the thickening agents described herein are also utilized as gelling agents for the gel formulations described herein.

In certain embodiments, other gel formulations may be used depending on the particular corticosteroid, other pharmaceutical agent, or excipient additive used, and are considered to be within the scope of the present disclosure. For example, other currently commercially available glycerin-based gels, glycerin-derived compounds, conjugated or crosslinked gels, matrices, hydrogen gels and polymers, as well as gelatin and its derivatives, alginate, and Alginate-based gels, and even natural and synthetic hydrogen gels and hydrogen gel-derived compounds, are contemplated for use in the corticosteroid formulations described herein. In certain embodiments, an auris-acceptable gel includes, but is not limited to, a alginate hydrogen gel SAF - Gel (ConvaTec, Princeton, New Jersey, USA), Duoderm Hydro Active Gel (ConvaTec), Nu-Gel (Johnson & Johnson Medical, Arlington, TX, USA; Carrasyn (V) Acemannan Hydrogel (Carrington Laboratories, Inc.); Glycerin Gel Elta Hydrogel (Swiss-American Products, Dallas, TX) and KY Sterile (Johnson & Johnson). In yet another embodiment, the biodegradable biocompatible gel is also a compound that can be present in the acceptable formulations described and disclosed herein.

In certain formulations for the formulation of compositions for mammalian administration and for human administration, the auris-acceptable gel comprises substantially all of the composition weight. In other embodiments, the auris-acceptable gel comprises, for example, about 98% by weight or about 99% by weight of the composition. This is desirable when a substantially non-liquid, or substantially viscous formulation is desired. In yet another embodiment, the biocompatible gel fraction of the formulation comprises at least about 50% by weight, at least about 60% by weight, at least when a slightly lower viscosity or slightly higher liquid ear acceptable pharmaceutical gel formulation is desired. About 70% by weight, or even at least about 80% by weight or 90% by weight of the compound. All intermediate integers in this range are considered to be within the scope of the present disclosure, and in certain embodiments, even more liquid (and therefore less viscous) auris-acceptable gel compositions, such mixtures, are formulated. The gel or matrix component comprises no more than about 50% by weight of the composition, no more than about 40% by weight, no more than about 30% by weight, or even no more than about 15% by weight or about 20% by weight. Round window film mucoadhesive

It is also contemplated in the context of the embodiments to incorporate a round window film mucoadhesive to the corticosteroid formulations and compositions disclosed herein. The term "mucosal binder" refers to a substance that is used to bind to the mucin layer of a biofilm, such as the outer membrane of a 3-layer circular window membrane. As a circular window film mucoadhesive polymer, the polymer should have some general physicochemical characteristics such as anionic hydrophilicity with mainly several hydrogen bond forming groups, suitable surface properties to wet mucus/mucosal tissue surface And enough flexibility to penetrate the mucosal network.

Round window film mucoadhesives for use with ear acceptable formulations include, but are not limited to, at least one soluble polyvinylpyrrolidone polymer (PVP); monohydrate-swellable but water-insoluble, fiber, crosslinked Carboxy-functional polymer; a cross-linked poly(acrylic acid) (such as carbomer 947P); a carbomer homopolymer; a carbomer copolymer; a hydrophilic glycan gum, maltodextrin, one cross An alginate gelatin gel, a water-dispersible polycarboxylate ethylene polymer, a particle component of at least two selected from the group consisting of titanium dioxide, cerium oxide, and clay or the like. The round window film mucoadhesive agent can be used in combination with an acceptable viscous excipient for the ear, or used alone to increase the interaction of the composition with the ear component of the mucosal layer. In a non-limiting embodiment, the mucoadhesive agent is maltodextrin and/or alginate gum. When used, the circular window film imparts a mucoadhesive property to the composition that is sufficient to deliver an effective amount of the corticosteroid composition to, for example, the inner ear round window mucosa or the cochlear cap crown, and the amount of which is a coatable mucosa, The composition can then be delivered to the affected area, including the inner ear vestibule and/or cochlear structure as exemplified. Those skilled in the art will be able to determine the characteristics of the mucoadhesive agent of the compositions described herein and may therefore determine the appropriate amount of use. A method of determining adequate mucoadhesiveness can include monitoring changes in the interaction of the composition with the mucosal layer, including but not limited to measuring the duration or duration of retention of the composition in the absence or presence of the excipient.

In a non-limiting embodiment, the round window membrane mucoadhesive agent is maltodextrin. Maltodextrin is a carbohydrate produced by hydrolyzing starch derived from corn, potato, wheat or other plants. Maltodextrin can be used alone or in combination with other round window film mucoadhesives to impart mucoadhesive properties to the compositions disclosed herein. In one embodiment, the combination of maltodextrin and carbomer polymer increases the round window film mucoadhesive of the compositions disclosed herein.

In another embodiment, the round window membrane mucoadhesive agent is an alkyl-glycoside and/or a monosaccharide alkyl ester. As used herein, an "alkyl-glycoside" means a compound containing any hydrophilic sugar (e.g., glucose, fructose, sucrose, or maltose) attached to a hydrophobic alkyl group. In certain embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside-containing surfactant, wherein the alkyl-glycoside comprises a link to a hydrophobic alkyl group (eg, one contains from about 6 to about 25 a sugar of an alkyl group of a carbon atom by a monoamine linkage, an amine linkage, a monocarbamate linkage, a monoether linkage, a monothioether linkage, a monoester linkage, a monothioester linkage, a monoglycosidic linkage , monothioglycoside linkage, and/or monothiol urea linkage. In certain embodiments, the round window membrane mucoadhesive agent is hexyl-, heptyl-, octyl-, decyl-, decyl-, undecyl-, dodecyl-, tridecyl -, tetradecyl, pentadecyl-, hexadecyl-, heptadecyl- and octadecyl- or β-D-maltoside; hexyl-, heptyl-, octyl-, Mercapto-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-, heptadecyl-, and Octadecyl-α- or β-D-glucoside; hexyl-, heptyl-, octyl-, decyl-, decyl-, undecyl-, dodecyl-, tridecyl -, tetradecyl, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl- or β-D-sucrose; hexyl-, heptyl-, octyl- , dodecyl-, tridecyl- and tetradecyl-β-D-thiomaltoside; heptyl- or octyl-1-sulfo-α- or β-D-gluconoside; alkyl Sulfose; alkyl maltotriose; long-chain aliphatic decylamine of sucrose β-amino-alkyl ether; sucrose or isomaltamine derivative linked to monoalkyl chain by monoamine Connected by urea An isomalt derivative to a monoalkyl chain; a long chain aliphatic guanidinium urea of sucrose β-amino-alkyl ether and a long chain aliphatic decylamine of sucrose β-amino-alkyl ether. In some embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside, wherein the alkyl glycoside is a combination of maltose, sucrose, glucose, or the like, wherein the monoglycan is attached to a 9 to 16 carbon atom. Alkyl chains (eg, decyl-, decyl-, dodecyl-, and tetradecyl sucralose; fluorenyl-, decyl-, dodecyl-, and tetradecyl glucoside; -, mercapto-, dodecyl- and tetradecyl maltoside). In certain embodiments, the round window membrane mucoadhesive agent is a mono-glycoside, wherein the alkyl glycoside is dodecyl maltoside, tridecyl maltoside, and tetradecyl maltoside. In certain embodiments, the auris-acceptable penetration enhancer is an alkyl-glycoside-containing surfactant, wherein the alkyl glycoside is tetradecyl-β-D-maltoside. The round window membrane mucoadhesive agent is a mono-glycoside, wherein the alkyl glycoside is a disaccharide having at least one glucose. In certain embodiments, the auris-acceptable penetration enhancer is a surfactant comprising an alpha-D-gluconosyl-beta-glycoside, n-dodecyl-4-O-alpha -D-gluconosidosyl-β-glycoside, and/or n-tetradecyl-4-O-α-D-glucopyranosyl-β-glycoside. In certain embodiments, the round window membrane mucoadhesive agent is a mono-glycoside wherein the alkyl glycoside has a critical micelle concentration (CMC) of less than about 1 mM in pure water or aqueous solution. In certain embodiments, the round window membrane mucoadhesive is an alkyl-glycoside wherein the oxygen atom in the alkyl-glycoside is replaced by a sulfur atom. In certain embodiments, the round window membrane mucoadhesive is an alkyl-glycoside, wherein the alkyl glycoside is a beta-helical isomer. In certain embodiments, the round window membrane mucoadhesive agent is an alkyl-glycoside, wherein the alkyl glycoside comprises 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, 99%, 99.1%, 99.5%, or 99.9% β-spin isomer.

Auricular cyclodextrin and other stable formulas

In a particular embodiment, the auris-acceptable formulation may alternatively comprise a cyclodextrin. The cyclodextrin is a cyclic oligosaccharide containing 6, 7, or 8 glucomannan units, respectively referred to as α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin. Cyclodextrins have a hydrophilic outer layer that enhances water-soluble, and hydrophobic inner layers to form a cavity. In an aqueous environment, other molecular hydrophobic moieties typically enter the hydrophobic pockets of the cyclodextrin to form a connotation compound. In addition, cyclodextrins can also interact in other forms with molecules that are not in hydrophobic pockets. Each glucomannan unit of the cyclodextrin has three free hydroxyl groups or 18 hydroxyl groups on the α-cyclodextrin, 21 hydroxyl groups on the β-cyclodextrin, and 24 hydroxyl groups on the γ-cyclodextrin. One of these hydroxyl groups reacts with more than one of a plurality of reagents to form a larger species of cyclodextrin derivative. Some of the more general cyclodextrin derivatives are hydroxypropyl ethers, sulfonates and sulfoalkyl ethers. The following shows the structure of β-cyclodextrin and hydroxypropyl β-cyclodextrin (HPβCD).

In certain embodiments, cyclodextrin is used in the pharmaceutical composition to improve the stability of the drug. Intrinsic compounds are associated with many examples of promoting solubility; however, interactions between other cyclodextrins and insoluble compounds can also improve solubility. Hydroxypropyl-β-cyclodextrin (HPβCD) is a commercially available pyrogen-free product. It is a moisture-proof white powder that is soluble in water. HPβCD is heat stable and does not degrade at neutral pH. Thus, the cyclodextrin improves the solubility of the therapeutic agent in the composition or formulation. Accordingly, in certain embodiments, cyclodextrin is included to enhance the solubility of an auris-acceptable corticosteroid in the formulations described herein. In other embodiments, the cyclodextrin is further used as a controlled release excipient of the formulations described herein.

Preferred cyclodextrin derivatives which may be used include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl β-cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β Cyclodextrin, sulfated γ-cyclodextrin, thiobutyl ether β-cyclodextrin.

The concentration of the cyclodextrin used in the compositions and methods described herein may depend on the physicochemical properties, pharmacokinetic properties, side effects or adverse conditions, formulation considerations, or concomitant effects of the therapeutic activator or its salts or prodrugs in the composition. Other factors, or other excipients, vary in nature. Thus, the concentration or amount of cyclodextrin of the compositions and methods described herein can vary as desired in a particular situation. When used, the solubility of the corticosteroid and/or the amount of cyclodextrin as a controlled release excipient in any of the formulations described herein is the use of the principles, examples, and teachings described herein.

Other stabilizers useful in the auris-acceptable formulations disclosed herein are those selected from, for example, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers. , polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and combinations thereof. In certain embodiments, the stabilizer decyl congener is also used. In yet another embodiment, the stabilizer is selected to alter the hydrophobicity of the formulation (eg, oleic acid, wax), or to improve the mixing of various components of the formulation (eg, ethanol) to control the amount of moisture in the formulation (eg, , PVP or polyvinylpyrrolidone), control the movement of the phase (substance above room temperature such as long chain fatty acids, alcohols, esters, ethers, guanamines, etc., or mixtures thereof; wax), and / or improved The compatibility of the formulation of the encapsulated substance (for example, oleic acid, wax). In still other embodiments, certain stabilizers are used as the solvent/co-solvent (e.g., ethanol). In yet another embodiment, the stabilizer is present in an amount sufficient to inhibit degradation of the corticosteroid. Illustrative of such stabilizers include, but are not limited to, (a) from about 0.5% to about 2% w/v glycerol, (b) from about 0.1% to about 1% w/v aminomethyl mercaptan butyrate, (c) From about 0.1% to about 2% w/v monothioglycerol, (d) from about 1 mM to about 10 mM EDTA, (e) from about 0.01% to about 2% w/v ascorbic acid, (f) from 0.003% to about 0.02% w/ v Polysorbate 80, (g) 0.001% to about 0.05% w/v polysorbate 20, (h) arginine, (i) heparin, (j) polyglucose sulfate, (k) ring Dextrin, (l) polypentose polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

An additional useful corticosteroid ear-acceptable formulation includes at least one anti-agglomeration additive to promote the stability of the corticosteroid formulation by reducing protein agglomeration. The choice of anti-agglomeration additives is based on the conditional nature of the exposed corticosteroid, such as a corticosteroid antibody. For example, specific formulations for agitation and thermal stress require different anti-agglomeration additives than formulations for freeze-drying and reconstitution. Useful anti-agglomeration additives include urea, barium chloride, simple amino acids such as glycine or arginine, sugars, polyalcohols, polysorbates, polymers such as polyethylene glycol, and poly-only for illustrative purposes. Glucose, alkyl sugars, such as alkyl glycosides, and surfactants.

Other useful compositions optionally include at least one ear acceptable antioxidant to promote the desired chemical stability. Suitable antioxidants include, for example, ascorbic acid, methionine, sodium thiosulfate and sodium metabisulfite. In one embodiment, the antioxidant is selected from the group consisting of metal chelating agents, thiol containing compounds, and other general purpose stabilizers.

Still other useful compositions include at least one ear acceptable surfactant to promote physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers with alkyl phenyl ethers such as octylphenol polyether 10. Octylphenol polyether 40.

In certain embodiments, the auris-acceptable pharmaceutical formulations described herein are stable to degradation of the compound during any of the following periods: at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least About 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least About 3 months, at least about 4 months, at least about 5 months, at least about 6 months. In other embodiments, the formulations described herein are stable on compound degradation over a period of at least about 1 week. Moreover, the formulations described herein are stable over the degradation of the compound for at least about one month.

In other embodiments, an additional surfactant (co-surfactant) and/or buffer is used in combination with at least one of the pharmaceutically acceptable carriers described hereinbefore, such that the surfactant and/or buffer maintains this The product is at a suitable pH for stability. Suitable co-surfactants include, but are not limited to, (a) natural and synthetic lipophilic agents, such as phospholipids, cholesterol and cholesterol fatty acid esters, and the like; (b) nonionic surfactants, These include, for example, polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Spans), polyoxyethylene sorbitan fatty acid esters (for example, polyoxyethylene (20) sorbitan monooleate (Tween 80), poly Oxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20) and other Tweens, sorbitan esters, glycerides such as Myrj and Triacetin (triethyl glycerol), polyethylene glycol, cetyl alcohol, hexadeca oleyl alcohol, stearic acid alcohol, polysorbate 80, poloxamer, poloxamine (poloxamine), polyoxyethylene castor oil derivative (for example, Kemo RH40, Cremphor A25, Cremphor A20, Kemo EL) and other grammore, sulfosuccinate, alkyl sulfate (SLS); PEG glyceryl fatty acid esters such as PEG-8 glyceryl octanoate / decanoate (Labrasol), PEG-4 glyceryl octanoate Ester/phthalic acid ester (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate (gelucire 444/14), PEG-6 glyceryl monooleate (Labrafil M 1944 CS), PEG-6 glyceryl linseed oil Acid ester (Labrafil M 2125 CS); propylene glycol mono- and di-fatty acid esters such as propylene glycol laurate, propylene glycol caprylate / phthalate; 700, ascorbyl-6-palmitate, stearic acid amine, sodium lauryl sulfate, polyoxyethylene glycerol triiricinoleate and any combination or mixture thereof; (c) anionic Surfactants include, but are not limited to, carboxymethylcellulose calcium, sodium carboxymethylcellulose, sodium sulfosuccinate, dioctyl ester, sodium alginate, alkyl polyoxyethylene sulfate, sodium lauryl sulfate, three Any combination or mixture of ethanolamine stearate, potassium laurate, bile salts, and the like; and d) cationic surfactants such as quaternary ammonium compounds, ammonium benzyl chloride, hexadecyl trimethyl bromide Ammonium and lauryl dimethyl benzyl-ammonium chloride.

In yet another embodiment, when at least one co-surfactant is used in the auris-acceptable formulation of the invention, it is combined with, for example, a pharmaceutically acceptable carrier and is present in the final formulation, for example at about 0.1% Up to about 20%, ranging from about 0.5% to about 10%.

In one embodiment, the diluent is used to stabilize corticosteroids or other pharmaceutical compounds because the diluent provides a more stable environment. The salt dissolved in the buffer solution (which also provides pH control or maintenance) is used as a diluent including, but not limited to, a phosphate buffered physiological saline solution. In other embodiments, the gel formulation is determined by cochlearization with peripheral lymphoid and/or endolymphatic isotonic: targeted targeting of a corticosteroid formulation. An isotonic formulation is provided by the addition of an isotonic agent. Suitable isotonic agents include, but are not limited to, any pharmaceutically acceptable sugar, salt or combination or mixture thereof, such as, but not limited to, glucose and sodium chloride. The amount of tonicity agent will depend on the identity of the pharmaceutical formulation as described herein.

An effective tensile composition includes one or more salts in an amount necessary to direct the osmotic pressure of the composition to an acceptable range for the peripheral lymph or endolymph. The salt includes a sodium, potassium or ammonium cation with a chloride, a citrate, an ascorbate, a borate, a phosphate, a hydrogencarbonate, a sulfate, a thiosulfate or a bisulfite anion; a suitable salt includes chlorine Sodium, potassium chloride, sodium carbonate, sodium hydrogen sulfate and ammonium sulfate.

In certain embodiments, the auris-acceptable gels disclosed herein may alternatively or additionally contain a preservative to prevent microbial growth. Suitable ear-acceptable preservatives for use in the adhesion-promoting formulations described herein include, but are not limited to, benzoic acid, boric acid, p-hydroxybenzyl ester, alcohol, quaternary compound, diazepam dioxide, organic mercury, Such as merfen and thiomersal, mixtures of the foregoing and the like.

In yet another embodiment, for purposes of illustration only, the preservative in the auris-acceptable formulations described herein is an antibacterial agent. In one embodiment, the formulation comprises a preservative such as methyl paraben, sodium bisulfite, sodium thiosulfate, ascorbate, butanol, thiomersal, for example only. Sodium, paraben, benzyl alcohol, phenylethyl alcohol and others. In another embodiment, the concentration of methyl paraben is from about 0.05% to about 1.0%, from about 0.1% to about 0.2%. In yet another embodiment, the gel is prepared by mixing water, methyl paraben, hydroxyethyl cellulose, and sodium citrate. In yet another embodiment, the gel is prepared by mixing water, methyl paraben, hydroxyethyl cellulose, and sodium acetate. In yet another embodiment, the mixture is sterilized in an autoclave at 120 °C for about 20 minutes, and the pH, methyl paraben concentration, and viscosity are tested prior to mixing with an appropriate amount of the corticosteroid disclosed herein.

Suitable water-soluble preservatives for drug delivery vehicles are sodium bisulfite, sodium thiosulfate, ascorbate, butanol, sodium thiomethic acid, parabens, benzyl Alcohol, butylated hydroxyxylene (BHT), phenylethyl alcohol and others. Such agents are typically present in amounts of from about 0.001% to about 5% by weight and preferably from about 0.01% to about 2% by weight. In certain embodiments, the otic compatible formulations described herein are non-preservatives.

Round window film penetration enhancer

In another embodiment, the formulation further comprises one or more round window film penetration enhancers. The penetration of the round window film can be enhanced by the presence of a penetration enhancer. The round window membrane penetration enhancer is a chemical entity that promotes the delivery of a co-administered drug substance through the round window membrane. Round window film penetration enhancers can be distinguished by chemical structure. Surfactant, both ionic and non-ionic, such as sodium lauryl sulfate, sodium laurate, polyoxyethylene-20-hexadecyl ether, Laureth-9, sodium lauryl sulfate, dioctylsulfonate Sodium succinate, polyoxyethylene-9-lauryl ether (PLE), Tween 80, nonylphenoxy polyethylene (NP-POE), polysorbate and the like can be used as round window membrane penetration Promoter. Bile salts (such as sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurostanosporin, sodium dihydrofufloxacin and the like), fatty acids and derivatives ( Such as oleic acid, octanoic acid, mono- and di-glycerides, lauric acid, guanylcholine, octanoic acid, mercaptocarnitine, sodium octanoate and the like), chelating agents (such as EDTA, citric acid, salicylate) And similar (), such as dimethyl hydrazine (DMSO), mercaptomethyl hydrazine and the like), and alcohols (such as ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, Glycerin, propane diol and the like) and as a round window membrane penetration enhancer.

Round window membrane can penetrate liposomes

Lipid globules or lipid particles can also be used to encapsulate the corticosteroid formulation or composition. The phospholipids gently dispersed in the aqueous medium form a multilamellar vesicle having a circle separating the lipid layers surrounding the aqueous medium region. Ultrasonic, or vortex, agitation of such multilamellar vesicles results in the formation of a single layer of vesicles, typically lipid globules having a size of about 10-1000 nm. These lipid globules have advantages such as corticosteroids or other pharmaceutical carriers. It is biologically inert, biodegradable, non-toxic and non-antigen. Lipid globules can be formed in different sizes and have different composition and surface properties. In addition, it is capable of encircling a variety of small molecule drugs and releasing the drug at the location where the lipid globules are broken.

Suitable phospholipids for use in the auris-acceptable lipids of the invention are, for example, phospholipid choline, ethanolamine and serine, occidental myelin, cardiolipin, plasmalogen, phosphatidic acid and cerebrosides, especially soluble in corticosteroids. For non-toxic, pharmaceutically acceptable organic solvents. Preferred phospholipids are, for example, phospholipid choline, phospholipid ethanolamine, phospholipid serine, phospholipid cyclohexanol, dephospholipid choline, phospholipid glycerol and the like, and mixtures thereof, especially lecithin, such as soybean Lecithin. The quality of the phospholipids used in the formulations of the present invention may range from about 10 to about 30%, preferably from about 15 to about 25%, and especially about 20%.

It may be advantageous to use a lipophilic additive to selectively modify the properties of the lipid globule. Examples of such additives include, for example, stearic acid amines, phosphatidic acid, vitamin E, cholesterol, cholesterol hemi-salicylate, and lanolin extracts. The amount of lipophilic additive used ranges from 0.5 to 8%, preferably from 1.5 to 4% and especially about 2%. Generally, the ratio of the amount of lipophilic additive to the amount of phospholipid ranges from about 1:8 to about 1:12 and especially about 1:10. The phospholipids, lipophilic additives and corticosteroids and other pharmaceutical compounds are used together with a non-toxic, pharmaceutically acceptable organic solvent system which dissolves the ingredients. The solvent system must not only completely dissolve the corticosteroid, but must also allow for the formulation of a single bilayer lipid globule. The solvent system comprises dimethyl isosorbide and tetraethylene glycol (tetrahydrofuran glycol ether, tetrahydrofuranol polyglycol ether) in an amount of from about 8 to about 30%. In the solvent system, the ratio of the amount of dimethyl isosorbide to tetraethylene glycol ranges from about 2:1 to about 1:3, especially from about 1:1 to about 1:2.5. Good for about 1:2 range. Thus, the amount of tetraethylene glycol in the final composition can vary from 5 to 20%, especially from 5 to 15% and preferably about 10%. Thus, the amount of dimethyl isosorbide in the final composition can vary from 3 to 10%, especially from 3 to 7% and preferably about 5%.

The term "organic component" as used hereinafter refers to a mixture containing the phospholipid, a lipophilic additive, and an organic solvent. Corticosteroids can be dissolved in organic components or other means to maintain the full activity of the agent. The amount of corticosteroid in the final formulation is in the range of 0.1 to 5.0%. In addition, other ingredients such as antioxidants can be added to the organic component. Examples include vitamin E, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, ascorbyl oleate, and the like.

In other embodiments, this includes gel formulations and viscous-promoting formulations, which include excipients, other pharmaceutical or pharmaceutical agents, carriers, adjuvants such as preservatives, stabilizers, humidifiers or emulsifiers. A combination of a agent, a solution accelerator, a salt, a solvent, an anti-foaming agent, an antioxidant, a dispersing agent, a wetting agent, a surfactant, and the like.

Suitable carriers for use in the auris-acceptable formulations described herein include, but are not limited to, any pharmaceutically acceptable solvent that is compatible with the physiological environment of the subject's ear structure. In other embodiments, the base is a combination of a pharmaceutically acceptable surfactant and a solvent.

In certain embodiments, other excipients include sodium stearate fumarate, diethanolamine hexadecane sulfate, isostearate, polyethoxylated castor oil, nonoxyl-10 (nonoxyl) -10), octylphenol polyether 9, sodium lauryl sulfate, sorbitan ester (sorbitol monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan single hard Fatty acid ester, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate , sorbitan stearate, sorbitan dioleate, sorbitan sesqui-isostearate, sorbitan sesquistearate, sorbitan triisostearate, A combination or mixture of the pharmaceutically acceptable salts of lecithin and the like.

In other embodiments, the carrier is a polysorbate. Polysorbate is a nonionic surfactant of sorbitan ester. Polysorbates useful in the present disclosure include, but are not limited to, any combination or mixture of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (Tween 80), and the like. . In yet another embodiment, polysorbate 80 is used as a pharmaceutically acceptable carrier.

In one embodiment, the water-soluble glycerin-early acceptable thickening formulation for preparing a pharmaceutical delivery vehicle comprising at least one corticosteroid comprises at least about 0.1% water-soluble glycerin compound or more. In certain embodiments, the percentage of corticosteroids is between about 1% and about 95%, between about 5% and about 80%, between about 5% and about 80%, and between about 10% and about 60% or more changes. In certain embodiments, the amount of the compound in each therapeutically effective corticosteroid formulation is prepared in such a manner that any particular dosage of the compound will result in a suitable dosage. Factors considered herein such as solubility, bioavailability, biological half-life, route of administration, product shelf life, and other medical considerations and preparation of this pharmaceutical formulation.

If desired, the ear acceptable pharmaceutical gel also contains a cosolvent and a buffer. Suitable water soluble buffers are alkali metal or alkaline earth metal carbonates, phosphates, hydrogencarbonates, citrates, borates, acetates, salicylates and the like, such as sodium phosphate, citric acid Sodium, sodium borate, sodium acetate, sodium bicarbonate, sodium carbonate, and sodium tripwood (TRIS). These agents are present in an amount sufficient to maintain the pH of the system at 7.4 ± 0.2 and preferably 7.4. Thus, the buffering agent can be as much as 5% by weight of the total composition.

However, some corticosteroids or other pharmaceutical compounds are insoluble and co-solvents are used to increase corticosteroid solubility. These are typically suspended in the polymeric carrier with the aid of a direct suspension aid or viscosity enhancer.

Furthermore, some pharmaceutical excipients, diluents or carriers are potentially ototoxic. For example, a commonly used preservative, chloroammonium chloride is ototoxic and therefore potentially harmful if applied to the vestibular or cochlear structure. In formulating controlled release ear formulations, it is recommended to avoid or combine appropriate pharmaceutical excipients, diluents or carriers to reduce or remove potential ototoxic components of the formulation, or to reduce the excipients, diluents or carriers. the amount. A controlled release corticosteroid formulation may optionally include an ear protectant such as an antioxidant, alpha lipoic acid, calcium, forskmycin or an iron chelator to counteract the use of a particular therapeutic agent or excipient, diluent or Potential ototoxic effects that may be caused by the carrier.

Treatment mode

Dosage method and procedure

The drug delivered to the inner ear is administered orally, intravenously or subcutaneously. However, systemic administration for the pathological location of the inner ear increases the likelihood of systemic toxicity and adverse side effects and produces an ineffective drug distribution that is found in high doses in serum but relatively low in the inner ear.

Intra-injection of a therapeutic agent is a technique of injecting a therapeutic agent into the eardrum to enter the middle ear and/or inner ear. In one embodiment, the formulations described herein are administered directly to the round window membrane via intra-injection. In another embodiment, the corticosteroid-acceptable formulations described herein are administered to the inner ear via a non-intra-injection. In additional embodiments, the formulations described herein are surgically administered to a round window membrane that includes snail ridge correction.

In one embodiment, the delivery system is a syringe and needle device that is capable of penetrating the eardrum and directly into the round window membrane or the inner cochlear ridge. In some embodiments, the needle is wider than the 18 gauge needle. In still other embodiments, the needle is from an 18 gauge needle to a 31 gauge needle. In yet another embodiment, the needle is a 25 gauge to a 30 gauge needle. The needle number of the syringe or hypodermic needle varies depending on the consistency or viscosity of the corticosteroid or composition formulation disclosed herein.

In another embodiment, the needle is a hypodermic needle for immediate delivery of a gel formulation. The hypodermic needle is a single needle or a disposable needle. In certain embodiments, a syringe is a pharmaceutically acceptable gel-containing corticosteroid composition for delivering a composition comprising the present invention, wherein the syringe has a press fit (Luer) or turn on (Luer-lock) ) Accessories. In one embodiment, the syringe is a hypodermic syringe. In still other embodiments, the syringe is made of plastic or glass. In still another, the hypodermic syringe is a single use syringe. In yet another embodiment, the glass syringe is capable of sterilization. In another embodiment, the sterilization is carried out in an autoclave. In still other embodiments, the syringe comprises a cylindrical syringe body in which the gel formulation prior to use is stored. In other embodiments, the syringe comprises a cylindrical syringe body in which the corticosteroid pharmaceutically acceptable ear gel-based composition disclosed herein is stored prior to use, suitably mixed with a suitable pharmaceutically acceptable buffer. In other embodiments, the syringe may contain other excipients, stabilizers, suspending agents, diluents, or combinations thereof, for sterilization, or may be stable to store corticosteroids or other pharmaceutical compounds contained therein.

In certain embodiments, the syringe comprises a cylindrical syringe body, wherein the syringe body compartment, and each compartment stores at least one component of an ear-acceptable corticosteroid gel formulation. In yet another embodiment, the syringe of the syringe body having the compartment allows mixing of the components prior to injection into the middle or inner ear. In other embodiments, the delivery system comprises a plurality of syringes, each syringe of the plurality of syringes containing at least one component of the gel formulation, such that each component is premixed prior to injection or mixed after subsequent injection. In yet another embodiment, the syringe disclosed herein contains at least one reservoir, wherein at least one reservoir comprises a corticosteroid, or a pharmaceutically acceptable buffer, or a viscous enhancer such as a gelling agent or a combination thereof . Alternatively, a commercially available injection device can be used in its simplest form, a plastic syringe having a syringe barrel, a needle assembly with a needle, a plunger with a plunger rod, and a gripping edge for performing Intra-ear injection.

In certain embodiments, the delivery device is a device designed to administer a therapeutic agent to the middle ear and/or inner ear. For the purpose of illustration only: GYRUS Medical GmbH provides a micro-ear endoscope for observation and drug delivery to the inner ear window; Arenberg describes a medical treatment device for delivery in U.S. Patent Nos. 5,421,818, 5,474,529, and 5,476,446. Liquid to inner ear structure, etc. are incorporated into this case for reference. U.S. Patent Application Serial No. 08/874,208, the disclosure of which is incorporated herein by reference in its entirety in the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all A combined ear aspirator and medical dispenser for in-the-ear liquid sampling and medical applications is further disclosed in U.S. Patent Application Publication No. 2007/0167918, the disclosure of which is incorporated herein by reference.

The formulations and modes of administration described herein can also be applied to direct instillation or perfusion methods in the inner ear space. Thus, the formulations described herein can also be used in surgery, and non-limiting examples include closed openings, blunt incisions, ear papillary severing, humeral pedicleectomy, endolymphatic balloon incision, or the like. .

An auris-acceptable composition comprising a corticosteroid compound as described herein is for use in prophylactic and/or medical treatment. In medical applications, the corticosteroid composition is administered to a patient already suffering from a disease, condition, or disorder in an amount sufficient to cure or at least partially arrest the disease, disorder, or condition. The effective amount to be used herein will be determined by the judgment of an experienced medical professional, depending on the severity and duration of the disease, disorder or condition, prior treatment, the patient's state of health, and the response to the medication.

In the case where the patient's symptoms have not improved, the corticosteroid compound administration can be administered in a long-term manner, that is, for an extended period of time, including a syndrome that improves, or controls or limits, the disease or symptom of the patient during the life of the patient. .

In the case where the patient's symptoms are indeed improved, the corticosteroid compound administration can be administered in a continuous manner at the discretion of the doctor; or, the dose can be temporarily lowered or temporarily stopped for a certain length of time (ie, a "drug holiday"). . The length of the drug holiday can vary from 2 days to 1 year, including examples for illustration purposes only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 Day, 28, 35, 50, 70, 100, 120, 150, 180, 200, 250, 280, 300, 320, 350, and 365 days. The doses reduced during the drug holiday range from 10% to 100%, including 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55, for illustrative purposes only. %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once the patient's autoimmune symptoms have improved, a maintenance dose is administered if needed. The symptomatic action can then reduce the dose or frequency of administration, or both, to maintain an improved disease, disorder, or condition. In certain embodiments, the patient may require an interval of treatment for any reproducibility of symptoms over a long period of time.

The amount of corticosteroid corresponding to a particular amount of this agent will vary depending on factors such as the particular compound, the condition and severity of the disease, and will be conventionally determined in a manner known to those skilled in the art, including, for example, a particular agent. Administration, route of administration, symptoms of treatment, and individual or subject of treatment. However, the therapeutic dose typically used to treat an adult is generally between 0.02 and 50 mg per dose, preferably between 1 and 15 mg per administration. The intended dose may conveniently be administered simultaneously (or in a short period of time) or at intervals in a single dose or in divided doses.

In certain embodiments, the initial administration is a specific corticosteroid and subsequent administration of a different formulation or corticosteroid.

Controlled release formulation pharmacokinetics

In one embodiment, the formulations disclosed herein additionally provide an immediate release of a corticosteroid of this formulation, either within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or at 30 minutes. Inside, or within 60 minutes or within 90 minutes. In other embodiments, a therapeutically effective amount of at least one corticosteroid is immediately released by the formulation, or within 1 minute, or within 5 minutes, or within 10 minutes, or within 15 minutes, or within 30 minutes. , or within 60 minutes or within 90 minutes. In a particular embodiment, the formulation comprises an otic-pharmaceutically acceptable gel formulation that provides immediate release of at least one corticosteroid. Additional embodiments of this formulation may also include an agent that promotes the viscosity of the formulations disclosed herein.

In other or additional embodiments, the formulation provides a controlled release formulation of at least one corticosteroid. In a particular embodiment, the formulation diffuses at least one corticosteroid for more than 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12 hours, or 18 hours, or 1 day , or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, or 25 days, or At least one corticosteroid is diffused from the formulation by 30 days, or 45 days, or 2 months or 3 months or 4 months or 5 months or 6 months or 9 months or 1 year. In other embodiments, the therapeutically effective amount of at least one corticosteroid released by the formulation is more than 5 minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12 hours, or 18 hours , or 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days, or 18 days, or 21 days, or A therapeutically effective amount of at least one corticosteroid released from the formulation at 25 days, or 30 days, or 45 days, or 2 months or 3 months or 4 months or 5 months or 6 months or 9 months or 1 year .

In other embodiments, the formulation provides an immediate release of corticosteroid and an extended release formulation. In yet another embodiment, the formulation contains a ratio of 0.25:1, or a ratio of 0.5:1, or a ratio of 1:1, or a ratio of 1:2, or a ratio of 1:3, or a ratio of 1:4. , or a 1:5 ratio, or a 1:7 ratio, or a 1:10 ratio, or a 1:15 ratio, or a 1:20 ratio of immediate release and extended release formulations. In yet another embodiment, the formulation provides immediate release of a first corticosteroid and extended release of a second corticosteroid or other therapeutic agent. In yet another embodiment, the formulation provides an immediate release and an extended release formulation of at least one ear, with at least one therapeutic agent. In certain embodiments, the formulation provides a ratio of 0.25:1, or a ratio of 0.5:1, or a ratio of 1:1, or a ratio of 1:2, or a ratio of 1:3, or a ratio of 1:4. , or a ratio of 1:5, or a ratio of 1:7, or a ratio of 1:10, or a ratio of 1:15, or a 1:20 ratio of the first corticosteroid to the second therapeutic agent Extended release formula.

In yet another embodiment, the formulation provides a therapeutically effective amount of at least one corticosteroid at the disease site and is substantially free of systemic exposure. In yet another embodiment, the formulation provides a therapeutically effective amount of at least one corticosteroid at the disease site without measurable systemic exposure. In other embodiments, a therapeutically effective amount of at least one ear agent is provided at the disease site with little or no detectable systemic exposure.

Combinations of immediate, delayed, and/or extended release of a corticosteroid composition or formulation can be combined with other pharmaceutical agents disclosed herein, as well as excipients, diluents, stabilizers, tonicity agents, and other components. Thus, depending on the corticosteroid used, the desired consistency and or viscosity, or the mode of delivery selected, another aspect of the embodiments disclosed herein can be combined with embodiments of immediate release, delayed release, and/or extended release.

In a particular embodiment, the pharmacokinetics of the corticosteroid formulations described herein are determined by injecting the formulation into or near the inner ear round window membrane of a test animal (example scorpion or squirrel). The pharmacokinetics of the formulation are tested at a measurement time (eg, at 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days for up to 1 week). Animals were euthanized and tested with 5 ml peripheral lymphocyte samples. Remove the inner ear and test for the presence of corticosteroids. Determine the amount of corticosteroid in other organs, if needed. In addition, the systemic amount of corticosteroid is determined by taking a blood sample from the test animal. To determine if this formulation interferes with hearing, test animal hearing selectable tests.

Alternatively, an inner ear (as removed from the test animal) is provided and the movement of the corticosteroid is measured. As another alternative, an in vitro model of an inner ear window membrane is provided and the movement of corticosteroids is measured.

Manufacturing kit/object

The invention also provides a kit for preventing, treating or ameliorating a disease or disorder in a mammal. This kit typically contains at least one of the cortisol controlled release compositions disclosed herein and instructions for using the kit. The present invention also contemplates the use of one or more corticosteroid controlled release compositions for the manufacture, reduction, reduction, and amelioration of a medical formulation for a disease, dysfunction, or disorder of a mammal, such as a human, the mammal If the human has, suspects, or is at risk of developing an inner ear disorder.

In certain embodiments, the kit includes a carrier, package, or container having compartments for holding one or more containers such as vials, tubes, and the like, each container including a separate component for use herein. The method described. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In other embodiments, the container is formed from a variety of materials such as glass or plastic.

The article of manufacture provided by the present invention comprises a packaging material. A packaging material for packaging the pharmaceutical product of the present invention. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any suitable formulation and packaging materials for the mode of administration and treatment. . The broad sequence formulation of the corticosteroid composition provided by the present invention is contemplated to be a variety of treatments for any disease, disorder, or condition, with the advantage of being administered to the inner ear by controlled release of corticosteroids.

In certain embodiments, a kit substantially comprises one or more additional containers, each having a different substance (eg, a reagent, optionally in a concentrated form, and used in the formulations described herein from a commercial and user perspective) / or device). Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packs, containers, vials, and/or tube labels indicating levels and/or instructions for use, and instructions for use. The package is inserted. Basically includes a set of instructions.

Example Example 1 - Preparation of a Thermoreversible Gel Methyl Dehydrocorticosterol Formulation

A 10-g batch of a gel formulation containing 2.0% methyl dehydrocorticosterol was suspended in 5.00 g TRIS HCl buffer (0.1 M) by suspending 1.80 g of poloxamer 407 (BASF) and It was prepared by shaking overnight at 4 ° C to ensure complete dissolution. Add methyl dehydrocorticosterol (200.0 mg), hydroxypropyl methylcellulose (100.0 mg), methyl paraben (10 mg) and additional TRIS HCl buffer (0.1 M) (2.89 g) ) and stirred again until complete dissolution was observed. This mixture was kept below room temperature until use.

Example 2 - Preparation of mucoadhesive, thermoreversible gel dehydrocortisol formulation

A 10-g batch of a mucoadhesive, gel formulation containing 2.0% dehydrocortisol was suspended in 5.00 g of TRIS HCl by 2.0 mg of Carbomo 934P and 1.80 g of Poloxamer 407 (BASF). It was prepared in a buffer (0.1 M) and shaken at 4 ° C overnight to ensure complete dissolution. Dehydrocortisol, hydroxypropyl methylcellulose (100.0 mg), methyl paraben (10 mg) and additional TRIS HCl buffer (0.1 M) (2.87 g) were added and stirred until observed completely dissolved. This mixture was kept below room temperature until use.

Example 3 - Preparation of a cyclodextrin-containing thermoreversible gel 2.5% methyl dehydrocorticosterol

Poloxamer 407 (BASF) was suspended in TRIS HCl buffer (0.1 M) and the components were shaken overnight at 4 °C to ensure complete dissolution. The cyclodextrin solution and methyl paraben were added and stirred until complete dissolution was observed. This mixture was kept below room temperature until use.

Example 4 - Preparation of a cyclodextrin-containing mucoadhesive, thermoreversible gel methyl dehydrocorticosterol

Carbomo 934P and Poloxamer 407 (BASF) were suspended in TRIS HCl buffer (0.1 M) and the components were shaken overnight at 4 °C to ensure complete dissolution. The cyclodextrin solution and methyl paraben were added and stirred until complete dissolution was observed. This mixture was kept below room temperature until use.

Example 5 - Preparation of a Thermoreversible Methyl Dehydrocorticosterol Formulation Containing Micronized Methyl Dehydrocorticosterol

2.0% micron methyl dehydrocorticosterol in a 10-g batch, 13.8 mg disodium phosphate dihydrate USP (Fisher Scientific) + 3.1 mg sodium phosphate monohydrate USP (Fisher Scientific) + 74 mg chlorine The gel formulation of Sodium USP (Fisher Scientific) was dissolved in 8.2 g of sterile filtered DI water and the pH was adjusted to 7.4 with 1 M NaoH. This buffer solution was iced and sprinkled with 1.6 g of poloxamer 407 (BASF Corporation containing about 100 ppm BHT) to the frozen PBS solution with stirring, and the solution was mixed until all the poloxamers dissolved. This poloxamer was sterilized and filtered using a 33 mm PVDF 0.22 μm sterile syringe filter (Millipore) and transferred to a 2 ml sterilized glass vial (Wheaton) in a sterile environment. The vial was sealed with a sterilized butyl rubber stopper (Kimble) and 13mm Al seal (Kimble) curling. 20 mg of micronized methyl dehydrocorticosteroid (Spectrum chemicals) was placed in a separate clean de-heated vial sealed with a sterilized butyl rubber stopper and crimped with a 13 mm Al seal (Kimble). Dry heat sterilization (Fisher SCientific Isotemp oven) was carried out at 140 ° C for 7 hours. Transfer 1 ml of cold poloxamer solution to 20 mg of sterilized micronized methyl dehydrocorticosteroid using a 21 G needle (Becton Dickinson) attached to a 1 mL sterile syringe (Becton Dickinson) prior to the experimental administration described herein. In the vial, the suspension was thoroughly mixed by shaking to ensure the homogeneity of the suspension. This suspension was then withdrawn using a 21G syringe and the needle was replaced with a 27G needle for administration.

Example 6 - Preparation of micronized Prysson formulation with a thermoreversible gel containing a penetration enhancer

A 10-g batch of a gel formulation containing 2.0% micronized Prysson was prepared by suspending 1.80 g of poloxamer 407 (BASF) in 5.00 g TRIS HCl buffer (0.1 M) and The components were shaken overnight at 4 ° C to ensure complete dissolution. Adding Prysson (200.0 mg), hydroxypropyl methylcellulose (100.0 mg), methyl paraben (10 mg) and dodecyl maltoside (10 mg) with additional TRIS HCl buffer ( 0.1 M) (2.89 g) and stirred again until complete dissolution was observed. This mixture was kept below room temperature until use.

Example 7 - Effect of pH on 17% poloxamer 407NF/2% methyl dehydrocorticosteroid phosphate (DSP) in autoclave treatment in PBS buffer

A 17% poloxamer 407/2% methyl dehydrocorticosteroid phosphate (DSP) stock solution by dissolving 351.4 mg sodium chloride (Fisher Scientific), 302.1 mg disodium phosphate anhydrate (Fisher Scientific) 122.1 mg of sodium phosphate anhydrate (Fisher Scientific) and 2.062 g of methyldehydrocorticosteroid phosphate (DSP) were prepared by sterilizing and filtering DI water with 79.3 g of an appropriate amount of ear. This solution was cooled in a freezing water bath and then sprinkled into 17.05 g of Poloxamer 407NF (Spectrum Chemicals) to a cold solution while mixing. The mixture was further mixed until the poloxamer was completely dissolved. The pH of this solution was measured.

17% poloxamer 407/2% methyl dehydrocorticosteroid phosphate (DSP) in PBS, pH 5.3. A portion (about 30 mL) of the above solution was taken and 1 M HCl was added to adjust the pH to 5.3.

17% poloxamer 407/2% methyl dehydrocorticosteroid phosphate (DSP) in PBS, pH 8.0. A portion (about 30 mL) of the aforementioned raw material solution was taken and 1 M NaOH was added to adjust the pH to 8.

PBS buffer (pH 7.3) by dissolving 805.5 mg of sodium chloride (Fisher Scientific), 606 mg of disodium phosphate anhydrous (Fisher Scientific), 247 mg of sodium phosphate anhydrate (Fisher Scientific), followed by sterile filtration of DI water to 200 g And prepared.

A 2% pH 7.3 solution of methyl dehydrocorticosteroid (DSP) in PBS by dissolving the appropriate amount of methyl dehydrocorticosterol phosphate (DSP) in PBS buffer and in PBS buffer Prepared in an appropriate amount to 10 g.

1 mL samples were placed in 3 mL screw cap glass vials (lined with rubber) and tightly sealed. The vial was placed in a Market Forge-Sterilmatic autoclave (set, slow liquid) and sterilized at 250 °F for 15 minutes. After the autoclave was applied, the sample was allowed to stand to cool to room temperature and then placed in a refrigerator. This sample was homogenized by mixing the vial when cooled.

Observe and record the appearance (eg, discoloration and/or precipitation). 2% DSP alone showed discoloration (light yellow) and partial precipitation in PBS, while samples containing poloxamer did not show discoloration. In the sample containing poloxamer, precipitation was observed only in the sample having a pH of 5.3.

HPLC analysis using Luna C18(2) 3μm, 100 Agilent 1200, 250 x 4.6 mm column, was run using a 30-80 acetonitrile gradient (1-10 min) containing 0.05% TFA water-acetonitrile mixture for a total of 15 minutes. The main peaks recorded are shown in the table below. The sample was diluted by taking 30 μL of the sample and dissolving it in 1.5 ml of a 1:1 propionitrile water mixture. The purity of the sample was greater than 99% prior to autoclaving.

Example 8 - Autoclave treatment in PBS The release profile and viscosity of 17% poloxamer 407NF/2% methyl dehydrocorticosteroid phosphate (DSP) in buffer.

A component of the sample of Example 6 (autoclave treated and not autoclaved) was used to evaluate the release profile and viscosity measurements to assess the impact of heat sterilization on the properties of the gel.

The dissolution was carried out at 37 ° C in Snapwells (6.5 mm diameter polycarbonate film having a pore size of 0.4 μm). A 0.2 mL gel formulation was placed in Snapwell and allowed to stand until hardened, then 0.5 mL of buffer was placed in the reservoir and shaken at 70 rpm using a Labline orbital shaker. The sample was taken every hour (0.1 mL was taken and replaced with warm buffer). The poloxamer concentration of the sample was analyzed by UV cation method using 624 nm UV and reference to an external calibration standard curve. Briefly, 20 μL of the sample was mixed with 1980 μL of 15 mM cobalt thiocyanate solution and the absorbance was measured at 625 nm using an Evolution 160 UV/Vis spectrometer (Thermo Scientific).

The release of the ear methyl dehydrocorticosteroid (DSP) conforms to the Korsmeyer-Peppas equation

Where Q is the amount of release of the ear agent at time t, Q _a is the total release of the ear agent, k is the release constant of the nth order, n is a number of no causes for the dissolution mechanism and b is the axis intercept, It is characterized by an initial burst mechanism, where n=1 refers to an erosion control mechanism. The mean dissolution time (MDT) is the sum of the drug molecules staying in the matrix during different time periods before release, divided by the total number of molecules and calculated by:

The viscosity measurement was performed using a Brookfield viscometer RVDV-II+P with a water jacketed temperature control unit (temperature increased at a slope of 1.6 ° C/min at 15-34 ° C) at 0.08 rpm (shear rate of 0.31 s ^-1 ). Rotating under the CPE-51 spindle. Tgel (Tgel) is defined as the curve inflection point due to the increase in viscosity due to peptide-gel conversion.

This result shows the minimal effect of release curve and viscosity after autoclaving in 17% poloxamer 407NF/2% methyldehydrocorticosterone phosphate (DSP) in PBS buffer.

Example 9 - Degradation products of a second polymer added to a formulation containing 2% methyldehydrocorticosteroid phosphate (DSP) and 17% poloxamer 407 NF after heat sterilization (autoclave treatment) Viscosity utility.

Solution A. A pH 7.0 solution containing sodium carboxymethylcellulose (CMC) in PBS buffer by dissolving 178.35 mg of sodium chloride (Fisher Scientific), 300.5 mg of disodium phosphate disodium (Fisher Scientific), 126.6 mg Sodium phosphate anhydrate (Fisher Scientific) was prepared by sterilizing and filtering DI water at 78.4 g, followed by sprinkling 1 g of Blanose 7M65 CMC (Hercules, viscous 5450 cP@ 2%) to the buffer solution and heating to aid dissolution, and the solution was followed by Cool down.

17% poloxamer 407 NF/1% CMC/2% methyldehydrocorticosterone phosphate (DSP) at pH 7.0 in PBS by cooling 8.1 g of solution A in a chilled water bath followed by 205 mg of A Sodium dehydrocorticosteroid sodium phosphate (DSP) is then prepared by mixing. 1.74 g of poloxamer 407 NF (Spectrum Chemicals) was sprinkled into a cold solution while mixing. The mixture was further mixed until the poloxamer was completely dissolved.

2 ml of the aforementioned sample was placed in a 3 mL screw cap glass vial (lined with rubber) and tightly sealed. The vial was placed in a Market Forge-Sterilmatic autoclave (set, slow liquid) and sterilized at 250 °F for 25 minutes. After the autoclave was applied, the sample was allowed to stand to cool to room temperature and then placed in a refrigerator. This sample was homogenized by mixing as the vial was cooled.

No precipitation or discoloration was observed after autoclaving. HPLC analysis as described in Example 6 was carried out. Less than 1% degradation product due to hydrolysis of the methyl dehydrocorticosteroid product was detected, i.e., the formulation was stabilized after autoclaving.

Viscosity measurements were made as described in Example 7. The results show that the autoclave treatment has a slight effect on the viscosity of the gel or the Tgel temperature. Less overall impurities were observed in the formulation containing the poloxamer compared to the control (2% DSP in PBS).

The dissolution test was carried out as described in Example 7. The results showed an MDT of 11.9 hr compared to a MDT of 3.2 without the CMC formulation. The addition of CMC or a primary polymer is a diffusion barrier that introduces a release rate that reduces methyl dehydrocorticosterol (i.e., increases MDT).

Example 10 Buffer Type The utility of the degradation product of the formulation containing poloxamer 407NF after heat sterilization (autoclave treatment).

A TRIS buffer was adjusted to 7.4 with 1 M HCl by dissolving 377.8 mg of sodium chloride (Fisher Scientific) and 602.9 mg of tributyrate (Tromethamine, Sigma Chemical) followed by sterile filtration of DI water to 100 g.

Stock solution containing 25% solution of TRIS buffer poloxamer 407: 45 g of TRIS buffer was weighed, frozen in a freezer bath, and then sprinkled with 15 g of poloxamer 407NF (Spectrum Chemicals) into a buffer while mixing. This mixture is further mixed until the poloxamer is completely dissolved.

Stock solution containing 25% poloxamer 407 solution in PBS buffer (pH 7.3): dissolve 704 mg of sodium chloride (Fisher Scientific), 601.2 mg of disodium phosphate disodium (Fisher Scientific), 242.7 mg of sodium phosphate anhydrate ( Fisher Scientific) in 140.4 g sterile filtered DI water. This solution was cooled in a freezing water bath and then sprinkled with 50 g of poloxamer 407 NF (SPECTRUM CHEMICALS) into a cold solution while mixing. The mixture is further mixed until the poloxamer is completely dissolved and a clear and transparent solution is obtained. The pH of the solution obtained was measured to be 7.3.

A series of formulations were prepared from the above stock solutions. Methyl dehydrocorticosteroid phosphate (DSP) from Micron Chemicals and micron dehydrocorticosteroid USP were used in the experiments used.

The 1 ml sample was placed in a 3 mL screw cap glass vial (lined with rubber) and tightly sealed. The vial was placed in a Market Forge-Sterilmatic autoclave (set, slow liquid) and sterilized at 250 °F for 25 minutes. After the autoclave was applied, the sample was allowed to stand to cool to room temperature and then placed in a refrigerator. This sample was homogenized by mixing as the vial was cooled.

HPLC analysis as described in Example 6 was carried out. Compare the stability in TRIS with PBS buffer.

Viscosity measurements were performed as described in Example 7.

The results show that in order to reduce the hydrolysis during the autoclave treatment, the buffer needs to maintain a pH between 7 and 8 when warming up. Increased drug hydrolyzability was observed in TRIS buffer compared to PBS (Table 3). The occurrence of other degradation products can be reduced by using the polymeric additives (e.g., P407) described herein. A reduction in degradation products was observed by comparison of formulations containing 20% poloxamer 407 with formulations containing no poloxamer 407 (Table 7).

Formulations containing suspended micronized methyl dehydrocorticosterol have greater stability in autoclave treatment than their solution counterparts

Example 11: Pulse Release Ear Formulation

A pulse release agent formulation was prepared using a combination of methyl dehydrocorticosterol and methyl dehydrocorticosterone phosphate (DSP) (1:1 ratio) according to the procedures described herein. 20% of the deliverable dose of methyl dehydrocorticosterol was dissolved in the 17% poloxamer solution of Example 7 with the aid of beta cyclodextrin. The remaining 80% of the deliverable methyl dehydrocorticosterol dose is then added to the mixture and the final formulation is prepared according to any of the processes described herein.

P A pulse release formulation containing methyl dehydrocorticosteroid was prepared according to the procedure of the examples described herein and tested using the procedures described herein to determine the pulse release profile.

Example 12: Preparation of 17% poloxamer 407/2% DSP agent / 78 ppm Evans blue in PBS

A stock solution of Evans blue (5.9 mg/mL) in PBS buffer was prepared by dissolving 5.9 mg of Evans Blue (Sigma Chemical) with 1 mL of PBS buffer (from Example 61).

A stock solution containing 25% poloxamer 407 solution in PBS buffer from Example 8 was used in this study. An appropriate amount of DSP was added to the stock solution of Example 8 to prepare a formulation containing 2% DSP (Table 4).

The foregoing formulation was dosed to the middle ear of guinea pigs according to the procedure described herein and the gelation ability of the formulation and the position of the gel upon contact were identified at the dose administered and 24 hours after the dose was administered.

Example 13: Final sterilization of a poloxamer 407 formulation with a visible dye and no visible dye.

17% poloxamer 407/2% DSP/in phosphate buffer, pH 7.3: dissolved 709 mg sodium chloride (Fisher Scientific), 742 mg disodium phosphate anhydrous USP (Fisher Scientific), 251.1 mg sodium phosphate monohydrate USP (Fisher Scientific) and an appropriate amount of ear and 158.1 g of sterile filtered DI water. This solution was cooled in an ice water bath and then sprayed with 34.13 g of poloxamer 407 NF (Spectrum chemicals) to the cooled solution while mixing. This mixture is further mixed until the poloxamer is completely dissolved and a clear transparent solution is obtained. The pH of this solution was 7.3.

17% poloxamer 407/2% DSP/59ppm Evans blue in phosphate buffer: Take 2mL of 17% poloxamer 407/2% ear / in phosphate buffer solution and add 2mL of 5.9mg / A solution of mL Ivan Blue (Sigma-Aldrich Chemical) in PBS buffer.

25% poloxamer 407/2% DSP/phosphate buffer: solvent 330.5 mg sodium chloride (Fisher Scientific), 334.5 mg disodium phosphate dihydrate USP (Fisher Scientific), 125.9 mg sodium phosphate monohydrate USP (Fisher Scientific) and an appropriate amount of otic agent in 70.5 g of sterile filtered DI water.

This solution was cooled in an ice water bath and then sprayed with 25.1 g of poloxamer 407 NF (Spectrum chemicals) to the cooled solution while mixing. This mixture is further mixed until the poloxamer is completely dissolved and a clear transparent solution is obtained. The pH of this solution was 7.3.

25% poloxamer 407/2% DSP/59ppm Evans blue in phosphate buffer: Take 2mL 25% poloxamer 407/2% DSP/phosphate buffer solution and add 2mL of 5.9mg/ A solution of mL Ivan Blue (Sigma-Aldrich Chemical) in PBS buffer.

A 2 ml formulation was placed in a 2 mL glass vial (Wheaton serum glass vial) sealed with a 13 mm Butylstr (kimble plug) and crimped with a 13 mm aluminum seal. The vial was placed in a Market Forge-Sterilmatic autoclave (set, slow liquid) and sterilized at 250 °F for 25 minutes. After the autoclave was applied, the sample was allowed to stand to cool to room temperature and then placed in a refrigerator. This vial was placed in a freezer and mixed while cooling to homogenize the sample. The sample was recorded for discoloration or precipitation after autoclaving.

HPLC analysis was performed as described in Example 6.

Viscosity measurements were performed as described in Example 7. The results show that the autoclave-containing formulation containing visible dyes is not effective in the degradation of the product and the viscosity of the formulation.

The average dissolution time of the 25% poloxamer 407 formulation was determined (the amount of methyldehydrocorticosteroid phosphate released by UV @ 245 nm as measured by Example 7) was 5.6 hr and 17% poise. The Losham 407 formula is shown as 3.2 hr.

Example 14: Comparison of in vitro release profiles

Dissolution was carried out at 37 ° C in Snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm), 0.2 mL of the gel formulation described herein was placed in Snapwell and allowed to stand until hardened, followed by 0.5 mL of buffer Place in a reservoir and shake at 70 rpm using a Labline orbital shaker. The sample was taken every hour (0.1 mL was taken and replaced with warm buffer). An external calibrated standard curve was compared with the concentration of the ear of the sample analyzed by UV at 245 nm. Pluronic The concentration was analyzed at 624 nm using a cobalt thiocyanate method. The relative ranking sequence of the mean dissolution time (MDT) as a function of % P407 was determined. A linear relationship between the mean dissolution time (MDT) and the P407 concentration in this formulation showed that this methyldehydrocorticosterol release was attributed to the erosion of the polymer gel (poloxamer) but not to diffusion. A none-linear relationship shows a combination of otic release via diffusion and/or polymer gel degradation.

Alternatively, the sample was analyzed using the method described in Li Xin-Yu [Acta Pharmaceutica Sinica 2008, 43(2): 208-203] and determined as a graded sequence of mean dissolution time (MDT) as a function of %P407.

Figure 1 illustrates in vitro release profiles of methyl dehydrocorticosterol formulations with different concentrations of poloxamer 407. Figure 2 illustrates the near linear relationship (1:1 correlation) between the mean dissolution time (MDT) and the P407 concentration of the formulation. This result indicates that the methyldehydrocorticosterol release is due to erosion by the polymer gel (poloxamer) but not diffusion.

Example 15: Comparison of gelation temperatures in vitro

The effect of poloxamer 188 and methyldehydrocorticosterol on the viscosity of the gelatinization temperature and the poloxamer 407 formulation was evaluated for the purpose of gelation temperature.

A 25% poloxamer 407 stock solution in PBS buffer (Example 9) was used with the PBS solution from Example 6. Poloxamer 188 NF from BASF was used.

The average dissolution time of 20% poloxamer 407/10% rossam 188 (method described in Example 7) was determined to be 2.2 hr and 20% poloxamer 407/5% poloxamer 188 showed It is 2.6 hr. Viscosity was determined using the method described in Example 7. Autoclave treatment is not effective on the viscous or Tgel of formulations containing poloxamer 188.

An equation suitable for the data obtained and which can be used to estimate the gelation temperature of the F127/F68 mixture (for 17-20% F127 and 0-10% F68) is as follows.

T _gel = -1.8 (% F127) + 1.3 (% F68) + 53

An equation suitable for the data obtained and which can be used to estimate the average dissolution (hr) based on the gelation temperature of the F127/F68 mixture (for 17-25% F127 and 0-10% F68), used in Example 12 and 14 results obtained.

MDT=-0.2(T _gel )+8

Example 16: Determination of the temperature range for sterile filtration

The viscosity at low temperatures is measured to help guide the temperature range that is required for sterilization filtration to reduce the likelihood of blockage.

Use a Brookfield viscometer RVDV-II+P with a water jacketed temperature control unit (temperature increased at 10-25 ° C with a slope of 1.6 ° C / min) at 1, 5 and 10 rpm (shear rate 7.5, 37.5 and 75 s) ^-1 ) Viscosity measurement was performed under a rotating CPE-40 mandrel.

A 17% Pluronic P407 Tgel oxime is measured by increasing concentration function. The Tgel increased by 17% Pluronic formula is estimated by the following equation:

ΔT _gel =0.93 [% ear preparation]

This result shows that sterile filtration of the formulations described herein can be carried out at about 19 °C.

Example 17: Determination of manufacturing conditions

A 7 liter batch of 17% P407 placebo was prepared to evaluate manufacturing/filtration conditions. Placebo was prepared by placing 6.4 liters of DI water in a 3 gallon SS pressure vessel and allowing to stand in the freezer for overnight cooling. The vessel was taken out the next morning and added (water temperature 5 ° C, RT 18 ° C) and 48 g of sodium chloride, 29.6 g of disodium phosphate anhydrous and 10 g of sodium phosphate monohydrate and dissolved in an overhead mixer (IKA RW20@1720 rpm). After half an hour, once the buffer was dissolved (solution temperature 8 ° C, RT 18 ° C), 1.36 kg of poloxamer 407 NF (Spectrum Chemicals) was slowly sprinkled into the buffer solution at 15 minute intervals (solution temperature 12 ° C, RT 18 ° C ), then the speed is increased to 2430 rpm. After mixing for another hour, the mixing speed was reduced to 1062 rpm (completely dissolved). .

The room temperature was maintained below 25 ° C to keep the temperature of the solution below 19 °C. The solution temperature was maintained below 19 °C for 3 hours of initial manufacture without the need for a freeze/cool container.

Evaluation of three different Sartoscale (Sartorius Stedim) filters with a surface area of 17.3 cm2 at 20 psi and 14 ° C solutions

Sartopore 2, 0.2μm 5445307HS-FF (PES), flow rate 16mL/min

Sartobran P, 0.2 μm 5235307HS-FF (cellulose ester), flow rate 12 mL/min

Sartopore 2 XLI, 0.2μm 5445307IS-FF (PES), flow rate 15mL/min

Filtration was carried out at a solution temperature using a Sartopore 2 strainer 5441307H4-SS at a solution temperature using a 0.45, 0.2 μm Sartopore 2 150 sterilization capsule (Sartorius Stedim) having a surface area of 0.015 m ² at a pressure of 16 psi. The flow rate was measured at 16 psi at about 100 mL/min, and the rate was unchanged when the temperature was maintained in the range of 6.5-14 °C. The reduced pressure of the solution and the increased temperature cause a decrease in the flow rate due to the increased viscosity of the solution. The discoloration of the solution was monitored during the process.

Viscosity, Tgel and UV/Vis absorbance were measured prior to filtration evaluation. Pluronic UV/Vis spectra were obtained by Evolution 160 UV/Vis (Thermo Scientific). The peak in the range of 250-300 nm is derived from the BHT stabilizer present in the raw material (poloxamer).

The foregoing process can be used to make a 17% P407 formulation and includes temperature analysis in ambient conditions. The temperature of 19 ° C reduces the cost of the cooling vessel during manufacturing. In some instances, a jacketed container is used to further control the temperature of the solution to alleviate manufacturing concerns.

Example 18 Methyl Dehydrocorticosterol Released in Vitro by Autoclave Treated Micronized Samples

17% poloxamer 407/1.5% ear in TRIS buffer: 250.8 mg sodium chloride (Fisher Scientific), and 302.4 mg tributyl ester (Sigma Chemical) dissolved in 39.3 g sterile filtered DI water, pH Adjust to 7.4 with 1 M HCl. 4.9 g of the foregoing solution was used and an appropriate amount of micronized methyldehydrocorticosterol USP (Spectrum Scientific) was suspended and well dispersed. 2 mL of this formulation was transferred to a 2 mL glass vial (Wheaton serum glass vial) sealed with 13 mm butyl styrene ester (kimble plug) and crimped with a 13 mm aluminum seal. The vial was placed in a Market Forge-Sterilmatic autoclave (set, slow liquid) and sterilized at 250 °F for 25 minutes. After the autoclave was applied, the sample was allowed to stand to cool to room temperature. This vial was placed in a freezer and mixed while cooling to homogenize the sample. The sample was precipitated or decolored after the autoclave was applied.

Dissolve in Snapwells (6.5 mm diameter polycarbonate membrane with a pore size of 0.4 μm) at 37 ° C, place 0.2 mL gel formulation in Snapwell and allow to stand until hardened, then place 0.5 mL PBS buffer in storage The Labline orbital oscillator was used to oscillate at 70 rpm. Samples were taken every hour [0.1 mL was taken and replaced with 2% PEG-40 hydrogenated castor oil (BASF) warm PBS buffer to promote methyl dehydrocorticosteroid solubility]. The sample was analyzed for methyl dehydrocorticosterol concentration using a 245 nm UV reference-external calibration standard curve. The release rate is compared to other formulations disclosed herein. The MDT time of each sample was calculated.

The solubility of methyl dehydrocorticosteroid in the 17% poloxamer system was assessed by the methyl dehydrocorticosterol concentration in the supernatant of the Eppendorf centrifuge 5424 centrifuged at 15,000 rpm for 10 minutes. The methyl dehydrocorticosterol concentration in the supernatant was determined using a 245 nm UV reference-external calibration standard curve. Figure 3 illustrates the release profile of corticosterone from different steroids containing 17% P407. Table 9 describes the solubility of methyl dehydrocorticosteroid in TRIS buffer and 17% P407 solution.

Example 19 The release rate or MDT and viscosity of a formulation containing sodium carboxymethylcellulose.

17% poloxamer 407/2% DSP/1% CMC (Hercules Blanose 7M): carboxymethylcellulose sodium (CMC) solution (pH 7.0) in PBS buffer by dissolving 205.6 mg of sodium chloride (Fisher) Scientific), 372.1 mg of disodium phosphate dihydrate (Fisher Scientific), 106.2 mg of sodium phosphate monohydrate (Fisher Scientific) were prepared by sterilizing and filtering DI water at 78.1 g. Then sprinkle 1 g of Blanose 7M CMC (Hercules, viscous 533 cP @ 2%) to the buffer solution and heat to aid dissolution, and the solution was then cooled and sprinkled into 17.08 g of Poloxamer 407NF (Spectrum Chemicals) to cold Mix in the solution at the same time. Prepare a formulation containing 17% poloxamer 407 NF/1% CMC/2% DSP in PBS buffer, add/dissolve an appropriate amount of methyl dehydrocorticosterol to 9.8 g of the above solution, and Mix until the ear is completely dissolved. The pH of this solution was 7.0.

17% poloxamer 407/2% DSP/0.5% CMC (Blanose 7M65): a solution of carboxymethylcellulose sodium (CMC) in PBS buffer (pH 7.2) by dissolving 257 mg of sodium chloride (Fisher Scientific) 375 mg of disodium phosphate dihydrate (Fisher Scientific) and 108 mg of sodium phosphate monohydrate (Fisher Scientific) were prepared by sterilizing and filtering DI water at 78.7 g. Sprinkle 0.502 g of Blanose 7M65 CMC (Hercules, viscous of 5450 cP @ 2%) to the buffer solution and heat to aid dissolution, and the solution was then cooled and sprinkled into 17.06 g of Poloxamer 407 NF (Spectrum Chemicals) Mix simultaneously into the cold solution. A solution containing 17% poloxamer 407 NF/1% CMC/2% DSP in PBS buffer was prepared, and 201 mg of DSP was added/dissolved to 9.8 g of the above solution, and mixed until the DSP was completely dissolved. The pH of this solution was 7.2.

17% poloxamer 407/2% DSP/0.5% CMC (Blanose 7H9): carboxymethylcellulose sodium (CMC) solution (pH 7.3) in PBS buffer by dissolving 256.5 mg of sodium chloride (Fisher) Scientific), 374 mg of disodium phosphate dihydrate (Fisher Scientific), 107 mg of sodium phosphate monohydrate (Fisher Scientific) were prepared by sterilizing and filtering DI water at 78.6 g, followed by sprinkling 0.502 g of Blanose 7H9 CMC (Hercules, viscous of 5600 cP) @1%) to the buffer solution and heated to aid dissolution, and the solution was then cooled and sprinkled into 17.03 g of poloxamer 407 NF (Spectrum Chemicals) to the cold solution while mixing. A solution containing 17% poloxamer 407 NF/1% CMC/2% DSP in PBS buffer was prepared, and 203 mg DSP was added/dissolved to 9.8 g of the above solution and mixed until the DSP was completely dissolved. The pH of this solution was 7.3.

The viscosity measurement was carried out as described in Example 7, and the dissolution was carried out as described in Example 7.

Figure 4 illustrates the correlation between the average dissolution time (MDT) of the formulation and the apparent viscosity of the formulation. The rate of release is modulated by the incorporation of a secondary polymer. The selection of the grade and concentration of the primary and secondary polymers can be facilitated by the use of one of the generally available water soluble polymerizations shown in Figures 5 and 6.

Example 20 - Dry Sterilization of Micro-Methyl Dehydrocorticosterol Powder

10 mg of micronized methyl dehydrocorticosterol powder (Spectrum lot XD0385) was filled into 2 ml glass vials and sealed with a 13 mm butyl rubber stopper and placed in an oven at different temperatures for 7-11 hours.

HPLC analysis using Luna C18(2) 3μm, 100 Agilent 1200 with 250x4.6mm column using 30-95 solution B (solvent A 35% methanol: 35% water: 30% acetate buffer, solvent B 70% methanol: 30% acetate buffer pH) 4) Gradient (1-6 min) followed by isocratic (95% solvent B) for 11 minutes for a total of 22 minutes. The sample was dissolved in ethanol and analyzed. Dry heat sterilization of micronized methyl dehydrocorticosterol at temperatures up to 138 °C does not affect the particle size distribution of the micronized methyl dehydrocorticosteroid. HPLC analysis showed 99% purity of the dry heat sterilized micronized methyl dehydrocorticosterol.

Example 21 - Application of a corticosteroid formulation for promoting adhesion to a round window membrane of the inner ear

The formulation was prepared as in Example 1 and loaded into a gas-tight disposable 5 ml deuterated glass syringe with a 15 gauge needle. Lidocaine is topically applied to the tympanic membrane and a small incision for viewing the middle ear chamber is made. The tip of the needle is placed to a position on the round window membrane of the inner ear and the anti-inflammatory corticosteroid formulation is applied directly to the round window membrane.

Example 22 - In vivo testing of intracerebral injections of a day's corticosteroid formulation.

A 21-day-old squirrel (Charles River, 200-300 g female) with the same attribute group was injected intra-early with a 20-120 μL 2% DSP formulation. Figure 7 shows the results of gelation after 5 days of intrathecal injection of guinea pig ears. Increased injection volume increased by up to 90 μL of injection volume of gel retention. However, an injection volume of 120 μL showed a lower gel retention.

A 21-day-old squirrel (Charles River, female weighing 200-300 g) of the same attribute group was injected intra-early with 50 μL of the different P407-DSP formulations containing 0 to 6% DSP described herein. Figure 8 shows the gel elimination time course for each formulation. The gel elimination time course of the 6% DSP formulation was faster than other formulations with lower concentrations of DSP (0, 0.6, and 2%, respectively) (lower mean dissolution time (MDT)). Furthermore, when the P407 concentration for the 6% DSP formulation (6% Dex-P(*)) was increased from 17% to 19%, a faster gel removal was observed, as shown in Figure 8. Therefore, the injection volume and concentration of corticosteroids in the formulations described herein are tested to determine the optimal parameters for preclinical and clinical trials. It has been observed that an in-ear formula with a high concentration of DSP has a release profile that is different from an in-ear formula with a lower concentration of DSP.

Example 23 - Prolonged release kinetic energy in vivo

21-day-old squirrel (Charles River, 200-300 g female) with the same attribute group as Pluronic F buffered at 50 μL 17% at 280 mOsm/kg and having a formulation of 1.5 wt% to 4.5 wt% methyl dehydrocorticosterol -127 formula for intra-ear injection. Animals were dosed on day 1. Figure 9 shows the release profile of the formulation based on the peripheral lymphatic analysis test. In the 1.5% methyl dehydrocorticosterol treatment, the exposure on days 7-10 was about 10% of the Cmax with an average residence time of about 3.5 days. In the 4.5% methyl dehydrocorticosterol treatment, the exposure was maintained at a similar or higher than the amount observed on day 1 for at least 10 days, and an expected average residence time was over 18 days.

Example 24 - Evaluation of corticosteroid formulations in an AIED animal model Method and substance Induction of immune response

A female white Swiss mouse (Swiss rat) weighing 20 to 24 g from the National Institutes of Health (Harlan Sprague-Dawley, Inc., Indianapolis, IN) was used. Keyhole limpet hemocyanin (KLH; Pacific Biomarine Supply, Vinis, Canada) was suspended in phosphate-buffered saline (PBS) (pH 6.4), dialyzed against PBS and centrifuged twice. The pellet (attached to KLH) was dissolved in PBS and injected subcutaneously into the back of the animal (0.2 mg emulsified in Freund's complete adjuvant). Animals were given a supplement (0.2 mg KLH in Freund's incomplete adjuvant) and then injected into the microwells through the cochlear sac with 0.1 mg KLH in 5 [mu]l PBS (pH 6.4) after 10 weeks. Use the operating microscope and sterilization technology to access the cochlea. The incision is made after one ear and a hole is drilled into the bubble to allow visibility of the cochlear gyrus, the radial artery and the rounded window of the inner ear. The iliac artery was cauterized and removed, and a 25 μm hole was drilled through the cochlear sac to the basal gyrus of the lateral basal gyrus. The KLH or PBS control group was slow to use a Hamilton syringe coupled to a plastic tube to inject a glass microtiter filled with antigen or control. This well is sealed with bone wax after injection and excess liquid is removed. Only one cochlear per animal was treated with KLH.

treatment

KLH and control mice were divided into two groups (n=10 per group). The corticosteroid formulation of Example 1 containing methyldehydrocorticosterol was applied to the inner ear round window membrane of a group of animals. A control formulation that did not contain methyl dehydrocorticosterol was administered to the second group. This methyl dehydrocorticosterol and control formulation was re-administered three days after the initial administration. The animals were killed after 7 days of treatment.

Result analysis Electrophysiological test

The hearing floor of the auditory brainstem response bottom (ABR) was measured by tapping each ear of each animal initially and after 1 week of the experimental procedure. Animals were placed in a single wall environmental chamber (Industrial Acoustics, Brooks, NY, USA) on a heating pad. A subcutaneous electrode (Grass Instrument Branch, Astro-Med, Siva Walk, Rhode Island, USA) was inserted into the cranial (active electrode), mastoid (reference electrode), and hind leg (grounding wire). The tap stimulus (0.1 ms) was generated by the computer and transmitted to the Beyer DT 48, 200 Ohm amplifier with an ear spectrometer placed in the external auditory canal. Amplify the recorded ABR and digitize it with a battery operated preamplifier and enter a Tucker-Davis Technologies ABR recording system that provides computer control for stimulation, recording, and averaging (Tucker Davis Technology, Ghana, Florida, USA) . The amplitude-stimulated stimulation was successively reduced to the animals in a 5-dB step, and the stimulus-appearing activity (n=512) was recorded on average and displayed. The bottom limit is defined as the amount of stimulus between the invisible detectable response and the clearly identifiable response.

Histochemical analysis

The animals were anesthetized and sacrificed by intracardiac perfusion of heparinized warm saline and then fixed with approximately 40 ml of periodic acid-aspartic acid-trimaldehyde (4% final concentration of paraformaldehyde). The right tibia was removed immediately and decalcified with buffered 5% ethylenediamine tetraacetate (pH 7.2) for 14 days (4 °C). After decalcification, the tibia is then immersed in increasing concentrations (50%, 75%, 100%) of ice embedding agent (OCT) compounds (Tissue-Tek, Miles, Inc., Ihart, USA), rapid freezing ( -70 ° C), and parallel section of the bone axis (4 μm). The collected sections were stained with hematoxylin and eosin (H&E) and immunohistochemical analysis.

The severity of inflammation was assessed by the amount of cell infiltration of the tympanic, and an unbiased estimate was given to each cochlea. A score of 0 indicates no inflammation, while a score of 5 indicates that all of the cochlear gyrus has severe inflammatory cell diafiltration.

Example 25 - Evaluation of a corticosteroid formulation in an animal model of otitis media Induction of otitis media

Healthy adult mice weighing 400 to 600 g with normal middle ear and examined with auroscope and tympanogram were used in these studies. The Eustachian tube disorder was performed for 24 hours prior to inoculation to prevent the inoculum from flowing out of the Eustachian tube. 1 ml of type 3 S. pneumoniae strain was placed directly on the low tympanic membrane of the middle ear of the long-tailed chinchilla in a 4-h-log phase (containing approximately 40 colony forming units (CFU)). Control rats were incubated with 1 ml of sterile PBS.

treatment

S. pneumoniae cultured and control mice were divided into two groups (n=10 per group). The dehydrocortisol formulation containing Example 2 was applied to the tympanic wall of a group of animals. A control formulation containing no dehydrocortisol was administered to the second group. This dehydrocortisol and control formulation was re-administered three days after the initial administration. The animals were killed after 7 days of treatment.

Result analysis

Middle ear fluid (MEF) was sampled at 1, 2, 6, 12, 24, 48 and 72 hours after streptococcal inoculation. Quantitative MEF medium was performed on amniotic fluid, and the limit was set at 50 CFU/ml. Inflammatory cells were measured by a hemocytometer and the number of differentiated cells was stained by Wright's stain.

Example 26 - AIED clinical trial using methyl dehydrocorticosterol formulation

Ten adult patients were selected who had previously responded to the system of methyl dehydrocorticosteroid treatment, but were currently discontinued due to adverse events. The methyl dehydrocorticosterol hot reversible gel formulation of Example 1 was administered via a puncture tympanic membrane to the round window membrane of each patient. The gel formulation of methyl dehydrocorticosterol was administered again 7 days after the initial administration and re-administered at 2 and 3 weeks of treatment.

A hearing assessment consisting of a pure tone hearing test (250-8,000 Hz) and a speech test using a French two-syllable word list was performed for each patient. The tests were performed prior to administration of the methyl dehydrocorticosterol formulation and at 1, 2, 3 and 4 weeks after the initial treatment.

Example 27 - Evaluation of dehydrocortisol in a rat model of hearing impairment Method and material Induction of ototoxicity

Twelve mice (Harlan Sprague-Dawley rats) weighing 20 to 24 grams were used. The baseline of the auditory brainstem evoked response (ABR) at 4-20 mHz was determined. The rats were anesthetized and exposed to a continuous pure tone of 6 kHz with a loudness of 120 dB for 30 minutes.

treatment

The control group (n=10) was given saline after hearing loss. The experimental group was given dehydrocortisol (2.0 mg/kg of body weight) prepared in Example 2 after hearing loss.

Electrophysiological test

The hearing deficit of the auditory brainstem evoked response low (ABR) was measured by tapping each ear of each animal initially and after 1 week of the experimental procedure. Animals were placed in a single wall environmental chamber (Industrial Acoustics, Brooks, NY, USA) on a heating pad. A subcutaneous electrode (Grass Instrument Branch, Astro-Med, Siva Walk, Rhode Island, USA) was inserted into the cranial (active electrode), mastoid (reference electrode), and hind leg (grounding wire). The tap stimulus (0.1 ms) was generated by the computer and transmitted to the Beyer DT 48, 200 Ohm amplifier with an ear spectrometer placed in the external auditory canal. Amplify the recorded ABR and digitize it with a battery operated preamplifier and enter a Tucker-Davis Technologies ABR recording system that provides computer control for stimulation, recording, and averaging (Tucker Davis Technology, Ghana, Florida, USA) . The amplitude-stimulated stimulation was successively reduced to the animals in a 5-dB step, and the stimulus-appearing activity (n=512) was recorded on average and displayed. The bottom limit is defined as the amount of stimulus between the invisible detectable response and the clearly identifiable response. .

Implementation Example 28 - Clinical study of methyl dehydrocorticosterol in patients with Meniere's disease Research purposes

The primary objective of this study was to evaluate the safety and efficacy of methyl dehydrocorticosteroid and placebo in improving the tinnitus symptoms in patients treated with Meniere's disease in human subjects.

Research design

This was a 3-phase, multicenter, double-blind, randomized, placebo-controlled, 3-arm parallel study to compare the treatment of tinnitus in the JB004/A versus placebo groups. Approximately 250 patients were enrolled in the study and were randomized (1:1) into 3 treatment groups in a random order prepared by the sponsor. Each group received 300 mg of methyl dehydrocorticosterol, which was reversely delivered by thermal gel, or a controlled release placebo formulation. The release of methyl dehydrocorticosterol was controlled release and occurred over 30 days. The route of administration is an intra-injection.

Main outcome indicator

Visual Analog Scale (VAS) was used to measure changes in tinnitus loudness (or relative pre-dose baseline at any other time point) measured after 2 hours of dosing. Alternatively, a hearing assay is used in a healthy ear to match the tinnitus tone in the affected ear.

Secondary outcome indicator

VAS measures tinnitus audio, pain and anxiety. Pure tone hearing test & psychoacoustic assessment. Safety, tolerability and pharmacokinetics of sleep and tinnitus questionnaires. [Time frame: perception at the time of measurement after 2 hours of administration (or relative pre-dose baseline at any other time point).

Selection principle

Patients who meet any of the following principles are selected:

- A male or female individual with a diagnosis of tinnitus.

- Individuals are willing to limit alcohol intake.

- Women who have the possibility of giving birth but agree to give up sexual intercourse or consent to birth control.

- Women without fertility.

Exclusion principle

Patients selected if they have any of the following principles are excluded:

- intermittent or pulsed tinnitus

- The individual has pathological grade anxiety or depression.

- The individual has no hearing impairment and has normal hearing.

- The individual does not respond to the lidocaine injection test or shows a large variation in the pre-injection value.

- There are any surgical or medical symptoms that may interfere with the PK of the drug.

- Individuals with a history of liver disability or abnormal liver function.

- Individual with kidney disability.

- Individuals with HIV, hepatitis C or hepatitis B positive.

- The individual has an abnormal laboratory, ECG or physical examination decision.

- The individual has no thyroid.

- Individual with liver, heart, kidney, nerve, cerebrovascular, metabolic or pulmonary disease.

- The individual has a myocardial infarction.

- Individuals with a history of epilepsy disorders.

- Individuals with a history of cancer.

- Individuals with medication or other allergies.

- The individual is positive for drug use and/or has a history of substance abuse or dependence.

- The individual takes a psychotropic or antidepressant at a specific time frame.

- Agents or foods known to interfere with liver enzymes (eg grapefruit or grapefruit juice).

- A non-psychotic abnormal drug with a mechanism of action of serotonergic.

- The individual has currently used a study medication or has recently participated in a clinical trial.

- Females have a positive pregnancy test.

- A female who wants to become pregnant or who will be a father within 4 weeks after the last study drug is administered.

- Individuals who donated blood in the first few months with one unit of blood donated or more or within one month of completing the study.

Example 29 - Evaluation of methyl dehydrocorticosteroid in an animal model of endolymphatic hydrops

This step is the performance of the methyl dehydrocorticosterol formulation prepared in Example 1.

Materials and Methods

A 35-day-old Hartley guinea pig was used which had a positive Preyer's reflex and weighed about 300 g. Five rats were used as a control group (normal ear group) for 5 weeks without or without treatment, while the other 30 were used as experimental animals. All experimental animals received an electrocauterized endolymphatic sac (Lee et al., Acta Otolaryngol. (1992) 112: 658-666; Takeda et al., Equilib. Res. (1993) 9: 139-143). Four weeks after the operation, the animals were divided into three groups: no-perfusion edema ear, carrier-treated edema ear and methyl dehydrocorticosteroid-treated edema ear, 10 animals per group. The non-perfused edema ear group was not treated except for electrocautery of the endolymphatic sac. In the vehicle-treated edema ear and methyl dehydrocorticosteroid-treated edema ear group, the liposome formulation was applied to the round window membrane. One week after the composition was administered, the animals used were sacrificed to assess changes in endolymphatic space. All animals were undisturbed and free to move in their respective cages in the quiet room, except during the entire experimental period.

In the assessment of changes in the endolymphatic space, all animals were perfused with a physiological saline solution under deep anesthesia with pentobarbital in the abdomen and fixed in 10% formalin. The left tibia was removed and fixed with 10% formalin solution for 10 days or longer. Next, it was decalcified with 5% trichloroacetic acid for 12 days and dehydrated in a graded ethanol series. It is embedded in paraffin and fire cotton glue. The prepared block was sliced 6 μm in the horizontal direction. Sections were stained with hematoxylin and eosin and observed under a light microscope. The assessment of endolymphatic space was performed according to the Takeda method (Takeda et al., Hearing Res. (2003) 182: 9-18).

real Example 30 - Evaluation of methyl dehydrocorticosteroid in the ear in spontaneous transient sensorineural hearing loss (ISSHL) Research purposes

The primary purpose of this study was to provide safety and efficacy in oral steroid therapy or in-the-ear (IT) steroid therapy.

Main outcome indicator

The average pure tone listening (PTA) and vocabulary recognition are the endpoint values of equal weight; for speech discrimination scoring, a 50-word monosyllabic system is used; in PTA or all or part of the frequency is greater than 20 dB, the frequency is missing greater than Improvements of 30 dB, and/or 20% or more of WDS; in addition to absolute changes, the recovery of the contralateral ear is also determined.

Full recovery - restored to 5% of the opposite side speech discrimination score, or within 5 dB9 of the opposite side PTA.

Research design

This was a multicenter, double-blind, randomized, placebo-controlled, parallel group study to compare ISSHL treatment with methyldehydrocorticosterol versus placebo. Approximately 140 individuals were enrolled in this study and were randomized (1:1) into 3 treatment groups in random order.

- Individuals in group I received oral Prysson (administered 1 mg/kg/day of prednisone for 14 days, followed by daily dose reduction of 10 mg until no longer administered steroids)

- Individuals in group II receive IT methyl dehydrocorticosterone sodium phosphate (administer 0.3-0.5 mL of methyl dehydrocorticosterol per month / 1 injection per mL of carrier until up to 3 injections) And oral Prysson (administration of 1 mg / kg / day of prednisone for 14 days, followed by daily dose reduction of 10 mg until no longer given steroids)

- Individuals in group III received placebo IT injection (up to 3 injections with 0.3-0.5 mL vehicle per month) and oral Prysson

Hearing assessment The hearing assessment includes:

- Average pure tone hearing (500 Hz, 1 & 2 kHz; 4, 6 & 8 kHz).

The two PTA values were determined: a low frequency value (500 Hz - 2 kHz) and a high frequency value (4-8 kHz).

- sacral muscle reflex

- tympanogram check & ring attenuation check

- speech recognition threshold

The hearing loss of each individual was measured before the start of treatment (twice before the study assignment and before the random assignment). Hearing was assessed at 1, 2, 4 & 8, and 4 & 6 months after the start of treatment.

Main selection principle

- Male or female patients between the ages of 18 and 75

- Unilateral SHL (sensorineural hearing loss) progresses within 72 hours

- the individual has hearing loss at any frequency not exceeding 70 dB

Exclusion principle

- More than 10 days of oral steroid therapy for any reason during the previous 30 days

- Prior to the first 14 days due to ISSHL for 5 or more days of oral steroid therapy

- a history of hearing changes in either ear

Example 31 - Evaluation of methyl dehydrocorticosterol in the administration of Meniere's disease in the ear Research purposes

The primary objective of this study was to evaluate the safety and efficacy of in-the-ear (IT) methyl dehydrocorticosteroids in improving individualized Meniere's disease in humans.

Main efficacy index

Stun

Self-description system with the following systems -

- No dizziness days - 0 points;

- days with mild attack -1;

- moderate severe attack lasts longer than 20 minutes -2;

- severe attack lasts 1 hour or more or is accompanied by nausea or vomiting-3;

- until now the worst attack attack to date-4;

- The monthly dizziness score is defined as a treatment failure for 50 consecutive months or greater than 50.

Selection principle

MD clinical diagnosis according to the 1995 AAO-HNS principle:

- At least two decisive dizzy attacks.

- A decisive long time to maintain spontaneous (rotation) dizziness for at least 20 minutes.

Exclusion principle

- an aminoglycoside or macrolide antibiotic;

- treatment with anticancer drugs

- platinum compounds,

- Difluoromethylornithine.

Research design

This was a multicenter, double-blind, randomized, placebo-controlled, parallel study to compare ISSHL treatment with methyl dehydrocorticosterol in the ear and placebo. Approximately 140 individuals were enrolled in this study and were randomized (1:1) into 3 treatment groups in random order.

- Individuals in group I receive standard care (nmt 1500 mg/day sodium diet, withdrawal of dihydroxy guanidine absorption and/or diuretics)

- Individuals in group II receive IT methyl dehydrocorticosterone sodium phosphate (administer 0.3-0.5 mL of methyl dehydrocorticosterol per month / 1 injection per mL of carrier until up to 3 injections) And standard care

- Individuals in group III received placebo IT injection (up to 3 injections with 0.3-0.5 mL vehicle per month) and standard care

Evaluation

Before the start of treatment, the severity of Meniere's disease was measured for each individual (two times before the study was assigned and before the randomization). The plums were administered at 1, 2, 4 & 8, and 4 & 6 months after the start of treatment. Niel's disease

Assessment of hearing

Evaluation

- the date, frequency, time and severity of dizziness and tinnitus;

- Reduce ear pressure perception, use standard VAS questionnaires and effective rating agreements

- Measurement of serum vasopressin

Although the preferred embodiment of the invention has been shown and described herein, the embodiments of the invention are provided for illustrative purposes. Many variations of the embodiments described herein can be selected to practice the invention. The method and structure of the invention and its equivalents are intended to be within the scope of the appended claims.

Figure 1 illustrates in vitro release profiles of methyl dehydrocorticosterol formulations with different concentrations of Poloxamer 407.

Figure 2 illustrates the correlation between the mean dissolution time (MDT) and the P407 concentration of the formulation.

Figure 3 illustrates the release profile of corticosterone from different steroids containing 17% P407.

Figure 4 illustrates the correlation between the average dissolution time (MDT) of the formulation and the apparent viscosity of the formulation.

Figure 5 illustrates the effect of concentration on the viscosity of an aqueous solution of Blanose refined CMC.

Figure 6 illustrates the effect of concentration on the viscosity of aqueous solutions of Methocel.

Figure 7 shows the results of gelation after 5 days of intrathecal injection of guinea pig ears.

Figure 8 shows the gel elimination time course of the formulations described herein.

Figure 9 shows the release profile of the formulations described herein.

Claims (19)

A pharmaceutical composition for treating an ear disease or symptom, comprising: a multiparticulate corticosteroid, or a pharmaceutically acceptable salt thereof; and an auris-acceptable thermoreversible polymer comprising a polyoxyethylene and a polyoxypropylene polymer a gel; wherein the composition provides sustained release of the corticosteroid through the round window membrane to the inner ear over a period of at least 5 days. The pharmaceutical composition of claim 1, wherein the composition comprises: multiparticulate methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 1, wherein the composition comprises: between about 0.1 wt% and about 10 wt% of multiparticulate methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol Or a pharmaceutically acceptable salt thereof; and a polymer of polyoxyethylene and polyoxypropylene between about 16 wt% and about 21 wt%. The pharmaceutical composition according to any one of claims 1 to 3, wherein the polymer of polyoxyethylene and polyoxypropylene is poloxamer 407. The pharmaceutical composition of any one of claims 1 to 3, wherein the composition provides a delivery volume osmotic concentration of between about 250 and 320 mOsm/L. The pharmaceutical composition of claim 2 or 3, wherein the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is released from the composition during at least 7 days. The pharmaceutical composition of claim 2 or 3, wherein the methyl dehydrocorticotrope The alcohol, methyl dehydrocortisol or dehydrocortisol is released from the composition over a period of at least 10 days. The pharmaceutical composition of claim 2 or 3, wherein the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is in the form of a free acid, a free alcohol, a salt, or a combination thereof. The pharmaceutical composition of claim 1, wherein the corticosteroid is methyl dehydrocorticosterol. The pharmaceutical composition of claim 2 or 3, wherein the methyl dehydrocorticosterol, methyl dehydrocortisol or dehydrocortisol is substantially in the form of micronized particles. The pharmaceutical composition of claim 1 further comprising an additional therapeutic agent. The pharmaceutical composition according to claim 11, wherein the additional therapeutic agent is a Na/K ATPase modulator, a chemotherapeutic agent, a collagen, a γ-globulin, an interferon, an antimicrobial agent, an antibiotic, a topical anesthetic, a platelet activating factor antagonist, an ear protectant, a nitric oxide synthase inhibitor, an anti-stun agent, a vasopressin antagonist, an antiviral agent, an anti-emetic agent, or the like combination. The pharmaceutical composition of claim 1, wherein the ear disease or symptom is Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, aging-related hearing loss, autoimmune ear disease or tinnitus. An use of an intraotic composition for the preparation of a medicament for treating an ear disease or condition, the intraotic composition comprising: a multiparticulate corticosteroid, or a pharmaceutically acceptable salt thereof; and a polyoxyethylene and poly The oxypropylene polymer can accept heat from the ear Inverse gel; wherein the composition provides sustained release of the corticosteroid through the round window membrane to the inner ear over a period of at least 5 days. The use of claim 14, wherein the corticosteroid is released from the composition over a period of at least 7 days. The use of claim 14, wherein the corticosteroid is released from the composition during at least 10 days. The use of claim 14, wherein the polymer of polyoxyethylene and polyoxypropylene is poloxamer 407. The use of claim 14, wherein the composition is administered to the round window film or the round window film. The use of claim 14, wherein the ear disease or symptom is Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, aging-related hearing loss, autoimmune ear disease or tinnitus .