JP2009519940A - Compositions and methods for treating dermatological conditions - Google Patents

Abstract

The present invention treats solidifying adhesive formulations, methods of drug delivery, and various dermatological conditions such as bacterial infections, viral infections, fungal infections, alopecia, dermatitis, psoriasis, or photodamaged skin Can be directed to a solidified layer for skin delivery of the drug. The formulation can include a drug, a solvent excipient, and a solidifying agent. The solvent excipient can comprise a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising at least one non-volatile solvent. The non-volatile solvent system can facilitate the delivery of the drug for a sustained time at a therapeutically effective rate. The non-volatile solvent system can act as a plasticizer for the solidifying agent. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system. When applied to the skin, the formulation can form a solidified layer after at least a portion of the volatile solvent system has evaporated.

Description

(Field of Invention)
The present invention relates generally to systems and methods for treating various dermatological conditions. More particularly, the present invention provides a solidifying adhesive formulation having a viscosity suitable for application to a dermatologically affected skin surface and forming a solid drug-delivery solidified adhesive layer on the skin. Related to things.

(Background of the Invention)
Skin or dermatological conditions affect millions of people worldwide. Such diseases include infection from fungal, bacterial, and viral sources, alopecia, light or sun-damaged skin, dermatitis, and psoriasis. Although treatments are generally available for each of these treatments, current treatments have some significant drawbacks. For example, one type of viral infection is a herpes infection. Herpes infections often occur in the lips (eg herpes simplex) and in the genitals. There are two common dosage forms available for treating herpes simplex and genital herpes: topical and oral. Both delivery systems have certain disadvantages. For example, oral delivery of the anti-viral drug acyclovir can cause undesirable side effects such as upset stomach, loss of appetite, nausea, vomiting, diarrhea, headache, dizziness or weakness. One drawback of current topical anti-herpes simplex formulations, which are in the form of ointments and creams such as Zovirax ointments and creams, is that they often eat, drink or lick his / her lips, etc. In some cases, it is accidentally wiped away from the treatment site. This is believed to be the reason why topical herpes simplex formulations often need to be applied many times a day, which is very inconvenient and often results in poor patient compliance. When topical anti-herpes formulations are applied to the genitals, the drug is often subject to inadvertent removal by underwear and adjacent healthy skin / mucosal surface contact. In addition, some topical formulations usually contain water and volatile solvents such as ethanol that tend to evaporate shortly after application. Complete evaporation of such a solvent can cause a significant reduction or even cessation of dermal drug delivery, thereby prematurely terminating the treatment. In addition, semi-solid formulations are often “rubbed into” the skin, which does not necessarily mean that the drug formulation has actually been delivered to the skin. Instead, this phrase often means that a very thin layer of drug formulation is applied to the surface of the skin. Such thin layers of traditional topical semisolid formulations cannot contain sufficient amounts of active drug to achieve sustained delivery over an extended period of time.

  Another example is photodamaged skin. Treat topical photodamage and premature aging characterized by fine lines, wrinkles, roughening, dryness, looseness, and / or irregular pigmentation using topical application of immune activators such as imiquimod It is considered possible. For example, treatment of visible signs of photoaging with imiquimod over several weeks can improve the morphology and appearance of photodamaged skin. However, Aldara Cream from 3M, the only commercial dosage form of imiquimod, is not designed or approved to treat photodamaged skin, ie it treats genital warts and basal cell carcinomas It was authorized by. After the cream is applied to the skin and rubbed “in” the skin, most of the drug does not actually enter the skin. Instead, most of the drug stays on the surface of the skin for a long time, during which it is exposed to unintentional removal. For example, cream applied to a subject's face and forehead before going to bed can be removed by a pillow or blanket during the night.

  Similar drawbacks can be found in many of the available treatments for other aforementioned dermatological conditions.

  In view of the shortcomings of current skin formulations for treating dermatological disorders, i) provide more sustained drug delivery over time, ii) less susceptible to unintended removal by contact with clothing, It would be desirable to provide a system, formulation, and / or method that provides a physical protective barrier that is beneficial in the treatment of certain diseases and / or iv) is easily removed after application and use Let's go.

SUMMARY OF THE INVENTION It has been recognized that it would be advantageous to provide formulations and related methods for treating dermatological conditions that can provide sustained release of drugs and do not suffer the disadvantages of unintentional removal. I came. Accordingly, the present invention is generally directed to a formulation for treating a dermatological condition comprising a drug, a solvent excipient, and a solidifying agent effective to treat the dermatological condition. The solvent excipient comprises a volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system comprising at least one non-volatile solvent, wherein the non-volatile solvent system is at a therapeutically effective rate. To facilitate the delivery of the drug over a period of time. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. Formulations applied to the skin surface can form a soft, cohesive solidified layer after at least partial evaporation of the volatile solvent system. Further, the drug can be delivered continuously after the volatile solvent system has at least substantially evaporated. Treatable dermatological conditions include bacterial infections, viral infections, fungal infections, alopecia, dermatitis, psoriasis, photodamaged skin, and combinations thereof.

  In another embodiment, a method of treating a dermatological condition can include applying a solidifying adhesive formulation to an infected skin surface. The formulation may be a formulation described in previous embodiments. A further step is to solidify the formulation by at least partial evaporation of the volatile solvent system to form a soft and cohesive solidified layer on the infected skin surface and then over a duration at a therapeutically effective rate. , Delivering the drug from the solidified layer to the infected skin site.

  In another embodiment, the soft, cohesive solidified layer for treating a dermatological condition, infection is a drug effective to treat the dermatological condition; a non-volatile comprising at least one non-volatile solvent An ionic solvent system, wherein the non-volatile solvent system can facilitate delivery of the drug over time at a therapeutically effective rate; and can include a solidifying agent. The solidified layer is preferably capable of stretching 5% (or even 10%) in one direction without cracking, breaking and / or separating from the skin surface to which it is applied.

  Further features and advantages of the present invention will become apparent from the following detailed description and drawings which illustrate, by way of example, features of the invention.

Detailed Description of Preferred Embodiments
Before disclosing and describing specific embodiments of the present invention, it should be understood that the present invention is not limited to the specific processes and materials disclosed herein, and may itself vary to some extent. . It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present invention This is because it is defined only by the appended claims and their equivalents.

  In describing and claiming the present invention, the following terminology will be used.

  The singular forms “a” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a drug” includes reference to one or more such compositions.

  “Skin” is usually at least in the air, such as human skin (intact, diseased, ulcerative, destroyed), finger and toe nail surfaces, and lips, genital and anal mucosa, and nasal and oral mucosa. Includes partially exposed mucosal surfaces.

  The phrase “dermatological condition” refers to any skin disease, or combination of skin diseases, including bacterial infections, viral infections, fungal infections, alopecia, psoriasis, dermatitis, or photodamaged skin.

  When referring to “photodamaged” skin, both acute and chronic photodamage are included herein. Acute light damage can manifest as sunburn, and chronic light damage can be observed as gradual changes in the skin caused by cumulative sun exposure over a period of months, more typically years. Thus, photodamage includes human skin with several types of experienced photodamage, which is premature aging, fine lines, wrinkles, roughening, dryness, loosening, irregular pigmentation, pre-cancer It can be expressed as a sex lesion and / or skin cancer. Similarly, “skin damage” can be defined as including skin photodamage, premature aging, fine lines, wrinkles, roughening, dryness, loosening, and / or irregular pigmentation.

  The term “drug” refers to any bioactive agent that can be used to effectively treat a dermatological condition. For example, antifungal drugs can be used when the dermatological condition is a fungal infection. Examples of antifungal drugs that can be used in the present invention include, but are not limited to, amorolfine, butenafine, naphthyfin, terbinafine, fluconazole, itraconazole, ketoconazole, posaconazole, rubconazole, voriconazole, clotrimazole, butconazole, econazole, Miconazole, oxyconazole, sulconazole, terconazole, thioconazole, caspofungin, micafungin, anidurafingin, amphotericin B, AmB, nystatin, pimalysin, griseofulvin, cyclopirox olamine, haloprozin, tolnaftate, and undecylate thereof Including.

  If the dermatological condition is a viral infection, but not limited to, acyclovir, pencyclobeer, famciclobeer, baracyclovir, behenyl alcohol, trifluridine, idoxyuridine, cidofovir, gancyclobeer, podophyllox, Podophyllotoxin, ribavirin, abaca beer, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zarcitabine, zidovudine, amprenabine, indina beer, nelfina beer, ritona beer, saquina beer, amantadine, interferon, oseltamivir , Anti-viral drugs including rimantadine, zanami beer, or combinations thereof can be used.

  If the dermatological condition is a bacterial infection, antibacterial drugs can be used, including but not limited to erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, ciproflaxin Or a combination thereof. Active drugs in the formulations and methods of the invention for treating infection can also include immunomodulators including, but not limited to, imiquimod.

  When the dermatological condition is photodamaged skin, drugs that can be used include, but are not limited to, immunomodulators or immune activators that can increase the immunity of human skin mucosa. Non-limiting examples of such drugs include imiquimod, rosikimod or combinations thereof.

  When the dermatological condition is alopecia, in general, any drug that can stimulate hair growth when administered dermally can be used. This includes compositions traditionally identified as drugs, as well as other bioactive agents that are not always considered "drugs" in the classical sense. Examples of drugs that can be used in the present invention include betamethasone, dipropionate, halobetasol propionate, diflorazone diacetate, triamcinolone acetonide, desoxymethazone, fluocinonide, harsinonide, mometasone furoate, betamethasone valerate, Fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, flulandenolide, dezonide, hydrocortisone butyrate, hydrocortisone valerate, alcromethasone dipropionate, flumethasone pivorate, hydrocortisone acetate And corticosteroids such as combinations thereof. Other drugs can also be used. Other drugs can also be used. Other examples include drugs that can irritate the skin to stimulate hair growth such as minoxidil, spironolactone, finasteride, anthralin, tretinoin topical immunity such as dinitrochlorobenzene, dibutyl squalinate, diphenylcyclopropenone Including therapeutic agents, other hair growth stimulants, or combinations thereof.

  When the dermatological condition is psoriasis or dermatitis, the drugs that can be used include, but are not limited to, corticosteroids, immune modulators, vitamin D3 and analogs thereof, retinoic acid and pharmaceutically active derivatives thereof. Or an agent selected from a drug class of a combination thereof. Specific non-limiting examples of such drugs are betamethasone dipropionate, clobetasol propionate, halobetasol propionate, diflorazone diacetate, amsinide, desoxymethasone, fluocinonide, harsinonide, mometasone fluoride Ate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, fluland lenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alcrometasone dipropionate, flumethasone pivorate , Hydrocortisone, hydrocortisone acetate, tacrolimus, picrolimus, tazarotene, isotretinoin, cyclosporine, anthralin, vitamin D3, cholecalcifer Chromatography including Le, calcitriol, calcipotriol, tacalcitol, calcipotriene or combinations thereof.

  In general, when referring to a “drug”, it is understood that there are various forms of a given drug, and that these various forms are expressly included. According to this, various drug forms include polymorphs, salts, hydrates, solvates, and co-crystals. This is a composition traditionally identified as a drug, as well as other organisms that are not always considered a “drug” in the classical sense, but that can provide a therapeutic effect for a particular disease. Contains an active agent. In one embodiment, a single agent can be effective in treating multiple dermatological conditions. In another embodiment, multiple drugs for treating a single dermatological condition can be simultaneously present and delivered from the same solidified formulation. In another embodiment, multiple drugs that target different dermatological conditions can be delivered from the same solidified formulation.

  The terms “emollient”, “moisturizing agent”, “moisturizer” and “humectant” can be used interchangeably to soften and soften the skin's ability to retain moisture in or on its surface. Or a substance that can be enhanced. Non-limiting examples of such compounds include honey derivatives such as glycerol, propylene glycol, dipropylene glycol, butylene glycol, sorbitol, honey, and honey quat, urea and urea derivatives such as hydroxyethylurea, ammonium lactate, Includes sodium lactate, potassium lactate, pyroglutamic acid and its salts, sodium malate, polydextrose, triacetin, mannitol, oxidized polyethylene, isomalt, maltitol and maltitol syrup, lactitol, xylitol, erythritol, and combinations thereof.

  The phrase “local delivery” or “local delivery of drug” shall mean delivery of the drug to the skin tissue and subsequent possible absorption to the skin.

  The phrase “skin drug delivery” or “skin drug delivery” includes both transdermal and topical drug delivery and includes drug delivery to, through and into the skin. “Transdermal delivery” of drugs can target skin tissue directly under the skin, regional tissues or organs under the skin, systemic circulation, and / or the central nervous system.

  The term “flux”, such as the relationship of “skin flux” or “transdermal flux”, respectively, refers to the amount of drug that permeates the skin per unit area per unit time or across the skin. A typical unit of flux is micrograms per square centimeter per hour. One way to measure flux is to place the formulation on the known skin area of a human volunteer and measure how much drug can penetrate into or across the skin within a certain time constraint It is. Various methods (in vivo methods) could be used in the measurement as well. The flux can also be measured using the method described in Example 1 or other similar methods (in vitro methods). The in vitro method uses human skin obtained from cadaver or freshly isolated skin tissue from hairless mice rather than measuring drug flux across the skin using human volunteers. It will generally be appreciated by those skilled in the art that the results from in vitro tests designed and executed can be used to estimate or predict in vivo test results with reasonable reliability. Accordingly, “flux” values referred to in this patent application can mean those measured by either in vivo or in vitro methods.

The term “flux-enabling” in relation to a non-volatile solvent system (or a solidified layer containing it) is selected so as to provide a therapeutically effective flux for a particular drug Or a specially formulated non-volatile solvent system (including one or more non-volatile solvents). For drugs that are delivered locally or locally, a fluxable non-volatile solvent system alone, when the non-volatile solvent system is saturated with the drug, without the aid of any other component, It is defined as a non-volatile solvent system capable of delivering a therapeutically sufficient level of drug across, onto or into the subject's skin. For systemically targeted drugs, a fluxable non-volatile solvent system is one where the non-volatile solvent system is saturated with the drug and it is in full contact with the subject's skin with a contact area of 500 cm ² or less. , A non-volatile solvent system that can provide a therapeutically effective daily dose over 24 hours. In one embodiment, the contact area for the non-volatile solvent system is 100 cm ² or less. A test using the state of the drug in a saturated solvent can be used to measure the maximum flux-producing capacity of the non-volatile solvent system. In order to determine the flux, the drug solvent mixture needs to remain on the skin for a clinically sufficient amount of time. In reality, it may be difficult to maintain a liquid solvent on the skin of a human volunteer for an extended period of time. Thus, another method for determining whether a solvent system is “fluxable” is the use of the apparatus and method described in Example 1, using a device that crosses hairless mouse skin or human cadaver skin. To measure vitro drug penetration. This method, and similar methods, are commonly used by those skilled in the art to assess the permeability and feasibility of a formulation. Alternatively, whether a non-volatile solvent system can be fluxed can be tested on the skin of a living human subject using means to maintain a non-volatile solvent system containing a saturated drug on the skin. And such means would not be practical for the product. For example, a saturated drug-free non-volatile solvent system can be immersed in the absorbent fabric material, which is then applied to the skin and covered with a protective film. Such a system is not practical as a pharmaceutical product, but tests whether a non-volatile solvent system has the inherent ability to provide sufficient drug flux or whether it can be fluxed. Suitable for

  Also, once the formulation has formed a solidified layer, even after the volatile solvent (including water) has substantially evaporated, some of the non-volatile solvent remains in the solidified layer while the solidified layer is a drug. May be “fluxable”.

  The phrases “effective amount”, “therapeutically effective amount”, “therapeutically effective rate” and the like refer to any recognizable level of therapeutic outcome in treating a disease to which the drug is delivered, as it relates to the drug. Refers to a sufficient amount or rate of delivery of a drug to achieve It is understood that a “recognizable level of treatment outcome” may or may not meet the efficiency standards of any government authority for authorizing product commercialization. Various biological factors can affect a substance's ability to perform its intended work. Thus, an “effective amount”, “therapeutically effective amount”, or “therapeutically effective rate” may in some cases depend to some extent on such biological factors. However, for each drug, there is usually consensus among those skilled in the art for a sufficient dose or flux range in most subjects. Furthermore, the achievement of a therapeutic effect can be measured by a physician or other qualified medical personnel using estimates known in the art, although individual variations and responses to treatment are subjective It is recognized that this can be a judgment. Determination of a therapeutically effective amount or delivery rate is within the ordinary skill in the medicinal chemistry and medical fields.

“Therapeutically effective flux” is defined as the osmotic flux of a selected drug that delivers a sufficient amount of drug into or across the skin to be clinically beneficial. It does not necessarily mean that most of the target population can benefit to some extent or is sufficiently profitable to be considered “effective” by relevant government authorities or pharmaceutical professionals. More specifically, for drugs that target the skin, or regional tissues or organs close to the skin surface (such as joints, specific muscles, or tissues / organs that are at least partially within 5 cm from the skin surface) “Therapeutically effective flux” refers to a drug flux capable of delivering a sufficient amount of drug into a target tissue within a clinically reasonable amount of time. For drugs that target the systemic circulation, “therapeutically effective flux” means that a sufficient amount of the selected drug is delivered through a clinically reasonable skin contact area and is clinically reasonable. A drug flux that can produce a clinically beneficial plasma or blood drug concentration within a short period of time. The clinically reasonable skin contact area is defined as the size of the skin application area that most subjects will tolerate. Typically, skin contact areas of 400 cm ² or less are considered reasonable. Therefore, in order to deliver the drug 4000Mcg the systemic circulation over 10 hours through a 400 cm ² skin contact area, the flux should be at least 4000mcg / 400cm ^2/10 hours, which is 1 mcg / cm ² / Time be equivalent to. According to this definition, different drugs have different “therapeutically effective fluxes”. The “therapeutically effective flux” can be different at different times in the same subject and / or even for the same subject. However, for each drug there is usually consensus in the art for a range of doses or fluxes that are sufficient for most subjects at most times.

  Below is an estimate of the flux for several drugs that are therapeutically effective or well over.

（ロピバカインを例外として）表Ａ中の治療上有効量のフラックス値は、実施例１に記載されたイン・ビトロ系における無毛マウスまたはヒト表皮膜を通じての市販製品の定常状態フラックス値を表す。これらの値は、見積もりであり、処方物の開発および最適化のための比較の基礎を提供することのみを意図する。選択された薬物についての治療上有効なフラックスは、異なる病気が、異なる段階の病気、および異なる個々の対象について治療されるのが非常に困難であり得る。リストしたフラックスは治療的に有効なものを超え得ることに注意すべきである。

The therapeutically effective amount of flux value in Table A (with the exception of ropivacaine) represents the steady state flux value of the commercial product through the hairless mouse or human epidermis in the in vitro system described in Example 1. These values are estimates and are intended only to provide a basis for comparison for formulation development and optimization. The therapeutically effective flux for a selected drug can be very difficult for different illnesses to be treated for different stages of illness and different individual subjects. It should be noted that the listed flux can exceed that which is therapeutically effective.

  The following example, listed in Table B, shows a screen for fluxable ability of non-volatile solvents for some of the specifically tested drugs. The experiment was performed as described in Example 1 below and the results are further discussed in subsequent Examples 2-9.

不揮発性溶媒からの表Ｂ中のイン・ビトロ定常状態フラックス値は、驚くべきフラックス化可能および非フラックス化可能溶媒を示す。この情報を用いて、処方物開発を導くことができる。

The in vitro steady state flux values in Table B from non-volatile solvents indicate surprising fluxable and non-fluxable solvents. This information can be used to guide formulation development.

  The term “plasticizing” in the context of a fluxable non-volatile solvent is defined as a fluxable non-volatile solvent that acts as a plasticizer for the solidifying agent. A “plasticizer” is an agent that can increase the percentage elongation of a formulation after the volatile solvent system has at least substantially evaporated. The plasticizer also has the ability to reduce the brittleness of the solidified formulation by making it more flexible and / or elastic. For example, propylene glycol is a “fluxable plasticizing non-volatile solvent” for the drug ketoprofen with polyvinyl alcohol as the chosen solidifying agent. However, propylene glycol in a formulation of ketoprofen with Gantrez S-97 or Avalure UR405 as a solidifying agent does not provide the same plasticizing effect. The combination of propylene glycol and Gantrez S-97 or Avale UR405 is less compatible and results in a less desirable formulation for topical application. Thus, whether a given non-volatile solvent is “plasticizing” or not depends on which solidifying agent is selected.

  Different drugs often have different matching fluxable non-volatile solvents that provide particularly good results. Such examples are found in Table C. The experiment was performed as described in Example 1 below and the results are further discussed in subsequent Examples 2-9.

「フラックス化可能な不揮発性溶媒」、「フラックス化可能可塑化不揮発性溶媒」または「高フラックス化可能な不揮発性溶媒」は、単一の化学物質、または２以上の化学物質の混合物であり得る。例えば、表Ｃ中のクロベタゾールプロピオネートについての定常状態フラックス値は、プロピレングリコールまたはＩＳＡ単独よりもかなり高いクロベタゾールフラックスを生じたプロピレングリコール：イソステアリン酸混合物について９：１である（表Ｂ参照）。従って、９：１プロピレングリコール：イソステアリン酸混合物は「高フラックス化可能な不揮発性溶媒」であるが、プロピレングリコールまたはイソステアリン酸単独はそうではない。

A “fluxable non-volatile solvent”, “fluxable plasticizing non-volatile solvent” or “high-fluxable non-volatile solvent” can be a single chemical or a mixture of two or more chemicals. . For example, the steady state flux value for clobetasol propionate in Table C is 9: 1 for the propylene glycol: isostearic acid mixture that produced a much higher clobetasol flux than propylene glycol or ISA alone (see Table B). Thus, the 9: 1 propylene glycol: isostearic acid mixture is a “non-volatile solvent capable of high flux”, but propylene glycol or isostearic acid alone is not.

  When referring to a solidified layer, the terms “adhesive” and “adhesive” are used herein to refer to the solidified layer and the skin so that the layer does not fall from the skin during intended use in most subjects. Refers to sufficient adhesion between. Thus, “adhesive” or the like, when used to describe a solidified layer, is that the solidified layer is adhesive to the body surface to which the initial formulation layer was originally applied (before evaporation of the volatile solvent). That can also mean. In one embodiment, it does not mean that the solidified layer is adhesive on the opposite side. In addition, it should be noted that whether the solidified layer can adhere to the skin surface for the desired extended time depends in part on the condition of the body surface. For example, excessive sweating or oily skin, or oily material on the skin surface, can reduce the adhesion of the solidified layer to the skin. Thus, the adhesive solidified layer of the present invention may maintain complete adhesion to the body surface and may not deliver the drug for the duration of each subject under any condition on the body surface. The standard is that it maintains good contact with most of the body surface, for example 70% of the total area, for a certain time for most subjects under normal conditions of the body surface and the external environment .

  The terms “flexible”, “elastic”, “elastic” and the like, as used herein, are in at least one direction with a solidified layer up to about 5%, often up to about 10%, or more. When it is stretched, it means sufficient elasticity of the solidified layer so that it does not break. For example, a solidified layer that exhibits acceptable elasticity and adhesion to the skin should adhere to human skin on flexible skin locations such as elbows, fingers, wrists, neck, lower back, lips, knees, etc. And will remain substantially intact on the skin as the skin stretches. It should be noted that the solidified layer of the present invention need not necessarily have any elasticity in some embodiments.

  The term “peelable” when used to describe a solidified layer means that the solidified layer can be lifted from the skin surface to one large piece or several large pieces, as opposed to many small pieces or pieces. .

  The term “sustained” refers to a therapeutically effective rate of dermal drug delivery for a continuous time of at least 30 minutes, and in some embodiments, at least about 2 hours, 4 hours, 8 hours, 12 hours. , About 24 hours or more.

  A “volatile solvent system” can be a single solvent or a mixture of solvents that are volatile, including water and solvents that are more volatile than water. Non-limiting examples of volatile solvents that can be used in the present invention include isoamyl acetate, denatured alcohol, methanol, ethanol, isopropyl alcohol, water, propanol, C4-C6 hydrocarbons, butane, isobutene, pentane, hexane, acetone, chloro Butanol, ethyl acetate, fluro-chloro-hydrocarbon, turpentine, methyl ethyl ketone, methyl ether, hydrofluorocarbon, ethyl ether, 1,1,1,2 tetrafluoroethane, 1,1,1,2,3,3- Includes heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, or combinations thereof.

  A “non-volatile solvent system” can be a single solvent or a mixture of such solvents that is less volatile than water. It can also include substances that are solid or liquid at room temperature, such as pH or ion-pairing agents. After evaporation of the volatile solvent system, most of the non-volatile solvent systems provide skin delivery to, into, or through the subject's skin with sufficient flux for a given drug over a period of time. Should be present in the solidified layer for a sufficient amount of time to go and provide a therapeutic effect. In some embodiments, a mixture of two or more non-volatile solvents is used to obtain the desired permeability to the active drug and / or compatibility with the solidifying agent, or other components of the formulation, A non-volatile solvent system can be formed. In one embodiment, the combination of two or more non-volatile solvents to form a solvent system individually provides a higher transdermal flux for the drug than the flux provided for the drug by each of the non-volatile solvents. To do. The non-volatile solvent system can also act as a plasticizer for the solidified layer so that the solidified layer is elastic and flexible.

  The term “solvent excipient” describes a composition comprising both volatile and non-volatile solvent systems. The volatile solvent system is selected to rapidly evaporate from the adhesive formulation to form a solidified layer, and the non-volatile solvent system is selected after evaporation of the volatile solvent system to provide continued delivery of the drug. Formulated or selected such that a portion of the solidified layer remains substantially. Typically, the drug as a whole can be partially or fully dissolved in the solvent excipient or formulation. Similarly, once the volatile solvent system has evaporated, the drug can be partially or completely solubilized in the non-volatile solvent system. Formulations in which the drug is only partially soluble in the non-volatile solvent system after evaporation of the volatile solvent system are capable of maintaining sustained delivery duration longer. This is because the undissolved drug can be dissolved in a non-volatile solvent system because the dissolved drug is depleted from the solidified layer during drug delivery.

  An “adhesive solidified formulation” or “solidified formulation” has a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent and solidifies after evaporation of at least a portion of the volatile solvent. A composition that can be a layer. The solidified layer is very sustainable once formed. In one embodiment, the formulation can form a peel once solidified on the skin surface. The peel can be a soft cohesive solid that can be removed by peeling large pieces from the skin relative to the size of the applied formulation, and can often peel from the skin as a single piece. it can. The applied viscosity is typically more viscous than a water-like liquid, but less viscous than a soft solid. Examples of preferred viscosities include materials having a consistency similar to pastes, gels, ointments, etc., for example viscous liquids that flow but are not prone to spilling. Thus, when a composition has a “suitable” viscosity to the skin surface, this has a viscosity that is sufficiently high that the composition does not substantially drop off the skin after application to the skin. However, it also has a sufficiently low viscosity that it can be easily extended onto the skin. A viscosity range that satisfies this definition may be from about 100 cP to about 3,000,000 cP (centipoise), more preferably from about 1,000 cP to about 1,000,000 cP.

  In some embodiments of the present invention, it may be desirable to add additional agents or substances to the formulation to provide enhanced or increased adhesive characteristics. The additional adhesive or substance can be an additional non-volatile solvent or an additional solidifying agent. Non-limiting examples of materials that can be used as additional adhesion enhancers include methyl vinyl ether and maleic anhydride (Gantrez polymer), copolymers of polyethylene glycol and polyvinyl pyrrolidone, gelatin, low molecular weight polyisobutylene rubber, acrylic sunalkyl / octylacrylamide (Dermacryl 79), and copolymers of various aliphatic resins and aromatic resins.

  The terms “washable”, “washing” or “removed from washing”, as used in connection with the adhesive formulation of the present invention, refer to the application of a washing solvent using a normal or moderate amount of washing power. Refers to the ability of the adhesive formulation to be removed. The necessary force to remove the formulation by washing should not cause significant skin irritation or wear. In general, the mild detergency associated with the application of a suitable cleaning solvent is sufficient to remove the adhesive formulations disclosed herein. Although many solvents can be used to remove the formulations of the present invention by washing, they are preferably selected from the commonly recognized solvents including the volatile solvents listed herein. Preferred solvents do not significantly irritate human skin and are generally available to the average subject. Examples of cleaning solvents include, but are not limited to, water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, propanol, or combinations thereof. In an embodiment of the invention, the cleaning solvent is selected from the group consisting of water, ethanol, isopropyl alcohol, or combinations thereof. Surfactants can also be used in some embodiments.

  An acceptable length of time for “drying time” is the time required for the formulation to form a non-dirty solidified surface under standard skin and ambient conditions and in standard test procedures after application. Say time. As used herein, the term “drying time” does not mean the time required to completely evaporate off the volatile solvent. Instead, it refers to the time required to form a solidified surface that is not dirty as described above.

  “Standard skin” is defined as healthy human skin dried at a surface temperature between about 30 ° C. and about 36 ° C. Standard ambient conditions are defined by a temperature range of 20 ° C. to 25 ° C. and a relative humidity range of 20% to 80%. The term “standard skin” by no means limits the types of skin or skin conditions in which the formulations of the present invention can be used. The formulations of the present invention can be used to treat all types of “skin”, including uninjured (standard skin), diseased skin, or damaged skin. Although skin diseases having different characteristics can be treated using the formulations of the present invention, the term “standard skin” is only used as a standard for testing the compositions of the various embodiments of the present invention. It is done. In reality, formulations that perform well on standard skin (eg, solidify and provide a therapeutically effective flux) can also perform well on diseased or damaged skin.

“Standard Test Procedure” or “Standard Test Conditions” are as follows: For standard skin at standard ambient conditions, apply approximately 0.1 mm layer of adhesive solidification formulation and measure dry time . The drying time is a surface that is not soiled so that the formulation does not lose mass by adhesion to a piece of 100% cotton cloth that has been pressed to the surface of the formulation for 5 seconds at a pressure between about 5 and about 10 g / cm ^2. Is defined as the time required for the formulation to form.

  “Solidified layer” describes a solidified or dried layer of an adhesive solidified formulation after at least a portion of the volatile solvent system has been evaporated. The solidified layer remains adhered to the skin and is preferably capable of maintaining good contact with the subject's skin for substantially the entire duration of application under standard skin and ambient conditions. The solidified layer is preferably the skin at the end of application to one piece or several large pieces (as opposed to a layer with weak tension that is broken into many small pieces or pieces when removed from the skin) Exhibit sufficient tension so that it can be peeled off.

  The use of the term “substantially” when referring to evaporation of a volatile solvent means that most of the volatile solvent contained in the initial formulation has evaporated. Similarly, if the solidified layer is “substantially lacking” volatile solvents including water, the solidified layer generally has less than 10 wt%, preferably less than 5 wt% volatile solvent in the solidified layer.

  Concentrations, amounts, and numerous other data can be expressed or shown herein in a range format. Such range formats are used for convenience and brevity only, and thus each numeric value and sub-range is explicitly cited as well as a number of values explicitly cited as range limitations. As such, it should be understood to include all individual numerical values or sub-ranges within that range. By way of illustration, the numerical range of “about 0.01 to 2.0 mm” not only includes explicitly cited values from about 0.01 mm to about 2.0 mm, but also individual values within the indicated range. And sub-ranges. Thus, this numerical range includes the indicated values such as 0.5, 0.7, and 1.5, and from 0.5 to 1.7, 0.7 to 1.5, and 1.0. Sub-ranges such as 1.5 are included. This same principle applies to ranges that refer to only one numerical range. Moreover, such an interpretation should apply regardless of the breadth of the range or the characteristics described.

  As used herein, multiple drugs, compounds, and / or solvents can be listed on a common list for convenience. However, these lists should be construed as if each member of the list is individually identified as a separate and unique member. Thus, an individual member of such a list, unless indicated to the contrary, is interpreted as a virtual equivalent of any other member of the same list based solely on its display in the normal group. Should be.

  With these definitions in mind, the present invention is generally directed to a formulation for treating an infection comprising drugs, solvent excipients, and solidifying agents effective to treat the infection. The solvent excipient can comprise a volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system comprising at least one non-volatile solvent, wherein the non-volatile solvent system is therapeutically effective The drug delivery can be facilitated over a sustained period at a moderate rate. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. Formulations applied to the skin surface can form a solidified layer after at least partial evaporation of the volatile solvent. Further, the drug can be delivered continuously after the volatile solvent system has at least substantially evaporated.

  In another embodiment, a method of treating a skin infection can include applying a solidifying adhesive formulation to the infected skin surface. The solidifying adhesive formulation can include drugs, solvent excipients, and solidifying agents that are effective to treat skin infections. The solvent system can include a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising at least one non-volatile solvent. The non-volatile solvent system can facilitate delivery of the drug over time at a therapeutically effective rate. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. Further steps solidify the formulation by at least partial evaporation of the volatile solvent system to form a solidified layer on the infected skin surface, and then the drug from the solidified layer is delivered at a therapeutically effective rate. Dermal delivery to the infected skin site for a duration of time.

  In another embodiment, the solidified layer for treating infection comprises a drug effective to treat skin infection; a non-volatile solvent system comprising at least one non-volatile solvent, wherein the non-volatile solvent system is Facilitates delivery of the drug over time at a therapeutically effective rate; and can include a solidifying agent. The solidified layer can stretch 5% (or even 10%) in one direction without cracking, breaking, and / or separating from the skin surface to which the layer is applied.

  In yet another embodiment, the formulation for treating an infection is a drug selected from the group consisting of acyclovir, baracyclovir, pencyclovir, or combinations thereof; volatilization comprising at least one volatile solvent And a solvent vehicle comprising a non-volatile solvent system comprising a non-volatile solvent system; and a solidifying agent. The non-volatile solvent can be selected from the group consisting of oleic acid, isostearic acid, olive oil or combinations thereof. The solidifying agent can be selected from the group consisting of ethyl acrylate-methyl methacrylate-trimethylammonioethyl chloride copolymer, butyl methacrylate and methyl copolymer, ethyl cellulose, and mixtures and copolymers thereof. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system, solidifies after at least partial evaporation of the volatile solvent system, is cohesive and flexible Thus, a continuous layer can be formed, and the drug can be continuously delivered at a therapeutically effective rate after at least substantially all of the volatile solvent system has evaporated.

  In another embodiment, the formulation for treating an infection is a drug selected from the group consisting of econazole, terbinafine, or a combination thereof; a volatile solvent system comprising at least one volatile solvent, and at least one non-volatile Solvent excipients that include a non-volatile solvent system that includes a neutral solvent, and a solidifying agent. The non-volatile solvent can be selected from the group consisting of tetrahydroxypropylethylenediamine, oleic acid, isostearic acid, olive oil, or combinations thereof. The solidifying agent may be selected from the group consisting of ethyl acrylate-methyl methacrylate-trimethylammonioethyl chloride copolymer, butyl methacrylate and methyl copolymer, ethyl cellulose, and mixtures and copolymers thereof. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system and is solidified, coherent and acceptable after at least partial evaporation of the volatile solvent system. It is flexible and can form a continuous layer, and the drug can be delivered continuously at a therapeutically effective rate after at least substantially all of the volatile solvent system has evaporated.

  In another embodiment, an adhesive solidifying formulation for treating nail infections can include drugs, solvent excipients, and solidifying agents effective to treat nail infections. The solvent excipient can comprise a volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system comprising at least one non-volatile solvent; wherein the non-volatile solvent system is therapeutically effective It can facilitate the delivery of the drug over time at a moderate rate. The formulation has a viscosity suitable for application and adhesion to the nail surface prior to evaporation of the volatile solvent system, and when applied to the nail surface it is at least partially evaporated of the volatile solvent system. A solidified layer is formed later. Furthermore, the drug is continuously delivered to the nail after the volatile solvent system has at least substantially evaporated.

  In another embodiment, a method of treating a nail fungal infection can include applying a layer of an adhesive solidifying formulation to the nail surface having the fungal infection and optionally to the surrounding skin. The formulation can include an anti-fungal drug, a volatile solvent system comprising at least one volatile solvent, and a solvent excipient comprising a non-volatile solvent system comprising at least one non-volatile solvent, and a solidifying agent. . Nonvolatile solvent systems can facilitate the delivery of anti-fungal drugs over time at a therapeutically effective rate and are suitable for application and adhesion to the nail surface prior to evaporation of the volatile solvent system Can have. Furthermore, the formulation applied to the nail surface can form a solidified layer after at least partial evaporation of the volatile solvent system, and the drug can be applied to the nail after the volatile solvent system is at least substantially evaporated. It can be delivered continuously from the solidified layer. Further steps can include keeping the solidified layer on the nail surface for a treatment time of at least 4 hours and then removing the solidified layer after the treatment time.

  In another embodiment, a formulation for treating dermatitis (such as hand dermatitis) or psoriasis can comprise a drug, a solvent vehicle, and a solidifying agent. The drug can include at least one member selected from the group consisting of clobetasol propionate, globetasol, derivatives thereof, or combinations thereof. The volatile solvent system includes at least one volatile solvent, the non-volatile solvent system includes propylene glycol and / or glycerol, and the other non-volatile solvent includes isostearic acid and / or oleic acid. The solidifying agent can include at least one member selected from the group consisting of polyvinyl alcohol, fish gelatin, zein, or combinations thereof. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. The formulation applied to the skin surface can form a coherent, flexible and continuous layer that has solidified after at least partial evaporation of the volatile solvent system. In addition, the drug can be continuously delivered at a therapeutically effective rate after at least substantially all of the volatile solvent system has evaporated.

  Although the formulations, methods, and solidified layers of the present invention can be used to treat dermatitis (eczema) or psoriasis in any skin area on the human body, a special feature of the formulations and methods of the present invention The characteristics are expected to be particularly beneficial in treating hand dermatitis and psoriasis.

  In yet another embodiment, the solidified layer for treating alopecia can include a drug for treating alopecia, a non-volatile solvent system, and a solidifying agent. The non-volatile solvent system may be fluxable. The solidified layer itself can also be fluxable (which means that the drug can be locally delivered from the solidified layer to the skin at a therapeutically effective rate). Furthermore, the solidified layer has sufficient flexibility, and to the skin surface, so that it can maintain good contact with the originally applied skin surface for at least most of the intended duration of application. Can have an adhesion of

  In another embodiment, a method of treating alopecia can include applying a layer of an adhesive formulation to a skin surface affected by alopecia (hair loss). The formulation can include drugs, solvent excipients, and solidifying agents that can stimulate hair growth when delivered to a hair follicle of a subject suffering from alopecia. The solvent excipient can comprise a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising at least one non-volatile solvent, wherein the non-volatile solvent system is preferably Can facilitate local delivery of the drug over time at a therapeutically effective rate. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. Another step is to solidify the formulation by at least partial evaporation of the volatile solvent system to form a solidified layer on the skin surface; then from the solidified layer for a duration at a therapeutically effective rate. Topical delivery of the drug to the skin.

  In another embodiment, the solidified layer for delivering a drug for treating alopecia is a drug capable of stimulating hair growth when delivered to a hair follicle of a subject suffering from alopecia, at least one A non-volatile solvent system comprising two non-volatile solvents, wherein the non-volatile solvent system can facilitate the delivery of the drug over time at a therapeutically effective rate and can include a solidifying agent. The solidified layer has sufficient flexibility and adhesion to the skin surface so that it can maintain good contact with the originally applied skin surface for at least most of the intended duration of application be able to.

  In another embodiment, a formulation for treating a subject suffering from alopecia can include a drug, a solvent excipient, and a solidifying agent. The drug can include a member selected from the group consisting of clobetasol propionate, clobetasol, derivatives thereof, and combinations thereof. The solvent excipient comprises a volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system comprising at least one solvent selected from the group consisting of propylene glycol, glycerol, and combinations thereof, and isostearic acid; At least one solvent selected from the group consisting of oleic acid and combinations thereof may be included. The solidifying agent can include a member selected from the group consisting of polyvinyl alcohol, fish gelatin, gluten, casein, zein, and combinations thereof. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and after being applied as a layer to the skin surface, at least a portion of the volatile solvent system. It is possible to form coherent, flexible and continuous layers that are solidified after extensive evaporation. It is continuously delivered locally at a therapeutically effective rate after at least substantially all of the volatile solvent system has been evaporated.

  In another embodiment, a method for treating alopecia comprises applying a 0.01 mm to 2 mm thick adhesive solidifying formulation to a skin area of a subject suffering from alopecia. Can be included. The formulation can include a drug comprising at least one member selected from the group consisting of clobetasol propionate, clobetasol, and combinations thereof, a volatile solvent system comprising at least one volatile solvent. The other component is a non-volatile solvent system comprising at least one solvent selected from the group consisting of propylene glycol, glycerol, and combinations thereof, and at least one solvent selected from the group consisting of isostearic acid, oleic acid, and combinations thereof Can be included. A solidifying agent can also be present, which can include at least one member selected from the group consisting of polyvinyl alcohol, fish gelatin, gluten, casein, zein, and combinations thereof. The formulation can have a viscosity suitable for application and adhesion to the palm skin surface prior to evaporation of the volatile solvent system, and has coagulated, solidified after at least partial evaporation of the volatile solvent system Thus, a flexible layer can be formed. The drug can be continuously delivered locally at a therapeutically effective rate after at least substantially all of the volatile solvent system has evaporated. Another step is to leave the formulation on the skin surface for an intended application time of at least 2 hours, and then remove the solidified cohesive and flexible layer from the skin surface after the intended application time. Including doing.

  In another embodiment, the adhesive solidifying formulation for treating photodamaged human skin is at least one selected from the group consisting of an immunomodulator and isostearic acid, triacetin, sorbitan monolaurate and combinations thereof. Can contain two members.

  In another embodiment, a solidified layer for treating photodamaged human skin can include an immunomodulator, a non-volatile solvent system, and a solidifying agent. The non-volatile solvent system can include at least one non-volatile solvent, and the system can facilitate delivery of the immunomodulating agent over time at a therapeutically effective rate. The solidified layer can adhere to the human skin surface for at least 2 hours.

  More particularly, the present invention relates to an immunoactivator, a volatile solvent system comprising at least one volatile solvent (defined as water or a solvent more volatile than water), and less volatile than water. Defined) to a formulation comprising a non-volatile solvent system comprising one or more non-volatile solvents, and a solidifying agent. Prior to application to the skin, the formulation is in its sub-solid form, such as a cream, gel, paste or ointment. After application of such a formulation layer to the skin area to be treated, evaporation of the volatile solvent is compliant and flexible, with the aid of a solidifying agent, allowing the formulation layer to be peeled off as desired. And can be converted to a coherent solid layer. The non-volatile solvent system in the formulation acts as an excipient solvent for delivering the drug to the skin that remains in the formulation for substantially the entire duration of application (some of the non-volatile solvent is applied during application) Can be absorbed by the skin). The soft, flexible and cohesive solid layer is designed to adhere to the skin for a substantial duration, preferably for more than 2 hours. If desired, emollient and / or moisturizing substances can be included in the formulation to provide a beneficial moisturizing effect as well as to soften the skin and minimize possible irritation caused by immune activators.

  The formulations of the present invention offer several advantages over Aldara cream. First, the immunoactivator in the formulations of the present invention is “tethered” to the surface of the skin to be treated and is thus not sensitive to unintentional removal. Any emollient and / or moisturizing agent can freshen and soothe the skin and provide additional therapeutic benefits. Any emollient and / or moisturizing agent can also offset possible irritation caused by the immunostimulant. In addition, the physical barrier provided by the solidifying agent and the water retention properties of the moisturizing agent can help maintain moisture in and / or on the skin surface. This is considered valuable. This is because skin hydration increases skin permeability, which in turn can purify the absorption of immune activators. Thus, a formulation containing both an immunoactivator and a moisturizing agent can be synergistic.

  Thus, the present invention relates to formulations that are typically semi-solid initial forms (including creams, gels, pastes, ointments and other viscous liquids), which can be used as a layer for drug delivery. It can be easily applied to the skin and can be quickly (from 15 seconds to about 5 minutes under standard skin and ambient conditions described above) or moderately quickly (standard) after at least some evaporation of the volatile solvent From about 4 to about 15 minutes under typical skin and ambient conditions) can be transformed into a solidified layer (eg, optionally peelable) that delivers the drug, eg, a coherent and soft solid layer. The solidified layer thus formed can deliver the drug over a duration, for example, several hours to tens of hours, so that most of the drug absorption occurs after the solidified layer is formed. it can.

  In addition, the solidified layer typically adheres to the skin but is substantially formed up to clothing or other objects that are formed relatively soon after application and can be worn by the subject or inadvertently contact the solidified layer. It has a solidified and minimally adhesive outer surface that does not move into or otherwise soil it. The solidified layer is highly flexible and extensible so that it can maintain good contact with the skin surface even if the skin stretches during normal day activity. It can also be prescribed.

  The formulations of the present invention can be applied to and used on various types of human body or skin surfaces. In one embodiment, the skin surface to be treated may be traditionally referred to as “skin”. The skin surface can be the epidermal layer of the skin. In another embodiment, the skin surface that can be treated is a mucosal surface such as the lips, oral mucosa, genital mucosa, nasal mucosa, or anal mucosa. In another embodiment, the skin surface to be treated can be a finger or toe nail surface. In yet another embodiment, the skin surface to be treated is a wound skin surface. In yet another embodiment, the skin surface is a bed surface or skin surface with one or more lesions or skin ulcers.

  Various variations can be considered in selecting the various components that can be used, such as drugs, volatile and non-volatile solvent-based solvent excipients, solidifying agents, and the like. For example, the volatile solvent system may be one or more volatile solvents (including water, at least as volatile as water). In one embodiment of the invention, the volatile solvent system is ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1 difluoroethane, 1,1,1,2 tetrafluoroethane, 1, Members of 1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone, or combinations thereof may be included. In another embodiment of the invention, the volatile solvent system is iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cyclopentasiloxane, cyclomethicone, methyl ethyl ketone, or combinations thereof Can be included. The volatile solvent system can comprise a mixture or combination of any of the volatile solvents described in the previous embodiments. These volatile solvents should be selected to be compatible with the rest of the formulation. It may be desirable to use an appropriate weight percent of volatile solvent in the formulation. Too many volatile solvent systems extend the drying time. Too few volatile solvent systems can make the formulation difficult to stretch on the skin. In most formulations, the weight percentage of volatile solvent can be from about 10 wt% to about 85 wt%, more preferably from about 20 wt% to about 50 wt%.

  The non-volatile solvent system can be selected or formulated to be compatible with the solidifying agent, drug, volatile solvent, and any other ingredients that may be present. For example, the solidifying agent can be selected such that it is dispersible or soluble in the non-volatile solvent system. Most non-volatile solvent systems and solvent excipients as a whole will be properly formulated after the experiment. For example, certain drugs have polyethylene glycol (PEG) with a molecular weight of 400 (PEG 400, non-volatile solvent), but poor solubility in glycerol (non-volatile solvent) and water (volatile solvent) . However, PEG 400 cannot effectively dissolve polyvinyl alcohol (PVA) and thus is not very compatible alone with PVA as the sole solidifying agent. In order to dissolve a sufficient amount of the active drug and at the same time use PVA as a solidifying agent, formulate a non-volatile solvent system containing PEG 400 and glycerol (compatible with PVA) in appropriate proportions to make a compatibility compromise. Can be achieved. As a further example of compatibility, non-volatile solvent / solidifying agent incompatibility is observed when Span 20 is formulated into a formulation containing PVA. With this combination, Span 20 can separate from the formulation and form an oily layer on the surface of the solidified layer. Thus, the selection of a suitable solidifying agent / nonvolatile solvent is desirable in developing vigorous formulations and compatible combinations.

  The non-volatile solvents that can be used alone or in combination to form the non-volatile solvent system can be selected from a variety of pharmaceutically acceptable liquids. In one embodiment of the invention, the non-volatile solvent system is glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, butanol , Or a combination thereof. In another embodiment, the non-volatile solvent system is benzoic acid, butyl alcohol, dibutyl sebacate, diglyceride, dipropylene glycol, eugenol, coconut oil, fish oil, coconut oil, grape seed oil fatty acids, isopropyl myristate, Mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan fatty acid surfactants, triethyl citrate, or combinations thereof can be included. In a further embodiment, the non-volatile solvent system is 1,2,6-hexanetriol, alkyltriol, alkyldiol, acetyl monoglyceride, tocopherol, alkyldioxolane, p-propenylanisole, anise oil, apricot oil, dimethylisosorbide, alkyl glucoside, Benzyl alcohol, beeswax, benzyl benzoate, butylene glycol, caprylic / capric triglyceride, caramel, cinnamon oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglyceride, coriander oil, corn oil , Coriander oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglyceride, diethanolamine, diethyleneglycol Monoethyl ether, diglyceride, ethylene glycol, eucalyptus oil, fat, fatty alcohol, flavoring, liquid sugar ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, limonene, Milk, monoacetin, monoglyceride, nutmeg oil, octyldodecanol, olive alcohol, orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil , Plant shortening, vinyl acetate, wax, 2- (2- (octadecyloxy) ethoxy) ethanol, benzyl benzoate, butylated hydroxyanisole, candelilla wax, carna Ba wax, ceteares-20, cetyl alcohol, polyglyceryl, dipolyhydroxystearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG stearate, PEG-oleate, PEG-laurate PEG fatty acid esters such as PEG-dioleate, PEG-fatty acid diesters such as PEG-distearate, PEG-castor oil, glyceryl behenate, PEG-glyceryl laurate, PEG glyceryl stearate, PEG such as PEG glyceryl oleate Glycerol fatty acid ester, hexylene glycerol, lanolin, lauric acid diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, methacrylic acid, multisterol extract, milli PEG-sorbitan such as still alcohol, neutral oil, PEG-octylphenyl ether, PEG-cetyl ether, PEG-alkyl ether such as PEG-stearyl ether, PEG-sorbitan diisostearate, PEG-sorbitan monostearate Fatty acid ester, propylene glycol stearate, propylene glycol, propylene glycol fatty acid ester such as caprylate / caprate, sodium pyrrolidonecarboxylate, sorbitol, squalene, stear-o-wet, triglyceride, alkylaryl poly Ether alcohol, polyoxyethylene derivative of sorbitan-ether, saturated polyglycolated C8-C10 glyceride, N-methylpyrrolidone, honey, poly Oxyethylated glycerides, dimethyl sulfoxide, azone and related compounds, dimethylformamide, N-methylformamide, fatty acid esters, fatty alcohol ethers, alkyl-amides (N, N-dimethylalkylamide), N-methylpyrrolidone related compounds, ethyl oleate Polyglycerolated fatty acid, glycerol monooleate, glyceryl monomyristate, glycerol ester of fatty acid, silk amino acid, PPG-3 benzyl ether myristate, Di-PPG2 milles 10-adipate, honey quat, pyroglutamate sodium, avicinica oil, Dimethicone, macadamia nut oil, limnanthes alba seed oil, cetearyl alcohol, PEG-50 shea butter, shea butter, aloe verajoux , Phenyl trimethicone, hydrolyzed wheat protein, or combinations thereof. In still further embodiments, the non-volatile solvent system can include a combination or mixture of non-volatile solvents as described in any of the above discussed embodiments.

  Certain volatile and / or non-volatile solvents that are irritating to the skin may be desirable to use to achieve the desired solubility and / or permeability of the drug. It is also desirable to add a compound that can both prevent or reduce skin irritation and is compatible with the formulation. For example, in a formulation where the solvent (either non-volatile or volatile) can irritate the skin, it would be helpful to use a non-volatile solvent that can reduce skin irritation. Examples of solvents known to be able to prevent or reduce skin irritation include, but are not limited to, glycerin, honey, and propylene glycol, although other irritation reducing solvents may be used.

  The formulations of the present invention are independently not a suitable non-volatile solvent for the drug, but can also contain two or more non-volatile solvents that, when formulated together, become a suitable non-volatile solvent. One possible reason for these initially unsuitable non-volatile solvents to be suitable non-volatile solvents when formulated together is by optimizing the ionization state of the drug to a physical form with a higher flux Yes, or non-volatile solvents act in several other synergistic ways. One further advantage of mixing non-volatile solvents is that it can optimize the pH of the formulation, or skin tissue under the formulation, to minimize irritation. Examples of suitable combinations of non-volatile solvents that provide a suitable non-volatile solvent system include, but are not limited to, isostearic acid / trolamine, isostearic acid / diisopropylamine, oleic acid / trolamine, and propylene glycol / isostearic acid. .

  The selection of the solidifying agent can also be made taking into account other components present in the solidifying adhesive formulation. Suitable solidifying agents are those in which the formulation is in a liquid or semi-solid state, e.g. cream, paste, gel, ointment, etc., prior to evaporation of the volatile solvent and is flexible after at least some evaporation of the volatile solvent, It is compatible with the formulation so as to be a coherent solid. The solidifying agent is selected to be compatible with the drug and solvent excipients (including volatile and non-volatile solvent systems) and provide the desired physical properties to the solidified layer once it is formed. Or can be prescribed. Depending on the drug, solvent excipient, and / or other ingredients that can be present, the solidifying agent can be selected from a variety of agents. In one embodiment, the solidifying agent is polyvinyl alcohol (Amresco) having a MW range of 20,000 to 70,000, an ester ISP of a polyvinyl methyl ether / maleic anhydride copolymer having a MW range of 80,000 to 160,000. Gantrez ES-425 and Gantrez ES-225), neutral copolymer of butyl methacrylate and methyl methacrylate (Degussa Plastoid B) with a MW range of 120,000 to 180,000, MW range of 100,000 to 200,000 Dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (Degussa Eudragit E100) with MW greater than 5,000, or Eudragit Ethyl acrylate-methyl methacrylate-trimethylammonioethyl chloride copolymer (Degussa) with MW similar to RLPO, Zein with over 5,000 MW (zein, MW around 35,000, Freeman Industries), pregelatinized starch with MW similar to Instant Pure-Cote B793 (MW) greater than 5,000, or MW similar to Aqualon EC N7, N10, N14, N22, N50 or N100 Ethylcellulose (Hercules), fish gelatin with a MW range of 20,000 to 250,000 (Norland Products), gelatin, 5, Other animal origin with a MW range greater than 00, can include acrylates / octylacrylamide copolymer with a MW similar MW range, or National Starch and Chemical Dermacryl 79, more than 5,000.

  In another embodiment, the solidifying agent is ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amide, corn starch, pregelatinized corn starch, polyether amide, shellac, polyvinyl It may include pyrrolidone, polyisobutylene rubber, poly vinyl acetate phthalate or combinations thereof. In a further embodiment, the solidifying agent is ammonia methacrylate, carrageenan, aqueous cellulose acetate phthalate such as CAPNF from Eastman, carboxypolymethylene, cellulose acetate (microcrystalline), cellulose polymer, divinylbenzene styrene, ethylene vinyl acetate, Silicone, guar gum, guarodin, gluten, casein, calcium caseinate, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate, PEG / PVP, xanthan gum, trimethyl Siloxysilicate, maleic acid / anhydride copolymer, polacrilin, poloxamer, polyethylene oxide, polygalactic acid / poly l-lactic acid, turpentine resin, locust bean gum, acrylic copolymer, polyurethane dispersion, dextrin, polyvinyl alcohol-polyethylene glycol copolymer, methacrylic acid-ethyl acrylate copolymer such as BASF 'Kollicoat polymer, methacrylic acid, and poly (methacrylic acid) ) Or a combination thereof. In still further embodiments, the solidifying agent can include a combination of solidifying agents described in any of the previously discussed embodiments. Other polymers may still be suitable as solidifying agents, depending on the solvent excipient component, the drug, and the specific functional requirements of a given formulation.

  In one embodiment of the invention, the solidifying agent is a methacrylic acid polymer, or a copolymer of methacrylic acid-ethyl acrylate, a copolymer of butyl methacrylate and methyl, a copolymer of aminoalkyl methacrylate, and / or an ammonioalkyl methacrylate. Copolymers, such as In another embodiment, the solidifying agent comprises a polyvinyl alcohol copolymer, such as polyvinyl alcohol, or a polyvinyl alcohol-polyethylene glycol copolymer.

  The non-volatile solvent system and the solidifying agent are preferably compatible with each other. Compatibility is that i) the solidifying agent does not substantially negatively affect the function of the non-volatile solvent system; ii) the solidifying agent solidifies so that substantially no non-volatile solvent escapes from the layer. The agent can retain the non-volatile solvent system in the solidified layer, and iii) the solidified layer formed with the selected non-volatile solvent system and solidifying agent has acceptable flexibility, stiffness, tensile tension, elasticity, and adhesion Can be defined. The weight ratio of the non-volatile solvent system to the solidifying agent can be from about 0.1: 1 to about 10: 1, more preferably from about 0.5: 1 to about 2: 1. In some embodiments, the non-volatile solvent system comprises about 20 to 60% of the total weight of the formulation.

  The thickness of the formulation layer applied to the skin should still be appropriate for the given formulation and desired drug delivery considerations. If the layer is too thin, the amount of drug will not be sufficient to support sustained delivery over the desired length of time. If the layer is too thick, it will take too long to form a clean outer surface of the solidified layer. If the drug is very good and the solidified layer has a very high tensile tension, a layer as thin as 0.01 mm would be sufficient. If the drug has rather low capacity and the solidified layer has a low tensile tension, a thickness and layer with an identity of 2-3 mm would be desirable. Thus, for most drugs and formulations, a suitable thickness can be about 0.01 mm to about 3 mm, 0.01 mm to about 2 mm, or about 0.2 mm to about 0.4 mm. In one embodiment, the formulations of the present invention can have sufficient gas volatile solvent so that the formulation can be contained in a compressed container and applied to the skin by spraying. In another embodiment, the formulation can be sprayed onto the skin surface of a subject experiencing alopecia.

The formulations of the present invention can be applied to various skin surfaces of subjects suffering from alopecia. In general, the skin surface can be of any size; however, in one embodiment, especially if the active drug is a corticosteroid, the area is limited to 100 cm ² or less, often 20 cm ² or less. Would be desirable. The desirability of limiting the skin area is that corticosteroids are applied topically, but a good portion of the delivered drug can enter the systemic circulation, which, in a sufficiently high amount, is an undesirable side effect. Based on the fact that it can cause. Therefore, it would be desirable to achieve a good balance of local effects and minimal systemic drug absorption. Since the site of action of corticosteroids is a hair follicle that is somewhat deep below the skin surface, the drug needs to travel along the relatively long path through the skin. Thus, the subject can experience some systemic inoculation. To state this, a significant number of alopecia subjects have only a relatively small skin area, where they are experiencing alopecia. Thus, limitations on the skin treatment area can stage the treatment needs of those subjects while minimizing systemic side effects. Even for subjects with larger alopecia skin areas, restrictions on the treated skin area may still be important. This is because it allows the alopecia skin area to be treated little by little with the possibility of minimized systemic side effects. Treatment of large alopecia skin areas in small increments is possible. This is because the treatment of each part is expected to be periodic instead of continuous.

  The flexibility and extensibility of the solidified layer, optionally in the form of a peel, may be desirable in some applications. High flux and elongation is particularly advantageous when the area to be treated is involved in frequent stretching or movement, such as the lips or mouth corners. Traditional ointments, creams, gels, pastes, etc. are often unsuitable for the treatment of these areas. This is because they are easily removed by licking the lips or through contact with food while eating. In contrast, the solidifiable composition of the present invention can be formulated to provide suitable flexibility and elongation without being easily licked, rubbed or scraped. Also, it is worth mentioning that the solidified layer of the present invention need not always be extensible, but some elasticity is preferred.

  A further feature of the formulation is the drying time. If the formulation is dried too quickly, the user cannot have enough time to spread the formulation into a thin layer on the skin surface before the formulation is solidified, Invite contact. If the formulation dries too slowly, the subject must wait a long time before resuming normal activities that can remove the unsolidified formulation (eg, wearing, eating, talking, etc.) I will. Thus, it is desirable that the drying time be greater than about 15 seconds, but less than 15 minutes, preferably from about 0.5 minutes to about 5 minutes.

  One way to conveniently use the formulations of the present invention is to apply the formulation to the skin to be treated within 1 hour of sleep and remove the solidified layer within 1 hour of waking up.

  Another method is to apply the formulation within 1 hour of waking up the formulation and remove the solidified layer within 1 hour of sleep.

  When using the formulations of the present invention to treat a dermatological condition of light-damaged skin, it may be advantageous to apply the formulation to cover the skin area slightly beyond the damaged skin area. Accordingly, one embodiment of the present invention is to apply the formulation at least 1 to 2 mm beyond the damaged skin area.

  Other advantages of the solidified layer of the present invention include the presence of a physical barrier that can be formed by the material itself. The physical barrier can protect the infected area from contact with objects or sources that cause irritation, pain, or further infection. For example, the solidified layer can act as a barrier against friction with the diaper or as a protective barrier against urine / stool. In addition, upon evaporation of the volatile solvent system, the dosage form is relatively thick and can contain more active drugs than typical layers such as traditional creams, gels, lotions, ointments, pastes, Furthermore, it is not exposed to unintentional removal.

  These and other advantages can be summarized by the following non-limiting application embodiments. The solidified layer of the present invention can be prepared in an initial form that is easy to apply as a semi-solid dosage form. In addition, upon evaporation of volatile solvents, the formulation layer applied to the skin is relatively thick and contains more active drugs than typical layers such as traditional creams, gels, lotions, ointments, pastes, etc. Furthermore, it is resistant to unintentional removal. Following evaporation of the volatile solvent and formation of the solidified layer, the drug in the solidified layer can be delivered at a therapeutically effective rate for a sustained period of time. Furthermore, since the solidified layer remains adhered to the skin, easy removal of the solidified layer can usually occur without the aid of a solvent or surfactant. In some embodiments, the adhesion to the skin and the elasticity of the material is such that the solidified layer does not separate from the skin during skin stretching in highly extensible skin areas, such as on joints and muscles. For example, in one embodiment, the solidified layer can be stretched 5% or even 10% or more in at least one direction without cracking, breaking, and / or separation from the skin surface to which the layer is applied.

  As a further note, it is a unique feature of the solidified layer that the solidified layer of the present invention can maintain a substantial amount of non-volatile solvent system, which is optimized to deliver the drug to the body surface. This feature can provide unique advantages over existing products. For example, Penlac is a widely used product for nail fungal infection. This includes the drug ciclopirox, volatile solvents (ethyl acetate and isopropyl), and polymeric materials. After being applied to the nail surface, the volatile solvent evaporates quickly and the formulation layer solidifies into a hard lacquer. Drug molecules are immobilized on a hard lacquer layer and are virtually unavailable for delivery to the nail. As a result, drug delivery may not be sustained for a long time. As a result, while not intending to be bound by any particular theory, this is believed to be at least one of the reasons why the widely used Penlac has an effectiveness rate of only about 10%. Conversely, in the solidified layer of the present invention, drug molecules can move significantly in non-volatile solvents that are in contact with the surface of the skin, such as skin, nails, mucous membranes, and thus maintain sustained delivery. Make sure.

  The following examples illustrate the best-known embodiments of the present invention. However, it is to be understood that the following are only examples of the application of the principles of the present invention or are illustrative thereof. Numerous modifications and alternative compositions, methods and systems can be devised by those skilled in the art without departing from the spirit and scope of the invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the invention has been described using specifics, the following examples provide further details relating to what is currently considered the most realistic and preferred embodiment of the invention.

Example 1
Hairless mouse skin (HMS) or human epithelium (HEM) is used as the model membrane noted for the in vitro flux experiments described herein. Hairless mouse skin (HMS) is used as a model membrane for the in vitro flux experiments described herein. A freshly isolated epidermis removed from the abdomen of hairless mice is carefully placed between the donor and receiver chambers of the Franz diffusion cell. The receiver chamber is filled with pH 7.4 phosphate buffered saline (PBS). The experiment begins by placing the test formulation (of Examples 2-5) on the stratum corneum (SC) of the skin sample. The Franz cell is placed in a heating block maintained at 37 ° C and the HMS temperature is maintained at 35 ° C. At predetermined time intervals, discard 800 μL aliquots and replace with fresh PBS solution. Skin flux (μg / cm ² / h) is determined from the steady state slope of the plot of cumulative amount of penetration-vs-time. It should be noted that human cadaver skin can be used as a model membrane for in vitro flux experiments as well. The skin placement and sampling technique was the same as described above for the HMS experiment.

Example 2
Acyclovir formulations in various non-volatile solvent systems are evaluated. There is excess acyclobeer. The transdermal flux of acyclovir from the test formulation through HMS is shown in Table 1 below.

示したように、アシクロビール皮膚フラックスの有意な増強が、トロラミンと混合したイソステアリン酸またはオレイン酸で達成される。比較的有意なフラックス増強（例えば、１０倍）が、トロラミンをオリーブ油、オレイン酸、およびイソステアリン酸に加えた場合に観察され、トロラミンをオレイン酸エチルに加えた場合には、認識可能なフラックス増強は観察されない。この驚くべき結果は、かなり高いアシクロビールフラックス値をもたらすトロラミン／脂肪酸組合せの相加または相乗増強効果結果でさえある。

As indicated, significant enhancement of acyclovir skin flux is achieved with isostearic acid or oleic acid mixed with trolamine. A relatively significant flux enhancement (eg, 10 times) is observed when trolamine is added to olive oil, oleic acid, and isostearic acid, and when trolamine is added to ethyl oleate, a recognizable flux enhancement is Not observed. This surprising result is even an additive or synergistic enhancing effect result of the trolamine / fatty acid combination resulting in a fairly high acyclovir flux value.

Examples 3 to 6
A prototype adhesive solidifying formulation is prepared as follows. Some acyclovir solidifying formulations are prepared according to embodiments of the present invention according to Table 2 as follows.

実施例３から６において、表２中の組成物を以下のように調製する。Ｅｕｄｒａｇｉｔ ＲＬ−ＰＯおよびエタノールをガラスジャー中で合わせ、ＲＬ−ＰＯが溶解するまで撹拌しつつ加熱する。イソステアリン酸およびトロラミンをＲＬ−ＰＯ／エタノール混合物に加え、混合物を激しく撹拌する。一旦均一な混合物が得られれば、アシクロビールを混合物に加え、処方物を激しく混合する。

In Examples 3 to 6, the compositions in Table 2 are prepared as follows. Eudragit RL-PO and ethanol are combined in a glass jar and heated with stirring until the RL-PO is dissolved. Isostearic acid and trolamine are added to the RL-PO / ethanol mixture and the mixture is stirred vigorously. Once a uniform mixture is obtained, acyclobeer is added to the mixture and the formulation is mixed vigorously.

Examples 7 to 8
Two acyclovir adhesive solidifying formulations are prepared according to embodiments of the present invention according to Table 3 as follows.

表３に示された実施例７および８の組成物は以下の通りに調製する。Ｅｕｄｒａｇｉｔ ＲＬ−ＰＯおよびエタノールをガラスジャー中で合わせ、ＲＬ−ＰＯが溶解するまで撹拌しつつ加熱する。イソステアリン酸およびジイソプロパノールアミンまたはＮｅｕｔｒｏｌ ＴＥ Ｐｏｌｙｏｌ（ＢＡＳＦ）をＲＬ−ＰＯ／エタノール混合物に加え、混合物を激しく撹拌する。一旦均一な混合物が得られれば、アシクロビールを混合物に加え、処方物を激しく混合する。

The compositions of Examples 7 and 8 shown in Table 3 are prepared as follows. Eudragit RL-PO and ethanol are combined in a glass jar and heated with stirring until the RL-PO is dissolved. Isostearic acid and diisopropanolamine or Neuteol TE Polyol (BASF) are added to the RL-PO / ethanol mixture and the mixture is stirred vigorously. Once a uniform mixture is obtained, acyclobeer is added to the mixture and the formulation is mixed vigorously.

Examples 9 to 10
Two acyclovir solidifying formulations are prepared according to embodiments of the present invention according to Table 4 as follows.

実施例９から１０においては、表４中の組成物は以下のように調製する。ＥＣ７またはＥＣ１００およびエタノールをガラスジャー中で合わせ、固体セルロースが溶解するまで撹拌しつつ加熱する。イソステアリン酸およびトロラミンをセルロース／エタノール混合物に加え、混合物を激しく撹拌する。一旦均一な混合物が得られれば、アシクロビールを混合物に加え、処方物を激しく混合する。

In Examples 9 to 10, the compositions in Table 4 are prepared as follows. EC7 or EC100 and ethanol are combined in a glass jar and heated with stirring until the solid cellulose is dissolved. Isostearic acid and trolamine are added to the cellulose / ethanol mixture and the mixture is stirred vigorously. Once a uniform mixture is obtained, acyclobeer is added to the mixture and the formulation is mixed vigorously.

Example 11
The formulations of Examples 3 to 10 are tested in the hairless mouse skin (HMS) in vitro model described in Example 1. Table 5 shows the data obtained using the experimental process outlined above.

先に示した本発明の処方物は、一般に、有効成分の有意な浸透を供し、さらに、実施例３から５および１０の処方物は、市販されている製品Ｚｏｖｉｒａｘ Ｃｒｅａｍ（対照）よりも浸透性がかなり大きいことが見出される。実施例３、４についての経時的にＨＭＳ角化層を横切って浸透するアシクロビール、およびＺｏｖｉｒａｘ Ｃｒｅａｍの量を図１に示す。各値は少なくとも３つの実験の平均±ＳＤを示す。

The formulations of the present invention shown above generally provide significant penetration of the active ingredient, and in addition, the formulations of Examples 3 to 5 and 10 are more permeable than the marketed product Zovirax Cream (control). Is found to be quite large. The amounts of acyclovir and Zovirax Cream that permeate across the HMS keratinized layer over time for Examples 3 and 4 are shown in FIG. Each value represents the mean ± SD of at least 3 experiments.

  Examples 3 to 6 show the impact of the ratio of trolamine to isostearic acid (ISA) on acyclovir flux enhancement. The optimal ISA: trolamine ratio is from 1: 1 to 2: 1, and ratios greater than 4: 1 indicate a significant reduction in acyclovir skin flux. Addition of diisopropanolamine instead of trolamine and Neutrol (Examples 7 and 8) in the formulation shows a significant decrease in acyclovir flux values. This may be due to a specific chemical interaction between trolamine and ISA that creates an environment within the formulation that promotes higher skin flux. Examples 9 and 10 utilize different solidifying agents to estimate the impact of the solidifying agent on acyclovir flux. Surprisingly, Example 9 shows a significant reduction in acyclovir skin flux, but Example 10, which differs from Example 9 by the molecular weight of the solidifying agent, compares to the similar ISA: trolamine ratio in Example 3. No impact on acyclovir skin flux.

  As can be seen from FIG. 1, Examples 3 and 4 showed sustained delivery of acyclovir up to 8 hours, and delivery of acyclovir was reported as long as the subject wanted to remove the solidified formulation attached to the skin. It would be reasonable to estimate what will continue at the flux value based on the drug load and the continued presence of the non-volatile solvent.

Example 12
A formulation similar to Example 4 (without acyclovir) is applied to the human skin surface, resulting in a thin, transparent and flexible stretchable film. A few minutes after evaporation of the volatile solvent (ethanol), a peelable solidified adhesive layer is formed. The stretchable film had good adhesion to the skin, did not separate from the skin, and could be easily peeled off from the skin. The absence of acyclovir is expected to have minimal or no impact on the physical and fatigue properties of the cohesive solid. Because if present, it is present at such a low concentration.

Examples 13 to 14
An anti-fungal formulation is prepared and a quantitative evaluation of peel flexibility and viscosity is made. The ingredients of the formulation are shown in Table 6 below.

実施例１３における処方物は、爪または皮膚表面への適用で望ましいであろうよりも低い粘度を有する。この処方物で固化ピールを形成するための時間は望まれる乾燥時間よりも長い。実施例１４における処方物は固化剤（Ｅｕｄｇｒａｇｉｔ ＲＬ−ＰＯ）の量の増加、およびエタノールの量の減少を有し、これは、粘度および乾燥時間を改良する。実施例１４は、適用に適した粘度、および改良された乾燥時間を有する。

The formulation in Example 13 has a lower viscosity than would be desirable for nail or skin surface application. The time to form a solidified peel with this formulation is longer than the desired drying time. The formulation in Example 14 has an increased amount of solidifying agent (Eudgragit RL-PO) and a decreased amount of ethanol, which improves viscosity and drying time. Example 14 has a viscosity suitable for application and an improved drying time.

Example 15
Formulations of betamethasone dipropionate (BDP) in various non-volatile solvent systems are evaluated according to the procedure described in Example 1. Excess BDP exists. The penetration of BDP from the test formulation through the HEM is shown in Table 7 below.

皮膚中の活性な酵素はＢＤＰをベタメタゾンに変換する。表７に報告された定常状態フラックス値は、外部ベタメタゾン標準を用いて定量し、単位面積および時間当たりに浸透するベタメタゾンの量として報告する。結果から分かるように、トリアセチン、ラブラゾール、オレイン酸および軽質鉱油は１０ ｎｇ／ｃｍ^２／時間に近いフラックス値を有する。固化剤および他の成分の添加は、おそらくは、フラックスを減少させ、従って、前記した溶媒は理想的な不揮発性溶媒ではないであろう。しかしながら、ソルビタンモノラウレートおよびプロピレングリコールは、各々、３０ ｎｇ／ｃｍ^２／時間および１９５ ｎｇ／ｃｍ^２／時間の平均フラックスを有し、従って、不揮発性溶媒に対する良好な候補である。

Active enzymes in the skin convert BDP to betamethasone. The steady state flux values reported in Table 7 are quantified using an external betamethasone standard and reported as the amount of betamethasone penetrating per unit area and time. As can be seen from the results, triacetin, labrazole, oleic acid and light mineral oil have flux values close to 10 ng / cm ² / hour. The addition of solidifying agent and other ingredients probably reduces the flux, so the above mentioned solvent will not be an ideal non-volatile solvent. However, sorbitan monolaurate and propylene glycol have average fluxes of 30 ng / cm ² / hr and 195 ng / cm ² / hr, respectively, and are therefore good candidates for non-volatile solvents.

Example 16
Evaluate formulations of clobetasol propionate in various non-volatile solvent systems. All solvents have 0.1% (w / w) clobetasol propionate. The penetration of clobetasol from the test formulation through HEM is listed in Table 8 below.

実験した全ての純粋な不揮発性溶媒は、３０時間の時間にわたっての４０ ｎｇ／ｃｍ^２／ｈｒ未満の平均フラックスを有する。プロピレングリコールおよびグリセロールはクロベタゾールプロピオネートについての最低浸透を有する。プロピレングリコールおよびイソステアリン酸の９：１の重量比率の混合物は、溶媒単独、またはテストした他の溶媒のいずれよりも有意に高いフラックスを有する。平均フラックスは、最良の混合していない溶媒である軽質鉱油のそれよりも２０倍高い。よって、クロベタゾールプロピオネートについては、プロピレングリコール／イソステアリン酸の組合せは理想的な不揮発性溶媒である。

All the pure non-volatile solvents tested have an average flux of less than 40 ng / cm ² / hr over a 30 hour time period. Propylene glycol and glycerol have the lowest penetration for clobetasol propionate. A 9: 1 weight ratio mixture of propylene glycol and isostearic acid has a significantly higher flux than either the solvent alone or the other solvents tested. The average flux is 20 times higher than that of light mineral oil, the best unmixed solvent. Thus, for clobetasol propionate, the propylene glycol / isostearic acid combination is an ideal non-volatile solvent.

Examples 17-22
An adhesive formulation containing 0.05% (w / w) clobetasol propionate is prepared with a non-volatile solvent and propylene glycol and isostearic acid as various solidifying agents. The formulation is prepared from the ingredients shown in Table 9.

先に示した組成物の各々を、以下のように、表１０に示したようにクロベタゾールプロピオネートのフラックスについて実験する。

Each of the previously shown compositions is tested for clobetasol propionate flux as shown in Table 10 as follows.

表１０から分かるように、固化剤としてポリビニルアルコールを含有する実施例１７に記載された処方物はクロベタゾールプロピオネートの高いフラックスを有する。ポリビニルアルコールは（もし適当な可塑剤で処方したならば）伸長性フイルムを形成することが知られており、この処方物は許容できる疲労特性を有するようである。得られたフイルムの靭性は、もし必要ならば、適当な可塑剤を加えることによって修飾することができる。また、適当な量の粘着剤を加えることによって、あるいは適当な量のＤｅｒｍａｃｒｙｌ ７９のようなもう１つの固化剤を加えることによって、粘着性を修飾することもできる。

As can be seen from Table 10, the formulation described in Example 17 containing polyvinyl alcohol as a solidifying agent has a high flux of clobetasol propionate. Polyvinyl alcohol is known to form extensible films (if formulated with a suitable plasticizer) and this formulation appears to have acceptable fatigue properties. The toughness of the resulting film can be modified, if necessary, by adding a suitable plasticizer. Also, the tackiness can be modified by adding an appropriate amount of an adhesive or by adding an appropriate amount of another solidifying agent such as Dermacry 79.

  For the formulation described in Example 22, a higher percentage of ethanol is required to dissolve the polymer. However, the polymer used in Example 22 provides the highest flux of clobetasol propionate among the experimental solidifying agents. The fatigue properties of this formulation can be modified by adding appropriate levels of other ingredients including, but not limited to, plasticizers, adhesives, non-volatile solvents and / or solidifying agents. .

Examples 23 to 25
A placebo formulation containing Gantrez ES 425 as an adhesive was prepared for fatigue experiments by volunteers. The formulation is shown as an example in Table 11. All formulations have polyvinyl alcohol as a solidifying agent. The amount of propylene glycol in the formulation is reduced from 19.6% (w / w) to 8.7% (w / w), and the amount of glycerol depends on the same amount that keeps the total non-volatile ratio constant. Increased. It is important to keep the non-volatile ratio constant. This is because it determines the drying time and the duration of delivery. The placebo formulation was applied to the palm and the percentage adhesion of the film formed after evaporation of the volatile solvent was observed after 5 to 6 hours.

３人のボランティアについての疲労実験結果は、実施例２３に記載された固化層の７０から８０％が５から６時間の持続の後に手のひらに留まっていたことを示す。しかしながら、実施例２５に示した、９０％を超える固化層がボランティアの手のひらに留まった。これらの実施例は、グリセロールが、ポリビニルアルコールポリマーについてプロピレングリコールよりも良好な可塑剤であることを示す。それは、不揮発性溶媒の比率が、手の皮膚炎の治療用の処方物を選択するのに非常に重要であることも示す。

The fatigue test results for three volunteers indicate that 70-80% of the solidified layer described in Example 23 remained in the palm after 5-6 hours duration. However, over 90% of the solidified layer shown in Example 25 remained in the volunteer's palm. These examples show that glycerol is a better plasticizer for propylene glycol for polyvinyl alcohol polymers. It also shows that the proportion of non-volatile solvents is very important in selecting a formulation for the treatment of hand dermatitis.

Example 26
The following composition: 10.4% polyvinyl alcohol, 10.4% polyethylene glycol 400, 10.4% polyvinyl pyrrolidone K-90, 10.4% glycerol, 27.1% water, and 31.3% ethanol. The object was applied to the human skin surface at the elbow and finger joints, resulting in a thin, transparent, flexible and stretchable film. A solidified peelable layer was formed that was peelable after several minutes of evaporation of volatile solvents (ethanol and water). The stretchable film had good adhesion to the skin and, when bent, did not separate from the skin on the joint and could be easily peeled off the skin.

Examples 27 to 28
In vitro adhesive peelable formulations containing 0.05% (w / w) clobetasol propionate and 0.15% (w / w) clobetasol propionate with polyvinyl alcohol as a solidifying polymer Prepare for flux evaluation. Propylene glycol and oleic acid are non-volatile solvents selected for enhanced clobetasol propionate delivery. As shown in Example 12, glycerol is added as a non-volatile solvent due to its plastic properties. The ratio of the components used in the two formulations is shown in Table 12.

前記で示した組成物の双方を、３人のドナーからの死体皮膚上でのクロベタゾールプロピオネートのフラックスについて調べた。浸透性結果は表１３に示す通りである。市販のクロベタゾール軟膏（０．０５％ ｗ／ｗ）を対照処方物として用いた。

Both of the compositions shown above were examined for clobetasol propionate flux on cadaver skin from three donors. The permeability results are as shown in Table 13. Commercial clobetasol ointment (0.05% w / w) was used as a control formulation.

表１３から分かるように、固化剤としてのポリビニルアルコール、および０．０５％クロベタゾールプロピオネートを含有する実施例２７に記載した処方物は、対照処方物と比較した場合に、クロベタゾールプロピオネートの４６％フラックスを有した。クロベタゾールプロピオネート濃度薬物濃度を０．１５％（ｗ／ｗ）まで増加させると、定常状態フラックスを増加させ、フラックス値は対照処方物の９４％であった。ピール処方物での適用のより長い持続は、累積送達をイン・ビボで増加させ皮膚炎の効果的な治療をもたらす。

As can be seen from Table 13, the formulation described in Example 27 containing polyvinyl alcohol as a solidifying agent and 0.05% clobetasol propionate was compared to the clobetasol propionate when compared to the control formulation. It had a 46% flux. Increasing the clobetasol propionate concentration drug concentration to 0.15% (w / w) increased the steady state flux with a flux value of 94% of the control formulation. Longer duration of application with peel formulations increases cumulative delivery in vivo, resulting in effective treatment of dermatitis.

Example 29
An adhesive solidifying formulation containing 0.05% (w / w) clobetasol propionate with fish gelatin as a solidifying agent is prepared for in vitro flux evaluation. Propylene glycol, isostearic acid, and oleic acid are used as non-volatile solvents to facilitate the delivery of clobetasol. Talc is added as a filler to reduce the drying time of the formulation. Table 14 shows the ratio of the components used in the formulation.

先の実施例に示したポリビニル系処方物とは異なり、実施例２９に示された魚ゼラチン系処方物は水で洗浄可能な処方物であり、手の皮膚炎に罹った対象によって容易に除去され得る。実施例２９に記載した処方物での３人のドナーからのヒト死体皮膚を通っての定常状態フラックスを市販のクロベタゾール軟膏と比較する。浸透性結果を表１５に示す。

Unlike the polyvinyl-based formulation shown in the previous example, the fish gelatin-based formulation shown in Example 29 is a water-washable formulation that is easily removed by subjects with hand dermatitis. Can be done. The steady state flux through human cadaver skin from three donors with the formulation described in Example 29 is compared to a commercial clobetasol ointment. The permeability results are shown in Table 15.

表１５から分かるように、実施例２９に記載された処方物は、市販の軟膏と比較した場合に６２％高い定常状態フラックスを有する。より高い定常状態フラックスは、治療が困難な皮膚炎および乾癬症例の炎症を低下させると予測される。

As can be seen from Table 15, the formulation described in Example 29 has a steady state flux that is 62% higher when compared to the commercial ointment. Higher steady state fluxes are expected to reduce inflammation in dermatitis and psoriasis cases that are difficult to treat.

Example 30
An adhesive solidifying formulation containing 0.05% (w / w) clobetasol propionate with fish gelatin as the solidifying polymer is prepared for in vitro flux evaluation. Propylene glycol and isostearic acid are used as non-volatile solvents to facilitate the delivery of clobetasol. Fumed silica is added as a filler to reduce the drying time of the formulation. Table 16 shows the ratio of the components used in the formulation.

実施例３０に示された魚ゼラチン系処方物は水で洗浄可能な処方物であり、手の皮膚炎を罹った対象によって容易に除去され得る。実施例３０に記載された処方物での４人のドナーからのヒト死体皮膚を横切っての定常状態フラックスを市販のクロベタゾール軟膏と比較する。浸透性結果を表１７に示す。

The fish gelatin-based formulation shown in Example 30 is a water washable formulation and can be easily removed by subjects with hand dermatitis. The steady state flux across human cadaver skin from four donors with the formulation described in Example 30 is compared to a commercial clobetasol ointment. The permeability results are shown in Table 17.

表１７から分かるように、平均して、実施例３０に記載された処方物は、市販の軟膏での定常状態フラックスと比較した場合、少なくとも同様な、または良好な定常状態フラックスを有する。実施例２９で用いたタルクとは異なり、ヒュームド・シリカは低い密度を有し、処方物から分離する低い能力を有すると予測される。

As can be seen from Table 17, on average, the formulation described in Example 30 has at least a similar or good steady state flux when compared to the steady state flux with commercial ointments. Unlike the talc used in Example 29, fumed silica has a low density and is expected to have a low ability to separate from the formulation.

Example 31
Examples 29 and 30 show that fish gelatin-based formulations that are protein-based solidifying agents (polymers) are the preferred polymers selected for the delivery of corticosteroid drugs. However, fish gelatin based formulations take longer to dry. Another adhesive formulation containing 0.05% (w / w) clobetasol propionate with corn, a corn-based protein, as a solidified polymer is prepared for in vitro flux evaluation. Propylene glycol and isostearic acid are used as non-volatile solvents to facilitate the delivery of clobetasol. Unlike fish gelatin, which has poor solubility in ethanol, zein is soluble in ethanol. Thus, zein-based formulations have shorter drying times. Table 18 shows the ratio of the components used in the formulation.

実施例３１に記載された処方物でのヒト死体皮膚を横切っての定常状態フラックスを、市販のクロベタゾール軟膏での皮膚フラックスと比較する。浸透性の結果を表１９に示す。

The steady state flux across human cadaver skin with the formulation described in Example 31 is compared to the skin flux with commercial clobetasol ointment. The permeability results are shown in Table 19.

表１９から分かるように、実施例３１に記載された処方物は市販の軟膏に対して匹敵する定常状態フラックスを有する（比率８６％）。この比率は、４６％の比率を有する、ポリビニルアルコールベースの処方物である実施例２７における処方物の比率よりも有意に高い。本実施例は、蛋白質ベースの固化剤がポリビニルベースの処方物よりも良好なコルチコステロイドのフラックスを維持することを示す。実施例３１における処方物の疲労特性は、可塑剤および充填剤の添加によって改良することができる。

As can be seen from Table 19, the formulation described in Example 31 has a steady state flux comparable to the commercial ointment (ratio 86%). This ratio is significantly higher than the ratio of the formulation in Example 27, which is a polyvinyl alcohol-based formulation with a ratio of 46%. This example shows that protein-based solidifying agents maintain better corticosteroid flux than polyvinyl-based formulations. The fatigue properties of the formulation in Example 31 can be improved by the addition of plasticizers and fillers.

Example 32
The following experiment was conducted to demonstrate the ability of the solidified solidifying formulation to reduce transepidermal water loss (TEWL).

  A placebo PVA formulation similar to the formulation described in Example 28 was applied to the top of the hand and TEWL was measured at the site immediately adjacent to the solidified layer and at the top of the solidified peel. The TEWL measurement of the area covered by the solidified layer was 33% lower than the untreated skin area.

  A placebo Plastoid B formulation similar to the formulation described in Example 20 was applied to the top of the hand and TEWL was measured at the site immediately adjacent to the solidified layer and at the top of the solidified peel. The TEWL measurement at the site covered by the solidified layer was 30% lower than the untreated skin site.

Examples 33 to 36
An adhesive solidifying formulation is made containing the following ingredients:

これらの処方物は実施例１に記載したようにＨＭＳ皮膚に適用し、イミキモドフラックスを測定する。実施例３３から３６における処方物で行ったイン・ビトロフラックス実験からの結果のまとめを表２１にリストする。

These formulations are applied to HMS skin as described in Example 1 to measure imiquimod flux. A summary of the results from the in vitro flux experiments performed with the formulations in Examples 33-36 is listed in Table 21.

実施例３３から３６のイン・ビトロフラックスは、Ａｌｄａｒａ対象のそれよりも実質的に高い。

The in vitro flux of Examples 33 to 36 is substantially higher than that of the Aldara subject.

  Although the present invention has been described with reference to certain preferred embodiments, those skilled in the art will recognize that various modifications, changes, omissions, and substitutions may be made without departing from the spirit of the invention. Will. Accordingly, it is intended that the invention be limited only by the claims.

FIG. 1 is a graphical representation of the cumulative amount of acyclovir delivered transdermally over time from two separate formulations according to embodiments of the present invention compared to the commercial product Zovirax cream.

Claims (121)

An adhesive solidifying formulation for treating a dermatological condition,
a) drugs for treating dermatological conditions;
b)
i) a volatile solvent system comprising at least one volatile solvent; and ii) a non-volatile solvent system comprising at least one non-volatile solvent;
A solvent excipient comprising:
The non-volatile solvent system can facilitate delivery of the drug over a sustained period at a therapeutically effective rate; and a solvent excipient; and c) a solidifying agent;
The formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and the formulation applied to the skin surface comprises the volatile solvent system Forming a solidified layer after at least partial evaporation, and the drug is continuously delivered through the skin after the volatile solvent system is at least substantially evaporated;
Solidifying formulation. The formulation of claim 1, wherein the non-volatile solvent system acts as a plasticizer for the solidifying agent. The formulation of claim 1, wherein the non-volatile solvent system is fluxable for the drug. The formulation of claim 1, further comprising an additional agent added to increase the adhesion of the formulation when applied to a body surface. The further agent comprises a copolymer of methyl vinyl ether and maleic anhydride, a copolymer of polyethylene glycol and polyvinyl pyrrolidone, gelatin, a low molecular weight polyisobutylene rubber, a copolymer of acrylic sun alkyl / octyl acrylamide, an aliphatic resin, an aromatic resin and combinations thereof. The formulation of claim 4 comprising a member selected from the group. The formulation of claim 1, wherein the volatile solvent system comprises water. The formulation of claim 1, wherein the solvent excipient is substantially free of water. The formulation of claim 1, wherein the volatile solvent system comprises at least one member selected from the group consisting of ethanol, isopropyl alcohol, and combinations thereof. The volatile solvent system comprises at least one solvent that is more volatile than water, and is ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1 difluoroethane, 1,1,1, 2 tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone, and combinations thereof The formulation of claim 1 comprising at least one member selected. The volatile solvent system comprises at least one solvent that is more volatile than water, and is iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclohexane The formulation of claim 1, comprising at least one member selected from the group consisting of methicone, methyl ethyl ketone and combinations thereof. The formulation of claim 1, wherein the volatile solvent system comprises a volatile solvent whose boiling point is less than 20 ° C. The formulation of claim 11, wherein the volatile solvent having a boiling point less than 20 ° C. is completely dissolved in the formulation. The formulation of claim 11, wherein the volatile solvent having a boiling point of less than 20 ° C is included in the formulation as a propellant for pressurized spray-on applications. The formulation of claim 11, wherein the volatile solvent having a boiling point of less than 20 ° C. is a hydrofluorocarbon. The at least one solvent whose boiling point is less than 20 ° C. is dimethyl ether, butane, 1,1 difluoroethane, 1,1,1,2 tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro 12. A formulation according to claim 11 selected from the group consisting of propane, 1,1,1,3,3,3 hexafluoropropane or mixtures thereof. The formulation of claim 1, wherein the non-volatile solvent system comprises a plurality of non-volatile solvents mixed together. The formulation of claim 1, wherein the non-volatile solvent system comprises at least one solvent selected from the group consisting of isostearic acid, oleic acid, olive oil, trolamine, and combinations thereof. The formulation of claim 1, wherein the non-volatile solvent system comprises at least one member selected from the group consisting of sorbitan monolaurate, isostearic acid, triacetin, benzoic acid, and combinations thereof. The non-volatile solvent system is selected from the group consisting of glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, butanol, and combinations thereof The formulation of claim 1 comprising at least one selected solvent. The non-volatile solvent system is benzoic acid, butyl alcohol, dibutyl sebacate, diglyceride, dipropylene glycol, eugenol, fatty acid, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglyceride, sorbitan fatty acid surfactant, triethyl citrate, The formulation of claim 1 comprising at least one solvent selected from the group consisting of and combinations thereof. The non-volatile solvent system is 1,2,6-hexanetriol, alkyltriol, alkyldiol, acetyl monoglyceride, tocopherol, alkyldioxolane, p-propenylanisole, anise oil, apricot oil, dimethylisosorbide, alkylglucoside, benzyl alcohol, beeswax , Benzyl benzoate, butylene glycol, caprylic / capric triglyceride, caramel, cinnamon oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglyceride, coriander oil, corn oil, coriander oil, Corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglyceride, diethanolamine, diethylene glycol monoethylate , Diglyceride, ethylene glycol, eucalyptus oil, fat, fatty alcohol, flavoring, liquid sugar, ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, limonene, milk, monoacetin , Monoglyceride, nutmeg oil, octyldodecanol, olive alcohol, orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, plant shortening , Vinyl acetate, wax, 2- (2- (octadecyloxy) ethoxy) ethanol, benzyl benzoate, butylated hydroxyanisole, candelilla wax, carnauba wax, setea -20, cetyl alcohol, polyglyceryl, dipolyhydroxystearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG fatty acid ester, PEG stearate, PEG-oleate, PEG Laurate, PEG-fatty acid diester, PEG-diolate, PEG-distearate, PEG-castor oil, glyceryl behenate, PEG glycerol fatty acid ester, PEG-glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate, hexylene glycerol, Lanolin, lauric acid diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, methacrylic acid, multisterol extract, myristyl alcohol, neutral oil, PEG-oct Tilphenyl ether, PEG-alkyl ether, PEG-cetyl ether, PEG-stearyl ether, PEG-sorbitan fatty acid ester, PEG-sorbitan diisostearate, PEG-sorbitan monostearate, propylene glycol fatty acid ester, propylene glycol stearate, Propylene glycol, caprylate / caprate, sodium pyrrolidonecarboxylate, sorbitol, squalene, stear-o-wet, triglyceride, alkylaryl polyether alcohol, polyoxyethylene derivatives of sorbitan-ether, saturated polyglycol C8-C10 glycerides, N-methylpyrrolidone, honey, polyoxyethylated glycerides, dimethyl sulfoxide, Azone And related compounds, dimethylformamide, N-methylformamide, fatty acid ester, fatty alcohol ether, alkyl-amide (N, N-dimethylalkylamide), N-methylpyrrolidone-related compound, ethyl oleate, polyglycerinated fatty acid, glycerol mono Oleate, glyceryl monomyristate, glycerol ester of fatty acid, silk amino acid, PPG-3 benzyl ether myristate, Di-PPG2 milles 10-adipate, honey quat, sodium pyroglutamate, abyssinica oil, dimethicone, macadamia nut oil , Limnanthes alba seed oil, cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice, husk Cycloalkenyl trimethicone, hydrolyzed wheat protein, and formulation of claim 1 comprising at least one solvent selected from the group consisting of a combination thereof. The solidifying agent is polyvinyl alcohol, an ester of polyvinyl methyl ether / maleic anhydride copolymer, a neutral copolymer of butyl methacrylate and methyl methacrylate, a copolymer of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate, ethyl acrylate- At least one member selected from the group consisting of methyl methacrylate-trimethylammonioethyl chloride copolymer, prolamin (zein), pregelatinized starch, ethylcellulose, fish gelatin, gelatin, acrylate / octylacrylamide copolymer, and combinations thereof The formulation of claim 1 comprising: The solidifying agent is ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amide, corn starch, pregelatinized corn starch, polyether amide, shellac, polyvinyl pyrrolidone, polyisobutylene rubber, The formulation of claim 1, comprising at least one member selected from the group consisting of polyvinyl acetate phthalate and combinations thereof. The solidifying agent is ammonia methacrylate, carrageenan, aqueous cellulose acetate phthalate, carboxypolymethylene, cellulose acetate (microcrystalline), cellulose polymer, divinylbenzenestyrene, ethylene vinyl acetate, silicone, guar gum, guarodin, gluten, casein, casein. Acid calcium, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate, PEG / PVP, xanthan gum, trimethylsiloxysilicate, maleic acid / anhydride copolymer, polacrilin , Poloxamer, polyethylene oxide, polygalactic acid / poly-1-lactic acid, turpen resin, locust bean Selected from the group consisting of acrylics, acrylic copolymers, polyurethane dispersions, dextrin, polyvinyl alcohol-polyethylene glycol copolymers, methacrylic acid-ethyl acrylate copolymers, methacrylic acid, and methacrylate polymers such as poly (methacrylic acid), and combinations thereof The formulation of claim 1, comprising at least one member. The formulation of claim 1, wherein the solidifying agent comprises a methacrylic acid polymer. The formulation of claim 1, wherein the solidifying agent comprises a methacrylic acid-ethyl acrylate copolymer. The formulation of claim 1, wherein the solidifying agent comprises a polyvinyl alcohol-polyethylene glycol copolymer. The formulation of claim 1, wherein the solidifying agent comprises a polyvinyl alcohol-polyethylene glycol copolymer. The formulation of claim 1, wherein the solidifying agent comprises a member selected from the group consisting of methacrylic acid copolymers, aminoalkyl methacrylate copolymers, ammonioalkyl methacrylate copolymers, and combinations thereof. The formulation of claim 1, wherein the drug comprises a plurality of pharmaceutically active agents. The formulation of claim 1, wherein the dermatological condition is a viral infection and the drug is an anti-viral agent. The anti-viral agent is acyclovir, pencyclobeer, famcyclovir, rosecyclobeer, behenyl alcohol, trifluridine, idoxyuridine, cidofovir, gancyclobeer, podophyllox, podophyllotoxin, ribavirin, abaca beer, delavirdine, didanosine , Efavirenz, lamivudine, nevirapine, stavudine, sarcitabine, zidovudine, amprena beer, indina beer, nelfina beer, ritona beer, saquina beer, amantadine, interferon, oseltami beer, ribavirin, rimantadine, zanami beer, and combinations thereof 32. The formulation of claim 31, comprising a member. 32. The method of claim 31, wherein the viral infection is a herpes infection and the drug is a steroid for treating the herpes infection. 34. The formulation of claim 33, wherein the herpes infection is herpes simplex and the drug is for treating the herpes simplex. 34. The formulation of claim 33, wherein the herpes infection is genital herpes and the drug is for treating the genital herpes infection. The formulation of claim 1, wherein the dermatological condition is nail infection and the drug is for treating nail infection. The formulation of claim 1, wherein the dermatological condition is a fungal infection and the drug is an antifungal agent. The antifungal agent is amorolfine, butenafine, naphthifine, terbinafine, fluconazole, itraconazole, ketoconazole, posaconazole, rubconazole, voriconazole, clotrimazole, butconazole, econazole, miconazole, oxyconazole, sulconazole, terconazole, ponconazole, ponconazole, 38. The formulation of claim 37, comprising a member selected from the group consisting of durafingin, amphotericin B, AmB, nystatin, pimalysin, griseofulvin, cyclopirox olamine, haloprogin, tolnaftate, and undecylenate, and combinations thereof. . The formulation of claim 1, wherein the dermatological condition is photodamaged skin and the drug is an immunomodulator. 40. The formulation of claim 39, wherein the immunomodulating agent comprises a plurality of immunomodulating agents. 40. The formulation of claim 39, wherein the immunomodulating agent comprises imiquimod. 40. The formulation of claim 39, wherein the immunomodulating agent comprises rosikimod. The formulation further comprises a member selected from the group consisting of allantoin, calamine, cod liver oil, dimethicone, kaolin, lanolin, mineral oil, petrolatum, talc, topical starch, white mineral oil, zinc oxide, and combinations thereof. The formulation of claim 1 comprising: 2. A formulation according to claim 1 comprising a moisturizing agent. The moisturizer is a honey derivative such as glycerol, propylene glycol, dipropylene glycol, butylene glycol, sorbitol, honey, and honey quat, urea and urea derivatives such as hydroxyethyl urea, ammonium lactate, sodium lactate, potassium lactate, At least one member selected from the group consisting of pyroglutamic acid and salts thereof, sodium malate, polydextrose, triacetin, mannitol, oxidized polyethylene, isomalt, maltitol and maltitol syrup, lactitol, xylitol, erythritol and combinations thereof 46. The formulation of claim 45, comprising: The formulation of claim 1, wherein the solidified layer provides a mechanical barrier to an external source of stimulation. The formulation of claim 1, wherein the solidified layer provides a barrier to urine or feces. The formulation of claim 1, wherein the solidified layer provides a barrier to friction with a diaper. The formulation of claim 1, wherein the dermatological condition is a bacterial infection and the drug is an antibacterial agent. 50. The formulation of claim 49, wherein the antibacterial agent comprises a member selected from the group consisting of erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones such as ciproflavine, and combinations thereof. . The formulation of claim 1, wherein the dermatological condition is a skin infection. The formulation of claim 1, wherein the dermatological condition is alopecia and the drug comprises a corticosteroid. The drug is betamethasone dipropionate, halobetasol propionate, diflorazone diacetate, triamcinolone acetonide, desoxymethasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone Steroids including acetonide, fluocinolone acetonide, florandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alcromethasone dipropionate, flumethasone pivorate, hydrocortisone, hydrocortisone acetate, and combinations thereof 53. The formulation of claim 52, wherein the formulation is a corticosteroid comprising a member selected from the group consisting of. The formulation of claim 1, wherein the dermatological condition is alopecia and the drug comprises a hair growth stimulant. The dermatological condition is alopecia, and the drug is a substance that stimulates the skin and stimulates hair growth, and a tretinoin local immunotherapeutic agent such as minoxidil, spironolactone, finasteride, anthralin, dinitrochlorobenzene, The formulation of claim 1, comprising a member selected from the group consisting of squaric acid dibutyl ester, diphenylcyclopropenone, and combinations thereof. The formulation of claim 1, wherein the dermatological condition is alopecia and the drug comprises clobetasol or a clobetasol derivative. 57. The formulation of claim 56, wherein the clobetasol derivative is clobetasol propionate. 57. The formulation of claim 56, wherein the concentration of clobetasol or clobetasol derivative is greater than about 0.03%. 57. The formulation of claim 56, wherein the concentration of clobetasol or clobetasol derivative is greater than about 0.14%. 57. The formulation of claim 56, wherein the concentration of clobetasol or clobetasol derivative is greater than about 0.29%. 57. The formulation of claim 56, wherein the drug is clobetasol, or a clobetasol derivative, and the solidifying agent comprises a member selected from the group consisting of gelatin, zein, gluten, polyvinyl alcohol, and combinations thereof. A drug wherein the dermatological condition is dermatitis or psoriasis and the drug is selected from the group consisting of corticosteroids, immune modulators, vitamin D3 analogs, retinoic acid, pharmaceutically active derivatives thereof, and combinations thereof The formulation of claim 1 comprising at least one member of the class. The dermatological condition is dermatitis or psoriasis, and the drug is betamethasone dipropionate, clobetasol propionate, halobetasol propionate, diflorazone diacetate, amsinonide, desoxymethasone, fluocinonide, halocinonide, Mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, fluland lenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alcrometasone dipropionate, flumetasone Sompivorate, hydrocortisone, hydrocortisone acetate, tacrolimus, picrolimus, tazarotene, isotretinoin, cyclosporine, anthralin, vitamin D3, Leka Cie Fellows Le, calcitriol, calcipotriol, tacalcitol, calcipotriene, and formulation of claim 1 comprising at least one member selected from the group consisting of a combination thereof. The formulation of claim 1, wherein the dermatological condition is dermatitis or psoriasis and the solidified layer can adhere to the skin of a human palm. The formulation of claim 1, wherein the dermatological condition is alopecia and the non-volatile solvent system comprises propylene glycol and isostearic acid in a weight ratio of 19: 1 to 4: 1. When the solidified layer is applied to the skin at an extensible skin surface, the solidified layer is sufficiently flexible to remain substantially intact on the skin upon stretching of the skin; 2. A formulation according to claim 1 which is adhesive to the skin. The formulation of claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 2 hours after formation of the solidified layer. The formulation of claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 4 hours after formation of the solidified layer. The formulation of claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 8 hours after formation of the solidified layer. The formulation of claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 12 hours after formation of the solidified layer. The formulation of claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 24 hours after formation of the solidified layer. The formulation of claim 1, wherein the solidifying agent is dispersed in the solvent excipient. The formulation of claim 1, wherein the solidifying agent is solvated in the solvent excipient. The formulation of claim 1, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.1: 1 to about 10: 1. The formulation of claim 1, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.5: 1 to about 2: 1. 2. The formulation of claim 1, wherein the non-volatile solvent system can cause human skin irritation and at least one non-volatile solvent of the non-volatile solvent system can reduce the skin irritation. 77. The formulation of claim 76, wherein the non-volatile solvent capable of reducing skin irritation comprises a member selected from the group consisting of glycerin, propylene glycol, and honey, and combinations thereof. The formulation of claim 1, wherein the solidified layer is formed within about 15 minutes of application to the skin surface under standard skin and ambient conditions. The formulation of claim 1, wherein the solidified layer is formed within about 5 minutes of application to the skin surface under standard skin and ambient conditions. The formulation of claim 1, wherein the solidified layer is removable from the skin surface by washing. The formulation of claim 1, wherein the formulation has an initial viscosity prior to skin application of about 100 to about 3,000,000 centipoise. The formulation of claim 1, wherein the formulation has an initial viscosity prior to skin application of about 1,000 to about 1,000,000 centipoise. The formulation of claim 1, wherein the weight percentage of the volatile solvent system is from about 10 wt% to about 85 wt%. The formulation of claim 1, wherein the weight percentage of the volatile solvent system is from about 20 wt% to about 50 wt%. The formulation of claim 1, wherein the non-volatile solvent system comprises a plurality of non-volatile solvents, and at least one of the non-volatile solvents improves the compatibility of the non-volatile solvent system with the solidifying agent. The formulation of claim 1, wherein the solidified layer is cohesive, flexible and continuous. The solidified layer according to claim 1, wherein the solidified layer is a soft cohesive solid that, when formed, can be peeled from the skin surface as a single piece of application size or as just a few large pieces. Formulation. The formulation of claim 1, wherein the solidified layer is a soft cohesive solid that can be removed by gentle washing upon formation. The formulation of claim 1, wherein the solidified layer is formulated to deliver the drug transdermally. The formulation of claim 1, wherein the dermatological condition is a bacterial infection, viral infection, fungal infection, alopecia, dermatitis, psoriasis, or photodamaged skin. A method for treating a dermatological condition comprising:
a) applying an adhesive solidifying formulation according to any one of claims 1 to 90 to the skin surface affected by the dermatological condition;
b) solidifying the formulation by at least partial evaporation of a volatile solvent system to form a soft, cohesive solidified layer on the skin surface; and c) duration at a therapeutically effective rate. Delivering the drug from the solidified layer to the infected skin site over the skin;
Including a method. 92. The method of claim 91, wherein the skin site is epidermal skin. 92. The method of claim 91, wherein the skin site is a mucosal site. 92. The method of claim 91, wherein the skin site is a nail having a fungal infection. 92. The method of claim 91, wherein the skin site is wound skin. 92. The method of claim 91, wherein the skin site is bed sores, skin lesions, or open sore. 92. The method of claim 91, wherein the applying step comprises applying the formulation at a thickness of about 0.01 mm to about 3 mm. 92. The method of claim 91, wherein the thickness of the formulation applied to the skin is between about 0.05 mm and about 3 mm. 92. The method of claim 91, wherein the applying step comprises applying the formulation at a thickness of about 0.05 mm to about 1 mm. 92. The method of claim 91, wherein the formulation is applied to the skin of a subject within 1 hour of sleep and removed within 1 hour of waking up. 92. The method of claim 91, wherein the formulation is applied to the skin of a subject after waking up and removed before sleeping. 92. The method of claim 91, wherein the solidified layer is left on the skin surface for at least 2 hours after formation of the solidified layer. 92. The method of claim 91, wherein the solidified layer is left on the skin surface for at least 12 hours after formation of the solidified layer. 92. The method of claim 91, wherein the formulation is applied in combination with sunscreen, either applied separately or included in the formulation. 92. The method of claim 91, wherein the dermatological condition is alopecia and the human skin covered by the formulation has an area of 100 cm < ² > or less. 92. The method of claim 91, wherein the dermatological condition is alopecia and the human skin covered by the formulation has an area of 20 cm < ² > or less. 92. The method of claim 91, wherein application of the formulation comprises spraying the formulation onto the skin. 92. The method of claim 91, wherein the dermatological condition is dermatosis or psoriasis and the skin surface is palm skin. 92. The method of claim 91, wherein the dermatological condition is a bacterial infection, a viral infection, a fungal infection, alopecia, dermatitis, psoriasis, photodamaged skin, and combinations thereof. A flexible cohesive solidified layer for treating dermatological conditions,
a) drugs for treating dermatological conditions;
b) a non-volatile solvent system comprising at least one non-volatile solvent, the non-volatile solvent system facilitating delivery of the drug over time at a therapeutically effective rate; and c) Solidifying agent;
Including
The solidified layer can adhere to the skin surface to which the layer is applied;
Solidified layer. 111. The solidified layer of claim 110, wherein the non-volatile solvent system acts as a plasticizer for the solidifying agent. 111. The solidified layer of claim 110, wherein the non-volatile solvent system is fluxable for the drug. 111. The solidified layer of claim 110, wherein the solidified layer is sufficiently adhesive and flexible to remain substantially intact on a standard skin surface under standard test conditions for at least about 2 hours. 111. The solidified layer of claim 110, wherein the solidified layer can extend in at least one direction by 5% without breaking or separating from the skin surface. 111. The solidified layer of claim 110, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.5: 1 to about 2: 1. 111. The solidified layer of claim 110, wherein the solidified layer is removable by washing with water, a surfactant, an alcohol solvent, or a combination thereof. 111. The solidified layer according to claim 110, wherein the solidified layer is a peel and can be removed by peeling from the skin surface as a single piece or a few large pieces for the application size. 111. The solidified layer of claim 110, wherein the solidified layer is fluxable for the drug. 111. The solidified layer of claim 110, wherein the solidified layer is adhesive to the skin surface at one surface and non-adhesive at the opposite surface. 110. In claim 110, wherein the solidified layer is formulated to deliver a majority of the drug that is then skin deliverable while substantially devoid of water and any solvent more volatile than water. The solidified layer described. 111. The solidified layer of claim 110, wherein the dermatological condition is a bacterial infection, viral infection, fungal infection, alopecia, dermatitis, psoriasis, or photodamaged skin.

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