HK1117029A - Transdermal method and patch for nausea - Google Patents

Description

Transdermal method and patch for treating nausea

Related citations

This application claims priority from the following U.S. patent applications: 11/380,268, application date 2006, 26/4/60/682,251, 2005, 18/5/2005, 60/702,744, 7/27/2005, 60/759,381, 2006, 1/17/2006.

Technical Field

The present application relates to transdermal devices and methods for treating nausea and vomiting, and more particularly to devices and methods involving 5-HT₃Transdermal methods, compositions and devices for receptor antagonists for the treatment of nausea and vomiting over a sustained period.

Background

Most patients undergoing anti-cancer therapy, whether chemotherapy or radiation therapy, are afflicted with common complaints among patients of side effects of the treatment, such as nausea and vomiting. To prevent or minimize the side effects of these anticancer treatments, the administration of antagonists of 5-hydroxytryptamine subtype 3 (hereinafter referred to as "5-hydroxytryptamine"), e.g., referred to as 5-hydroxytryptamine antagonists or 5-HT, over multiple days in parenteral or oral form, is widely used₃Drugs of receptor antagonists: ondansetron, granisetron, tropisetron, dolasetron, hydrogenated dolasetron, azasetron, ramosetron, lerisetron, lisisetron, itasetron, palonosetron, lamosetron, alosetron, and mixtures thereof.

Nausea and vomiting may also be caused by other causes, such as post-operative, by motion sickness, or by side effects from other medications taken by the patient. Examples of drugs that can cause nausea and vomiting side effects are certain antibacterial and antiviral agents, biologically active agents that control glucose levels, such as insulin and rat amylin (amylin) or their natural and synthetic analogs, alpha-glucosidase (glucodase) inhibitors, sulfonylureas, meglitinides, thiazolidinone compounds (thiazolididinones), biguanides (biguanides), dual PPAR alpha/gamma agonists, PPAR gamma agonists, and insulin secretagogues.

In any case where the patient experiences nausea and vomiting, oral administration of an antiemetic is difficult and the patient experiences more discomfort. Intravenous (IV) or Intramuscular (IM) administration is not generally practical for home use. While these routes of administration, oral, IM and IV, produce fluctuating plasma levels of the antiemetic agent, the oral, IM and IV doses given to the patient must be multiple doses over a period of time to achieve a continuous antiemetic effect. Also, because nausea and vomiting are difficult to reverse, prophylactic administration of antiemetics is most effective.

In order to solve these problems, attempts have been made to formulate an antiemetic composition in the form of a patch so that the antiemetic can be administered transdermally.

Attempts to develop transdermally administered antiemetics have presented other problems. For example, some penetration enhancers (e.g., terpenes) used in transdermal compositions can cause skin irritation. Alcohols that are often needed to stabilize antiemetics for transdermal administration can also be irritating to the skin. Also, due to the rapid depletion of alcohol, it is difficult to obtain a continuous delivery over several hours. When a transdermal composition consisting of a solution with low viscosity is used, the blood level of the drug is easily lowered below an effective level, thereby reducing the desired pharmacological effect.

Other attempts to transdermally administer antiemetics have included sophisticated application devices or techniques, such as supplemental energy to enhance transdermal penetration of the drug. Current techniques describing transdermal antiemetic treatments generally focus on mimicking oral or IV formulations to achieve therapeutic plasma levels. For typical delivery of such formulations, attempts have been made to maintain the stability of the active agent in the form of a salt of the drug. However, the salt forms of antiemetics have relatively low transdermal penetration and it is difficult to obtain therapeutic plasma levels over a sustained period. The use of the free base form is generally not contemplated because it may cause irritation or be unstable in formulation form.

Accordingly, it would be desirable to provide transdermal compositions of antiemetics that are easy to use, non-irritating to the skin, and can stay on the skin for 24 hours, 2 days, 3 days, or longer to continuously and effectively prevent, ameliorate, or treat nausea and vomiting. Also, while active penetration enhancers are used at moderate but significantly efficacious concentrations, it is possible to follow current teachings to formulate a patch that delivers an antiemetic agent over a fairly sustained period of time and maintains delivery at good blood levels even after removal of the composition.

Prolonged delivery to the blood has been reported, but transdermal delivery devices lacking a permeation enhancer have been used. See WO 2004/069141. According to the present invention, a significantly sustained delivery is obtained at a concentration of permeation enhancer that has significant efficacy. The lack of a penetration enhancer is taught in the' 141 application to limit instability and irritation. The same benefits are obtained with the teachings of the present invention, despite the use of moderate, but significantly efficacious concentrations of permeation enhancers.

Disclosure of Invention

In one embodiment, a method is provided for treating acute, delayed or anticipatory emesis for a sustained period in an individual, the method comprising: applying to partially intact skin or mucosa of an individual for 24 hours or more a composition comprising:

i. an antiemetically effective amount of 5-HT₃A receptor antagonist;

a penetration enhancing amount of a penetration enhancer comprising 0.5% to 15% by weight of the skin contact layer; and

(ii) a binder,

wherein a therapeutically effective range of 5-HT from the start to 12 hours or more after removal of the composition is provided₃Plasma concentration of the receptor antagonist. In some embodiments, 12 hours or more after removal of the composition, a second of the compositions is applied, wherein a therapeutically effective range of 5-HT from the start to 12 hours or more after removal of the second composition is provided₃Plasma concentration of the receptor antagonist.

In some embodiments, 5-HT₃The receptor antagonist is administered with other antiemetics or the same formulation in a different administration form.

Also provided is a composition for transdermal administration of an antiemetic comprising: a skin contact composition comprising:

i. an antiemetically effective amount of 5-HT₃A receptor antagonist; a penetration enhancing amount of a penetration enhancer;

comprising from 0.5% to 15% by weight of a skin contact layer; and

(ii) a binder,

wherein, after being applied to partially intact skin of an individual for 24 hours (or more) and then removed, the composition provides the individual with a therapeutically effective range of 5-HT from the onset to 12 hours or more after removal of the composition₃Plasma concentration of the receptor antagonist.

Further provided is a device comprising a patch for transdermal prevention, amelioration or treatment of nausea and vomiting in an individual, the device comprising:

(a) a support layer; and (b) a skin contact layer comprising:

i. an antiemetically effective amount of 5-HT₃A receptor antagonist;

a penetration enhancing amount of a penetration enhancer comprising 0.5% to 15% by weight of the skin contact layer; and

(ii) a binder,

wherein, after being applied to partially intact skin of an individual for 24 hours (or more) and then removed, the device provides the individual with 5-HT within a therapeutically effective range from the onset to 12 hours or more after removal of the composition₃Plasma concentration of the receptor antagonist.

Drawings

FIG. 1 is a graph of the in vitro flow of granisetron (granisetron) through human cadaver skin using an embodiment of the device of the invention;

FIG. 2 is a graph of in vitro cumulative delivery of granisetron (granisetron) through human cadaver skin using an embodiment of the device of the invention;

figure 3 shows the pharmacokinetic profile obtained using the device of the invention.

Detailed Description

The term "5-HT" as used herein₃Receptor antagonists "refers to any class of drugs that act as 5-hydroxytryptamine receptor antagonists to provide anti-nausea and anti-vomiting effects in an individual.

The term "antiemetic" as used herein refers to the prevention, amelioration, or treatment of nausea and vomiting in an individual.

The term "antiemetic agent" as used herein refers to a drug or material used to prevent, ameliorate, or treat nausea and vomiting in an individual.

The term "antiemetically effective amount" as used herein refers to a dose or blood level (depending on context) of an antiemetic agent that provides relief (including improvement) of nausea and vomiting in an individual. Where blood levels are considered, such levels, if well maintained, would provide relief (including improvement) of nausea and vomiting in an individual. The effective amount is an amount expected to be effective in the target patient/subject population and may be reasonably divided into multiple deliveries by the delivery device or delivery medium.

The term "individual" as used herein refers to a living mammal, including but not limited to humans or other primates, domestic and wild animals such as cows, pigs and horses, and pets such as cats and dogs.

The term "initially" as used herein means that an antiemetically effective amount is obtained in the blood of an individual after application of the transdermal device or composition to the individual.

The term "penetration enhancement" as used herein refers to an increase in the permeability of the skin to a therapeutic agent in the presence of a penetration enhancer, relative to the permeability of the skin to a therapeutic agent in the absence of the penetration enhancer.

The term "permeation enhancer" as used herein refers to a formulation or mixture of formulations that acts to increase the permeability of the skin to a therapeutic formulation.

The term "permeation enhancing amount" as used herein refers to the amount of permeation enhancer that provides permeation enhancement over a comparable period of administration.

The term "partially intact skin" as used herein refers to a defined area of intact skin or mucosal tissue that is not damaged. This area is typically around 5cm²To about 100cm²The range of (1).

The term "salt" as used herein means, without limitation, a pharmaceutically acceptable organic or inorganic salt. Typical inorganic salts include hydrogen halides such as hydrochlorides, carbonates, phosphates, sulfates, bisulfates, hydrobromides, nitrates and sulfides. Organic salts include, but are not limited to: acid addition salts, including monocarboxylates and polycarboxylic acids such as acetic acid, malic acid, maleic acid, propionic acid, succinic acid, fumaric acid, citric acid, benzoic acid, cinnamic acid, tartaric acid, and the like.

The term "sustained period" as used herein refers to a period of about 24 hours or more, and generally refers to a period ranging from about 48 or 72 hours to 168 hours.

The term "transdermal" as used herein refers to transdermal or transmucosal administration, i.e., the passage of a drug, such as an antiemetic, through a body surface or membrane, e.g., intact skin or intact mucosal tissue, into the circulatory system.

The term "transcutaneous device wear time" or "patch wear time" as used herein refers to the time interval during which a transcutaneous device is retained on a skin or mucosal portion of an individual.

The term "percutaneously absorbable" as used herein refers to the ability of a drug to pass through a body surface or membrane, such as intact skin or mucosal tissue, into the circulatory system when formulated in a transdermal device of the present invention.

The term "acute nausea and vomiting" as used herein refers to nausea and vomiting in an individual that persists for up to 24 hours after the individual has received chemotherapy, radiation therapy or drug therapy. This may also be postoperative nausea and vomiting, as well as nausea and vomiting caused by nausea and dizziness due to motion sickness.

The term "delayed nausea and vomiting" as used herein refers to nausea and vomiting in an individual up to five (5) days after the individual has received chemotherapy, radiation therapy, surgery or drug treatment.

The term "expected nausea and vomiting" as used herein relates to the conditioned response of an individual after receiving chemotherapy, radiation therapy or drug therapy if the individual is expected to experience nausea and vomiting resulting from the therapy or if the individual has previously experienced nausea and vomiting resulting from the therapy. The expected nausea and vomiting may also be experienced post-operatively or caused by nausea and dizziness caused by motion sickness.

The term "skin contact layer" as used herein is a layer of a transdermal device for contacting the skin or mucosa.

The term "flow rate" as used herein refers to the rate at which the device is applied to a simulation of human cadaver skin.

The present invention relates to methods of preventing, ameliorating or treating nausea and vomiting for a sustained period by transdermal administration of an antiemetic agent. The antiemetic agent for use in the present invention is 5-HT in free base form when placed in a transdermal device₃Examples of receptor antagonists include ondansetron (ondansetron), granisetron (granisetron), tropisetron (tropisetron), dolasetron (dolasetron), hydrogenated dolasetron (hydolasetron), azasetron (azasetron), ramosetron (ramosetron), lerisetron (lerisetron), indisetron (indisetron), itasetron (itasetron), palonosetron (palonosetron), lamosetron (lamosetron), and alosetron (alloetron), and mixtures thereof. It will be appreciated that upon administration of the antagonist, a salt or metabolite will be formed that is similar to the salt form formed or administered by administration of the other administration form. The invention also relates to devices and compositions for use with the methods of the invention.

The present invention is effective in preventing, ameliorating or treating nausea and vomiting caused by chemotherapy, radiotherapy, other medications, by motion sickness, or by post-operative reactions. Since the method includes transdermal administration of an antiemetic agent over multiple days, nausea and vomiting can be effectively prevented, ameliorated or treated for an extended period of time. Other benefits of the present invention include the following: because the method includes placing the percutaneous device in place in certain embodiments for 2, 3, 4, 5, 6, 7 days or more, patient compliance is improved; the patient is protected against nausea and vomiting from the start of application of the device until it is removed, or for an extended period of time after removal, e.g. 6, 9, 12, 18 or 24 hours or more; this increases patient confidence in leaving the hospital or doctor's office after chemotherapy, as the device is known to prevent or reduce nausea and vomiting. Furthermore, it may maintain the blood level of the antiemetic agent within a therapeutically effective range until the device is removed. In some embodiments, after carrying the device for 24 hours or more (36 hours or more, or 48 hours or more, or 72 hours or more), the blood level will remain in a therapeutically effective range for an extended period after removal of the device, e.g., 6, 9, 12, 18, or 24 hours or more. Because the device delivers the antiemetic agent at a controlled rate, when the agent is administered (e.g., by IV), there is no initial peak plasma concentration; thus, the method reduces side effects such as headache and constipation that sometimes occur with other forms of administration.

In certain embodiments, 5-HT₃Therapeutically effective blood levels of the receptor antagonist are obtained within 24 hours, 18 hours, 12 hours, or 9 hours, or 8 hours, or 7 hours, or 6 hours after administration. Such a start period will be based on 5-HT₃The receptor antagonist and the particular skin contact layer formulation will vary.

In some embodiments, after an onset period, the patch provides 1 μ g/cm²/hr or higher (e.g., 1-25. mu.g/cm)²Hr) of 5-HT₃The receptor antagonist is administered at a flow rate of 24 hours or more, 48 hours or more, or 72 hours or more, or 96 hours or more, or 120 hours or more, or 144 hours or more, or 168 hours or more. In some embodiments, after an onset period, the patch provides 2 μ g/cm²/hr or higher (e.g., 2-10. mu.g/cm)²Hr) of 5-HT₃The receptor antagonist is administered at a flow rate of 24 hours or more, 48 hours or more, or 72 hours or more, or 96 hours or more, or 120 hours or more, or 144 hours or more, or 168 hours or more.

In some embodiments, the patch is delivering 10 μ g/day (micro-g/day) to the subject from the beginning period to 24 hours or more, 48 hours or more, or 72 hours or more, or 96 hours or more, or 120 hours or more, or 144 hours or more, or 168 hours or moreG/day) or more (e.g., 10-10,000. mu.g/day)₃A receptor antagonist. In some embodiments, the patch delivers 20 μ g/day (microgram/day) or more, 50 μ g/day or more, 100 μ g/day or more, 200 μ g/day or more, 500 μ g/day or more, 1,000 μ g/day or more, 2,000 μ g/day or more, 4,000 μ g/day or more, 6,000 μ g/day or more of 5-HT to a subject from the beginning to 24 hours or more, 48 hours or more, 72 hours or more, or 96 hours or more, or 120 hours or more, or 144 hours or more, or 168 hours or more₃A receptor antagonist. It should be recognized that the amount delivered will vary with 5-HT₃Receptor antagonists. For example, the need for the amount of ondansetron may be higher than the need for granisetron.

The permeation enhancer used in the device of the present invention may function to increase 5-HT in the skin-to-skin contact layer₃Permeability of receptor antagonists. In general, the greater the amount of permeation enhancer, the greater the increase in permeability of the skin; however, at higher amounts of penetration enhancer, cold flow of the adhesive may also occur, requiring premature removal of the transdermal patch. "cold flow" is the phenomenon of stored material flowing down its mat or the like. In addition, at higher amounts of penetration enhancer, 5-HT₃The receptor antagonist may crystallize from the matrix, thereby limiting its permeability. Thus, it is desirable to use an amount of permeation enhancer that reliably enhances the permeability of the drug while still limiting or preventing cold flow of the binder and crystallization of the drug. In one embodiment of the device of the present invention, the amount of permeation enhancer is 15% or less (or about 14% or less, or about 13% or less, or about 12% or less, or about 11% or less, or about 10% or less, or about 9% or less) by weight of the skin contact layer (or composition) to increase the permeability of the drug without causing significant cold flow of the adhesive and crystallization of the drug. The permeation enhancer is present in a permeation enhancing amount. The permeation enhancer may be present at about 0.5% or more (or about 1% or more, or about 2% or more, or about 3% or more, or about 4% or more, orAbout 5% or more, or about 7% or more).

Changeable 5-HT₃The amount of receptor antagonist, for example, varies from one of the lower limits (limits excluding or including the endpoints) or from one of the upper limits (excluding or including) described below. The lower limit is 0.1%, 0.2%, 0.5%, 1%, 2%, 3% or 4% based on the weight of the skin contact layer or composition. The upper limit is 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7% or 6% based on the weight of the skin contact layer or composition. And, these amounts may further be dependent on the particular 5-HT₃Receptor antagonists.

One embodiment of the device of the present invention is a transdermal patch that is applied to the skin or mucosa of an individual. The patch has a skin or mucosa contact layer (simply referred to as "skin contact layer") laminated or otherwise attached to a support layer. Typically, the skin contact layer is covered with a release liner that is removable prior to use to protect the skin contact surface and keep it clean prior to application to the skin or mucosa.

The support layer serves to support the skin contact layer and to provide a barrier layer that prevents the drug in the skin contact layer from being lost to the environment. The material selected for such a support should be compatible with the adhesive, drug, permeation enhancer, and should minimally penetrate any patch components. The support may be opaque so as to protect the components of the matrix patch from degradation by exposure to ultraviolet light. In addition, the support should be capable of bonding to or supporting the adhesive layer, and should be flexible to accommodate the movements of the person using the patch. Suitable materials for use as a carrier include metal foils, metallized polymeric films, composite foils or films comprising polyesters such as polyester terephthalate, polyester or aluminum alloy polyesters, polytetrafluoroethylene, polyether block amide copolymers, polyethylene methyl methacrylate block copolymers, polyurethanes, polyvinylidene chloride, nylon, silicone elastomers, rubber-based polyisobutylene, styrene-butadiene and styrene-isoprene copolymers, polyethylene and polypropylene. A thickness of about 0.0005-0.01 inch, for example, may be used. The release liner may be made of the same material as the carrier or other suitable film coated with a suitable release surface.

If present, the penetration enhancer is typically of chain length C₁₂-C₁₈Fatty acid esters of fatty acyl groups of (a). The alcohol moiety in the ester is typically C₁-C₆Or C₂-C₄Such as isopropyl alcohol.

The patch may further comprise various additives other than adhesives, antiemetics, and penetration enhancers. These additives are generally those pharmaceutically acceptable ingredients known in the art of drug delivery, particularly transdermal drug delivery. Non-limiting additive ingredients include diluents, excipients, emollients, plasticizers, skin irritation reducing agents (which may also include agents that reduce mucosal irritation), carriers, and mixtures thereof. For example, suitable diluents may include mineral oil, low molecular weight polymers, plasticizers, and the like. Many transdermal drug formulations are prone to irritation after prolonged exposure to the skin or mucosa, and therefore additional irritation reducing agents are needed to help achieve a more tolerable composition to the skin or mucosa.

For delivery of an antiemetic agent according to embodiments of the present invention, a binder, 5-HT will be included₃The patch device of receptor antagonist, and permeation enhancer is contacted with the skin or mucosa intact at the selected site and adhered thereto by the adhesive.

In certain embodiments, the transdermal composition (prior to application to a patient) is substantially free of water. In certain embodiments, the transdermal compositions are substantially free of tetraethylene glycol (also known as glycofurol or tetrahydrofurfuryl polyethylene glycol ether). in certain embodiments, the transdermal compositions are substantially free of hydrophilic organic solvents, including substantially free of ethanol, isopropanol, butanol, benzyl alcohol, propylene glycol, glycerol, polyethylene glycols having a molecular weight of 600 or less, diethylene glycol monoethyl ether, triacetin, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, decylmethyl sulfoxide, dioxygen sulfoxide, and mixtures thereofA heterocyclic ethane, a lactone, or a mixture thereof. Within the aforementioned limits, the term "hydrophilic organic solvent" does not include chain lengths C₁₂-C₁₈Fatty acid esters of fatty acyl groups of (a). It will be appreciated that when the transdermal composition is substantially free of such ingredients, such ingredients may still be present in an insignificant amount consistent with the process parameters, but in an amount that does not significantly affect function, handling, storage, or other factors important to the effective use or marketing of the transdermal device.

In another embodiment of the invention, a method is provided for preventing, ameliorating or treating nausea and vomiting caused by chemotherapy, radiation therapy, other drug treatment, by motion sickness, or post-operative response by transdermally administering 5-HT₃Receptor antagonists in combination with another antiemetic agent (e.g. a corticosteroid) administered (e.g. orally, by injection (e.g. IV, IP, IM, SC) transdermally, buccally, rectally) or by the same 5-HT route of administration as a separate route of administration₃A receptor antagonist. The second administration form may be administered according to a separate administration plan appropriate for the dosage form administered.

It is known that 5-HT can be administered simultaneously₃Receptor antagonists and corticosteroids. For example, US5,929,059(Sanger et al) discloses a method of treating and/or preventing nausea and vomiting comprising administering granisetron and a steroid, such as dexamethasone or a pharmaceutically acceptable salt or ester thereof, to a human or animal subject. Sanger et al further discloses that the two ingredients can be administered orally, rectally, parenterally or buccally, with oral administration being preferred.

However, as described earlier, oral administration of antiemetic compounds is challenging and can cause more discomfort to the patient. Furthermore, the oral, IV, IM, rectal, buccal administration of the active ingredient produces fluctuations in the plasma levels of the active ingredient. Thus, 5-HT is administered transdermally₃Receptor antagonists to prevent, ameliorate or treat nausea and vomiting, followed by administration of an antiemetically effective amount of an antiemetic corticosteroid to potentiate 5-HT₃The antiemetic properties of receptor antagonists would be advantageous. Antiemetic cortexSteroid administration 5-HT may be administered initially transdermally₃Simultaneous onset of receptor antagonist, or 5-HT₃The receptor antagonist has been administered transdermally for 1 hour or more, 12 hours or more, or 24 hours or more. Administration may be for 12 hours or more, or 24 hours or more, 48 hours or more, 72 hours or more, 96 hours or more, 120 hours or more, 144 hours or more, or 168 hours or more. Administration of the corticosteroid can be in a single dose, or additional doses can be administered at selected intervals. Useful routes of administration are, for example, oral or parenteral routes.

Antiemetic corticosteroids suitable for use in embodiments of the present invention may include, for example, dexamethasone, methyl dehydrocortisol, physiologically acceptable salts or esters thereof, or combinations thereof. Dexamethasone can be administered in the form of dexamethasone alcohol or a pharmaceutically acceptable salt or ester. Suitable salts and esters include acetate, isonicotinate, phenylpropionate, pivalate, t-butyl acetate, trioxaundecanoate, disodium metabisulphonate, and disodium hydrogenphosphate.

The dosage of steroids such as dexamethasone employed in accordance with this embodiment of the invention may be in the range of, for example, 0.5 to 20mg per dosage unit. The unit dose may be administered 1-4 times per day. The exact dosage will, however, depend on the route of administration and the condition to be treated and it will therefore be understood that routine variations will be necessary depending on the age and weight of the patient and the nature and severity of the condition to be treated.

Compositions for oral administration of dexamethasone, such as tablets and capsules, can be formulated with pharmaceutically acceptable excipients, such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch, or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate) by conventional methods. The tablets may be coated by methods known in the art. Liquid formulations for oral administration may take such forms as solutions, slurries, or suspensions, or they may be presented as a dry product and constructed with water or other suitable vehicle prior to use. Such liquid preparations may be prepared by conventional means from pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, or fractionated vegetable oils); and preservatives (e.g. parabens or parabens, or sorbic acid). The formulations may also suitably contain buffer salts, flavouring agents, colouring agents and sweetening agents.

Orally administered formulations of corticosteroids may be suitably formulated in a form that provides controlled release of the active ingredient.

For parenteral administration, the compositions may be in a form suitable for bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in syringes, ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In addition, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In some embodiments of the present invention, a transdermal patch having a skin contact layer comprises:

i. an antiemetically effective amount of 5-HT in free base form₃A receptor antagonist;

a penetration enhancing amount of a penetration enhancer selected from the group consisting of isopropyl myristate, isopropyl palmitate and chain length C₁₂-C₁₈Fatty acid esters of fatty acyl groups of (a); and

an adhesive selected from the group consisting of acrylic resins (including alkyl acrylic resins), vinyl acetates, natural and synthetic rubbers, ethylene vinyl acetate copolymers, polysiloxanes, polyacrylates, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene-butadiene rubber block copolymers, and mixtures thereof;

it is applied to the skin or mucosa of an individual in need of anti-emetic treatment or prevention. Then, administering an antiemetically effective amount of a systemic corticosteroid to the oral cavity of the subject to enhance 5-HT₃Antiemetic effects of receptor antagonists.

In a further embodiment, the transdermal device is provided with a systemic corticosteroid, such as dexamethasone, in the form of a kit.

In another embodiment, the invention provides methods for preventing, ameliorating (including ameliorating symptoms resulting from prophylactic administration), or treating nausea and vomiting caused by chemotherapy, radiation therapy, other drug therapy, by motion sickness, or by post-operative reactions by transdermal administration of 5-HT₃A receptor antagonist in combination with an antiemetic agent for oral administration or for injection. The antiemetic agent is selected from 5-HT₃Receptor antagonists, cannabinoids, NK1 receptor antagonists, dopamine antagonists, corticosteroids, or any other known antiemetic agent. In some embodiments, the antiemetic agent is administered to the individual while the transdermal device is applied to the individual's skin. In other embodiments, additional antiemetics may be administered at selected times to provide initial delivery to the plasma during the lag phase of transdermal administration.

In one embodiment, the transdermal device is provided in the form of a kit along with an antiemetic agent. In a further embodiment, the kit includes a label describing administration of the antiemetic agent to the individual at about the same time as the transdermal device is applied to the individual's skin. Examples of the second component include dosage forms containing an antiemetic agent that is the same as or separate from the antiemetic agent in the first transdermal device. The second dosage form can be, e.g., administration orally, by injection (e.g., IV, IP, IM, SC), transdermally, buccally, rectally, etc.

In another embodiment, the transcutaneous device may be applied to the skin of the individual up to 24 hours before the individual is subjected to an event which may lead to a risk of emesis. Such events include administration of pharmaceutical compounds that pose a risk of emesis, such as chemotherapeutic agents used in anti-cancer therapies, and surgery or other pharmaceutical procedures that pose a risk of emesis. In further embodiments, the transdermal device is applied to the skin of the individual 0.5 hours or more (1 hour or more, or 2 hours or more, or 4 hours or more, or 8 hours or more, or 10 hours or more, or 12 hours or more) before the individual is subjected to an event that can lead to a risk of emesis.

In other suitable devices for long-term delivery of granisetron (granisetron) to a transdermal device, the long-term delivery is achieved by avoiding the use of permeation enhancers. The present invention provides a device comprising the enhancement agent, yet provides long-term delivery while avoiding irritation and instability that may be associated with the enhancement agent. Also, in certain embodiments, the present devices provide better transdermal delivery to plasma, as measured by peak plasma levels or AUC (area under the curve), on a device area normalized basis, than corresponding devices without permeation enhancers. In some embodiments, the value measured 24, 48, 72, 96, or 120 hours after such delivery to the application device is 1.5 times or more, or 1.7 times or more, or 2 times or more.

Example 1: preparation of adhesive mixtures and transdermal delivery devices

Table 1:

composition comprising a metal oxide and a metal oxide	Formulation A	Formulation B
			Size of patch	15.0cm2	15.0cm2
Predicted target daily dose	1.2mg	1.2mg
				Dried%	Dried%
Styrene-butadiene rubber pressure sensitive adhesive	44.04	--
			Acrylate-vinyl acetate pressure sensitive adhesives	--	43.8
Isopropyl myristate	3.01	4.07
			Granisetron base	3.05	3.05
Polyester release liner	35.8	35.8
			Polyester cushion	13.3	13.3

Components

Formulations a and B were prepared using the amounts of the components in table 1 above.

The styrene-butadiene rubber pressure sensitive adhesive used in this example was DURO-TAK ® 87-6173 adhesive available from National Starch and Chemical of Bridgewater, NJ. The acrylate-vinyl acetate pressure sensitive adhesive used in this example was DURO-TAK ® 87-2516 adhesive available from National Starch and Chemical of Bridgewater, NJ. The isopropyl myristate used in this example was NF grade. The polyester release liner used in this example is available from Loparex, inc, while the polyester mat used in this example is available from 3M 2610F.

Step (ii) of

Granisetron base is dissolved in a suitable solvent, such as toluene, and mixed with the selected binder. Then, isopropyl myristate was added to the mixture, and the ingredients were mixed until a homogeneous solution was obtained.

The homogeneous solution was coated onto the siliconized surface of the polyester release liner to obtain the desired thickness. The coated release liner is then passed through a drying oven until the solvent evaporates. The dried adhesive coated release liner was removed from the oven and laminated with a polyester cushion. The multi-layered laminate is cut into die-cut units of desired size and shape for delivery of the desired target dose, or may be wound into rolls for storage or transport elsewhere. The rolled laminate may then be opened and cut into die cut units of the desired size and shape. These die cut units are then placed into individual packages and sealed for later use as patches.

Stimulation data

No irritation or toxicity was found by the irritation test in rabbits, sensitivity test in guinea pigs, toxicology in dogs and irritation test in humans with formulation A.

Example 2: flow testing of granisetron base from transdermal delivery devices

Step (ii) of

The heat-separated human cadaver skin was cut to the desired size and mounted on Franz diffusion cells. The release liner was peeled from a patch prepared according to formulation B described in example 1 above. The patch is placed on the skin and the patch and skin are pressed together. Receptor solution was added to the diffusing cells and assembly was maintained at 32 ℃. The measured amounts of receptor solution were removed periodically (24 hours, 48 hours, 72 hours, 96 hours, and 120 hours). The granisetron concentration in the receptor solution at each time was measured and the flow rates in samples a and B were calculated. The resulting data are shown in figure 1. Similarly, the cumulative granisetron delivery over the indicated time is calculated from the granisetron concentration in the receptor solution at each time and is shown in fig. 2.

Example 3: stability of granisetron in the example embodiments

Table 2:

composition comprising a metal oxide and a metal oxide	Formulation C	Formulation D
				Dried%	Dried%
Styrene-butadiene rubber pressure sensitive adhesive	49.88％	-
			Acrylate-vinyl acetate pressure sensitive adhesives	-	43.77％
Isopropyl myristate	-	5.09％
			Granisetron base*	1.02％	2.04％
Polyester release liner	35.8％	35.8％
			Polyester cushion	13.3％	13.3％

Using the formulation in Table 2, a patch was prepared according to the procedure described in example 1. The patch was then tested for stability of granisetron using the method described below.

The patch samples were stored at 50 ℃ for 2 months. Product stability was evaluated by periodically testing granisetron content and total impurities using high performance liquid chromatography. The results are shown in table 3 below.

Table 3:

time of day	Granisetron potency (% w/w)		Total impurities (% granisetron)
						Formulation C	Formulation D	Formulation C	Formulation D
T0	99.9	99.5	0.05	0.25
					51 month at 0 DEG C	99.8	99.2	0.12	0.41
2 months at 50 DEG C	99.6	98.4	0.19	0.81

The data in Table 3 show that granisetron remains stable at 50 ℃ for at least 2 months in the compositions of the examples of the invention, relative to the time of onset T₀The formulation of (a) has only a small loss of potency and a small amount of impurities.

Example 4: samples for in vivo testing

Using the ingredients in Table 4 and the corresponding amounts, patches were made according to the method described above.

ingredient/Components	Weight (mg/cm)2)	% (composition)	Wt (mg/25 cm) in the final product2Paster)
				Granisetron base isopropyl myristate	0.751.20	2.544.06	18.7530.00

Acrylic adhesive	13.05	44.13	326.25
				Total of	15.00	50.73	375.00
Polyester pad release liner	3.9110.66	13.2236.05	97.75266.50
				Total weight of	29.57	100.00	739.25

The acrylic adhesive used in example 4 was DURO-TAK ® 87-2516 available from National Starch and Chemical of Bridgewater, NJ.

A randomized crossover clinical study was performed in 11 individuals who received either transdermal patches or IV granisetron solution. Each 25cm²The patches were all formulated to deliver 2 mg/day of granisetron. 25cm in example 4²The patch of (a) was attached to the skin of the individual and left for 96 hours and then removed. The same individuals who received granisetron IV at a once daily dose of 2 mg/day were eluted 10 days thereafter. Individuals who received IV therapy during the first session received a transdermal patch in a cross-treatment. Plasma levels of granisetron for all individuals in the test were measured periodically over a 96 hour period during which the patch was worn and an IV dose was administered, with IV administration being stopped two days after removal of the patch.

The results (fig. 3A) indicate that individuals receiving IV granisetron experienced peak plasma levels of granisetron after each daily dose administration, and that plasma levels decreased very rapidly. In another aspect, the plasma level of granisetron in a subject using the patch is steadily increased to a plateau and maintained on the plateau for up to 96 hours before removal of the patch, at which time the plasma level slowly steadily decreases but remains within the therapeutically effective range for at least 24 hours after removal of the patch. Typical plasma levels of granisetron observed throughout the depletion period and for two additional days after patch removal were in the range of 0.1-25 ng/ml. Thus, the patch of the present embodiment provides plasma levels within a therapeutically effective range over the entire patch wearing time and at least 24 hours after its removal.

All documents, including but not limited to patents and patent applications, cited in this specification are herein incorporated in their entirety into the present application as if each individual publication or document were specifically and individually indicated to be incorporated herein in its entirety. Any patent application that is the basis of priority of this application is also incorporated into this application as if it were the above disclosure and literature.

While the invention has been described with emphasis on certain embodiments, those skilled in the art will appreciate that variations in the preferred devices and methods may be employed and that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims.

Claims (34)

1. A method for treating acute, delayed or anticipatory emesis for a sustained period in an individual, the method comprising:

applying to an intact portion of skin or mucosa in an individual for 24 hours or more a composition comprising:

i. an antiemetically effective amount of 5-HT₃A receptor antagonist;

a penetration enhancing amount of a penetration enhancer comprising 0.5% to 15% by weight of the skin contact layer; and

(ii) a binder,

wherein a therapeutically effective range of 5-HT from the start to 12 hours or more after removal of the composition is provided₃Plasma concentration of the receptor antagonist.

2. The method of claim 1, wherein a second said composition is applied to an intact portion of skin or mucosa in the subject 12 hours or more after removal of the composition, wherein a therapeutically effective range of 5-HT is provided from the onset to 12 hours or more after removal of the second said composition₃Plasma concentration of the receptor antagonist.

3. The method of claim 1, further comprising administering an antiemetically effective amount of a corticosteroid.

4. The method of claim 3, wherein the corticosteroid is administered transdermally.

5. The method of claim 3, wherein the corticosteroid is administered orally or by injection.

6. The method of claim 1, further comprising administering an antiemetically effective amount of an antiemetic agent in the second dosage form.

7. The method of claim 1, wherein 5-hydroxytryptamine 5-HT₃The receptor antagonist is selected from the group consisting of ondansetron (ondansetron), granisetron (granisetron), tropisetron (tropisetron), dolasetron (dolasetron), hydrogenated dolasetron (hydolasetron), azasetron (azasetron), ramosetron (ramosetron), lerisetron (lerisetron), indisetron (indisetron), itasetron (itasetron), palonosetron (palosetron), lamosetron (lamosetron), alosetron (alloetron), and mixtures thereof.

8. The method of claim 1, which isMiddle, 5-HT₃The receptor antagonist is granisetron (granisetron).

9. The method of claim 8, further comprising administering an antiemetically effective amount of a corticosteroid.

10. The method of claim 1, wherein the permeation enhancer consists essentially of 15% or less by weight of the skin contact layer of chain length C₁₂-C₁₈Or a fatty acid ester of a fatty acyl group or a mixture thereof.

11. The method of claim 1 wherein the penetration enhancer consists essentially of 15% or less isopropyl myristate by weight of the skin contact layer.

12. The method of claim 1, further comprising the step of administering to the individual, in coordination with said application, a drug or process that causes a risk of emesis.

13. The method of claim 12, wherein said applying occurs prior to administration that results in said vomiting hazard.

14. A composition for transdermal administration of an antiemetic agent comprising: a skin contact composition comprising:

i. an antiemetically effective amount of 5-HT₃A receptor antagonist;

a penetration enhancing amount of a penetration enhancer comprising 0.5% to 15% by weight of the skin contact layer; and

(ii) a binder,

wherein, when removed after 24 hours of application to an intact portion of skin in an individual, the composition provides to the individual a therapeutically effective range of 5-HT from the onset to 12 hours or more after removal of the composition₃Plasma concentration of the receptor antagonist.

15. A device comprising a patch for transdermal prevention, amelioration or treatment of nausea and vomiting in an individual, the device comprising:

a. a support layer; and

b. a skin contact layer comprising:

i. an antiemetically effective amount of 5-HT₃A receptor antagonist;

a penetration enhancing amount of a penetration enhancer comprising 0.5% to 15% by weight of the skin contact layer; and

(ii) a binder,

wherein, when removed after 24 hours of application to an intact portion of skin in an individual, the device provides to the individual a therapeutically effective range of 5-HT from the start to 12 hours or more after removal of the device₃Plasma concentration of the receptor antagonist.

16. The device of claim 15, wherein, when removed after 48 hours of application to an intact portion of skin in an individual, the device provides the individual with a therapeutically effective range of 5-HT from onset to 12 hours or more after removal of the device₃Plasma concentration of the receptor antagonist.

17. The device of claim 15, wherein, when removed 72 hours after application to an intact portion of skin in an individual, the device provides the individual with a therapeutically effective range of 5-HT from onset to 12 hours or more after removal of the device₃Plasma concentration of the receptor antagonist.

18. The device of claim 15, wherein, when removed after 96 hours of application to an intact portion of skin in an individual, the device provides the individual with a therapeutically effective range of 5-HT from onset to 12 hours or more after removal of the device₃Plasma concentration of the receptor antagonist.

19. The device of claim 15, wherein 5-HT₃The receptor antagonist is in the form of a free base.

20. A kit comprising the device of claim 15, and a dosage form comprising an antiemetically effective amount of a corticosteroid.

21. The kit of claim 20, wherein the dosage form is for oral administration or injection of a corticosteroid.

22. The kit of claim 20, wherein the dosage form is for transdermal administration of a corticosteroid.

23. A kit comprising the device of claim 15 and a dosage form comprising an antiemetic form suitable for oral administration or injection.

24. The kit of claim 23, wherein the agent in dosage form is 5-HT₃Receptor antagonists, cannabinoids, NK1 receptor antagonists, dopamine antagonists, corticosteroids, or mixtures thereof.

25. The device of claim 15, wherein 5-HT₃The receptor antagonist is selected from the group consisting of ondansetron (ondansetron), granisetron (granisetron), tropisetron (tropisetron), dolasetron (dolasetron), hydrogenated dolasetron (hydolasetron), azasetron (azasetron), ramosetron (ramosetron), lerisetron (lerisetron), indisetron (indisetron), itasetron (itasetron), palonosetron (palosetron), lamosetron (lamosetron), alosetron (alloetron), or mixtures thereof.

26. The device of claim 15, wherein 5-HT₃The receptor antagonist is granisetron (granisetron).

27. The device of claim 26 wherein the antiemetically effective amount of granisetron comprises 0.1% to 15% by weight of the skin contact layer.

28. The device of claim 15, wherein the permeation enhancer consists essentially of 15% or less of the chain length C by weight of the skin contact layer₁₂-C₁₈Or a fatty acid ester of a fatty acyl group or a mixture thereof.

29. The device of claim 15, wherein the penetration enhancer consists essentially of 15% or less isopropyl myristate by weight of the skin contact layer.

30. The device of claim 15, further comprising packaging to display a label description for application of the device to the skin of an individual to fit one or both of the following (a) and (b): (a) administering to the individual a drug that creates a risk of emesis, or (b) performing an operation or other medical procedure to the individual that creates a risk of emesis.

31. The device of claim 30, wherein the label describes application of the device 30 minutes or more prior to application or implementation.

32. The device of claim 15, wherein the device provides 1-25 μ g/cm when applied to human cadaver skin for 168 hours or more²Flow rate of between 1 and 25 mug/cm²168 hours or more between/hr.

33. The device of claim 15, wherein the device delivers 10-10,000 μ g/day of 5-HT to the individual daily after the onset period when applied to an intact portion of skin for 168 hours in the individual₃A receptor antagonist.

34. The device of claim 15, wherein the device is applied to an intact portion of skin in an individual for 24-144 hours and removed, daily, within 12 hours after the initial period to the removalThe subject delivers 10-10,000 μ g/day of 5-HT₃A receptor antagonist.