HK40009000A

HK40009000A - Transdermal delivery system containing galantamine or salts thereof

Info

Publication number: HK40009000A
Application number: HK19132284.1A
Authority: HK
Inventors: Catherine Lee; Taijung WU
Original assignee: 泰合生技药品股份有限公司; 凯瑟琳‧李
Priority date: 2016-07-11
Filing date: 2017-07-10
Publication date: 2020-06-19

Description

Transdermal delivery system comprising galantamine or salts thereof

1. Summary of the invention

Disclosed herein is a transdermal delivery system comprising galantamine or a pharmaceutically acceptable salt thereof as an active ingredient. Also provided are methods of delivering a therapeutically effective amount of galantamine to a subject to treat a disease condition. Such disease conditions include neurological disorders, such as Alzheimer's disease. Kits comprising transdermal delivery systems and methods of making such delivery systems are also provided.

2. Background of the invention

Alzheimer's disease is reported to be the most common neurological disorder characterized by complex sensory disturbances such as loss of mental capacity, memory loss, mental deterioration, character changes and abnormal activities, and occurs mainly in the elderly. The average survival of such patients is reported to be about 8 years. Brookmeyer R, Corrada MM, Curriero FC, KawasC. Survival following a diagnosis of Alzheimer disease. Arch neuron 2002; 59(11):1764-7.

It has been reported that although the pathogenesis of alzheimer's disease has not been fully studied, it is known that the concentration of acetylcholine and acetylcholine transferase in the brain of dementia patients is reduced by about 16% to 30% compared to the concentration of acetylcholine (a neurotransmitter) and acetylcholine transferase (used to synthesize acetylcholine, Ach) in the brain of normal humans. Nordberg A and Svensson AL. Cholinester enzymes inhibitors in the treatment of Alzheimer's disease a company of 1{10403/005195-US0/01526624.1} together with drug Saf 1998; 19:465-480. One treatment approach recently investigated involves the inhibition of cholinesterases responsible for the hydrolysis of acetylcholine. By inhibiting cholinesterase, neurons are activated by increasing acetylcholine in the brain of a patient. Galantamine (trade name:) Donepezil (trade name:) And rivastigmine (trade name:) Is one of the cholinesterase inhibitors used.

Galantamine, a tertiary alkaloid, is reported to be an acetylcholinesterase inhibitor and is sold in tablets or liquid formulations for oral administration. It is useful for the treatment of mild to moderate symptoms of Alzheimer's disease. Giacobiini 2000: "Cholinesterase inhibitors stabilize Alzheimer disease", neurochemical research vol.25(9-10): 1185-. When administered orally, galantamine undergoes first pass metabolism and is believed to cause side effects such as abdominal pain, nausea, vomiting, diarrhea, and loss of appetite. See Reminyl product information, Razadyne product information.

It has been reported that galantamine, if administered as a transdermal delivery system, not only reduces these side effects associated with gastric disorders, but also provides benefits such as avoidance of first pass metabolism, improved bioavailability and regulated drug concentration in the plasma. U.S. patent No. 5,700,480 discloses a transdermal drug delivery system comprising a drug storage layer containing galantamine, a plasticizer and a polyacrylate (e.g., acrylate copolymer/methacrylate copolymer) as an adhesive. However, the transmittance (transmittance) of this system is as low as 2.7. mu.g/cm²And/hr. This low drug permeability is inefficient for delivering galantamine to patients for meaningful disease treatment.

Therefore, there is a need to develop an optimized galantamine formulation with high efficiency, increased drug loading capacity and drug release sustainability to improve the life of alzheimer's patients. The formulations disclosed herein help to eliminate or minimize the side effects associated with oral administration and achieve desirable skin permeation rates and adhesion properties. Galantamine and its pharmaceutically acceptable salts crystallize readily and generally have low permeability. In addition, galantamine and pharmaceutically acceptable salts thereof are rapidly degraded at room temperature and are easily oxidized in the formulation. It has been a challenge to provide a stable transdermal galantamine delivery system that does not have crystallization and oxidation problems and has an acceptably high drug permeation rate. It would be challenging to provide a transdermal galantamine delivery system that is stable, immune to crystallization and oxidation problems, and has acceptably high drug permeation rates.

3. Summary of the invention

It is an object of the present disclosure to provide methods and devices for transdermal delivery of galantamine or salts thereof as an active ingredient to a subject through the skin or other body surface.

The transdermal delivery system includes a backing layer, a drug-containing matrix layer, and a release liner. The subject may wear the device for an extended period of time without side effects.

Also disclosed is a transdermal system having improved drug and enhancer loading to provide the desired viscosity and adhesion. In one embodiment, the transdermal system includes a copolymer as the adhesive.

Further provided herein are drug delivery systems and methods for the controlled and sustained delivery of a therapeutic amount of galantamine or salts thereof to a subject. In certain embodiments, the drug delivery system comprises a matrix comprising galantamine or a salt thereof dispersed therein. In certain embodiments, the systems and methods include a matrix formed of a polymer and galantamine or salts thereof uniformly dispersed within the polymer.

In certain embodiments, provided herein is a transdermal delivery system comprising a drug-containing matrix layer comprising: (i) galantamine or a pharmaceutically acceptable salt thereof; (ii) a binder comprising an acrylic polymer free of functional groups or an acrylate-vinyl acetate polymer having at least one carboxyl functional group (COOH); (iii) an enhancer composition comprising: (a) oleic acid oleyl ester and oleic acid; or (b) oleic acid oil ester and propylene glycol and an antioxidant; or (c) a medium chain fatty acid triglyceride and an antioxidant.

In certain embodiments, the medium chain fatty acid triglyceride comprises about 50-80% caprylic acid and about 20-50% capric acid. In certain embodiments, the weight of the galantamine or pharmaceutically acceptable salt thereof is about 7 to about 14% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the galantamine or pharmaceutically acceptable salt thereof is about 7, about 8 or about 14% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the binder is about 75% to about 78% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the acrylic polymer has a glass transition temperature of about-15 ℃ to about-30 ℃. In certain embodiments, the compound is a compound of formula (I)The olefine acid polymer is Duro87-9301. In certain embodiments, the acrylate polymer has a glass transition temperature of about-30 ℃ to about-60 ℃. In certain embodiments, the vinyl acetate containing acrylate polymer is Duro387-2054. In certain embodiments, the medium chain fatty acid triglyceride is labrafac^TMLipophile WL 1349. In certain embodiments, the weight of the oleic acid comprises about 10% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the oleic acid oleyl ester comprises about 5% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the medium chain fatty acid triglyceride is about 10% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the medium chain fatty acid triglyceride is labrafac^TMLipophile WL 1349. In certain embodiments, the antioxidant is butylated hydroxytoluene. In certain embodiments, the weight of the antioxidant comprises about 0.05% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the drug-containing matrix layer has a thickness of about 20 μm to about 48 μm. In certain embodiments, the system has about 8-10 μ g/cm²hr of flux. In certain embodiments, the galantamine or pharmaceutically acceptable salt thereof is about 7-8% by weight, wherein the binder is about 78% by weight, wherein the oleic acid is about 10% by weight, wherein the oleyl oleate is about 5% by weight, based on the total weight of the drug-containing matrix layer, wherein the drug-containing matrix layer has a thickness of about 20-48 μ ι η.

In certain embodiments, provided herein are transdermal delivery systems comprising a drug-containing matrix layer comprising: (i) about 7-8% galantamine or a pharmaceutically acceptable salt thereof; (ii) an adhesive comprising an acrylic polymer free of functional groups; (iii) an enhancer composition comprising: (a) about 10% oleic acid and about 5% oleic acid oleyl ester, wherein the oil isThe dermal system has a thickness of about 20-48 μm. In certain embodiments, the adhesive has a glass transition temperature of about-15 ℃ to about-30 ℃. In certain embodiments, the binder is Duro87-9301。

In certain embodiments, provided herein are transdermal delivery systems comprising a drug-containing matrix layer comprising: (i) about 14% galantamine or a pharmaceutically acceptable salt thereof; (ii) a binder comprising an acrylate-vinyl acetate polymer having at least one functional group COOH; (iii) an enhancer composition comprising about 10% medium chain fatty acid triglycerides; (iv) about 0.05% antioxidant, wherein the transdermal system has a thickness of about 15-45 μm. In certain embodiments, the adhesive has a glass transition temperature of about-30 ℃ to about-60 ℃. In certain embodiments, the binder is Duro387-2054. In certain embodiments, the medium chain fatty acid triglyceride is labrafac^TMLipophile WL 1349. In certain embodiments, the antioxidant is butylated hydroxytoluene, vitamin E, ascorbyl palmitate, bronopol, erythorbic acid, thioglycerol, sodium metabisulfite, sodium sulfite, sulfur dioxide, sodium thiosulfate, or a combination thereof. In certain embodiments, the system has about 8 μ g/cm²hr of flux.

In certain embodiments, provided herein are transdermal delivery systems comprising a drug-containing matrix layer comprising: (i) about 14% galantamine or a pharmaceutically acceptable salt thereof; (ii) a binder comprising an acrylate-vinyl acetate polymer having at least one functional group COOH; (iii) an enhancer composition comprising about 5% propylene glycol (polypeleglycol) and about 5% oleic acid oil ester; (iv) about 0.05% antioxidant, wherein the transdermal system has a thickness of about 15-45 μm. In certain embodiments, the adhesive has a chemical composition ofA glass transition temperature of from-30 ℃ to about-60 ℃. In certain embodiments, the binder is Duro387-2054. In certain embodiments, the system has about 9.3 to about 9.5 μ g/cm²hr of flux.

Provided herein are transdermal delivery systems comprising a drug-containing matrix layer comprising: based on the total weight of the drug-containing matrix layer, (a) about 14% by weight of galantamine or a pharmaceutically acceptable salt thereof; (b) about 76% by weight of a binder; (c) about 5% by weight oleic acid oil ester; (d) about 10% medium chain fatty acid triglycerides; (e) about 5% polyethylene glycol; (f) about 0.05 wt.% of an antioxidant comprising butylated hydroxytoluene. In certain embodiments, the drug-containing matrix layer has a thickness of about 15-45 μm. In certain embodiments, the system has about 1-15 μ g/cm²hr of flux. In certain embodiments, the medium chain fatty acid triglyceride is labrafac^TMLipophile WL1349。

In certain embodiments, provided herein are transdermal delivery systems comprising a drug-containing matrix layer comprising: (i) galantamine or a pharmaceutically acceptable salt thereof; (ii) an adhesive comprising a styrene-butadiene-styrene block copolymer ("SBS block copolymer"); (iii) an enhancer composition comprising oleic acid oil ester and propylene glycol monolaurate; and (iv) antioxidants, solvents, and adhesive modifiers. In certain embodiments, the antioxidant is butylated hydroxytoluene, the solvent is diethylene glycol monoethyl ether, and the binder modifier is a cyclic terpene. In certain embodiments, the antioxidant is vitamin E, ascorbyl palmitate, bronopol, Butylated Hydroxytoluene (BHT), erythorbic acid, thioglycerol, sodium metabisulfite, sodium sulfite, sulfur dioxide, sodium thiosulfate, and combinations thereof. In certain embodiments, the weight of the galantamine or pharmaceutically acceptable salt thereof is about 0.01 to about 5% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the styrene-butadiene-styrene block copolymer comprises about 60 to 97.5 weight percent of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the enhancer composition is about 3% to about 15% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the propylene glycol monolaurate is about 0.1-15% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the oleic acid oleyl ester comprises from about 0.1% to about 20% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the antioxidant is butylated hydroxytoluene and is present in an amount of about 0.001 to about 0.5 weight percent based on the total weight of the drug-containing matrix layer. In certain embodiments, the solvent is diethylene glycol monoethyl ether and is present in an amount of about 0.1 to 20 wt% based on the total weight of the drug-containing matrix layer. In certain embodiments, the adhesive modifier is a cyclic terpene and is present in an amount of about 0.1 to about 15 weight percent based on the total weight of the drug-containing matrix layer. In certain embodiments, the propylene glycol monolaurate is propylene glycol monolaurate type I or propylene glycol monolaurate type II. In certain embodiments, the drug-containing matrix layer has a thickness of about 45 μm to about 85 μm. In certain embodiments, the galantamine or pharmaceutically acceptable salt thereof is about 2.5 wt%, wherein the styrene-butadiene-styrene block copolymer is about 60-97.5 wt%, wherein the propylene glycol monolaurate is about 0.1-15 wt%, wherein the oleyl oleate is about 0.1-20 wt%, wherein the antioxidant is butylated hydroxytoluene and is about 0.001-0.5 wt%, wherein the solvent is diethylene glycol monoethyl ether and is about 0.1-20 wt%, based on the total weight of the drug-containing matrix layer, wherein the adhesive modifier is a cyclic terpene and is about 0.1-15 wt%. In certain embodiments, the propylene glycol monolaurate is propylene glycol monolaurate type I or propylene glycol monolaurate type II.

In certain embodiments, provided herein are transdermal delivery systems comprising a drug-containing matrix layer comprising: (i) from about 0.01% to about 5% galantamine or a pharmaceutically acceptable salt thereof; (ii) about 60-97.7% of a binder comprising a styrene-butadiene-styrene block copolymer; (iii) an enhancer composition comprising from about 0.1% to about 20% oleic acid oil ester and from about 0.1% to about 15% propylene glycol monolaurate; (v) about 0.001-0.5% of an antioxidant; (vi) about 0.1-20% solvent; and (vii) about 0.1-15% of an adhesive modifier.

In certain embodiments, the weight of the galantamine is about 2.5% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the enhancer composition is about 3% to about 8% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the propylene glycol monolaurate is propylene glycol monolaurate type I or propylene glycol monolaurate type II. In certain embodiments, the antioxidant is butylated hydroxytoluene, vitamin E, ascorbyl palmitate, bronopol, erythorbic acid, thioglycerol, sodium metabisulfite, sodium sulfite, sulfur dioxide, sodium thiosulfate, and combinations thereof. In certain embodiments, the solvent is diethylene glycol monoethyl ether. In certain embodiments, the adhesive modifier is a cyclic terpene. In certain embodiments, the weight of the enhancer composition comprises about 3, about 5, or about 8 weight percent of the total weight of the drug-containing matrix layer.

The invention also provides a method of making a transdermal delivery system. In some embodiments, the method comprises a controlled and sustained drug delivery system for delivering galantamine and salts thereof to a patient. The system includes delivering substantially uniform particles. In certain embodiments, the substantially uniform particles are dispersed in a polymer matrix. Methods of making the polymer matrix are also disclosed.

The present invention provides a release rate 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, or 11-12 times higher than other galantamine transdermal delivery systems when compared to other galantamine transdermal delivery systems.

Provided herein is a method for delivering a drug to a patient comprising the step of administering the transdermal delivery system disclosed herein.

Also described herein are transdermal delivery systems for treating or preventing a disease in a subject. In a specific embodiment, the subject is a mammal. In a specific embodiment, the subject is a human. In one embodiment, provided herein is a method of treating a disease comprising administering to a subject a transdermal delivery system comprising a therapeutically effective amount of galantamine or a salt thereof. Methods of making the transdermal delivery systems are provided herein.

Also disclosed are kits comprising the transdermal delivery systems provided herein. The kit includes a carrier that is compartmentalized to receive, within the confines of a closure, one or more containers containing one of the individual components used in the method. The kit also includes instructions for administering the transdermal delivery system.

The kits provided herein comprise a unit dose of galantamine or salts thereof provided herein such that when administered to a subject, therapeutically or prophylactically effective plasma levels of the compound or composition can be maintained in the subject for at least 1,3, 5, and 7 days.

These and other aspects, features and advantages will be understood from the accompanying description of certain embodiments of the disclosure, and the drawings and claims.

4.1 definition

The terms "subject" and "patient" as used herein are used interchangeably. The term "subject" refers to animals, e.g., mammals, including non-primates (e.g., cows, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys such as cynomolgus monkeys, chimpanzees, and humans), and e.g., humans. In one embodiment, the subject is a human.

In one embodiment, "treating" or "treatment" of any disease or disorder refers to ameliorating the disease or disorder present in the subject. In another embodiment, "treating" or "treatment" comprises improving at least one physical parameter, which may be difficult for the subject to perceive. In another embodiment, "treating" or "treatment" includes physically modulating the disease or disorder (e.g., stabilizing an appreciable symptom) or physiologically modulating the disease or disorder (e.g., stabilizing a physical parameter), or both. In another embodiment, "treating" or "treatment" includes delaying the onset of the disease or disorder.

As used herein, the terms "preventing" and "prevention" of any disease or disorder refer to the prevention of the disorder or one or more symptoms thereof. Prevention (prevention) and prevention (prevention) is the prevention of the onset, development and progression of a disease or condition.

The term "about," as used herein, is defined as ± 5% deviation from a numerical value.

As used herein, the term "acrylate-vinyl acetate polymer" is defined as a copolymer of a soft monomer of acrylic acid and a hard monomer comprising a vinyl acetate polyacrylate.

As used herein, the term "enhancer composition" is defined as a composition comprising one or more enhancers for improving the penetration of an active agent.

As used herein, the term "medium chain fatty acid triglyceride" is defined as a triglyceride whose fatty acids have an aliphatic tail of 6-12 carbon atoms. The medium chain fatty acid triglycerides consist essentially of a mixture of triglycerides of saturated fatty acids comprising 50-80% caprylic acid and 20-50% capric acid. In certain embodiments, the medium chain fatty acid triglyceride is labrafac^TMLipophile WL1349。

4.2 description of the drawings

Figure 1 shows various amounts of galantamine in acrylate-vinyl acetate copolymers.

Fig. 2 shows various amounts of galantamine in styrene-butadiene block copolymer rubber.

5. Detailed description of the invention

In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of claimed subject matter. However, it will be understood by those skilled in the art that claimed subject matter may be practiced without these specific details. In other instances, methods, devices, or systems that would be known by one of ordinary skill have not been described in detail so as not to obscure claimed subject matter. It should be appreciated that the particular features, structures, or characteristics described may be combined in various ways in one or more embodiments.

5.1 Components of transdermal delivery systems

The transdermal delivery systems described herein include a drug-containing matrix layer, a backing layer, and a release layer. The drug-containing matrix layer contains galanthamine or pharmaceutically acceptable salts thereof. "pharmaceutically acceptable salt" refers to a salt of galantamine that induces a desired pharmacological or physiological effect and includes agents that are therapeutically or prophylactically effective. In certain embodiments, the drug-containing matrix layer comprises one or more active agents that are galantamine and pharmaceutically acceptable salts thereof.

5.1.1 drug-containing matrix layer

The amount of galantamine and pharmaceutically acceptable salts thereof present in the drug-containing matrix layer can vary. In certain embodiments, galantamine and pharmaceutically acceptable salts thereof delivers galantamine in an amount of from about 4mg to about 24 mg. In certain embodiments, the galantamine and pharmaceutically acceptable salts thereof range from about 4-8mg, about 8-10mg, about 10-12mg, about 12-14mg, about 14-16mg, about 16-18mg, about 18-20mg, or about 20-24mg per unit transdermal delivery system. In one embodiment, the unit of the transdermal delivery system is a dosage of the transdermal delivery system. In one embodiment, a dose is a patch. In certain embodiments, galantamine and pharmaceutically acceptable salts thereof are present in the drug-containing matrix layer from about 0.01% to about 0.05%, from about 0.05% to about 0.1%, from about 0.1% to about 0.2%, from about 0.2% to about 0.5%, from about 0.5% to about 1%, from about 1% to about 2%, from about 2% to about 4%, from about 2% to about 5%, from about 5% to about 6%, from about 6% to about 7%, from about 7% to about 8%, from about 8% to about 9%, from about 9% to about 10%, from about 10% to about 13%, from about 13% to about 14%, from about 14% to about 15%, from about 15% to about 16%, from about 16% to about 17%, from about 17% to about 18%, from about 18% to about 19%, from about 19% to about 20%, or from about 20%. In certain embodiments, the galantamine and pharmaceutically acceptable salts thereof is about 0.01 to 5% by weight based on the total weight of the drug-containing matrix layer. In certain embodiments, the galantamine and pharmaceutically acceptable salts thereof is about 1-16% by weight based on the total weight of the drug-containing matrix layer. In certain embodiments, the galantamine and pharmaceutically acceptable salts thereof is about 0.5-1, 1-2.5, 2.5-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13 or 13-14% by weight based on the total weight of the drug-containing matrix layer.

In certain embodiments, the drug-containing matrix layer comprises an adhesive. In certain embodiments, the adhesive is present in the drug-containing matrix layer from about 10% to about 30%, from about 30% to about 50%, from about 50% to about 60%, from about 60% to about 65%, from about 65% to about 70%, from about 70% to about 75%, from about 75% to about 80%, from about 80% to about 90%, from about 90% to about 95%, from about 95% to about 96%, from about 96% to about 97%, from about 97% to about 98%, from about 98% to about 99% by weight, based on the total weight of the drug-containing matrix layer. In certain embodiments, the adhesive is about 75-85% by weight based on the total weight of the drug-containing matrix layer. In certain embodiments, the adhesive is about 60 to 97.5 weight percent based on the total weight of the drug-containing matrix layer.

In certain embodiments, the adhesive present in the drug-containing matrix layer comprises a polymer. In certain embodiments, the polymer is an acrylic polymer or an acrylate-vinyl acetate polymer. In certain embodiments, the adhesive is an acrylic polymer that does not contain functional groups. In certain embodiments, the binder is an acrylic polymer having one or more functional groups (including-COOH or-OH). In certain embodiments, the binder is an acrylate-vinyl acetate polymer having one or more functional groups (including-COOH or-OH). In certain embodiments, the acrylic polymer without functional groups has a gas transition temperature of about-15 ℃ to about-30 ℃. In certain embodiments, the acrylic polymer with functional groups has a gas transition temperature of about-30 ℃ to-60 ℃. In certain embodiments, the acrylic polymer with functional groups has a gas transition temperature of about-30 ℃ to-60 ℃. In certain embodiments, the acrylate-vinyl acetate polymer with functional groups has a gas transition temperature of about-15 ℃ to about-30 ℃. In certain embodiments, the acrylate-vinyl acetate polymer with functional groups has a gas transition temperature of about-30 ℃ to-60 ℃.

In certain embodiments, the adhesive comprises a styrene-butadiene-styrene block copolymer.

In certain embodiments, the polymers include, but are not limited to, polyurethanes, acrylates, styrene block copolymers, and silicones. In certain embodiments, the polymer includes, but is not limited to, acrylate polymers, polysiloxanes, Polyisobutylene (PIB), polyisoprene, polybutadiene, styrene block polymers, and combinations thereof. Suitable styrene block copolymer-based adhesives include, but are not limited to, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene copolymer (SBS), styrene-ethylene butylene-styrene copolymer (SEBS), and diblock analogs and combinations thereof.

The drug-containing matrix layer may include a pressure sensitive adhesive. The term "pressure sensitive adhesive" refers to an adhesive that forms an adhesive bond when pressure is applied to adhere the adhesive to a surface. In certain embodiments, the degree of bond strength is directly proportional to the amount of pressure used to apply the adhesive to the surface. Pressure sensitive adhesives include, but are not limited to, acrylate polymers.

The acrylate polymer may comprise a copolymer of various monomers, which may be "soft" or "hard" monomers, or a combination thereof. Soft monomers are characterized by relatively low glass transition temperatures and include, for example and without limitation, n-butyl acrylate, 2-ethylhexyl acrylate, and isooctyl acrylate. Hard monomers are characterized by having a relatively high glass transition temperature and include examples such as, but not limited to, styrene, methyl methacrylate, ethyl acrylate, and methyl acrylate. The acrylate polymer may be composed of a copolymer including a binary copolymer (e.g., made of two monomers), a ternary copolymer (e.g., made of three monomers), or a quaternary polymer (e.g., made of four monomers), or a copolymer made of a greater number of monomers. The acrylate polymer may include crosslinked and uncrosslinked polymers. The polymer may be crosslinked by a crosslinking agent to provide the desired crosslinked polymer. The polymer may be crosslinked by a crosslinking agent to provide the desired crosslinked polymer. In certain embodiments, the polymer is a non-crosslinked polymer. In certain embodiments, the polymer is cured. In certain embodiments, the polymer is uncured.

The monomers for preparing the acrylate polymer include at least two or more components selected from acrylic acid, alkyl acrylates, methacrylates. Other examples of acrylic Adhesive monomers are described in Satas, "acrylic adhesives," Handbook of Pressure-Sensitive Adhesive Technology,2nd ed., pp.396-456(D.Satas, ed.), Van Nostrand Reinhold, New York (1989).

In certain embodiments, the adhesive comprises Duro87-9301(Henkel)、Duro387-2054(Henkel) or styrene-butadiene-styrene block copolymers.

In certain embodiments, the adhesive comprises Duro87-4098、Duro87-2510、Duro87-2516、Duro87-4287、Duro87-235A、Duro87-2852、Duro87-2353、Duro87-2196、Duro87-2979、Duro87-502b、Duro87-504b、Duro87-6908、Duro87-6911、And

in certain embodiments, useful binders include those disclosed in tables 3, 5-11, 12, and 16 below.

In certain embodiments, the drug-containing matrix layer comprises an enhancer composition that enhances drug penetration. The enhancer composition facilitates absorption of the active agent through the skin of the subject.

In certain embodiments, the enhancer composition comprises: (a) oleic acid oleyl ester and oleic acid; (b) oleic acid oleyl ester and propylene glycol and antioxidants; or (c) a medium chain fatty acid triglyceride and an antioxidant. In certain embodiments, the medium chain fatty acid triglycerides consist essentially of a mixture of triglycerides of saturated fatty acids comprising 50-80% caprylic acid and 20-50% capric acid. In certain embodiments, the medium chain fatty acid triglyceride is labrafac^TMLipophile WL1349。

In certain embodiments, the enhancer composition includes oleic acid oleyl ester and propylene glycol monolaurate. In certain embodiments, the propylene glycol monolaurate is form I or form II. In certain embodiments, the propylene glycol monolaurate is lauroglycol FCC or lauroglycol 90. In certain embodiments, the propylene glycol monolaurate is a propylene glycol mono-and diester of lauric acid. In certain embodiments, the enhancer composition comprises propylene glycol monolaurate form I containing 45-70% monoester and 30-55% diester. In certain embodiments, the enhancer composition comprises propylene glycol monolaurate form II containing 90-100% monoester and 0-10% diester.

In certain embodiments, suitable enhancer compositions may include, but are not limited to, fatty alcohols, such as, but not limited to, saturated or unsaturated higher alcohols having 12 to 22 carbon atoms, such as oleyl alcohol and lauryl alcohol; fatty acids such as, but not limited to, linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid, and palmitic acid; fatty acid esters such as, but not limited to, isopropyl myristate, diisopropyl adipate, and isopropyl palmitate; alcohol amines such as, but not limited to, triethanolamine hydrochloride, and diisopropanolamine; polyol alkyl ethers, such as, but not limited to, alkyl ethers of polyols, e.g. glycerol, ethylene glycol, propylene glycol, 1, 3-butanediol, diglycerol, polyglycerolsOil, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, isosorbide, methyl glucoside, oligosaccharide, and reduced oligosaccharide, wherein the number of carbon atoms of the alkyl moiety in the polyol alkyl ether is preferably 6 to 20; polyoxyethylene alkyl ethers, such as, but not limited to, polyoxyethylene alkyl ethers in which the number of carbon atoms of the alkyl moiety is 6 to 20, and repeating units of the polyoxyethylene chain (e.g., -OCH)₂CH₂-) is from 1 to 9, such as, but not limited to, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyoxyethylene oleyl ether; glycerides (i.e., fatty acid esters of glycerol), such as, but not limited to, glycerides of fatty acids having 6 to 18 carbon atoms, where the glycerides can be monoglycerides (i.e., a glycerol molecule covalently bonded to one fatty acid chain by an ester chain), diglycerides (i.e., a glycerol molecule covalently bonded to two fatty acid chains by an ester chain), triglycerides (i.e., a glycerol molecule covalently bonded to three fatty acid chains by an ester chain), or combinations thereof, where the fatty acid components forming the glycerides include, but are not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid (i.e., stearic acid), and oleic acid; medium chain fatty acid esters of polyhydric alcohols; an alkyl lactate; a dibasic acid alkyl ester; an acylated amino acid; a pyrrolidone; a pyrrolidone derivative; and combinations thereof.

In certain embodiments, suitable enhancer compositions include, but are not limited to, lactic acid, tartaric acid, 1,2, 6-hexanetriol, benzyl alcohol, lanolin, potassium hydroxide (KOH), and tris (hydroxymethyl) aminomethane. Specific examples of penetration enhancers include, but are not limited to, Glycerol Monooleate (GMO) and Sorbitan Monolaurate (SML), lactates such as lauryl lactate, methyl laurate, caproyl lactate, Lauramide Diethanolamine (LDEA), dimethyl lauramide, polyethylene glycol-4 lauryl ether (Laureth-4), Lauryl Pyroglutamate (LP), sorbitan monolaurate, ethanol, and combinations thereof. In certain embodiments, the enhancer composition enhances penetration of the active agent of the surface active dosage form. Examples of such enhancer compositions include combinations of semi-polar solvents such as propylene glycol, butylene glycol, N-methyl pyrrolidone, dimethyl sulfoxide, diethylene glycol methyl ether, and dimethyl isosorbide, surfactants such as isopropyl myristate, oleic acid, lauryl lactate, and combinations thereof.

In certain embodiments, the enhancer composition comprises squalane, isopropyl palmitate, isopropyl myristate, sorbitan laurate, DL-limonene, ethyl oleate, methyl dodecanoate, propylene glycol dicaprylate/dicaprate, Labrafac^TMPG, octanol, dodecanol, polyoxyethylene (4) lauryl ether,Oleyl alcohol, polyoxyethylene sorbitan monooleate,Propylene glycol, diethylene glycol, monoethyl ether, propylene glycol monocaprylate, Capryol PGMC, 1-methyl-2-pyrrolidone, glyceryl triacetate (glyceryl triacetate), triacetin (triacetin), polyoxyethylene castor oil (polyoxyl castor oil), propylene glycol, diethylene glycol, monoethyl ether, propylene glycol monocaprylate, propylene glycol PGMC, 1-methyl-2-pyrrolidone, glyceryl triacetate (triacetin), polyoxyethylene castor oil (polyoxyl castor oil), propylene glycol monocaprylate, propylene glycol,Oleoyl polyethylene glycol-6 glyceride, Labrafil^TMM1944CS, linoleoyl polyethylene glycol (linoleoyl polyoxyl) -6 glyceride, Labrafil^TMM2125CS, caprylic/capric polyethylene glycol-8 glyceride,Polyoxyethylene castor oil (polyoxylcaster oil), oleoyl polyethylene glycol-6 glyceride, linoleoyl polyethylene glycol (linoleoyl polyoxyl) -6 glyceride, caprylic capric polyethylene glycol-8 glyceride and N-methylpyrrolidone.

In certain embodiments, the weight of the enhancer composition is about 1-3%, about 3-5%, about 5-10%, about 10-15%, about 15-25% by weight of the total weight of the drug-containing matrix layer. In certain embodiments, the weight of the enhancer composition comprises about 3%, about 5%, about 8%, about 10% by weight of the total weight of the drug-containing matrix layer.

In certain embodiments, the enhancers for the transdermal delivery system include those disclosed in table 4 below.

In certain embodiments, the drug-containing matrix layer comprises one or more antioxidants, such as, but not limited to, tocopherols and derivatives (e.g., tocopheryl acetate or tocopheryl polyethylene glycol succinate), ascorbic acid and derivatives (e.g., ascorbyl palmitate), butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, metabisulfites (metabisulfates), and derivatives, and the like. In one embodiment, the antioxidant is butylated hydroxytoluene. In certain embodiments, the antioxidant is vitamin E, ascorbyl palmitate, bronopol, erythorbic acid, thioglycerol, sodium metabisulfite, sodium sulfite, sulfur dioxide, sodium thiosulfate, and combinations thereof.

In certain embodiments, the antioxidant is present in an amount ranging from about 0.001 to 5.0%, about 0.05%, about 0.001-0.005%, about 0.005-0.01%, about 0.01-0.05%, about 0.05-0.1%, about 0.1-0.5%, about 0.5-1%, about 1-3%, about 3-5% by weight, based on the total weight of the drug-containing matrix layer.

In certain embodiments, the drug-containing matrix layer may contain fillers including, but not limited to: metal oxides (such as zinc oxide and titanium oxide), metal salts (such as calcium carbonate, magnesium carbonate and zinc stearate), silicic acid compounds (such as kaolin, talc, bentonite, aerosil, hydrated silica, aluminum silicate, magnesium silicate and magnesium aluminum metasilicate) and metal hydroxides (such as aluminum hydroxide). Such fillers, if present, may be 1 to 75%, for example 2 to 50% by weight, based on the total weight of the drug-containing matrix layer.

In certain embodiments, the drug-containing matrix layer includes a solvent, including but not limited to a volatile or non-volatile solvent (i.e., non-volatile as compared to acetone, isopropanol, or water, but which may exhibit behaviorCertain volatile solvents) such as dimethyl sulfoxide (DMSO), N-methylpyrrolidone, dimethyl isosorbide, propylene glycol, hexylene glycol, and benzyl alcohol. In one embodiment, the solvent is diethylene glycol monoethyl ether. In one embodiment, the solvent isThe drug-containing matrix layer comprises a solvent in an amount of about 0.1-1%, about 1-5%, about 5-10%, about 10-15%, about 15-20%, about 20-30% by weight, based on the total weight of the drug-containing matrix layer.

In certain embodiments, the solvent used includes, but is not limited to, ethyl acetate, hexane, ethanol, heptane, methanol, cyclohexane, acetylacetone, xylene, butanone, toluene, 2, 4-pentanedione, or isopropanol.

In certain embodiments, the drug-containing matrix layer includes an adhesive modifier. In one embodiment, the adhesive modifier may be a cyclic terpene or hydrogenated rosin. In one embodiment, the adhesive modifier is85. In one embodiment, the adhesive modifier is limonene. The drug-containing matrix layer comprises an adhesive modifier in an amount of about 0.1-1%, about 1-5%, about 5-10%, about 10-15%, and about 15-20% by weight based on the total weight of the drug-containing matrix layer.

5.2 delivery of active Agents

Although the actual flux may vary, in certain embodiments (e.g., as determined using the skin permeation assay in the example of section 6, infra), the skin permeability is about 3-4 μ g/cm²Per hr, about 4-5 μ g/cm²Per hr, about 5-6 μ g/cm²Hr, about 6-7 μ g/cm²Hr, about 7-8 μ g/cm²Per hr, about 8-9 μ g/cm²Hr, about 9-10 μ g/cm²Per hr, about 10-11 μ g/cm²/hr or about 11-12 μ g/cm²Hr, about 12-15 μ g/cm²Hr, about 15-20μg/cm²Per hr, about 20-25 μ g/cm²Per hr, about 25-30 μ g/cm²Per hr, about 30-35 μ g/cm²Per hr, about 35-40 μ g/cm²Per hr, about 40-45 μ g/cm²/hr or about 45-50 μ g/cm²/hr。

In certain embodiments, the flux is about 8mg/24hr/23cm²To about 24mg/24hr/127cm²。

In certain embodiments, the transdermal delivery system is formulated to provide a cumulative delivered amount of active agent (also referred to herein as cumulative flux) when the formulation is administered to the skin of a subject over an extended period of time, as described below. In certain embodiments, the transdermal formulation is formulated to provide cumulative delivery of the active agents as follows: about 1 to 100. mu.g/cm²About 100-²About 150. mu.g/cm²About 200-²About 250 μ g/cm²About 300-²About 350-²About 400-²About 450. mu.g/cm²About 500-²About 550. mu.g/cm²About 600-650. mu.g/cm²,650-700μg/cm²About 700. mu.g/cm and 750. mu.g/cm²,750m-800μg/cm²,800-850μg/cm²About 850-²About 900-²Or about 950-²。

The size (i.e., area) of the transdermal delivery system can vary, but is within the range of the active agent administered to the subject. It is also important for subjects wearing the transdermal delivery system to find the system easy to use and comfortable to use over a period of time to improve compliance. In certain embodiments, the size of the formulation is selected having regard to the desired transdermal flux rate of the active agent and the target dose. In certain embodiments, the transdermal delivery system has a size of about 2-6cm²About 6-10cm²About 10-20cm²About 20-30cm²About 30-40cm²About 40-50cm²About 50-100cm²About 100 and 130cm²About 130 and 140cm²About 140 and 150cm²Or about 150 and 200cm²。

The transdermal delivery systems of the present invention are formulated to provide a therapeutically effective amount of an active agent to a subject when the topical patch is applied to a skin site of the subject for an extended period of time (e.g., a period of multiple days). For example, the extended period of time can be a period of about 6-12 hours, about 12-24 hours, about 1-2 days, about 2-3 days, about 3-4 days, about 4-5 days, about 5-6 days, about 6-7 days.

In certain embodiments, the various formulations, human pharmacokinetic profiles and skin permeation properties are shown in tables 1,2, 13-14 below.

The thickness of the drug-containing matrix layer of the transdermal delivery system may vary. In certain embodiments, the drug-containing matrix layer has a thickness in a range sufficient to provide for delivery of a therapeutically effective amount of the active agent to the subject for a desired extended period of time. In certain embodiments, the thickness of the formulation is selected in view of the desired transdermal delivery rate of the active agent and the target dose. In certain embodiments, the drug-containing matrix layer has a thickness of from about 10 μm to about 15 μm, from about 15 μm to about 20 μm, from about 20 μm to about 25 μm, from about 25 μm to about 30 μm, from about 30 μm to about 35 μm, from about 35 μm to about 40 μm, from about 40 μm to about 45 μm, from about 45 μm to about 50 μm, from about 50 μm to about 55 μm, or from about 55 μm to about 120 μm.

One aspect of the transdermal delivery system of the present invention is that it can be stored for extended periods of time without significant degradation and/or significant reduction in the activity of the active agent. In certain embodiments, the drug-containing matrix layer comprising galantamine or a pharmaceutically acceptable salt thereof is stable for at least 1 year, 2 years, 3 years, 4 years, 5 years, or 6 years. In certain embodiments, the transdermal delivery system is maintained at 25 ℃ ± 2 ℃/60% RH ± 5% RH.

5.3 Multi-layer construction of transdermal delivery devices

5.3.1. Backing layer

In certain embodiments, the transdermal delivery system comprises a backing layer (e.g., a support layer). The backing may be flexible such that it may be brought into intimate contact with a desired local location of the subject. The backing may be made of a material that does not absorb the active agent and does not allow release of the active agent from the backing side of the transdermal formulation. The backing material of interest may be closed (i.e., impermeable), semi-closed, or breathable (permeable). The backing may include, but is not limited to, nonwoven fabrics, woven fabrics, films (including sheets), foils, porous bodies, foams, papers, composites obtained by laminating a film onto a nonwoven fabric or fabric, and combinations thereof. Nonwoven fabrics may include, but are not limited to, the following: polyolefin resins such as polyethylene and polypropylene; polyester resins such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate; rayon, polyamide, poly (ester ether), polyurethane, polyacrylic resin, polyvinyl alcohol, styrene-isoprene-styrene copolymer, and styrene-ethylene-propylene-styrene copolymer; and combinations thereof.

The fabric may include, but is not limited to: cotton, rayon, polyacrylic resins, polyester resins, polyvinyl alcohol, and combinations thereof. Membranes may include, but are not limited to, the following: polyolefin resins such as polyethylene (including low and high density polyethylene (LDPE, HDPE) and polypropylene; polyacrylic resins such as polymethyl methacrylate and polyethyl methacrylate; polyester resins such as polyethylene terephthalate, polychlorotrifluoroethylene, acrylonitrile methyl acrylate copolymers, polybutylene terephthalate and polyethylene naphthalate; and polyvinyl alcohol, ethylene-vinyl alcohol copolymers, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluororesin, styrene-isoprene-styrene copolymers, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymers, polyamides and polysulfones; and combinations thereof Kraft paper, japanese paper, glassine paper, synthetic paper and combinations thereof. The composite material may include, but is not limited to, a composite material obtained by laminating the above-described film onto the above-described nonwoven fabric or fabric. In certain embodiments, the backing comprises a polyester, such as polyethylene terephthalate (PET).

In certain embodiments, the backing layer is in contact with a surface of the drug-containing matrix layer. For example, when the transdermal delivery system is formulated such that one surface of the drug-containing matrix layer contacts the skin upon application, the backing will be in contact with the opposite surface of the drug-containing matrix layer.

5.3.2 peeling off layers

In certain embodiments, the transdermal delivery system comprises a release layer. In certain embodiments, a release layer is provided on the drug-containing matrix layer, particularly on the surface of the drug-containing matrix layer distal to (i.e., opposite) the backing layer. The release liner can facilitate protection of the drug-containing matrix layer prior to use of the transdermal delivery system. In certain embodiments, the release layer is formulated to be removable from the drug-containing matrix layer without leaving the drug-containing matrix layer.

The release layer may be any convenient material. In certain embodiments, the release layer comprises a polyester, such as polyethylene terephthalate, polypropylene, and combinations thereof. In certain embodiments, the release layer comprises a coated substrate, which may be prepared, for example, by treating one side of a polyethylene-coated wood-free paper, a polyolefin-coated cellophane, a polyethylene terephthalate (polyester) film, a polypropylene film with a silicone treatment. In some cases, the release layer comprises a silicone treated polyester film.

5.4 methods for preparing the transdermal delivery systems

Aspects of the invention also include methods of making the transdermal delivery systems as described above. In certain embodiments, the method comprises mixing galantamine or a pharmaceutically acceptable salt thereof with one or more solvents, binders, enhancers, and antioxidants to form a drug-containing matrix layer.

In certain embodiments, the adhesive comprises an acrylic polymer containing no functional groups or an acrylic having at least one carboxyl functional groupEster-vinyl acetate polymers. In certain embodiments, the enhancer composition comprises oleic acid oleyl ester and oleic acid. In one embodiment, the enhancer composition comprises oleic acid oleyl ester, propylene glycol, and an antioxidant. In one embodiment, the enhancer composition comprises medium chain fatty acid triglycerides and an antioxidant. In certain embodiments, the medium chain fatty acid triglyceride is labrafac^TMLipophile WL 1349. In one embodiment, the enhancer composition comprises oleic acid oleyl ester and propylene glycol monolaurate and an antioxidant.

The mixture is then applied to a backing. The method may further comprise applying a release liner to the drug-containing matrix layer on a side opposite the backing. In some cases, the method of preparing a transdermal delivery system further comprises placing the transdermal formulation in a package that forms a kit. After placing the transdermal formulation in the package, the method may include sealing the package.

5.5 doses

The amount of the composition effective in the therapeutic or prophylactic treatment of Alzheimer's disease can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help determine optimal dosage ranges. The precise dose employed will also depend on the severity of the disease or condition and should be determined at the discretion of the physician and the condition of each patient.

Suitable dosages of drugs for transdermal delivery range from 0.001 mg to 1 mg, depending on the area to which the compound is administered. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. These animal models and systems are well known in the art.

6. Examples of the embodiments

The following examples illustrate the synthesis and use of representative embodiments provided herein. These examples are not intended, and should not be construed, as limiting the scope of the claimed subject matter. It will be apparent that the scope of the subject matter may be practiced otherwise than as specifically described herein. Many modifications and variations of the subject matter described are possible in light of the teachings herein, and thus, are within the scope of the claimed subject matter.

6.1 materials and methods

Transdermal systems are manufactured according to known methods, for example by blending (mixing) appropriate amounts of polymer, drug and other excipients in the presence of an appropriate solvent (e.g. a volatile organic solvent), casting the wet blend onto a release liner, then evaporating the volatile solvent under appropriate drying conditions, and laminating the dried drug-containing matrix onto a backing film on the release liner.

Flux can be measured using Franz diffusion cells using standard procedures and experiments are performed on human cadaver skin. For Franz cells, a circular disk of human cadaver skin (25 mm in diameter) was placed on the receptor compartment in each Franz diffusion cell. The transdermal delivery system was cut to the same size as the skin and placed over a diffusion area in the center of the receptor. The donor compartment is then added and clamped to the assembly. At time 0, 14mL of receptor medium solution was added to the receptor compartment and the cell was maintained at 32 ℃. Samples of the receptor compartment were periodically sampled to determine skin flux and analyzed by HPLC.

Pharmacokinetic studies of transdermal patches containing galantamine (acetylcholinesterase inhibitor) were evaluated in 12 healthy volunteers. The transdermal system is topically administered to the arm or lower or upper back of a healthy subject for one day. Blood samples were collected periodically. Measurements of galantamine serum concentrations were performed and analyzed for LC-MS.

6.1.1 human pharmacokinetic profiles

Human pharmacokinetic profiles were determined for various formulations tested using the formulations provided in table 1.

TABLE 1

6.1.2. Adhesive formulations

Various adhesives were tested to determine the maximum amount of galantamine that can be dissolved. The results are shown in table 2 below.

TABLE 2

6.1.3. Enhancer composition

Various enhancers were tested to determine the maximum amount of galantamine that can be dissolved. The results are shown in Table 3.

TABLE 3

Reinforcing agent	Categories	Solubility (mg/mL)
			Squalane	Solvent(s)	1.3
Oleic acid oleyl ester	Fatty acid esters	5.2
			IPP	FatAcid esters	6.0
IPM	Fatty acid esters	7.6
			Span 20	Typical surfactants	7.8
Limonene	Solvent(s)	9.3
			Oleic acid ethyl ester	Fatty acid esters	9.6
Lauric acid methyl ester	Fatty acid esters	12.6
			Labrafac PG	Fatty acid esters	15.7
Labrafac Lipophile WL1349	Fatty acids	16.7
			Octanol (I)	Fatty alcohols	24.1
Lauryl alcohol	Fatty alcohols	30.3
			Brij 30	Typical surfactants	34.8
Oleyl alcohol	Fatty alcohols	40.1
			Lauroglycol FCC	Fatty acid esters	40.6
Tween 80	Typical surfactants	41.3
			Propylene glycol	Solvent(s)	112.9
Transcutal P	Solvent(s)	122.4
			Oleic acid	Fatty acids	139.2

6.1.4. Antioxidant action

Various antioxidants were tested under normal and pressure conditions to determine the effect of the antioxidants in stabilizing galantamine. The results are shown in Table 4.

6.1.5. Skin penetration

Various formulations were tested for skin penetration. The results are provided in fig. 1 and 2 and tables 5 and 6. Higher amounts of galantamine in the adhesive will increase the permeability, but when the saturation point is exceeded, the transdermal system will crystallize and result in a low permeability.

When an enhancer is added, the permeability may be increased. Enhancers may increase permeability, but functional enhancers may not produce the same effect. When the amount of the enhancer is increased, it may not increase the permeability. When used in combination with any two enhancers, the permeability is not always increased. The results are shown in tables 5 and 6.

TABLE 5-1 Single enhancer Effect of galantamine with 14% W/W in acrylate-vinyl acetate copolymers

TABLE 5-2 Single enhancer Effect of galantamine with 3% W/W in styrene-butadiene Block copolymer rubber

Reinforcing agent	Categories	Enhancer% w/w	Enhancement ratio
				Control
Brij 30	Surface active agent	3	2
				Oleic acid ethyl ester	Fatty acid esters	3	2
IPM	Fatty acid esters	3	2
				IPP	Fatty acid esters	3	2
Lauroglycol	Fatty acid esters	3	2
				Oleic acid	Fatty acids	3	1
Oleic acid oleyl ester	Fatty acid esters	3	2
				Squalane	Surface active agent	3	1
Glycerol triacetate	Solvent(s)	3	0
				Vitamin E TPGS	Surface active agent	3	1

TABLE 6-1 Dual enhancer Effect with antioxidants in acrylate-vinyl acetate copolymers with 14% W/W galanthamine

TABLE 6-2 Dual enhancer Effect with antioxidants in styrene-butadiene Block copolymer rubber with 2.5% W/W galantamine

The co-solvent helps to dissolve the drug in the binder, but it may also help with permeability. As shown in the table 7 below, the following examples,p helps to dissolve galantamine in the adhesive and at the same time increases the permeability.

TABLE 7 Effect of co-solvent in styrene-butadiene Block copolymer rubber adhesive, wherein the amount of galantamine is 2.5% w/w

% enhancer	Antioxidant agent	Cosolvent 5%	Enhancement ratio
				5% Ethyl oleate	BHT	-
5% Ethyl oleate	BHT	Transcutol P	5

6.1.6. Crystallization of

Various binders were tested to find the best drug solubility to optimize permeation. Polymers of the same functionality do not show the same observations. To prevent crystallization problems, the reinforcing agent acts as a solubilizer to increase the amount of galantamine dissolved in the adhesive. The results are shown in tables 8 and 9.

TABLE 8 No enhancer

Adhesive agent	Galantamine w/w	Observation of
			Duro-Tak 387-2054	10	Not crystallized
Duro-Tak 387-2054	22	Crystallization of
			Duro-Tak 387-2196	10	Not crystallized
Duro-Tak 387-2196	22	Crystallization of
			Duro-Tak 502b	5	Crystallization of
Duro-Tak 504b	10	Crystallization of
			Duro-Tak 87-6911	1	Not crystallized
Duro-Tak 87-6911	9	Crystallization of
			Duro-Tak87-6911	20	Separation of

TABLE 9 enhancer

Exemplary systems and methods are listed in the following:

a transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) galantamine or a pharmaceutically acceptable salt thereof;

(ii) a binder comprising an acrylic polymer free of functional groups or an acrylate-vinyl acetate polymer having at least one carboxyl functional group (COOH);

(iii) an enhancer composition comprising: (a) oleic acid oleyl ester and oleic acid; (b) oleic acid oleyl ester and propylene glycol and antioxidants; or (c) a medium chain fatty acid triglyceride and an antioxidant.

The transdermal delivery system of item 2. item 1, wherein the medium chain fatty acid triglyceride comprises about 50-80% caprylic acid and about 20-50% capric acid.

The transdermal delivery system according to any of the previous claims, wherein the transdermal delivery system consists of a backing layer, a drug-containing matrix layer and a release layer.

The transdermal delivery system according to any one of the preceding claims, wherein the galantamine or pharmaceutically acceptable salt thereof is from about 7 to about 14% by weight based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the galantamine or pharmaceutically acceptable salt thereof is about 7, about 8 or about 14% by weight based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the previous claims, wherein the adhesive is about 75-78 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the acrylic polymer has a glass transition temperature of about-15 ℃ to about-30 ℃.

The transdermal delivery system according to any one of the preceding claims, wherein the acrylate-vinyl acetate polymer has a glass transition temperature of about-30 ℃ to about-60 ℃.

The transdermal delivery system according to any one of the previous claims, wherein the oleic acid is about 10 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the oleic acid ester is about 5 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the medium chain fatty acid triglyceride is about 10 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any of the preceding claims, wherein the antioxidant is butylated hydroxytoluene.

The transdermal delivery system according to any one of the previous claims, wherein the antioxidant is about 0.05 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the previous claims, wherein the drug-containing matrix layer has a thickness of about 20 μm to about 48 μm.

The transdermal delivery system according to any one of the preceding claims, wherein the system has about 8-10 μ g/cm²hr of flux.

The transdermal delivery system according to any one of the previous items, wherein the galantamine or pharmaceutically acceptable salt thereof is about 7-8 wt% based on the total weight of the drug-containing matrix layer, wherein the adhesive is about 78 wt%, wherein the oleic acid is about 10 wt%, wherein the oleic acid ester is about 5 wt%, wherein the drug-containing matrix layer has a thickness of about 20-48 μ ι η.

An item 17. a transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) about 7-8% galantamine or a pharmaceutically acceptable salt thereof;

(ii) an adhesive comprising an acrylic polymer free of functional groups;

(iii) an enhancer composition comprising (a) about 10% oleic acid and about 5% oleic acid oleyl ester, wherein the transdermal system has a thickness of about 20-48 μm.

The transdermal delivery system according to any one of the previous claims, wherein the adhesive has a glass transition temperature of about-15 ℃ to about-30 ℃.

(i) about 14% galantamine or a pharmaceutically acceptable salt thereof;

(ii) a binder comprising an acrylate-vinyl acetate polymer having at least one functional group COOH;

(iii) an enhancer composition comprising about 10% medium chain fatty acid triglycerides;

(iv) about 0.05% of an antioxidant agent,

wherein the transdermal system has a thickness of about 15-45 μm.

The transdermal delivery system according to any one of the preceding claims, wherein the adhesive has a glass transition temperature of about-30 ℃ to about-60 ℃.

An item 21. the transdermal delivery system according to any one of the preceding items, wherein the antioxidant is butylated hydroxytoluene, vitamin E, ascorbyl palmitate, bronopol, erythorbic acid, thioglycerol, sodium metabisulfite, sodium sulfite, sulfur dioxide or sodium thiosulfate.

The transdermal delivery system according to any one of the preceding claims, wherein the system has about 8 μ g/cm²hr of flux.

An item 23. a transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) about 14% galantamine or a pharmaceutically acceptable salt thereof;

(iii) an enhancer composition comprising about 5% propylene glycol and about 5% oleic acid oleyl ester;

(iv) about 0.05% of an antioxidant agent,

wherein the transdermal system has a thickness of about 15-45 μm.

The transdermal delivery system according to any one of the previous claims, wherein the adhesive has a glass transition temperature of about-30 ℃ to about-60 ℃.

The transdermal delivery system according to any one of the previous items, wherein the system has from about 9.3 to about 9.5 μ g/cm²hr of flux.

An transdermal delivery system according to any one of the preceding items, wherein the galantamine or pharmaceutically acceptable salt thereof is about 14 wt%, wherein the adhesive is about 76 wt%, wherein the oleic acid ester is about 5 wt%, wherein the medium chain fatty acid triglyceride is about 10%, wherein the polyethylene glycol is about 5%, wherein the antioxidant is butylated hydroxytoluene, which is about 0.05 wt%, based on the total weight of the drug-containing matrix layer, and wherein the drug-containing matrix layer has a thickness of about 15-45 μ ι η.

The transdermal delivery system according to any of the preceding claims, wherein the system has about 1-15 μ g/cm²hr of flux.

An item 28. transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) galantamine or a pharmaceutically acceptable salt thereof;

(ii) an adhesive comprising a styrene-butadiene-styrene block copolymer;

(iii) an enhancer composition comprising oleic acid oil ester and propylene glycol monolaurate; and

(iv) antioxidants, solvents, and adhesive modifiers.

The transdermal delivery system according to any one of the previous items, wherein the antioxidant is butylated hydroxytoluene, vitamin E, ascorbyl palmitate, bronopol, erythorbic acid, thioglycerol, sodium metabisulfite, sodium sulfite, sulfur dioxide, sodium thiosulfate, and combinations thereof, wherein the solvent is diethylene glycol monoethyl ether, and wherein the adhesive modifier is a cyclic terpene.

A transdermal delivery system according to any one of the preceding claims, wherein the transdermal delivery system consists of a backing layer, a drug-containing matrix layer and a release layer.

The transdermal delivery system according to any one of the preceding claims, wherein the galantamine or pharmaceutically acceptable salt thereof is from about 0.01 to about 5% by weight based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding items, wherein the styrene-butadiene-styrene block copolymer is about 60 to 97.5 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the previous items, wherein the enhancer composition is about 3-15% by weight based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the previous items, wherein the propylene glycol monolaurate is about 0.1-15 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the oleic acid ester is from about 0.1 to 20 weight percent based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the antioxidant is butylated hydroxytoluene and is present in an amount of about 0.001 to 0.5 weight percent based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the solvent is diethylene glycol monoethyl ether and is present in an amount of about 0.1-20 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the adhesive modifier is a cyclic terpene and is present in an amount of about 0.1 to 15 wt% based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the previous items, wherein the propylene glycol monolaurate is propylene glycol monolaurate type I or propylene glycol monolaurate type II.

The transdermal delivery system according to any one of the preceding claims, wherein the drug-containing matrix layer has a thickness of about 45 μm to about 85 μm.

The transdermal delivery system according to any one of the previous items, wherein the galantamine or pharmaceutically acceptable salt thereof is about 2.5 wt%, wherein the styrene-butadiene-styrene block copolymer is about 60-97.5 wt%, wherein the propylene glycol monolaurate is about 0.1-15 wt%, wherein the oleyl oleate is about 0.1-20 wt%, wherein the antioxidant is butylated hydroxytoluene and is about 0.001-0.5 wt%, wherein the solvent is diethylene glycol monoethyl ether and is about 0.1-20 wt%, and wherein the adhesive modifier is a cyclic terpene and is about 0.1-15 wt%, based on the total weight of the drug-containing matrix layer.

An item 43. a transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) from about 0.01% to about 5% galantamine or a pharmaceutically acceptable salt thereof;

(ii) about 60-97.7% of a binder comprising a styrene-butadiene-styrene block copolymer;

(iii) an enhancer composition comprising from about 0.1% to about 20% oleic acid oil ester and from about 0.1% to about 15% propylene glycol monolaurate;

(v) about 0.001-0.5% of an antioxidant;

(vi) about 0.1-20% solvent; and

(vii) about 0.1-15% of an adhesive modifier.

The transdermal delivery system according to any one of the preceding items, wherein the galantamine is about 2.5% by weight based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the previous claims, wherein the enhancer composition is about 3-8% by weight based on the total weight of the drug-containing matrix layer.

The transdermal delivery system according to any one of the preceding claims, wherein the antioxidant is butylated hydroxytoluene.

The transdermal delivery system according to any one of the previous items, wherein the solvent is diethylene glycol monoethyl ether.

The transdermal delivery system according to any one of the previous claims, wherein the adhesive modifier is a cyclic terpene.

The transdermal delivery system according to any one of the previous claims, wherein the enhancer composition is about 3, about 5, or about 8 weight percent based on the total weight of the drug-containing matrix layer.

The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

1. A transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) galantamine or a pharmaceutically acceptable salt thereof;

2. The transdermal delivery system of claim 1, wherein the medium chain fatty acid triglyceride comprises about 50-80% caprylic acid and about 20-50% capric acid.

3. The transdermal delivery system according to any of the previous claims, wherein the transdermal delivery system consists of a backing layer, a drug-containing matrix layer and a release layer.

4. The transdermal delivery system according to any one of the preceding claims, wherein the galantamine or pharmaceutically acceptable salt thereof is from about 7 to about 14% by weight based on the total weight of the drug-containing matrix layer.

5. The transdermal delivery system according to any one of the preceding claims, wherein the galantamine or pharmaceutically acceptable salt thereof is about 7, about 8 or about 14% by weight based on the total weight of the drug-containing matrix layer.

6. The transdermal delivery system according to any one of the previous claims, wherein the adhesive is about 75-78 wt% based on the total weight of the drug-containing matrix layer.

7. The transdermal delivery system according to any one of the preceding claims, wherein the acrylic polymer has a glass transition temperature of about-15 ℃ to about-30 ℃.

8. The transdermal delivery system according to any one of the preceding claims, wherein the acrylate-vinyl acetate polymer has a glass transition temperature of about-30 ℃ to about-60 ℃.

9. The transdermal delivery system according to any one of the previous claims, wherein the oleic acid is about 10 wt% based on the total weight of the drug-containing matrix layer.

10. The transdermal delivery system according to any one of the previous claims, wherein the oleic acid ester is about 5 wt% based on the total weight of the drug-containing matrix layer.

11. The transdermal delivery system according to any one of the previous claims, wherein the medium chain fatty acid triglyceride is about 10% by weight based on the total weight of the drug-containing matrix layer.

12. A transdermal delivery system according to any one of the preceding claims wherein the antioxidant is butylated hydroxytoluene.

13. The transdermal delivery system according to any one of the previous claims, wherein the antioxidant is about 0.05 wt% based on the total weight of the drug-containing matrix layer.

14. The transdermal delivery system according to any one of the previous claims, wherein the drug-containing matrix layer has a thickness of about 20 μm to about 48 μm.

15. The transdermal delivery system according to any one of the preceding claims, wherein the system has about 8-10 μ g/cm²hr of flux.

16. The transdermal delivery system according to any one of the previous claims, wherein the galantamine or pharmaceutically acceptable salt thereof is about 7-8% by weight, wherein the adhesive is about 78% by weight, wherein the oleic acid is about 10% by weight, wherein the oleic acid ester is about 5% by weight, based on the total weight of the drug-containing matrix layer, wherein the drug-containing matrix layer has a thickness of about 20-48 μ ι η.

17. A transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) about 7-8% galantamine or a pharmaceutically acceptable salt thereof;

(ii) an adhesive comprising an acrylic polymer free of functional groups;

(iii) an enhancer composition comprising (a) about 10% oleic acid and about 5% oleic acid oleyl ester,

wherein the transdermal system has a thickness of about 20-48 μm.

18. The transdermal delivery system according to any one of the previous claims, wherein the adhesive has a glass transition temperature of about-15 ℃ to about-30 ℃.

19. A transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) about 14% galantamine or a pharmaceutically acceptable salt thereof;

(iv) about 0.05% of an antioxidant,

wherein the transdermal system has a thickness of about 15-45 μm.

20. The transdermal delivery system according to any one of the previous claims, wherein the adhesive has a glass transition temperature of about-30 ℃ to about-60 ℃.

21. A transdermal delivery system according to any one of the preceding claims wherein the antioxidant is butylated hydroxytoluene, vitamin E, ascorbyl palmitate, bronopol, erythorbic acid, thioglycerol, sodium metabisulphite, sodium sulphite, sulphur dioxide or sodium thiosulphate.

22. The transdermal delivery system according to any one of the preceding claims, wherein the system has about 8 μ g/cm²hrThe flux of (c).

23. A transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) about 14% galantamine or a pharmaceutically acceptable salt thereof;

(iv) about 0.05% of an antioxidant agent,

wherein the transdermal system has a thickness of about 15-45 μm.

24. The transdermal delivery system according to any one of the previous claims, wherein the adhesive has a glass transition temperature of about-30 ℃ to about-60 ℃.

25. The transdermal delivery system according to any one of the preceding claims, wherein the system has from about 9.3 to about 9.5 μ g/cm²hr of flux.

26. The transdermal delivery system according to any one of the previous claims, wherein the galantamine or pharmaceutically acceptable salt thereof is about 14% by weight, wherein the adhesive is about 76% by weight, wherein the oleic acid oleyl ester is about 5% by weight, wherein the medium chain fatty acid triglyceride is about 10%, wherein the polyethylene glycol is about 5%, wherein the antioxidant is butylated hydroxytoluene, which is about 0.05% by weight, and wherein the drug-containing matrix layer has a thickness of about 15-45 μ ι η, based on the total weight of the drug-containing matrix layer.

27. The transdermal delivery system according to any one of the preceding claims, wherein the system has about 1-15 μ g/cm²hr of flux.

28. A transdermal delivery system comprising a drug-containing matrix layer comprising:

(i) galantamine or a pharmaceutically acceptable salt thereof;

(ii) an adhesive comprising a styrene-butadiene-styrene block copolymer;

(iv) antioxidants, solvents, and adhesive modifiers.

29. The transdermal delivery system according to any one of the preceding claims, wherein the antioxidant is butylated hydroxytoluene, vitamin E, ascorbyl palmitate, bronopol, erythorbic acid, thioglycerol, sodium metabisulfite, sodium sulfite, sulfur dioxide, sodium thiosulfate, and combinations thereof, wherein the solvent is diethylene glycol monoethyl ether, and wherein the adhesive modifier is a cyclic terpene.

30. The transdermal delivery system according to any of the previous claims, wherein the transdermal delivery system consists of a backing layer, a drug-containing matrix layer and a release layer.

31. The transdermal delivery system according to any one of the preceding claims, wherein the galantamine or pharmaceutically acceptable salt thereof is from about 0.01 to about 5% by weight based on the total weight of the drug-containing matrix layer.

32. The transdermal delivery system according to any one of the previous claims, wherein the styrene-butadiene-styrene block copolymer is about 60 to 97.5 wt% based on the total weight of the drug-containing matrix layer.

33. A transdermal delivery system according to any one of the previous claims wherein the enhancer composition is from about 3 to about 15% by weight based on the total weight of the drug-containing matrix layer.

34. The transdermal delivery system according to any one of the previous claims, wherein the propylene glycol monolaurate is about 0.1-15 wt% based on the total weight of the drug-containing matrix layer.

35. The transdermal delivery system according to any one of the previous claims, wherein the oleic acid ester is from about 0.1 to 20% by weight based on the total weight of the drug-containing matrix layer.

36. A transdermal delivery system according to any one of the previous claims wherein the antioxidant is butylated hydroxytoluene and is present in an amount of about 0.001 to 0.5% by weight based on the total weight of the drug-containing matrix layer.

37. A transdermal delivery system according to any one of the preceding claims wherein the solvent is diethylene glycol monoethyl ether and is present in an amount of about 0.1-20 wt% based on the total weight of the drug-containing matrix layer.

38. The transdermal delivery system according to any one of the previous claims, wherein the adhesive modifier is a cyclic terpene and is present in an amount of about 0.1 to 15% by weight, based on the total weight of the drug-containing matrix layer.

39. The transdermal delivery system according to any one of the preceding claims, wherein the propylene glycol monolaurate is propylene glycol monolaurate type I or propylene glycol monolaurate type II.

40. The transdermal delivery system according to any one of the previous claims, wherein the drug-containing matrix layer has a thickness of about 45 μm to about 85 μm.

41. The transdermal delivery system according to any one of the previous claims, wherein the galantamine or pharmaceutically acceptable salt thereof is about 2.5 wt%, wherein the styrene-butadiene-styrene block copolymer is about 60-97.5 wt%, wherein the propylene glycol monolaurate is about 0.1-15 wt%, wherein the oleic acid oleoresin is about 0.1-20 wt%, wherein the antioxidant is butylated hydroxytoluene and is about 0.001-0.5 wt%, wherein the solvent is diethylene glycol monoethyl ether and is about 0.1-20 wt%, and wherein the adhesive modifier is a cyclic terpene and is about 0.1-15 wt%, based on the total weight of the drug-containing matrix layer.

42. The transdermal delivery system according to any one of the preceding claims, wherein the propylene glycol monolaurate is propylene glycol monolaurate type I or propylene glycol monolaurate type II.

43. A transdermal delivery system comprising a drug-containing matrix layer comprising:

(v) about 0.001-0.5% of an antioxidant;

(vi) about 0.1-20% solvent; and

(vii) about 0.1-15% of an adhesive modifier.

44. The transdermal delivery system according to any one of the preceding claims, wherein the galantamine is about 2.5% by weight based on the total weight of the drug-containing matrix layer.

45. A transdermal delivery system according to any one of the previous claims wherein the enhancer composition is from about 3 to 8% by weight based on the total weight of the drug-containing matrix layer.

46. The transdermal delivery system according to any one of the preceding claims, wherein the propylene glycol monolaurate is propylene glycol monolaurate type I or propylene glycol monolaurate type II.

47. A transdermal delivery system according to any one of the preceding claims wherein the antioxidant is butylated hydroxytoluene.

48. A transdermal delivery system according to any one of the preceding claims wherein the solvent is diethylene glycol monoethyl ether.

49. A transdermal delivery system according to any one of the preceding claims wherein the adhesive modifier is a cyclic terpene.

50. The transdermal delivery system according to any one of the previous claims, wherein the enhancer composition is about 3, about 5 or about 8 weight percent based on the total weight of the drug-containing matrix layer.