US20180028463A1 - Transdermal formulation and delivery method of low solubility or unstable unionized neutral drugs by in situ salt-to-neutral drug conversion of salt drug - Google Patents

Transdermal formulation and delivery method of low solubility or unstable unionized neutral drugs by in situ salt-to-neutral drug conversion of salt drug Download PDF

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US20180028463A1
US20180028463A1 US15/660,935 US201715660935A US2018028463A1 US 20180028463 A1 US20180028463 A1 US 20180028463A1 US 201715660935 A US201715660935 A US 201715660935A US 2018028463 A1 US2018028463 A1 US 2018028463A1
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composition
drug reservoir
active agent
drug
adhesive
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Eun Soo Lee
Amit K. Jain
Parminder Singh
Appala Sagi
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Corium LLC
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Corium International Inc
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Publication of US20180028463A1 publication Critical patent/US20180028463A1/en
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Definitions

  • compositions, devices, and methods for transdermal administration of active agents provided in their salt form instead of neutral form relate to compositions, devices, and methods for transdermal administration of active agents provided in their salt form instead of neutral form.
  • Active agents for transdermal delivery are typically provided in their neutral form because the neutral form is typically much more skin permeable than a corresponding salt form.
  • a neutral form of an active agent is solubilized in a drug reservoir (also referred to sometimes as an adhesive matrix), and the active agent diffuses from the drug reservoir and into the skin.
  • Transdermal patches therefore, typically contain as much active agent dissolved in the drug reservoir as the agent's solubility in the components of the 23-30 allows, often with solubilizers to enhance its solubility.
  • neutral, solid particles of active agent are sometimes dispersed in the drug reservoir, so long as the particles' dissolution rate is such that a constant supply of dissolved active agent is provided.
  • a neutral form is difficult to solubilize, formulate, and/or administer to a patient or subject.
  • a drug has a low solubility as a unionized neutral form in a drug reservoir, it is difficult to incorporate sufficient amount as a solubilized form to deliver at a therapeutic level for multiple days.
  • a dissolved active agent may recrystallize as large crystals during the process of solvation, coating, and drying. Further, many active agents are less stable in neutral form than in salt form.
  • compositions for transdermal delivery comprises a drug reservoir comprising a salt form of an active agent and a proton accepting and/or proton donating entity.
  • composition for transdermal delivery comprises a drug reservoir comprising an amine salt form of an active agent and a proton accepting entity.
  • the active agent is donepezil, rivastigmine, memantine, fingolimod, or tamsulosin.
  • the drug reservoir comprises between about 1-70 w/w of the active agent.
  • the proton accepting entity is a proton accepting polymer.
  • the proton accepting entity is an amine functionalized polystyrene miscrosphere or a dimethyl aminoethyl methacrylate-based acrylate.
  • the proton accepting entity is sodium bicarbonate. In other embodiments, the proton accepting entity excludes sodium bicarbonate.
  • the drug reservoir comprises between about 0.5-35% w/w of the proton accepting entity.
  • a composition for transdermal delivery comprises a drug reservoir comprising an acid salt form of an active agent and a proton donating polymer.
  • the active agent is an acid salt drug selected from the group consisting of sodium alendronate, tresprostinil sodium, sodium diclofenac, naproxen sodium, and ketoprofen sodium.
  • the drug reservoir comprises between about 5-35% w/w of the active agent.
  • the proton donating polymer is an anionic copolymer based on methacrylic acid or a carboxylated polystyrene microsphere.
  • the drug reservoir comprises between about 0.5-35% w/w of the proton donating polymer.
  • the composition can further comprise a salt form solubilizer selected from the group consisting of water, alcohols, glycerol, propylene glycol, ethylene glycol, dimethyl sulfoxide, and N-methylpyrrolidone.
  • a salt form solubilizer selected from the group consisting of water, alcohols, glycerol, propylene glycol, ethylene glycol, dimethyl sulfoxide, and N-methylpyrrolidone.
  • the drug reservoir comprises up to 15% w/w of the salt form solubilizer.
  • the composition can further comprise a neutral form solubilizer selected from the group consisting of a fatty acid ester, a dicarboxylic acid ester, a glycerol ester, a lactate, a fatty alcohol, sorbitan monolaurate, sorbitan monooleate, lauryl lactate, propylene glycol monolaurate, dimethyl succinate, lauryl alcohol, and oleyl alcohol.
  • a neutral form solubilizer selected from the group consisting of a fatty acid ester, a dicarboxylic acid ester, a glycerol ester, a lactate, a fatty alcohol, sorbitan monolaurate, sorbitan monooleate, lauryl lactate, propylene glycol monolaurate, dimethyl succinate, lauryl alcohol, and oleyl alcohol.
  • the drug reservoir comprises up to 15% w/w of the neutral form solubilizer.
  • the composition can comprises a plasticizer selected from the group consisting of a dicarboxylic acid ester, an adipate, a sebacate, a maleate, a tricarboxylic ester, triethyl citrate, tributyl citrate, a glycerol esters, and triacetin.
  • a plasticizer selected from the group consisting of a dicarboxylic acid ester, an adipate, a sebacate, a maleate, a tricarboxylic ester, triethyl citrate, tributyl citrate, a glycerol esters, and triacetin.
  • the drug reservoir comprises up to 20% w/w of the plasticizer.
  • the composition comprises an additive selected from the group consisting of crospovidone and colloidal silicone dioxide.
  • the drug reservoir comprises up to 25% w/w of additive.
  • the drug reservoir comprises an adhesive agent selected from the group consisting of an acrylate, polyisobutylene, silicone adhesive, and styrene block copolymer based adhesive.
  • the drug reservoir comprises up to 65% w/w of the adhesive agent.
  • transdermal patch comprising a drug reservoir layer as described herein, a backing layer, and a contact adhesive layer is provided.
  • the backing layer is an occlusive polymer film.
  • the contact adhesive layer comprises an adhesive selected from the group consisting of an acrylate, polyisobutylene, silicone adhesive, and styrene block copolymer based adhesive.
  • the transdermal patch further comprises a nonwoven tie layer between the drug reservoir and the contact adhesive layer.
  • the transdermal patch further comprises a rate-controlling membrane between the drug reservoir and the contact adhesive layer.
  • the transdermal patch comprises at least two drug reservoir layers.
  • the at least two drug reservoir layers are separated by a nonwoven tie layer.
  • FIGS. 1-3 are illustrations of exemplary embodiments of transdermal patch configurations.
  • FIG. 4 is a graph of average skin flux for donepezil transdermal delivery devices, in ⁇ g/cm 2 ⁇ hr, in vitro as a function of time, in hours, in an in vitro skin permeation test for devices having formulations according to Example 1 (squares), Example 2 (triangles), and Example 7 (circles).
  • FIG. 5 is a graph of average skin flux for memantine transdermal delivery devices, in ⁇ g/cm 2 ⁇ hr, in vitro as a function of time, in hours, in an in vitro skin permeation test for devices having a formulation according to Example 4.
  • compositions, devices, and methods described herein are not limited to the specific polymers, excipients, cross-linking agents, additives, manufacturing processes, or adhesive products described herein. It will be understood that the particular terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting.
  • active agent refers to a chemical material or compound suitable for topical or transdermal administration and that induces a desired effect.
  • the terms include agents that are therapeutically effective, prophylactically effective, and cosmetically effective agents.
  • active agent drug
  • therapeutic agent are used interchangeably herein.
  • an “adhesive matrix” as described herein includes matrices made in one piece, for example, matrices made via solvent casting or extrusion as well as matrices formed in two or more portions that are then pressed or joined together.
  • skin refers to skin or mucosal tissue, including the interior surface of body cavities that have a mucosal lining.
  • skin should be interpreted as including “mucosal tissue” and vice versa.
  • therapeutically effective amount refers to the amount of an active agent that is nontoxic but sufficient to provide the desired therapeutic effect.
  • amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like as known to those skilled in the art.
  • transdermal refers to administration of an active agent to a body surface of an individual so that the agent passes through the body surface (e.g., through the skin) and into the individual's blood stream.
  • transdermal is intended to include transmucosal administration, i.e., administration of a drug to the mucosal (e.g., sublingual, buccal, vaginal, rectal, etc.) surface of an individual so that the agent passes through the mucosal tissue and into the individual's blood stream.
  • compositions and/or devices are provided for transdermal administration of active agents.
  • Compositions may be used in devices, patches, and/or systems for transdermal delivery of one or more active agents.
  • Compositions described herein are contemplated for use in transdermal delivery systems, devices, patches, and/or methods as described herein.
  • Active agents for transdermal delivery are typically provided in their neutral form because the neutral form is typically much more skin permeable than a corresponding salt form. Many active agents, however, are difficult to solubilize in a sufficient amount in a neutral form, difficult to administer in a neutral form at a steady rate for multiple days, and/or less stable in a neutral form than a salt form. As such, the present invention encompasses the recognition that certain active agents are better suited for administration in their salt forms.
  • compositions described herein provide an active agent in its salt form and at least one proton donating or proton accepting entity.
  • the proton donating or proton accepting entity promotes conversion of the active agent from a salt to its neutral form to improve skin permeability of the active agent.
  • compositions contain one or more additional ingredients (for example, solubilizers, plasticizers, matrix modifying additives, and/or adhesives).
  • active agent compositions described herein can be provided in the form of a transdermal drug delivery device, such as a patch.
  • compositions for Transdermal Delivery of Active Agents A. Compositions for Transdermal Delivery of Active Agents
  • compositions comprising a layer or matrix comprised of an adhesive, a salt form of at least one active agent and at least one proton accepting or proton donating entity are provided.
  • the salt form of a provided active agent will react with a provided proton accepting or proton donating entity in order to generate a neutral form of the active agent that is more skin permeable than the salt form.
  • the adhesive composition may include one or more additional ingredients that cause the neutral form of the active agent to be generated at a specified and/or desired rate.
  • Such compositions can provide, in some embodiments, a relatively constant activity of an active agent.
  • compositions may further include one or more of the following: one salt form solubilizer (total 0-50% w/w), one neutral form solubilizer (total 0-50% w/w), one plasticizer for a proton accepting entity and/or proton donating entity (total 0-50% w/w), matrix modifying additives (total 0-50% w/w), and adhesive polymers (total 0-95% w/w).
  • w/w % or wt % described herein may refer to wet or dry weight of the composition.
  • compositions comprise micronized particles of a salt form of one or more active agents dispersed in an adhesive matrix or a drug reservoir.
  • the salt form of at least one active agent is present in the drug reservoir in an amount between about 1-70 wt %, about 1-50 wt %, about 1-35 wt %, about 1-25 wt %, about 2-70 wt %, about 2-50 wt %, about 2-35 wt %, about 5-70 wt %, about 5-50 wt %, about 5-35 wt %, about 5-30 wt %, about 5-25 wt %, about 5-20 wt %, about 5-15 wt %, about 5-10 wt %, about 10-35 wt %, about 10-30 wt %, about 10-25 wt %, about 10-20 wt %, about 10-15 wt %, about 20-35 wt %, about 20-30 wt
  • the drug reservoir further comprises a solubilizer that has a limited solubility for the salt form of an active agent (the “salt form solubilizer”).
  • the micronized particles of a salt form of an active agent will ionize in the salt form solubilizer.
  • the micronized salt form particles will be maintained in equilibrium with the dissolved, ionized salt form.
  • the salt form solubilizer has only a limited degree of solubility for the micronized salt particles, such that the equilibrium favors the micronized salt particles over the dissolved, ionized salt form.
  • a salt form solubilizer has a solubility for the salt of at least about 0.1% w/w, at least about 0.2% w/w, at least about 0.3% w/w, at least about 0.4% w/w, at least about 0.5% w/w, or at least about 1.0% w/w. In some embodiments, the salt form solubilizer has a solubility for the salt of less than about 30% w/w or less than about 25% w/w or 20% w/w.
  • a salt form solubilizer is a protic solvent (e.g., a solvent that has a hydrogen atom bound to an oxygen (e.g., as in a hydroxyl group) or a nitrogen (e.g., as in an amine group), and/or any solvent that contains labile protons).
  • exemplary salt form solubilizers include, but are not limited to, water, alcohols (e.g., ethanol, methanol, etc.), glycerol, propylene glycol, ethylene glycol, dimethyl sulfoxide, N-methylpyrrolidone, and/or combinations thereof.
  • the drug reservoir comprises about 0-50 wt %, about 0-20 wt %, about 0-10 wt %, about 0-5 wt %, about 1-50 wt %, about 1-20 wt %, about 2-50 wt %, about 2-20 wt %, about 5-50 wt %, about 5-20 wt %, about 5-15 wt %, about 5-10 wt %, or about 10-15 wt % of at least one salt form solubilizer.
  • the dissolved, ionized salt form will react with a proton accepting entity (for amine drug salt) or a proton donating entity (for carboxylic drug salt), also provided in the matrix.
  • proton accepting entities have primary, secondary, or tertiary amine groups.
  • proton donating entities have carboxylic groups.
  • proton accepting entities and/or proton donating entities are dissolved and intermixed with the drug reservoir.
  • proton accepting entities and/or proton donating entities are dispersed as fine particles.
  • proton accepting entities and/or proton donating entities are plasticized.
  • a drug reservoir comprises about 0.5-30 wt %, about 1-30 wt %, about 5-30 wt %, about 10-30 wt %, about 15-30 wt %, about 20-30 wt %, about 25-30 wt %, about 0.5-25 wt %, about 1-25 wt %, about 5-25 wt %, about 10-25 wt %, about 15-25 wt %, about 20-25 wt %, about 0.5-20 wt %, about 1-20 wt %, about 5-20 wt %, about 10-20 wt %, about 15-20 wt %, about 0.5-15 wt %, about 1-15 wt %, about 5-15 wt %, about 10-15 wt %, about 0.5-10 wt %, about 1-10 wt %, about 5-10 wt %, about 0.5-5 wt %, or about 1-5 wt %, about
  • a proton accepting entity or proton donating entity is a polymer.
  • proton accepting entities are amine-functional polymers.
  • Exemplary proton accepting polymers include, but are not limited to, amine-functionalized polystyrene miscrosphere, dimethyl aminoethyl methacrylate based acrylates (e.g., EUIDRAGIT® EPO or EUDRAGIT® E100), and/or combinations thereof.
  • proton donating entities are carboxylic-functional polymers.
  • Exemplary proton donating polymers include, but are not limited to, anionic copolymers based on methacrylic acid and polyacrylic acid (e.g., EUDRAGIT® L100, EUDRAGIT® L100-55, EUDRAGIT® S100), carboxylated polystyrene microsphere, and/or combinations thereof.
  • anionic copolymers based on methacrylic acid and polyacrylic acid e.g., EUDRAGIT® L100, EUDRAGIT® L100-55, EUDRAGIT® S100
  • carboxylated polystyrene microsphere e.g., carboxylated polystyrene microsphere, and/or combinations thereof.
  • the reaction of a salt form of an active agent with a proton accepting polymer or proton donating polymer will generate a skin permeable, neutral form of the active agent and a solid polymer.
  • the neutral active agent is depleted (by diffusion into the skin) and the polymer becomes separated as a solid phase in the matrix, the reaction continues to move forward, maintaining a relatively steady concentration and/or activity of the neutral form.
  • the proton accepting entity for an amine drug salt is an inorganic salt with mild basicity whose pKa is lower than that of the amine drug salt.
  • the proton accepting entity for an amine drug salt is a sodium bicarbonate.
  • the reaction products include a skin permeable, neutral form of the active agent, water, and carbon dioxide. As the neutral active agent and CO 2 are depleted (by diffusion into the skin and escaped gas, respectively), the reaction continues to move forward, maintaining a relatively steady concentration and/or activity of the neutral form.
  • compositions further comprise one or more solubilizers for the neutral form of the active agent (a “neutral form solubilizer”).
  • a neutral form solubilizer helps ensure that a neutral active agent, once formed, can persist long enough to diffuse into the skin.
  • a neutral form solubilizer has a solubility for the neutral form of the active agent of at least about 0.1% w/w. In some embodiments, the neutral form solubilizer has a solubility for the neutral form of the active agent of less than about 30% w/w.
  • exemplary neutral form solubilizers generally include, but are not limited to, fatty acid esters, lactate esters, dicarboxylic esters, citrate esters, glycerol esters, fatty alcohols, and/or combinations thereof.
  • exemplary neutral form solubilizers include, but are not limited to, sorbitan monooleate, sorbitan monolaurate (Span® 20), propylene glycol monolaurate, lauryl lactate, dimethyl succinate, triethyl citrate, triacetin, lauryl alcohols, oleyl alcohols, and/or combinations thereof.
  • the drug reservoir comprises about 0-40 wt %, about 0-30 wt %, about 0-20 wt %, about 0-15 wt %, about 0-10 wt %, about 0-5 wt %, about 1-40 wt %, about 1-30 wt %, about 1-20 wt %, about 2-40 wt %, about 2-30 wt %, about 2-20 wt %, about 5-20 wt %, about 1-15 wt %, about 2-15 wt %, about 5-15 wt %, about 5-10 wt %, or about 10-15 wt % of at least one neutral form solubilizer.
  • active agents include amine salt drugs or acid salt drugs.
  • the active agent is an amine salt drug.
  • amine salt drugs have a solubility of at least about 0.1 mg/g, at least about 0.2 mg/g, at least about 0.3 mg/g, at least about 0.4 mg/g, at least about 0.5 mg/g, or at least about 1.0 mg/g in the drug reservoir. In some embodiments, amine salt drugs have a solubility of less than about 100 mg/g in the drug reservoir.
  • Exemplary amine salt drugs include, but are not limited to, donepezil, rivastigmine, memantine, tamsulosin, rotigotine, fentanyl, escitalopram, ropinirole, pramipexole, buprenorphine, fingolimod and lidocaine.
  • a micronized amine salt form of an active agent is dispersed in a matrix that further comprises at least one salt form solubilizer.
  • the salt form of the active agent (“DHCl”) is partially dissolved and ionized, as shown in Equation 1:
  • the dissolved, ionized active agent (“DH + ”) interacts with a proton acceptor amine polymer (“PolymerN”) as shown in Equation 2. As the neutral form of the active agent (“D”) is depleted by diffusion, the reaction moves toward continuous formation of D.
  • reaction byproduct (“Polymer NHCl”) is sequestered as solid phase in the matrix.
  • the neutral form of the active agent (“D”) is depleted by diffusion through into the skin.
  • a basic inorganic salt whose pKa is lower than an amine salt drug can also be used to generate a neutral form of the drug.
  • sodium bicarbonate can be used as a proton accepting entity for an amine salt drug.
  • sodium bisulfate is the protein accepting entity for an amine salt drug.
  • Equation 5 Ionization of sodium bicarbonate is shown in Equation 5, which generates a sodium ion and a bicarbonate ion:
  • a bicarbonate ion accepts a proton from the amine salt drug to form carbonic acid.
  • Carbonic acid decomposes into water and carbon dioxide, which escapes from the patch.
  • the neutral active agent “D” is depleted by diffusion into the skin, the equilibrium of Equation (8) moves toward the right (continuous formation of neutral drug “D”).
  • the active agent is an acid salt drug.
  • acid salt drugs have a solubility of at least about 0.1 mg/g, at least about 0.2 mg/g, at least about 0.3 mg/g, at least about 0.4 mg/g, at least about 0.5 mg/g, or at least about 1.0 mg/g in the drug reservoir. In some embodiments, acid salt drugs have a solubility of less than about 100 mg/g in the drug reservoir. Exemplary acid salt drugs include, but are not limited to sodium alendronate, tresprostinyl sodium, sodium diclofenac, ketoprofen sodium, etc.
  • a micronized acid salt form of an active agent is dispersed in a matrix that further comprises at least one salt form solubilizer.
  • the salt form of the active agent (“ANa”) is partially dissolved and ionized, as shown in Equation 9:
  • the dissolved, ionized active agent (“A′”) interacts with a proton donor polymer (“PolymerCOOH”) as shown in Equation 10.
  • AH proton donor polymer
  • reaction byproduct (“Polymer COONa”) is sequestered as solid phase in the matrix.
  • the neutral form of the active agent (“AH”) is depleted by diffusion through into the skin.
  • Equation 11 the equilibrium constant is expressed as in Equation 11:
  • a composition for transdermal delivery of an active agent further comprises one or more plasticizers for the proton accepting or proton donating entity.
  • plasticizers for the proton accepting or proton donating entity may also serve as plasticizers for the proton accepting or proton donating entities.
  • a plasticizer that does not also serve as a salt form and/or neutral form solubilizer is included in a composition.
  • Exemplary plasticizers include, but are not limited to, dicarboxylic acid esters (e.g., adipates, sebacates, maleates, etc.), tricarboxylic esters (e.g., triethyl citrate, tributyl citrate, etc.), esters of glycerol (e.g., triacetin, etc.), and/or combinations thereof.
  • dicarboxylic acid esters e.g., adipates, sebacates, maleates, etc.
  • tricarboxylic esters e.g., triethyl citrate, tributyl citrate, etc.
  • esters of glycerol e.g., triacetin, etc.
  • an adhesive matrix or drug reservoir comprises about 0-20 wt %, about 0-15 wt %, about 0-10 wt %, about 0-5 wt %, about 5-20 wt %, about 5-15 wt %, about 5-10 wt %, about 10-20 wt %, about 10-15 wt %, or about 15-20 wt % of at least one plasticizer.
  • a composition for transdermal delivery of an active agent further comprises at least one additive, also referred to as a matrix modifying additive.
  • matrix modifying additives modify cohesion and/or diffusivity of described active agent compositions.
  • matrix modifying additives can absorb moisture and/or water emanating from the skin under occlusion, which improves adhesion to the skin.
  • matrix modifying additives facilitate homogenization of the drug reservoir.
  • Exemplary matrix modifying additives include, but are not limited to, crospovidone (KOLLIDON® CL-M, etc.), cross-linked polyvinylpyrrolidone (PVP), a soluble polyvinylpyrrolidone (PVP), fumed silica, colloidal silicone dioxide, a cellulose derivative (e.g. hydroxypropyl cellulose (HPC), hydroxyethylcellulose (HEC)), a polyacrylamide, a polyacrylic acid, a polyacrylic acid salt, a clay (e.g., kaolin, bentonite, etc.), fumed silica, and/or combinations thereof.
  • crospovidone KLLIDON® CL-M, etc.
  • PVP cross-linked polyvinylpyrrolidone
  • PVP a soluble polyvinylpyrrolidone
  • fumed silica colloidal silicone dioxide
  • a cellulose derivative e.g. hydroxypropyl cellulose (HPC), hydroxyethy
  • An exemplary commercial fumed silica product is AEROSIL® 200P, an amorphous, anhydrous colloidal silicon dioxide (Evonik Industries).
  • Another exemplary fumed silica product is Cab-O-Sil® (Cabot Corporation, Boston, Mass.).
  • the drug reservoir comprises about 0-25 wt %, about 0-20 wt %, about 0-15 wt %, about 0-10 wt %, about 0-5 wt %, about 5-25 wt %, about 5-20 wt %, about 5-15 wt %, about 5-10 wt %, about 10-25 wt %, about 10-20 wt %, about 10-15 wt %, about 15-25 wt %, about 15-20 wt %, or about 20-25 wt % of at least one matrix modifying additive.
  • a composition for transdermal delivery of an active agent further comprises an adhesive or adhesive polymer.
  • adhesives and adhesive polymers include, but are not limited to, acrylates, polyisobutylene, silicone adhesive, styrene block copolymer based adhesives, and/or combinations thereof.
  • proton accepting and/or proton donating polymers are film-formable in the presence of salt form and/or neutral form solubilizers. In such embodiments, compositions may not require a separate adhesive polymer.
  • the drug reservoir comprises about 0-65 wt %, about 0-60 wt %, about 0-55 wt %, about 0-50 wt %, about 0-45 wt %, about 0-40 wt %, about 0-35 wt %, about 0-30 wt %, about 0-25 wt %, about 0-20 wt %, about 0-15 wt %, about 0-10 wt %, about 0-5 wt %, 5-65 wt %, about 5-60 wt %, about 5-55 wt %, about 5-50 wt %, about 5-45 wt %, about 5-40 wt %, about 5-35 wt %, about 5-30 wt %, about 5-25 wt %, about 5-20 wt %, about 5-15 wt %, about 5-10 wt %, 10-65 wt %, about
  • the composition may also include other conventional additives such as adhesive agents, antioxidants, crosslinking agents, curing agents, pH regulators, pigments, dyes, refractive particles, conductive species, antimicrobial agents, opacifiers, gelling agents, viscosity modifiers, thickening agents, stabilizing agents, and the like as known in the art.
  • adhesive agents such as adhesive agents, antioxidants, crosslinking agents, curing agents, pH regulators, pigments, dyes, refractive particles, conductive species, antimicrobial agents, opacifiers, gelling agents, viscosity modifiers, thickening agents, stabilizing agents, and the like as known in the art.
  • conventional detackifying agents may also be used.
  • agents such as antimicrobial agents are included to prevent spoilage upon storage, e.g., to inhibit growth of microbes such as yeasts and molds.
  • Suitable antimicrobial agents are typically selected from the group consisting of the methyl and propyl esters of p-hydroxybenzoic acid (e.g., methyl and propyl paraben), sodium benzoate, sorbic acid, imidurea, and/or combinations thereof. These additives, and amounts thereof, are selected in such a way that they do not significantly interfere with the desired chemical and physical properties of the adhesive and/or active agent.
  • Compositions may also contain irritation-mitigating additives to minimize or eliminate the possibility of skin irritation and/or skin damage resulting from the active agent, the proton donating or proton accepting entity, salt form solubilizer, neutral form solubilizer, plasticizer, matrix modifying additive, adhesive and/or other components of the composition.
  • Suitable irritation-mitigating additives include, for example: corticosteroids; ⁇ -tocopherol; monoamine oxidase inhibitors, particularly phenyl alcohols such as 2-phenyl-1-ethanol; glycerin; salicylic acids and salicylates; ascorbic acids and ascorbates; ionophores such as monensin; amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanic acid; capsaicin; and chloroquine; and/or combinations thereof.
  • corticosteroids include, for example: corticosteroids; ⁇ -tocopherol; monoamine oxidase inhibitors, particularly phenyl alcohols such as 2-phenyl-1-ethanol; glycerin; salicylic acids and salicylates; ascorbic acids and ascorbates; ionophores such as monensin; amphiphilic amines; ammonium chloride; N-acet
  • Methods for preparing or manufacturing active agent compositions are also provided. Exemplary methods are set forth in the Examples section. Methods for preparing active agent compositions generally involve mixing an active agent at 5-35% w/w with a proton accepting or proton donating entity at 0.5-30% w/w, optionally along with a salt form solubilizer at 0-15% w/w, a neutral form solubilizer at 0-15% w/w, a matrix modifying additive at 0-25% w/w, a plasticizer at 0-20% w/w, an adhesive polymer at 0-65% w/w, and/or combinations thereof.
  • transdermal devices e.g., patches
  • transdermal patches comprise a backing layer, at least one drug reservoir, and a contact adhesive layer.
  • the drug reservoir and contact adhesive layer can be in the form of a single layer or matrix comprised of an adhesive and a drug.
  • transdermal patches further comprise one or more release liners, tie layers, rate-controlling membranes, and/or various combinations of the foregoing.
  • transdermal patches comprise one or more of the following components: backing layer, drug reservoir, contact adhesive layer, release liner, tie layer, rate-controlling membrane, and/or various combinations of the foregoing.
  • FIG. 1 shows an exemplary transdermal patch 10 comprising a backing layer 12 , multiple drug reservoirs 14 , 16 separated by a nonwoven tie layer or a rate controlling membrane 18 , a contact adhesive layer 20 , and a release liner 22 .
  • This particular example presents multiple drug reservoirs separated by a tie layer or a rate controlling membrane 18 , but in some embodiments, multiple adhesive layers may be in direct contact with each other without a tie layer, such as optional tie layer 19 .
  • each drug reservoir may comprise the same or different active agents.
  • each drug reservoir may comprise different concentrations of the same active agent.
  • FIG. 2 shows an exemplary transdermal patch 30 comprising a backing layer 32 , a drug reservoir 34 , a tie layer or rate-controlling membrane 36 , a contact adhesive layer 38 , and a release liner 39 .
  • FIG. 3 shows an exemplary transdermal patch 40 comprising a backing layer 42 , a drug reservoir 44 , a contact adhesive layer 46 , and a release liner 48 .
  • a backing layer provides a structural element for holding or supporting the adhesive layer.
  • a backing layer may be formed of any suitable material as known in the art.
  • a backing layer is occlusive.
  • a backing layer is preferably impermeable or substantially impermeable to moisture.
  • the barrier layer has an MVTR (moisture vapor transmission rate) of less than about 50 g/m 2 -day.
  • a backing layer is preferably inert and/or does not absorb components of the adhesive layer, including the active agent.
  • a backing layer preferably prevents release of components of the adhesive layer through the backing layer.
  • a backing layer may be flexible or nonflexible.
  • a backing layer is preferably at least partially flexible such that the backing layer is able to conform at least partially to the shape of the skin where the patch is applied.
  • a backing layer is flexible such that the backing layer conforms to the shape of the skin where the patch is applied.
  • a backing layer is sufficiently flexible to maintain contact at the application site with movement, e.g., skin movement.
  • the material used for a backing layer should permit the device to follow the contours of the skin or other application site and be worn comfortably on areas of skin such as at joints or other points of flexure, that are normally subjected to mechanical strain with little or no likelihood of the device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device.
  • a backing layer is formed of one or more of a film, non-woven fabric, woven fabric, laminate, and combinations thereof.
  • the film is a polymer film comprised of one or more polymers. Suitable polymers are known in the art and include, but are not limited to, elastomers, polyesters, polyethylene, polypropylene, polyurethanes, polyether amides, and/or combinations thereof.
  • a backing layer is formed of one or more of polyethylene terephthalate, various nylons, polypropylene, metalized polyester films, polyvinylidene chloride, aluminum foil, and/or combinations thereof.
  • a backing layer is a fabric formed of one or more of polyesters such as polyethylene terephthalate, polyurethane, polyvinyl acetate, polyvinylidene chloride, polyethylene, and/or combinations thereof.
  • the backing layer is formed of a polyester film laminate.
  • Exemplary particular polyester film laminates include, but are not limited to, the polyethylene and/or polyester laminates such as those sold under the names ScotchpakTM #9723, ScotchpakTM #1012, and the like.
  • the drug reservoir generally comprises a salt form of an active ingredient(s) (total 5-35% w/w), at least one salt form solubilizer (total 0-20% w/w), at least one neutral form solubilizer (total 0-20% w/w), at least one proton accepting entity and/or proton donating entity (total 0.5-30% w/w), optionally at least one plasticizer for a proton accepting entity and/or proton donating entity (total 0-20% w/w), matrix modifying additives (total 0-25% w/w), and optionally adhesive polymers (total 0-65% w/w).
  • the drug reservoir comprises any of the compositions for transdermal delivery described herein, e.g., in the Examples and in Section II.A.
  • a tie layer comprises a nonwoven fabric and/or a rate controlling polymer membrane.
  • devices further include one or more fabric or tie layers within or between the drug reservoir layers. It will be appreciated that a tie layer may be included between one, some, or all of the layers. In some embodiments, a tie layer is useful to increase bonding between layers of the device. Tie layers may increase bonding by providing chemical groups for the polymers to bind. In some embodiments, a tie layer is useful as a separation for adhesive matrix layers.
  • tie layer does not affect the rate of release of an active agent from the adhesive layers.
  • tie layers may comprise nonwoven films that include, but are not limited to, nonwoven polyesters (e.g., REEMAY®), porous polyethylene film (DELNET®), nylon, cotton, and the like, and/or combinations thereof.
  • tie layers may comprise rate controlling polymer membranes.
  • rate controlling polymer membranes include, but are not limited to, microporous polymer films such as CELGARD® 2400 (microporous polypropylene), polyethylenes (e.g., microporous polyethylene), vinyl acetate polymers and copolymers, and the like, and/or combinations thereof.
  • a rate controlling polymer membrane allows for a rate-controlled release of the drug from the drug reservoir layer.
  • the tie layer comprises a nonwoven fabric and does not comprise a rate controlling polymer membrane. In some embodiments, a tie layer comprises a rate controlling polymer membrane and does not comprise a nonwoven fabric. In some embodiments, a tie layer comprises both a nonwoven fabric and a rate controlling polymer membrane. To give but one example, a nonwoven fabric and a rate controlling polymer membrane may both be used when the tie layer is embedded within the drug reservoir to help improve drug reservoir cohesion (see, e.g., FIG. 1 ).
  • the device includes at least one adhesive layer.
  • at least one of the adhesive layers is an adhesive matrix comprising one or more active agents as described below.
  • the adhesive layer adheres to a drug reservoir, an adjacent adhesive layer, a tie layer, a release liner, and/or skin at the administration site.
  • an adhesive layer serves to release the active agent to the skin.
  • one or more of the drug reservoir adhesive and/or the contact layer adhesive are formed of an adhesive matrix.
  • Exemplary adhesives include, but are not limited to, acrylates, polyisobutylene, a silicone adhesive, a styrene block copolymer based adhesive, or the like, and/or combinations thereof.
  • the drug reservoir of the delivery system provides an in vitro skin flux of an active agent between about 0.5-30 ⁇ g/cm 2 -hr for a period of at least about 2 days.
  • a release liner is at least partially in contact with at least one of the adhesive layers to protect the adhesive layer(s) prior to application.
  • a release liner is typically a disposable layer that is removed prior to application of the device to the treatment site.
  • a release liner does not absorb components of the adhesive layer(s), including the active agent.
  • a release liner is impermeable to components of the adhesive layer(s) (including the active agent) and prevents release of components of the adhesive layer(s) through the release liner.
  • a release liner is formed of one or more of a film, non-woven fabric, woven fabric, laminate, and/or combinations thereof.
  • a release liner is a silicone-coated polymer film or paper.
  • a release liner is a silicone-coated polyethylene terephthalate (PET) film, a fluorocarbon film, a fluorocarbon coated PET film, and/or combinations thereof.
  • Transdermal devices and systems may be prepared by any suitable methods as known in the art.
  • transdermal devices are prepared by coating an appropriate amount of an adhesive polymer composition (with or without an active agent) onto a substrate such as a release liner or a backing layer.
  • the adhesive polymer composition is coated onto the release liner.
  • the adhesive polymer composition is coated onto the substrate or liner to a desired thickness. The thickness and/or size of the device and/or drug reservoir may be determined by one skilled in the art based at least on considerations of wearability and/or required dose.
  • the administration site for the device will affect the wearability considerations due to the available size of the administration site and the use of the administration site (e.g., need for flexibility to support movement).
  • the device and/or drug reservoir has a thickness of between about 25-500 ⁇ m.
  • the adhesive polymer composition and substrate are at least partially dried to remove any solvents.
  • a release liner or backing layer is applied to the opposite side of the substrate. Where the substrate is not a release liner or backing layer, the substrate is replaced with the appropriate release liner or substrate.
  • a first adhesive polymer composition is applied or coated onto the substrate, a tie layer material is applied to the formulation, and the second adhesive polymer composition is applied to the tie layer material.
  • Adhesive polymer compositions and tie layers are laminated using any suitable methods known in the art.
  • adhesive layers are coated onto separate substrates or liners and then joined to form the transdermal delivery device.
  • the delivery device includes a reservoir adhesive layer and a contact adhesive layer
  • adhesive polymer compositions may be coated onto the substrate or liner and laminated. It will be appreciated that any or all of the adhesive polymer composition layers may be dried before laminating the layers.
  • transdermal compositions, devices, and/or systems described herein are provided, and several non-limiting exemplary embodiments are set forth.
  • compositions comprise methylphenidate (RITALIN®) as an active agent and are used for treating attention deficit hyperactivity disorder (ADHD), narcolepsy, and/or depression, e.g., through administration of methylphenidate by a transdermal patch.
  • ADHD attention deficit hyperactivity disorder
  • narcolepsy narcolepsy
  • depression e.g., through administration of methylphenidate by a transdermal patch.
  • the FDA has approved doses of methylphenidate of 2.5 mg, 5 mg, 10 mg, 15 mg, 18 mg, 20 mg, 27 mg, 30 mg, 36 mg, 40 mg, 50 mg, 54 mg, and 60 mg.
  • compositions as described herein comprising donepezil (ARICEPT®) as an active agent are used for treating Alzheimer's disease, e.g., through administration of donepezil by a transdermal patch.
  • the FDA has approved doses of donepezil of 5 mg, 7 mg, 10 mg, 14 mg, and 23 mg.
  • compositions described herein allow for administration of doses that correspond to FDA approved doses.
  • compositions as described herein comprising rivastigmine (Exelon®) as an active agent are used for treating Alzheimer's disease and/or Parkinson's disease dementia, e.g., through administration of rivastigmine by a transdermal patch.
  • the FDA has approved daily doses of rivastigmine of 1.5 mg, 2.0 mg, 3.0 mg, 4.5 mg, 4.6 mg, 6.0 mg, 9.0 mg, 9.5 mg, and 13.3 mg.
  • compositions as described herein comprising memantine as an active agent are used for treating Alzheimer's disease, obsessive compulsive disorder, anxiety disorder, ADHD, and opioid dependence, e.g., through administration of memantine by a transdermal patch.
  • the FDA has approved doses of memantine of 2 mg, 5 mg, 7 mg, 10 mg, 14 mg, 21 mg, and 28 mg.
  • compositions as described herein comprising tamsulosin as an active agent are used for treating benign prostatic hyperplasia and/or acute urinary retention, e.g., through administration of tamsulosin by a transdermal patch.
  • the FDA has approved doses of tamsulosin of 0.4 mg and 0.5 mg.
  • Transdermal compositions, devices, and/or systems described herein may be designed for long term use and/or continuous administration of at least one active agent. It will be appreciated that the total dose of the active agent per transdermal device will be determined by the nature of the active agent(s), the size of the device, and/or the loading of the active agent within the drug reservoir.
  • the application period for the transdermal device is between about 1-10 days, 1-7 days, 1-5 days, 1-2 days, 1-3 days, 1-4 days, 3-10 days, 3-7 days, 3-5 days, 5-10 days, and 5-7 days, inclusive.
  • the active agent is released from the drug reservoir as a continuous and/or sustained release over the application period.
  • the backing layer was SCOTCHPAKTM 9723
  • the release liner was a silicone-coated polyester (PET) film
  • the nonwoven tie layer was REEMAY® 2250
  • the rate controlling membrane was CELGARD® 2400 microporous polypropylene
  • the contact adhesive layer was acrylate, polyisobutene (PIB), and/or silicone adhesive.
  • EUDRAGIT® EPO a proton accepting polymer
  • CELGARD® 2400 rate controlling membrane or REEMAY® 2250 was laminated onto the adhesive side of the drug reservoir. Contact adhesive was then laminated on top of the CELGARD® 2400 membrane laminated with drug reservoir. The release liner on the drug reservoir side was replaced and laminated with backing film. The final five-layer laminate was die-cut into patches.
  • Dermatomed human cadaver skin was obtained from a skin bank and frozen until ready for use. The skin was placed in water at 60° C. for 1-2 mins minute after thawing and the epidermis carefully separated from dermis. The epidermis was either used immediately or wrapped and frozen for later use.
  • the receptor compartment was filled with 0.01 M phosphate buffer, pH 6.5, containing 0.01% gentamicin.
  • the solution in the receptor compartment was continually stirred using a magnetic stirring bar in the receptor compartment. The temperature was maintained at 32 ⁇ 0.5° C. Samples were drawn from the receptor solution at periodic intervals and the receptor solution was replaced with fresh phosphate buffers solution. Drug content in the samples was analyzed using HPLC for donepezil.
  • FIG. 4 shows the in vitro skin flux profile of donepezil formulated according to Example 1 (squares).
  • CELGARD® 2400 rate controlling membrane or REEMAY® 2250 was laminated on adhesive side of the drug reservoir. Then contact adhesive was laminated on top of the CELGARD® 2400 membrane laminated with drug reservoir. The release liner on the drug reservoir side was replaced and laminated with backing film. The final five-layer laminate was die-cut into patches.
  • FIG. 4 shows the in vitro skin flux profile of donepezil (triangles).
  • EUDRAGIT® EPO An amount of 3.00 grams of EUDRAGIT® EPO was dissolved in 24.51 g of ethyl acetate. To the resulting solution, 2.00 grams of triethyl citrate, 2.00 grams of glycerin, and 1.00 grams of SPAN® 20 (sorbitan monolaurate) were added/mixed. To the mixture, 4.00 grams of tamsulosin hydrochloride powder was dispersed. After addition of 2.4 grams of KOLLIDON® CL-M to the drug dispersed solution, the mixture was homogenized well. To the homogenized drug dispersion, 11.09 grams of DURO-TAK® 387-2287 (solid content 50.5%) was added and well mixed. The wet adhesive formulation was coated on a release liner and dried using a lab coater (Werner Mathis coater) to get a dry coat weight of 10 mg/cm 2 .
  • CELGARD® 2400 rate controlling membrane or REEMAY® 2250 was laminated on adhesive side of the drug reservoir. Then contact adhesive was laminated on top of CELGARD® 2400 membrane laminated with drug reservoir. The release liner on the drug reservoir side was replaced and laminated with backing film. The final five-layer laminate was die-cut into patches.
  • CELGARD® 2400 rate controlling membrane was laminated to the drug reservoir. Then contact adhesive was laminated to the other side of CELGARD® 2400 membrane laminated with the drug reservoir. The release liner on the drug reservoir was replaced and laminated with backing film. The final five-layer laminate was die-cut into patches.
  • Example 2 The in vitro skin flux of memantine from the transdermal system was measured as described in Example 1, where memantine content in the samples drawn from receptor solution were analyzed for memantine using LCMS.
  • FIG. 5 shows the in vitro skin flux profile of memantine.
  • FIG. 4 shows a flux profile of donepezil formulated according to the formulation identified as Example No. 7 in Table 1 below (circles).

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US15/660,924 Abandoned US20180028663A1 (en) 2016-07-27 2017-07-26 Sodium bicarbonate in situ conversion driven transdermal delivery of amine drug
US15/660,943 Active US9993466B2 (en) 2016-07-27 2017-07-26 Donepezil transdermal delivery system
US15/660,939 Active US10300025B2 (en) 2016-07-27 2017-07-26 Donepezil transdermal delivery system
US15/957,858 Active US10307379B2 (en) 2016-07-27 2018-04-19 Donepezil transdermal delivery system
US16/392,544 Abandoned US20190247321A1 (en) 2016-07-27 2019-04-23 Donepezil transdermal delivery system
US16/392,513 Active 2037-08-08 US11103463B2 (en) 2016-07-27 2019-04-23 Methods for treating alzheimer's disease with donepezil transdermal system
US17/065,302 Pending US20210015761A1 (en) 2016-07-27 2020-10-07 Sodium bicarbonate in situ conversion driven transdermal delivery of amine drug
US17/395,359 Abandoned US20220016045A1 (en) 2016-07-27 2021-08-05 Methods for treating alzheimer's disease with donepezil transdermal system
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US15/660,939 Active US10300025B2 (en) 2016-07-27 2017-07-26 Donepezil transdermal delivery system
US15/957,858 Active US10307379B2 (en) 2016-07-27 2018-04-19 Donepezil transdermal delivery system
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US16/392,513 Active 2037-08-08 US11103463B2 (en) 2016-07-27 2019-04-23 Methods for treating alzheimer's disease with donepezil transdermal system
US17/065,302 Pending US20210015761A1 (en) 2016-07-27 2020-10-07 Sodium bicarbonate in situ conversion driven transdermal delivery of amine drug
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