CN115715770B - Apixaban transdermal patch and preparation method thereof - Google Patents

Apixaban transdermal patch and preparation method thereof Download PDF

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Publication number
CN115715770B
CN115715770B CN202110978570.8A CN202110978570A CN115715770B CN 115715770 B CN115715770 B CN 115715770B CN 202110978570 A CN202110978570 A CN 202110978570A CN 115715770 B CN115715770 B CN 115715770B
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apixaban
acid
transdermal patch
layer
skin
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CN115715770A (en
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唐俭生
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Xinling Pharmaceutical Technology Shenzhen Co ltd
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Xinling Pharmaceutical Technology Shenzhen Co ltd
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Priority to PCT/CN2022/114527 priority patent/WO2023025195A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

The invention relates to apixaban transdermal patch, and a preparation method and application thereof. In particular, the present invention provides a transdermal apixaban patch comprising a backing layer, a drug layer, a semipermeable membrane layer, an adhesive layer and optionally a release layer, and a method for preparing and using the same.

Description

Apixaban transdermal patch and preparation method thereof
Technical Field
The present invention relates to a patch preparation for transdermal administration. More particularly, it relates to a patch preparation comprising apixaban and pharmaceutically acceptable salts thereof and a method for preparing the same.
Background
Transdermal administration is a route of administration that is superior to oral administration and maintains the concentration of the drug in the blood at a constant level by constantly delivering the drug to the systemic blood system. Transdermal administration route not only reduces the fluctuation of drug concentration in blood between peaks and valleys, but also avoids first pass effect. In addition, because the transdermal administration route avoids the direct contact of the drugs and auxiliary materials with the gastrointestinal system, the side effects such as nausea, vomiting and the like which are often accompanied by the oral administration route are obviously reduced or eliminated. Another advantage of the transdermal route of administration is that it is not affected by the diet. Administration can be easily terminated by removing the transdermal patch from the skin if necessary. Moreover, transdermal patches improve patient compliance by reducing the frequency of administration. This is especially important for elderly and pediatric patients.
Common dosage forms for transdermal routes of administration include transdermal patch formulations. Transdermal patch formulations that are currently common include, but are not limited to, drug reservoir type patches, matrix type patches, and the like. The drug reservoir type patch preparation is a patch preparation in which a drug is contained in a reservoir having a drug permeable substrate surface, and the matrix type patch preparation is a patch preparation in which a drug is dissolved or dispersed in a polymer matrix layer.
Anticoagulants are commonly in the form of injections and oral tablets. For example, apixaban is a good quality oral anticoagulant drug. The indications include: reducing the risk of stroke and systemic embolism in non-valvular tremor patients by 60%; preventing deep venous thrombosis after hip and knee joint replacement; treatment of deep vein thrombosis; treatment of pulmonary embolism; reducing the risk of recurrence of DVT and PE, etc. However, oral administration of apixaban often results in bleeding, for example, about 11.71% of hip replacement patients develop bleeding symptoms each year; about 6.93% of knee replacement patients experience bleeding symptoms; bleeding symptoms occur in about 14.9% of patients with deep vein thrombosis and pulmonary embolism. Moreover, over 70% of patients with atrial fibrillation are over 65 years old, and there are difficulties for them to swallow pills or to fully remember the oral dosage. The need to orally administer apixaban multiple times per day makes patients less compliant with apixaban.
Thus, in order to solve the above-mentioned problems, there is an urgent need for a transdermal drug delivery patch capable of continuously delivering a therapeutically effective amount of apixaban for an extended period of time.
Apixaban oral tablets have two specifications, 2.5mg tablet and 5mg tablet. Taken twice daily. The oral bioavailability is about 50%. Thus, the required transdermal delivery strength should be 2.5 mg/24 hours and 5 mg/24 hours. However, the molar mass of apixaban is 459.5, and no precedent is currently available to provide 5mg of transdermal patch per day for molecules with molar masses greater than 400 daltons. Furthermore, apixaban has poor solubility in both aqueous and lipophilic organic solvents. The solubility in water was about 40. Mu.g/ml (https:// pubchem. Ncbi. Lm. Nih. Gov/component/Apixaban # section=drug-Warning), the solubility in ethanol was 0.42mg/ml, the solubility in ethyl acetate was 0.15mg/ml, and the solubility in toluene was 0.05mg/ml. Ethanol, ethyl acetate, and toluene are conventional solvents widely used to dissolve pressure sensitive adhesives and drugs to prepare transdermal patches. Sustained delivery of apixaban at a dose of 5 mg/24 hours over a long period of time by the transdermal route of administration is a challenge.
Disclosure of Invention
It is an object of the present invention to provide a reservoir transdermal patch of apixaban which can continuously deliver apixaban or a pharmaceutically acceptable salt thereof for an extended period of time at a therapeutically effective amount of blood concentration.
It is an object of the present invention to provide a reservoir transdermal patch of apixaban which can have good skin adhesion properties over a period of sustained delivery of apixaban or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide a depot transdermal patch of apixaban which is free from skin irritation and sensitization.
It is another object of the present invention to provide a method for preparing a depot transdermal patch of apixaban which can deliver a therapeutically effective amount of apixaban or a pharmaceutically acceptable salt thereof for an extended period of time without irritation and sensitization to the skin.
It is another object of the present invention to provide a method of treating or preventing thrombotic disorders comprising administering to a subject in need thereof a therapeutically effective amount of apixaban transdermal patch.
It is another object of the present invention to provide the use of a therapeutically effective amount of apixaban depot transdermal patch for the manufacture of a medicament for the treatment or prevention of thrombotic disorders.
In one embodiment, the present invention provides a reservoir transdermal patch of apixaban comprising:
1. a backing layer;
2. a drug reservoir layer;
3. a semipermeable membrane layer;
4. an adhesive layer; and
5. and (5) a release layer.
In one embodiment, the drug reservoir layer further comprises a skin permeation enhancer.
In one embodiment, the skin penetration enhancer comprises any one or any combination of a solvent, a polymeric solubilizing agent, a surfactant, a medium molecular weight organic acid, and a low molecular weight organic acid.
In one embodiment, the skin permeation enhancer comprises a polymeric solubilizing agent, a surfactant, and a medium molecular weight organic acid.
In one embodiment, the skin penetration enhancer further comprises a solvent and/or a low molecular weight organic acid.
In one embodiment, wherein the skin permeation enhancer comprises a solvent, a polymeric solubilizing agent, a surfactant, and a low molecular weight organic acid.
In one embodiment, the polymeric solubilizing agent is a carboxyl-containing polymer, preferably hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl cellulose.
In one embodiment, the apixaban or pharmaceutically acceptable salt thereof is present in an amount of 0.5% to 50%, preferably 1% to 20%, more preferably 2% to 10% of the drug layer.
In one embodiment, the polymeric solubilizing agent is present in an amount of 2% to 50%, preferably 5% to 25%, more preferably 10% to 20% of the drug layer and the weight ratio of apixaban or a pharmaceutically acceptable salt thereof to polymeric solubilizing agent is about 1:1 to 1:15.
In one embodiment, the surfactant is present in an amount of 1% to 50%, preferably 5 to 30% of the drug layer.
In one embodiment, the medium molecular weight organic acid is present in an amount of 1-60%, preferably 1 to 30%, more preferably 1 to 15% of the drug layer.
In one embodiment, the low molecular weight organic acid is present in an amount of 0.1 to 10%, preferably 0.5 to 5%, more preferably 0.5 to 3% by weight of the drug layer.
In one embodiment, the medium molecular weight organic acid comprises C 5 To C 8 Organic acids, preferably including levulinic acid, sorbic acid, itaconic acid, mesaconic acid, ketoglutaric acid, glutaric acid, methylsuccinic acid, valeric acid, isovaleric acid, pivalic acid, cis aconitic acid, trans aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, caproic acid, benzoic acid, salicylic acid, gentisic acid, protocatechuic acid, gallic acid, cyclohexane carboxylic acid, pimelic acid, phthalic acid, isophthalic acid, terephthalic acid, phenylacetic acid, toluic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogenetic acid, suberic acid, caprylic acid, or combinations thereof, more preferably including levulinic acid, glutaric acid, adipic acid, and combinations thereof.
In one embodiment, the low molecular weight organic acid comprises C 1 To C 4 Organic acids, preferably including formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3-hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxaloacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methylmalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid, hydroxybutyric acid, or combinations thereof, more preferably including lactic acid.
In one embodiment, the adhesive layer comprises a skin contact adhesive and optionally an antioxidant, an anti-skin irritation agent, a cohesion accelerator, a plasticizer, a tackifier.
In one embodiment, the skin contact adhesive comprises an acrylic adhesive, a methacrylic adhesive, a polyisobutylene adhesive, a styrene-isoprene-styrene block copolymer, a silicone adhesive, an acrylic-co-polysiloxane copolymer adhesive, or a combination of two or more thereof.
In one embodiment, the skin contact adhesive is a crosslinked adhesive or a non-crosslinked adhesive.
In one embodiment, the cohesion accelerator comprises colloidal silica, zinc oxide, polyvinylpyrrolidone, acrylate copolymers, crospovidone, croscarmellose, ethylcellulose, acrylic copolymers, bentonite, clay, or a combination of two or more of the foregoing.
In one embodiment, the present invention provides a method of preparing the above apixaban transdermal patch comprising:
1) Mixing apixaban or a pharmaceutically acceptable salt thereof with a skin penetration enhancer to form a homogeneous liquid, semi-solid or solid mixture;
2) Uniformly dispensing or coating the resulting liquid, semi-solid, or solid mixture onto a backing film; and laminating the side of the backing film dispensed or coated with the mixture with the side of the semipermeable membrane layer remote from the adhesive layer/release layer; or alternatively
A uniform liquid, semi-solid or solid is dispensed or coated on the side of the semipermeable membrane layer remote from the adhesive layer/release layer and the side of the semipermeable membrane layer dispensed or coated with the mixture is laminated to the backing layer.
In one embodiment, the method further comprises the step of sealing the peripheral edges of the backing layer membrane and the semipermeable membrane by heat, pressure, or a combination of both heat and pressure such that the liquid, semi-solid, or solid mixture is confined within the peripheral edges.
In one embodiment, the present invention provides a method of preparing the above apixaban transdermal patch comprising:
1) Mixing apixaban or a pharmaceutically acceptable salt thereof with a skin penetration enhancer to form a homogeneous liquid, semi-solid or solid mixture;
2) Laminating the backing layer with the side of the semipermeable membrane layer remote from the adhesive layer/release layer and sealing a portion of the peripheral edges of the backing layer and semipermeable membrane layer by heat, pressure or a combination of both heat and pressure and filling the resulting liquid, semi-solid or solid mixture from the unsealed peripheral edge portion to the area between the backing layer and semipermeable membrane layer;
3) The unsealed peripheral edge portions of the backing layer and semipermeable membrane layer are then sealed by heat, pressure, or a combination of both heat and pressure, thereby forming a sealed drug layer.
In one embodiment, the present invention provides the use of a therapeutically effective amount of an apixaban transdermal patch as described above for the manufacture of a medicament for the treatment or prevention of thrombotic disorders.
In one embodiment, the thrombotic disorder comprises ventricular thrombus, atrial fibrillation, acute coronary syndrome, non-valvular atrial fibrillation, deep vein thrombosis, pulmonary embolism.
In one embodiment, the present invention provides a method of treating or preventing a thrombotic disorder comprising administering to a subject in need thereof a therapeutically effective amount of an apixaban transdermal patch as described above.
In one embodiment, the apixaban transdermal patch is administered once every 24 hours, every 32 hours, every 48 hours, every 72 hours, every 84 hours, every 96 hours, every 120 hours, every 144 hours, or every 168 hours.
In one embodiment, the apixaban transdermal patch delivers about 1mg to about 40mg, preferably 2.5mg to 10mg, of apixaban to the subject every 24 hours.
Surprisingly, the apixaban transdermal patch of the present invention can continuously deliver apixaban or a pharmaceutically acceptable salt thereof at high skin flux for a period of time of about 24 hours, 32 hours, 48 hours, 72 hours, 84 hours, 96 hours, 120 hours, 144 hours, and 168 hours or more. In addition, the apixaban transdermal patch of the present invention has the advantage of no skin irritation and sensitization.
Drawings
Fig. 1 shows a schematic view of a drug reservoir type patch according to the present invention.
Fig. 2 shows a schematic diagram of a drug solid matrix type patch.
Fig. 3 shows a measurement of skin flux for transdermal patches of examples 87-90.
Fig. 4 shows a measurement curve of skin flux of the transdermal patches described in example 91 and comparative example 1.
Fig. 5 shows a measurement curve of skin flux of the transdermal patch of example 92.
Fig. 6 shows a measurement of skin flux for transdermal patches of examples 95-98.
Fig. 7 shows a measurement of skin flux for transdermal patches of examples 99-101.
Fig. 8 shows a measurement curve of skin flux of the transdermal patches described in example 102 and comparative example 2.
Fig. 9 shows a measurement of skin flux for transdermal patches of examples 103-106.
Fig. 10 shows a measurement of skin flux for transdermal patches of examples 107-110.
Detailed Description
Definition of the definition
As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the subject (e.g., a human subject) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. The "pharmaceutically acceptable salts" as described herein include inorganic acid addition salts and organic acid addition salts, which may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in free base form (e.g., apixaban) with a suitable organic or inorganic acid and isolating the salt thus formed. Examples of inorganic acid addition salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, phosphite, borate, and the like. Examples of organic acid addition salts include, but are not limited to, acetates, propionates, butyrates, isobutyrates, valerates, caprates, caprylates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzates, dinitrobenzoates, phthalates, benzenesulfonates, tosylates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates oleates, palmitates, stearates, laurates, benzoates, lactates, tosylates, succinates, tartrates, naphthalenesulfonates, glucoheptonates, lactobionic aldehyde, laurylsulfonates, and hydroxyethylsulfonates, and the like.
As used herein, the term "medium molecular weight organic acid" includes, but is not limited to, C 5 To C 8 An organic acid. Non-limiting examples thereof include levulinic acid, sorbic acid, itaconic acid, mesaconic acid, ketoglutaric acid, glutaric acid, methylsuccinic acid, valeric acid, isovaleric acid, pivalic acid, cis aconitic acid, trans aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, caproic acid, benzoic acid, salicylic acid, gentisic acid, protocatechuic acid, gallic acid, cyclohexane carboxylic acid, pimelic acid, phthalic acid, isophthalic acid, terephthalic acid, phenylacetic acid, toluic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogenetic acid, suberic acid, caprylic acid, or combinations thereof. Preferably, the medium molecular weight organic acids include levulinic acid, glutaric acid, adipic acid, and combinations thereof, which have low skin irritation and non-sensitization.
As used herein, the term "low molecular weight organic acid" includes, but is not limited to, C 1 To C 4 An organic acid. Non-limiting examples include formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3-hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxaloacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methylmalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid, hydroxybutyric acid, or combinations thereof. Preferably, the low molecular organic acid is lactic acid.
As used herein, the term "therapeutically effective amount" is an amount that represents the amount of a compound or molecule of the invention, when administered to a subject, (i) treats or prevents a particular disease, disorder or condition, (ii) reduces, ameliorates or eliminates one or more symptoms of a particular disease, disorder or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, disorder or condition described herein.
As used herein, the term "about" refers to plus or minus 10% of the indicated number. For example, "about 10%" may represent a range of 9% to 11%, and "about 1" may represent 0.9-1.1.
As used herein, the term "treatment" refers to clinical intervention that attempts to alter the natural course of the treated individual, and may be for prevention or in the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of a disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of a disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating a disease state, and alleviating or improving prognosis.
The present invention provides an apixaban transdermal patch comprising:
1.backing layer
The backing layer serves as the upper surface of the patch preparation and as the primary structural element provides flexibility to the patch preparation. Preferably, the backing layer is substantially impermeable to the transdermal drug composition.
The backing layer is preferably made of a sheet or film of flexible elastomeric material. The backing layer is preferably impermeable to air. The backing layer for the patch of the present invention is preferably made of a flexible, biocompatible material that mimics the elastic properties of skin and conforms to the skin during movement. The non-occlusive backing layer allows the area to breathe (i.e., promotes the transport of water vapor at the skin surface), while the occlusive backing layer reduces air/vapor permeation. Preferably, the backing layers of the reservoir type transdermal patch (fig. 1) and the matrix type transdermal patch (fig. 2) are closed.
Preferably, the backing layer comprises synthetic polymers such as polyolefins, polyesters, polyethylene, polyvinylidene chloride and polyurethane. Preferably, the backing layer has a thickness of about 0.5 mil (mil) to about 5 mil; more preferably, the backing layer has a thickness of about 1 mil to about 3 mils. Preferably, the oxygen transmission rate is from about 2cc/m/24hr to about 100cc/m/24hr, more preferably, the oxygen transmission rate is from about 70g/m/24hr to about 90g/m/24hr. Preferably, the MVTR is from about 0.3g/m/24hr to about 50g/m/24hr, more preferably, the MVTR is from about 5g/m/24hr to about 30g/m/24hr.
In a preferred embodiment, the backing layer is an occlusive polyester film layer (commercially available, such as Scotchpak 9733,3M Drug Delivery Systems,St.Paul Minn.) that is about 2.0 mils thick. Scotchpak 9733 consists of polyester and a medium density polyethylene/ethylene vinyl acetate heat seal layer, the laminate being translucent, conformable, closed and heat sealable. Which can be used in a reservoir type patch formulation as shown in fig. 1.
2.Drug reservoir layer
The drug reservoir layer comprises apixaban or a pharmaceutically acceptable salt thereof, a skin permeation enhancer, and the like, wherein the permeation enhancer comprises any one or any combination of a solvent, a polymeric solubilizing agent, a surfactant, a medium molecular weight organic acid, and a low molecular weight organic acid.
Solvents, also known as type a skin penetration enhancers, may not only partially or completely dissolve one or more other skin penetration enhancers, but may also partially or completely dissolve apixaban or a pharmaceutically acceptable salt thereof. In addition, the solvent itself is also beneficial for enhancing the skin permeability of apixaban or a pharmaceutically acceptable salt thereof. Non-limiting examples of solvents include C 1 To C 6 Alkyl alcohol, propylene glycol, butylene glycol, dipropylene glycol, hexylene glycol, transcutol, DMSO, N, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, glycerol, water, or a combination of two or more thereof. Preferably, the solvent is selected from ethanol, DMSO, or a combination of both.
Other skin penetration enhancers include polymeric solubilizing agents (type B skin penetration enhancers), surfactants (type C skin penetration enhancers), medium molecular weight organic acids (type D skin penetration enhancers), low molecular weight organic acids (type E skin penetration enhancers), and the like.
Polymeric solubilizing agents include, but are not limited to, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hyaluronic acid, pectin, carboxymethyl cellulose, alginic acid, eudragit S, eudragit L-55, carrageenan, or a combination of two or more of the foregoing. Preferably, the polymeric solubilizing agent is a carboxyl-containing polymer including, but not limited to, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and the like.
The polymer solubilizing agent is present in an amount of 2% to 50%, preferably 2 to 30%, more preferably 5 to 25% by weight of the drug reservoir layer. If the content of the polymer solubilizing agent is less than 2% of the drug reservoir layer, it may result in an excessive maximum value (Cmax) of the blood concentration of apixaban; if the content of the polymer solubilizing agent exceeds 30% of the drug layer, the rate of the apixaban diffusing out from the reservoir layer is excessively suppressed, resulting in a significant decrease in skin permeability. And, the weight ratio of apixaban or a pharmaceutically acceptable salt thereof to the polymeric solubilizing agent is about 1:1 to 1:20, preferably 1:1 to 1:5, more preferably 1:1 to 1:2.
Surfactants include, but are not limited to, lauryl lactate, myristyl lactate, cetyl lactate, palmityl lactate, ceraxyl 31, ethyl laurate, methyl laurate, isopropyl myristate, isopropyl palmitate, fatty alcohols, menthol, saturated or unsaturated C 9 To C 30 Fatty acids, fatty acid esters, diisoadipate, medium chain fatty acid triglycerides, diethyl sebacate, sequimountain pear glycans, span 20, span 40, span 80, tween 20, tween 40, tween 80, pentadecanolide, glycerol monolactate, glycerol monostearate, glycerol monooleate, or combinations thereof. Preferably, the surfactant comprises lauryl lactate, isopropyl myristate, isopropyl palmitate and/or oleic acid and the like.
The term fatty alcohol refers to a compound having the formula ROH, wherein R is C 7 -C 30 Alkyl or C containing one, two, three or four double bonds 3 -C 30 Alkenyl groups. The fatty alcohols may include, but are not limited to, one or more saturated, monounsaturated or polyunsaturated fatty alcohols; which may include, but are not limited to, one or more of the following: octanol, nonanol, decanol, undecanol, lauryl alcohol, and isostearyl alcoholReverse isostearyl alcohol, tridecyl alcohol, myristyl alcohol, isostearyl alcohol, reverse isosmyristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitol, isopalmitol, reverse isopalmitol, heptadecyl alcohol, stearyl alcohol, isostearyl alcohol, reverse isostearyl alcohol, oleyl alcohol, linoleyl alcohol, nonadecyl alcohol, arachidonyl alcohol, octyldodecyl alcohol, behenyl alcohol, sinapyl alcohol, lignan alcohol, and the like. In some embodiments, the saturated fatty alcohols may include, but are not limited to, one or more of the following: lauryl alcohol, isostearyl alcohol, counter-isostearyl alcohol, myristyl alcohol, isostearyl alcohol, counter-isostearyl alcohol, cetyl alcohol, isopalmityl alcohol, counter-isopalmityl alcohol, stearyl alcohol, isostearyl alcohol, and counter-isostearyl alcohol. In some embodiments, the fatty alcohol is myristyl alcohol.
The term fatty acid ester refers to an ester resulting from the combination of a fatty acid and an alcohol, wherein the fatty acid and alcohol are compounds having the formula RCOOH and R 'OH, respectively, wherein R and R' are each C 1 -C 30 An alkyl group.
Exemplary saturated or unsaturated C 9 To C 30 Fatty acids include, but are not limited to, capric acid, lauric acid, palmitic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, polyacid, erucic acid, nervonic acid, and Siemens acid, hexadecatrienoic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, calendic acid, stearic acid, midate acid, eicosadienoic acid, eicosatrienoic acid, dihomo-gamma-linolenic acid, arachidonic acid, and docosadienoic acid.
Surfactants also include, but are not limited to, glycerides (mono-, di-, tri-, polyoxyethylene), mixtures of tetra-4-and di-ethylene glycol palmitostearate, mixtures of poly-3-diisostearate, one or more of PEG-6-and poly-ethylene glycol palmitostearate, oleoyl polyoxy-6-glyceride, lauroyl polyoxy-6-glyceride, caprylyl polyoxy-8-glyceride, propylene glycol monocaprylate type I, propylene glycol monolaurate type II, propylene glycol monolaurate type I, type II propylene glycol monocaprylate, poly-3-dioleate, mixtures of PEG-6-stearate and PEG-32-stearate, lecithin, cetyl alcohol, cholesterol, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, polyoxyethylene fatty alcohol ether, glyceryl monostearate, sorbitan monolaurate, lanolin alcohol and ethoxylated lanolin alcohol, sucrose fatty acid esters.
The weight percentage of surfactant is 1% to 50%, preferably 5 to 30% of the drug reservoir layer.
Medium molecular weight organic acids include, but are not limited to, C 5 To C 8 An organic acid. Non-limiting examples include levulinic acid, sorbic acid, itaconic acid, mesaconic acid, ketoglutaric acid, glutaric acid, methylsuccinic acid, valeric acid, isovaleric acid, pivalic acid, cis aconitic acid, trans aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, caproic acid, benzoic acid, salicylic acid, gentisic acid, protocatechuic acid, gallic acid, cyclohexane carboxylic acid, pimelic acid, phthalic acid, isophthalic acid, terephthalic acid, phenylacetic acid, toluic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogenetic acid, suberic acid, caprylic acid, or combinations thereof. Preferably, the medium molecular weight organic acids include levulinic acid, glutaric acid, adipic acid, and combinations thereof, which have low skin irritation and non-sensitization.
The medium molecular weight organic acid is present in an amount of 1-60%, preferably 1-30%, more preferably 1-15% of the drug reservoir layer. If the content of the medium molecular weight organic acid is less than 1% of the drug reservoir layer, the skin permeation enhancement effect becomes insignificant. If the content of the medium molecular weight organic acid exceeds 60%, it may not be completely dissolved by the solvent.
Low molecular weight organic acids include, but are not limited to, C 1 To C 4 Monocarboxylic or dicarboxylic acids. Non-limiting examples include formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3-hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxaloacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methyl methacrylateMalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid, hydroxybutyric acid, or combinations thereof. Preferably, the low molecular organic acid is lactic acid.
The low molecular weight organic acid is present in an amount of 0.1 to 10%, preferably 0.5 to 5%, more preferably 0.5 to 3% by weight of the reservoir layer. If the content of the low molecular weight organic acid is less than 0.1% by weight of the reservoir layer, the skin permeation enhancing effect becomes insignificant. If the low molecular weight organic acid content exceeds 10% by weight of the reservoir layer, it may result in unacceptable levels of skin irritation.
In one embodiment, the drug reservoir layer comprises apixaban or a pharmaceutically acceptable salt thereof and a skin permeation enhancer comprising a polymeric solubilizing agent (type B skin permeation enhancer), a surfactant (type C skin permeation enhancer) and a medium molecular weight organic acid (type D skin permeation enhancer); wherein, the polymer solubilizer and the medium molecular weight organic acid can dissolve the apixaban. Only dissolved apixaban molecules are able to penetrate the skin, while undissolved apixaban crystals are not permeable to the skin. Both medium molecular weight organic acids and dissolved apixaban molecules penetrate the skin. As more and more medium molecular weight organic acids penetrate the skin, less and less organic acids remain in the drug layer. However, the polymeric solubilizing agent does not penetrate the skin but remains in the drug layer, and thus the polymeric solubilizing agent provides a more durable permeation enhancing effect than the medium molecular weight organic acid for a duration of about 24 hours, 48 hours, 72 hours, 84 hours, 96 hours, 120 hours, 144 hours or 168 hours or more. The polymeric solubilizing agent also increases the viscosity of the drug layer, which may reduce the rate of out-diffusion of dissolved apixaban from the drug layer to reduce Cmax. The decrease in Cmax helps provide a more constant skin penetration over 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours and 168 hours.
In another embodiment, the drug reservoir layer comprises apixaban or a pharmaceutically acceptable salt thereof and a skin permeation enhancer comprising a solvent (type a skin permeation enhancer), a polymeric solubilizing agent (type B skin permeation enhancer), a surfactant (type C skin permeation enhancer), a medium molecular weight organic acid (type D skin permeation enhancer). Medium molecular weight organic acids have low skin irritation.
In a preferred embodiment, the drug reservoir layer comprises apixaban or a pharmaceutically acceptable salt thereof and a skin permeation enhancer, wherein the skin permeation enhancer comprises a solvent (type a skin permeation enhancer), a polymeric solubilizing agent (type B skin permeation enhancer), a surfactant (type C skin permeation enhancer), a medium molecular weight organic acid (type D skin permeation enhancer), and a low molecular weight organic acid (type E skin permeation enhancer). Medium molecular weight organic acids have low skin irritation. The low molecular weight organic acid has low skin irritation at low concentration. The low molecular weight organic acid dissolves the drug and penetrates the skin faster than the medium molecular weight organic acid, but it also disappears faster. Thus, the skin permeation of low molecular weight organic acids is transient. The low molecular weight organic acid enhances skin penetration of apixaban by at least its dual action. It dissolves apixaban into a solution and also improves the physiological properties of apixaban by forming acid-base addition salts to increase skin permeability. The medium molecular weight organic acid dissolves apixaban at a lower concentration and can form acid base addition salts. Medium molecular weight organic acids have a delayed skin penetration enhancement but also have a longer lasting penetration enhancement, i.e. an enhancement time longer than low molecular weight organic acids.
If the drug reservoir layer contains only low molecular weight organic acids, the skin permeation enhancement lasts from several hours to 24 hours. If the drug reservoir layer contains only medium molecular weight organic acids, there is no significant permeation of apixaban during the first 24 hours. There is no meaningful skin penetration of apixaban if the drug reservoir layer contains only solvent and polymeric solubilizer. If the drug reservoir layer contains only surfactant, there is no meaningful skin permeation of apixaban because the drug is not in a permeated dissolved state.
The drug reservoir layer coating has a weight of about 55 grams to about 1000 grams per square meter. The thickness of the drug reservoir layer coating is from about 40 microns to about 1000 microns.
3.Semipermeable membrane layer
The semipermeable membrane layer is used to contain a liquid or semi-solid matrix material within the drug layer and its function is to control the diffusion of apixaban from the liquid or semi-solid drug layer to the adhesive layer. The semipermeable membrane layer and the backing layer may be sealed together around the peripheral edge.
Semipermeable membrane layers include, but are not limited to, ethylene-co-vinyl acetate copolymer membranes, polyethylene polymer membranes, polypropylene polymer membranes. Non-limiting examples of ethylene-co-vinyl acetate include 3m Cotran 9709, cotran 9712, context 9716, and context 9728. Non-limiting examples of polyethylene films include Solupore. Non-limiting examples of polypropylene films include Celgard 2400.
Suitable semipermeable membrane layers include continuous membranes and microporous membranes, which may be woven or nonwoven materials. The semipermeable membrane is preferably made of a flexible polymeric material commonly used by those skilled in the art. Polymeric membranes useful in making the semipermeable membrane layer include, but are not limited to, those comprising low density polyethylene, high density polyethylene, ethyl vinyl acetate copolymer, polypropylene, and other suitable polymers. In one embodiment, the semipermeable membrane layer is made from a microporous membrane made from an ethylene-vinyl acetate copolymer containing from about 0.5 to about 28wt.% vinyl acetate. Suitable woven materials include the Saatifil PES, such as PES 105/52 available from Saatitech, inc. A suitable nonwoven is Sontara from DuPont Nonwovens Sontara Technologies. In a preferred embodiment, the semipermeable membrane layer is an ethylene-vinyl acetate copolymer membrane obtainable from 3MTM, such as Cotran 9702, cotran 9705, cotran 9706, cotran 9707, cotran 9712, cotran 9715, cotran 9716, and Cotran 9728 (obtainable from 3 MTM).
The semipermeable membrane layer may generally have a thickness of about 10um to about 100um, preferably about 15 um to about 50 um.
4.Adhesive layer
The adhesive layer functions to adhere the apixaban transdermal patch to the skin surface. It can also be used to control the rate of apixaban delivery to the skin after the release layer is removed. The adhesive includes, but is not limited to, an acrylic adhesive, a methacrylic adhesive, a polyisobutylene adhesive, a styrene-isoprene-styrene block copolymer adhesive, a silicone adhesive, an acrylic-co-silicone copolymer adhesive, or a combination of two or more of the foregoing. Non-limiting examples of acrylic adhesives include the Herkel Duro-Tak adhesives 387-2051, 387-2054, 387-2353, 87-235, 387-2516, 387-2287, 387-2510, 87-287-2054, 87-210294 (Sanyo chemical Co., ltd.). Non-limiting examples of polyisobutylene adhesives include Oppanol N150, oppanol B150, oppanol N100, oppanol B100, oppanol N80, oppanol B10, B11, B12, and low molecular weight polybutene H1900 from Ineos and mineral oil tackifiers. Non-limiting examples of silicone adhesives include DuPont Bio-PSA 7-4100, 7-4200, 7-4300, 7-4400, and 7-4500. Non-limiting examples of acrylic-co-polysiloxane copolymer adhesives include DuPont Bio-PSA 7-6100, 7-6200, and 7-6300. Combinations of acrylic adhesives with silicone adhesives, and combinations of polyisobutylene adhesives with styrene-isoprene-styrene block copolymer adhesives are also acceptable adhesive options. Preferably, the adhesive is a polyisobutylene adhesive, a styrene-isoprene-styrene block copolymer adhesive, a silicone adhesive, and an acrylic-co-polysiloxane copolymer adhesive.
The inventors have found that crosslinked adhesives such as Duro-Tak 387-2054 adhere better to skin than uncrosslinked adhesives 387-2051, and that crosslinked 387-2516 adhere better to skin than uncrosslinked 387-2287.
The inventors have also found that the adhesion of the skin contact adhesive layer can be further improved by adding additives Eudragit E100, plastoid B, crospovidone CML, colloidal silicon dioxide under the trade name Cabo-Sil-5 or magnesium aluminum metasilicate (e.g. Neusilin from Fuji chemical industry) and kaolin. The magnesium aluminum metasilicate is preferably an amorphous composite oxide formed by three-dimensional polymerization of aluminum, magnesium and silicon atoms through oxygen atoms. Such a composite oxide is more specifically represented by the following formula: al (Al) 2 O 3 /aMgO/bSiO 2 -nH 2 O, wherein a=0.3-3 and b=0.3-5. Such magnesium metaaluminosilicate is considered to have further improved adhesion in the presence of water due to its porous structure.
The skin contact adhesive layer may also contain one or more pharmaceutically acceptable additives, non-limiting examples of which include antioxidants, anti-skin irritants, cohesion accelerators, plasticizers, tackifiers, and the like.
The amount of additive included in the skin-contact adhesive layer is from about 0.05% to about 40%, preferably from about 1% to about 30%, more preferably from about 3% to about 30%, and most preferably about 20% by weight of the adhesive material.
Non-limiting examples of antioxidants include tocopherol, tocopheryl acetate, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, sodium sulfite, propyl gallate, thioglycerol, sodium thiosulfate, sodium dioxide, sodium formaldehyde sulfoxylate, chelating agents as synergistic antioxidants including citric acid, tartaric acid, disodium calcium edetate, disodium edentate, EDTA and the like.
Non-limiting examples of cohesion accelerators include colloidal silica, zinc oxide, polyvinylpyrrolidone, acrylate copolymers, crospovidone, croscarmellose (croscarmellose), ethylcellulose, acrylic copolymers, bentonite, clay, and mixtures thereof. In a preferred embodiment, the cohesion accelerator is colloidal silica. The cohesion accelerator is present in the adhesive layer in an amount of about 3% to about 40% by weight of the adhesive material, preferably about 5% to about 30% by weight of the adhesive material. The inventors have found that when the skin contact layer adhesive is a polyisobutylene adhesive, a silicone adhesive or a styrene-isoprene-styrene based adhesive, the addition of the cohesion enhancer effectively maintains the integrity of the adhesive.
Non-limiting examples of plasticizers include mineral oil, silicone oil, triethyl citrate, and combinations thereof. The plasticizer is present in the adhesive layer in an amount of about 0% to about 40% by weight of the adhesive material, preferably about 0% to about 30% by weight of the adhesive material, more preferably about 0% to about 30% by weight of the adhesive material, and most preferably about 20% by weight of the adhesive material.
Non-limiting examples of tackifiers include silicone oils, mineral oils, polybutenes, terpenes, and mixtures thereof. The tackifier is present in the adhesive layer in an amount of about 0% to about 40% by weight of the adhesive material, preferably about 0% to about 30% by weight of the adhesive material.
Preparation method
In one embodiment, the present invention provides a method of preparing a transdermal apixaban patch comprising a backing layer, a drug reservoir layer, a semipermeable membrane layer, a skin contact layer, and optionally a protective release liner layer, comprising:
1) Mixing apixaban or a pharmaceutically acceptable salt thereof with a skin penetration enhancer to form a homogeneous liquid, semi-solid or solid mixture;
2) Uniformly dispensing or coating the resulting liquid, semi-solid, or solid mixture onto a backing film; and laminating the side of the backing film dispensed or coated with the mixture with the side of the semipermeable membrane layer remote from the adhesive layer/release layer; or alternatively
A uniform liquid, semi-solid or solid is dispensed or coated on the side of the semipermeable membrane layer remote from the adhesive layer/release layer and the side of the semipermeable membrane layer dispensed or coated with the mixture is laminated to the backing layer.
In one embodiment, first, a liquid, semi-solid, or solid drug reservoir layer is prepared. The polymeric solubilizing agent (type B skin permeation enhancer) is fully dissolved in the solvent (type a skin permeation enhancer) at room temperature or elevated temperature (e.g., 85 ℃) and then apixaban or a pharmaceutically acceptable salt thereof is added, mixed at room temperature or elevated temperature (e.g., 85 ℃) to fully or partially dissolve, followed by the surfactant (type C skin permeation enhancer), medium molecular weight organic acid (type D skin permeation enhancer) and optionally low molecular weight organic acid (type E skin permeation enhancer) which are mixed at room temperature or elevated temperature (e.g., 85 ℃) to form a homogeneous liquid, semi-solid or solid. And then cooled to room temperature. A uniform liquid, semi-solid or solid is dispensed or coated onto the backing film and laminated to the side of the semipermeable membrane layer remote from the adhesive layer/release layer.
In another embodiment, a uniform liquid, semi-solid or solid prepared as described above may be dispensed or coated on the side of the semipermeable membrane layer remote from the adhesive layer/release layer and laminated with the backing layer.
In another embodiment, the method of preparing an apixaban transdermal patch may further comprise the step of sealing the peripheral edges of the backing layer membrane and the semipermeable membrane by heat, pressure, or a combination of both heat and pressure such that the liquid, semi-solid, or solid mixture is confined within the peripheral edges.
In another embodiment, the three edges of the backing layer film on the side closest to the skin and the three edges of the semipermeable membrane layer on the side remote from the skin contact adhesive layer/protective release liner layer may be sealed first, the liquid or semi-solid drug reservoir material filled into the three-sided sealed reservoir from the unsealed fourth edge, and then the fourth edge sealed to form a four-sided sealed drug reservoir layer.
In one embodiment, the present invention provides a method of treating a thrombotic disorder comprising administering to a patient in need thereof a therapeutically effective amount of apixaban transdermal patch comprising:
1) A backing layer;
2) A drug reservoir layer comprising apixaban or a pharmaceutically acceptable salt thereof;
3) A semipermeable membrane layer;
4) An adhesive layer; and optionally
5) And (5) a release layer.
In one embodiment, the apixaban transdermal patch may be delivered continuously at a high skin flux, for example, a skin flux of about 1 μg/cm2.hr to about 10 μg/cm2.hr, preferably about 1 μg/cm2.hr to about 5 μg/cm2.hr, more preferably about 3 to about 5 μg/cm 2.hr.
In one embodiment, the apixaban transdermal patch can be delivered for at least 24 hours, 32 hours, 48 hours, 72 hours, 84 hours, 96 hours, 120 hours, 144 hours, or 168 hours or more.
In one embodiment, the apixaban transdermal patch delivers about 1mg to about 40mg, preferably about 2.5mg to about 10mg, of apixaban to the subject every 24 hours.
The following examples are presented to illustrate the technical aspects of the present invention and are not intended to limit the scope of the present invention.
Examples
Solubility study of apixaban
Examples 1 to 63
Before the drug penetrates the skin transdermally, the drug crystals need to be first dissolved in the drug layer, since only the dissolved drug molecules can penetrate the skin transdermally. We determined the solubility of apixaban in various polymer solubilisers and the results are presented in Table 1. Surprisingly, the present inventors found that the solubility of apixaban in carboxyl group containing polymer solubilizers (water insoluble hydroxypropyl methylcellulose phthalate HPMCP, hydroxypropyl methylcellulose acetate succinate HPMCAS, eudragit L100) is significantly greater than in conventional crystallization inhibitors (e.g. povidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl cyclodextrin, etc.). Thus, we have surprisingly found that the carboxylic group containing polymeric solubilizing agents (water insoluble hydroxypropyl methylcellulose phthalate HPMCP, hydroxypropyl methylcellulose acetate succinate HPMCAS, eudragit L100) have better crystallization inhibition than conventional crystallization inhibitors (e.g. povidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl cyclodextrin, etc.). When the ratio of HPMCP to apixaban is 6:1 or more, apixaban does not cause crystallization phenomenon when the solvent evaporates to be semi-dry (about 1 g). In contrast, when the ratio of PVP K30, K90, HPC or hydroxypropyl cyclodextrin to apixaban reaches 6:1 or higher, apixaban will recrystallize to form a solid after solvent evaporation.
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And (3) injection: APX is apixaban; PVP K30 is polyvinylpyrrolidone K30; PVP K90 is polyvinylpyrrolidone K90; HPC LF is hydroxypropyl cellulose LF; HPMCAS is hydroxypropyl methylcellulose acetate succinate; eudragit L100 is a copolymer based on methacrylic acid and methyl methacrylate from Evonik corporation; HPMCP is hydroxypropyl methylcellulose phthalate.
Examples 64 to 67 solubility studies of apixaban in films containing Polymer solubilizers
When the ratio of HPMCP to apixaban is 6:1, no apixaban crystals are generated in the film containing HPMCP and apixaban. HPMCP and apixaban were dissolved in DMSO at a ratio of 2:1 to 5:1 to form a viscous solution. The solution was coated on Scotchpak 9733 backing film and dried in a forced air oven at 100 ℃ for 60 minutes to form a dry film. At a ratio of HPMCP to apixaban of 5:1 or higher, no crystals formed on the dry film (Table 2).
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Furthermore, we also measured the solubility of apixaban in other types of skin permeation enhancers such as solvents (type a skin permeation enhancers), surfactants (type C skin permeation enhancers), medium molecular weight organic acids (type D skin permeation enhancers) and low molecular weight organic acids (type E skin permeation enhancers), respectively, and the results are shown in table 3.
TABLE 3 solubility of apixaban in various types of skin penetration enhancers at room temperature
In vitro skin flux assay of apixaban
In vitro permeation testing was performed using a vertical static modified Franz unit. The receiving unit had a volume of 28ml and was filled with a buffer solution of pH 7.4 containing monopotassium phosphate, sodium chloride and sodium azide. The effective skin penetration size was 0.61cm2. Human cadaver skin 700 to 800um thick was mounted on the receiving unit with the dermis layer side facing upwards. An O-ring was placed on top of the skin. A pre-weighed reservoir layer of liquid or semi-solid formulation is filled into the O-ring. The donor cells were fixed on top of the receiving unit with clips. The Franz unit was placed in a 32℃incubator on a magnetic stir plate. At each pre-set time point 2ml of solution was taken, the remaining solution was poured off and the new receiving solution was replenished. The amount of apixaban in the received solution was immediately analyzed by HPLC.
Examples 68 to 86
Liquid or semisolid formulations are prepared by mixing apixaban and other excipients in a glass bottle and heating in an oven with the apixaban completely or partially dissolved. Skin flux testing was performed as described previously. The results are summarized in table 4. It can be seen that the skin flux of the formulation combinations 68 to 78 is low. These formulations comprise a single solvent (ethanol and dimethyl sulfoxide) or a combination of a D-type skin permeation enhancer (levulinic acid) or a solvent and a skin permeation enhancer such as a combination of a solvent (dimethyl sulfoxide) and a B-type skin permeation enhancer (HPMCP, i.e., hydroxypropyl methylcellulose phthalate), a combination of a solvent (ethanol and dimethyl sulfoxide) and a C-type skin permeation enhancer (lauryl lactate), a combination of a solvent (ethanol and dimethyl sulfoxide) and a D-type skin permeation enhancer (levulinic acid), a combination of a solvent (ethanol and dimethyl sulfoxide) and an E-type skin permeation enhancer (lactic acid), and a combination of three skin permeation enhancers such as a-type skin permeation enhancer (ethanol and dimethyl sulfoxide) and a B-type skin permeation enhancer (HPMCP) and a D-type skin permeation enhancer (levulinic acid). The 72 hour cumulative skin permeation flux of the formulation combination 79 comprising 4 skin permeation enhancers A, B, C and D and the formulation combination 80 to 86 comprising 5 skin permeation enhancers A, B, C, D and E was very high, 2.5 to 670 times that of the formulation combination 68 to 78.
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Example 87
Apixaban was mixed with levulinic acid and heated to dissolve. The mixture was cooled to room temperature. The skin flux of formulation 87 (table 5, fig. 3) containing the D-type skin permeation enhancer (levulinic acid) but no B-type skin permeation enhancer (HPMCP) was higher at an early time point, but the skin flux of formulation 87 was rapidly decreased as the amount of levulinic acid remaining in the formulation was reduced due to skin permeation. GC analysis of the semi-solid sample remaining in the Franz cell showed little levulinic acid residue at the end of 96 hours.
Example 88
Apixaban was mixed with levulinic acid and heated to dissolve. Add lauryl lactate and mix. The mixture was cooled to room temperature. The skin flux of formulation 88 (table 5, fig. 3) containing both a type C skin permeation enhancer (lauryl lactate) and a type D skin permeation enhancer (levulinic acid) was 3 times that of formulation 87 containing only a type D skin permeation enhancer. However, since formulation 88 does not contain a type B skin permeation enhancer, its skin flux is higher at an early time point, but as the amount of levulinic acid remaining in the formulation decreases due to skin permeation, the skin flux of formulation 88 rapidly decreases. GC analysis of the semi-solid sample remaining in the Franz cell showed little levulinic acid residue at the end of 96 hours.
Example 89 and example 90
Apixaban and HPMCP were mixed with DMSO and levulinic acid and heated to 85℃for dissolution. Add lauryl lactate and mix. The material was warmed to room temperature. The skin flux of both formulations (table 5, fig. 3) remained almost unchanged for 96 hours. Although the amount of HPMCP, a polymer solubiliser, remains unchanged as the amount of levulinic acid remaining in the formulation is lower, because its high molecular weight does not penetrate the skin. The presence of the polymeric solubilizing agent maintains a substantial amount of apixaban in solution, thereby maintaining the transdermal delivery rate of apixaban nearly constant.
Table 5 (drug reservoir type patch)
APX = apixaban; HPMCP = hydroxypropyl methylcellulose phthalate; DMSO = dimethyl sulfoxide
Example 91
Apixaban and HPMCP were mixed with DMSO and levulinic acid and heated to 85℃for dissolution. Add lauryl lactate and mix. The material was warmed to room temperature. The skin flux of the example 91 formulation containing the polymer solubiliser HPMCP (table 6, fig. 4) was 5 times higher than that of comparative example 1 without HPMCP. The skin flux of comparative example 1 was unacceptably low. Thus, the patch size required to reach therapeutic flux levels is 180cm2. Furthermore, the skin adhesiveness and physical properties of comparative example 1 were also unacceptably poor. When an attempt is made to remove the release layer prior to use, a large amount of adhesive is transferred to the release layer. When a finger touches the adhesive layer, a large amount of adhesive is transferred to the finger.
Comparative example 1
Apixaban and acrylic acid were mixed in a tank to dissolve apixaban. Lactic acid, octanoic acid and tween 20 were added in mixture. Duro-Tak 87-2196 was then added and mixed. The wet mixture was coated on a backing layer film Scotchpak9733, dried in a forced air oven at 40 ℃ for 5 minutes and at 85 ℃ for 15 minutes. The dried film was removed and a release layer was laminated on top of the adhesive layer to prepare an adhesive layer (containing drug)/release layer laminate. Unfortunately, the release layer may not be peeled off without damaging the adhesive layer. In an attempt to peel the release layer, approximately half of the adhesive was transferred to the release layer. In the finger grip test, the adhesive layer was pressed with the index finger for 5 seconds, and then the index finger was lifted. A number of adhesives are transferred to the finger. In addition, the skin flux of this formulation was very low, far from meeting the required 25858 μg/patch 96hr flux, approximately 5 times lower than that of example 91, which contained four types of skin permeation enhancers.
TABLE 6 (drug depot type patch vs matrix type patch)
APX = apixaban; HPMCP = hydroxypropyl methylcellulose phthalate; DMSO = dimethyl sulfoxide
Examples 92, 93 and 94
Apixaban, HPMCP, DMSO and levulinic acid were mixed and heated at 85 ℃. Adding lauryl lactate or/and methyl caprate, mixing and heating to form uniform semi-solid, and cooling to room temperature. Skin flux experiments were performed with 3 skin donors. As shown in table 6 and fig. 3, the skin flux of the formulation of example 92 and the formulation of example 94, containing A, B, C, and D-type penetration enhancer, was able to be maintained between 3 μg/cm2.H and 6 μg/cm2.h between 8 hours and 96 hours (table 7, fig. 5). The formulation of example 93 containing two different D-type permeation enhancers (lauryl lactate and methyl decanoate) was also able to maintain a high skin flux for 4 days. Fig. 5 shows a 3 day skin flux profile based on formulation 92 (patch size 31.5cm 2) obtained by internal IVIVR.
Although the amount of residual levulinic acid and the amount of residual DMSO of formulation 92 were lower and lower, after 96 hours, which was even less than 1% of the theoretical amount (table 8), the polymer solubilizer HPMCP remained in solution because it remained unchanged (because of its high molecular weight, it did not penetrate the skin), so that the transdermal delivery rate of apixaban was nearly constant over 4-96 hours.
Table 7 (drug reservoir type patch)
APX = apixaban; HPMCP = hydroxypropyl methylcellulose phthalate; DMSO = dimethyl sulfoxide
TABLE 8
HPMCP = hydroxypropyl methylcellulose phthalate; DMSO = dimethyl sulfoxide
Examples 95, 96 and 97
HPMCP and levulinic acid are mixed and dissolved with heat. Apixaban was added, mixed and heated. Lauryl lactate was added, mixed and heated to form a semi-solid. The results of the skin flux study over 7 days are shown in table 9 and fig. 6. The skin flux of the formulation compositions 95, 96 and 97 was high, with estimated patch sizes of about 16cm2, 29cm2 and 23cm2, respectively.
Table 10 shows that example 95 had zero residual levulinic acid at the end of 168 hours (7 days). Table 11 shows the amount of levulinic acid that permeated through the skin into the receiving solution at 4, 8, 10, 24, 32, 48, 56 hours. At the time point of 56 hours, more than half of the levulinic acid had permeated.
Example 98
An adhesive layer: apixaban, levulinic acid and lauryl lactate are added to the tank and mixed and dissolved. 4302 and 4202 solutions were added and mixed to form a homogeneous viscous liquid. The liquid is treatedCoated onto a release layer coated with silicon, dried at 40 ℃ for 4 minutes and 85 ℃ for 4 minutes. The skin flux of formulation composition 98 was also high, with an estimated patch size estimated to be 24cm 2 。
In vitro skin flux assay
In vitro permeation testing was performed using a vertical static modified Franz unit. The receiving unit had a volume of 28ml and was filled with a buffer solution of pH 7.4 containing monopotassium phosphate, sodium chloride and sodium azide. The effective skin penetration size was 0.61cm2. Human cadaver skin of 700 to 800um thickness of 4.5cm2 was mounted on the receiving unit with the dermis layer side facing upwards. The adhesive layer was adhered to the dermis layer, the release layer was removed and an O-ring was placed over the adhesive layer. Pre-weighed reservoir liquid or semi-solid formulations are filled into the O-rings. The donor unit is secured to the top of the receiving unit with a clip. The Franz unit was placed in a 32℃incubator on a magnetic stir plate. At each pre-set time point 2ml of solution was taken, the remaining solution was poured off and the new receiving solution was replenished. The amount of apixaban in the received solution was immediately analyzed by HPLC.
Table 9 (drug reservoir type patch)
APX = apixaban; HPMCP = hydroxypropyl methylcellulose phthalate; DMSO: dimethyl sulfoxide
Table 10
TABLE 11
Examples 99 to 101
HPMCP, propylene glycol or ethanol, adipic acid or levulinic acid or lactic acid are mixed and heated for dissolution. Apixaban and lauryl lactate are added, mixed and heated to form a semi-solid, and then cooled to room temperature. Skin flux assays were performed (table 12, fig. 7). The adipic acid-containing formulations 99 and 100 had a high flux at the 24 hour time point and remained for 96 hours, while the lactic acid-containing example 101 had a good flux at the 4 hour time point but the flux dropped rapidly below the 24 hour-hour time point. The 4 day patch sizes for formulations 99, 100 and 101 were approximately 53cm2,49cm2 and 62cm2, respectively. Adipic acid is safe to use as an adjuvant because it only slightly irritates the skin even at high concentrations of 50% (OECD SIDS Initial Assessment Report For SIAM Paris, france,20-23april 2004).
Watch 12 (drug reservoir type patch)
APX = apixaban; HPMCP = hydroxypropyl methylcellulose phthalate; DMSO = dimethyl sulfoxide
Example 102
Formulations 99 and 100, which contained only adipic acid but no lactic acid, had no flux at the 10 hour time point, but the flux was good starting at the 24 hour time point and maintaining to the 96 hour time point. Formulation 102 contained five penetration enhancer system skin fluxes including lactic acid (3% w/w, penetration enhancer type E), adipic acid (8% w/w, penetration enhancer type D), ethanol (penetration enhancer type a), DMSO (type a penetration enhancer), HPMCP (type B penetration enhancer), and lauryl lactate (type C penetration enhancer). The skin flux of formulation 102 was high as early as the 4 hour time point and maintained for more than 72 hours (table 13 and fig. 8). In contrast, the skin flux of formula 101 with lactic acid (E) and no adipic acid (D) was only higher for a period of 4 hours to 24 hours, but lower after a period of more than 24 hours (table 12).
Comparative example 2
Example formulation 9-2 of U.S. patent application 2020/0338012A1 is reproduced: apixaban, polypropylene glycol, HPC, lactic acid and methanol were mixed, heated and dissolved. As shown in table 12 and fig. 7, the formulation of comparative example 2 was very low in skin flux due to the absence of polymer solubilizer B (e.g., HPMCP) and medium molecular weight organic acid D (e.g., adipic acid). 1, 2-propanediol and HPC were used as tackifiers (to increase liquid viscosity), and the HPC data in Table 1 and the polypropylene glycol (PPG) data in Table 3 indicated that they were not solubilizers for apixaban.
Table 13 (drug reservoir type patch)
APX = apixaban; HPMCP = hydroxypropyl methylcellulose phthalate; DMSO = dimethyl sulfoxide
Examples 103 to 106
The patch compositions 104 and 105 contained permeation enhancer types a, B, C and E, which had much higher skin flux than the patch compositions 103 and 106 containing permeation enhancer types a, B and C alone (table 14, fig. 9). Here, oleic acid forms not only adducts with apixaban which readily penetrate the skin, but also acts as surfactant C to increase the skin penetration properties.
Examples 107 to 110
Surprisingly, the skin flux of the drug depot type patch composition 107 containing skin permeation enhancer types a, B, C and D and the drug depot type patch composition 108 containing skin permeation enhancer types a, B, C, D and E was significantly higher than the skin flux of the matrix type patch compositions 109 and 110 containing skin permeation enhancer types a, B, C, D and E (table 15, fig. 10).
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Skin adhesion performance and skin irritation test of placebo patch
The placebo patches described in table 18 were prepared using the same procedure as the active patches described earlier except that the drug reservoir layer did not contain apixaban. The adhesive layer weighs 60 grams per square meter. The upper arm skin or thigh of healthy volunteers was cleaned with a wet paper towel and dried with a dry paper towel. After the placebo patch was applied, it was flattened to ensure that there were no air bubbles under the surface of the patch. The start date and time of the experiment was recorded. Adhesion and irritation scores were recorded daily.
As shown in table 18, the adhesive matrix of placebo 1 lost integrity after 9 hours of application to the skin. After removal of the patch, a significant amount of adhesive was transferred to the skin, with a low skin adhesion score. Because the skin contact adhesive is non-crosslinked Duro-Tak 387-2287 and does not contain a cohesion accelerator. When the crosslinking adhesives Duro-Tak387-2504 and Duro-Tak387-2516 are used as skin contact adhesives in combination with cohesion accelerators such as crospovidone CLM and Eudragit E100, the skin adhesion is greatly improved. Silicone adhesives and polyisobutylene adhesives have also been found to have good skin adhesion. Placebo 2, containing 10% adipic acid but no lactic acid, had less skin irritation. Placebo 2 to placebo 5, which contained 8% to 10% adipic acid and low levels of lactic acid (1.5% to 5%), also had very low skin irritation. In contrast, the skin irritation of comparative placebo 1, which contained a high content of lactic acid (13%), was high.
Adhesion performance evaluation and classification table
Adhesion was scored using a five-point scoring method of 0-4 points (table 16).
TABLE 16 skin adhesion
Primary skin irritation was scored using an octave score of 0-7 (table 17).
Table 17 skin irritation score
TABLE 18
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Claims (26)

1. A transdermal apixaban patch comprising:
1) A backing layer;
2) A drug reservoir layer comprising apixaban or a pharmaceutically acceptable salt thereof, a solvent, a polymeric solubilizing agent, a surfactant, and a medium molecular weight organic acid and/or a low molecular weight organic acid; wherein the polymer solubilizer is a polymer containing carboxyl,
which is selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and carboxymethyl cellulose; the medium molecular weight organic acid is selected from levulinic acid, glutaric acid, adipic acid, and combinations thereof, and the low molecular weight organic acid is selected from lactic acid;
3) A semipermeable membrane layer;
4) An adhesive layer; and optionally
5) And (5) a release layer.
2. The apixaban transdermal patch of claim 1, wherein the weight percent of apixaban or pharmaceutically acceptable salt thereof is 0.5% to 50% of the drug reservoir layer.
3. The apixaban transdermal patch of claim 1, wherein the weight percent of apixaban or pharmaceutically acceptable salt thereof is 1% to 20% of the drug reservoir layer.
4. The apixaban transdermal patch of claim 1, wherein the weight percent of apixaban or pharmaceutically acceptable salt thereof is 2% to 10% of the drug reservoir layer.
5. The apixaban transdermal patch of claim 2, wherein the weight percent of the polymeric solubilizing agent is 2% to 50% of the drug reservoir layer and the weight ratio of apixaban or pharmaceutically acceptable salt thereof to polymeric solubilizing agent is 1:1 to 1:20.
6. The apixaban transdermal patch of claim 2, wherein the polymeric solubilizing agent is present in an amount of 5% to 25% by weight of the drug reservoir layer and the weight ratio of apixaban or pharmaceutically acceptable salt thereof to polymeric solubilizing agent is 1:1 to 1:15.
7. The apixaban transdermal patch of claim 2, wherein the weight percent of the polymeric solubilizing agent is 10% to 20% of the drug reservoir layer and the weight ratio of apixaban or pharmaceutically acceptable salt thereof to polymeric solubilizing agent is 1:1 to 1:10.
8. The apixaban transdermal patch of claim 5, wherein the surfactant is present in an amount of 1% to 50% by weight of the drug reservoir layer.
9. The apixaban transdermal patch of claim 5, wherein the surfactant is present in an amount of 5 to 30% by weight of the drug reservoir layer.
10. The apixaban transdermal patch of claim 8, wherein the weight percent of the medium molecular weight organic acid is 1-60% of the drug reservoir layer.
11. The apixaban transdermal patch of claim 8, wherein the weight percent of the medium molecular weight organic acid is 1 to 30% of the drug reservoir layer.
12. The apixaban transdermal patch of claim 8, wherein the weight percent of the medium molecular weight organic acid is 1 to 15% of the drug reservoir layer.
13. The apixaban transdermal patch of claim 10, wherein the weight percent of the low molecular weight organic acid is 0.1 to 10% of the drug reservoir layer.
14. The apixaban transdermal patch of claim 10, wherein the weight percent of the low molecular weight organic acid is 0.5 to 5% of the drug reservoir layer.
15. The apixaban transdermal patch of claim 10, wherein the weight percent of the low molecular weight organic acid is 0.5 to 3% of the drug reservoir layer.
16. The apixaban transdermal patch according to any one of claims 1-15, wherein the adhesive layer comprises a skin contact adhesive and optionally an antioxidant, an anti-skin irritant, a cohesion accelerator, a plasticizer, a tackifier.
17. The apixaban transdermal patch of claim 16, wherein the skin contact adhesive comprises an acrylic adhesive, a methacrylic adhesive, a polyisobutylene adhesive, a styrene-isoprene-styrene block copolymer adhesive, a silicone adhesive, an acrylic-co-polysiloxane copolymer adhesive, or a combination of two or more thereof.
18. The apixaban transdermal patch of claim 16, wherein the skin contact adhesive is a crosslinked adhesive or a non-crosslinked adhesive.
19. The apixaban transdermal patch of claim 16, wherein the cohesion accelerator comprises colloidal silica, zinc oxide, polyvinylpyrrolidone, acrylate copolymer, crospovidone, croscarmellose, ethylcellulose, acrylic copolymer, bentonite, clay, or a combination of two or more of the foregoing.
20. The apixaban transdermal patch of claim 19, wherein the cohesion accelerator is in the amount of 3 to 50% by weight of the adhesive layer.
21. The apixaban transdermal patch of claim 19, wherein the cohesion accelerator is 5 to 30% by weight of the adhesive layer.
22. Use of a therapeutically effective amount of an apixaban transdermal patch according to any one of claims 1-21 in the manufacture of a medicament for the treatment or prevention of thrombotic disorders.
23. The use of claim 22, wherein the thrombotic disorder comprises left ventricular thrombosis, atrial fibrillation, acute coronary syndrome, non-valvular atrial fibrillation, deep vein thrombosis, pulmonary embolism.
24. The use of claim 22 or 23, wherein the apixaban transdermal patch is administered once every 24 hours, every 32 hours, every 48 hours, every 72 hours, every 84 hours, every 96 hours, every 120 hours, every 144 hours, or every 168 hours.
25. The use according to claim 22 or 23, wherein the apixaban transdermal patch delivers 1mg to 40mg of apixaban to the subject's blood system every 24 hours.
26. The use according to claim 22 or 23, wherein the apixaban transdermal patch delivers 2.5mg to 10mg of apixaban to the subject's blood system every 24 hours.
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CN102802608A (en) * 2009-06-16 2012-11-28 美国辉瑞有限公司 Dosage forms of apixaban
WO2019110306A1 (en) * 2017-11-21 2019-06-13 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system on the basis of adhesive plasticizer-polymer matrices
TW202106297A (en) * 2019-04-26 2021-02-16 泰合生技藥品股份有限公司 Apixaban transdermal delivery system and uses thereof

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CN102802608A (en) * 2009-06-16 2012-11-28 美国辉瑞有限公司 Dosage forms of apixaban
WO2019110306A1 (en) * 2017-11-21 2019-06-13 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system on the basis of adhesive plasticizer-polymer matrices
CN111372575A (en) * 2017-11-21 2020-07-03 Lts勒曼治疗系统股份公司 TTS based on an adhesive plasticiser polymer matrix
TW202106297A (en) * 2019-04-26 2021-02-16 泰合生技藥品股份有限公司 Apixaban transdermal delivery system and uses thereof

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