WO2023025195A1 - 阿哌沙班透皮贴剂及其制备方法 - Google Patents

阿哌沙班透皮贴剂及其制备方法 Download PDF

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Publication number
WO2023025195A1
WO2023025195A1 PCT/CN2022/114527 CN2022114527W WO2023025195A1 WO 2023025195 A1 WO2023025195 A1 WO 2023025195A1 CN 2022114527 W CN2022114527 W CN 2022114527W WO 2023025195 A1 WO2023025195 A1 WO 2023025195A1
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acid
apixaban
transdermal patch
skin
hours
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PCT/CN2022/114527
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English (en)
French (fr)
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唐俭生
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新领医药技术(深圳)有限公司
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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

Definitions

  • the present invention relates to a patch preparation for transdermal administration. More specifically, it relates to a patch preparation containing apixaban and a pharmaceutically acceptable salt thereof and a preparation method thereof.
  • the transdermal drug delivery route is a drug delivery route superior to the oral drug delivery route, which keeps the drug concentration in the blood at a constant level by continuously delivering the drug to the blood system throughout the body.
  • the transdermal route of administration not only reduces the fluctuation of the drug concentration in the blood between peaks and valleys, but also avoids the first-pass effect.
  • the transdermal route of administration avoids the direct contact of the drug and the excipients with the gastrointestinal system, it significantly reduces or eliminates side effects such as nausea and vomiting often associated with the oral route of administration.
  • Another advantage of the transdermal route of delivery is that it is not affected by diet. Administration can be easily terminated by removing the transdermal patch from the skin if necessary.
  • transdermal patches improve patient compliance by reducing the frequency of dosing. This is especially important for elderly patients and pediatric patients.
  • transdermal patch formulations include transdermal patch formulations.
  • transdermal drug delivery patch preparations include but are not limited to drug reservoir type patches and matrix type patches.
  • a drug reservoir type patch preparation is a patch preparation that contains a drug in a reservoir having a drug-permeable substrate surface
  • a matrix type patch preparation is a patch preparation that dissolves or disperses a drug in a polymer matrix layer.
  • Anticoagulant medications are usually available as injections and oral tablets.
  • Apixaban for example, is an excellent oral anticoagulant. Its indications include: reducing the risk of stroke and systemic embolism in patients with non-valvular fibrillation by 60%; prevention of deep vein thrombosis after hip and knee replacement; treatment of deep vein thrombosis; treatment of pulmonary embolism; reduction of DVT and PE recurrence risk etc.
  • oral administration of apixaban often causes bleeding, for example, about 11.71% of hip replacement patients experience bleeding symptoms each year; about 6.93% of knee replacement patients experience bleeding symptoms; about 14.9% of deep vein Patients with blood clots and pulmonary embolisms experience bleeding symptoms.
  • more than 70 percent of AF patients are over the age of 65 and have difficulty swallowing pills or fully remembering oral doses. The need for oral apixaban several times a day makes the patient's compliance with apixaban poor.
  • transdermal drug delivery patch capable of continuously delivering a therapeutically effective amount of apixaban over a prolonged period of time.
  • Apixaban oral tablets are available in two strengths, 2.5mg tablets and 5mg tablets. Take it twice daily. Its oral bioavailability is about 50%. Therefore, the desired transdermal delivery strength should be 2.5 mg/24 hours and 5 mg/24 hours.
  • the molar mass of apixaban is 459.5, and for molecules with a molar mass greater than 400 Daltons, there is no precedent for providing a transdermal patch of 5 mg per day.
  • apixaban has poor solubility in both aqueous and lipophilic organic solvents.
  • An object of the present invention is to provide an apixaban depot-type transdermal patch, which can have good skin-adhesive properties over a period of sustained delivery of apixaban or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide an apixaban reservoir type transdermal drug delivery patch, which has no skin irritation and sensitization.
  • Another object of the present invention is to provide a method for the preparation of apixaban reservoir type transdermal drug delivery patch, which can continuously deliver a therapeutically effective amount of apixaban or its Pharmaceutically acceptable salt, and non-irritating and sensitizing to the skin.
  • Another object of the present invention is to provide a method for treating or preventing thrombotic diseases, which comprises administering a therapeutically effective amount of apixaban transdermal patch to a subject in need.
  • Another object of the present invention is to provide a use of a therapeutically effective dose of apixaban reservoir-type transdermal patch in the preparation of medicines for treating or preventing thrombotic diseases.
  • the present invention provides an apixaban depot transdermal patch comprising:
  • the drug reservoir layer further comprises a skin penetration enhancer.
  • the skin penetration enhancer comprises any one or any combination of solvents, polymer solubilizers, surfactants, medium molecular weight organic acids and low molecular weight organic acids.
  • the skin penetration enhancer comprises a polymeric solubilizer, a surfactant, and a medium molecular weight organic acid.
  • the skin penetration enhancer further comprises a solvent and/or a low molecular weight organic acid.
  • the skin penetration enhancer comprises a solvent, a polymer solubilizer, a surfactant, and a low molecular weight organic acid.
  • the polymer solubilizer is a carboxyl-containing polymer or povidone, crospovidone, copovidone, and the carboxyl-containing polymer is preferably hydroxypropylmethyl phthalate Cellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose.
  • the content of apixaban or a pharmaceutically acceptable salt thereof is 0.5% to 50%, preferably 1% to 20%, more preferably 2% to 10%, of the drug layer.
  • the content of the polymer solubilizer is 0.1% to 50%, preferably 2% to 50%, 5% to 25%, more preferably 10% to 20%, of the drug layer, and the api
  • the weight ratio of saban or its pharmaceutically acceptable salt to the polymer solubilizer is about 0.1:1 to 1:20, preferably about 1:1 to 1:20, 1:1 to 1:15, more preferably About 1:1 to 1:10.
  • the content of the surfactant is 1% to 50%, preferably 5 to 30%, of the drug layer.
  • the content of the medium molecular weight organic acid is 0.1-60%, preferably 1-60%, 1-30%, more preferably 1-15% of the drug layer.
  • the content of the low molecular weight organic acid is 0.1 to 10% by weight of the drug layer, preferably 0.5 to 5%, more preferably 0.5 to 3%.
  • the medium molecular weight organic acids include C5 to C8 organic acids, preferably levulinic acid, sorbic acid, itaconic acid, mesaconic acid, ketoglutaric acid, glutaric acid, methyl Succinic 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, Dragon Cholic acid, protocatechuic acid, gallic acid, cyclohexanecarboxylic acid, pimelic acid, phthalic acid, isophthalic acid, isophthalic acid, terephthalic acid, terephthalic acid, phenylacetic acid, toluene Formic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogentistic acid, suberic acid, caprylic acid,
  • the low molecular weight organic acids include C1 to C4 organic acids, preferably 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.
  • organic acids preferably formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, prop
  • the adhesive layer comprises a skin contact adhesive and optionally antioxidants, anti-skin irritation agents, cohesion promoters, plasticizers, tackifiers.
  • the skin contact adhesive comprises acrylic glue, methacrylic glue, polyisobutylene glue, styrene-isoprene-styrene block copolymer, silicone adhesive, acrylic- Copolysiloxane copolymer adhesive, or a combination of two or more of the above.
  • the skin contact adhesive is a cross-linked adhesive or a non-cross-linked adhesive.
  • the cohesion promoter includes colloidal silicon dioxide, zinc oxide, polyvinylpyrrolidine, acrylate copolymers, crospovidone, croscarmellose, ethyl cellulose, acrylic acid Copolymer, bentonite, clay or a combination of two or more of the above.
  • the present invention provides a method for preparing the above-mentioned apixaban transdermal patch, which comprises:
  • the present invention provides a method for preparing the above-mentioned apixaban transdermal patch, which comprises:
  • the unsealed peripheral edge portions of the backing layer and the semipermeable membrane layer are sealed by heat, pressure, or a combination of both, thereby forming a sealed drug layer.
  • the present invention provides the use of the above-mentioned apixaban transdermal patch with a therapeutically effective amount in the preparation of a medicament for treating or preventing thrombotic diseases.
  • said thrombotic disease comprises ventricular thrombosis, atrial microfibrillation, acute coronary artery disease, non-valvular atrial fibrillation, deep vein thrombosis, pulmonary embolism.
  • the present invention provides a method for treating or preventing thrombotic diseases, which comprises administering a therapeutically effective amount of the above-mentioned apixaban transdermal patch to a subject in need.
  • the apixaban transdermal patch 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 Apply once every 168 hours.
  • the apixaban transdermal patch delivers from about 1 mg to about 40 mg of apixaban, preferably from 2.5 mg to 10 mg of apixaban, to said subject every 24 hours.
  • the apixaban transdermal patch of the present invention can continuously deliver apixaban or a pharmaceutically acceptable salt thereof with high skin flux for about 24 hours, 32 hours, 48 hours, 72 hours, 84 hours hours, 96 hours, 120 hours, 144 hours, and 168 hours or more.
  • the apixaban transdermal patch of the present invention also has the advantages of no skin irritation and sensitization.
  • Fig. 1 shows a schematic diagram of a drug reservoir type patch according to the present invention.
  • Fig. 2 shows a schematic diagram of a drug solid matrix type patch.
  • Figure 3 shows the measured skin flux of the transdermal patches described in Examples 87-90.
  • FIG. 4 shows the measurement curves of the skin flux of the transdermal patches described in Example 91 and Comparative Example 1.
  • Figure 5 shows the measured skin flux of the transdermal patch described in Example 92.
  • Figure 6 shows the measured skin flux of the transdermal patches described in Examples 95-98.
  • Figure 7 shows the measured skin flux of the transdermal patches described in Examples 99-101.
  • FIG. 8 shows the measurement curves of the skin flux of the transdermal patches described in Example 102 and Comparative Example 2.
  • Figure 9 shows the measured skin flux of the transdermal patches described in Examples 103-106.
  • Figure 10 shows the measured skin flux of the transdermal patches described in Examples 107-110.
  • the term "pharmaceutically acceptable salt” means a salt suitable for use in contact with a subject (eg, a human subject) without undue toxicity, irritation, allergic response, etc., within reasonable medical judgment, with reasonable benefit/risk ratio and are those salts that are effective for their intended use.
  • the "pharmaceutically acceptable salt” mentioned in the present invention includes inorganic acid addition salts and organic acid addition salts, which can be prepared in situ during the final isolation and purification of the compound, or can be prepared by adding the free base form of the purified compound (eg apixaban) are prepared by reacting separately with a suitable organic or inorganic acid and isolating the salt thus formed.
  • inorganic acid addition salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates , pyrophosphate, hydrochloride, hydrobromide, hydroiodide, phosphite, borate, etc.
  • organic acid addition salts include, but are not limited to, acetate, propionate, butyrate, isobutyrate, valerate, caproate, caprylate, oxalate, malonate, succinate, salt, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate salt, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, mesylate oleate, palmitate Naphthoate, Stearate, Lunate, Benzoate, Lactate, Tosylate, Succinate, Tartrate, Mesylate Naphthoate, Glucoheptonate, Lactfuraldehyde salt, laurylsulfonate and isethionate etc.
  • the term "medium molecular weight organic acid” includes, but is not limited to, C5 to C8 organic acids.
  • 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 Acid, trans-aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, caproic acid, benzoic acid, salicylic acid, gentisic acid, protocatechuic acid, gallic acid, cyclohexanecarboxylic acid, heptanoic acid Diacid, phthalic acid, isophthalic acid, isophthalic acid, terephthalic acid, terephthalic acid, phenylacetic acid, toluic acid, o-toluic acid, m-toluic acid, p-to
  • the term "low molecular weight organic acid” includes, but is not limited to, C1 to C4 organic 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, oxalic acid, Acetoacetic 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 acid, hydroxybutyric acid, or combinations thereof.
  • the low molecular organic acid is lactic acid.
  • the term "therapeutically effective amount” means an amount of a compound or molecule of the invention which, when administered to a subject, (i) treats or prevents a particular disease, disorder or condition, (ii) attenuates, Ameliorate or eliminate one or more symptoms of a particular disease, disorder or condition, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, disorder or condition described herein.
  • the term "about” refers to plus or minus 10% of the indicated figure.
  • “about 10%” can mean a range of 9% to 11%, and “about 1” can mean 0.9-1.1.
  • treatment refers to clinical intervention that attempts to alter the natural course of the individual being treated, and may be performed for prophylaxis or during the course of clinical pathology. Desired effects of treatment include, but are not limited to, prevention of occurrence or recurrence of disease, alleviation of symptoms, attenuation of any direct or indirect pathological consequences of disease, prevention of metastasis, reduction of the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • the present invention provides a kind of apixaban transdermal patch, which comprises:
  • the backing layer serves as the upper surface of the patch preparation and provides flexibility to the patch preparation as a main structural element.
  • the backing layer is substantially impermeable to transdermally administered pharmaceutical compositions.
  • the backing layer is preferably made of a sheet or film of flexible elastic material.
  • the backing layer is preferably air impermeable.
  • the backing layer used in the patch of the invention is preferably made of a flexible, biocompatible material that mimics the elastic properties of the skin and conforms to the skin during movement.
  • the non-occlusive backing layer allows the area to breathe (ie facilitates water vapor transmission from the skin surface), while the occlusive backing layer reduces air/vapor penetration.
  • the backing layer of the reservoir type transdermal patch (Fig. 1) and the matrix type transdermal patch (Fig. 2) is closed.
  • the backing layer comprises a synthetic polymer such as polyolefin, polyester, polyethylene, polyvinylidene chloride and polyurethane.
  • the thickness of the backing layer is from about 0.5 mil to about 5 mils; more preferably, the thickness of the backing layer is from about 1 mil to about 3 mils.
  • the oxygen delivery rate is from about 2 cc/m/24hr to about 100 cc/m/24hr, more preferably, the oxygen delivery rate is from about 70 g/m/24hr to about 90 g/m/24hr.
  • the MVTR is from about 0.3 g/m/24hr to about 50 g/m/24hr, more preferably, the MVTR is from about 5 g/m/24hr to about 30 g/m/24hr.
  • the backing layer is an approximately 2.0 mil thick occlusive polyester film layer (commercially available, e.g., Scotchpak 9733, 3M Drug Delivery Systems, St. Paul Minn.).
  • Scotchpak 9733 consists of polyester and medium density polyethylene/ethylene vinyl acetate heat seal layers, the laminate is translucent, conformable, closed and heat sealable. It can be used in the depot type patch formulation shown in FIG. 1 .
  • the drug storage layer also known as the drug layer, contains apixaban or its pharmaceutically acceptable salt, skin penetration enhancers, etc., wherein the penetration enhancers include solvents, polymer solubilizers, surfactants, medium molecular weight organic acids and any one or any combination of low molecular weight organic acids.
  • a solvent also known as a type A dermal penetration enhancer, which can partially or completely dissolve not only one or more other dermal penetration enhancers, but also partially or completely dissolve apixaban or its pharmaceutically acceptable Accepted salt.
  • the solvent itself is also beneficial in enhancing the skin penetration of apixaban or a pharmaceutically acceptable salt thereof.
  • Non-limiting examples of solvents include C1 to C6 alkyl alcohols, propylene glycol, butylene glycol, dipropylene glycol, hexylene glycol, transcutol, DMSO, N,N-dimethylacetamide, N,N-dimethylacetamide, Formamide, N-methylpyrrolidone, glycerin, water, or a combination of two or more of the above.
  • the solvent is selected from ethanol, DMSO or a combination of both.
  • Other skin penetration enhancers include polymeric solubilizers (Type B skin penetration enhancers), surfactants (Type C skin penetration enhancers), medium molecular weight organic acids (Type D skin penetration enhancers), and low molecular weight organic acids (Type D skin penetration enhancers). E-type skin penetration enhancer), etc.
  • Polymer solubilizers include but are not limited to hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hyaluronic acid, fruit Gum, carboxymethyl cellulose, alginic acid, Eudrgit S, Eudragit L, Eudrgit L-55, carrageenan, povidone, crospovidone, copovidone, or two or more of the above combination.
  • the polymer solubilizer is a carboxyl-containing polymer, including but not limited to hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and the like.
  • the weight percentage of the polymer solubilizer is 2% to 50%, preferably 2 to 30%, more preferably 5 to 25% of the drug storage layer. If the content of polymer solubilizer is lower than 2% of drug storage layer, the blood drug concentration maximum (Cmax) of apixaban will be too high; if the content of polymer solubilizer exceeds 30% of drug layer, apixaban The rate of outward diffusion of Pixaban from the reservoir layer is over-inhibited, resulting in a significant decrease in its skin penetration. And, the weight ratio of apixaban or its pharmaceutically acceptable salt to the polymer solubilizer 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, Ceraphyl 31, Ethyl Laurate, Methyl Laurate, Isopropyl Myristate, Isopropyl Palmitate , fatty alcohol, menthol, saturated or unsaturated C 9 to C 30 fatty acid, fatty acid ester, diisoadipate, medium chain fatty acid triglyceride, diethyl sebacate, sesquisorbide, Span 20, Span 40, Span 80, Tween 20, Tween 40, Tween 80, pentadecalactone, glyceryl monolactate, glyceryl monostearate, glyceryl monooleate, or combinations thereof.
  • the indicated active agent includes lauryl lactate, isopropyl myristate, isopropyl palmitate and/or oleic acid and the like.
  • fatty alcohol refers to compounds having the formula ROH, wherein R is a C7 - C30 alkyl group or a C3 - C30 alkenyl group containing one, two, three or four double bonds.
  • Fatty alcohols may include, but are not limited to, one or more saturated, monounsaturated, or polyunsaturated fatty alcohols; they may include, but are not limited to, one or more of the following: octanol, nonanol, decanol, undecanol Alcohol, Lauryl Alcohol, Isolauryl Alcohol, Trans-Isolauryl Alcohol, Tridecyl Alcohol, Myristyl Alcohol, Isomyristyl Alcohol, Trans-Isomyristyl Alcohol, Pentadecyl Alcohol, Cetyl Alcohol, Palmitoleyl Alcohol, Isopalmityl Alcohol, Trans-Isomyristyl Alcohol Isopalmityl Alcohol, Heptadecanyl Alcohol, Stearyl Alcohol, Isostearyl
  • saturated fatty alcohols may include, but are not limited to, one or more of the following: lauryl alcohol, isolauryl alcohol, anteisomyristyl alcohol, myristyl alcohol, isomyristyl alcohol, anteisomyristyl alcohol, cetyl alcohol Waxy Alcohol, Isopalmityl Alcohol, Trans-Isostearyl Alcohol, Stearyl Alcohol, Isostearyl Alcohol, and Trans-Isostearyl Alcohol.
  • the fatty alcohol is myristyl alcohol.
  • fatty acid ester refers to an ester resulting from the combination of a fatty acid and an alcohol, wherein the fatty acid and the alcohol are compounds having the formula RCOOH and R'OH, respectively, wherein R and R' are each C 1 -C 30 alkyl.
  • Exemplary saturated or unsaturated C9 to C30 fatty acids include, but are not limited to, capric acid, lauric acid, palmitic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, rigidoic acid, erucic acid , nervonic acid, and cimenic acid, hexadecatrienoic acid, linoleic acid, ⁇ -linolenic acid, ⁇ -linolenic acid, calendulaic acid, stearic acid, meadic acid, eicosadienoic acid, di Decatrienoic acid, dihomo-gamma-linolenic acid, arachidonic acid, and docosadienoic acid.
  • Surfactants also include, but are not limited to, glycerides (monoglycerides, diglycerides, triglycerides), polyoxyethylene stearate, octacosatetraenyl-4 phosphate, and ethylene glycol palm stearin
  • glycerides monoglycerides, diglycerides, triglycerides
  • polyoxyethylene stearate polyoxyethylene stearate
  • octacosatetraenyl-4 phosphate ethylene glycol palm stearin
  • Oleoyl Polyoxy-6 Glyceride Lauroyl Polyoxy-6 Glyceride
  • Caprylyl Polyoxy-8 Glyceride Propylene Glycol Monocaprylate Type
  • the weight percent content of the surfactant is 1% to 50%, preferably 5 to 30%, of the drug storage layer.
  • Medium molecular weight organic acids include, but are not limited to, C5 to C8 organic acids.
  • 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, cyclohexanecarboxylic acid, heptene Acid, phthalic acid, isophthalic acid, isophthalic acid, terephthalic acid, terephthalic acid, phenylacetic acid, toluic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogent
  • the content of medium molecular weight organic acid is 1-60%, preferably 1-30%, more preferably 1-15% of the drug reservoir layer. If the content of medium molecular weight organic acid is less than 1% of the drug reservoir layer, the skin penetration enhancement effect will become meaningless. 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, C1 to C4 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, oxalic acid, Acetoacetic 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 acid, hydroxybutyric acid, or combinations thereof.
  • the low molecular organic acid is lactic acid.
  • the content of low molecular weight organic acid is 0.1 to 10% by weight of the reservoir layer, preferably 0.5 to 5%, more preferably 0.5 to 3%. If the content of the low molecular weight organic acid is less than 0.1% by weight of the reservoir layer, the skin penetration enhancement effect becomes meaningless. If the content of low molecular weight organic acids exceeds 10% by weight of the reservoir layer, unacceptable levels of skin irritation can result.
  • the drug reservoir layer comprises apixaban or a pharmaceutically acceptable salt thereof and a skin penetration enhancer comprising a polymer solubilizer (type B skin penetration enhancer), surface Active agent (type C skin penetration enhancer) and medium molecular weight organic acid (type D skin penetration enhancer); wherein both polymer solubilizer and medium molecular weight organic acid can dissolve apixaban. Only dissolved apixaban molecules are able to penetrate the skin, while undissolved apixaban crystals do not. Medium molecular weight organic acids and dissolved apixaban molecules were able to 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.
  • a skin penetration enhancer comprising a polymer solubilizer (type B skin penetration enhancer), surface Active agent (type C skin penetration enhancer) and medium molecular weight organic acid (type D skin penetration enhancer); wherein both polymer solubilizer and medium molecular weight organic acid can dissolve apixaban
  • polymeric solubilizers do not penetrate the skin and remain in the drug layer, so polymeric solubilizers provide a longer-lasting penetration enhancement than medium molecular weight organic acids, lasting approximately 24 hours, 48 hours, 72 hours, 84 hours hours, 96 hours, 120 hours, 144 hours or more than 168 hours.
  • the polymer solubilizer also increases the viscosity of the drug layer, which can reduce the rate at which dissolved apixaban diffuses outward from the drug layer to reduce Cmax. The reduction in Cmax helps to provide a more constant amount of skin penetration over the 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours and 168 hours.
  • the drug reservoir layer comprises apixaban or a pharmaceutically acceptable salt thereof and a skin penetration enhancer comprising a solvent (type A skin penetration enhancer), a polymer enhancer, and a skin penetration enhancer.
  • Solvent type B skin penetration enhancer
  • surfactant type C skin penetration enhancer
  • medium molecular weight organic acid type D skin penetration enhancer
  • Medium molecular weight organic acid has low skin irritation.
  • the drug reservoir layer comprises apixaban or a pharmaceutically acceptable salt thereof and a skin penetration enhancer
  • the skin penetration enhancer includes a solvent (type A skin penetration enhancer), a polymer enhancer Solvent (type B skin penetration enhancer), surfactant (type C skin penetration enhancer), medium molecular weight organic acid (type D skin penetration enhancer) and low molecular weight organic acid (type E skin penetration enhancer).
  • the skin penetration enhancer includes a solvent (type A skin penetration enhancer), a polymer enhancer Solvent (type B skin penetration enhancer), surfactant (type C skin penetration enhancer), medium molecular weight organic acid (type D skin penetration enhancer) and low molecular weight organic acid (type E skin penetration enhancer).
  • Low molecular weight organic acids are less irritating to the skin at low concentrations. Low molecular weight organic acids dissolve drugs and penetrate the skin faster than medium molecular weight organic acids, but they also disappear more quickly. Therefore, skin penetration of low molecular weight organic acids
  • Low molecular weight organic acids enhance the skin penetration of apixaban through their at least 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 penetration.
  • Medium molecular weight organic acids dissolve apixaban at lower concentrations and can form acid-base addition salts.
  • Medium molecular weight organic acids have a delayed skin penetration enhancement, but also a longer-lasting penetration enhancement, ie, enhancement for a longer period of time than low molecular weight organic acids.
  • the duration of enhanced skin penetration ranges from a few hours to 24 hours. If the drug reservoir contained only moderate molecular weight organic acids, there was no significant penetration of apixaban during the first 24 hours. There was no meaningful skin penetration of apixaban if the drug reservoir contained only solvent and polymeric solubilizer. If the drug reservoir layer contained only surfactant, there would be no meaningful skin penetration of apixaban because the drug was not in solution for osmosis.
  • the weight of the drug reservoir layer coating is from about 55 grams per square meter to about 1000 grams per square meter.
  • the thickness of the drug reservoir coating is from about 40 microns to about 1000 microns.
  • the semi-permeable membrane layer is used to contain the liquid or semi-solid matrix material in 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 semi-permeable membrane layer and the backing layer can 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, Contan 9716, and Contran 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 non-woven materials.
  • the semipermeable membrane is preferably made of flexible polymeric materials commonly used by those skilled in the art.
  • Polymeric membranes that can be used to make 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.
  • the semipermeable membrane layer is made of a microporous membrane made from ethylene-vinyl acetate copolymer containing from about 0.5 to about 28 wt.% vinyl acetate.
  • Suitable weaving materials include Saatifil PES, such as PES 105/52 available from Saatitech, Inc.
  • a suitable nonwoven is Sontara from DuPont Nonwovens Sontara Technologies.
  • the semipermeable membrane layer is an ethylene-vinyl acetate copolymer membrane available from 3MTM, such as Cotran 9702, Cotran 9705, Cotran 9706, Cotran 9707, Cotran 9712, Cotran 9715, Cotran 9716 and Cotran 9728 ( available from 3MTM).
  • the thickness of the semipermeable membrane layer may generally be about 10 um to about 100 um, preferably about 15 ⁇ m to about 50 ⁇ m.
  • the adhesive layer serves to adhere the apixaban transdermal patch to the skin surface. After the release layer is removed, it can also be used to control the rate of delivery of apixaban to the skin.
  • adhesives include, but are not limited to, acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives, silicone adhesives agent, acrylic-copolysiloxane copolymer adhesive, or a combination of two or more of the above.
  • Non-limiting examples of acrylic adhesives include Henkel's Duro-Tak adhesives 387-2051, 387-2054, 387-2353, 87-235, 387-2516, 387-2287, 387-2510, 87-287- 2054, 87-210294 (Sanyo Chemical Industry Co., Ltd.).
  • Non-limiting examples of polyisobutylene binders include Oppanol N150, Oppanol B150, Oppanol N100, Oppnaol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12 and low molecular weight polybutene H1900 from Ineos with mineral oil tackifier agent.
  • 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 choices.
  • the adhesives are polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives, silicone adhesives and acrylic-co-polysiloxane copolymer adhesives agent.
  • cross-linked adhesives such as Duro-Tak 387-2054 adhere better to the skin than non-cross-linked adhesive 387-2051 and cross-linked 387-2516 does better than non-cross-linked 387-2287 adhere to the skin.
  • the skin contact adhesive layer may also comprise one or more pharmaceutically acceptable additives, non-limiting examples of which include antioxidants, anti-skin irritants, cohesion promoters, plasticizers, tackifiers wait.
  • pharmaceutically acceptable additives non-limiting examples of which include antioxidants, anti-skin irritants, cohesion promoters, plasticizers, tackifiers wait.
  • the additives are included in the skin contact adhesive layer in an amount of from about 0.05% to about 40%, preferably from about 1% to about 30%, more preferably from about 3% to about 30%, most preferably adhesive about 20% by weight of the agent material.
  • Non-limiting examples of antioxidants include tocopherol, tocopheryl acetate, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, Thioglycerol, sodium thiosulfate, sodium dioxide, sodium formaldehyde sulfoxylate, and chelating agents as synergistic antioxidants include citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA, among others.
  • cohesion promoters include colloidal silicon dioxide, zinc oxide, polyvinylpyrrolidine, acrylate copolymers, crospovidone, croscarmellose (croscarmellose), Ethyl cellulose, acrylic acid copolymer, bentonite, clay and mixtures thereof.
  • the cohesion promoter is colloidal silicon dioxide.
  • the cohesion promoter is present in the adhesive layer in an amount from about 3% to about 40% by weight of the adhesive material, preferably from about 5% to about 30% by weight of the adhesive material.
  • the skin contact layer adhesive is a polyisobutylene adhesive, a silicone adhesive or a styrene-isoprene-styrene based adhesive
  • the addition of a cohesion enhancer effectively The integrity of the adhesive is maintained.
  • Non-limiting examples of plasticizers include mineral oil, silicone oil, triethyl citrate, and combinations thereof.
  • the amount of plasticizer present in the adhesive layer is from about 0% to about 40% by weight of the adhesive material, preferably from about 0% to about 30% by weight of the adhesive material, more preferably the adhesive From about 0% to about 30% by weight of the adhesive material, 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 from about 0% to about 40% by weight of the adhesive material, preferably from about 0% to about 30% by weight of the adhesive material.
  • the present invention provides a method for preparing apixaban transdermal 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:
  • a liquid, semi-solid or solid drug reservoir layer is prepared.
  • apixaban or its pharmaceutically Acceptable salts mixed at room temperature or elevated temperature (e.g., 85°C) for complete or partial dissolution, followed by addition of surfactant (type C skin penetration enhancer), medium molecular weight organic acid (type D skin penetration enhancer) and any Selected low molecular weight organic acid (type E skin penetration enhancer), mixed at room temperature or elevated temperature (eg 85°C) to form a homogeneous liquid, semi-solid or solid.
  • surfactant type C skin penetration enhancer
  • type D skin penetration enhancer medium molecular weight organic acid
  • type E skin penetration enhancer any Selected low molecular weight organic acid
  • the uniform liquid, semi-solid or solid prepared as described above can be distributed or coated on the side of the semi-permeable membrane layer away from the adhesive layer/release layer, and then combined with the backing layer laminated.
  • the method for preparing the 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 heat and pressure , the step of causing said liquid, semi-solid or solid mixture to be confined within said peripheral edge.
  • the three edges of the side of the backing layer film close to the skin and the three edges of the side of the semipermeable membrane layer away from the skin contacting the adhesive layer/protective release liner layer Edge sealing, filling the liquid or semi-solid drug reservoir material from the unsealed fourth edge into the three-sided sealed reservoir, and then sealing the fourth edge to form a four-sided sealed drug reservoir layer.
  • the present invention provides a method for treating thrombotic diseases, comprising administering a therapeutically effective amount of apixaban transdermal patch to a patient in need, comprising:
  • a drug reservoir layer comprising apixaban or a pharmaceutically acceptable salt thereof
  • the apixaban transdermal patch can have a high skin flux, for example about 1 ⁇ g/cm2.hr to about 10 ⁇ g/cm2.hr, preferably about 1 ⁇ g/cm2.hr to about 5 ⁇ g/cm2 .hr, more preferably a sustained delivery of a skin flux of from about 3 to about 5 ⁇ g/cm2.hr.
  • the apixaban transdermal patch can deliver sustained delivery for at least 24 hours, 32 hours, 48 hours, 72 hours, 84 hours, 96 hours, 120 hours, 144 hours, or 168 hours or more.
  • the apixaban transdermal patch delivers from about 1 mg to about 40 mg of apixaban, preferably from about 2.5 mg to about 10 mg of apixaban, to said subject every 24 hours .
  • apixaban is effective in carboxyl-containing polymer solubilizers (water-insoluble hydroxypropylmethylcellulose phthalate HPMCP, hydroxypropylmethylcellulose acetate succinate
  • carboxyl-containing polymer solubilizers water-insoluble hydroxypropylmethylcellulose phthalate HPMCP, hydroxypropylmethylcellulose acetate succinate
  • HPMCAS solubility in esters HPMCAS, Eudragit L100
  • crystallization inhibitors such as povidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl cyclodextrin, etc.
  • carboxyl-containing polymer solubilizers water-insoluble hydroxypropylmethylcellulose phthalate HPMCP, hydroxypropylmethylcellulose acetate succinate HPMCAS, Eudragit L100
  • crystallization inhibitors such as povidone (PVP), hydroxypropyl cellulose (HPC), hydroxypropyl cyclodextrin, etc.
  • PVP povidone
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cyclodextrin, etc.
  • traditional crystallization inhibitors have better crystallization inhibitory effect.
  • apixaban does not crystallize when the solvent is evaporated to semi-dryness (approximately 1 g).
  • apixaban recrystallized to form a solid after solvent evaporation.
  • APX is apixaban
  • PVP K30 is polyvinylpyrrolidone K30
  • PVP K90 is polyvinylpyrrolidone K90
  • HPC LF is hydroxypropylcellulose LF
  • HPMCAS is hydroxypropylmethylcellulose acetate succinate
  • Eudragit L100 is based on a copolymer of methacrylic acid and methyl methacrylate from Evonik
  • HPMCP is hydroxypropylmethylcellulose phthalate.
  • HPMCP:apixaban ratio When the HPMCP:apixaban ratio was 6:1, no apixaban crystals were formed in the membranes 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 a Scotchpak 9733 backing film and dried in a forced-air oven at 100°C for 60 minutes to form a dry film. No crystals formed on the dry film at ratios of HPMCP:apixaban of 5:1 or higher (Table 2).
  • apixaban on other types of skin penetration enhancers such as solvents (type A skin penetration enhancers), surfactants (type C skin penetration enhancers), medium molecular weight organic acids (type D skin penetration enhancers). Penetration enhancer) and low molecular weight organic acid (type E skin penetration enhancer), the results are listed in Table 3.
  • the receiving unit has a volume of 28 ml and is filled with a pH 7.4 buffer solution containing monopotassium phosphate, sodium chloride and sodium azide.
  • the effective skin penetration size is 0.61cm2.
  • the receiving solution was immediately analyzed by HPLC for the amount of apixaban.
  • 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 tests were performed as previously described. The results are summarized in Table 4. It can be seen that the skin flux for formulation combinations 68 to 78 is low. These formulations contain solvents alone (ethanol and dimethyl sulfoxide) or type D skin penetration enhancers (levulinic acid) or combinations of solvents and skin penetration enhancers such as solvents (dimethyl sulfoxide) and type B skin penetration enhancers.
  • HPMCP hydroxypropyl methylcellulose phthalate
  • solvent ethanol and dimethyl sulfoxide
  • type C skin penetration enhancer laauryl lactate
  • solvent ethanol and dimethyl sulfoxide
  • sulfone solvent with a type D skin penetration enhancer (levulinic acid)
  • solvents ethanol and dimethyl sulfoxide
  • lactic acid solvents
  • three skin penetration enhancers such as type A Combination of skin penetration enhancers (alcohol and dimethyl sulfoxide) with type B skin penetration enhancers (HPMCP) and type D skin penetration enhancers (levulinic acid).
  • the 72-hour cumulative skin permeation fluxes for formulation combination 79 containing 4 skin penetration enhancers A, B, C and D and formulation combinations 80 to 86 containing 5 skin penetration enhancers A, B, C, D and E were very high. High, 2.5 to 670 times that of formulation combinations 68 to 78.
  • Apixaban is mixed with levulinic acid and heated to dissolve. Cool the mixture to room temperature.
  • the dermal flux of Formulation 87 (Table 5, Figure 3) containing a type D skin penetration enhancer (levulinic acid) but no type B skin penetration enhancer (HPMCP) was higher at early time points, but increased with residual The skin flux of Formulation 87 decreased rapidly when the amount of levulinic acid in the formulation was reduced due to skin penetration. GC analysis of the semi-solid sample remaining in the Franz unit showed little levulinic acid remaining at the end of 96 hours.
  • Apixaban is mixed with levulinic acid and heated to dissolve. Add Lauryl Lactate and mix. Cool the mixture to room temperature.
  • the dermal flux of Formulation 88 (Table 5, Figure 3) containing both a Type C skin penetration enhancer (lauryl lactate) and a Type D skin penetration enhancer (levulinic acid) was that of a formulation containing only a Type D skin penetration enhancer 3 times the skin flux of 87.
  • Formulation 88 did not contain a type B skin penetration enhancer, its skin flux was higher at early time points, but as the amount of levulinic acid remaining in the formulation decreased due to skin penetration, the skin flux of Formulation 88 quickly lowered.
  • GC analysis of the semi-solid sample remaining in the Franz unit showed little levulinic acid remaining at the end of 96 hours.
  • Apixaban and HPMCP were mixed with DMSO and levulinic acid and heated to 85°C to dissolve. Add Lauryl Lactate and mix. The material was warmed to room temperature. Skin flux for both formulations (Table 5, Figure 3) remained almost unchanged over 96 hours. Although the amount of residual levulinic acid in the formulation was lower and lower, the amount of polymer solubilizer HPMCP remained constant because of its high molecular weight and did not penetrate the skin. Since the presence of the polymer solubilizer can maintain a large amount of apixaban in a dissolved state, the transdermal delivery rate of apixaban is almost kept constant.
  • APX apixaban
  • HPMCP hydroxypropylmethylcellulose phthalate
  • DMSO dimethylsulfoxide
  • the index finger is pressed against the adhesive layer for 5 seconds, and then the index finger is lifted. Much of the adhesive is transferred to the fingers.
  • the skin flux of this preparation is very low, far from meeting the required flux of 25858 ⁇ g/patch ⁇ 96hr, which is about 5 times lower than that of Example 91 containing four types of skin penetration enhancers.
  • APX apixaban
  • HPMCP hydroxypropylmethylcellulose phthalate
  • DMSO dimethylsulfoxide
  • Example 92 and the formulation of Example 94 containing penetration enhancers types A, B, C, and D were able to maintain a skin flux of 3 ⁇ g between 8 hours and 96 hours /cm2.h and 6 ⁇ g/cm2.h (Table 7, Figure 5).
  • the formulation of Example 93 containing two different type D penetration enhancers (lauryl lactate and methyl caprate) was also able to maintain high dermal flux for 4 days.
  • Figure 5 shows the 3-day skin flux profile for Formulation 92 (patch size 31.5 cm2) obtained based on internal IVIVR.
  • APX apixaban
  • HPMCP hydroxypropylmethylcellulose phthalate
  • DMSO dimethylsulfoxide
  • HPMCP hydroxypropylmethylcellulose phthalate
  • DMSO dimethyl sulfoxide
  • HPMCP and levulinic acid are mixed and heated to dissolve.
  • Table 9 and Figure 6. formulation compositions 95, 96 and 97 had high skin flux with estimated patch sizes of about 16 cm2, 29 cm2 and 23 cm2, 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 permeated through the skin into the receiver solution at 4, 8, 10, 24, 32, 48, 56 hours. At the 56 hour time point, more than half of the levulinic acid had been permeated.
  • Adhesive layer Add apixaban, levulinic acid, and lauryl lactate to the tank and mix and dissolve. Add the 4302 and 4202 solutions and mix to form a homogeneous viscous liquid. The liquid was coated onto a silicon-coated release layer and dried at 40°C for 4 minutes and at 85°C for 4 minutes. Skin flux was also high for Formulation Composition 98 with an estimated patch size of 24 cm 2 .
  • the receiving unit has a volume of 28 ml and is filled with a pH 7.4 buffer solution containing monopotassium phosphate, sodium chloride and sodium azide.
  • the effective skin penetration size is 0.61cm2.
  • 4.5cm2 of 700 to 800um thick human cadaver skin was mounted on the receiving unit with the dermis side facing up.
  • Stick the adhesive layer on the dermis remove the release layer, and place the O-ring on top of the adhesive layer.
  • Fill the O-ring with a pre-weighed reservoir of liquid or semi-solid formulation.
  • the receiving solution was immediately analyzed by HPLC for the amount of apixaban.
  • APX apixaban
  • HPMCP hydroxypropylmethylcellulose phthalate
  • DMSO dimethyl sulfoxide
  • APX apixaban
  • HPMCP hydroxypropylmethylcellulose phthalate
  • DMSO dimethylsulfoxide
  • Formulation 99 and Formulation 100 containing only adipic acid but no lactic acid, had no flux at the 10 hour time point, but good flux starting at the 24 hour time point and maintained through the 96 hour time point.
  • Formulation 102 contains a five-penetration enhancer system skin flux, including lactic acid (3% w/w, penetration enhancer type E), adipic acid (8% w/w%, penetration enhancer type D), ethanol (penetration enhancer type D), ethanol (penetration enhancer type Type A), DMSO (penetration enhancer type A), HPMCP (penetration enhancer type B) and lauryl lactate (penetration enhancer type C).
  • Skin flux for Formulation 102 was high as early as the 4 hour time point and was maintained over 72 hours (Table 13 and Figure 8). In contrast, the skin flux of Formulation 101 with lactic acid (E) and no adipic acid (D) was higher only in the time period from 4 hours to 24 hours, but lower after the time period beyond 24 hours (Table 12).
  • Reproducing Example Formulation 9-2 of US Patent Application 2020/0338012A1 Apixaban, polypropylene glycol, HPC, lactic acid and methanol were mixed, heated and dissolved.
  • the formulation of Comparative Example 2 has very low skin flux because it does not contain polymer solubilizer B (such as HPMCP) and medium molecular weight organic acid D (such as adipic acid).
  • polymer solubilizer B such as HPMCP
  • medium molecular weight organic acid D such as adipic acid
  • 1,2-Propanediol and HPC were used as viscosifiers (to increase liquid viscosity)
  • the HPC data in Table 1 and the polypropylene glycol (PPG) data in Table 3 indicate that they are not solubilizers for apixaban.
  • APX apixaban
  • HPMCP hydroxypropylmethylcellulose phthalate
  • DMSO dimethylsulfoxide
  • Patch compositions 104 and 105 containing penetration enhancer types A, B, C and E had much higher skin flux than patch compositions 103 and 106 containing only penetration enhancer types A, B and C (Table 14, Figure 9).
  • oleic acid not only forms an adduct with apixaban that is easy to penetrate the skin, but also acts as a surfactant C to increase the skin's permeability.
  • drug reservoir type patch compositions 107 containing skin penetration enhancers types A, B, C and D and drug reservoirs containing skin penetration enhancers types A, B, C, D and E Type patch composition 108 its skin flux is significantly higher than the skin flux of matrix type patch compositions 109 and 110 containing skin penetration enhancer types A, B, C, D, E (Table 15 , Figure 10).
  • the placebo patches described in Table 18 were prepared using the same procedure described earlier for the active patches, except that the drug reservoir contained no apixaban.
  • the adhesive layer weight was 60 grams per square meter.
  • the outer skin of the upper arm or thigh of healthy volunteers was cleaned with wet paper towels and dried with dry paper towels. After applying the placebo patch, smooth it out to make sure there are no air bubbles under the surface of the patch. Record the start date and time of the experiment. Adhesion and irritation scores were recorded daily.
  • the adhesive matrix of Placebo 1 lost its integrity 9 hours after application to the skin. After the patch was removed, a large amount of adhesive was transferred to the skin and the skin adhesion score was low. Because the skin contact adhesive is non-crosslinked Duro-Tak 387-2287 and contains no cohesion promoters. When the crosslinking adhesives Duro-Tak 387-2504 and Duro-Tak 387-2516 are used in combination with cohesion promoters such as Crospovidone CLM and Eudragit E100 as skin contact adhesives, skin adhesion is obtained Great improvement. Silicone adhesives and polyisobutylene adhesives were also found to have good skin adhesion.
  • Placebo 2 which contained 10% adipic acid but no lactic acid, was less irritating to the skin. Skin irritation was also low for placebos 2 to 5, which contained 8% to 10% adipic acid and low levels of lactic acid (1.5% to 5%). In contrast, placebo 1, which contained a high content of lactic acid (13%), was highly irritating to the skin.

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Abstract

本发明涉及一种阿哌沙班透皮贴剂及其制备方法和用途。具体来说，本发明提供了一种包含背衬层、药物层、半透膜层、粘合剂层和任选的离型层的阿哌沙班透皮贴剂及其制备方法和用途。

Description

阿哌沙班透皮贴剂及其制备方法 技术领域
本发明涉及一种用于透皮给药的贴剂制剂。更具体地，它涉及一种包含阿哌沙班及其药学上可接受的盐的贴剂制剂及其制备方法。
背景技术
透皮给药途径是一种优于口服给药途径的给药途径，其通过不断地向全身血液系统输送药物，使血液中的药物浓度维持在恒定的水平。透皮给药途径不仅减少了血液中的药物浓度在峰谷之间的波动，还避免了首过效应。此外，由于透皮给药途径避免了药物和辅料与胃肠系统的直接接触，从而显著地减少了或消除了恶心、呕吐等常与口服给药途径伴随的副作用。透皮给药途径的另一个优点就是它不受饮食的影响。必要时通过从皮肤上取下透皮贴剂就可以很容易地终止给药。而且，透皮贴剂通过减少给药频率提高了患者的依从性。这对于老年患者和儿科患者显得尤其重要。
透皮给药途径常见的剂型包括透皮给药贴剂制剂。目前常见的透皮给药贴剂制剂包括但不限于药物储库类型贴剂和基质类型贴剂等。药物储库类型贴剂制剂是将药物包含在具有药物可渗透基底表面的储库中的贴剂制剂，基质类型贴剂制剂是将药物溶解或分散在聚合物基质层中的贴剂制剂。
抗凝药物通常以注射剂和口服片剂形式存在。例如，阿哌沙班就是一种优质的口服抗凝药物。其适应症包括：将非瓣膜性颤动患者中风和全身栓塞的风险降低60％；预防髋膝关节置换术后深静脉血栓形成；深静脉血栓的治疗；肺栓塞的治疗；降低DVT和PE复发的风险等。然而，阿哌沙班的口服施用经常会导致出血的发生，例如每年约11.71％的髋关节置换患者会出现出血症状；约6.93％的 膝关节置换患者会出现出血症状；约14.9％的深静脉血栓和肺栓塞的患者会出现出血症状。而且，70％以上的房颤患者的年龄在65岁以上，吞咽药丸或完全记住口服剂量对于他们来说存在困难。每天需要多次口服阿哌沙班使得患者对于阿哌沙班的依从性较差。
因此，为了解决上述问题，目前急需一种能够在延长的时间段内持续递送治疗有效量的阿哌沙班的透皮给药贴剂。
阿哌沙班口服片剂有两种规格，2.5mg片剂和5mg片剂。每天服用两次。其口服生物利用度约为50％。因此，所需的透皮递送强度应当为2.5毫克/24小时和5毫克/24小时。但是，阿哌沙班的摩尔质量是459.5，针对对于摩尔质量大于400道尔顿的分子，目前尚无每天提供5毫克的透皮贴剂的先例。此外，阿哌沙班在水性和亲脂性有机溶剂中的溶解度都很差。在水中的溶解度约40μg/ml(https://pubchem.ncbi.nlm.nih.gov/compound/Apixaban#section＝Drug-Warning)，在乙醇中的溶解度为0.42mg/ml，在乙酸乙酯中的溶解度为0.15mg/ml，在甲苯中的溶解度为0.05mg/ml。乙醇、乙酸乙酯和甲苯是广泛用于溶解压敏粘合剂和药物以制备透皮贴剂的常规溶剂。通过透皮给药途径以5毫克/24小时的剂量长时间持续递送阿哌沙班是一项挑战。
发明内容
本发明的一个目的是提供一种阿哌沙班储库型透皮贴剂，其可以以治疗有效量的血药浓度在延长的时间段内持续递送阿哌沙班或其药学上可接受的盐。
本发明的一个目的是提供一种阿哌沙班储库型透皮贴剂，其可以在持续递送阿哌沙班或其药学上可接受的盐的时间段内具有良好的皮肤粘合特性。
本发明的另一个目的是提供一种阿哌沙班储库型透皮给药贴剂，其无皮肤刺激性和致敏性。
本发明的另一个目的是提供一种制备阿哌沙班储库型透皮给药 贴剂的方法，所述贴剂可以在延长的时间段内持续递送治疗有效量的阿哌沙班或其药学上可接受的盐，并且对皮肤无刺激性和致敏性。
本发明的另一个目的是提供一种治疗或预防血栓疾病的方法，其包括向有需要的受试者施用治疗有效量的阿哌沙班透皮贴剂。
本发明的另一个目的是提供一种治疗有效量的阿哌沙班储库型透皮贴剂在制备用于治疗或预防血栓疾病的药物中的用途。
在一个实施方案中，本发明提供了一种阿哌沙班储库型透皮贴剂，其包括：
1.背衬层；
2.药物储库层；
3.半透膜层；
4.粘合剂层；和
5.离型层。
在一个实施方案中，所述药物储库层还包含皮肤渗透促进剂。
在一个实施方案中，所述皮肤渗透促进剂包含溶剂、聚合物增溶剂、表面活性剂、中等分子量有机酸和低分子量有机酸中的任一项或其任意组合。
在一个实施方案中，所述皮肤渗透促进剂包含聚合物增溶剂、表面活性剂、和中等分子量有机酸。
在一个实施方案中，所述皮肤渗透促进剂还包含溶剂和/或低分子量有机酸。
在一个实施方案中，其中所述皮肤渗透促进剂包含溶剂、聚合物增溶剂、表面活性剂、和低分子量有机酸。
在一个实施方案中，所述聚合物增溶剂为含羧基的聚合物或聚维酮、交联聚维酮、共聚维酮，含羧基的聚合物优选地为邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、羧甲基纤维素。
在一个实施方案中，阿哌沙班或其药学上可接受的盐的含量为药物层的0.5％至50％，优选1％至20％，更优选2％至10％。
在一个实施方案中，所述聚合物增溶剂的含量为药物层的0.1％ 至50％，优选2％至50％，5％至25％，更优选10％至20％，并且所述阿哌沙班或其药学上可接受的盐与聚合物增溶剂的重量比为约0.1:1至1:20，优选为约1:1至1:20、1:1至1:15，更优选为约1:1至1:10。
在一个实施方案中，所述表面活性剂的含量为药物层的1％至50％，优选5至30％。
在一个实施方案中，所述中等分子量有机酸的含量为药物层的0.1-60％，优选1-60％、1至30％，更优选1至15％。
在一个实施方案中，所述低分子量有机酸的含量为药物层重量的0.1至10％，优选0.5至5％，更优选0.5至3％。
在一个实施方案中，所述中等分子量有机酸包括C 5至C 8有机酸，优选地包括乙酰丙酸、山梨酸、衣康酸、中康酸、酮戊二酸、戊二酸、甲基琥珀酸、戊酸、异戊酸、新戊酸、顺式乌头酸、反式乌头酸、抗坏血酸、柠檬酸、异柠檬酸、己二酸、己酸、苯甲酸、水杨酸、龙胆酸、原儿茶酸、没食子酸、环己烷羧酸、庚二酸、邻苯二甲酸、间苯二甲酸、间苯二甲酸、对苯二甲酸、对苯二甲酸、苯乙酸、甲苯甲酸、邻甲苯甲酸酸、间甲苯甲酸、对甲苯甲酸、扁桃酸、homogentistic酸、辛二酸、辛酸、或其组合，更优选地包括乙酰丙酸、戊二酸、己二酸及其组合。
在一个实施方案中，所述低分子量有机酸包括C 1至C 4有机酸，优选地包括甲酸、乙醛酸、草酸、乙酸、乙醇酸、丙烯酸、丙酮酸、丙二酸、丙酸、3-羟基丙酸、乳酸、甘油酸、富马酸、马来酸、草酰乙酸、巴豆酸、乙酰乙酸、2-氧代丁酸、甲基丙二酸、琥珀酸、苹果酸、L-酒石酸、DL-酒石酸、内消旋酒石酸、二羟基酒石酸、丁酸、异丁酸、羟基丁酸、或其组合，更优选地，包括乳酸。
在一个实施方案中，所述粘合剂层包含皮肤接触粘合剂和任选的抗氧化剂、抗皮肤刺激剂、内聚促进剂、增塑剂、增粘剂。
在一个实施方案中，所述皮肤接触粘合剂包括丙烯酸胶、甲基丙烯酸胶、聚异丁烯胶、苯乙烯-异戊二烯-苯乙烯嵌段共聚物、硅氧烷 粘合剂、丙烯酸-共聚硅氧烷共聚物粘合剂，或上述两种或多种的组合。
在一个实施方案中，所述皮肤接触粘合剂为交联粘合剂或非交联粘合剂。
在一个实施方案中，所述内聚促进剂包括胶体二氧化硅、氧化锌、聚乙烯吡咯烷、丙烯酸酯共聚物、交聚维酮、交联羧甲基纤维素、乙基纤维素、丙烯酸共聚物、膨润土、粘土或以上两种或更多种的组合。
在一个实施方案中，本发明提供了一种制备上述阿哌沙班透皮贴剂的方法，其包括：
1)将阿哌沙班或其药学上可接受的盐与皮肤渗透促进剂混合形成均匀的液体、半固体或固体混合物；
2)将所得的液体、半固体或固体混合物均匀地分配或涂覆在背衬膜上；并将背衬膜上被所述混合物分配或涂覆的一侧与半透膜层的远离粘合剂层/离型层的一侧进行层压；或者
将均匀的液体、半固体或固体分配或涂覆在半透膜层的远离粘合剂层/离型层的一侧，再将半透膜层上被所述混合物分配或涂覆的一侧与背衬层进行层压。
在一个实施方案中，还包括通过热、压力或热和压力两者的组合来密封背衬层膜和半透膜的外围边缘，使得所述液体、半固体或固体混合物被限制在所述外围边缘范围内的步骤。
在一个实施方案中，本发明提供了一种制备上述阿哌沙班透皮贴剂的方法，其包括：
1)将阿哌沙班或其药学上可接受的盐与皮肤渗透促进剂混合形成均匀的液体、半固体或固体混合物；
2)将背衬层与半透膜层的远离粘合剂层/离型层的一侧进行层压，并通过热、压力或热和压力两者的组合来密封背衬层和半透膜层的部分外围边缘，并将所得的液体、半固体或固体混合物从未密封的外围边缘部分填充至背衬层与半透膜层之间的区域；
3)然后，通过热、压力或热和压力两者的组合来密封背衬层和半透膜层的尚未密封的外围边缘部分，从而形成密封的药物层。
在一个实施方案中，本发明提供了治疗有效量的上述阿哌沙班透皮贴剂在制备用于治疗或预防血栓疾病的药物中的用途。
在一个实施方案中，所述血栓疾病包括心室血栓、心房微颤、急性冠状动脉症、非瓣膜性心房颤动、深静脉血栓、肺栓塞。
在一个实施方案中，本发明提供了一种治疗或预防血栓疾病的方法，其包括向有需要的受试者施用治疗有效量的上述的阿哌沙班透皮贴剂。
在一个实施方案中，所述阿哌沙班透皮贴剂每24小时、每32小时、每48小时、每72小时、每84小时、每96小时、每120小时、每144小时、或每168小时施用一次。
在一个实施方案中，所述阿哌沙班透皮贴剂每24小时向所述受试者递送约1mg至约40mg的阿哌沙班，优选为2.5mg至10mg的阿哌沙班。
令人惊奇地，本发明的阿哌沙班透皮贴剂可以以高皮肤通量持续递送阿哌沙班或其药学上可接受的盐约24小时、32小时、48小时、72小时、84小时、96小时、120小时、144小时和168小时以上的时间。另外，本发明的阿哌沙班透皮贴剂还具有无皮肤刺激性和致敏性的优点。
附图说明
图1示出了本发明所述的药物储库类型贴剂的示意图。
图2示出了药物固体基质类型贴剂的示意图。
图3示出了实施例87-90所述透皮贴剂的皮肤通量的测量曲线。
图4示出了实施例91与比较例1所述透皮贴剂的皮肤通量的测量曲线。
图5示出了实施例92所述透皮贴剂的皮肤通量的测量曲线。
图6示出了实施例95-98所述透皮贴剂的皮肤通量的测量曲线。
图7示出了实施例99-101所述透皮贴剂的皮肤通量的测量曲线。
图8示出了实施例102与比较例2所述透皮贴剂的皮肤通量的测量曲线。
图9示出了实施例103-106所述透皮贴剂的皮肤通量的测量曲线。
图10示出了实施例107-110所述透皮贴剂的皮肤通量的测量曲线。
具体实施方式
定义
如本文所使用，术语“药学上可接受的盐”是指在合理的医学判断范围内适用于与受试者(例如人类受试者)接触而没有过度毒性、刺激、过敏反应等，具有合理的益处/风险比，并且对于它们的预期用途有效的那些盐。本发明所述的“药学上可接受的盐”包括无机酸加成盐和有机酸加成盐，其可以在化合物的最终分离和纯化过程中原位制备，也可以通过将游离碱形式的纯化化合物(例如阿哌沙班)与合适的有机酸或无机酸单独反应并分离由此形成的盐来制备。无机酸加成盐的实例包括但不限于硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、亚磷酸盐、硼酸盐等。有机酸加成盐的实例包括但不限于乙酸盐、丙酸盐、丁酸盐、异丁酸盐、戊酸盐、己酸盐、辛酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、邻苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐油酸盐、棕榈酸盐、硬脂酸盐、月硅酸盐、苯甲酸盐、乳酸盐、甲苯磺酸盐、琥珀酸盐、酒石酸盐、甲磺酸萘甲酸盐、葡庚糖酸盐、乳糖醛酸盐、月桂基磺酸盐和羟乙基磺酸盐等。
如本文所使用，术语“中等分子量有机酸”包括但不限于C 5至C 8有机酸。其非限制性实例包括乙酰丙酸、山梨酸、衣康酸、中康酸、酮戊二酸、戊二酸、甲基琥珀酸、戊酸、异戊酸、新戊酸、顺式乌头酸、反式乌头酸、抗坏血酸、柠檬酸、异柠檬酸、己二酸、己酸、苯甲酸、水杨酸、龙胆酸、原儿茶酸、没食子酸、环己烷羧酸、庚二酸、邻苯二甲酸、间苯二甲酸、间苯二甲酸、对苯二甲酸、对苯二甲酸、苯乙酸、甲苯甲酸、邻甲苯甲酸酸、间甲苯甲酸、对甲苯甲酸、扁桃酸、homogentistic酸、辛二酸、辛酸、或其组合。优选地，中等分子量有机酸包括乙酰丙酸、戊二酸、己二酸及其组合，它们具有较低的皮肤刺激性和非致敏性。
如本文所使用，术语“低分子量有机酸”包括但不限于C 1至C 4有机酸。非限制性实例包括甲酸、乙醛酸、草酸、乙酸、乙醇酸、丙烯酸、丙酮酸、丙二酸、丙酸、3-羟基丙酸、乳酸、甘油酸、富马酸、马来酸、草酰乙酸、巴豆酸、乙酰乙酸、2-氧代丁酸、甲基丙二酸、琥珀酸、苹果酸、L-酒石酸、DL-酒石酸、内消旋酒石酸、二羟基酒石酸、丁酸、异丁酸、羟基丁酸、或其组合。优选地，低分子有机酸是乳酸。
如本文所使用，术语“治疗有效量”是表示本发明的化合物或分子的量，当将其施用于受试者时，(i)治疗或预防特定疾病、病症或疾患，(ii)减弱、改善或消除特定疾病、病症或疾患的一种或多种症状，或(iii)预防或延迟本文所述的特定疾病、病症或疾患的一种或多种症状的发作。
如本文所使用，术语“约”指所指示的数字的正负10％。例如，“约10％”可以表示9％至11％的范围，并且“约1”可以表示0.9-1.1。
如本文所用，术语“治疗”是指试图改变所治疗个体的自然进程的临床干预，并且可以是为了预防或在临床病理学的进程中进行。治疗的期望效果包括但不限于预防疾病的发生或复发、减轻症状、削弱疾病的任何直接或间接病理学后果、预防转移、降低疾病进展的速率、改善或减轻疾病状态，以及缓解或改善预后。
本发明提供了一种阿哌沙班透皮贴剂，其包括：
1. 背衬层
背衬层用作贴剂制剂的上表面并作为主要结构元件为贴剂制剂提供柔韧性。优选地，背衬层对于透皮给药的药物组合物基本上是不可渗透的。
背衬层优选由柔性弹性材料的片材或薄膜制成。背衬层优选是不透气的。用于本发明贴剂的背衬层优选由柔性的、生物相容的材料制成，其模仿皮肤的弹性特性并在运动过程中贴合皮肤。非封闭性背衬层允许该区域呼吸(即促进皮肤表面的水蒸气传输)，而封闭性背衬层则减少空气/蒸汽的渗透。优选地，储库类型透皮贴剂(图1)和基质类型透皮贴剂(图2)的背衬层是封闭的。
优选地，背衬层包含合成聚合物，例如聚烯烃、聚酯、聚乙烯、聚偏二氯乙烯和聚氨酯。优选地，背衬层的厚度为约0.5密耳(mil)至约5密耳；更优选地，背衬层的厚度为约1密耳至约3密耳。优选地，氧气的传输速率为约2cc/m/24hr至约100cc/m/24hr，更优选地，氧气的传输速率为约70g/m/24hr至约90g/m/24hr。优选地，MVTR为约0.3g/m/24hr至约50g/m/24hr，更优选地，MVTR为约5g/m/24hr至约30g/m/24hr。
在优选的实施方案中，背衬层是约2.0密耳厚的闭塞聚酯膜层(可商购获得，例如Scotchpak 9733，3M Drug Delivery Systems，St.Paul Minn.)。Scotchpak 9733由聚酯和中密度聚乙烯/乙烯醋酸乙烯酯热封层组成，层压板是半透明的、贴合的、封闭的和可热封的。其可用于图1所示的储库类型贴剂制剂。
2. 药物储库层
药物储库层，又称药物层，包含阿哌沙班或其药学上可接受的盐、皮肤渗透促进剂等，其中渗透促进剂包含溶剂、聚合物增溶剂、表面活性剂、中等分子量有机酸和低分子量有机酸中的任一项或其 任意组合。
溶剂，也称为A型皮肤渗透促进剂，其不仅可以部分地或完全地溶解一种或多种其它的皮肤渗透促进剂，还可以部分地或完全地溶解阿哌沙班或其药学上可接受的盐。此外，溶剂自身也有利于增强阿哌沙班或其药学上可接受的盐的皮肤渗透性。溶剂的非限制性实例包括C 1至C 6烷基醇、丙二醇、丁二醇、二丙二醇、己二醇、transcutol、DMSO、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甘油、水或以上两种或更多种的组合。优选地，溶剂选自乙醇、DMSO或二者的组合。
其它的皮肤渗透促进剂包括聚合物增溶剂(B型皮肤渗透促进剂)、表面活性剂(C型皮肤渗透促进剂)、中等分子量有机酸(D型皮肤渗透促进剂)和低分子量有机酸(E型皮肤渗透促进剂)等。
聚合物增溶剂包括但不限于邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、透明质酸、果胶、羧甲基纤维素、海藻酸、Eudrgit S、Eudragit L、Eudrgit L-55、角叉菜胶、聚维酮、交联聚维酮、共聚维酮，或以上两种或更多种的组合。优选地，聚合物增溶剂为含羧基聚合物，包括但不限于邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素等。
聚合物增溶剂的重量百分含量为药物储库层的2％至50％，优选2至30％，更优选5至25％。如果聚合物增溶剂的含量低于药物储库层的2％，会导致阿哌沙班的血药浓度最大值(Cmax)过高；如果聚合物增溶剂的含量超过药物层的30％，阿哌沙班从储库层中向外扩散的速度就会被过度抑制，导致其皮肤渗透率显著降低。并且，阿哌沙班或其药学上可接受的盐与所述聚合物增溶剂的重量比为约1:1至1:20，优选为1:1至1:5，更优选为1:1至1:2。
表面活性剂包括但不限于乳酸月桂酯、乳酸肉豆蔻酯、乳酸鲸蜡酯、乳酸棕榈酯、Ceraphyl 31、月桂酸乙酯、月桂酸甲酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、脂肪醇、薄荷醇、饱和的或不饱和的 C 9至C 30脂肪酸、脂肪酸酯、二异己二酸酯、中链脂肪酸甘油三酯、癸二酸二乙酯、倍半山梨聚糖、Span 20、Span 40、Span 80、吐温20、吐温40、吐温80、十五内酯、单乳酸甘油酯、单硬脂酸甘油酯、单油酸甘油酯或其组合。优选地，表明活性剂包括乳酸月桂酯、肉豆蔻酸异丙酯、棕榈酸异丙酯和/或油酸等。
术语脂肪醇是指具有式ROH的化合物，其中R是C 7-C 30烷基或包含一个、两个、三个或四个双键的C 3-C 30烯基。脂肪醇可包括但不限于一种或多种饱和、单不饱和或多不饱和脂肪醇；其可包括但不限于以下中的一种或多种：辛醇、壬醇、癸醇、十一醇、月桂醇、异月桂醇、反异月桂醇、十三醇、肉豆蔻醇、异肉豆蔻醇、反异肉豆蔻醇、十五醇、鲸蜡醇、棕榈油醇、异棕榈醇、反异棕榈醇、十七烷醇、硬脂醇、异硬脂醇、反异硬脂醇、油醇,亚油醇,十九烷醇,花生四烯醇,辛基十二烷醇、山萮醇、芥子醇、木蜡醇和木蜡醇等。在一些实施方案中，饱和脂肪醇可以包括但不限于以下的一种或多种：月桂醇、异月桂醇、反异月桂醇、肉豆蔻醇，异肉豆蔻醇，反异肉豆蔻醇，鲸蜡醇，异棕榈醇、反异棕榈醇、硬脂醇、异硬脂醇和反异硬脂醇。在一些实施方案中，脂肪醇是肉豆蔻醇。
术语脂肪酸酯是指由脂肪酸与醇结合产生的酯，其中脂肪酸和醇分别是具有式RCOOH和R’OH的化合物，其中R和R’各自是C 1-C 30烷基。
示例性的饱和的或不饱和的C 9至C 30脂肪酸包括但不限于癸酸、月桂酸、棕榈酸、硬脂酸、异硬脂酸，油酸，反油酸、刚多酸、芥酸、神经酸、和西门酸、十六碳三烯酸、亚油酸、α-亚麻酸、γ-亚麻酸、金盏花酸、硬脂酸、米德酸、二十碳二烯酸、二十碳三烯酸、二高-γ-亚麻酸、花生四烯酸酸和二十二碳二烯酸。
表面活性剂还包括但不限于甘油酯(甘油单酯、甘油二酯、甘油三酯)、聚氧乙烯硬脂酸酯、三十八碳四烯酯-4磷酸酯与乙二醇棕榈硬脂酸酯和二乙二醇棕榈硬脂酸酯的混合物、聚甘油-3二异硬脂酸酯的混合物中的一种或多种PEG-6硬脂酸酯与乙二醇棕榈硬脂 酸酯和PEG-32硬脂酸酯、油酰聚氧基-6甘油酯、月桂酰聚氧基-6甘油酯、辛酰基聚氧基-8甘油酯、丙二醇单辛酸酯I型、丙二醇单月桂酸酯II型、丙二醇单月桂酸酯I型、II型丙二醇单辛酸酯、聚甘油-3二油酸酯、PEG-6硬脂酸酯与PEG-32硬脂酸酯的混合物、卵磷脂、鲸蜡醇、胆固醇、磺基琥珀酸二辛酯钠、十二烷基硫酸钠、硬脂酸三乙醇胺、钾月桂酸酯、聚氧乙烯脂肪醇醚、单硬脂酸甘油酯、脱水山梨糖醇单月桂酸酯、羊毛脂醇和乙氧基化羊毛脂醇、脱水山梨糖醇脂肪酸酯、蔗糖二硬脂酸酯。
表面活性剂的重量百分含量为药物储库层的1％至50％，优选5至30％。
中等分子量有机酸包括但不限于C 5至C 8有机酸。非限制性实例包括乙酰丙酸、山梨酸、衣康酸、中康酸、酮戊二酸、戊二酸、甲基琥珀酸、戊酸、异戊酸、新戊酸、顺式乌头酸、反式乌头酸、抗坏血酸、柠檬酸、异柠檬酸、己二酸、己酸、苯甲酸、水杨酸、龙胆酸、原儿茶酸、没食子酸、环己烷羧酸、庚二酸、邻苯二甲酸、间苯二甲酸、间苯二甲酸、对苯二甲酸、对苯二甲酸、苯乙酸、甲苯甲酸、邻甲苯甲酸酸、间甲苯甲酸、对甲苯甲酸、扁桃酸、homogentistic酸、辛二酸辛二酸、辛酸、或其组合。优选地，中等分子量有机酸包括乙酰丙酸、戊二酸、己二酸及其组合，它们具有较低的皮肤刺激性和非致敏性。
中等分子量有机酸的含量为药物储库层的1-60％，优选1-30％，更优选1-15％。如果中等分子量有机酸的含量低于药物储库层的1％，会导致皮肤渗透增强效果变得没有意义。如果中等分子量有机酸的含量超过60％，则其可能无法完全被溶剂溶解。
低分子量有机酸包括但不限于C 1至C 4一元羧酸或二元羧酸。非限制性实例包括甲酸、乙醛酸、草酸、乙酸、乙醇酸、丙烯酸、丙酮酸、丙二酸、丙酸、3-羟基丙酸、乳酸、甘油酸、富马酸、马来酸、草酰乙酸、巴豆酸、乙酰乙酸、2-氧代丁酸、甲基丙二酸、琥珀酸、苹果酸、L-酒石酸、DL-酒石酸、内消旋酒石酸、二羟基酒 石酸、丁酸、异丁酸、羟基丁酸、或其组合。优选地，低分子有机酸是乳酸。
低分子量有机酸的含量为储库层重量的0.1至10％，优选0.5至5％，更优选0.5至3％。如果低分子量有机酸的含量低于储库层重量的0.1％，会导致皮肤渗透增强效果变得没有意义。如果低分子量有机酸的含量超过储库层重量的10％，则会导致皮肤刺激达到不可接受的水平。
在一个实施方案中，药物储库层包含阿哌沙班或其药学上可接受的盐和皮肤渗透促进剂，所述皮肤渗透促进剂包括聚合物增溶剂(B型皮肤渗透促进剂)、表面活性剂(C型皮肤渗透促进剂)和中等分子量有机酸(D型皮肤渗透促进剂)；其中，聚合物增溶剂和中等分子量有机酸均可溶解阿哌沙班。只有溶解的阿哌沙班分子才能够渗透皮肤，而未溶解的阿哌沙班晶体是不会渗透皮肤的。中等分子量的有机酸和溶解的阿哌沙班分子都能渗透皮肤。随着越来越多的中等分子量有机酸渗入皮肤，残留在药物层中的有机酸也越来越少。然而，聚合物增溶剂不会渗透皮肤而保留在药物层中，因此聚合物增溶剂提供了比中等分子量有机酸更持久的渗透增强效果，持续时间为约24小时、48小时、72小时、84小时、96小时、120小时、144小时或168小时以上。聚合物增溶剂还增加了药物层的粘度，从而可以降低溶解的阿哌沙班从药物层向外扩散的速率以降低Cmax。Cmax的降低有助于在24小时、48小时、72小时、96小时、120小时、144小时和168小时期间提供更加恒定的皮肤渗透量。
在另一个实施方案中，药物储库层包含阿哌沙班或其药学上可接受的盐和皮肤渗透增强剂，所述皮肤渗透增强剂包括溶剂(A型皮肤渗透促进剂)、聚合物增溶剂(B型皮肤渗透促进剂)、表面活性剂(C型皮肤渗透促进剂)、中等分子量有机酸(D型皮肤渗透促进剂)。中等分子量有机酸对皮肤的刺激性低。
在一个优选的实施方案中，药物储库层包含阿哌沙班或其药学 上可接受的盐和皮肤渗透增强剂，其中皮肤渗透增强剂包括溶剂(A型皮肤渗透促进剂)、聚合物增溶剂(B型皮肤渗透促进剂)、表面活性剂(C型皮肤渗透促进剂)、中等分子量有机酸(D型皮肤渗透促进剂)和低分子量有机酸(E型皮肤渗透促进剂)。中等分子量有机酸对皮肤刺激性低。低分子量有机酸在低浓度下对皮肤的刺激性低。低分子量有机酸溶解药物和渗透皮肤的速度比中等分子量有机酸更快，但其消失得也更快。因此，低分子量有机酸的皮肤渗透作用是短暂的。低分子量有机酸通过其至少双重作用增强阿哌沙班的皮肤渗透。它将阿哌沙班溶解成溶液，还通过形成酸碱加成盐以提高皮肤渗透性来改善阿哌沙班的生理特性。中等分子量有机酸在较低浓度下溶解阿哌沙班并能形成酸碱加成盐。中等分子量有机酸具有延迟的皮肤渗透增强作用，但也具有更持久的渗透增强作用，即增强时间比低分子量有机酸更长。
如果药物储库层仅包含低分子量有机酸，则皮肤渗透增强的持续时间为数小时至24小时。如果药物储库层仅包含中等分子量的有机酸，则在前24小时内没有明显的阿哌沙班渗透。如果药物储库层仅包含溶剂和聚合物增溶剂，则没有有意义的阿哌沙班的皮肤渗透。如果药物储库层仅包含表面活性剂，则没有有意义的阿哌沙班的皮肤渗透，因为药物不处于渗透的溶解状态。
药物储库层涂层的重量为每平方米大约55克至大约1000克。药物储库层涂层的厚度为大约40微米至大约1000微米。
3. 半透膜层
半透膜层用于将液体或半固体基质材料包含在药物层内，它的作用是控制阿哌沙班从液体或半固体药物层向粘合剂层的扩散。半透膜层和背衬层可以围绕外围边缘密封在一起。
半透膜层包括但不限于乙烯-共-乙酸乙烯酯共聚物膜、聚乙烯聚合物膜、聚丙烯聚合物膜。乙烯-共-乙酸乙烯酯的非限制性实例包括3M Cotran 9709、Cotran 9712、Contan 9716和Contran 9728。聚乙烯 薄膜的非限制性实例包括Solupore。聚丙烯膜的非限制性实例包括Celgard 2400。
合适的半透膜层包括连续膜和微孔膜，可以是编织的或非编织的材料。半透膜优选由本领域技术人员通常使用的柔性聚合材料制成。可用于制造半透膜层的聚合物膜包括但不限于包含低密度聚乙烯、高密度聚乙烯、乙基醋酸乙烯酯共聚物、聚丙烯和其他合适聚合物的那些。在一个实施方案中，半透膜层是由含有约0.5至约28wt.％乙酸乙烯酯的乙烯-乙酸乙烯酯共聚物制备的微孔膜制成。合适的编织材料包括Saatifil PES，如可从Saatitech,Inc.获得的PES 105/52。合适的无纺布是来自DuPont Nonwovens Sontara Technologies的Sontara。在优选实施方案中，半透膜层是可从3MTM获得的乙烯-乙酸乙烯酯共聚物膜，例如Cotran 9702、Cotran 9705、Cotran 9706、Cotran 9707、Cotran 9712、Cotran 9715、Cotran 9716和Cotran 9728(可从3MTM获得)。
半透膜层的厚度通常可以为约10um至约100um，优选地，为约15μm至约50μm。
4. 粘合剂层
粘合剂层起到将阿哌沙班透皮贴剂粘附到皮肤表面的作用。取下离型层后，它还可以用于控制阿哌沙班向皮肤递送的速率。所述粘合剂包括但不限于丙烯酸粘合剂、甲基丙烯酸粘合剂、聚异丁烯粘合剂、苯乙烯-异戊二烯-苯乙烯嵌段共聚物粘合剂、硅氧烷粘合剂、丙烯酸-共聚硅氧烷共聚物粘合剂，或上述两种或多种的组合。丙烯酸粘合剂的非限制性实例包括Henkel的Duro-Tak粘合剂387-2051、387-2054、387-2353、87-235、387-2516、387-2287、387-2510、87-287-2054、87-210294(三洋化学工业株式会社)。聚异丁烯粘合剂的非限制性实例包括Oppanol N150、Oppanol B150、Oppanol N100、Oppnaol B100、Oppanol N80、Oppanol B80、Oppanol B10、B11、B12和来自Ineos的低分子量聚丁烯H1900及矿物油 增粘剂。硅氧烷粘合剂的非限制性实例包括杜邦Bio-PSA 7-4100、7-4200、7-4300、7-4400和7-4500。丙烯酸-共-聚硅氧烷共聚物粘合剂的非限制性实例包括杜邦Bio-PSA 7-6100、7-6200和7-6300。丙烯酸粘合剂与硅氧烷粘合剂的组合以及聚异丁烯粘合剂与苯乙烯-异戊二烯-苯乙烯嵌段共聚物粘合剂的组合也是可接受的粘合剂选择。优选地，粘合剂是聚异丁烯粘合剂、苯乙烯-异戊二烯-苯乙烯嵌段共聚物粘合剂、硅氧烷粘合剂和丙烯酸-共-聚硅氧烷共聚物粘合剂。
本发明人发现诸如Duro-Tak 387-2054的交联粘合剂比非交联粘合剂387-2051能够更好地粘附皮肤，交联387-2516比非交联387-2287能够更好地粘附皮肤。
本发明人还发现通过添加添加剂Eudragit E100、Plastoid B、交聚维酮CML、商品名为Cabo-Sil-5的胶体二氧化硅或偏硅酸铝镁(例如来自富士化学工业的Neusilin)和高岭土可以进一步提高皮肤接触粘合剂层的粘附力。偏硅酸铝镁优选为铝、镁和硅原子通过氧原子三维聚合形成的无定形复合氧化物。这种复合氧化物更具体地是由下式表示：Al 2O 3/aMgO/bSiO 2-nH 2O，其中a＝0.3-3和b＝0.3-5。由于其多孔结构，这种偏硅铝酸镁被认为在水的存在下的粘合性得到进一步改善。
皮肤接触粘合剂层还可以包含一种或多种药学上可接受的添加剂，所述添加剂的非限制性实例包括抗氧化剂、抗皮肤刺激剂、内聚促进剂、增塑剂、增粘剂等。
皮肤接触粘合剂层中所包含的添加剂的量为粘合剂重量的约0.05％至约40％，优选约1％至约30％，更优选约3％至约30％，最优选粘合剂材料重量的约20％。
抗氧化剂的非限制性实例包括生育酚、生育酚乙酸酯、丁基化羟基甲苯、丁基化羟基茴香醚、焦亚硫酸钾、焦亚硫酸钠、亚硫酸氢钠、亚硫酸钠、没食子酸丙酯、硫代甘油、硫代硫酸钠、二氧化钠、甲醛合次硫酸氢钠、作为协同抗氧化剂的螯合剂包括柠檬酸、酒石酸、依地酸钙二钠、依地酸二钠和EDTA等。
内聚促进剂的非限制性实例包括胶体二氧化硅、氧化锌、聚乙烯吡咯烷、丙烯酸酯共聚物、交聚维酮、交联羧甲基纤维素(交联羟甲基纤维素)、乙基纤维素、丙烯酸共聚物、膨润土、粘土及其混合物。在优选的实施方案中，内聚促进剂是胶体二氧化硅。粘合剂层中存在的内聚促进剂的量为粘合剂材料重量的约3％至约40％，优选地为粘合剂材料重量的约5％至约30％。本发明人发现，当皮肤接触层粘合剂是聚异丁烯粘合剂、硅氧烷粘合剂或苯乙烯-异戊二烯-苯乙烯基粘合剂时，内聚增强剂的添加有效地保持了粘合剂的完整性。
增塑剂的非限制性实例包括矿物油、硅油、柠檬酸三乙酯及其组合。粘合剂层中存在的增塑剂的量为粘合剂材料重量的约0％至约40％，优选地为粘合剂材料重量的约0％至约30％，更优选地为粘合剂材料重量的约0％至约30％，最优选地为粘合剂材料重量的约20％。
增粘剂的非限制性实例包括硅油、矿物油、聚丁烯、萜烯及其混合物。粘合剂层中存在的增粘剂的量为粘合剂材料重量的约0％至约40％，优选粘合剂材料重量的约0％至约30％。
制备方法
在一个事实方案中，本发明提供了一种制备阿哌沙班透皮贴剂的方法，所述透皮贴剂包括背衬层、药物储库层、半透膜层、皮肤接触层、和任选地保护性释放衬垫层，其包括：
1)将阿哌沙班或其药学上可接受的盐与皮肤渗透促进剂混合形成均匀的液体、半固体或固体混合物；
2)将所得的液体、半固体或固体混合物均匀地分配或涂覆在背衬膜上；并将背衬膜上被所述混合物分配或涂覆的一侧与半透膜层的远离粘合剂层/离型层的一侧进行层压；或者
将均匀的液体、半固体或固体分配或涂覆在半透膜层的远离粘合剂层/离型层的一侧，再将半透膜层上被所述混合物分配或涂覆的一侧与背衬层进行层压。
在一个实施方案中，首先，制备液体、半固体或固体药物储库层。在室温或升高的温度(例如85℃)下将聚合物增溶剂(B型皮肤渗透促进剂)完全溶解在溶剂(A型皮肤渗透促进剂)中，然后加入阿哌沙班或其药学上可接受的盐，在室温或高温(例如85℃)下混合以完全或部分溶解，再加入表面活性剂(C型皮肤渗透促进剂)、中等分子量有机酸(D型皮肤渗透促进剂)和任选的低分子量有机酸(E型皮肤渗透促进剂)，在室温或高温(例如85℃)下混合以形成均匀的液体、半固体或固体。然后冷却至室温。将均匀的液体、半固体或固体分配或涂覆在背衬膜上，并与半透膜层的远离粘合剂层/离型层的一侧层压。
在另一个实施方案中，可以将如上所述制备的均匀的液体、半固体或固体分配或涂覆在半透膜层的远离粘合剂层/离型层的一侧，再与背衬层层压。
在另一个实施方案中，所述制备阿哌沙班透皮贴剂的方法还可以包括通过热、压力或热和压力两者的组合来密封背衬层膜和半透膜的外围边缘的步骤，使得所述液体、半固体或固体混合物被限制在所述外围边缘范围内的步骤。
在另一个实施方案中，可以首先将背衬层膜的靠近皮肤的一侧的三个边缘和半透膜层的远离皮肤接触粘合剂层/保护性隔离衬垫层的一侧的三个边缘密封，将液体或半固体的药物储库材料从未密封的第四边缘填充到三边密封的储库中，然后密封第四边缘，形成四边密封的药物储库层。
在一个实施方案中，本发明提供了一种治疗血栓疾病的方法，其包括向有需要的患者施用治疗有效量的阿哌沙班透皮贴剂，其包括：
1)背衬层；
2)药物储库层，其包含阿哌沙班或其药学上可接受的盐；
3)半透膜层；
4)粘合剂层；和任选地
5)离型层。
在一个实施方案中，所述阿哌沙班透皮贴剂可以高皮肤通量，例如约1μg/cm2.hr至约10μg/cm2.hr，优选为约1μg/cm2.hr至约5μg/cm2.hr，更优选为约3至约5μg/cm2.hr的皮肤通量持续递送。
在一个实施方案中，所述阿哌沙班透皮贴剂可以持续递送至少24小时、32小时、48小时、72小时、84小时、96小时、120小时、144小时、或168小时以上。
在一个实施方案中，所述阿哌沙班透皮贴剂每24小时向所述受试者递送约1mg至约40mg的阿哌沙班，优选为约2.5mg至约10mg的阿哌沙班。
以下实施例用于说明本发明的技术方案，并不旨在限制本发明的保护范围。
实施例
阿哌沙班的溶解度研究
实施例1至63
在药物透皮渗透皮肤之前，药物晶体需要首先溶解在药物层中，因为只有溶解了的药物分子才能透皮渗透皮肤。我们测定了阿哌沙班在各种聚合物增溶剂中的溶解度，其结果列于表1中。令人惊讶的是，本发明人发现阿哌沙班在含羧基的聚合物增溶剂(水不溶性羟丙基甲基纤维素邻苯二甲酸酯HPMCP、羟丙基甲基纤维素乙酸琥珀酸酯HPMCAS、Eudragit L100)中的溶解度比在传统的结晶抑制剂(例如聚维酮(PVP)、羟丙基纤维素(HPC)、羟丙基环糊精等)中的溶解度明显更大。因此，我们惊奇地发现含羧基的聚合物增溶剂(水不溶性羟丙基甲基纤维素邻苯二甲酸酯HPMCP、羟丙基甲基纤维素乙酸琥珀酸酯HPMCAS、Eudragit L100)比传统的结晶抑制剂(例如聚维酮(PVP)、羟丙基纤维素(HPC)、羟丙基环糊精等)传统结晶抑制剂有更好的结晶抑制作用。当HPMCP与阿哌沙班的比例为6:1或更高时，阿哌沙班在溶剂蒸发至半干(约1g)时不会产生结晶现象。相反，当PVP K30、K90、HPC或羟丙基环 糊精与阿哌沙班的比例达到6:1或更高时，阿哌沙班在溶剂蒸发后会重结晶形成固体。
Figure PCTCN2022114527-appb-000001
Figure PCTCN2022114527-appb-000002
Figure PCTCN2022114527-appb-000003
注：APX是阿哌沙班；PVP K30是聚乙烯吡咯烷酮K30；PVP K90是聚乙烯吡咯烷酮K90；HPC LF是羟丙基纤维素LF；HPMCAS是乙酸羟丙基甲基纤维素琥珀酸酯；Eudragit L100是基于Evonik公司的甲基丙烯酸和甲基丙烯酸甲酯的共聚物；HPMCP是羟丙基甲基纤维素邻苯二甲酸酯。
实施例64至67阿哌沙班在含聚合物增溶剂的膜中的溶解度研究
当HPMCP:阿哌沙班的比率为6:1时，含HPMCP和阿哌沙班的膜中没有阿哌沙班晶体生成。将HPMCP和阿哌沙班以2:1至5:1的比率溶解在DMSO中以形成粘性溶液。将该溶液涂覆在Scotchpak 9733背衬层膜上，在100℃的强制通风烘箱中干燥60分钟，形成干膜。HPMCP:阿哌沙班的比率为5:1或更高时，干膜上无晶体形成(表2)。
Figure PCTCN2022114527-appb-000004
此外，我们还测定了阿哌沙班分别在其它类型的皮肤渗透促进剂如溶剂(A型皮肤渗透促进剂)、表面活性剂(C型皮肤渗透促进剂)、中等分子量有机酸(D型皮肤渗透促进剂)和低分子量有机酸(E型皮肤渗透促进剂)中的溶解度，结果列于表3中。
表3.阿哌沙班在室温下在各类型皮肤渗透促进剂中的溶解度
Figure PCTCN2022114527-appb-000005
阿哌沙班的体外皮肤通量实验
使用垂直静态修饰的Franz单元进行体外渗透测试。接收单元的体积为28ml，填充有pH 7.4的缓冲溶液，其中含有磷酸一钾、氯化钠和叠氮化钠。有效皮肤渗透尺寸为0.61cm2。将700至800um厚的人体尸体皮肤安装在接收单元上，真皮层一侧朝上。将O形环置于皮肤顶部。将预先称重的储库层液体或半固体制剂填充到O形环中。用夹子将供体细胞固定在接受单元的顶部。将Franz单元置于磁力搅拌板上的32℃培养箱中。在每个预先安排的时间点取2ml溶液，倒掉剩余的溶液，并补充新的接收溶液。立即通过HPLC分析接收溶液的阿哌沙班的量。
实施例68至86
通过在玻璃瓶中混合阿哌沙班和其他辅料，并在阿哌沙班完全地或部分地溶解的情况下在烘箱中加热来制备液体或半固体制剂。皮肤通量测试按前述的程序进行。结果总结在表4中。可以看出，制剂组合68至78的皮肤通量低。这些制剂包含单一的溶剂(乙醇和二甲基亚砜)或D型皮肤渗透促进剂(乙酰丙酸)或溶剂与皮肤渗透促进剂的组合如溶剂(二甲基亚砜)与B型皮肤渗透促进剂 (HPMCP，即邻苯二甲酸羟丙基甲基纤维素)、溶剂(乙醇和二甲基亚砜)与C型皮肤渗透促进剂(乳酸月桂酯)、溶剂(乙醇和二甲基亚砜)与D型皮肤渗透促进剂(乙酰丙酸)、溶剂(乙醇和二甲基亚砜)与E型皮肤渗透促进剂(乳酸)的组合，以及三种皮肤渗透促进剂的组合如A型皮肤渗透促进剂(乙醇和二甲基亚砜)与B型皮肤渗透促进剂(HPMCP)和D型皮肤渗透促进剂(乙酰丙酸)的组合。包含4种皮肤渗透促进剂A、B、C和D的制剂组合79和包含5种皮肤渗透促进剂A、B、C、D和E的制剂组合80至86的72小时累积皮肤渗透通量非常高，是制剂组合68至78的2.5倍至670倍。
Figure PCTCN2022114527-appb-000006
Figure PCTCN2022114527-appb-000007
实施例87
将阿哌沙班与乙酰丙酸混合并加热至溶解。冷却混合物至室温。含有D型皮肤渗透促进剂(乙酰丙酸)但不含有B型皮肤渗透促进剂(HPMCP)的制剂87的皮肤通量(表5，图3)在早期时间点较高，但是随着残留在制剂中的乙酰丙酸量由于皮肤渗透而减少时，制剂87的皮肤通量迅速降低。保留在Franz单元中的半固体样品的GC分析表明在96小时结束时几乎没有乙酰丙酸残留。
实施例88
将阿哌沙班与乙酰丙酸混合并加热至溶解。加入乳酸月桂酯并混合。冷却混合物至室温。同时含有C型皮肤渗透促进剂(乳酸月桂酯)和D型皮肤渗透促进剂(乙酰丙酸)的制剂88的皮肤通量(表5，图3)是仅含有D型皮肤渗透促进剂的制剂87的皮肤通量的3倍。然而，由于制剂88不含有B型皮肤渗透促进剂，其皮肤通量在早期时间点较高，但是随着残留在制剂中的乙酰丙酸量由于皮肤渗透而减少时，制剂88的皮肤通量迅速降低。保留在Franz单元中的半固体样品的GC分析表明在96小时结束时几乎没有乙酰丙酸残留。
实施例89和实施例90
阿哌沙班和HPMCP与DMSO和乙酰丙酸混合，加热至85℃溶解。加入乳酸月桂酯并混合。将该材料加热至室温。两种制剂的皮肤通量(表5，图3)在96小时内几乎保持不变。尽管随着制剂中残留的乙酰丙酸量越来越低，但是聚合物增溶剂HPMCP的量却保持不变，因为它的高分子量不会渗透皮肤。由于聚合物增溶剂的存在能够维持大量的阿哌沙班处于溶解状态，从而使得阿哌沙班的透皮递送速率几乎保持恒定。
表5(药物储库类型贴剂)
Figure PCTCN2022114527-appb-000008
APX＝阿哌沙班；HPMCP＝邻苯二甲酸羟丙基甲基纤维素；DMSO＝二甲基亚砜
实施例91
阿哌沙班和HPMCP与DMSO和乙酰丙酸混合，加热至85℃溶解。加入乳酸月桂酯并混合。将该材料加热至室温。含有聚合物增溶剂HPMCP的实施例91制剂的皮肤通量(表6，图4)比不含HPMCP的比较例1的皮肤通量高5倍。比较例1的皮肤通量低得不可接受。因此，达到治疗通量水平所需的贴片尺寸为180cm2。此外，比较例1的皮肤粘附性和物理性能也差得令人无法接受。当试图在使用前将离型层进行移除时，大量的粘合剂被转移到了离型层上。当手指接触到粘合剂层时，大量的粘合剂被转移到了手指上。
比较例1
在罐中混合阿哌沙班和丙烯酸以溶解阿哌沙班。混合加入乳酸、 辛酸和吐温20。然后加入Duro-Tak 87-2196并混合。将湿混合物涂覆在背衬层膜Scotchpak9733上，在40℃强制空气烘箱中干燥5分钟，在85℃干燥15分钟。除去干燥的膜并将离型层层压在粘合剂层的顶部以制备粘合剂层(含有药物)/离型层层压材料。不幸的是，剥离离型层时不可能在不损坏粘合剂层的情况下进行。在试图剥离离型层时，大约一半量的粘合剂被转移到离型层上。在手指附着力测试中，用食指按压粘合剂层5秒钟，然后提起食指。许多粘合剂被转移到手指上。此外，该制剂的皮肤通量非常低，远不能满足所需的25858μg/贴片·96hr的通量，比含有四种类型的皮肤渗透促进剂的实施例91的皮肤通量低大约5倍。
表6(药物储库类型贴剂vs基质类型贴剂)
Figure PCTCN2022114527-appb-000009
APX＝阿哌沙班；HPMCP＝邻苯二甲酸羟丙基甲基纤维素；DMSO＝二甲基亚砜
实施例92、93和94
将阿哌沙班、HPMCP、DMSO和乙酰丙酸混合并在85℃加热。加入乳酸月桂酯或/和癸酸甲酯，混合并加热形成均匀的半固体，然后冷却至室温。进行了3个皮肤供体的皮肤通量实验。如表6和图3所示，含有A、B、C、和D型渗透促进剂的实施例92的制剂和 实施例94的制剂的皮肤通量能够在8小时至96小时之间保持在3μg/cm2.h和6μg/cm 2.h之间(表7，图5)。含有两种不同的D型渗透促进剂(乳酸月桂酯和癸酸甲酯)的实施例93的制剂也能够保持4天的高皮肤通量。图5显示了基于内部IVIVR获得的制剂92(贴片尺寸31.5cm2)的3天皮肤通量曲线。
尽管制剂92的残留乙酰丙酸量和残留DMSO量越来越低，在96小时以后，其甚至小于理论量的1％(表8)，但由于聚合物增溶剂HPMCP的量保持不变(因为它的高分子量,它不会渗透皮肤)，聚合物增溶剂HPMCP维持大量的阿哌沙班仍处于溶解状态，从而使得阿哌沙班透皮递送速率在4–96小时内几乎恒定。
表7(药物储库类型贴剂)
Figure PCTCN2022114527-appb-000010
APX＝阿哌沙班；HPMCP＝邻苯二甲酸羟丙基甲基纤维素；DMSO＝二甲基亚砜
表8
Figure PCTCN2022114527-appb-000011
HPMCP＝邻苯二甲酸羟丙基甲基纤维素；DMSO＝二甲基亚砜
实施例95、96和97
HPMCP和乙酰丙酸混合并加热溶解。加入阿哌沙班，混合并加热。加入乳酸月桂酯，混合并加热以形成半固体。为期7天的皮肤通量研究的结果于表9和图6。，制剂组合物95，96和97的皮肤通量很高，其估计的贴片尺寸分别为约16cm2，29cm2和23cm2。
表10显示实施例95在168小时(7天)结束时乙酰丙酸残留量为零。表11显示了在4、8、10、24、32、48、56小时时通过皮肤渗透到接收溶液中的乙酰丙酸的量。在56小时的时间点，超过一半的乙酰丙酸已被渗透。
实施例98
粘合层：将阿哌沙班、乙酰丙酸和乳酸月桂酯加入罐中并混合并溶解。加入4302和4202溶液并混合形成均匀的粘稠液体。将该液体涂覆到涂有硅的离型层上，在40℃下干燥4分钟并在85℃下干燥4分钟。制剂组合物98的的皮肤通量也很高，其估计的贴片尺寸估计为24cm 2。
体外皮肤通量实验
使用垂直静态修饰的Franz单元进行体外渗透测试。接收单元的体积为28ml，填充有pH 7.4的缓冲溶液，其中含有磷酸一钾、氯化钠和叠氮化钠。有效皮肤渗透尺寸为0.61cm2。将4.5cm2的700至800um厚的人体尸体皮肤安装在接收单元上，真皮层一侧朝上。将粘合层粘贴在真皮层上，取下离型层，将O形环置于粘 合剂层上面。将预先称重的储层液体或半固体制剂填充到O形环中。用夹子将供体单元固定在接收单元的顶部。将Franz单元置于磁力搅拌板上的32℃培养箱中。在每个预先安排的时间点取2ml溶液，倒掉剩余的溶液，并补充新的接收溶液。立即通过HPLC分析接收溶液的阿哌沙班的量。
表9(药物储库类型贴剂)
Figure PCTCN2022114527-appb-000012
APX＝阿哌沙班；HPMCP＝邻苯二甲酸羟丙基甲基纤维素；DMSO：二甲基亚砜
表10
Figure PCTCN2022114527-appb-000013
表11
Figure PCTCN2022114527-appb-000014
实施例99至101
HPMCP、丙二醇或乙醇、己二酸或乙酰丙酸或乳酸混合加热溶解。加入阿哌沙班和乳酸月桂酯，混合并加热形成半固体，然后冷却至室温。进行皮肤通量试验(表12，图7)。含有己二酸的制剂99和100在24小时时间点具有高通量并保持96小时，而含有乳酸的实施例101在4小时时间点具有良好的通量但通量迅速下降至低于24小时-小时时间点。制剂99，100和101的4天贴片尺寸分别约为53cm2,49cm2和62cm2。由于己二酸即使在50％的高浓度(OECD SIDS Initial Assessment Report For SIAM18 Paris,France,20-23 April 2004)下只是轻微刺激皮肤，因此将其用作辅料是安全的。
表12(药物储库类型型贴剂)
Figure PCTCN2022114527-appb-000015
APX＝阿哌沙班；HPMCP＝邻苯二甲酸羟丙基甲基纤维素；DMSO＝二甲基亚砜
实施例102
只含有己二酸但不含乳酸的制剂99和制剂100，在10小时时间点没有通量，但在24小时时间点开始并维持到96小时时间点的通量良好。制剂102包含五渗透促进剂系统皮肤通量，包括乳酸(3％w/w，渗透促进剂E型)、己二酸(8％w/w％，渗透促进剂D型)、乙醇(渗透促进剂A型)、DMSO(A型渗透促进剂)、HPMCP(B型渗透促进剂)和乳酸月桂酯(C型渗透促进剂)。制剂102的皮肤通量早在4小时时间点就很高，并维持了72小时以上(表13和图8)。相比之下，含乳酸(E)不含己二酸(D)的配方101的皮肤通量仅在4小时至24小时的时间段内较高，但在超过24小时的时间段后较低(表12)。
比较例2
复制美国专利申请2020/0338012A1的实例配方9-2：将阿哌沙班、聚丙二醇、HPC、乳酸和甲醇混合、加热和溶解。如表12和图7所示，比较例2的处方因不含聚合物增溶剂B(例如HPMCP)和中等分子量有机酸D(例如己二酸)，其皮肤通量非常低。1,2-丙二醇和HPC用作增粘剂(以增加液体粘度)，表1中的HPC数据和表3中的聚丙二醇(PPG)数据表明不是阿哌沙班的增溶剂。
表13(药物储库类型贴剂)
Figure PCTCN2022114527-appb-000016
APX＝阿哌沙班；HPMCP＝邻苯二甲酸羟丙基甲基纤维素；DMSO＝二甲基亚砜
实施例103至106
贴剂组合物104及105含有渗透促进剂类型A,B,C和E,其皮肤通量比只含渗透促进剂类型A,B和C的贴剂组合物103及106要高得多(表14，图9)。在这里，油酸不仅同阿哌沙班形成易于渗透皮肤的加合物，同时还可作为表面活性剂C增加皮肤的渗透性能。
Figure PCTCN2022114527-appb-000017
实施例107至110
令人惊奇地是，含有皮肤渗透促进剂类型A,B,C和D的药物储库类形贴剂组合物107及含有皮肤渗透促进剂类型A,B,C,D和E的药物储库类形贴剂组合物108，其皮肤通量比含有皮肤渗透促进剂类型A,B，C，D，E的基质类型贴剂组合物109及110的皮肤通量要明显高得多(表15，图10)。
Figure PCTCN2022114527-appb-000018
安慰剂贴剂的皮肤黏附性能和皮肤刺激性测试
表18中描述的安慰剂贴剂使用早先描述的与活性贴剂相同的程序制备，不同之处在于药物储库层不含阿哌沙班。粘合剂层重量为每平方米60克。健康志愿者的上臂外皮或大腿用湿纸巾清洁并用干纸巾擦干。贴上安慰剂贴片后，将其弄平以确保贴片表面下没有气泡。记录实验的开始日期和时间。每天记录粘附和刺激评分。
如表18所示，安慰剂1的粘合剂基质在黏贴皮肤9小时后失去了完整性。去除贴片后，大量粘合剂转移到皮肤上，皮肤粘附评分低。因为皮肤接触粘合剂是非交联的Duro-Tak 387-2287并且不含内聚促进剂。当将交联粘合剂Duro-Tak387-2504和Duro-Tak 387-2516与内聚促进剂(如交聚维酮CLM和Eudragit E100)结合使用作为皮肤接触粘合剂时，皮肤粘合力得到很大改善。还发现硅氧烷粘合剂和聚异丁烯粘合剂具有良好的皮肤粘附性。含有10％己二酸但不含乳酸的安慰剂2的皮肤刺激性较低。含有8％至10％己二酸和低水平乳酸(1.5％至5％)的安慰剂2至安慰剂5的皮肤刺激性也很低。相比之下，含有高含量乳酸(13％)的对比安慰剂1的皮肤刺激性高。
黏附性能评估计分表
使用0-4分的五分评分法对粘附进行评分(表16)。
表16皮肤黏附性
Figure PCTCN2022114527-appb-000019
使用0-7分的八分评分法对原发性皮肤刺激进行评分(表17)。 表17皮肤刺激性计分
皮肤外观 得分
没有刺激的证据 0
几乎看不到的最小红斑 1
明显可见的红斑，轻微水肿或轻微丘疹 2
红斑和丘疹 3
明确水肿 4
红斑，浮肿和丘疹 5
水疱疹 6
贴剂范围有强烈的反应 7
表18
Figure PCTCN2022114527-appb-000020
Figure PCTCN2022114527-appb-000021

Claims (25)

  1. 一种阿哌沙班透皮贴剂，其包括：
    1)背衬层；
    2)药物储库层，其包含阿哌沙班或其药学上可接受的盐；
    3)半透膜层；
    4)粘合剂层；和任选地
    5)离型层。
  2. 根据权利要求1所述的阿哌沙班透皮贴剂，其中所述药物储库层还包含皮肤渗透促进剂。
  3. 根据权利要求2所述的阿哌沙班透皮贴剂，其中所述皮肤渗透促进剂包含溶剂、聚合物增溶剂、表面活性剂、中等分子量有机酸和低分子量有机酸中的任一项或其任意组合。
  4. 根据权利要求3所述的阿哌沙班透皮贴剂，其中所述皮肤渗透促进剂包含聚合物增溶剂、表面活性剂、和中等分子量有机酸。
  5. 根据权利要求4所述的阿哌沙班透皮贴剂，其中所述皮肤渗透促进剂还包含溶剂和/或低分子量有机酸。
  6. 根据权利要求3所述的阿哌沙班透皮贴剂，其中所述皮肤渗透促进剂包含溶剂、聚合物增溶剂、表面活性剂、和低分子量有机酸。
  7. 根据权利要求3-6中任一项所述的阿哌沙班透皮贴剂，其中所述聚合物增溶剂为含羧基的聚合物或聚维酮、交联聚维酮、共聚维酮或，含羧基的聚合物优选地为邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、羧甲基纤维素。
  8. 根据权利要求1-7中任一项所述的阿哌沙班透皮贴剂，其中阿哌沙班或其药学上可接受的盐的重量百分含量为药物储库层的0.5％至50％，优选1％至20％，更优选2％至10％。
  9. 根据权利要求3-8中任一项所述的阿哌沙班透皮贴剂，其中所述聚合物增溶剂的重量百分含量为药物储库层的0.1％至50％，优 选2％至50％，5％至25％，更优选10％至20％，并且所述阿哌沙班或其药学上可接受的盐与聚合物增溶剂的重量比为约1:0.1至1:20，优选为约1:1至1:20、约1:1至1:15，更优选为约1:1至1:10。
  10. 根据权利要求3-8中任一项所述的阿哌沙班透皮贴剂，其中所述表面活性剂的重量百分含量为药物储库层的1％至50％，优选5至30％。
  11. 根据权利要求3-8中任一项所述的阿哌沙班透皮贴剂，其中所述中等分子量有机酸的重量百分含量为药物储库层的0.1-60％，优选1-60％、1至30％，更优选1至15％。
  12. 根据权利要求3-8中任一项所述的阿哌沙班透皮贴剂，其中所述低分子量有机酸的重量百分含量为药物储库层的0.1至10％，优选0.5至5％，更优选0.5至3％。
  13. 根据权利要求3-8中任一项所述的阿哌沙班透皮贴剂，其中所述中等分子量有机酸包括C 5至C 8有机酸，优选地包括乙酰丙酸、山梨酸、衣康酸、中康酸、酮戊二酸、戊二酸、甲基琥珀酸、戊酸、异戊酸、新戊酸、顺式乌头酸、反式乌头酸、抗坏血酸、柠檬酸、异柠檬酸、己二酸、己酸、苯甲酸、水杨酸、龙胆酸、原儿茶酸、没食子酸、环己烷羧酸、庚二酸、邻苯二甲酸、间苯二甲酸、间苯二甲酸、对苯二甲酸、对苯二甲酸、苯乙酸、甲苯甲酸、邻甲苯甲酸酸、间甲苯甲酸、对甲苯甲酸、扁桃酸、homogentistic酸、辛二酸、辛酸、或其组合，更优选地包括乙酰丙酸、戊二酸、己二酸及其组合。
  14. 根据权利要求3-8中任一项所述的阿哌沙班透皮贴剂，其中所述低分子量有机酸包括C 1至C 4有机酸，优选地包括甲酸、乙醛酸、草酸、乙酸、乙醇酸、丙烯酸、丙酮酸、丙二酸、丙酸、3-羟基丙酸、乳酸、甘油酸、富马酸、马来酸、草酰乙酸、巴豆酸、乙酰乙酸、2-氧代丁酸、甲基丙二酸、琥珀酸、苹果酸、L-酒石酸、DL-酒石酸、内消旋酒石酸、二羟基酒石酸、丁酸、异丁酸、羟基丁酸、或其组合，更优选地，包括乳酸。
  15. 根据权利要求1所述的阿哌沙班透皮贴剂，其中所述粘合剂层包含皮肤接触粘合剂和任选的抗氧化剂、抗皮肤刺激剂、内聚促进剂、增塑剂、增粘剂。
  16. 根据权利要求16所述的阿哌沙班透皮贴剂，其中所述皮肤接触粘合剂包括丙烯酸粘合剂、甲基丙烯酸粘合剂、聚异丁烯粘合剂、苯乙烯-异戊二烯-苯乙烯嵌段共聚物粘合剂、硅氧烷粘合剂、丙烯酸-共聚硅氧烷共聚物粘合剂，或上述两种或多种的组合。
  17. 根据权利要求15或16所述的阿哌沙班透皮贴剂，其中所述皮肤接触粘合剂为交联的粘合剂或非交联的粘合剂。
  18. 根据权利要求15所述的阿哌沙班透皮贴剂，其中所述内聚促进剂包括胶体二氧化硅、氧化锌、聚乙烯吡咯烷、丙烯酸酯共聚物、交聚维酮、交联羧甲基纤维素、乙基纤维素、丙烯酸共聚物、膨润土、粘土或以上两种或更多种的组合。
  19. 根据权利要求18所述的阿哌沙班透皮贴剂，其中所述内聚促进剂的重量百分含量为粘合剂层的约3％至约50％，优选为约5％至约30％。
  20. 治疗有效量的根据权利要求1-19中任一项所述的阿哌沙班透皮贴剂在制备用于治疗或预防血栓疾病的药物中的用途。
  21. 根据权利要求20所述的用途，其中所述血栓疾病包括左心室血栓、心房微颤、急性冠状动脉症、非瓣膜性心房颤动、深静脉血栓、肺栓塞。
  22. 一种治疗或预防血栓疾病的方法，其包括向有需要的受试者施用治疗有效量的根据权利要求1-19中任一项所述的阿哌沙班透皮贴剂。
  23. 根据权利要求22所述的方法，其中所述血栓疾病包括左心室血栓、心房微颤、急性冠状动脉症、非瓣膜性心房颤动、深静脉血栓、肺栓塞。
  24. 根据权利要求22所述的方法，其中所述阿哌沙班透皮贴剂每24小时、每32小时、每48小时、每72小时、每84小时、每96 小时、每120小时、每144小时、或每168小时施用一次。
  25. 根据权利要求22所述的方法，其中所述阿哌沙班透皮贴剂每24小时递送约1mg至约40mg的阿哌沙班，优选为约2.5mg至约10mg的阿哌沙班至所述受试者的血液系统。
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TW202106297A (zh) * 2019-04-26 2021-02-16 泰合生技藥品股份有限公司 一種阿哌沙班透皮釋放系統及其使用方法

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WO2024020549A1 (en) * 2022-07-21 2024-01-25 Integurx Therapeutics, Ll Transdermal anticoagulant compositions

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