WO2021037199A1 - 一种经皮吸收的含酰胺类局部麻醉药的药物组合物及其制备方法 - Google Patents

一种经皮吸收的含酰胺类局部麻醉药的药物组合物及其制备方法 Download PDF

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WO2021037199A1
WO2021037199A1 PCT/CN2020/112064 CN2020112064W WO2021037199A1 WO 2021037199 A1 WO2021037199 A1 WO 2021037199A1 CN 2020112064 W CN2020112064 W CN 2020112064W WO 2021037199 A1 WO2021037199 A1 WO 2021037199A1
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pharmaceutical composition
sensitive adhesive
silicone pressure
amine
composition according
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PCT/CN2020/112064
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English (en)
French (fr)
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王美娜
罗琳
王祥
宋波
宋瑞杰
邬玉玉
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江苏恒瑞医药股份有限公司
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present disclosure belongs to the field of pharmacy, and relates to a medicinal composition containing an amide-type local anesthetic for transdermal absorption and a preparation method thereof.
  • Local anaesthetics is a class of drugs that can reversibly block the occurrence and transmission of sensory nerve impulses when the drug is used. In the case of keeping consciousness awake, it can reversibly cause the loss of local tissue pain.
  • the conventional administration method of topical anesthetics is subcutaneous or intradermal injection, which is not only inconvenient to administer but also frightens patients. Percutaneous administration of local anesthetics to penetrate into the body to produce anesthesia is a new trend in clinical superficial anesthesia.
  • amide local anesthetics are used for local anesthesia and analgesia for transdermal delivery products.
  • the US FDA has approved lidocaine patches for post-herpetic neuralgia, and the weight content of lidocaine is 5%.
  • Lidocaine And 1.8% by weight In the Japanese market, Nitto, Youde Pharmaceuticals and Nipro have successively marketed patch products with lidocaine concentrations ranging from 10% to 60%, which are mainly used for superficial surgical operations. Pain relief, such as pain relief during intravenous indwelling needle puncture, pain relief after resection of infectious soft cartilage, and pain relief during skin laser irradiation treatment.
  • Silicone Pressure Sensitive Adhesive is composed of polymer and adhesive resin.
  • Medical-grade silicone pressure-sensitive adhesive contains low-viscosity dimethylsiloxane polymer (12000 ⁇ 15000cp), and its molecular end contains silanol groups; silicone resin has the steric structure of silicate, and its end contains trimethyl Siloxy.
  • a silicone pressure-sensitive adhesive is prepared by dissolving a resin (such as a hydroxyl-containing silicone resin) and a polymer (such as a hydroxyl-containing silicone polymer) in a suitable solvent. It is known that silicone pressure-sensitive adhesives have advantages over other polymer-based pressure-sensitive adhesives such as acrylic resins, such as non-irritation and non-sensitivity to the skin.
  • US8153151 discloses a method for selectively controlling transdermal drug delivery, which includes adopting at least one hydroxyl-terminated silicone pressure-sensitive adhesive and at least one partially hydroxyl-terminated silicone pressure-sensitive adhesive in a matrix, which reliably prevents / Inhibit the crystallization of the active agent and achieve a controlled and constant release rate for a predetermined duration of application, especially 3 days or more.
  • the purpose of the present disclosure is to provide a transdermal absorption amide-containing local anesthetic composition to improve the release rate of the drug.
  • compositions for transdermal absorption comprising a skin adhesive layer, wherein the skin adhesive layer comprises: (1) at least one amide-based local anesthetic, (2) a first amine compatible Silicone pressure-sensitive adhesive, and (3) the second amine compatible silicone pressure-sensitive adhesive.
  • the amine compatible silicone pressure-sensitive adhesive refers to a pressure-sensitive adhesive that does not react with functional groups of amide local anesthetics, such as amino groups.
  • the pharmaceutical composition described in the present disclosure is a patch, preferably a non-aqueous patch.
  • the amide-based local anesthetic structure described in the present disclosure comprises a lipophilic part and a hydrophilic part, which are connected by a -NHCO- bond near the center of the molecule.
  • Suitable amide local anesthetics include, but are not limited to, lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, enocaine, prilocaine or them
  • the hydroxyl groups in the amine-compatible silicone pressure-sensitive adhesives described in the present disclosure are completely terminated by, for example, trimethylsilyl (TMS)-type groups.
  • the silicone pressure-sensitive adhesive in the skin adhesion layer described in the present disclosure does not include a non-fully hydroxyl-terminated silicone pressure-sensitive adhesive.
  • the silicone pressure-sensitive adhesive in the skin adhesion layer does not include amine-incompatible silicone pressure-sensitive adhesive.
  • the weight ratio of silicone resin to siloxane polymer used to prepare the first amine compatible silicone pressure-sensitive adhesive is not less than 58:42, for example, it can be 60:40 or 65:35. .
  • the weight ratio of the silicone resin to the silicone polymer used to prepare the second amine compatible silicone pressure-sensitive adhesive is less than 58:42, for example, it can be 55:45.
  • the weight ratio of the first amine-compatible silicone pressure-sensitive adhesive to the second amine-compatible silicone pressure-sensitive adhesive in the pharmaceutical composition may be 0.1:9.9-9.9:0.1, preferably 9:1-8:2, more preferably 8:2-4:6.
  • the weight ratio of silicone resin to siloxane polymer used to prepare the first amine compatible silicone pressure-sensitive adhesive is 60:40 or 65:35, and the second amine compatible silicone is prepared.
  • the weight ratio of silicone resin to siloxane polymer used in the ketone pressure-sensitive adhesive is 55:45.
  • the amine-compatible silicone pressure-sensitive adhesive in the pharmaceutical composition comprises a mixture of at least one medium-viscosity silicone pressure-sensitive adhesive and at least one high-viscosity silicone pressure-sensitive adhesive.
  • the first amine-compatible silicone pressure-sensitive adhesive in the pharmaceutical composition is a medium-viscosity silicone pressure-sensitive adhesive
  • the second amine-compatible silicone pressure-sensitive adhesive is a high-viscosity silicone pressure-sensitive adhesive. Silicone pressure sensitive adhesive.
  • the weight ratio of the medium-viscosity silicone pressure-sensitive adhesive to the high-viscosity silicone pressure-sensitive adhesive in the pharmaceutical composition may be 0.1:9.9-9.9:0.1, preferably 9:1-8: 2, more preferably 8:2-4:6.
  • Tack has been defined as the property that allows pressure-sensitive adhesives to form adhesion to the surface of another substance under light pressure and short contact.
  • the moderate viscosity of silicone pressure-sensitive pressure-sensitive adhesives indicates that the rapid adhesion to the surface of another substance is weaker than that of high-viscosity silicone pressure-sensitive adhesives.
  • the clear viscosity value of the silicone pressure-sensitive adhesive used in the present disclosure can be determined, for example, by Dow Corning's Corporate Test Method (CTM) 0991.
  • the initial adhesion of the pharmaceutical composition is 7-23, preferably 15-22 , More preferably 17-21.
  • the cumulative drug permeation percentage after the pharmaceutical composition is applied to the skin for about 12 hours is not less than about 10%, for example, not less than about 11%, not less than about 12%, and not less than About 13%, not less than about 14%, not less than about 15%, not less than about 16%, not less than about 17%, not less than about 18%, not less than about 19%, not less than about 20%, not less than about 21%, not less than about 22%, not less than about 23%, not less than about 24%, or not less than about 25%, preferably not less than about 15%, more preferably not less It is less than about 20%, and most preferably not less than about 22%.
  • the cumulative drug permeation percentage is not less than about 8% after the pharmaceutical composition is attached to the skin for about 12 hours, for example, about 11.5, 11, 10.5, 10, 9.5, 9 8.5, 8, 7.5, 7, 6.5, 6, 5.5 or 5 hours later, the cumulative drug penetration percentage is not less than 8%, preferably about 10 hours later, more preferably about 8 hours, most preferably about 5 hours after the drug cumulative penetration The excess percentage is not less than about 8%.
  • the skin to which the pharmaceutical composition is attached is pig skin, preferably pig ear skin.
  • the preferred amine-compatible silicone pressure-sensitive adhesive includes at least one BIO-PSA silicone pressure-sensitive adhesive produced by Dow Corning, such as BIO-PSA7-410X, BIO-PSA 7-420X, BIO -PSA 7-430X, etc., such as 7-4101, 7-4201, 7-4301, 7-4102, 7-4202, and 7-4302, etc.
  • BIO-PSA silicone pressure-sensitive adhesive produced by Dow Corning, such as BIO-PSA7-410X, BIO-PSA 7-420X, BIO -PSA 7-430X, etc., such as 7-4101, 7-4201, 7-4301, 7-4102, 7-4202, and 7-4302, etc.
  • X represents different solvents in pressure-sensitive adhesives, for example, 1 represents n-heptane, 2 represents ethyl acetate and so on.
  • BIO-PSA silicone pressure-sensitive adhesive The relevant parameters of BIO-PSA silicone pressure-sensitive adhesive are as follows (from Dow Corning's BIO-PSA silicone pressure-sensitive adhesive product manual):
  • the pressure-sensitive adhesive generally has a viscosity of about 0.1 Pa ⁇ s to 30000 Pa ⁇ s, preferably about 1 Pa ⁇ s to 100 Pa ⁇ s at 25°C.
  • the first amine compatible silicone pressure-sensitive adhesive is selected from one or more of BIO-PSA 7-410X and BIO-PSA 7-420X.
  • the second amine compatible silicone pressure-sensitive adhesive is selected from one or more of BIO-PSA 7-430X.
  • the first amine compatible silicone pressure sensitive adhesive is selected from one or more of BIO-PSA 7-420X, preferably 7-4202, the second amine compatible silicone The pressure-sensitive adhesive is selected from one or more of BIO-PSA 7-430X, preferably 7-4302.
  • the pharmaceutical composition described in the present disclosure may also include other types of pressure-sensitive adhesives, such as silicone, polyisobutylene and its derivatives, acrylic resins, natural rubber, natural and synthetic polyisoprene, polyisoprene, and polyisoprene.
  • pressure-sensitive adhesives such as silicone, polyisobutylene and its derivatives, acrylic resins, natural rubber, natural and synthetic polyisoprene, polyisoprene, and polyisoprene.
  • the weight ratio of the first amine-compatible silicone pressure-sensitive adhesive to the second amine-compatible silicone pressure-sensitive adhesive is about 0.1:9.9-9.9:0.1, preferably 8:2 -2:8, more preferably 8:2-4:6.
  • the content of the silicone pressure-sensitive adhesive in the skin adhesion layer may be about 0.1% to 99.9%, such as 10% to 99.5%, such as 20% to 99%, based on the total weight of the skin adhesion layer. %, such as 30% to 99%.
  • the amount of pressure-sensitive adhesive in the transdermal composition is 70% by weight or more, such as 75% by weight or more, such as 80% by weight or more, of the total weight of the transdermal composition. Such as 85% by weight or more, such as 90% by weight or more, such as 95% by weight or more, such as 97% by weight or more.
  • the content of the active ingredient amide local anesthetic in the present disclosure is about 0.01%-65% of the total weight of the skin adhesion layer, for example about 0.1%-40%, preferably about 0.1%- 20%, more preferably about 0.5%-10%.
  • the content of the amide local anesthetic in the patch described in the present disclosure may be about 0.1-1 mg/cm 2 , preferably 0.1-0.7 mg/cm 2 .
  • the pharmaceutical composition comprises a skin adhesion layer, wherein the skin adhesion layer comprises: (1) about 0.1%-20%, preferably about 0.5%-10, based on the total weight of the skin adhesion layer % Lidocaine free base, (2) 0.1% to 99.9% amine compatible silicone pressure sensitive adhesive, which is the first amine compatible silicone pressure sensitive adhesive and the second amine compatible silicone pressure sensitive adhesive A combination of sensitive adhesives, wherein the weight ratio of silicone resin to siloxane polymer used to prepare the first amine-compatible silicone pressure-sensitive adhesive is not less than 58:42, and the second amine-compatible silicone pressure-sensitive adhesive is prepared The weight ratio of silicone resin to siloxane polymer used in the glue is less than 58:42, preferably a combination of BIO-PSA 7-420X and BIO-PSA 7-430X, and the weight ratio is 8:2-2:8, preferably 8:2-4:6.
  • the weight ratio of silicone resin to siloxane polymer used in the glue is less than 58:42, preferably a combination of BIO-
  • the amine compatible silicone pressure-sensitive adhesive is a combination of BIO-PSA 7-4202 and BIO-PSA 7-4302.
  • the pharmaceutical composition described in the present disclosure may also contain other excipients, such as dissolving agents, antioxidants, plasticizers, tackifiers, fillers, crosslinking agents, crystallization inhibitors, and penetration enhancers. Wait.
  • excipients such as dissolving agents, antioxidants, plasticizers, tackifiers, fillers, crosslinking agents, crystallization inhibitors, and penetration enhancers. Wait.
  • the dissolving agents or penetration enhancers described in the present disclosure include, but are not limited to, polyols, such as dipropylene glycol, propylene glycol, tert-butanol, and polyethylene glycol; oils, such as liquid paraffin, olive oil, squalene, and lanolin; fatty ethers, Examples include cetyl ether and oleyl ether; fatty acid esters, such as isopropyl myristate (IPM) and medium chain triglycerides (MCT); urea and urea derivatives, such as allantoin; polar Solvents, such as dimethyldecylphophoxide (dimethyldecylphophoxide), methyl octyl sulfoxide, dimethyl lauramide, dodecyl pyrrolidone, isosorbide, dimethyl acetonide, dimethyl sulfoxide, decane Alkylmethyl sulfoxide and dimethylformamide;
  • dissolving agents include oleic acid and linoleic acid, ascorbic acid, pantothenic acid, butylated hydroxytoluene, tocopherol, tocopherol acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate.
  • Preferred dissolving agents or penetration enhancers are substances compatible with silicone pressure-sensitive adhesives, such as fatty acid esters (isopropyl myristate, medium-chain triglycerides, methyl laurate, di-adipate Isopropyl ester, etc.), oils (liquid paraffin, olive oil, squalene and lanolin, etc.); fatty ethers (cetyl ether, oleyl ether, etc.) and aliphatic surfactants (lauryl sulfate, ten Sodium dialkyl sulfonate, etc.).
  • fatty acid esters isopropyl myristate, medium-chain triglycerides, methyl laurate, di-adipate Isopropyl ester, etc.
  • oils liquid paraffin, olive oil, squalene and lanolin, etc.
  • fatty ethers cetyl ether, oleyl ether, etc.
  • aliphatic surfactants
  • plasticizers described in the present disclosure include, but are not limited to, fatty acid esters, such as lactate (ethyl lactate, cetyl lactate, etc.), diisopropyl adipate, phthalate (phthalate Dibutyl formate, etc.), diethyl sebacate, triethyl citrate, benzyl acetate, isopropyl myristate, medium chain triglycerides, etc.
  • fatty acid esters such as lactate (ethyl lactate, cetyl lactate, etc.), diisopropyl adipate, phthalate (phthalate Dibutyl formate, etc.), diethyl sebacate, triethyl citrate, benzyl acetate, isopropyl myristate, medium chain triglycerides, etc.
  • the tackifiers described in the present disclosure include, but are not limited to, rosin-based resins, polyterpene resins, coumarone-indene resins, petroleum-based resins, terpene-phenolic resins, xylene resins, and the like.
  • the antioxidants described in the present disclosure include, but are not limited to, tea polyphenols (TP), tocopherols, flavonoids, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), tert-butyl hydroquinone (TBHQ) and so on.
  • TP tea polyphenols
  • BHA butylhydroxyanisole
  • BHT dibutylhydroxytoluene
  • TBHQ tert-butyl hydroquinone
  • the patch of the present disclosure includes a backing layer and a peelable protective layer (e.g., release film).
  • a peelable protective layer e.g., release film
  • One surface of the backing layer is directly connected with the polymer matrix layer, and the backing layer plays a role in protecting the contact between the polymer matrix layer and the surrounding environment when in use, and prevents the loss of drugs.
  • the material of the backing layer generally includes polyester, polyethylene polyvinyl acetate resin, copolymer of polyethylene and vinyl acetate, polyvinyl chloride, polyurethane, metal foil, non-woven fabric, etc.
  • the thickness is generally 20-120 ⁇ m, such as 3M The company’s ScotchPakTM 1109, 9700, 9720, 9722, 9738, 1012, 9758, etc.
  • CotranTM 9720 These films may or may not be coated with, for example, an aluminum film, or aluminum vapor, or a silicone layer.
  • the thickness of the backing layer may be 10 to 120 ⁇ m, preferably 15 to 60 ⁇ m.
  • the peelable protective layer (such as a release film) is connected to the other side of the polymer matrix layer, such as ScotchpakTM 9744, 9742, 1020, 1022, 9744, 9755, 9741, 9709 from 3M Company. Before the patch is used, the protective film needs to be removed.
  • compositions for transdermal absorption comprising a skin adhesive layer, wherein the skin adhesive layer comprises: (1) at least one amide-based local anesthetic, (2) amine-compatible silicon Ketone pressure-sensitive adhesive, and (3) a dissolving agent, wherein the dissolving agent is selected from one or more of fatty acid esters, fatty ethers, oils or fatty surfactants.
  • Suitable amide local anesthetics include, but are not limited to, lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, enocaine, prilocaine or them
  • the dissolving agent is selected from isopropyl myristate, medium chain triglycerides, liquid paraffin, olive oil, squalene, lanolin, cetyl ether, oleyl ether, One or more of lauryl sulfate and sodium dodecyl sulfonate, preferably isopropyl myristate.
  • the content of the dissolving agent can be about 0.01%-20%, such as 0.05%-15%, such as 0.1%-10%, such as 0.5%- 8%, such as 1%-5%.
  • the weight ratio of the amide-based local anesthetic to the dissolving agent may be 1:0.1-1:10.
  • the initial adhesion of the pharmaceutical composition is 7-23, preferably 15-22 , More preferably 17-21.
  • the cumulative drug permeation percentage after the pharmaceutical composition is applied to the skin for about 12 hours is not less than about 10%, for example, not less than about 11%, not less than about 12%, and not less than About 13%, not less than about 14%, not less than about 15%, not less than about 16%, not less than about 17%, not less than about 18%, not less than about 19%, not less than about 20%, not less than about 21%, not less than about 22%, not less than about 23%, not less than about 24%, or not less than about 25%, preferably not less than about 15%, more preferably not less It is less than about 20%, and most preferably not less than about 22%.
  • the cumulative drug permeation percentage is not less than about 8% after the pharmaceutical composition is attached to the skin for about 12 hours, for example, about 11.5, 11, 10.5, 10, 9.5, 9 8.5, 8, 7.5, 7, 6.5, 6, 5.5 or 5 hours later, the cumulative drug penetration percentage is not less than 8%, preferably about 10 hours later, more preferably about 8 hours, most preferably about 5 hours after the drug cumulative penetration The excess percentage is not less than about 8%.
  • the skin to which the pharmaceutical composition is attached is pig skin, preferably pig ear skin.
  • the amine-compatible silicone pressure-sensitive adhesive includes BIO-PSA silicone pressure-sensitive adhesive produced by Dow Corning, such as BIO-PSA7-410X, BIO-PSA 7-420X, BIO-PSA 7 -430X, such as one or more of 7-4101, 7-4201, 7-4301, 7-4102, 7-4202, and 7-4302.
  • BIO-PSA silicone pressure-sensitive adhesive produced by Dow Corning, such as BIO-PSA7-410X, BIO-PSA 7-420X, BIO-PSA 7 -430X, such as one or more of 7-4101, 7-4201, 7-4301, 7-4102, 7-4202, and 7-4302.
  • X represents different solvents in pressure-sensitive adhesives, for example, 1 represents n-heptane, 2 represents ethyl acetate and so on.
  • the pressure-sensitive adhesive generally has a viscosity of about 0.1 Pa ⁇ s to 30000 Pa ⁇ s, preferably about 1 Pa ⁇ s to 100 Pa ⁇ s at 25°C.
  • the pharmaceutical composition does not include a silicone gel adhesive applied on the skin adhesion layer.
  • the pharmaceutical composition comprises a skin adhesion layer, wherein the skin adhesion layer comprises: (1) about 0.1%-20%, preferably about 0.5%-10, based on the total weight of the skin adhesion layer % Lidocaine free base, (2) 0.1%-99.9% at least one amine compatible silicone pressure sensitive adhesive, and (3) 0.1%-10% isopropyl myristate.
  • the weight ratio of silicone resin to siloxane polymer used to prepare the amine-compatible silicone pressure-sensitive adhesive is not less than 58:42, for example, it can be 60:40 or 65:35. .
  • the amine compatible silicone pressure-sensitive adhesive is selected from BIO-PSA 7-410X or BIO-PSA 7-420X.
  • Another aspect of the present disclosure provides a method for preparing a percutaneously absorbed pharmaceutical composition, the pharmaceutical composition comprising a skin adhesive layer, wherein the skin adhesive layer comprises: (1) at least one amide-based local anesthetic, (2) The first amine compatible silicone pressure sensitive adhesive, and (3) the second amine compatible silicone pressure sensitive adhesive,
  • the method includes the step of mixing an amide-based local anesthetic with a first amine-compatible silicone pressure-sensitive adhesive and a second amine-compatible silicone pressure-sensitive adhesive.
  • Another aspect of the present disclosure provides a method for preparing a percutaneously absorbed pharmaceutical composition, the pharmaceutical composition comprising a skin adhesive layer, wherein the skin adhesive layer comprises: (1) at least one amide-based local anesthetic, (2) At least one amine compatible silicone pressure-sensitive adhesive, and (3) a dissolving agent,
  • the method includes the step of mixing an amide-based local anesthetic with an amine-compatible silicone pressure-sensitive adhesive and a dissolving agent.
  • the method includes mixing the amide-based local anesthetic with a dissolving agent, and then mixing with an amine-compatible silicone pressure sensitive adhesive.
  • the method for preparing the transdermal pharmaceutical composition described in the present disclosure further includes the step of combining the skin adhesion layer with the peelable protective layer and/or the backing layer.
  • the method of combining the skin adhesion layer with the peelable protective layer and the backing layer can be conventional methods in the art, such as transfer coating, the skin adhesion layer is coated on the release film, and the backing layer is covered after drying .
  • Another aspect of the present disclosure provides a use of the percutaneously absorbed pharmaceutical composition of the present disclosure for analgesia or anesthesia.
  • the present disclosure uses a combined amine-compatible silicone pressure-sensitive adhesive, even without the addition of auxiliary materials such as co-solvents, it can still significantly improve the percentage of drugs passing through the skin, reduce the side effects of lidocaine, and improve the formulation The safety and effectiveness.
  • auxiliary materials such as co-solvents
  • the percentage of the drug through the skin can also be significantly improved.
  • the skin permeability of the drug is higher, and the safety and effectiveness of the preparation are also improved.
  • the term "about” means that the quantities, dimensions, formulations, parameters, and other quantities and characteristics are inaccurate and need not be precise, but may be the desired approximation and/or larger or smaller values, thereby reflecting tolerances , Conversion factor, rounding, measurement error, etc., and other factors known to those skilled in the art.
  • the meaning can include a change of ⁇ 10%, preferably a change of ⁇ 5%.
  • Figure 1 is a graph showing the average drug-time curve of 12 subjects.
  • IPM Isopropyl myristate
  • Backing layer backing 3M company ScotchPak9738
  • Release film Release film ScotchPak9709 from 3M Company
  • lidocaine and other auxiliary materials Accurately weigh the pressure-sensitive adhesive (based on the weight of the dry glue), lidocaine and other auxiliary materials according to the prescriptions of the examples, add the lidocaine and other auxiliary materials to the pressure-sensitive adhesive, stir evenly, stand for degassing, and evenly Coated on the release film, heated and dried, composite backing layer, cut into lidocaine patch.
  • Prescription containing dissolving agent accurately weigh the pressure-sensitive adhesive (based on the weight of the dry glue), lidocaine and other auxiliary materials according to the prescription of each example, dissolve the lidocaine in the dissolving agent, and then add it to the pressure-sensitive adhesive together with other auxiliary materials.
  • the glue stir evenly, stand to degas, and evenly coat on the release film. After drying, composite the backing layer and cut into lidocaine patch.
  • Cumulative Permeation Percentage Cumulative Permeation Amount/Dosing Amount
  • the cumulative permeable content of the patch per unit area is shown in the following table:
  • the obtained patch has a higher drug penetration rate after being attached to the skin for 12 hours, and no drug is observed from the patch.
  • the situation of precipitation in the agent appears.
  • the drug permeability of a single pressure-sensitive adhesive or a patch containing a non-hydroxy-terminated pressure-sensitive adhesive is low.
  • the drug penetration rate of 7-4302 alone is not low, the patch is too sticky and it is difficult to remove the patch from the skin, which will inevitably lead to poor patient compliance.
  • Soluble agent isopropyl myristate (IPM), tert-butyl alcohol (T-BA), methyl laurate (ML), diisopropyl adipate (DIPA);
  • the lidocaine patch was prepared according to the method of Example 1, and the patch was placed at room temperature to observe the precipitation of the raw material lidocaine in the patch, as shown in the table.
  • the fourth general rule 0952 adhesion force measurement method first method (measurement of initial adhesion)
  • the samples of the foregoing examples were cut into 10 ⁇ 2.5cm size, 3 copies each; the sample and the viscosity tester (CBY -1Y) Place it for 2 hours under the same experimental conditions.
  • the glue is smoothly fixed from the starting point of the steel ball to the upper end of the sample; the steel ball is wiped clean with absolute ethanol and dust-free paper, placed on the starting line, and falls freely from the top of the inclined surface. Record the largest steel ball that the sample can stick.
  • the ratio of the pressure-sensitive adhesive 7-4202 and 7-4302 in the patch of Example 1 was changed to prepare the patch, and the adhesive force measurement method first method (measurement of initial adhesion) was used in accordance with the 2015 edition of the Chinese Pharmacopoeia, the fourth general rule 0952 , Test the initial adhesion of different proportions of patches, as shown in the table below.
  • the adhesiveness is too large, and the patch is difficult to remove from the skin, which will inevitably lead to poor patient compliance.
  • the initial adhesion of the patch is too small at 7 o'clock, and the patch is easy to fall off.
  • This study adopts a single-center, randomized, open-ended, three-period, cross-controlled experimental design, and a single-dose administration study.
  • a total of 12 healthy subjects were selected, both men and women.
  • the administration area of the test formulation and the reference formulation are both 420 cm 2 (that is, 3 patches), the application time is 12 hours, and the cleaning period between weeks is 5 days.
  • the blood sampling time points are: 0:00 before administration (within 1h before administration) and 0.5, 2, 4, 6, 8, 10, 11, 12, 13, 15, 18, 24, 30, 36 and 48h after administration .
  • the random sequence of subjects grouping is as follows:
  • Test preparation T1 Example 1 preparation, specification: 27mg/tablet, 10 ⁇ 14cm;
  • Test preparation T2 Example 6 preparation, specification: 36mg/tablet, 10 ⁇ 14cm;
  • Reference preparation R commercial lidocaine patch (trade name: ), Specification: 700mg/tablet, 10 ⁇ 14cm, manufactured by Endo Pharmaceuticals Inc.

Abstract

一种经皮吸收的含酰胺类局部麻醉药的药物组合物及其制备方法。具体涉及一种经皮吸收的药物组合物，包含皮肤粘附层，其中皮肤粘附层包含酰胺类局部麻醉药以及胺相容的硅酮压敏胶，所述药物组合物具有改进的释放特性。

Description

一种经皮吸收的含酰胺类局部麻醉药的药物组合物及其制备方法 技术领域
本公开属于制药领域，涉及一种经皮吸收的含酰胺类局部麻醉药的药物组合物及其制备方法。
背景技术
局部麻醉药(local anaesthetics)是一类能在用药局部可逆性的阻断感觉神经冲动发生与传递的药品。在保持意识清醒的情况下，可逆的引起局部组织痛觉消失。常规的表面麻醉药给药方法是皮下或皮内注射，该方法不仅给药不便而且使患者畏惧。通过经皮给药使局麻药渗透进入体内从而产生麻醉作用是目前临床浅表性麻醉用药的新趋势。
目前市场上用于局部麻醉镇痛的酰胺类局部麻醉药经皮给药产品，如美国FDA先后批准用于带状疱疹后神经痛利多卡因贴剂，分别为利多卡因重量含量为5％的利多卡因
Figure PCTCN2020112064-appb-000001
以及重量含量为1.8％的
Figure PCTCN2020112064-appb-000002
在日本市场上，如日东电工(Nitto)、佑德药业和尼普洛(Nipro)先后上市了利多卡因浓度从10％到60％的贴剂产品，主要用于浅表手术操作的止痛，如静脉留置针穿刺时疼痛缓解、感染性软体软骨切除术后疼痛缓解和皮肤激光照射治疗过程中疼痛缓解等。
硅酮压敏胶(PSA)是由聚合物及具有粘着性的树脂组成的。医用级硅酮压敏胶含有低粘性二甲基硅氧烷聚合物(12000～15000cp)，其分子末端含有硅烷醇基；硅酮树脂具有硅酸盐的空间立体结构，其末端含有三甲基硅氧基。通过将树脂(例如含羟基的硅树脂)及聚合物(例如含羟基的硅氧烷聚合物)溶解于适当溶媒中，制成硅酮压敏胶。已知硅酮压敏胶相比于其它聚合物基压敏胶如丙烯酸树脂具有优势，例如对皮肤无刺激性和非敏感性等等。
US8153151公开了种选择性控制透皮药物递送的方法，包括在基质中采用至少一种的羟基封端的硅酮压敏胶以及至少一种的部分羟基封端的硅酮压敏胶，其可靠地防止/抑制活性剂的结晶并在预定的施用持续时间内实现受控和恒定的释放速率，特别是3天或更长时间。
发明内容
本公开的目的在于提供一种经皮吸收的含酰胺类局部麻醉药的组合物，改善药物的释放率。
本公开一方面提供了一种经皮吸收的药物组合物，包含皮肤粘附层，其中皮肤粘附层包含：(1)至少一种酰胺类局部麻醉药，(2)第一胺相容的硅酮压敏胶，和(3)第二胺相容的硅酮压敏胶。
所述的胺相容的硅酮压敏胶是指不与酰胺类局部麻醉药的官能团，例如氨基基团发生反应的压敏胶。
在某些实施方式中，本公开所述的药物组合物为贴剂，优选非水性贴剂。
在某些实施方式中，本公开所述的酰胺类局部麻醉药结构包含亲脂部分和亲水部分，其通过靠近分子中心的-NHCO-键连接。合适的酰胺类局部麻醉药包括但不限于利多卡因、布比卡因、左旋布比卡因、罗哌卡因、甲哌卡因、吡咯卡因、依那卡因、丙胺卡因或它们的可药用盐，优选利多卡因或其可药用盐，例如可以是利多卡因盐酸盐、利多卡因游离碱、利多卡因乳酸盐和利多卡因枸橼酸盐，优选为利多卡因游离碱。
在某些实施方式中，本公开所述的胺相容的硅酮压敏胶中的羟基基团完全被例如三甲基硅烷基(TMS)类基团封端。
在某些实施方式中，本公开所述的皮肤粘附层中的硅酮压敏胶不包含非完全羟基封端的硅酮压敏胶。
在某些实施方式中，所述的皮肤粘附层中的硅酮压敏胶不包含胺不相容的硅酮压敏胶。
在某些实施方式中，制备第一胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比不低于58:42，例如可以是60:40或65:35。
在某些实施方式中，制备第二胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比低于58:42，例如可以是55:45。
在某些实施方式中，所述药物组合物中第一胺相容的硅酮压敏胶与第二胺相容的硅酮压敏胶的重量比可以是0.1:9.9-9.9:0.1，优选9:1-8:2，更优选8:2-4:6。
在某些实施方式中，制备第一胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比为60:40或65:35，制备第二胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比为55:45。
在某些实施方式中，所述药物组合物中的胺相容的硅酮压敏胶包含至少一种中等粘性硅酮压敏粘合剂和至少一种高粘性硅酮压敏胶的混合物。
在某些实施方式中，所述药物组合物中的第一胺相容的硅酮压敏胶为中等粘性硅酮压敏粘合剂，第二胺相容的硅酮压敏胶为高粘性硅酮压敏胶。
在某些实施方式中，所述药物组合物中中等粘性硅酮压敏粘合剂与高粘性硅酮压敏胶的重量比可以是0.1:9.9-9.9:0.1，优选9:1-8:2，更优选8:2-4:6。
粘性已被定义为使得压敏胶可以在轻压力和短暂的接触下与另一种物质的表面形成粘合的性质。硅酮压敏压敏胶的中等粘性表明：相比高粘性硅酮压敏胶，与另外一种物质表面的迅速粘合是较弱的。用于本公开的硅酮压敏胶的明确的粘性值例如可通过Dow Corning的Corporate Test Method(CTM)0991确定。
在某些实施方式中，根据2015版中国药典第四部通则0952黏附力测定法第一法(初黏力的测定)，所述药物组合物的初黏力为7-23，优选15-22，更优选17-21。
在某些实施方式中，所述药物组合物贴附于皮肤约12小时后药物累积透过百分比不低于约10％，例如不低于约11％、不低于约12％、不低于约13％、不低于约14％、不低于约15％、不低于约16％、不低于约17％、不低于约18％、不低于约19％、不低于约20％、不低于约21％、不低于约22％、不低于约23％、不低于约24％或不低于约25％，优选不低于约15％，更优选不低于约20％，最优选不低于约22％。
在某些实施方式中，所述药物组合物贴附于皮肤约12小时后药物累积透过百分比不低于约8％，例如贴附于皮肤约11.5、11、10.5、10、9.5、9、8.5、8、7.5、7、6.5、6、5.5或5小时后药物累积透过百分比不低于8％，优选约10小时后、更优选约8小时后，最优选约5小时 后药物累积透过百分比不低于约8％。
在某些实施方式中，所述药物组合物贴附的皮肤为猪皮肤，优选猪耳背皮肤。
在某些实施方式中，优选的胺相容的硅酮压敏胶包括至少一种Dow Corning生产的BIO-PSA硅酮压敏胶，例如BIO-PSA7-410X、BIO-PSA 7-420X、BIO-PSA 7-430X等，例如7-4101、7-4201、7-4301、7-4102、7-4202和7-4302等等。X代表压敏胶中不同的溶剂，例如1代表正庚烷，2代表乙酸乙酯等。
BIO-PSA硅酮压敏胶的相关参数如下表(来源于Dow Corning公司的BIO-PSA硅酮压敏胶的产品手册)：
Figure PCTCN2020112064-appb-000003
在某些实施方式中，所述的压敏胶通常具有25℃时约0.1Pa·s至30000Pa·s、优选约1Pa·s至100Pa·s的粘度。
在某些实施方式中，所述的第一胺相容的硅酮压敏胶选自BIO-PSA7-410X、BIO-PSA 7-420X中的一种或多种。
在某些实施方式中，所述的第二胺相容的硅酮压敏胶选自BIO-PSA 7-430X中的一种或多种。
在某些实施方式中，所述的第一胺相容的硅酮压敏胶选自BIO-PSA 7-420X中的一种或多种，优选7-4202，第二胺相容的硅酮压敏胶选自BIO-PSA 7-430X中的一种或多种，优选7-4302。
本公开所述的药物组合物还可包含其他类型的压敏胶，例如可以是硅酮、聚异丁烯和其衍生物、丙烯酸类树脂、天然橡胶、天然的和合成的聚异戊二烯、聚丁烯和聚异丁烯、苯乙烯/丁二烯聚合物、苯乙烯-异戊二烯-苯乙烯嵌段聚合物、烃类聚合物例如丁基橡胶、卤素聚氯 乙烯(halogen polyvinylchloride)、聚偏二氯乙烯和聚氯二烯(polychlorodiene)，及其组合。
在某些实施方式中，所述的第一胺相容的硅酮压敏胶与第二胺相容的硅酮压敏胶的重量比大约为0.1:9.9-9.9:0.1，优选8:2-2:8，更优选8:2-4:6。
在某些实施方式中，皮肤粘附层中的硅酮压敏胶的含量可以是占皮肤粘附层总重量的约在0.1％至99.9％，如10％至99.5％、如20％至99％、如30％至99％。
在某些实施方式中，经皮组合物中的压敏胶的量是经皮组合物的总重量的70重量％或更多，如75重量％或更多、如80重量％或更多、如85重量％或更多、如90重量％或更多、如95重量％或更多、如97重量％或更多。
在某些实施方式中，本公开所述的活性成分酰胺类局部麻醉药的含量为占皮肤粘附层总重量的约0.01％-65％，例如约0.1％-40％，优选约0.1％-20％，更优选约0.5％-10％。
在某些实施方式中，本公开所述的贴剂中酰胺类局部麻醉药的含量可以是约0.1-1mg/cm 2，优选0.1-0.7mg/cm 2。
在某些实施方式中，所述的药物组合物包含皮肤粘附层，其中皮肤粘附层包含基于皮肤粘附层总重量的：(1)约0.1％-20％，优选约0.5％-10％的利多卡因游离碱，(2)0.1％至99.9％的胺相容的硅酮压敏胶，其为第一胺相容的硅酮压敏胶和第二胺相容的硅酮压敏胶的组合，其中制备第一胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比不低于58:42，制备第二胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比低于58:42，优选BIO-PSA 7-420X和BIO-PSA 7-430X的组合，重量比为8:2-2:8，优选8:2-4:6。
在某些实施方式中，所述的胺相容的硅酮压敏胶为BIO-PSA 7-4202和BIO-PSA 7-4302的组合。
在某些实施方式中，本公开所述的药物组合物还可含有其它辅料，例如溶解剂、抗氧化剂、增塑剂、增粘剂、填充剂、交联剂、结晶抑制剂和促透剂等。
本公开所述的溶解剂或促透剂包括但不限于多元醇，例如二丙二 醇、丙二醇、叔丁醇和聚乙二醇；油，例如液体石蜡、橄榄油、鲨烯和羊毛脂；脂肪醚，例如十六烷基醚和油烯基醚；脂肪酸酯，例如肉豆蔻酸异丙酯(IPM)和中链三甘油酸脂(MCT)；脲和脲衍生物，例如尿囊素；极性溶剂，例如二甲基癸基氧化膦(dimethyldecylphophoxide)、甲基辛基亚枫、二甲基月桂酰胺、十二烷基吡咯烷酮、异山梨醇、二甲基缩丙酮、二甲基亚枫、癸基甲基亚枫和二甲基甲酰胺；水杨酸；氨基酸；烟酸苄酯；脂肪族表面活性剂，例如月桂基硫酸盐、十二烷基磺酸钠。其他溶解剂包括油酸和亚麻油酸、抗坏血酸、泛酸、丁基化羟基甲苯、生育酚、生育酚乙酸酯、生育酚亚油酸酯、油酸丙酯和棕榈酸异丙酯。优选的溶解剂或促透剂为可以与硅酮类压敏胶相容的物质，例如脂肪酸酯(肉豆蔻酸异丙酯，中链三甘油酸脂，月桂酸甲酯，己二酸二异丙酯等)，油(液体石蜡，橄榄油，鲨烯和羊毛脂等)；脂肪醚(十六烷基醚，油烯基醚等)以及脂肪族表面活性剂(月桂基硫酸盐，十二烷基磺酸钠等)。
本公开所述的增塑剂包括但不限于脂肪酸酯，例如乳酸酯(乳酸乙酯、乳酸鲸蜡酯等)、己二酸二异丙酯、邻苯二甲酸酯(邻苯二甲酸二丁酯等)、癸二酸二乙酯、柠檬酸三乙酯、乙酸苄酯、肉豆蔻酸异丙酯、中链三甘油酸脂等。
本公开所述的增粘剂包括但不限于松香系树脂、聚萜烯树脂、苯并呋喃-茚树脂、石油系树脂、萜烯-酚醛树脂、二甲苯树脂等。
本公开所述的抗氧化剂包括但不限于茶多酚(TP)、生育酚、黄酮类、丁基羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)、叔丁基对苯二酚(TBHQ)等。
在某些实施方式中，本公开的贴剂包括一个背衬层和可剥离保护层(例如离型膜)。所述背衬层的一个面直接和高分子基质层连接，在使用的时候背衬层起到保护高分子基质层和周边环境的接触的作用，防止药物的损失。背衬层的材料一般包括聚酯、聚乙烯聚醋酸乙烯树脂、聚乙烯和醋酸乙烯酯的共聚物、聚氯乙烯、聚氨酯、金属箔，无纺布等，厚度一般在20～120μm，比如3M公司的ScotchPakTM1109，9700，9720，9722，9738，1012，9758等或CotranTM9720。这些膜可以或不可以涂覆有例如铝膜、或铝蒸气、或有机硅层。背衬层的厚度可为10 至120μm,优选15至60μm。所述可剥离保护层(例如离型膜)和高分子基质层的另一面相连接，比如3M公司的ScotchpakTM9744，9742，1020，1022，9744，9755，9741，9709等。在贴剂使用前，需要将保护膜去掉。
本公开另一方面提供了一种经皮吸收的药物组合物，包含皮肤粘附层，其中皮肤粘附层包含：(1)至少一种酰胺类局部麻醉药，(2)胺相容的硅酮压敏胶，和(3)溶解剂，其中所述溶解剂选自脂肪酸酯、脂肪醚、油或脂肪族表面活性剂中的一种或多种。
合适的酰胺类局部麻醉药包括但不限于利多卡因、布比卡因、左旋布比卡因、罗哌卡因、甲哌卡因、吡咯卡因、依那卡因、丙胺卡因或它们的可药用盐，优选利多卡因或其可药用盐，例如可以是利多卡因盐酸盐、利多卡因游离碱、利多卡因乳酸盐和利多卡因枸橼酸盐，优选为利多卡因游离碱。
在某些实施方式中，所述溶解剂选自肉豆蔻酸异丙酯、中链三甘油酸脂、液体石蜡、橄榄油、鲨烯、羊毛脂、十六烷基醚、油烯基醚、月桂基硫酸盐、十二烷基磺酸钠中的一种或多种，优选肉豆蔻酸异丙酯。
在某些实施方式中，所述的溶解剂的含量可以是占皮肤粘附层总重量的约在0.01％-20％，如0.05％-15％、如0.1％-10％、如0.5％-8％、如1％-5％。
在某些实施方式中，所述酰胺类局部麻醉药与溶解剂的重量比可以是1:0.1-1:10。
在某些实施方式中，根据2015版中国药典第四部通则0952黏附力测定法第一法(初黏力的测定)，所述药物组合物的初黏力为7-23，优选15-22，更优选17-21。
在某些实施方式中，所述药物组合物贴附于皮肤约12小时后药物累积透过百分比不低于约10％，例如不低于约11％、不低于约12％、不低于约13％、不低于约14％、不低于约15％、不低于约16％、不低于约17％、不低于约18％、不低于约19％、不低于约20％、不低于约21％、不低于约22％、不低于约23％、不低于约24％或不低于约25％，优选不低于约15％，更优选不低于约20％，最优选不低于约 22％。
在某些实施方式中，所述药物组合物贴附于皮肤约12小时后药物累积透过百分比不低于约8％，例如贴附于皮肤约11.5、11、10.5、10、9.5、9、8.5、8、7.5、7、6.5、6、5.5或5小时后药物累积透过百分比不低于8％，优选约10小时后、更优选约8小时后，最优选约5小时后药物累积透过百分比不低于约8％。
在某些实施方式中，所述药物组合物贴附的皮肤为猪皮肤，优选猪耳皮。
在某些实施方式中，所述胺相容的硅酮压敏胶包括Dow Corning生产的BIO-PSA硅酮压敏胶，例如BIO-PSA7-410X、BIO-PSA 7-420X、BIO-PSA 7-430X，例如7-4101、7-4201、7-4301、7-4102、7-4202和7-4302中的一种或多种。X代表压敏胶中不同的溶剂，例如1代表正庚烷，2代表乙酸乙酯等。
在某些实施方式中，所述的压敏胶通常具有25℃时约0.1Pa·s至30000Pa·s、优选约1Pa·s至100Pa·s的粘度。
在某些实施方式中，所述药物组合物不包含应用在皮肤粘附层上的有机硅凝胶粘合剂。
在某些实施方式中，所述药物组合物，包含皮肤粘附层，其中皮肤粘附层包含基于皮肤粘附层总重量的：(1)约0.1％-20％，优选约0.5％-10％的利多卡因游离碱，(2)0.1％-99.9％的至少一种胺相容的硅酮压敏胶，和(3)0.1％-10％的肉豆蔻酸异丙酯。
在某些实施方式中，制备所述胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比不低于58:42，例如可以是60:40或65:35。
在某些实施方式中，所述胺相容的硅酮压敏胶选自BIO-PSA7-410X或BIO-PSA 7-420X。
本公开另一方面提供了一种经皮吸收的药物组合物的制备方法，所述药物组合物包含皮肤粘附层，其中皮肤粘附层包含：(1)至少一种酰胺类局部麻醉药，(2)第一胺相容的硅酮压敏胶，和(3)第二胺相容的硅酮压敏胶，
所述方法包括将酰胺类局部麻醉药与第一胺相容的硅酮压敏胶和第二胺相容的硅酮压敏胶混合的步骤。
本公开另一方面提供了一种经皮吸收的药物组合物的制备方法，所述药物组合物包含皮肤粘附层，其中皮肤粘附层包含：(1)至少一种酰胺类局部麻醉药，(2)至少一种胺相容的硅酮压敏胶，和(3)溶解剂，
所述方法包括将酰胺类局部麻醉药与胺相容的硅酮压敏胶和溶解剂混合的步骤。
在某些实施方式中，所述方法包括将酰胺类局部麻醉药先与溶解剂混合，再与胺相容的硅酮压敏胶混合。
在某些实施方式中，本公开所述的经皮吸收的药物组合物制备方法还包括将皮肤粘附层与可剥离保护层和/或背衬层结合的步骤。
皮肤粘附层与可剥离保护层、背衬层结合的方法可采用本领域常规的方法，例如采用转移式涂布，将皮肤粘附层涂布在离型膜上，干燥后加盖背衬。
本公开另一方面提供了一种本公开的经皮吸收的药物组合物用于镇痛或麻醉的用途。
本公开通过采用组合的胺相容的硅酮压敏胶，即便在不添加助溶剂等辅料的情况下，仍能够显著地改善药物透过皮肤的百分比，降低利多卡因的副作用，改善了制剂的安全性和有效性。通过采用胺相容的硅酮压敏胶与特定的溶解剂的组合，也能够显著地改善药物透过皮肤的百分比。相比于市售的酰胺类局部麻醉药贴剂产品，药物皮肤透过率更高，同样改善了制剂的安全性和有效性。
术语“约”是指数量、尺寸、配方、参数、以及其他量和特性是不精确的并且不必是精确的，但可以是期望的近似值和/或较大值或较小值，由此反映公差、转换因子、四舍五入、测量误差等、以及本领域的技术人员已知的其他因子。其含义可包括±10％的变化，优选±5％的变化。
附图说明
图1为12例受试者平均药时曲线图。
具体实施方式
实施例1-6、对比例1-5：利多卡因贴剂的制备
所采用的组分：
压敏胶：Dow Corning生产的BIO-PSA硅酮压敏胶7-4102、7-4202、7-4302(均为完全羟基封端)、7-4503(部分羟基封端)；
溶解剂：肉豆蔻酸异丙酯(IPM)
填充剂：二氧化硅
背衬层：背衬3M公司ScotchPak9738
离型膜：离型膜3M公司ScotchPak9709
Figure PCTCN2020112064-appb-000004
按照各实施例处方精确称量压敏胶(以干胶重量计)以及利多卡因和其他辅料，将利多卡因与其它辅料一起加入到压敏胶中，搅拌均匀，静置脱气，均匀涂布于离型膜上，经加热干燥后复合背衬层，切割成即得利多卡因贴剂。
含溶解剂处方：按照各实施例处方精确称量压敏胶(以干胶重量计)以及利多卡因和其他辅料，将利多卡因先溶于溶解剂，再与其它辅料一起加入到压敏胶中，搅拌均匀，静置脱气，均匀涂布于离型膜上，经干燥后复合背衬层，切割成即得利多卡因贴剂。
实施例7：体外透皮实验
将采购的猪耳背皮从零下20摄氏度冰箱取出，用刀具将其裁成直 径为2.5厘米的圆形，减去猪毛清洗干净后将其置于润湿的孔径为0.22微米的水相滤膜上，固定于弗朗茨渗透池的两室之间，有角质层的一面朝向供给室，皮肤与药物的有效接触面积为直径2.0厘米的圆形。将上述实施例和对比例贴剂以及市售利多卡因贴剂
Figure PCTCN2020112064-appb-000005
裁剪成直径2.0cm的圆形，贴于猪皮角质层上，接收池中充满pH7.4的PBS缓冲液(5.5毫升)，32摄氏度干加热，分别于预设时间点从接收池中取样2.5ml，同时向接收池中补加等量的相同的PBS缓冲溶液。
药物的累积透过量计算公式：
Q＝[5.5*Ci+∑2.5*(C1+C2+……+Ci)]/A
其中Q代表单位面积累积透过量，Ci代表不同时间点接受室中药物浓度，A为有效皮肤面积
药物的透过百分比计算公式：
累积透过百分比＝累积透过量/给药量
实验结果：
贴剂单位面积累积透过药物的含量，如下表：
Figure PCTCN2020112064-appb-000006
贴剂中累积透过药物的百分比，如下表：
Figure PCTCN2020112064-appb-000007
从实验结果可知，采用羟基封端的混合压敏胶或者压敏胶与溶解剂组合使用，得到的贴剂在贴附于皮肤12小时后药物的透过率更高， 并且未观察到药物从贴剂中析出的情况出现。而使用单一压敏胶或包含非羟基封端压敏胶的贴剂的药物透过率较低。单独使用7-4302的贴剂虽然药物透过率不低，但贴剂粘性过大，贴剂难以从皮肤上除去，必然导致患者顺应性差。
实施例8-13
所采用的组分：
压敏胶：Dow Corning生产的BIO-PSA硅酮压敏压敏胶7-4202、7-4302；
溶解剂：肉豆蔻酸异丙酯(IPM)，叔丁基醇(T-BA)，月桂酸甲酯(ML)，己二酸二异丙酯(DIPA)；
Figure PCTCN2020112064-appb-000008
根据实施例1的方法制备利多卡因贴剂，并将贴剂置于室温下，观察贴剂中原料利多卡因的析出情况，如表中所示。
实施例14：黏性测试
按2015版中国药典第四部通则0952黏附力测定法第一法(初黏力的测定)，将前述实施例样品裁剪成10×2.5cm尺寸，各3份；将样品和粘度测定仪(CBY-1Y)于同一实验条件下放置2小时。调整倾斜板角度至30°；样品粘性面向上，用双面胶平整固定在倾斜板上，样品下端位于倾斜板水平下线位置，去掉离型膜，另取10×2.5cm背衬用双 面胶平整固定在钢球起点至样品上端；将钢球用无水乙醇和无尘纸擦拭干净，放在起始线上，自斜面顶端自由落下，记录样品能粘住的最大号钢球。
实验结果与讨论
贴剂黏性测定实验结果见下表，可见。
实施例 黏性
实施例1 17
实施例4 20
实施例15：不同比例的混合胶的黏性测试
改变实施例1贴剂中的压敏胶7-4202与7-4302的比例，制备贴剂，并根据2015版中国药典第四部通则0952黏附力测定法第一法(初黏力的测定)，测试不同比例贴剂的初黏力，如下表所示。
Figure PCTCN2020112064-appb-000009
贴剂初黏力在24或以上时黏性过大，贴剂难以从皮肤上除去，必然导致患者顺应性差。贴剂初黏力在7时黏性过小，贴剂易脱落。
实施例16
考察空腹单剂量贴敷利多卡因改良贴剂的药代动力学特征，以
Figure PCTCN2020112064-appb-000010
作为参比制剂，评价制剂的人体生物利用度水平，考察利多卡因改良型贴剂的粘附性。
1、实验设计
本研究采用单中心、随机、开放、三周期、交叉对照的试验设计，单剂量给药研究。共入选12例健康受试者，男女均有。受试制剂和参比制剂的给药面积均为420cm 2(即3贴)，贴敷时长12小时，周期间的清洗期为5天。采血时间点为：给药前0时(给药前1h内)和给药后0.5，2，4，6，8，10，11，12，13，15，18，24，30，36和48h。受试者分组随机序列如下：
受试者试验号 第一周期 第二周期 第三周期
K001 R T2 T1
K002 T2 R T1
K003 T1 T2 R
K004 R T2 T1
K005 T1 T2 R
K006 R T1 T2
K007 T1 R T2
K008 T1 R T2
K009 T2 T1 R
K010 T2 T1 R
K011 R T1 T2
K012 T2 R T1
(R-参比制剂，T1-受试制剂1，T2-受试制剂2；)
2、药物信息
受试制剂T1：实施例1制剂，规格：27mg/片，10×14cm；
受试制剂T2：实施例6制剂，规格：36mg/片，10×14cm；
参比制剂R：市售利多卡因贴剂(商品名：
Figure PCTCN2020112064-appb-000011
)，规格：700mg/片，10×14cm，Endo Pharmaceuticals Inc公司生产。
3、实验结果
本研究中受试者贴敷受试制剂T1、T2及参比制剂R后体内利多卡因的主要药代动力学参数如下表及图1所示。结果表明，受试制剂的生物利用度水平整体优于参比制剂。
各制剂的利多卡因主要药代动力学参数(N＝12)
Figure PCTCN2020112064-appb-000012
Figure PCTCN2020112064-appb-000013
按照FDA相关指导原则(Assessing Adhesion With Transdermal and Topical Delivery Systems for ANDAs)，本研究在给药后5分钟内与贴敷给药后2h(±5min)、4h(±5min)、6h(±5min)、8h(±5min)、10h(±5min)、12h(±5min)拍摄透皮贴剂状态的照片，依据五点粘着量表进行粘附性评分。结果表明受试制剂的粘附性整体优于参比制剂，具体结果如下表。
利多卡因改良贴剂T1粘附性评估结果(N＝12)
Figure PCTCN2020112064-appb-000014
利多卡因改良贴剂T2粘附性评估结果(N＝12)
Figure PCTCN2020112064-appb-000015
利多卡因参比制剂R粘附性评估结果(N＝12)
Figure PCTCN2020112064-appb-000016
Figure PCTCN2020112064-appb-000017
虽然为了清楚理解的目的，已经通过说明和实施例较详细地描述了上述公开，但是对一般技术人员来说容易显而易见的是，根据本公开的教导，可以对其进行某些改变和修改而不脱离所附权利要求书的精神或范围。因此，本公开的范围并非意图限于本文所示和描述的示例性实施方案。相反，本公开的范围和精神由所附权利要求书体现。

Claims (32)

  1. 一种经皮吸收的药物组合物，包含皮肤粘附层，其中皮肤粘附层包含：(1)至少一种酰胺类局部麻醉药，(2)第一胺相容的硅酮压敏胶，和(3)第二胺相容的硅酮压敏胶。
  2. 根据权利要求1所述的药物组合物，其为贴剂，优选非水性贴剂。
  3. 根据权利要求1所述的药物组合物，其中所述的皮肤粘附层中的硅酮压敏胶不包含非完全羟基封端的硅酮压敏胶。
  4. 根据权利要求1所述的药物组合物，其中制备第一胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比不低于58:42。
  5. 根据权利要求1所述的药物组合物，其中制备第二胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比低于58:42。
  6. 根据权利要求1所述的药物组合物，其中所述的第一胺相容的硅酮压敏胶选自BIO-PSA7-410X、7-420X中的一种或多种。
  7. 根据权利要求1所述的药物组合物，其中所述的第二胺相容的硅酮压敏胶选自BIO-PSA 7-430X中的一种或多种。
  8. 根据权利要求1所述的药物组合物，其中所述的第一胺相容的硅酮压敏胶选自BIO-PSA 7-420X中的一种或多种，优选7-4202，第二胺相容的硅酮压敏胶选自BIO-PSA 7-430X中的一种或多种，优选7-4302。
  9. 根据权利要求1-8任意一项所述的药物组合物，其中所述的第一胺相容的硅酮压敏胶与第二胺相容的硅酮压敏胶的重量比为0.1:9.9-9.9:0.1，优选9:1-2:8，更优选8:2-4:6。
  10. 根据权利要求1所述的药物组合物，其中皮肤粘附层包含基于皮肤粘附层总重量的：(1)约0.1％-20％，优选约0.5％-10％，更优选0.5％-3.0％的利多卡因游离碱，(2)0.1％至99.9％的胺相容的硅酮压敏胶，其为第一胺相容的硅酮压敏胶和第二胺相容的硅酮压敏胶的组合，其中制备第一胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比不低于58:42，制备第二胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比低于58:42，优选BIO-PSA 7-420X和BIO-PSA 7-430X的组合，重量比为9:1-2:8，优选8:2-4:6。
  11. 根据权利要求10所述的药物组合物，所述的胺相容的硅酮压敏胶为BIO-PSA 7-4202和BIO-PSA 7-4302的组合。
  12. 一种经皮吸收的药物组合物，包含皮肤粘附层，其中皮肤粘附层包含：(1)至少一种酰胺类局部麻醉药，(2)至少一种胺相容的硅酮压敏胶，和(3)溶解剂，其中所述溶解剂选自脂肪酸酯、脂肪醚、油或脂肪族表面活性剂中的一种或多种。
  13. 根据权利要求12所述的药物组合物，其中所述溶解剂选自肉豆蔻酸异丙酯、中链三甘油酸脂、液体石蜡、橄榄油、鲨烯、羊毛脂、十六烷基醚、油烯基醚、月桂基硫酸盐、十二烷基磺酸钠中的一种或多种，优选肉豆蔻酸异丙酯。
  14. 根据权利要求12所述的药物组合物，其中所述的溶解剂的含量占皮肤粘附层总重量的约0.01％-20％，优选0.05％-15％、更优选0.1％-10％。
  15. 根据权利要求12所述的药物组合物，其中所述的皮肤粘附层中的硅酮压敏胶不包含非完全羟基封端的硅酮压敏胶。
  16. 根据权利要求12所述的药物组合物，其中所述酰胺类局部麻醉药与溶解剂的重量比为1:0.1-1:10。
  17. 根据权利要求12所述的药物组合物，其中所述的胺相容的硅酮压敏胶选自完全羟基封端的硅酮压敏胶，优选制备所述胺相容的硅酮压敏胶所采用的硅树脂与硅氧烷聚合物的重量比不低于58:42，更优选所述胺相容的硅酮压敏胶选自BIO-PSA 7-410X、7-420X和7-430X中的一种或多种，更优选7-4101、7-4201、7-4301、7-4102、7-4202和7-4302中的一种或多种。
  18. 根据权利要求1-17任意一项所述的药物组合物，其中皮肤粘附层中的硅酮压敏胶的含量占皮肤粘附层总重量的约0.1％-99.9％，优选10％-99.5％、更优选20％-99％。
  19. 根据权利要求1-17任意一项所述的药物组合物，其中所述药物组合物贴附于皮肤约12小时后药物累积透过百分比不低于约10％，优选不低于约15％，更优选不低于约20％，最优选不低于约22％。
  20. 根据权利要求1-17任意一项所述的药物组合物，其中所述药物组合物贴附于皮肤约12小时后药物累积透过百分比不低于约8％，优选约10小时后、更优选约8小时后，最优选约5小时后药物累积透过百分比不低于约8％。
  21. 根据权利要求19或20所述的药物组合物，其中所述皮肤为猪皮肤，优选猪耳皮。
  22. 根据权利要求1-17任意一项所述的药物组合物，其中所述的酰胺类局部麻醉药选自利多卡因、布比卡因、左旋布比卡因、罗哌卡因、甲哌卡因、吡咯卡因、依那卡因、丙胺卡因或它们的可药用盐，优选利多卡因或其可药用盐。
  23. 根据权利要求1-17任意一项所述的药物组合物，其中所述的酰胺类局部麻醉药的含量为占皮肤粘附层总重量的约0.01％-65％，优选约0.1％-40％，更优选约0.1％-20％，最优选约0.5％-10％。
  24. 根据权利要求1-17任意一项所述的药物组合物，其中所述药物组合物为贴剂，所述的贴剂中酰胺类局部麻醉药的含量为约0.1-1mg/cm 2。
  25. 根据权利要求1-17任意一项所述的药物组合物，根据2015版中国药典第四部通则0952黏附力测定法第一法(初黏力的测定)，所述药物组合物的初黏力为7-23，优选15-22，更优选17-21。
  26. 根据权利要求1-25任意一项所述的经皮吸收的药物组合物，其中所述经皮吸收的药物组合物还包括背衬层和可剥离保护层。
  27. 一种如权利要求1-11任意一项所述的经皮吸收的药物组合物的制备方法，包括将酰胺类局部麻醉药与第一胺相容的硅酮压敏胶和第二胺相容的硅酮压敏胶混合的步骤。
  28. 一种如权利要求12-17任意一项所述的经皮吸收的药物组合物的制备方法，包括将酰胺类局部麻醉药与胺相容的硅酮压敏胶和溶解剂混合的步骤。
  29. 根据权利要求28所述的制备方法，其中将酰胺类局部麻醉药先与溶解剂混合，再与胺相容的硅酮压敏胶混合。
  30. 根据权利要求27-29任意一项所述的制备方法，其中所述制备方法还包括将皮肤粘附层与可剥离保护层和/或背衬层结合的步骤。
  31. 根据权利要求22所述的药物组合物，其中所述的利多卡因或其可药用盐选自盐酸利多卡因、利多卡因游离碱、利多卡因乳酸盐、利多卡因碳酸盐和利多卡因枸橼酸盐等的一种或几种，优选利多卡因游离碱。
  32. 权利要求1-26任意一项所述的经皮吸收的药物组合物在制备 用于镇痛或麻醉的药物中的用途。
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