WO2022063294A1 - 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和用途 - 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和用途 Download PDF

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WO2022063294A1
WO2022063294A1 PCT/CN2021/120939 CN2021120939W WO2022063294A1 WO 2022063294 A1 WO2022063294 A1 WO 2022063294A1 CN 2021120939 W CN2021120939 W CN 2021120939W WO 2022063294 A1 WO2022063294 A1 WO 2022063294A1
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pharmaceutical composition
sensitive adhesive
silicone pressure
composition according
amine
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PCT/CN2021/120939
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English (en)
French (fr)
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罗琳
王祥
邬玉玉
岳晓虹
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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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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

Definitions

  • the invention belongs to the field of pharmacy, and relates to a percutaneously absorbed pharmaceutical composition containing an amide local anesthetic and a preparation method and application thereof.
  • Local anaesthetics are a class of drugs that can reversibly block the generation and transmission of sensory nerve impulses locally. In the case of maintaining consciousness, reversible loss of local tissue pain.
  • the conventional method of administering topical anesthetics is subcutaneous or intradermal injection, which is not only inconvenient to administer but also daunting for patients. It is a new trend of clinical superficial anesthesia to make local anesthetics penetrate into the body through percutaneous administration to produce anesthesia.
  • the transdermal administration products of amide local anesthetics on the market for local anesthesia and analgesia has successively approved lidocaine patches for post-herpetic neuralgia, respectively, the weight content of lidocaine is 5%. lidocaine and 1.8% by weight In the Japanese market, such as Nitto, Youde Pharmaceutical and Nipro have successively launched patch products with lidocaine concentration ranging from 10% to 60%, which are mainly used for superficial surgical operations. Pain relief, such as pain relief during venous indwelling needle puncture, pain relief after infective soft cartilage excision, and pain relief during skin laser irradiation treatment.
  • Silicone pressure sensitive adhesives are composed of polymers and resins with adhesive properties. Medical grade silicone pressure-sensitive adhesive contains low-viscosity dimethylsiloxane polymer (12000 ⁇ 15000cp), and its molecular end contains silanol group; silicone resin has silicate steric structure, and its end contains trimethyl group Siloxy. Silicone pressure sensitive adhesives are prepared by dissolving a resin (eg, a hydroxyl-containing silicone resin) and a polymer (eg, a hydroxyl-containing silicone polymer) in a suitable vehicle. Silicone pressure-sensitive adhesives are known to have advantages over other polymer-based pressure-sensitive adhesives such as acrylic resins, such as being non-irritating and non-sensitizing to the skin, and the like.
  • thermoplastic polyurethane polymer also known as polyurethane rubber
  • polyurethane rubber is a special synthetic rubber, which is a kind of elastomeric polymer material containing more urethane groups (-NHCOO-) in the molecular chain.
  • Plastic processing performance and physical and mechanical properties of rubber with good high elasticity, wear resistance, high adhesion, low temperature resistance, solvent resistance, ozone resistance, shock absorption, radiation resistance, air permeability and good electrical insulation Its products are widely used in many industries.
  • TPU also has functional characteristics such as good chemical stability and biological adaptability, and its usability as a human medical material has been unanimously recognized.
  • WO2019079291 discloses a series of transdermal drug delivery products containing polymeric additives that have acceptable drug release while also providing good adhesion to the skin or other surfaces.
  • the purpose of the present disclosure is to provide a percutaneously absorbed amide-based local anesthetic composition, which can improve the drug release rate and composition rheological properties.
  • a percutaneously absorbed pharmaceutical composition comprising a skin adhesion layer, wherein the skin adhesion layer comprises: (1) at least one amide-based local anesthetic, (2) a silicone pressure-sensitive adhesive, and (3) additives, which are selected from one or more of thermoplastic polyurethane, povidone, and poly(meth)acrylate polymers.
  • the content of the additive may be about 0.01%-40%, preferably 0.05%-15%, more preferably 0.1%-10%, most preferably 0.5% by weight of the total skin adhesive layer. -5%, eg 0.5% or 2.0%.
  • thermoplastic polyurethane and poly(meth)acrylate polymers described do not possess the viscoelastic properties of pressure sensitive adhesives.
  • thermoplastic polyurethane and poly(meth)acrylate polymers do not have the viscous properties of liquids and the elastic properties of solids that both pressure-sensitive adhesives have, and cannot The ability to bond any adherend to a smooth surface immediately with finger pressure alone, or the individual viscoelastic properties of the thermoplastic polyurethane and poly(meth)acrylate polymers are not sufficient to make them suitable for use as pressure. Sensitive glue is used.
  • WO2019079291 describes a series of thermoplastic polyurethane polymers, the disclosure of which is hereby incorporated by reference in its entirety.
  • thermoplastic polyurethane polymer comprises a product obtained by the reaction of:
  • thermoplastic polyurethane polymer has a hard segment content of at least 4 wt% and a soft segment content of at least 90 wt%.
  • the chain extender is selected from the group consisting of 1,4-butanediol, 1,10-decanediol, and combinations thereof.
  • the reactant of the thermoplastic polyurethane polymer satisfies at least one of the conditions:
  • the molecular weight of the first polyether polyol A is at least 4000 Daltons; when present, the molecular weight of the second polyether polyol B is not more than 2000 Daltons;
  • the ratio of the molecular weight of the first polyether polyol to the second polyether polyol is at least 1.4:1;
  • the weight ratio of the second polyether polyol to the first polyether polyol is at least 1:1;
  • the molecular weight of the chain extender is up to 300 Daltons.
  • polyisocyanate is selected from cycloaliphatic and aromatic diisocyanates.
  • thermoplastic polyurethane polymer comprises a product obtained by reacting:
  • a first polyether polyol A comprising poly(ethylene glycol) having an average molecular weight of 7000-9000 Daltons;
  • a second polyether polyol B comprising a polyether copolymer diol with polypropylene glycol and polyethylene oxide segments having an average molecular weight of about 2000 Daltons;
  • the chain extender includes at least one of 1,4-butanediol and 1,10-decanediol, and the polyisocyanate includes dicyclohexylmethane-4,4'-diisocyanate.
  • thermoplastic polyurethane polymer comprises a product obtained by reacting:
  • a second polyether polyol B comprising polyether copolymer diol with polypropylene glycol and polyethylene oxide segments, and having an average molecular weight of 1800-2200 Daltons;
  • thermoplastic polyurethane polymer comprises a product obtained by reacting:
  • thermoplastic polyurethane polymer comprises a product obtained by reacting:
  • one or more additional polymer forming components and optionally, up to 2 wt% catalyst.
  • thermoplastic polyurethane polymer comprises a total of 100 wt % of the reactant reacted product %:
  • one or more additional polymer forming components and optionally up to 2 wt% catalyst.
  • thermoplastic polyurethane polymers include hard segments typically consisting of polyisocyanate and chain extender E, soft segments typically consisting of polyols A and/or B, and optionally a polyisocyanate-linked polyol, typically The middle segment of alcohols A and B is the middle segment. The hardness of the hard segment is greater than that of the soft segment.
  • Exemplary TPUs are the product of a combined reaction of reactants selected from the group consisting of:
  • Polyol A is a polyether polyol and can have an average molecular weight of at least 3000, or at least 4000, or at least 6000 Daltons, and in some embodiments, at most 15,000 Daltons, or at most 12,000 Daltons, or at most 10,000 Dalton.
  • Polyol A may have the general form HO-(R1(R2)O) n - H, where: R1 is selected from C2 - C4 alkyl and mixtures thereof, such as CH2CH or CH2CH2CH , R 2 is selected from H and C 1 -C 2 alkyl groups and mixtures thereof, and n is an integer representing the average number of ether units by weight in each polyol, and wherein n is at least 20.
  • n for polyol A may be at least 60 or at least 100 or at least 150, and may be at most 500 or at most 240.
  • the first polyol B (referred to as polyol B1 for convenience) comprises or consists of at least one average molecular weight not exceeding 2500 Daltons, or not exceeding 2000 or greater than or equal to 1600 Daltons, or no greater than 1200 Daltons, and in some embodiments, at least 800 Daltons, or at least 1000 Daltons, or at least 1200 Daltons.
  • polyol B1 may be of the general form HO-(R1(R2)O) n - H, wherein R1 is selected from C2 - C4 alkyl and mixtures thereof, such as CH2CH or CH2CH2CH , R2 is selected from H and C1 - C2 alkyl groups and mixtures thereof, and n is an integer representing the average number of ether units by weight in each polyol. In one embodiment, at least a portion of the R 2 groups in polyol B1 are not H. In one embodiment, polyol B1 is a copolymer in which some of the R2 groups are H and some of the R2 groups are C1 - C2 alkyl groups.
  • n depends on R1 and R2 to provide a total molecular weight in the desired range.
  • the n value of polyol B1 may be at least 20 or at least 25 or at least 30, and may be as high as 50 or as high as 45.
  • examples of polyols suitable as polyol B1 include copolymers of ethylene oxide and propylene oxide, such as PTMEG, and mixtures thereof.
  • Polyol B (referred to for convenience as Polyol B2) comprises or consists of at least one polyether polyol having a molecular weight of at least 1200 Daltons and/or at most 2500 Daltons.
  • Polyol B2 may have the general form HO-(R 1 O) n -H, where: R 1 is selected from C 2 -C 4 alkyl and mixtures thereof, such as CH 2 CH 2 or CH 2 CH 2 CH 2 , and n is an integer representing the mean value.
  • the ether units have a weight unit of n, where n is at least 20.
  • the n value of polyol B2 depends on the choice of R1 to provide a total molecular weight in the desired range.
  • examples of polyols suitable for use as polyol B2 include polyalkylene ether glycols such as polyethylene glycol (PEG), polytrimethylene glycol, poly(tetramethylene ether) Glycol (PTMG), poly(trimethylene-vinyl ether) glycol (copolymer of polytrimethylene glycol and ethylene glycol) (PTEMG) and mixtures thereof.
  • polyalkylene ether glycols such as polyethylene glycol (PEG), polytrimethylene glycol, poly(tetramethylene ether) Glycol (PTMG), poly(trimethylene-vinyl ether) glycol (copolymer of polytrimethylene glycol and ethylene glycol) (PTEMG) and mixtures thereof.
  • polyol B2 is of polyethylene glycol (eg, molecular weight 1300-1600 Daltons) and poly(tetramethylene ether) glycol (PTMG) (eg, molecular weight 1300-1600 Daltons) mixture.
  • PTMG poly(tetramethylene ether) glycol
  • polyol A is optional and both polyols Bl and B2 are present.
  • polyol A is present, and at least one of polyols Bl and B2 is present.
  • polyol A is absent and at least one of polyols Bl and B2 is present.
  • polyol B1 that contains at least some C1 - C2 alkyl groups as R2.
  • the molecular weight of polyol C may be at least 200 or at least 250 or at least 300 Daltons, and may be as high as 800 or as high as 500 or as high as 400 Daltons.
  • Polyol C may be a polyether of polyols A and B.
  • the value of n depends on the choice of R1 and R2 so as to provide a total molecular weight within the specified range. For example, n is at least 3 or at least 5 or at least 7, and can be up to 20 or up to 12.
  • Suitable hydroxyl-terminated polyether polyols for use as polyols A, B and C are derived from diols or polyols having a total of, for example, 2 to 15 carbon atoms, such as alkyl diols or ethylene glycol, with compounds containing, for example, Ethers of alkylene oxides of 2 to 6 carbon atoms, for example ethylene oxide, propylene oxide or mixtures thereof, or by acid-catalyzed polycondensation.
  • polyether polyols can be prepared by first reacting propylene glycol with propylene oxide and then with ethylene oxide.
  • polyether polyols examples include poly(ethylene glycol) formed by the reaction of ethylene oxide with ethylene glycol, poly(propylene glycol) formed by the reaction of propylene oxide with propylene glycol, ethylene oxide with C3- Copolymers of C12 alkylene oxides, in particular, C3 to C9 alkylene oxides, such as polypropylene glycol), such as copolymers comprising poly(1,2 - propylene glycol) and poly(ethylene oxide) segments
  • Suitable polyether polyols also include polyamide adducts of alkylene oxides, and can include, for example, ethylenediamine adducts formed by the reaction of ethylenediamine with propylene oxide, by the reaction of diethylenetriamine with propylene oxide Diethylenetriamine formed, as well as similar polyamide-type polyether polyols.
  • Copolyethers can also be used in the composition.
  • Typical copolyethers include the reaction products of THF and ethylene oxide or THF and propylene oxide. These are available from BASF, is a block copolymer, is a random copolymer.
  • Exemplary TPU compositions can be made using Chain Extender D.
  • Chain Extender D can be used in addition to or in place of Polyol C.
  • Chain extenders can likewise be polyols, such as C1 - C20 or C1 - C12 , or C2 - C10 alkyl and/or aryl polyols.
  • the molecular weight of the chain extender can be up to 300 Daltons, or up to 250 Daltons, or up to 200 Daltons.
  • Chain extenders include diols, diamines, and combinations thereof.
  • the molecular weight of the chain extender can be up to 500 Daltons or up to 300 Daltons, eg, at least 46 Daltons.
  • One or more short chain polyols having 2 to 20 or 2 to 12, or 2 to 10 or 2-8 carbon atoms can be used as chain extenders in the polyurethane-forming composition to increase the molecular weight of the polyurethane.
  • chain extenders include lower aliphatic polyols and short-chain aromatic diols having a molecular weight of less than 500 or less than 300.
  • Suitable chain extenders include organic diols (including diols) having a total of 2 to 20 carbon atoms, such as alkanediols, cycloaliphatic diiodides, alkylaryldiols, and the like.
  • alkanediols include ethylene glycol, diethylene glycol, 1,3-propanediol, 1,3-butanediol, 1,4-butanediol (BDO), 1,3-butanediol, 1,5-pentanediiodo, 2,2-dimethyl-1,3-propanediol, propylene glycol, dipropylene glycol, 1,6-hexanediol, heptanediol, nonanediol, 1,10-decanediol , dodecanediol, tripropylene glycol, triethylene glycol and 3-methyl-1,5-pentanediol.
  • Suitable cycloaliphatic diols include 1,2-cyclopentanediol and 1,4-cyclohexanedimethanol (CHDM).
  • suitable aryl and alkylaryl diols include hydroquinone bis(2-hydroxyethyl) ether (HQEE), 1,2-dihydroxybenzene, 1,3-dihydroxybenzene, 1,4 -Dihydroxybenzene, 1,2,3-Trihydroxybenzene, 1,2-Bis(hydroxymethyl)benzene, 1,4-Bis(hydroxymethyl)benzene, 1,3-Bis(2-hydroxyethyl) ) benzene, 1,2-bis(2-hydroxyethoxy)benzene, 1,4-bis(2-hydroxyethoxy)benzene, bisethoxybisphenol, 2,2-bis(4-hydroxybenzene) ) propane (i.e.
  • bisphenol A bisphenol A
  • bisphenol A ethoxylate bisphenol F ethoxylate
  • 4,4'-isopropyldienediol 4,4'-isopropyldienediol
  • 2,2-bis[4-(2-hydroxyl) Ethoxy)phenyl]propane (HEPP) and mixtures thereof and the like.
  • Chain extenders with functionality greater than 2 can be used as long as the resulting TPU retains its thermoplastic properties.
  • chain extenders include trimethylolpropane (TMP), glycerol and pentaerythritol.
  • TMP trimethylolpropane
  • glycerol glycerol
  • pentaerythritol glycerol
  • the addition of such chain extenders should not exceed 10% by weight relative to the bifunctional chain extender.
  • the chain extender is selected from 1,4-butanediol and 1,10-decanediol.
  • Chain extenders can also be based on diamines.
  • Exemplary diamines can have molecular weights less than 500 and include, for example, ethylenediamine, diethylenediamine, tetramethylphenylenediamine, hexamethylenediamine, diethylenetriamine, triethylenetetramine, tetramine Ethylenepentamine, pentadienehexamine, piperazine, morpholine, substituted morpholine, piperidine, substituted piperidine, 2-amino-1-ethylpiperazinehydrazine, 1,4-cyclohexanedi Amines and mixtures thereof.
  • Alkanolamines such as ethanolamine, diethanolamine and triethanolamine can also be used.
  • chain extenders include aniline and the like.
  • the molar amount or molar ratio of the total hydroxyl groups of the chain extender(s) used to the total hydroxyl groups of the polyols A, B and C (if present) may be from 0.1 to 5.0, or from 0.2 to 4.0, or from 0.4 to 2.5.
  • Polyisocyanates include one or more polyisocyanates. Suitable polyisocyanates include aromatic diisocyanates, aliphatic diisocyanates and mixtures thereof.
  • difunctional or polyfunctional isocyanates are used.
  • one or more diisocyanates are used.
  • the polyisocyanates useful in the present invention generally have the formula R(NCO)n, wherein n is at least 2.
  • R can be aromatic, cycloaliphatic, aliphatic or a combination thereof having 2 to 20 carbon atoms.
  • aromatic diisocyanates examples include 4,4'-diphenylmethane diisocyanate (MDI), m-xylene diisocyanate (XDI), phenylene 1,4 diisocyanate, naphthalene 1,5 diisocyanate, 2,4 -Toluene diisocyanate (2,4-TDI), 2,6-toluene diisocyanate (2,6-TDI), 1,4-phenylenediisocyanate, 1,3-phenylenediisocyanate, 4,4-diphenylenedi Isocyanate, 3,3-dimethoxy-4,4-biphenyl diisocyanate, 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 4,4-diisocyanate diphenyl Ether, 2,4-naphthalene diisocyanate, 1,5-naphthalene diisocyanate, 1,3-xylene diisocyanate
  • aliphatic diisocyanates examples include 1,4-butane diisocyanate (BDI), tetramethylene ethylene diisocyanate, hexamethylene diisocyanate (HDI), 1,4-cyclohexyl diisocyanate (CHDI), decyl Alkane-1,10-diisocyanate, lysine diisocyanate (LDI)), dicyclohexylmethane-4,4'-diisocyanate (H12MDI), 1,3-diisocyanate methylcyclohexane, 1,4 - Diisocyanate methylcyclohexane, 4,4-diisocyanate dicyclohexane, 4,4-diisocyanate dicyclohexylmethane, isophorone diisocyanate and isomers, dimers, trimers and its mixture.
  • BDI 1,4-butane diisocyanate
  • HDI tetramethylene
  • the isocyanate is selected from cycloaliphatic and aromatic diisocyanates. In one embodiment, the isocyanate is selected from MDI and H12MDI.
  • Suitable polyisocyanates are commercially available, for example, from Bayer Corporation of Pittsburgh, Pennsylvania, BASF Corporation of Parsippany, NJ, The Dow Chemical Company of Midland, Michigan, and Huntsman Chemical Company of Utah.
  • One or more polymerization catalysts may be present during the polymerization reaction.
  • the diisocyanate can be reacted with the polyol intermediate and/or chain extender using any conventional catalyst.
  • Suitable catalysts especially for promoting the reaction between the NCO groups of the diisocyanate and the hydroxyl groups of the polyol and the chain extender include organotin compounds such as dibutyltin diacetate, dibutyltin dilaurate (DBTL), dioctyltin dilaurate (DOTDL) and dibutyldibutyltin (ethoxy-3-mercaptopropionate); titanic acid; organotitanium compounds such as tetraisopropyl titanate, tetra-n-butyl titanate, polyhydroxy titanium stearate and titanium acetylacetonate; tertiary amines such as triethylenediamine, triethylamine, N-methylmorpholine, N,N,N
  • thermoplastic polyurethane examples include thermoplastic polyurethane
  • the thermoplastic polyurethanes described herein have soft segments and hard segments.
  • the soft segment may be derived from at least one of polyols A and B.
  • the hard segment may be derived from a polyisocyanate (or diisocyanate) and at least one of a third polyol (polyol C) and a chain extender D.
  • the TPU includes soft segments derived from a first polyether polyol (polyol A) having a lower molecular weight than polyol A and a second polyether polyol B (eg, at least polyol B1 ).
  • the ratio of the n-value of polyol A to the n-value of polyol B may be at least 1.5:1 or at least 2:1, or at least 3:1, or at least 4:1, and may be at most 20:1 or at most 10:1 1.
  • the molecular weight ratio of polyol A to polyol B may be at least 1.4:1 or at least 2:1, and may be at most 15:1 or at most 10:1 or at most 8:1. Therefore, the soft segments have a bimodal distribution of the average length of the polyether segments.
  • the molar ratio of polyol B to polyol A in the reaction mixture used to form TPU1 may be at least 5:1 or at least 8:1, eg up to 20:1.
  • the weight ratio of polyol B1 to polyol A may be at least 1:1 to 8:1, eg, at least 1.5:1, or at least 8:1.
  • thermoplastic polyurethane TPU1 can be the reaction product of: 20-30 wt% polyol A, 40-70 wt% polyol B (eg B2), 5-20 wt% polyisocyanate, 0.2-5 wt% polyol C, 0 - 5 wt% chain extender, eg at least 0.2 wt%, optionally one or more additional polymer forming components, and optionally up to 2 wt% catalyst (total 100 wt%).
  • the combination of polyols A and B may comprise at least 60 wt% or at least 70 wt% of the total weight of the polymer-forming components in the reaction mixture. In this embodiment, the molecular weight of Polyol B may not exceed 2500 Daltons.
  • the weight average molecular weight of TPU1 may be 50,000 to 1,000,000 Daltons, or 75,000 to 500,000 Daltons, or 100,000 to 300,000 Daltons.
  • the TPU (denoted as TPU2) is as described for TPU1 but contains polyol A but no polyol B (or only a small amount, eg up to 5 wt%). It may further include polyol C.
  • thermoplastic polyurethane TPU2 is the reaction product of: 70-90 wt% Polyol A, 5-20 wt% Polyisocyanate, 0-15 wt% Polyol C, 0-10 wt% Chain Extender, optionally, one or Various additional polymer-forming components, and optionally up to 2 wt% catalyst (100 wt% total).
  • TPU3 is as described for TPU1 but includes polyol B but not polyol A (or no more than 5 wt% polyol A).
  • TPU3 includes soft segments derived from at least one polyether polyol B, such as at least two polyether polyols B of similar molecular weight but with different R groups, such as B1, where R can be H and C1- A mixture of C2 alkyl and B2.
  • thermoplastic polyurethane TPU3 can be the reaction product of: 30-90wt% polyol B, 5-50wt% polyisocyanate, 0-5wt% polyol C, 0-20wt% chain extender, optionally, a or more additional polymer-forming components, and optionally up to 2 wt% catalyst (100 wt% total).
  • the weight average molecular weight of the TPU3 may be 50,000 to 1,000,000 Daltons, or 75,000 to 500,000 or 100,000 to 300,000 Daltons.
  • the thermoplastic polyurethane can also be a blend of two or more of TPU1, TPU2 and TPU3.
  • the weight ratio of TPU1:TPU2 and/or TPU3 may be at least 1:2. In one embodiment, the ratio is at least 1:1.5, or at least 1:1, or at least 2:1, and can be as high as 100:1, or higher, such as at most 20:1, or at most 10:1.
  • TPUs examples include TPU-EX1452, TPU-TMPT75AS450, TPU-HP-93A-100, TPU-Tecoflex SG-85, and the like, such as TPU-TMPT75AS450.
  • the content of TPU in the skin adhesion layer may be about 0.1% to 80%, such as 0.1% to 40%, such as 0.5% to 30%, such as 0.5% to 15%, such as 2.0%, based on the total weight of the skin adhesion layer. %.
  • poly(meth)acrylate polymer is meant that the skin adhesive layer may comprise at least one polymethacrylate and/or polyacrylate polymer. It can be derived from a mixture based on methacrylic acid and acrylic acid monomers, allowing the polymer to behave differently than pressure sensitive adhesives.
  • Functional poly(meth)acrylate polymers are homopolymers, copolymers or terpolymers that contain monomeric units with free functional groups and may also be present with other non-functional monomeric units such as (methyl) Acrylates or (meth)acrylamides. Monomers can be monofunctional or polyfunctional. These functional groups include carboxyl, hydroxyl, amino, amide, epoxy, and the like.
  • Polymerizable functional monomers include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate esters, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate And other monomers with at least one unsaturated double bond involved in the copolymerization reaction in the molecule, as well as functional groups on its side chain, such as carboxyl, hydroxyl, mercapto, amino, pyrrolyl and alkoxyl groups.
  • Further examples include monomers having at least one of the following moieties: alkylene, hydroxy substituted alkylene, carboxylic acid substituted alkylene, vinyl alkanoate, vinylpyrrolidone, vinylpyridine, vinylpyridine oxazine, vinylpyrrole, vinylimidazole, vinylcaprolactam, vinyloxazole, vinyl acetate, vinyl propionate and vinylmorpholine.
  • carboxyl functional monomers include acrylic acid, methacrylic acid, itaconic acid, maleic acid and crotonic acid.
  • Exemplary hydroxy-functional monomers include 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethyl acrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxy acrylate Propyl, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate, hydroxypentyl acrylate, hydroxyhexyl methacrylate, hydroxyhexyl acrylate.
  • These functional monomers can be copolymerized with non-functional (meth)acrylic acid alkyl esters and (meth)acrylic acid alkyl amides.
  • the poly(meth)acrylate polymer is selected from poly(butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate) ; poly(methacrylic acid - methyl methacrylate); poly(ethyl acrylate - methyl methacrylate - trimethylaminoethyl methacrylate); poly(methyl methacrylate - methyl methacrylate) ester); one or more of poly(methacrylic acid-ethyl acrylate).
  • the poly(meth)acrylate polymer is selected from poly(ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate (1:2:0.2) ), poly(butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate (1:2:1)), and poly(ethyl acrylate-methyl methacrylate) - one or more of trimethylaminoethyl methacrylate chloride (1:2:0.1)).
  • the poly(meth)acrylate polymer is selected from poly(ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate (1:2:0.2) ).
  • poly(meth)acrylate polymers include, but are not limited to PO, RL100, RL PO, RL30, RS100, RS PO, RS30, NE 30 and One or more of FS 30. E.g RL100 and One or more of RS100.
  • povidones examples include, but are not limited to, PVP K12, PVP K17, PVP K25, PVP K30, PVP K85, PVP K90, such as PVP K90.
  • the additives of the present disclosure may also be selected from aluminum acetylacetonate (ACAL).
  • ACAL aluminum acetylacetonate
  • the additives of the present disclosure are selected from one or more of thermoplastic polyurethanes, povidones, poly(meth)acrylate polymers, and aluminum acetylacetonate.
  • the content of the active ingredient amide-based local anesthetics described in the present disclosure is about 0.01%-65% of the total weight of the skin adhesion layer, such as about 0.1%-40%, preferably about 0.1%- 20%, more preferably about 0.5%-10%, such as 1.2%, 1.25%, 1.5%, 2.5% or 5%.
  • the pharmaceutical compositions described in the present disclosure are patches, preferably non-aqueous patches.
  • the content of the amide-based local anesthetic in the patch of the present disclosure may be about 0.1-1 mg/cm 2 , preferably 0.1-0.7 mg/cm 2 , such as 0.13 mg/cm 2 , 0.15 mg /cm 2 , 0.16 mg/cm 2 or 0.19 mg/cm 2 .
  • the patches of the present disclosure include a backing layer and a peelable protective layer (eg, a release film).
  • a peelable protective layer eg, a release film.
  • One surface of the backing layer is directly connected with the polymer matrix layer, and the backing layer plays the role of protecting the contact between the polymer matrix layer and the surrounding environment and preventing the loss of the drug during use.
  • 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
  • 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 eg release film
  • the peelable protective layer is connected with the other side of the polymer matrix layer, such as ScotchpakTM 9744, 9742, 1020, 1022, 9744, 9755, 9741, 9709 and so on from 3M Company. Before using the patch, the protective film needs to be removed.
  • Most patches will typically use a relatively large volume of adhesive layer to hold a large amount of drug in the adhesive layer.
  • components of the adhesive layer tend to overflow (ie, cold flow) from the edges of the adhesive patch and cause problems in adhering to the skin layer.
  • the occurrence of cold flow depends on the properties of the adhesive.
  • Adverse effects of cold flow include, for example, poor removal of the patch product from the package (caused by sticking of the protruding adhesive layer components to the interior of the package), sticking to clothing, during sticking to the skin Patch products are warped and colored, and adhesive patches with medicinal properties are less effective.
  • the pharmaceutical compositions described in the present disclosure have improved rheological properties and good drug release rates.
  • the amide-based local anesthetic structures of the present disclosure comprise a lipophilic moiety and a hydrophilic moiety linked by a -NHCO- bond near the center of the molecule.
  • Suitable amide-type local anesthetics include, but are not limited to, lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrocaine, enacaine, prilocaine, or the like.
  • the content of the silicone pressure sensitive adhesive in the skin adhesive layer may be about 10% to 99.9%, such as 30% to 99.5%, such as 40% to 99%, based on the total weight of the skin adhesive layer. %, such as 60% to 99%, eg 95.0%, 95.5%, 96.3%, 96.55%, 96.60%, 97.8%, 98.5% or 98.8%.
  • the amount of pressure sensitive adhesive in the composition is 70% by weight or more, such as 75% by weight or more, such as 80% by weight or more, such as 85% by weight, based on the total weight of the composition or more, such as 90% by weight or more, such as 95% by weight or more, such as 97% by weight or more, such as 95.0%, 95.5%, 96.3%, 96.55%, 96.60%, 97.8%, 98.5% or 98.8%).
  • the silicone pressure-sensitive adhesive generally includes a linear siloxane polymer and is composed of triorganosiloxane (M) units (ie, R3SiOi/2 units, where R represents a monovalent organic group) and MQ silicone resin composed of silicate (Q) units (ie SiO-t/a units).
  • M triorganosiloxane
  • Q silicate
  • silicone pressure sensitive adhesives examples include BIO-PSA silicone pressure sensitive adhesives produced by Dow Corning, such as BIO-PSA7-4102, BIO-PSA7-4202, BIO-PSA7-4301, BIO-PSA7-4302, BIO-PSA7-4503 , BIO-PSA7-4560, etc.
  • BIO-PSA7-4102 BIO-PSA7-4102
  • BIO-PSA7-4202 BIO-PSA7-4202
  • BIO-PSA7-4301 BIO-PSA7-4301
  • BIO-PSA7-4302 BIO-PSA7-4503
  • BIO-PSA7-4560 examples include BIO-PSA7-4560, etc.
  • BIO-PSA7-4202 BIO-PSA7-4302.
  • the silicone pressure sensitive adhesive comprises an 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-based local anesthetics, such as amino groups.
  • the silicone pressure sensitive adhesive in the skin adhesive layer does not comprise an amine incompatible silicone pressure sensitive adhesive.
  • the hydroxyl groups in the amine-compatible silicone pressure sensitive adhesives described in the present disclosure are fully capped with groups such as trimethylsilyl (TMS)-type groups.
  • the silicone pressure sensitive adhesive in the skin adhesion layer described in the present disclosure does not comprise a non-fully hydroxyl terminated silicone pressure sensitive adhesive.
  • the silicone pressure sensitive adhesive comprises a first amine compatible silicone pressure sensitive adhesive and a second amine compatible silicone pressure sensitive adhesive.
  • the weight ratio of silicone resin to silicone polymer used to prepare the first amine-compatible silicone pressure sensitive adhesive is not less than 58:42, for example, it may be 60:40 or 65:35 .
  • the weight ratio of silicone resin to silicone polymer used to prepare the second amine compatible silicone pressure sensitive adhesive is less than 58:42, for example, it may 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 9:1-2:8, more preferably 8:2-4:6 or 9:1-7:3, eg 8:2, 7:3, 6:4, 5:5 or 4:6, most preferably 8 :2-7:3.
  • 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 The weight ratio of silicone resin to silicone 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 tack silicone pressure sensitive adhesive and at least one high tack silicone pressure sensitive adhesive.
  • the first amine-compatible silicone pressure-sensitive adhesive in the pharmaceutical composition is a medium-tack 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 9:1-2: 8, more preferably 8:2-4:6 or 9:1-7:3, eg 8:2, 7:3, 6:4, 5:5 or 4:6, most preferably 8:2-7:3 .
  • Increasing the proportion of medium viscosity silicone pressure sensitive adhesives is beneficial to improve the rheological properties of the composition.
  • preferred amine compatible silicone pressure sensitive adhesives include at least one BIO-PSA silicone pressure sensitive adhesive from DowCorning, eg, BIO-PSA7-410X, BIO-PSA7-420X, BIO-PSA7 -430X etc., eg 7-4101, 7-4201, 7-4301, 7-4102, 7-4202 and 7-4302 etc.
  • X represents different solvents in the pressure-sensitive adhesive, such as 1 for n-heptane, 2 for ethyl acetate, etc.
  • the silicone pressure sensitive adhesive is a combination of BIO-PSA7-420X and BIO-PSA7-430X, preferably a combination of BIO-PSA7-4202 and BIO-PSA7-4302.
  • BIO-PSA silicone pressure-sensitive adhesive The relevant parameters of BIO-PSA silicone pressure-sensitive adhesive are as follows (from the product manual of BIO-PSA silicone pressure-sensitive adhesive of DowCorning):
  • the pressure-sensitive adhesive generally has a viscosity of about 0.1 Pa ⁇ s to 30,000 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-PSA7-410X and BIO-PSA7-420X.
  • the second amine-compatible silicone pressure-sensitive adhesive is selected from one or more of BIO-PSA7-430X.
  • the first amine-compatible silicone pressure-sensitive adhesive is selected from one or more of BIO-PSA7-420X, preferably 7-4202
  • the second amine-compatible silicone pressure-sensitive adhesive is selected from one or more of BIO-PSA7-420X, preferably 7-4202
  • the sensitive adhesive is selected from one or more of BIO-PSA7-430X, preferably 7-4302.
  • compositions described in the present disclosure may also contain other types of pressure-sensitive adhesives, which may be, for example, silicones, polyisobutylene and its derivatives, acrylic resins, natural rubber, natural and synthetic Butene and polyisobutylene, styrene/butadiene polymers, styrene-isoprene-styrene block polymers, hydrocarbon polymers such as butyl rubber, halogenpolyvinylchloride, polyvinylidene Vinyl chloride and polychlorodiene, and combinations thereof.
  • silicone pressure-sensitive adhesives can achieve more drug release by carrying relatively small amounts of active substances.
  • the pharmaceutical compositions described in the present disclosure may also contain other excipients, such as dissolving agents, antioxidants, plasticizers, tackifiers, fillers, cross-linking agents, crystallization inhibitors, and penetration enhancers Wait.
  • excipients such as dissolving agents, antioxidants, plasticizers, tackifiers, fillers, cross-linking agents, crystallization inhibitors, and penetration enhancers Wait.
  • Dissolving agents or penetration enhancers described in this 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, For example 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, methyl octyl sulfoxide, dimethyl lauramide, dodecyl pyrrolidone, isosorbide, dimethyl acetal, dimethyl sulfoxide, decyl salicylic acid; amino acids; benzyl nicotinate; aliphatic surfactants such as lauryl sul
  • solubilizing agents include oleic and linoleic acids, ascorbic acid, pantothenic acid, butylated hydroxytoluene, tocopherol, tocopheryl 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, diadipate isopropyl ester, etc.), oils (liquid paraffin, olive oil, squalene and lanolin, etc.); fatty ethers (hexadecyl ether, oleyl ether, etc.) and aliphatic surfactants (lauryl sulfate, ten Sodium dialkyl sulfonate, etc.).
  • fatty acid esters isopropyl myristate, medium chain triglycerides, methyl laurate, diadipate isopropyl ester, etc.
  • oils liquid paraffin, olive oil, squalene and lanolin, etc.
  • fatty ethers hexadecyl ether, oleyl ether, etc.
  • Plasticizers described in this 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, benzofuran-indene resins, petroleum-based resins, terpene-phenolic resins, xylene resins, and the like.
  • Antioxidants described in this disclosure include, but are not limited to, tea polyphenols (TP), tocopherols, flavonoids, butylated hydroxyanisole (BHA), dibutylhydroxytoluene (BHT), tert-butylhydroquinone (TBHQ) and the like, such as dibutylhydroxytoluene (BHT).
  • TP tea polyphenols
  • BHA butylated hydroxyanisole
  • BHT dibutylhydroxytoluene
  • TBHQ tert-butylhydroquinone
  • compositions described herein may also contain antioxidants.
  • the pharmaceutical composition comprises a skin-adhesive layer, wherein the skin-adhesive layer comprises, based on the total weight of the skin-adhesive layer:
  • amine-compatible silicone pressure-sensitive adhesive which is a combination of a first amine-compatible silicone pressure-sensitive adhesive and a second amine-compatible silicone pressure-sensitive adhesive, wherein the first amine-compatible silicone pressure-sensitive adhesive is prepared
  • the weight ratio of the silicone resin and the siloxane polymer used in the first amine compatible silicone pressure sensitive adhesive is not less than 58:42, and the silicone resin and the silicone resin used in the preparation of the second amine compatible silicone pressure sensitive adhesive
  • the weight ratio of oxane polymer is lower than 58:42, preferably the combination of BIO-PSA7-420X and BIO-PSA7-430X, the weight ratio is 9:1-2:8, preferably 8:2-4:6 or 9: 1-7:3, more preferably 8:2-7:3;
  • additives selected from thermoplastic polyurethane, povidone, poly(butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate); poly(methacrylic acid-methyl methacrylate); poly(ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate); poly(methyl methacrylate-methyl methacrylate) ); one or more of poly(methacrylic acid-ethyl acrylate);
  • the pharmaceutical composition comprises a skin-adhesive layer, wherein the skin-adhesive layer comprises, based on the total weight of the skin-adhesive layer: (1) about 0.1%-20%, preferably about 0.5%-10% % lidocaine free base; (2) 60% to 99% amine compatible silicone pressure sensitive adhesive, which is a first amine compatible silicone pressure sensitive adhesive and a second amine compatible silicone pressure sensitive adhesive; A combination of sensitive adhesives, wherein the weight ratio of the silicone resin to the 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 the silicone resin used in the glue to the siloxane polymer is lower than 58:42, preferably the combination of BIO-PSA7-420X and BIO-PSA7-430X, the weight ratio is 9:1-2:8, preferably 8: 2-4:6 or 9:1-7:3, more preferably 8:2-7:3; (3) 0.1%-10% additives, selected from thermoplastic polyurethane, povidone, aluminum acetylacetonate, poly( Butyl methacrylate-(2-dimethylaminoethyl)methacrylate-methyl methacrylate); poly(methacrylic acid-methyl methacrylate); poly(ethyl acrylate-methacrylic acid) Methyl methacrylate-trimethylaminoethyl methacrylate); poly(methyl methacrylate-methyl methacrylate); one or more of poly(methacrylic acid-ethyl acrylate); (4 ) optional 0.01%-10% antioxidant.
  • the amine compatible silicone pressure sensitive adhesive is a combination of BIO-PSA7-4202 and BIO-PSA7-4302.
  • the poly(meth)acrylate polymer is selected from poly(butyl methacrylate-(2-dimethylaminoethyl) methacrylate-methyl methacrylate) ; poly(methacrylic acid - methyl methacrylate); poly(ethyl acrylate - methyl methacrylate - trimethylaminoethyl methacrylate); poly(methyl methacrylate - methyl methacrylate) ester); one or more of poly(methacrylic acid-ethyl acrylate).
  • Tack has been defined as the property that allows a pressure sensitive adhesive to form a bond with the surface of another substance under light pressure and brief contact.
  • the moderate tack of silicone pressure-sensitive adhesives indicates that rapid adhesion to another surface is weaker than that of high-tack silicone pressure-sensitive adhesives.
  • Definite tack values for the silicone pressure sensitive adhesives of 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 penetration percentage after the pharmaceutical composition is attached 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%, not less than about 12% about 13%, no less than about 14%, no less than about 15%, no less than about 16%, no less than about 17%, no less than about 18%, no less than about 19%, no less than about 20%, no less than about 21%, no less than about 22%, no less than about 23%, no less than about 24%, no less than about 25%, no less than about 26%, no less than about 27% %, no less than about 28%, no less than about 29%, no less than about 30%, preferably no less than about 15%, more preferably no less than about 20%, most preferably no less than about 25%.
  • the pharmaceutical composition is adhered to the skin for about 12 hours after the cumulative drug penetration percentage is not less than about 8%, for example, about 11.5, 11, 10.5, 10, 9.5, 9, After 8.5, 8, 7.5, 7, 6.5, 6, 5.5 or 5 hours, the cumulative drug penetration percentage is not less than 8%, preferably after about 10 hours, more preferably after about 8 hours, most preferably after about 5 hours. The over percentage is not less than about 8%.
  • the skin to which the pharmaceutical composition is attached is pig skin, preferably pig back skin.
  • Another aspect of the present disclosure provides a method for preparing the percutaneously absorbed pharmaceutical composition of the present disclosure, the method comprising the steps of mixing an amide-based local anesthetic with a silicone pressure-sensitive adhesive and additives.
  • the method for preparing a transdermal pharmaceutical composition described in the present disclosure further comprises the step of combining the skin-adhesive layer with the peelable protective layer and/or the backing layer.
  • the method of combining the skin adhesive layer with the peelable protective layer and the backing layer can be a conventional method in the art, such as transfer coating, the skin adhesive layer is coated on the release film, and the backing is covered after drying. .
  • Another aspect of the present disclosure provides use of the percutaneously absorbed pharmaceutical composition of the present disclosure for analgesia or anesthesia.
  • the term "about” means that quantities, dimensions, formulations, parameters, and other quantities and characteristics are imprecise and need not be exact, but can be approximations and/or greater or lesser than desired, thereby reflecting tolerances , conversion factors, rounding, measurement error, etc., as well as other factors known to those skilled in the art.
  • the meaning may include a change of ⁇ 10%, preferably a change of ⁇ 5%.
  • Fig. 1 is the experimenter's mean drug time curve diagram of embodiment 13;
  • Fig. 2 is the subject's mean drug time curve diagram of embodiment 19;
  • Figure 3 is a comparative example of cold flow pictures
  • FIG. 4 is a picture of cold flow in Example 8.
  • FIG. 4 is a picture of cold flow in Example 8.
  • Backing layer Shanghai Yingfa 3201 polyethylene terephthalate backing, 3302 polypropylene backing, 3301 polypropylene backing, or 4202 polypropylene covered non-woven backing;
  • Release film Shanghai Yingfa 2301 coated fluorine release film.
  • This study adopted a single-center, randomized, open-label, three-cycle, cross-controlled trial design with a single-dose study.
  • the administration area of both the test preparation and the reference preparation was 420 cm 2 (ie, 3 patches), the application time was 12 hours, and the cleaning period during the cycle was 5 days.
  • the blood collection time points were: 0 hours before administration (within 1 hour before administration) and 0.5, 2, 4, 6, 8, 10, 11, 12, 13, 15, 18, 24, 30, 36 and 48 hours after administration .
  • the random sequence for the grouping of subjects is as follows:
  • Test preparation T1 preparation of Example 1, specification: 27mg/tablet, 10 ⁇ 14cm;
  • Test preparation T2 preparation of Example 3, specification: 21.6 mg/tablet, 10 ⁇ 14 cm;
  • Reference preparation R commercially available lidocaine patch (trade name: ), specification: 700mg/tablet, 10 ⁇ 14cm, produced by Endo Pharmaceuticals Inc.
  • Embodiment 14-16, comparative example 1-5 preparation of lidocaine patch
  • Backing layer Backing 3M company ScotchPak9738
  • Release film release film 3M company ScotchPak9709
  • Each patch composition was prepared according to the method of Example 1.
  • the above-mentioned embodiment patch was cut into a circle with a diameter of 2.0 cm, and each patch was cut into 4 discs, which were respectively attached to 4 pieces of pigskin cuticle, and the receiving pool was filled with PBS buffer (5.5 ml of pH 7.4). ), dry heating at 32 degrees Celsius, sample 2.5 ml from the receiving tank at a preset time point, and add the same amount of the same PBS buffer solution to the receiving tank at the same time.
  • PBS buffer 5.5 ml of pH 7.4
  • Q represents the cumulative permeation per unit area
  • Ci represents the drug concentration in the receiving chamber at different time points
  • A is the effective skin area (the cumulative permeation per unit area of each patch is expressed as the average of 4 channels)
  • Cumulative permeation percentage cumulative permeation amount/administration amount (the cumulative permeation percentage of each patch is expressed as the average of 4 channels)
  • This study adopted a single-center, randomized, open-label, three-cycle, cross-controlled trial design with a single-dose study.
  • the administration area of both the test preparation and the reference preparation was 420 cm 2 (ie, 3 patches), the application time was 12 hours, and the cleaning period during the cycle was 5 days.
  • the blood collection time points were: 0 hours before administration (within 1 hour before administration) and 0.5, 2, 4, 6, 8, 10, 11, 12, 13, 15, 18, 24, 30, 36 and 48 hours after administration .
  • the random sequence for the grouping of subjects is as follows:
  • Test preparation T1 preparation of Example 11, specification: 22.5 mg/tablet, 10 ⁇ 14 cm;
  • Test preparation T2 preparation of Example 11, specification: 18 mg/tablet, 10 ⁇ 14 cm;
  • Reference preparation R commercially available lidocaine patch (trade name: ), specification: 700 mg/tablet, 10 ⁇ 14 cm, produced by Endo Pharmaceuticals Inc.
  • Example 11 was packaged in an aluminum-plastic bag, set out under accelerated conditions (40° C./75% RH), and the impurity content of the sample was investigated at 0 days and 1 month, respectively, as described in the following table.
  • Pressure-sensitive adhesive DURO TAK acrylic pressure-sensitive adhesive 4098, 2287, 2852, 2677 produced by Henkel;
  • Backing layer Backing 3M company ScotchPak9738
  • Release film release film 3M company ScotchPak9709
  • Each patch composition was prepared according to the method of Example 1, and the skin penetration amount of the drug was tested according to the method of Example 17, as shown in the following table.
  • the lidocaine patch formulation (4% lidocaine, acrylic pressure sensitive adhesive 87-2516 and TPU1-1 (mass ratio 1:1), 0.5% polysorbate 80 and 0.5% propylene glycol) is disclosed in Example 23 of WO2019079291 , According to the method of Example 13, the content and cumulative percentage of permeated drug per unit area of the patch were determined, as described in the following table.

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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和用途，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、硅酮压敏胶及添加剂，所述药物组合物具有改进的释放特性和流变性质。

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和用途
本申请要求申请日为2020年9月28日的中国专利申请202011040778.7、2021年6月7日的中国专利申请202110631792.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于制药领域，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和用途。
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 PCTCN2021120939-appb-000001
以及重量含量为1.8％的
Figure PCTCN2021120939-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。
热塑性聚氨酯(thermoplastic polyurethane polymer,TPU)又称聚氨酯橡胶，它属于特种合成橡胶，是一类在分子链中含有较多氨基甲酸酯基团(-NHCOO-)的弹性体聚合物材料，兼有塑料加工工艺性能和橡胶的物理机械特性，具有良好的高弹性、耐磨性、高粘结性、耐低温性、耐溶剂性、耐臭氧、吸震、抗辐射、耐透气性以及良好的电绝缘性等，可采用挤出、注塑、吹膜、压延、纺丝等加工方法，其制品广泛应用于许多行业。TPU也具有 良好化学稳定性、生物适应性等功能特点，作为人体医疗用材料其可用性已得到一致认可。
WO2019079291公开了一系列含有聚合物添加剂的经皮给药产品，其具有可接受的药物释放，同时还提供对皮肤或其他表面的良好粘附性。
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，改善药物的释放率和组合物流变性质。
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)硅酮压敏胶，和(3)添加剂，所述添加剂选自热塑性聚氨酯、聚维酮、聚(甲基)丙烯酸酯聚合物中的一种或多种。
在某些实施方式中，所述的添加剂的含量可以是占皮肤粘附层总重量的约在0.01％-40％，优选0.05％-15％、更优选0.1％-10％，最优选0.5％-5％，例如0.5％或2.0％。
所述的热塑性聚氨酯和聚(甲基)丙烯酸酯聚合物不具有压敏胶的粘弹性。
本公开所述的不具有压敏胶的粘弹性是指所述的热塑性聚氨酯和聚(甲基)丙烯酸酯聚合物不具有压敏胶均同时具备的液体的粘性性质和固体的弹性性质，不能仅采用指能压力就能使立即具备粘接任何被粘物光洁表面的能力，或所述的热塑性聚氨酯和聚(甲基)丙烯酸酯聚合物各自单独的粘弹性等性质不足以使其作为压敏胶使用。
WO2019079291描述了一系列热塑性聚氨酯聚合物，本公开在此全部引用。
在某些实施方式中，所述的热塑性聚氨酯聚合物包含通过以下物质反应所得的产物：
(i)至少以下之一：
a)分子量至少为3000道尔顿的第一聚醚多元醇A，和b)分子量不大于2500道尔顿的第二聚醚多元醇B；
(ii)至少以下之一：
c)分子量最多800道尔顿的第三种多元醇C.
d)扩链剂；
(iii)多异氰酸酯；和
(iv)任选地，催化剂。
在某些实施方式中，所述热塑性聚氨酯聚合物具有至少4wt％的硬链段含量和至少为90wt％的软链段含量。
在某些实施方式中，所述扩链剂选自1,4-丁二醇，1,10-癸二醇及其组合。
在某些实施方式中，所述热塑性聚氨酯聚合物的反应物满足其中至少一个条件：
1)第一聚醚多元醇A的分子量至少为4000道尔顿；当存在时，第二聚醚多元醇B的分子量不超过2000道尔顿；
2)当存在第二聚醚多元醇时，第一聚醚多元醇与第二聚醚多元醇的分子量之比至少为1.4：1；
3)当存在第二聚醚时，第二聚醚多元醇与第一聚醚多元醇的重量比为至少1：1；和
4)扩链剂的分子量最多300道尔顿。
在某些实施方式中，其中多异氰酸酯选自脂环族和芳族二异氰酸酯。
在某些实施方式中，其中所述热塑性聚氨酯聚合物包含通过以下物质反应所得的产物：
(i)第一聚醚多元醇A，其包含平均分子量为7000-9000道尔顿的聚(乙二醇)；
(ii)第二聚醚多元醇B，其包含聚醚共聚物二醇与聚丙二醇和聚环氧乙烷链段，平均分子量为约2000道尔顿；
(iii)第三多元醇和扩链剂中的至少一种；和
(iv)多异氰酸酯，
其中扩链剂包含1,4-丁二醇和1,10-癸二醇中的至少一种，多异氰酸酯包括二环己基甲烷-4,4'-二异氰酸酯。
在某些实施方式中，其中所述热塑性聚氨酯聚合物包含通过以下物质反应所得的产物：
(i)任选地，第一聚醚多元醇A；
(ii)第二聚醚多元醇B，其包含聚醚共聚物二醇与聚丙二醇和聚环氧乙烷链段，平均分子量为1800-2200道尔顿；
(iii)扩链剂；和
(iv)多异氰酸酯。
在某些实施方式中，其中所述热塑性聚氨酯聚合物包含通过以下物质反应所得的产物：
20-30wt％多元醇A；
40-70wt％多元醇B；
5-20wt％多异氰酸酯；
0.2-5wt％多元醇C；
0-5wt％扩链剂；
任选地，一种或多种另外的聚合物形成组分；
任选地最多2wt％的催化剂。
在某些实施方式中，其中所述热塑性聚氨酯聚合物包含通过以下物质反应所得的产物：
70-90wt％多元醇A；
不超过5wt％多元醇B；
5-20wt％多异氰酸酯；
0-15wt％多元醇C；
0-10wt％扩链剂；
任选地，一种或多种另外的聚合物形成组分；并且任选地，最多2wt％催化剂。
在某些实施方式中，其中所述热塑性聚氨酯聚合物包含总计100wt％的反应物反应所得的产物％：
不超过5wt％多元醇A；
30-90wt％多元醇B；
5-50wt％多异氰酸酯；
0-5wt％多元醇C；
0-20wt％扩链剂；
任选地，一种或多种另外的聚合物形成组分，和任选地最多2wt％催化剂。
示例性热塑性聚氨酯聚合物(或TPU)包括通常由多异氰酸酯和扩链剂E组成的硬链段，通常由多元醇A和/或B组成的软链段以及任选的通常是多异氰酸酯连接多元醇A和B的中间链段中间链段。硬链段的硬度大于软链段的硬度。
除非另有说明，否则本文提及的所有分子量均为重均分子量，并以道尔顿表示。
示例性的TPU是选自以下反应物的组合反应所得的产物：
a.多元醇A
多元醇A是聚醚多元醇并且可以具有至少3000，或至少4000或至少6000道尔顿的平均分子量，并且在一些实施方案中，至多15,000道尔顿，或至多12,000道尔顿，或至多10,000道尔顿。
多元醇A可以具有一般形式HO-(R 1(R 2)O) n-H，其中：R 1选自C 2-C 4烷基及其混合物，例如CH 2CH或CH 2CH 2CH，R 2选自H和C 1-C 2烷基及其混合物，并且n是整数，其表示每种多元醇中按重量计的醚单元的平均数目，并且其中n为至少20。
多元醇A的n值可以是至少60或至少100或至少150，并且可以至多500或至多 240。
b.多元醇B
在一个实施方案中，第一多元醇B(为方便起见称为多元醇B1)包括或由至少一种平均分子量不超过2500道尔顿，或不超过2000或大于或等于1600道尔顿，或不大于1200道尔顿，并且在一些实施方案中，至少800道尔顿，或至少1000道尔顿，或至少1200道尔顿。在该实施方案中，多元醇B1可以是一般形式的HO-(R 1(R 2)O) n-H，其中R 1选自C 2-C 4烷基及其混合物，例如CH 2CH或CH 2CH 2CH，R 2选自H和C 1-C 2烷基及其混合物，并且n是整数，其表示每种多元醇中按重量计的醚单元的平均数目。在一个实施方案中，多元醇B1中的R 2基团的至少一部分不是H。在一个实施方案中，多元醇B1是其中一些R 2基团为H且一些R2基团为C1-C 2烷基的共聚物。n的值取决于R 1和R 2，以提供所需范围内的总分子量。在该实施方案中，多元醇B1的n值可以为至少20或至少25或至少30，并且可以高达50或高达45。在该实施方案中，适合作为多元醇B1的多元醇的实例包括环氧乙烷和环氧丙烷的共聚物，例如PTMEG，及其混合物。
在另一个实施方案中，多元醇B(为方便起见称为多元醇B2)包括或由至少一种分子量为至少1200道尔顿和/或至多2500道尔顿的聚醚多元醇组成。多元醇B2可以具有HO-(R 1O) n-H的一般形式，其中：R 1选自C  2-C  4烷基及其混合物，例如CH 2CH 2或CH 2CH 2CH 2，并且n是代表平均值的整数。在每种多元醇中，醚单元的重量单位为n，其中n至少为20。在该实施方案中，多元醇B2的n值取决于R 1的选择，以提供期望范围内的总分子量。
在该实施方案中，适合用作多元醇B2的多元醇的例子包括聚亚烷基醚二醇，例如聚乙二醇(PEG)，聚三亚甲基二醇，聚(四亚甲基醚)二醇(PTMG)，聚(三亚甲基-乙烯醚)二醇(聚三亚甲基二醇和乙二醇的共聚物)(PTEMG)及其混合物。
在一个实施方案中，多元醇B2是聚乙二醇(例如，分子量1300-1600道尔顿)和聚(四亚甲基醚)二醇(PTMG)(例如分子量1300-1600道尔顿)的混合物。
在一个实施方案中，多元醇A是任选的并且多元醇B1和B2均存在。
在一个实施方案中，存在多元醇A，并且存在多元醇B1和B2中的至少一种。
在一个实施方案中，不存在多元醇A，并且存在多元醇B1和B2中的至少一种。
在一个实施方案中，存在多元醇B1，其包含至少一些C 1-C 2烷基作为R 2。
c.多元醇C
多元醇C的分子量可以为至少200或至少250或至少300道尔顿，并且可以高达800或高达500或高达400道尔顿。多元醇C可以是多元醇A和B的聚醚。n的值取决于R 1 和R 2的选择，以便提供指定范围内的总分子量。例如，n为至少3或至少5或至少7，并且可以最多20或最多12。
用作多元醇A，B和C的合适的羟基封端的聚醚多元醇衍生自具有总计例如2至15个碳原子的二醇或多元醇，例如烷基二醇或乙二醇，与包含例如2至6个碳原子的环氧烷烃的醚，例如环氧乙烷，环氧丙烷或其混合物反应，或通过酸催化的缩聚反应。例如，可以通过首先使丙二醇与环氧丙烷反应，然后与环氧乙烷反应来制备聚醚多元醇。
聚醚多元醇的实例包括通过环氧乙烷与乙二醇的反应形成的聚(乙二醇)，通过环氧丙烷与丙二醇的反应形成的聚(丙二醇)，环氧乙烷与C 3-C 12环氧烷的共聚物，特别是，C 3至C 9的环氧烷烃，例如聚丙二醇)，例如包含聚(1,2-丙二醇)和聚(环氧乙烷)链段的共聚物多元醇，通过水与四氢呋喃的反应形成的聚(四甲基醚二醇)，它也可以描述为聚合的四氢呋喃，在本文中称为PTMG。合适的聚醚多元醇还包括环氧烷的聚酰胺加合物，并且可以包括例如由乙二胺与环氧丙烷反应形成的乙二胺加合物，由二乙三胺与环氧丙烷反应形成的二乙三胺，以及类似的聚酰胺型聚醚多元醇。
共聚醚也可以用于所述组合物中。典型的共聚醚包括THF与环氧乙烷或THF与环氧丙烷的反应产物。这些可从BASF获得，
Figure PCTCN2021120939-appb-000003
为嵌段共聚物，
Figure PCTCN2021120939-appb-000004
为无规共聚物。
d.扩链剂D
示例性的TPU组合物可以使用扩链剂D制成。扩链剂D可被用作多元醇C的补充或替代。扩链剂同样可为多元醇，例如C 1-C 20或C 1-C 12，或C 2-C 10烷基和/或芳基多元醇。扩链剂的分子量可最多300道尔顿，或最多250道尔顿，或最多200道尔顿。
扩链剂包括二醇，二胺及其组合。扩链剂的分子量可最多500道尔顿或最多300道尔顿，例如至少46道尔顿。
可以将一种或多种具有2至20或2至12，或2至10或2-8个碳原子的短链多元醇用作聚氨酯形成组合物中的扩链剂以增加聚氨酯的分子量。扩链剂的实例包括分子量小于500或小于300的低级脂族多元醇和短链芳族二醇。合适的扩链剂包括总共具有2至20个碳原子的有机二醇(包括二醇)，例如链烷二醇，脂环族二碘，烷基芳基二醇等。
示例性的烷二醇包括乙二醇，二乙撑二醇，1,3-丙二醇，1,3-丁二醇，1,4-丁二醇(BDO)，1,3-丁二醇，1,5-戊二碘，2,2-二甲基-1,3-丙二醇，丙二醇，二丙二醇，1,6-己二醇，庚二醇，壬二醇，1,10-癸二醇，十二烷二醇，三丙二醇，三甘醇和3-甲基-1,5-戊二醇。合适的脂环族二醇的实例包括1，2-环戊二醇和1，4-环己烷二甲醇(CHDM)。合适的芳基和烷基芳基二醇的实例包括对苯二酚双(2-羟乙基)醚(HQEE)，1,2-二羟基苯，1,3-二羟 基苯，1,4-二羟基苯，1,2,3-三羟基苯，1,2-双(羟甲基)苯，1,4-双(羟甲基)苯，1,3-双(2-羟乙基)苯，1,2-双(2-羟乙氧基)苯，1,4-双(2-羟乙氧基)苯，双乙氧基双酚，2,2-双(4-羟基苯)丙烷(即双酚A)，双酚A乙氧基化物，双酚F乙氧基化物，4,4'-异丙基二烯二酚，2,2-双[4-(2-羟基乙氧基)苯基]丙烷(HEPP)及其混合物等。
也可以使用一种或多种上述扩链剂的混合物。
可以使用官能度大于2的扩链剂，只要所得的TPU保持其热塑性即可。这种扩链剂的例子包括三羟甲基丙烷(TMP)，甘油和季戊四醇。通常，此类扩链剂的添加相对于双官能扩链剂的重量不应超过10％。
在一个实施方案中，扩链剂选自1,4-丁二醇和1,10-癸二醇。
扩链剂也可以基于二胺。示例性的二胺的分子量可小于500，并且包括例如乙二胺，二乙二胺，四甲基苯二胺，六亚甲基二胺，二亚乙基三胺三亚乙基四胺，四亚乙基五胺，戊二烯六胺，哌嗪，吗啉，取代的吗啉，哌啶，取代的哌啶，2-氨基-1-乙基哌嗪肼，1，4-环己二胺及其混合物。也可以使用链烷醇胺，例如乙醇胺，二乙醇胺和三乙醇胺。增链剂的其他例子包括苯胺等。所使用的一种或多种扩链剂的总羟基与多元醇A，B和C(如果存在)的总羟基的摩尔量或摩尔比例可以为0.1至5.0，或0.2至4.0，或为0.4至2.5。
e.多异氰酸酯
多异氰酸酯包括一种或多种多异氰酸酯。合适的多异氰酸酯包括芳族二异氰酸酯，脂族二异氰酸酯及其混合物。
为了形成相对长的线性聚氨酯链，使用了双官能或多官能异氰酸酯。在一个实施方案中，使用一种或多种二异氰酸酯。可用于本发明的多异氰酸酯通常具有式R(NCO)n，其中n为至少2。R可以是具有2至20个碳原子的芳族，环脂族族，脂族族或它们的组合。
芳族二异氰酸酯的实例包括4,4'-二苯基甲烷二异氰酸酯(MDI)，间二甲苯二异氰酸酯(XDI)，亚苯基1,4二异氰酸酯，萘1,5二异氰酸酯，2,4-甲苯二异氰酸酯(2,4-TDI)，2,6-甲苯二异氰酸酯(2,6-TDI)，1,4-苯二异氰酸酯，1,3-苯二异氰酸酯，4,4-二苯二异氰酸酯，3,3-二甲氧基-4,4-联苯二异氰酸酯，3,3'-二甲基-4,4'-联苯二异氰酸酯(TODI)，4,4-二异氰酸酯二苯醚，2,4-萘二异氰酸酯，1,5-萘二异氰酸酯，1,3-二甲苯二异氰酸酯，1，4-二甲苯二异氰酸酯。
脂族二异氰酸酯的实例包括1,4-丁烷二异氰酸酯(BDI)，四亚甲基乙二异氰酸酯，六亚甲基二异氰酸酯(HDI)，1,4-环己基二异氰酸酯(CHDI)，癸烷-1、10-二异氰酸酯，赖氨酸二异氰酸酯(LDI))，二环己基甲烷-4,4'-二异氰酸酯(H12MDI)，1,3-二异氰酸酯 甲基环己烷，1,4-二异氰酸酯甲基环己烷，4,4-二异氰酸酯二环己烷，4,4-二异氰酸酯二环己基甲烷，异佛尔酮二异氰酸酯和异构体，二聚体，三聚体及其混合物。
在一个实施方案中，异氰酸酯选自脂环族和芳族二异氰酸酯。在一个实施方案中，异氰酸酯选自MDI和H12MDI。
合适的多异氰酸酯可商购，例如购自宾夕法尼亚州匹兹堡的拜耳公司，新泽西州帕西帕尼的巴斯夫公司，密歇根州米德兰的陶氏化学公司和犹他州的亨斯曼化学公司。
f.催化剂
在聚合反应期间可以存在一种或多种聚合催化剂。通常，可以使用任何常规催化剂使二异氰酸酯与多元醇中间体和/或扩链剂反应。尤其能促进二异氰酸酯的NCO基团与多元醇和扩链剂的羟基之间的反应的合适催化剂包括有机锡化合物，例如二乙酸二丁锡，二月桂酸二丁基锡(DBTL)，二月桂酸二辛基锡(DOTDL)和二丁基二丁基锡(乙氧基-3-巯基丙酸酯)；钛酸；有机钛化合物，例如钛酸四异丙酯，钛酸四正丁酯，硬脂酸多羟基钛和乙酰丙酮钛；叔胺，例如三乙二胺，三乙胺N-甲基吗啉，N，N，N'，N'-四甲基乙二胺，N，N，N'，N'-四甲基六亚甲基二胺，三乙胺，N，N'-二甲基哌嗪，N，N-二甲基氨基乙醇，二甲基环己胺，二氮杂双环[2.2.2]辛烷；及其两种或更多种的混合物。相对于每100重量份的多元醇A，B和C，催化剂的使用总量可以为0.0001至0.1重量份。
热塑性聚氨酯实例
本文所述的热塑性聚氨酯具有软链段和硬链段。所述软链段可以衍生自多元醇A和B中的至少一种。所述硬链段可以衍生自多异氰酸酯(或二异氰酸酯)以及第三多元醇(多元醇C)和扩链剂D中的至少一种。
i.TPU1
TPU(表示为TPU1)包括衍生自分子量低于多元醇A的第一聚醚多元醇(多元醇A)和第二聚醚多元醇B(例如至少多元醇B1)的软链段。多元醇A的n值与多元醇B的n值之比可以为至少1.5：1或至少2：1，或至少3：1，或至少4：1，并且可以是最多20：1或最多10：1。
多元醇A与多元醇B的分子量比可以为至少1.4：1或至少2：1，并且可以最多15：1或最多10：1或最多8：1。因此，软链段具有聚醚链段的平均长度的双峰分布。
用于形成TPU1的反应混合物中的多元醇B与多元醇A的摩尔比可以为至少5：1或至少8：1，例如最多20：1。在形成的热塑性聚氨酯中，多元醇B1与多元醇A的重量比可以为至少1：1至8：1，例如至少1.5：1，或至少8：1。
热塑性聚氨酯TPU1的实例可以是以下物质的反应产物：20-30wt％多元醇A，40-70 wt％多元醇B(例如B2)，5-20wt％多异氰酸酯，0.2-5wt％多元醇C，0-5wt％的扩链剂，例如至少0.2wt％，任选地，一种或多种另外的聚合物形成组分，和任选地至多2wt％的催化剂(总计100重量％)。多元醇A和B的组合可包含反应混合物中形成聚合物的组分的总重量的至少60wt％或至少70wt。在该实施方案中，多元醇B的分子量可以不超过2500道尔顿。
TPU1的重均分子量可为50,000至1,000,000道尔顿，或75,000至500,000道尔顿，或100,000至300,000道尔顿。
ii.TPU2
TPU(表示为TPU2)如TPU1所述，但包含多元醇A但不包含多元醇B(或仅少量，例如至多5wt％)。它可以进一步包括多元醇C。
示例性热塑性聚氨酯TPU2是以下物质的反应产物：70-90wt％多元醇A，5-20wt％多异氰酸酯，0-15wt％多元醇C，0-10wt％扩链剂，任选地，一种或多种另外的聚合物形成组分，和任选地至多2wt％的催化剂(总计100重量％)。
iii.TPU3
TPU(TPU3)如TPU1所述，但包括多元醇B但不包括多元醇A(或不超过5wt％的多元醇A)。TPU3包括软链段，其衍生自至少一种聚醚多元醇B，例如至少两种分子量相似但具有不同R 3基团的聚醚多元醇B，例如B1，其中R 2可以是H和C1-C2烷基和B2的混合物。
热塑性聚氨酯TPU3的实例可以是以下物质的反应产物：30-90wt％多元醇B，5-50wt％多异氰酸酯，0-5wt％多元醇C，0-20wt％扩链剂，任选地，一种或多种另外的聚合物形成组分，和任选地至多2wt％的催化剂(总计100wt％)。
TPU3的重均分子量可为50,000至1,000,000道尔顿，或75,000至500,000或100,000至300,000道尔顿。
热塑性聚氨酯还可以是TPU1，TPU2和TPU3中的两种或更多种的共混物。TPU1：TPU2和/或TPU3的重量比可以为至少1：2。在一个实施方案中，该比率为至少1：1.5，或至少1：1，或至少2：1，并且可以高达100：1，或更高，例如最多20：1，或最多10：1。
TPU的实例包括TPU-EX1452、TPU-TMPT75AS450、TPU-HP-93A-100、TPU-Tecoflex SG-85等等，例如TPU-TMPT75AS450。
皮肤粘附层中的TPU的含量可以是占皮肤粘附层总重量的约在0.1％至80％，如0.1％至40％、如0.5％至30％、如0.5％至15％，例如2.0％。
聚(甲基)丙烯酸酯聚合物是指皮肤粘附层可以包括至少一种的聚甲基丙烯酸酯和/或聚丙烯酸酯聚合物。其可以衍生自基于甲基丙烯酸和丙烯酸单体的混合物，从而使聚合物的性能与压敏胶不同。具有官能团的聚(甲基)丙烯酸酯聚合物是均聚物，共聚物或三元共聚物，其含有具有游离官能团的单体单元，还可以存在其他非官能单体单元，例如(甲基)丙烯酸酯或(甲基)丙烯酰胺。单体可以是单官能的或多官能的。这些官能团包括羧基，羟基，氨基，酰胺基，环氧基等。
可聚合的功能单体包括丙烯酸，甲基丙烯酸，马来酸，马来酸酐，丙烯酸羟乙酯，丙烯酸羟丙酯，丙烯酰胺，二甲基丙烯酰胺，丙烯腈，丙烯酸二甲基氨基乙基酯，甲基丙烯酸二甲基氨基乙基酯，丙烯酸叔丁基氨基乙基酯，甲基丙烯酸叔丁基氨基乙基酯，丙烯酸甲氧基乙基酯和甲基丙烯酸甲氧基乙基酯以及其他在分子中具有至少一个参与共聚反应的不饱和双键的单体，以及在其侧链上的具有官能团，例如羧基，羟基，巯基，氨基，吡咯基和烷氧基等。进一步的实例包括具有以下至少一个部分的单体：亚烷基，羟基取代的亚烷基，羧酸取代的亚烷基，链烷酸乙烯基酯，乙烯基吡咯烷酮，乙烯基吡啶，乙烯基吡嗪，乙烯基吡咯，乙烯基咪唑，乙烯基己内酰胺，乙烯基恶唑，乙酸乙烯基酯，丙酸乙烯基酯和乙烯基吗啉。羧基官能单体的例子包括丙烯酸，甲基丙烯酸，衣康酸，马来酸和巴豆酸。示例性的羟基官能单体包括甲基丙烯酸2-羟乙酯，丙烯酸2-羟乙酯，丙烯酸羟甲酯，甲基丙烯酸羟甲酯，丙烯酸羟乙酯，甲基丙烯酸羟乙酯，丙烯酸羟丙酯，甲基丙烯酸羟丙酯，丙烯酸羟丁酯，甲基丙烯酸羟丁酯，丙烯酸羟戊酯，甲基丙烯酸羟己酯，丙烯酸羟己酯。这些官能单体可以与非官能(甲基)丙烯酸烷基酯和(甲基)丙烯酸烷基酰胺共聚。
在某些实施方式中，所述的聚(甲基)丙烯酸酯聚合物选自聚(甲基丙烯酸丁酯-(2-二甲基氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-甲基丙烯酸甲酯)；聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯)；聚(甲基丙烯酸甲酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-丙烯酸乙酯)中的一种或多种。在某些实施方式中，所述的聚(甲基)丙烯酸酯聚合物选自聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2))，聚(甲基丙烯酸丁酯-(2-二甲基氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯(1:2:1))和聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1))中的一种或多种。在某些实施方式中，所述的聚(甲基)丙烯酸酯聚合物选自聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2))。
聚(甲基)丙烯酸酯聚合物的实例包括但不限于
Figure PCTCN2021120939-appb-000005
PO，
Figure PCTCN2021120939-appb-000006
RL100，
Figure PCTCN2021120939-appb-000007
RL PO，
Figure PCTCN2021120939-appb-000008
RL30，
Figure PCTCN2021120939-appb-000009
RS100，
Figure PCTCN2021120939-appb-000010
RS PO，
Figure PCTCN2021120939-appb-000011
RS30，
Figure PCTCN2021120939-appb-000012
NE 30和
Figure PCTCN2021120939-appb-000013
FS 30的一种或多种。例如
Figure PCTCN2021120939-appb-000014
RL100和
Figure PCTCN2021120939-appb-000015
RS100中的一种或多种。
聚维酮的实例包括但不限于PVP K12、PVP K17、PVP K25、PVP K30、PVP K85、PVP K90，例如PVP K90。
在某些实施方式中，本公开的添加剂还可选自乙酰丙酮铝(ACAL)。
在某些实施方式中，本公开的添加剂选自热塑性聚氨酯、聚维酮、聚(甲基)丙烯酸酯聚合物和乙酰丙酮铝中的一种或多种。
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％，例如1.2％、1.25％1.5％、2.5％或5％。
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，例如0.13mg/cm 2、0.15mg/cm 2、0.16mg/cm 2或0.19mg/cm 2。
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ScotchPakTM1109，9700，9720，9722，9738，1012，9758，9723，9735，9754，9733等或CotranTM9720，9702，9712，9716，9718，9700，9722，9728等。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。
大部分贴剂通常会使用较大体积的粘合剂层来在粘合剂层中保持大量的药物。然而，粘合剂层的组分容易从粘合贴剂边缘溢出(即冷流)，且在粘附到皮肤层过程中引起问题。冷流的发生取决于粘合剂的性质。此外，当贴剂制品长时间处于载荷下，即当贴剂制品包含在包装之内并且长期贮存等等时，其常会发生。冷流的不利影响包括例如贴剂制品从包装中的取出性能变差(这由突出的粘合剂层组分对包装内部的粘附引起)、附着到衣物、在粘附到皮肤的过程中贴剂制品翘边和着色、具有药用功效的粘合贴剂效果变差等。本公开所述的药物组合物具有改善流变性质以及良好的药物的释放率。
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，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10％至99.9％，如30％至99.5％、如40％至99％、如60％至99％，例如95.0％、95.5％、96.3％、96.55％、96.60％、97.8％、98.5％或98.8％。
在某些实施方式中，组合物中的压敏胶的量是组合物的总重量的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，例如95.0％、95.5％、96.3％、96.55％、96.60％、97.8％、98.5％或98.8％)。
在某些实施方式中，所述的硅酮压敏胶通常包括线性硅氧烷聚合物和由三有机硅氧烷(M)单元(即R3SiOi/2单元，其中R表示单价有机基团)和硅酸盐(Q)单元(即SiO-t/a单元)组成的MQ硅树脂。标准和胺相容的有机硅粘合剂都可用。由于聚合物组分赋予的高粘度，硅酮压敏胶可以分散在有机溶剂中。硅酮压敏胶的实例包括DowCorning生产的BIO-PSA硅酮压敏胶，例如BIO-PSA7-4102、BIO-PSA7-4202、BIO-PSA7-4301、BIO-PSA7-4302、BIO-PSA7-4503、BIO-PSA7-4560等。例如BIO-PSA7-4202、BIO-PSA7-4302中的一种或多种。
在某些实施方式中，所述的硅酮压敏胶包含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，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，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，所述的硅酮压敏胶包括第一胺相容的硅酮压敏胶，和第二胺相容的硅酮压敏胶。
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9:1-2:8，更优选8:2-4:6或9:1-7:3，例如8:2、7:3、6:4、5:5或4:6，最优选8:2-7:3。
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9:1-2:8，更优选8:2-4:6或9:1-7:3，例如8:2、7:3、6:4、5:5或4:6，最优选8:2-7:3。增加中等粘性硅酮压敏胶的比例有利于改善组合物的流变性质。
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DowCorning生产的BIO-PSA硅酮压敏胶，例如BIO-PSA7-410X、BIO-PSA7-420X、BIO-PSA7-430X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。
在某些实施方式中，所述硅酮压敏胶为BIO-PSA7-420X和BIO-PSA7-430X的组合，优选为BIO-PSA7-4202和BIO-PSA7-4302的组合。
BIO-PSA硅酮压敏胶的相关参数如下表(来源于DowCorning公司的BIO-PSA硅酮压敏胶的产品手册)：
Figure PCTCN2021120939-appb-000016
Figure PCTCN2021120939-appb-000017
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-PSA7-420X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-PSA7-430X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-PSA7-420X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-PSA7-430X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(halogenpolyvinylchloride)、聚偏二氯乙烯和聚氯二烯(polychlorodiene)，及其组合。与其他类型的压敏胶相比，硅酮压敏胶可通过载有相对少量的活性物质达到更多的药物释放。
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，例如二丁基羟基甲苯(BHT)。
在某些实施方式中，本公开所述的药物组合物还可含有抗氧化剂。
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)60％至99％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-PSA7-420X和BIO-PSA7-430X的组合，重量比为9:1-2:8，优选8:2-4:6或9:1-7:3，更优选8:2-7:3；
(3)0.1％-10％的添加剂，选自热塑性聚氨酯、聚维酮、聚(甲基丙烯酸丁酯-(2-二甲基氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-甲基丙烯酸甲酯)；聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯)；聚(甲基丙烯酸甲酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-丙烯酸乙酯)中的一种或多种；
(4)任选的0.01％-10％的抗氧化剂。
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)60％至99％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-PSA7-420X和BIO-PSA7-430X的组合，重量比为9:1-2:8，优选8:2-4:6或9:1-7:3，更优选8:2-7:3；(3)0.1％-10％的添加剂，选自热塑性聚氨酯、聚维酮、乙酰丙酮铝、聚(甲基丙烯酸丁酯-(2-二甲基氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-甲基丙烯酸甲酯)；聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三 甲胺基乙酯)；聚(甲基丙烯酸甲酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-丙烯酸乙酯)中的一种或多种；(4)任选的0.01％-10％的抗氧化剂。
在某些实施方式中，所述的胺相容的硅酮压敏胶为BIO-PSA7-4202和BIO-PSA7-4302的组合。
在某些实施方式中，所述的聚(甲基)丙烯酸酯聚合物选自聚(甲基丙烯酸丁酯-(2-二甲基氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-甲基丙烯酸甲酯)；聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯)；聚(甲基丙烯酸甲酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-丙烯酸乙酯)中的一种或多种。
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％、不低于约25％、不低于约26％、不低于约27％、不低于约28％、不低于约29％、不低于约30％，优选不低于约15％，更优选不低于约20％，最优选不低于约25％。
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。
本公开另一方面提供了一种本公开所述的经皮吸收的药物组合物的制备方法，所述方法包括将酰胺类局部麻醉药与硅酮压敏胶和添加剂混合的步骤。
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。
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为实施例13的受试者平均药时曲线图；
图2为实施例19的受试者平均药时曲线图；
图3为对比例冷流图片；
图4为实施例8冷流图片。
具体实施方式
实施例1-11：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硅酮压敏压敏胶7-4202、7-4302；
抗氧化剂：二丁基羟基甲苯(BHT)
添加剂：乙酰丙酮铝(ACAL)，热塑性聚氨酯(TPU-TMPT75AS450)，聚维酮(pvp K90)，尤特奇RL100(Eudragit RL100，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺乙酯(1:2:0.2)共聚物)，尤特奇E100(Eudragit E100，甲基丙烯酸丁酯、甲基丙烯酸二甲氨基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物)，尤特奇RS100(Eudragit RS100，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺乙酯(1:2:0.1)共聚物)；
背衬层：上海赢发3201聚对苯二甲酸乙二醇酯背衬，3302聚丙烯背衬，3301聚丙烯背衬，或4202聚丙烯覆无纺布背衬；
离型膜：上海赢发2301涂氟离型膜。
Figure PCTCN2021120939-appb-000018
Figure PCTCN2021120939-appb-000019
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。
实施例12：加速冷流实验
将上述制备的贴剂裁剪成小圆片后，置于两片载玻片中间，压上500g砝码，分别于20小时和44小时观察贴剂边缘是否有压敏胶溢出，其中1表示边缘未出现溢胶，2表示连续有零星溢胶，3表示边缘出现少量溢胶，4表示边缘出现溢胶，5表示边缘有明显溢胶，观察结果如表中所示。
Figure PCTCN2021120939-appb-000020
从实验结果发现，对比例贴剂边缘有较多的压敏胶溢出，冷流较严重(如图3所示)；实施例贴剂在20小时时边缘均无压敏胶溢出(实施例8冷流图片如图4所示)，无冷流；实施例10虽无冷流但交联剂的加入增大了压敏胶的交联度，贴剂变硬，影响贴剂的贴合度和舒适度。
实施例13
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 PCTCN2021120939-appb-000021
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9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(参比制剂) T1(受试制剂1) T2(受试制剂2)
K002 T2(受试制剂2) R(参比制剂) T1(受试制剂1)
K003 T1(受试制剂1) T2(受试制剂2) R(参比制剂)
K004 T2(受试制剂2) R(参比制剂) T1(受试制剂1)
K005 T1(受试制剂1) T2(受试制剂2) R(参比制剂)
K006 T1(受试制剂1) T2(受试制剂2) R(参比制剂)
K007 R(参比制剂) T1(受试制剂1) T2(受试制剂2)
K008 R(参比制剂) T1(受试制剂1) T2(受试制剂2)
K009 T2(受试制剂2) R(参比制剂) T1(受试制剂1)
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3制剂，规格：21.6mg/片，10×14cm；
参比制剂R：市售利多卡因贴剂(商品名：
Figure PCTCN2021120939-appb-000022
)，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＝9)
Figure PCTCN2021120939-appb-000023
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＝9)
Figure PCTCN2021120939-appb-000024
利多卡因改良贴剂T2粘附性评估结果(N＝9)
Figure PCTCN2021120939-appb-000025
Figure PCTCN2021120939-appb-000026
利多卡因参比制剂R粘附性评估结果(N＝9)
Figure PCTCN2021120939-appb-000027
实施例14-16、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)；
背衬层：背衬3M公司ScotchPak9738
离型膜：离型膜3M公司ScotchPak9709
Figure PCTCN2021120939-appb-000028
Figure PCTCN2021120939-appb-000029
根据实施例1的方法制备各贴剂组合物。
实施例17：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。将上述实施例贴剂裁剪成直径2.0cm的圆形，每个贴剂裁剪4个圆片，分别贴于4片猪皮角质层上，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(各贴剂的单位面积累积透过量以4个通道的平均值表示)
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(各贴剂的累积透过百分比以4个通道的平均值表示)
测定实施例1-11、14-16及对比例1-5贴剂单位面积累积透过药物的含量和累计透过百分比，如下表中所述。
Figure PCTCN2021120939-appb-000030
Figure PCTCN2021120939-appb-000031
Figure PCTCN2021120939-appb-000032
Figure PCTCN2021120939-appb-000033
贴剂中累积透过药物的百分比
Figure PCTCN2021120939-appb-000034
注：UCP％：累积透过药物的百分比(％)，SD：标准编差
贴剂单位面积累积透过药物的含量
Figure PCTCN2021120939-appb-000035
注：UCP：单位面积累积透过量(ug/cm 2)，SD：标准偏差
实施例19
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 PCTCN2021120939-appb-000036
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9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(参比制剂) T1(受试制剂1) T2(受试制剂2)
K002 T2(受试制剂2) R(参比制剂) T1(受试制剂1)
K003 T1(受试制剂1) T2(受试制剂2) R(参比制剂)
K004 T2(受试制剂2) R(参比制剂) T1(受试制剂1)
K005 T1(受试制剂1) T2(受试制剂2) R(参比制剂)
K006 T1(受试制剂1) T2(受试制剂2) R(参比制剂)
K007 R(参比制剂) T1(受试制剂1) T2(受试制剂2)
K008 R(参比制剂) T1(受试制剂1) T2(受试制剂2)
K009 T2(受试制剂2) R(参比制剂) T1(受试制剂1)
2、药物信息
受试制剂T1：实施例11制剂，规格：22.5mg/片，10×14cm；
受试制剂T2：实施例11制剂，规格：18mg/片，10×14cm；
参比制剂R：市售利多卡因贴剂(商品名：
Figure PCTCN2021120939-appb-000037
)，规格：700mg/片，10×14 cm，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和图2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＝9)
Figure PCTCN2021120939-appb-000038
按FDA相关指导原则，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，依据附表进行粘附性评分。结果表明两受试制剂较参比制剂粘附性方面均更具优势，且贴剂皮肤刺激性良好，试验期间未发生局部刺激性相关不良事件。
利多卡因改良贴剂T1粘附性评估结果(N＝8)
T1药(N＝8) 0 1 2 3 4 mean
给药后5min内 24 0 0 0 0 0
2h 24 0 0 0 0 0
4h 24 0 0 0 0 0
6h 24 0 0 0 0 0
8h 24 0 0 0 0 0
10h 24 0 0 0 0 0
12h 24 0 0 0 0 0
总计 168 0 0 0 0 0
利多卡因改良贴剂T2粘附性评估结果(N＝9)
T2药(N＝9) 0 1 2 3 4 mean
给药后5min内 27 0 0 0 0 0.00
2h 25 2 0 0 0 0.07
T2药(N＝9) 0 1 2 3 4 mean
4h 25 2 0 0 0 0.07
6h 26 1 0 0 0 0.04
8h 26 1 0 0 0 0.04
10h 26 1 0 0 0 0.04
12h 26 1 0 0 0 0.04
总计 181 8 0 0 0 0.04
利多卡因改良贴剂R粘附性评估结果(N＝8)
R药(N＝8) 0 1 2 3 4 mean
给药后5min内 23 1 0 0 0 0.04
2h 22 2 0 0 0 0.08
4h 17 6 0 0 1 0.42
6h 18 5 0 0 1 0.38
8h 15 6 1 0 2 0.67
10h 14 7 1 1 1 0.67
12h 13 7 0 1 3 0.92
总计 122 34 2 2 8 0.45
实施例20：
将实施例11包装于铝塑袋中，加速条件(40℃/75％RH)下放样，分别于0天和1月时对样品进行杂质含量考察，如下表中所述。
Figure PCTCN2021120939-appb-000039
实施例21：
所采用的组分：
压敏胶：Henkel公司生产的DURO TAK丙烯酸压敏胶4098、2287、2852、2677；
背衬层：背衬3M公司ScotchPak9738
离型膜：离型膜3M公司ScotchPak9709
Figure PCTCN2021120939-appb-000040
根据实施例1的方法制备各贴剂组合物，并根据实施例17的方法测试药物的皮肤透过量，如下表。
Figure PCTCN2021120939-appb-000041
Figure PCTCN2021120939-appb-000042
实施例22：
采用WO2019079291实施例23公开了利多卡因贴剂处方(4％利多卡因，丙烯酸压敏胶87-2516和TPU1-1(质量比1:1)，0.5％聚山梨酯80和0.5％丙二醇)，根据实施例13的方法，测定贴剂单位面积累积透过药物的含量和累计透过百分比，如下表中所述。
Figure PCTCN2021120939-appb-000043
Figure PCTCN2021120939-appb-000044
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，本发明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，本发明的范围和精神由所附权利要求书体现。

Claims (36)

  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)硅酮压敏胶，和(3)添加剂，所述添加剂选自热塑性聚氨酯、聚维酮、聚(甲基)丙烯酸酯聚合物中的一种或多种。
  2. 根据权利要求1所述的经皮吸收的药物组合物，其特征在于，所述的热塑性聚氨酯和聚(甲基)丙烯酸酯聚合物不具有压敏胶的粘弹性。
  3. 根据权利要求1所述的经皮吸收的药物组合物，其特征在于，所述的热塑性聚氨酯聚合物包含通过以下物质反应所得的产物：
    (i)至少以下之一：
    a)分子量至少为3000道尔顿的第一聚醚多元醇A，和b)分子量不大于2500道尔顿的第二聚醚多元醇B；
    (ii)至少以下之一：
    c)分子量最多800道尔顿的第三种多元醇C；
    d)扩链剂；
    (iii)多异氰酸酯；和
    (iv)任选地，催化剂。
  4. 根据权利要求1所述的经皮吸收的药物组合物，其特征在于，所述的聚(甲基)丙烯酸酯聚合物选自聚(甲基丙烯酸丁酯-(2-二甲基氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-甲基丙烯酸甲酯)；聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯)；聚(甲基丙烯酸甲酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-丙烯酸乙酯)中的一种或多种，优选聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯)。
  5. 根据权利要求1-4任一项所述的经皮吸收的药物组合物，其特征在于，所述的聚维酮选自PVP K12、PVP K17、PVP K25、PVP K30、PVP K85或PVP K90。
  6. 根据权利要求1-5任一项所述的经皮吸收的药物组合物，其特征在于，所述的热塑性聚氨酯聚合物选自TPU-EX1452、TPU-TMPT75AS450、TPU-HP-93A-100和TPU-Tecoflex SG-85中的一种或多种，例如TPU-TMPT75AS450；
    所述的聚(甲基)丙烯酸酯聚合物选自
    Figure PCTCN2021120939-appb-100001
    Figure PCTCN2021120939-appb-100002
    Figure PCTCN2021120939-appb-100003
    和
    Figure PCTCN2021120939-appb-100004
    Figure PCTCN2021120939-appb-100005
    的一种或多种。
  7. 根据权利要求1-6任一项所述的经皮吸收的药物组合物，其特征在于，所述的添加剂的含量可以是占皮肤粘附层总重量的约在0.01％-40％，优选0.05％-15％、更优选0.1％-10％，最优选0.5％-5％，例如0.5％或2.0％。
  8. 根据权利要求1-7任一项所述的经皮吸收的药物组合物，其特征在于，所述添加剂还选自乙酰丙酮铝(ACAL)，较佳地，所述添加剂选自热塑性聚氨酯、聚维酮、聚(甲基)丙烯酸酯聚合物和乙酰丙酮铝中的一种或多种。
  9. 根据权利要求1-8任一项所述的经皮吸收的药物组合物，其特征在于，所述的硅酮压敏胶包含胺相容的硅酮压敏胶。
  10. 根据权利要求1-9任一项所述的经皮吸收的药物组合物，其特征在于，所述的硅酮压敏胶包括第一胺相容的硅酮压敏胶，和第二胺相容的硅酮压敏胶。
  11. 根据权利要求10所述的经皮吸收的药物组合物，其特征在于，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。
  12. 根据权利要求10所述的经皮吸收的药物组合物，其特征在于，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。
  13. 根据权利要求10-12任一项所述的经皮吸收的药物组合物，其特征在于，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9:1-2:8，更优选8:2-4:6或9:1-7:3，例如8:2、7:3、6:4、5:5或4:6，最优选8:2-7:3。
  14. 根据权利要求10-13任一项所述的经皮吸收的药物组合物，其特征在于，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。
  15. 根据权利要求10-14任一项所述的经皮吸收的药物组合物，其特征在于，所述的第一胺相容的硅酮压敏胶选自BIO-PSA7-420X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-PSA7-430X中的一种或多种，优选7-4302。
  16. 根据权利要求1-15任一项所述的经皮吸收的药物组合物，其特征在于，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。
  17. 根据权利要求1-16任一项所述的经皮吸收的药物组合物，其特征在于，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10％-99.5％，优选30％-99.5％、 更优选60％-99％，例如95.0％、95.5％、96.3％、96.55％、96.60％、97.8％、98.5％或98.8％。
  18. 根据权利要求1-17任一项所述的经皮吸收的药物组合物，其特征在于，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。
  19. 根据权利要求1-18任一项所述的经皮吸收的药物组合物，其特征在于，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％，例如1.2％、1.25％1.5％、2.5％或5％。
  20. 根据权利要求1-19任一项所述的经皮吸收的药物组合物，其特征在于，所述的药物组合物为贴剂，优选非水性贴剂。
  21. 根据权利要求20所述的经皮吸收的药物组合物，其特征在于，所述的贴剂中酰胺类局部麻醉药的含量为约0.1-1mg/cm 2，优选0.1-0.7mg/cm 2，例如0.13mg/cm 2、0.15mg/cm 2、0.16mg/cm 2或0.19mg/cm 2。
  22. 根据权利要求1-21任一项所述的经皮吸收的药物组合物，其特征在于，所述的药物组合物还包含抗氧化剂，所述抗氧化剂优选选自茶多酚(TP)、生育酚、黄酮类、丁基羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)和叔丁基对苯二酚(TBHQ)中的一种或多种。
  23. 根据权利要求1-22任一项所述的经皮吸收的药物组合物，其特征在于，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)60％至99％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-PSA7-420X和BIO-PSA7-430X的组合，重量比为9:1-2:8，优选9:1-7:3，更优选8:2-7:3；
    (3)0.1％-10％的添加剂，选自热塑性聚氨酯、聚维酮、聚(甲基丙烯酸丁酯-(2-二甲基氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-甲基丙烯酸甲酯)；聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯)；聚(甲基丙烯酸甲酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-丙烯酸乙酯)中的一种或多种；
    (4)任选的0.01％-10％的抗氧化剂。
  24. 根据权利要求1-23任一项所述的经皮吸收的药物组合物，其特征在于，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)60％至99％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-PSA7-420X和BIO-PSA7-430X的组合，重量比为9:1-2:8，优选9:1-7:3，更优选8:2-7:3；
    (3)0.1％-10％的添加剂，选自热塑性聚氨酯、聚维酮、乙酰丙酮铝、聚(甲基丙烯酸丁酯-(2-二甲基氨基乙基)甲基丙烯酸酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-甲基丙烯酸甲酯)；聚(丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯)；聚(甲基丙烯酸甲酯-甲基丙烯酸甲酯)；聚(甲基丙烯酸-丙烯酸乙酯)中的一种或多种；
    (4)任选的0.01％-10％的抗氧化剂。
  25. 根据权利要求23或24所述的经皮吸收的药物组合物，其特征在于，所述的胺相容的硅酮压敏胶为BIO-PSA7-4202和BIO-PSA7-4302的组合。
  26. 根据权利要求1-25任一项所述的经皮吸收的药物组合物，其特征在于，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25％。
  27. 根据权利要求1-26任一项所述的经皮吸收的药物组合物，其特征在于，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％。
  28. 根据权利要求26或27所述的经皮吸收的药物组合物，其特征在于，所述药物组合物贴附的皮肤为猪皮肤，优选猪耳背皮肤。
  29. 根据权利要求1-28任一项所述的经皮吸收的药物组合物，其特征在于，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。
  30. 根据权利要求1-29任一项所述的经皮吸收的药物组合物，其特征在于，其中所述热塑性聚氨酯聚合物满足其中至少一个条件：
    1)第一聚醚多元醇A的分子量至少为4000道尔顿；当存在时，第二聚醚多元醇B的分子量不超过2000道尔顿；
    2)当存在第二聚醚多元醇时，第一聚醚多元醇与第二聚醚多元醇的分子量之比至少为1.4：1；
    3)当存在第二聚醚时，第二聚醚多元醇与第一聚醚多元醇的重量比为至少1：1；和
    4)扩链剂的分子量最多300道尔顿。
  31. 根据权利要求1-30任一项所述的经皮吸收的药物组合物，其特征在于，其中所述热塑性聚氨酯聚合物包含通过以下物质反应所得的产物：
    (i)第一聚醚多元醇A，其包含平均分子量为7000-9000道尔顿的聚(乙二醇)；
    (ii)第二聚醚多元醇B，其包含聚醚共聚物二醇与聚丙二醇和聚环氧乙烷链段，平均分子量为约2000道尔顿；
    (iii)第三多元醇和扩链剂中的至少一种；和
    (iv)多异氰酸酯，
    其中扩链剂包含1,4-丁二醇和1,10-癸二醇中的至少一种，多异氰酸酯包括二环己基甲烷-4,4'-二异氰酸酯。
  32. 根据权利要求1-31任一项所述的经皮吸收的药物组合物，其特征在于，其中所述热塑性聚氨酯聚合物包含通过以下物质反应所得的产物：
    (i)任选地，第一聚醚多元醇A；
    (ii)第二聚醚多元醇B，其包含聚醚共聚物二醇与聚丙二醇和聚环氧乙烷链段，平均分子量为1800-2200道尔顿；
    (iii)扩链剂；和
    (iv)多异氰酸酯。
  33. 根据权利要求3、30-32任一项所述的经皮吸收的药物组合物，其特征在于，所述扩链剂选自1,4-丁二醇，1,10-癸二醇及其组合。
  34. 根据权利要求3、30-32任一项所述的经皮吸收的药物组合物，其特征在于，其中多异氰酸酯选自脂环族和芳族二异氰酸酯。
  35. 一种如权利要求1-34任一项所述的经皮吸收的药物组合物的制备方法，其包括将酰胺类局部麻醉药与硅酮压敏胶和添加剂混合的步骤。
  36. 一种如权利要求1-34任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。
PCT/CN2021/120939 2020-09-28 2021-09-27 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和用途 WO2022063294A1 (zh)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1771025A (zh) * 2003-02-07 2006-05-10 Lts勒曼治疗系统股份公司 适于应用热能来促进活性物质渗透的透皮治疗系统及其应用
CN101494976A (zh) * 2005-12-14 2009-07-29 扎尔斯制药公司 用于经皮肤治疗痛的组合物和方法
CN101563381A (zh) * 2006-11-14 2009-10-21 迈图高新材料集团 粘合剂形成组合物和由其获得的粘合剂共混物
CN102670567A (zh) * 2005-12-14 2012-09-19 扎尔斯制药公司 用于皮肤输送药物的促通量组合物及方法
WO2017153441A1 (en) * 2016-03-09 2017-09-14 Tesa Labtec Gmbh Topical composition
WO2019079291A1 (en) * 2017-10-17 2019-04-25 Lubrizol Advanced Materials, Inc. COMPOSITION AND DEVICE FOR ADMINISTERING ACTIVE AGENTS ON SKIN SURFACES
US10307380B1 (en) * 2014-03-04 2019-06-04 Prosolus, Inc. Composition and method for transdermal lidocaine delivery

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1771025A (zh) * 2003-02-07 2006-05-10 Lts勒曼治疗系统股份公司 适于应用热能来促进活性物质渗透的透皮治疗系统及其应用
CN101494976A (zh) * 2005-12-14 2009-07-29 扎尔斯制药公司 用于经皮肤治疗痛的组合物和方法
CN102670567A (zh) * 2005-12-14 2012-09-19 扎尔斯制药公司 用于皮肤输送药物的促通量组合物及方法
CN101563381A (zh) * 2006-11-14 2009-10-21 迈图高新材料集团 粘合剂形成组合物和由其获得的粘合剂共混物
US10307380B1 (en) * 2014-03-04 2019-06-04 Prosolus, Inc. Composition and method for transdermal lidocaine delivery
WO2017153441A1 (en) * 2016-03-09 2017-09-14 Tesa Labtec Gmbh Topical composition
WO2019079291A1 (en) * 2017-10-17 2019-04-25 Lubrizol Advanced Materials, Inc. COMPOSITION AND DEVICE FOR ADMINISTERING ACTIVE AGENTS ON SKIN SURFACES

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WOLFF, HANS-MICHAEL ET AL. .: "Investigations on the Viscoelastic Performance of Pressure Sensitive Adhesives in Drug-in-Adhesive Type Transdermal Films.", PHARMACEUTICAL RESEARCH, vol. 31, no. 8, 6 March 2014 (2014-03-06), XP035385230, ISSN: 0724-8741, DOI: 10.1007/s11095-014-1318-2 *

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