WO2022007917A1 - 一种含麻醉药物活性成分的透皮制剂及其制备方法 - Google Patents

一种含麻醉药物活性成分的透皮制剂及其制备方法 Download PDF

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WO2022007917A1
WO2022007917A1 PCT/CN2021/105366 CN2021105366W WO2022007917A1 WO 2022007917 A1 WO2022007917 A1 WO 2022007917A1 CN 2021105366 W CN2021105366 W CN 2021105366W WO 2022007917 A1 WO2022007917 A1 WO 2022007917A1
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Prior art keywords
transdermal formulation
elastomer
weight
lidocaine
transdermal
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PCT/CN2021/105366
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English (en)
French (fr)
Inventor
罗琳
肖文娇
王捷
陈姣
韩江彬
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江苏恒瑞医药股份有限公司
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Publication of WO2022007917A1 publication Critical patent/WO2022007917A1/zh

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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a transdermal preparation containing an anesthetic active ingredient and a preparation method thereof.
  • Transdermal delivery system refers to a type of drug delivery method in which drugs pass through the skin at a certain rate and are absorbed into the systemic circulation through capillaries to produce systemic or local therapeutic effects.
  • Transdermal absorption preparations have the following advantages: 1 can produce lasting, constant and controllable blood concentration, reduce the number of administrations and doses, thereby reducing adverse reactions; 2 avoid the first-pass effect of the liver and the interference of gastrointestinal factors and degradation, improve the bioavailability of the drug; 3The patient can use the drug by himself, and the drug can be stopped in time if there is a problem, which is convenient to use.
  • Lidocaine has anesthesia and analgesia, because it has the characteristics of fast onset, strong and durable effect, strong penetrating power and large safety range. It is used for various forms of local anesthesia for pain relief, such as the treatment of post-herpetic neuralgia, local procedural pain, etc.
  • transdermal preparations of lidocaine including emulsions, patches, gel preparations, and the like.
  • EMLA ointment product
  • EMLA eutectic mixture of 2.5% lidocaine and 2.5% prilocaine
  • a lidocaine patch Penles Tape, was launched in Japan, which can be used for skin anesthesia before intravenous needle placement. The product is applied once 30 minutes before puncture to achieve the effect of local anesthesia.
  • WO2010008601 discloses a local anesthetic administration and delivery system, comprising a local anesthetic, an alkanediol, a fatty acid or a corresponding alcohol or ester with a melting point below 40°C and a volatile component, which, when applied to a surface, volatilizes After the components are volatilized, the remaining solution is nearly saturated with the anesthetic at this temperature, and it takes effect 15-20 minutes after administration;
  • ZL97180639.X discloses a transdermal absorption type local anesthetic gel for external use, and the second page of the manual discloses that it contains Lido A topical local anesthetic of caine, transdermal absorption enhancer, ethanol and water, at a dose of 8.3 mg/cm 2 .
  • the present invention provides a fast-acting local anesthesia transdermal preparation, which can act as anesthesia within 10-30 minutes when applied to intact skin, and is used for skin anesthesia before intravenous needle placement.
  • the present disclosure provides a transdermal formulation comprising an anesthetic active ingredient and a silicone elastomer oily base.
  • transdermal formulations described in the present disclosure include, but are not limited to, patches, ointments, gels, emulsions, lotions or solutions, preferably gels.
  • the organosilicon elastomer can be a variety of different organosilicon elastomer bases, such as organosilicon elastomer powder, organosilicon elastomer oily base (gel-like) or organosilicon elastomer aqueous base (emulsion form). Certain embodiments of the present disclosure may also use silicone elastomers other than the silicone elastomer oily base (gel-like).
  • the silicone elastomer oily base may be a mixture comprising a silicone cross-linked copolymer and a carrier liquid.
  • the organosilicon cross-linked copolymer can be selected from polydimethylsiloxane cross-linked polymer, polydimethylsiloxane/vinyl polydimethylsiloxane cross-linked polymer, polydimethylsiloxane One or more of siloxane/bis-isobutyl PPG-20 cross-linked polymer, preferably polydimethylsiloxane cross-linked polymer.
  • the carrier liquid may be selected from dimethicone, hexamethyldisiloxane, trisiloxane, cyclopentasiloxane, octylmethicone, isododecane, petrolatum , one or more of isodecyl neopentanoate and dimethiconol.
  • the carrier liquid may also be selected from one or more of isohexadecane, decamethylcyclopentasiloxane, beeswax, silica, and silica silylate.
  • the carrier liquid is preferably selected from the group consisting of polydimethylsiloxane, cyclopentasiloxane, petrolatum, beeswax, silica, silica silylate, isododecane, and isohexadecane
  • polydimethylsiloxane and/or cyclopentasiloxane are preferred from the group consisting of polydimethylsiloxane, cyclopentasiloxane, petrolatum, beeswax, silica, silica silylate, isododecane, and isohexadecane
  • polydimethylsiloxane and/or cyclopentasiloxane is preferably selected from the group consisting of polydimethylsiloxane, cyclopentasiloxane, petrolatum, beeswax, silica, silica silylate, isododecane, and isohe
  • the silicone elastomer oily base can be a mixture comprising a dimethicone crosspolymer and cyclopentasiloxane.
  • the silicone elastomer oily base can be a mixture comprising a polydimethylsiloxane crosspolymer and a polydimethylsiloxane.
  • the silicone elastomer oily base can be selected from commercially available products DOWSIL 9040 Silicone Elastomer Blend, DOWSIL 9045 Silicone Elastomer Blend, DOWSIL 9041 Silicone Elastomer Blend, DOWSIL EL-9140 DM Silicone Elastomer Blend, DOWSIL 9046 Silicone Elastomer Blend, DOWSIL 9546 Silicone Elastomer Blend, DOWSIL FB-9586 Silicone Elastomer Blend, DOWSIL EL-9240 Silicone Elastomer Blend, DOWSIL EL-9241 DM Silicone Elastomer Blend, DOWSIL EL-9048 Silicone Elastomer Blend, DOWSIL 9576 Smooth Away Elastomer, DOWSIL EL-8050 ID Silicone Organic Elastomer Blend(SOEB), DOWSIL EL-
  • Dow ST-Elastomer 10 is a blend comprising dimethicone crosspolymer and cyclopentasiloxane, specifically a dimethicone crosspolymer and decamethylcyclopentasiloxane mixture.
  • Dow TI-3021 is a blend comprising dimethicone crosspolymer and dimethicone.
  • the weight ratio of the organosilicon elastomer oily base to the anesthetic active ingredient is 10:1 to 1:10, preferably 8:1 to 1:8, more preferably 6:1 to 1:6, and more preferably 5:1 to 1:5, more preferably 4:1 to 1:5, more preferably 3:1 to 1:5, more preferably 2:1 to 1:5, more preferably 1.5:1 to 1:5, more preferably It is preferably 1.5:1 to 1:3 or 1.5:1 to 1:1.5, more preferably 1.5:1 to 1:1.
  • transdermal formulations described in the present disclosure may further comprise a lipophilic carrier, at least one penetration enhancer and a short-chain alcohol.
  • the lipophilic carrier may be a vegetable oil such as sesame oil, sunflower oil, palm kernel oil, corn oil, safflower oil, olive oil, avocado oil, jojoba oil, almond oil, canola oil, coconut oil, Cottonseed oil, peanut oil, soybean oil, wheat germ oil, grape kernel oil, etc., can also be highly purified vegetable oils, such as medium chain triglycerides, long chain triglycerides, castor oil, etc.
  • the lipophilic carrier can be a synthetic oil, eg, a fatty alcohol ester of a C 10-18 alkanoic acid, eg, selected from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl linoleate Propyl ester, isopropyl monooleate and isostearyl isostearate, etc., preferably isopropyl myristate.
  • a synthetic oil eg, a fatty alcohol ester of a C 10-18 alkanoic acid, eg, selected from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl linoleate Propyl ester, isopropyl monooleate and isostearyl isostearate, etc., preferably isopropyl myristate.
  • the lipophilic carrier may be a mineral oil, such as liquid paraffin or a hydrocarbon or mixture of hydrocarbons having a chain length of C5 to C60, preferably liquid paraffin.
  • the lipophilic carrier can be a volatile silicone oil, such as Dow Cornin Q7-9180 Silicone Fluid, Dow Cornin ST-Cyclomethicone 5-NF, Dow Cornin ST-Cyclomethicone 56-NF.
  • the lipophilic carrier may be a non-volatile silicone oil, such as Dow Corning Q7-9120 Silicone Fluid, Dow Corning ST-Dimethiconol 40, preferably Dow Corning Q7-9120 Silicone Fluid.
  • the lipophilic carrier may comprise two oils or optionally a mixture of three oils.
  • the weight ratio of the silicone elastomer oily base to the lipophilic carrier is 10:1 to 1:10, preferably 8:1 to 1:8, more preferably 6:1 to 1:6, More preferably 5:1 to 1:5, more preferably 5:1 to 1:2, more preferably 5:1 to 1:1, more preferably 4:1 to 1:1, more preferably 3:1 to 1:1, More preferably 3:1 to 2:1, more preferably 11:4.
  • the weight ratio of the lipophilic carrier to the anesthetic active ingredient is 10:1 to 1:30, preferably 10:1 to 1:20, preferably 10:1 to 1:15, more preferably 5 : 1 to 1:15, more preferably 4:1 to 1:15, more preferably 3:1 to 1:15, more preferably 2:1 to 1:15, more preferably 1:1 to 1:15, more preferably 1 : 1.5 ⁇ 1:13, more preferably 8:25, more preferably 8:15, more preferably 2:25
  • the short-chain alcohol is an aliphatic alcohol containing 1-6 carbon atoms and 1-3 hydroxyl groups, preferably one of ethanol, n-propanol, isopropanol, n-butanol, isobutanol or butanediol and propylene glycol.
  • ethanol n-propanol
  • isopropanol n-butanol
  • the transdermal formulations of the present disclosure contain 20-70% by weight of short-chain alcohol, preferably 20-50% short-chain alcohol, more preferably 30-50% short-chain alcohol, and most preferably 35-45% short chain alcohols are preferred.
  • the penetration enhancer described in the present disclosure can be selected from one or more of phosphonates, cholesterol and surfactants.
  • the phospholipids are preferably natural phospholipids and/or synthetic phospholipids.
  • the natural phospholipid may be selected from egg yolk lecithin, hydrogenated egg yolk phospholipid, egg yolk phosphatidylglycerol, egg yolk phosphatidylserine, hydrogenated egg yolk cephalin-PEG2000, soybean lecithin, hydrogenated soybean lecithin, soybean phosphatidylglycerol, soybean phosphatidylserine and hydrogenated One or more of soybean cephalin-PEG2000, preferably one or more of egg yolk lecithin and soybean lecithin, more preferably egg yolk lecithin.
  • the synthetic phospholipid may be selected from the group consisting of dioleoylphosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine, dilaurin Acylphosphatidylcholine, dioleoylphosphatidylglycerol, distearoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dilauroylphosphatidylglycerol, distearoylphosphatidylethanolamine -One or more of PEG2000, dipalmitoylphosphatidylethanolamine-PEG2000, and dimyristoylphosphatidylethanolamine-PEG2000.
  • the weight ratio of the anesthetic active ingredient to the phospholipid in the present disclosure is 5:1-1:5, preferably 4:1-1:4, more preferably 3:1-1:3, more preferably 2:1-1:2 , more preferably 1:1.
  • the weight ratio of the anesthetic active ingredient and egg yolk lecithin in the present disclosure is 5:1-1:5, preferably 4:1-1:4, more preferably 3:1-1:3, more preferably 2:1-1 :2, more preferably 1:1.
  • the weight ratio of the anesthetic active ingredient to cholesterol in the present disclosure is 100:1-1:10, preferably 50:1-1:1, more preferably 30:1-10:1.
  • the surfactant may be selected from one or more of amphoteric surfactants, anionic surfactants, cationic surfactants and nonionic surfactants.
  • the surfactant can be selected from sodium dodecyl sulfate (SDS), sodium deoxycholate, sodium pentanesulfonate, Tween, Span, Poloxamer, polyoxyethylene lauryl ether, hexadecyl Trimethylammonium bromide, dodecylethyldimethylammonium bromide, cetylpyridinium chloride (CPC), benzalkonium chloride (BAC) and benzethonium chloride (BZT) ) in one or more, preferably one or more in sodium lauryl sulfate, Tween (such as Tween 80), Span (such as Span 85, Span 80) and polyoxyethylene lauryl ether kind.
  • SDS sodium dodecyl sulfate
  • Span Poloxa
  • the weight ratio of the surfactant content is 0.01% to 5%, preferably 0.1% to 2.5%, more preferably 0.5% to 1.0% (eg 0.6%).
  • the amount of different types of surfactants can be selected according to actual needs, and is generally the same amount.
  • the penetration enhancer is preferably one or more of natural lecithin, cholesterol and surfactant, preferably selected from surfactant or a mixture of natural lecithin, cholesterol and surfactant.
  • the penetration enhancers described in the present disclosure may be selected from surfactants, such as sodium lauryl sulfate.
  • the penetration enhancer of the present disclosure may be a mixture of egg yolk lecithin, cholesterol, sodium lauryl sulfate, Tween and Spann.
  • the penetration enhancer of the present disclosure may be a mixture of egg yolk lecithin, cholesterol, and sodium lauryl sulfate.
  • the penetration enhancer of the present disclosure may be a mixture of egg yolk lecithin, cholesterol, Tween, Span, and polyoxyethylene lauryl ether.
  • the transdermal formulations of the present disclosure comprise from 1% to 30% by weight anesthetic active ingredient, preferably from 1% to 20% anesthetic active ingredient, more preferably from 1% to 10% anesthetic active ingredient, More preferably, 2% to 5% of the anesthetic active ingredient (eg, 3% to 5% of the anesthetic active ingredient).
  • the anesthetic active ingredient in the present disclosure may be selected from amide-type local anesthetics.
  • the amide local anesthetics can be lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, etiducaine, prilocaine and their pharmaceutically acceptable salts One or more of them, preferably one or more of bupivacaine, levobupivacaine, ropivacaine, lidocaine and their pharmaceutically acceptable salts, more preferably lidocaine or its pharmaceutically acceptable salts.
  • the anesthetic active ingredient may also be selected from non-steroidal anti-inflammatory drugs such as celecoxib, diclofenac sodium, flurbiprofen, ibuprofen, indomethacin, meloxicam, and the like , and can be selected from acetaminophen, tramadol, fentanyl, codeine and the like.
  • non-steroidal anti-inflammatory drugs such as celecoxib, diclofenac sodium, flurbiprofen, ibuprofen, indomethacin, meloxicam, and the like , and can be selected from acetaminophen, tramadol, fentanyl, codeine and the like.
  • the transdermal formulations described in the present disclosure may also contain thickening agents.
  • the thickening agent can be selected from one or more of carbomer, xanthan gum, sodium polyacrylate, methyl cellulose and hydroxypropyl methyl cellulose; preferably the thickening agent is carbomer (such as Carbomer 974).
  • the transdermal formulations described in the present disclosure may further comprise one or more of an aqueous medium, an antioxidant, a bacteriostatic agent, and a pH adjusting agent.
  • the aqueous medium can be selected from water, buffered saline solution or sodium chloride solution and the like.
  • the content of the aqueous medium may be 30%-80% by weight, preferably 40%-70%, more preferably 45-60%, most preferably 40%-50% (for example, 42%-50%, such as 42.4%) , 45.8%, 47.1%, 49.8%).
  • the antioxidant can be selected from thioglycerol, ascorbic acid, sodium ascorbate, butylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT), tocopherol, sodium bisulfite and one or more of sodium metabisulfite, etc., preferably one or more of butylated hydroxyanisole, 2,6-di-tert-butyl-4-methylphenol and thioglycerol.
  • the content of the antioxidant may be 0.01%-10% by weight, preferably 0.01%-5%, more preferably 0.1%-2%, most preferably 0.1%-1% (eg 0.5%).
  • the antioxidant may be butylated hydroxyanisole (BHA).
  • the antioxidant may be 2,6-di-tert-butyl-4-methylphenol (BHT).
  • the antioxidant may be thioglycerol.
  • bacteriostatic agent can be selected from a kind of in propylparaben, capric acid, lauric acid, chitosan, sodium benzoate, fumaric acid, potassium sorbate, chlorobutanol, benzyl alcohol and phenol etc. or more, preferably propylparaben.
  • the content of the bacteriostatic agent can be 0.01%-10% by weight, preferably 0.01%-5%, more preferably 0.1%-2%, most preferably 0.1%-1% (eg 0.5%).
  • the pH adjusting agent can be selected from one or more of vitamin C (also known as ascorbic acid), lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, hydrochloric acid, triethanolamine, phosphoric acid and acetic acid; Hydrochloric acid (eg, 50% aqueous hydrochloric acid, v/v) or triethanolamine (eg, 50% aqueous triethanolamine, v/v) is preferred.
  • the pH of the transdermal formulation is adjusted to 6.0-8.0, preferably 7.0-8.0, using a pH adjuster.
  • a transdermal formulation of the present disclosure comprises the anesthetic active ingredient, the silicone elastomer oily base, the lipophilic carrier, the short-chain alcohol, the penetration enhancer, the enhancer thickener and the aqueous medium.
  • a transdermal formulation of the present disclosure comprises the anesthetic active ingredient, the silicone elastomer oily base, the lipophilic carrier, the short-chain alcohol, the penetration enhancer, the enhancer Thickening agent, the aqueous medium and the pH adjusting agent.
  • a transdermal formulation of the present disclosure comprises the anesthetic active ingredient, the silicone elastomer oily base, the lipophilic carrier, the short-chain alcohol, the penetration enhancer, the enhancer Thickening agent, the aqueous medium, the antioxidant and the antibacterial agent.
  • a transdermal formulation of the present disclosure comprises the anesthetic active ingredient, the silicone elastomer oily base, the lipophilic carrier, the short-chain alcohol, the penetration enhancer, the enhancer Thickening agent, the aqueous medium, the pH adjusting agent, the antioxidant and the antibacterial agent.
  • the transdermal formulations of the present disclosure comprise 1% to 30% by weight of an anesthetic active ingredient, 1% to 10% of a silicone elastomer oily base, 1% to 5% of a lipophilic carrier, 30% to 50% of short chain alcohol, 0.1% to 1% of surfactant, 0.1% to 1% of thickener, 30% to 65% of aqueous medium.
  • lidocaine Preferably, 1% to 30% by weight of lidocaine, 1% to 10% by weight of a mixture comprising cyclopentasiloxane and dimethicone crosspolymer, 1% to 5% of nutmeg Isopropyl acid, 30%-50% ethanol, 0.1%-1% surfactant, 0.1%-1% carbomer, 30%-65% water. More preferably 10% to 30% by weight of lidocaine, 1% to 10% of Dow ST-Elastomer 10, 1% ⁇ 5% isopropyl myristate, 30% ⁇ 50% ethanol, 0.1% ⁇ 1% surfactant, 0.1% ⁇ 1% carbomer, 30% ⁇ 65% % water.
  • the transdermal formulations of the present disclosure comprise 1% to 10% by weight of an anesthetic active ingredient, 1% to 10% of a silicone elastomer oily base, 1% to 5% of a lipophilic carrier, 30% ⁇ 50% short chain alcohol, 1% ⁇ 10% egg yolk lecithin, 0.01% ⁇ 1% cholesterol, 0.1% ⁇ 1% surfactant, 0.1% ⁇ 1% thickener, 30% ⁇ 65% aqueous medium.
  • lidocaine preferably comprises 1-10% by weight of lidocaine, 1-10% of a mixture comprising cyclopentasiloxane and dimethicone crosspolymer, 1-5% of nutmeg Isopropyl acid, 30%-50% ethanol, 1%-10% egg yolk lecithin, 0.01%-1% cholesterol, 0.1%-1% surfactant, 0.1%-1% carbomer , 30% to 65% of water.
  • It preferably contains 1% to 10% by weight of lidocaine, 1% to 10% of Dow ST-Elastomer 10, 1%-5% isopropyl myristate, 30%-50% ethanol, 1%-10% egg yolk lecithin, 0.01%-1% cholesterol, 0.1%-1% Surfactant, 0.1%-1% carbomer, 30%-65% water.
  • a transdermal formulation of the present disclosure comprises by weight 3% lidocaine, 3% egg yolk lecithin, 0.2% cholesterol, 0.2% sodium dodecyl sulfonate, 0.2% Tween 80, Span 85 0.2%, Carbomer (eg Carbomer 974) 0.8%, Hydrochloric acid 0.6%, Isopropyl myristate 1.6%, Dow 4.4% ST-Elastomer 10, 0.5% butylated hydroxyanisole, 0.5% propylparaben, 35% ethanol and 49.8% water (Formulation 1).
  • a transdermal formulation of the present disclosure comprises by weight 5% lidocaine, 5% egg yolk lecithin, 0.2% cholesterol, 0.6% sodium dodecyl sulfonate, 0.5% Carbomer (eg Carbomer 974), 0.6% triethanolamine, 1.6% liquid paraffin, 4.4% Dow ST-Elastomer 10, 35% ethanol and 47.1% water (Formulation 2).
  • a transdermal formulation of the present disclosure comprises by weight 5% lidocaine, 5% egg yolk lecithin, 0.2% cholesterol, 0.2% sodium dodecyl sulfonate, 0.2% Tween 80, Span 85 0.2%, Carbomer (eg Carbomer 974) 0.5%, Hydrochloric acid 0.6%, Isopropyl myristate 1.6%, Dow 4.4% ST-Elastomer 10, 35% ethanol and 47.1% water (Formulation 3).
  • a transdermal formulation of the present disclosure comprises by weight 5% lidocaine, 5% egg yolk lecithin, 0.2% cholesterol, 0.2% Tween 80, 0.2% Span 85, 0.2% polyoxyethylene lauryl ether, 0.5% carbomer (eg Carbomer 974), 0.6% hydrochloric acid, 1.6% isopropyl myristate, 4.4% Dow ST-Elastomer 10, 35% ethanol and 47.1% water (Formulation 4).
  • a transdermal formulation of the present disclosure comprises by weight 5% lidocaine, 5% egg yolk lecithin, 0.2% cholesterol, 0.2% sodium dodecyl sulfonate, 0.2% Tween 80, Span 85 0.2%, Carbomer (eg Carbomer 974) 0.8%, Hydrochloric acid 0.6%, Isopropyl myristate 1.6%, Dow 4.4% ST-Elastomer 10, 0.5% butylated hydroxyanisole, 0.5% propylparaben, 35% ethanol and 45.8% water (Formulation 5).
  • a transdermal formulation of the present disclosure comprises by weight 5% lidocaine, 0.6% sodium dodecyl sulfonate, 0.8% carbomer, 0.2% hydrochloric acid, 1.6% Isopropyl myristate, Dow 4.4% ST-Elastomer 10, 45% ethanol and 42.4% water (Formulation 6).
  • a transdermal formulation of the present disclosure comprises, by weight, 3% lidocaine, 3% egg yolk lecithin, 0.2% cholesterol, 0.2% sodium lauryl sulfate, 0.2% ethoxylate Warm 80, 0.2% Span 80, 35% Ethanol, 50.75% Water, 0.85% Carbomer, 4.4% Dow ST-Elastomer 10, 1.6% isopropyl myristate, 0.2% thioglycerol, 0.2% propylparaben and 0.2% hydrochloric acid (Formulation 7).
  • a transdermal formulation of the present disclosure comprises, by weight, 3% lidocaine, 3% egg yolk lecithin, 0.2% cholesterol, 0.2% sodium lauryl sulfate, 0.2% ethoxylate Warm 80, 0.2% Span 80, 35% Ethanol, 50.65% Water, 0.85% Carbomer, 4.4% Dow ST-Elastomer 10, 1.6% isopropyl myristate, 0.1% BHT, 0.2% thioglycerol, 0.2% propylparaben and 0.2% hydrochloric acid (Formulation 8).
  • a transdermal formulation of the present disclosure comprises by weight 20% lidocaine, 0.2% sodium lauryl sulfate, 0.2% Tween 80, 0.2% Span 80, 45% ethanol, 26.2% water, 1.5% carbomer, 4.4% E10, 1.6% isopropyl myristate, 0.2% propylparaben, and 0.5% hydrochloric acid (Formulation 9).
  • a transdermal formulation of the present disclosure comprises, by weight, 3% lidocaine, 3% egg yolk lecithin, 0.2% cholesterol, 0.2% sodium lauryl sulfate, 0.2% ethoxylate Warm 80, 0.2% Span 80, 35% Ethanol, 54% Water, 0.8% Carbomer, 1% Dow ST-Elastomer 10, 2% isopropyl myristate, 0.2% thioglycerol and 0.2% propylparaben (Formulation 10).
  • a transdermal formulation of the present disclosure comprises, by weight, 3% lidocaine, 3% egg yolk lecithin, 0.2% cholesterol, 0.2% sodium lauryl sulfate, 0.2% ethoxylate Warm 80, 0.2% Span 80, 35% Ethanol, 51% Water, 0.8% Carbomer, 5% Dow ST-Elastomer 10, 1% isopropyl myristate, 0.2% thioglycerol and 0.2% propylparaben (Formulation 11).
  • a transdermal formulation of the present disclosure comprises, by weight, 3% lidocaine, 3% egg yolk lecithin, 0.2% cholesterol, 0.2% sodium lauryl sulfate, 0.2% ethoxylate Warm 80, 0.2% Span 80, 35% Ethanol, 51% Water, 0.8% Carbomer, 4.4% Dow TI-3021, 1.6% isopropyl myristate, 0.2% thioglycerol, and 0.2% propylparaben (Formulation 12).
  • the transdermal formulations described in the present disclosure provide one or more of the following skin exposure characteristics as determined by in vitro percutaneous penetration assays: a) skin after 10 minutes of administration The exposure is not less than 30 ⁇ g/cm 2 , preferably not less than 50 ⁇ g/cm 2 , more preferably not less than 80 ⁇ g/cm 2 ; b) After 30 minutes of administration, the skin exposure is not less than 30 ⁇ g/cm 2 , preferably not less than 80 ⁇ g/cm 2 50 ⁇ g/cm 2 , more preferably not less than 80 ⁇ g/cm 2 .
  • the dosage of the test skin in the in vitro percutaneous penetration test is 0.34mg/cm 2 ⁇ 1.2mg/cm 2
  • the test skin is preferably pig ear back skin, and the resistance value is higher than 3000 ⁇ .
  • the specific experimental operation refers to the operation described in Example 2 Steps, not detailed refer to "Ueda, CT, Shah, VP, Derdzinski, K., Ewing, G., Flynn, G., Maibach, H., ... & Yacobi, A. (2009). Topical and Transdermal Drug Products.” or “Transdermal and Topical Delivery Systems-Product Development and Quality Considerations Guidance for Industry DRAFT GUIDANCE November 2019”, where the skin exposure is the lidocaine content in the skin extract sample.
  • the transdermal formulation of the present disclosure when used for pain threshold detection in animals, provides one or more of the following characteristics of the percentage increase in pain threshold: a) 10 minutes after administration , the percentage of increase in pain threshold is not less than 200%, preferably not less than 300%, more preferably not less than 400%; b) 20min after administration, the percentage of increase in pain threshold is not less than 200%, preferably not less than 300%, More preferably not less than 400%; c)
  • the percentage of increase in pain threshold is not less than 300%, preferably not less than 400%, more preferably not less than 500%; d) 10 minutes after administration, 30 minutes after the end of administration, the percentage of increase in pain threshold is not less than 100%, preferably not less than 200%, more preferably not less than 300%; e) After 10 minutes of administration, and 60 minutes after the end of administration, the percentage of pain threshold increase is not higher than 200%, preferably not higher than 150%, more preferably Not higher than 100%; f) After 10 minutes of administration, and 120 minutes after the end of administration, the percentage of pain threshold increase is not higher than 100%, preferably not higher than 50%, more preferably not higher than 30%; wherein the pain threshold measured value is a pain threshold after administration of guinea pig IITC electronic measuring pain cytometry, the animal is preferably a guinea pig, the dose of 2cm circle 1.2mg / cm 2 diameter, to escape response in guinea pigs appeared positive sign, pain thresholds recorded
  • the skin surface agent is usually removed after 10 minutes of application on the skin surface, and the pain threshold is measured immediately. More preferably 0 to 2 min, most preferably 0 to 1 min. 30 minutes after the end of administration is usually to remove the drug on the skin surface after the drug is applied on the skin surface for a period of time, and 30 minutes after the drug is removed, the pain threshold is measured immediately.
  • the pain threshold is measured immediately.
  • the present disclosure provides a preparation method of the transdermal formulation, comprising the following steps: mixing the anesthetic active ingredient and the silicone elastomer oily base, optionally with the lipophilic carrier, the short One or more of the chain alcohol, the penetration enhancer, the thickener, the aqueous medium, the pH adjuster, the antioxidant and the antibacterial agent are mixed; preferably, the following steps are included:
  • the preparation method of the transdermal formulation described in the present disclosure includes: 1) mixing an alcoholic phase containing an anesthetic active ingredient and an aqueous phase; 2) mixing a thickening agent, a lipophilic carrier and an organosilicon elastomer oily base; 3) mixing The resulting mixtures of 1) and 2) are mixed.
  • the alcohol phase is an alcohol solution formed by dissolving the anesthetic active ingredients in short-chain alcohol, and the alcohol phase may also contain penetration enhancers dissolved in short-chain alcohol, such as egg yolk lecithin, cholesterol and Tween, Span and other surfactants.
  • the water phase is an aqueous medium containing a penetration enhancer, and the penetration enhancer is preferably a surfactant such as sodium lauryl sulfate.
  • the transdermal formulation of the present disclosure contains 20-70% by weight of short-chain alcohols.” That is, short-chain alcohols The weight of the alcohol is 20-70% by weight of the transdermal formulation.
  • the "pain threshold” described in this disclosure is the minimum stimulus intensity at which pain begins to be perceived; the “pain threshold” is the administration site of the guinea pigs that is respectively acupuncture with the needle of the IITC electronic pain measuring instrument, and the avoidance reaction of the guinea pigs is positive. The sign is displayed as the pain threshold with the pain meter.
  • the "percent increase in pain threshold” referred to in the present disclosure is the percentage increase in pain threshold compared to normal pain threshold after administration.
  • the "skin exposure amount" described in the present disclosure is after a period of time after the application of the agent containing the active ingredient on the skin surface, after the surface of the test skin is cleaned, the content of the active ingredient in the test skin is detected, that is, the active ingredient in the skin extract content.
  • mixing and “mixing” mean that the order of adding components is not limited.
  • mixing A into B can express the meaning of adding A to B, or expressing the meaning of adding B to A, and mix A and B.
  • mixing A and B can express the meaning of adding A to B to mix, or it can express the meaning of B adding A to mix.
  • the transdermal preparation of the present disclosure can take effect quickly within 10-30 minutes, has high skin exposure and low irritation, and can be used for local anesthesia before medical treatment, especially puncture before venous indwelling needle.
  • the transdermal preparation of the present disclosure has good stability under long-term storage, and after storage for one month, the content of related substances and the content uniformity meet the pharmaceutical standards.
  • the content of impurities in the following examples was detected by HPLC, and the detection conditions were to use HPLC of Thermo U3000 model, DAD detector, ACE Excel 3 Super C18 column (4.6*150mm, 3 ⁇ m) chromatographic column, and the mobile phase was acetonitrile/phosphate buffer solution, detection wavelength 230nm.
  • the multifunctional transdermal diffusion instrument used for the determination of in vitro transdermal penetration test was developed by Shenyang Pharmaceutical University & Yanbian University, and the model was SYT102.
  • the patch was purchased by Nitto Denko.
  • the manufacturer of the IITC electronic pain measuring instrument used in Example 5 is IITC Life Science, the model is 2450, the mechanical pain threshold test range is 0 ⁇ 200g, and the test accuracy is 0.01g.
  • TI-3021 was purchased from DuPont, and is referred to as TI-3021 in the following examples.
  • API refers to lidocaine
  • phospholipid refers to egg yolk lecithin
  • the preparation method of prescription 1-5 and comparative example 1-3 Weigh the prescription amount of lidocaine (API-anesthetic active ingredient), egg yolk lecithin (penetration enhancer), cholesterol (penetration enhancer) and surfactant ( The penetration enhancer (except SDS) is dissolved in absolute ethanol (short-chain alcohol) to obtain a mono-alcohol phase. Meanwhile, the SDS (sodium dodecylbenzenesulfonate, surfactant) of the recipe quantity is weighed and dissolved in water (aqueous medium) to obtain an aqueous phase. Then the alcoholic phase was slowly poured into the aqueous phase, and stirring was started at the same time.
  • lidocaine API-anesthetic active ingredient
  • egg yolk lecithin penetration enhancer
  • cholesterol penetration enhancer
  • surfactant The penetration enhancer (except SDS) is dissolved in absolute ethanol (short-chain alcohol) to obtain a mono-alcohol phase. Meanwhile, the SDS (s
  • antioxidant butylated hydroxyanisole (BHA)
  • bacteriostatic agent propylparaben
  • carbomer 974 thickener
  • IPM-lipophilic carrier isopropyl myristate
  • ST-Elastomer 10 silicone elastomer oily base
  • liquid paraffin lipophilic carrier
  • Recipe 6 Preparation method of Comparative Example 4: Weigh the recipe amount of lidocaine (API-anesthetic active ingredient) and dissolve it in absolute ethanol (short-chain alcohol) to obtain an alcohol phase. Meanwhile, SDS (sodium dodecylbenzenesulfonate, surfactant) of the recipe quantity was weighed and dissolved in ultrapure water (aqueous medium) to obtain an aqueous phase. Mix the alcohol phase with the water phase, and stir evenly, add carbomer (thickener) to recipe 6, stir until swelling is complete, continue to add IPM (lipophilic carrier) and E10, stir and mix, and finally use hydrochloric acid. Adjust pH to a suitable range (7.0-8.0).
  • IVPT in vitro percutaneous penetration test
  • the purchased pig ear dorsal skin is cut into several pieces with an area of 1.48cm 2 round, surgical scissors were used to remove hair, washed with PBS buffer (pH 7.4), and the resistance value of pig skin was detected, and pig skin with a resistance value higher than 3000 ⁇ was selected for the experiment.
  • Divide the cut round pigskin into groups of 4, install them in the middle of the supply cell and the receiving cell of the Franz flow cell and seal them.
  • the flow cell After adding quantitative PBS buffer (pH7.4) to the receiving cell, the flow cell is placed Put it in a water bath or dry heat heating device, let the skin temperature rise to 32 ⁇ 1°C and then equilibrate for 30 minutes, and load the samples according to the dosage in Table 2.
  • Two groups of pig skins are used for each prescription, and one group is administered for 10 minutes. After the results, another group measured the results after 30 minutes of administration. After the administration, 200 microliters were sampled from the sampling arm. Immediately after the sampling, the receiving medium in the receiving tank was removed, and the pigs were washed with ethanol, a proven recovery medium. The surface of the skin (1ml ⁇ 5), then the pig skin was cut into pieces and extracted with methanol to recover the lidocaine.
  • the receiving liquid, washing liquid and pigskin extract samples were quantified by HPLC method respectively to determine the penetration amount of lidocaine, the residual amount on the skin surface and the exposure in the skin, where the skin exposure was the lidocaine in the pigskin extract sample. content.
  • the efficacy of local anesthesia was positively correlated with the exposure of lidocaine in the skin by in vivo efficacy tests.
  • Preparation recipe 7 was carried out according to the preparation method described in Example 1.
  • the preparation obtained was divided into 20ml vials, sealed with a cap, and placed under long-term conditions (25°C, 60% RH) and accelerated conditions (40°C, 75% RH), wherein the long-term conditions (25°C, 60% RH) RH) at 0d and 1M for stability testing, and under accelerated conditions (40°C, 75% RH) for stability testing at 0d, 7d and 1M, see Table 6 for specific stability data, when placed for 1 month The stability is good, and the content and content uniformity of single impurity and total impurity meet the standard of pharmacopoeia.
  • IVPT in vitro percutaneous penetration test
  • Embodiment 4 animal experiment of lidocaine transdermal preparation
  • the Penles, blank preparation, prescription 8 and prescription 9 were administered according to the administration information in Table 8. According to the measurement time of the pain threshold of guinea pigs before and after administration in each stage of the experiment, the needles of IITC electronic pain measuring instrument were used for acupuncture respectively. At the administration site of guinea pigs, the avoidance reaction of guinea pigs was regarded as a positive sign, and the pain threshold of guinea pigs was recorded. There were 10 guinea pigs in each group, and they were respectively detected 10/20/30 minutes after administration. Immediately after the preparation was removed, 0.5h, 1h, and 2h were respectively detected The pain threshold at the administration site was measured 3 times each time, and the average value of the 3 times was calculated.
  • pain threshold increase (g) pain threshold after administration - pain threshold before administration
  • the formula for calculating the percentage of pain threshold increase (pain threshold [after administration] - pain threshold [before administration]) / (pain threshold [before administration]) ⁇ 100%
  • Prescriptions 10-12 were prepared according to the preparation method described in Example 1, and the prepared recipes 10-12 were subjected to in vitro percutaneous penetration experiments according to the operation method used in Example 2, and the dosage was 0.47 mg/cm 2 .

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Abstract

本公开涉及一种含麻醉药物活性成分的透皮制剂及其制备方法，所述透皮制剂包含麻醉活性成分、有机硅弹性体混合物。具有稳定性好，起效快的特点。

Description

一种含麻醉药物活性成分的透皮制剂及其制备方法
本申请要求申请日为2020年7月10日的中国专利申请202010664706.3以及申请日为2021年2月18日的中国专利申请202110189899.6的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物制剂领域，具体涉及一种含麻醉药物活性成分的透皮制剂及其制备方法。
背景技术
透皮给药系统(Transdermal delivery system，TDS)，是指药物以一定的速率通过皮肤，经毛细血管吸收进入体循环而产生全身或局部治疗作用的一类给药方式。透皮吸收制剂有以下几个优点：①可产生持久、恒定和可控的血药浓度，减少给药次数和剂量，从而减轻不良反应；②避免肝脏的首过效应和胃肠道因素的干扰与降解作用，提高药物的生物利用度；③患者可以自己用药，出现问题可及时停药，使用方便。
利多卡因(Lidocaine)具有麻醉和镇痛作用，因为起效快、作用强而持久、穿透力强及安全范围较大等特点，同时无扩张血管作用，对组织几乎没有刺激性，因此广泛用于多种形式的局部麻醉止痛，如治疗带状疱疹后神经痛，局部操作性疼痛等。目前已上市销售的利多卡因的透皮制剂种类较多，包括乳剂、贴剂、凝胶制剂等。美国阿斯利康开发了一种膏剂产品EMLA，该产品包括2.5％利多卡因和2.5％的丙胺卡因混合而成的共融混合物，并与水一起形成膏剂。将该产品施用于皮肤上后，需60～70分钟才能起效，使痛觉消失。在日本上市了一种利多卡因的贴剂Penles Tape，可用于静脉置留针前的皮肤麻醉，在穿刺前30min一次性施用该产品，达到局部麻醉的效果。WO2010008601中公开了一种局部麻醉剂的给药输送系统，包含局部麻醉剂、烷二醇、脂肪酸或熔点低于40℃的相应的醇或酯和易挥发的成分，将其施用在表面上时，挥发成分挥发后，使得剩余溶液在该温度下麻醉剂接近饱和，在给药15-20分钟后起效；ZL97180639.X公开了一种透皮吸收型外用局麻药凝胶，说明书第2页公开含有利多卡因、透皮吸收促进剂、乙醇和水的外用局麻药，药剂量为8.3mg/cm 2。
现有的利多卡因透皮制剂中，半固体制剂起效较慢，贴剂容易导致皮肤过敏、泛红，生产工艺和条件也较为复杂。本发明提供了一种快速起效的局部麻醉透皮制剂，施用在 完整皮肤上可以在10-30min内起到麻醉的作用，用于静脉置留针前的皮肤麻醉。
发明内容
本公开提供了一种透皮制剂，包含麻醉活性成分和有机硅弹性体油性基质。
本公开所述的透皮制剂，制剂的形态包括但不限于贴剂、软膏剂、凝胶剂、乳剂、洗剂或溶液剂，优选为凝胶剂。
其中所述有机硅弹性体可为有机硅弹性体粉末、有机硅弹性体油性基质(凝胶状)或有机硅弹性体水性基质(乳液状)等多种不同的有机硅弹性体基质。本公开的某些实施方案还可以使用除有机硅弹性体油性基质(凝胶状)外其他的有机硅弹性体。
所述有机硅弹性体油性基质可为包含有机硅交联共聚物和载液的混合物。其中所述有机硅交联共聚物可选自聚二甲基硅氧烷交联聚合物、聚二甲基硅氧烷/乙烯基聚二甲基硅氧烷交联聚合物、聚二甲基硅氧烷/双-异丁基PPG-20交联聚合物中的一种或几种，优选聚二甲基硅氧烷交联聚合物。
所述载液可选自聚二甲基硅氧烷、六甲基二硅氧烷、三硅氧烷、环戊硅氧烷、辛基聚甲基硅氧烷、异十二烷、矿脂、新戊酸异癸酯、聚二甲基硅氧烷醇的一种或几种。
所述载液还可选自异十六烷、十甲基环戊硅氧烷、蜂蜡、硅石和甲硅烷基化硅石中的一种或多种。
在某些实施方案中，所述载液优选选自聚二甲基硅氧烷、环戊硅氧烷、矿脂、蜂蜡、硅石、甲硅烷基化硅石、异十二烷和异十六烷中的一种或多种；进一步优选聚二甲基硅氧烷和/或环戊硅氧烷。
在某些实施方案中，所述有机硅弹性体油性基质可为包含聚二甲基硅氧烷交联聚合物和环戊硅氧烷的混合物。
在某些实施方案中，所述有机硅弹性体油性基质可为包含聚二甲基硅氧烷交联聚合物和聚二甲基硅氧烷的混合物。所述有机硅弹性体油性基质可选自市售产品DOWSIL 9040 Silicone Elastomer Blend、DOWSIL 9045 Silicone Elastomer Blend、DOWSIL 9041 Silicone Elastomer Blend、DOWSIL EL-9140 DM Silicone Elastomer Blend、DOWSIL 9046 Silicone Elastomer Blend、DOWSIL 9546 Silicone Elastomer Blend、DOWSIL FB-9586 Silicone Elastomer Blend、DOWSIL EL-9240 Silicone Elastomer Blend、DOWSIL EL-9241 DM Silicone Elastomer Blend、DOWSIL EL-9048 Silicone Elastomer Blend、DOWSIL 9576 Smooth Away Elastomer、DOWSIL EL-8050 ID Silicone Organic Elastomer Blend(SOEB)、DOWSIL EL-8051 IN Silicone Organic Elastomer Blend(SOEB)、DOWSIL EL-8052 IH  Silicone Organic Elastomer Blend(SOEB)、Dow
Figure PCTCN2021105366-appb-000001
ST-Elastomer 10、Dow
Figure PCTCN2021105366-appb-000002
TI-3021，优选Dow
Figure PCTCN2021105366-appb-000003
ST-Elastomer 10、Dow
Figure PCTCN2021105366-appb-000004
TI-3021中的一种或组合。
其中Dow
Figure PCTCN2021105366-appb-000005
ST-Elastomer 10是包含聚二甲基硅氧烷交联聚合物和环戊硅氧烷的混合物，具体为包含聚二甲基硅氧烷交联聚合物和十甲基环戊硅氧烷的混合物。Dow 
Figure PCTCN2021105366-appb-000006
TI-3021是包含聚二甲基硅氧烷交联聚合物和聚二甲基硅氧烷的混合物。
其中所述有机硅弹性体油性基质与所述麻醉活性成分的重量比为10∶1～1∶10，优选8∶1～1∶8，更优选为6∶1～1∶6，更优选为5∶1～1∶5，更优选4∶1～1∶5，更优选3∶1～1∶5，更优选2∶1～1∶5，更优选为1.5∶1～1∶5，更优选为1.5∶1～1∶3或1.5∶1～1∶1.5，更优选为1.5∶1～1∶1。
本公开所述的透皮制剂，还可包含亲脂性载体、至少一种促渗剂和短链醇。
所述亲脂性载体可以是植物油，例如为芝麻油，向日葵油，棕榈仁油，玉米油，红花油，橄榄油，鳄梨油，霍霍巴油，杏仁油，低芥酸菜子油，椰子油，棉籽油，花生油，大豆油，小麦胚芽油，葡萄仁油等，也可以是高度纯化的植物油，例如中链甘油三酸酯，长链甘油三酸酯，蓖麻油等。
在某些实施方案中，所述亲脂性载体可以是合成油，例如C 10-18链烷酸的脂肪醇酯，例如选自肉豆蔻酸异丙酯，棕榈酸异丙酯，亚油酸异丙酯，单油酸异丙酯和异硬脂基异硬脂酸酯等，优选肉豆蔻酸异丙酯。
在某些实施方案中，所述亲脂性载体可以是矿物油，例如液体石蜡或链长为C5至C60的烃或烃的混合物，优选液体石蜡。
在某些实施方案中，所述亲脂性载体可以是挥发性硅油，例如Dow Cornin Q7-9180 Silicone Fluid、Dow Cornin ST-Cyclomethicone 5-NF、Dow Cornin ST-Cyclomethicone 56-NF。在某些实施方案中，亲脂性载体可以是非挥发性硅油，如Dow Cornin Q7-9120 Silicone Fluid、Dow Corning ST-Dimethiconol 40，优选Dow Corning Q7-9120 Silicone Fluid。
在某些实施方案中，所述亲脂性载体可包含两种油或任选地三种油的混合物。
在某些实施方案中，所述有机硅弹性体油性基质与亲脂性载体的重量比为10∶1～1∶10，优选8∶1～1∶8，更优选6∶1～1∶6，更优选5∶1～1∶5，更优选5∶1～1∶2，更优选5∶1～1∶1，更优选4∶1～1∶1，更优选3∶1～1∶1，更优选3∶1～2∶1，更优选11∶4。
在某些实施方案中，所述亲脂性载体的与麻醉活性成分的重量比为10∶1～1∶30，优选10∶1～1∶20，优选10∶1～1∶15，更优选5∶1～1∶15，更优选4∶1～1∶15，更优选3∶1～1∶15，更优选2∶1～1∶15，更优选1∶1～1∶15，更优选1∶1.5～1∶13，更优选8∶25，更优选8∶15，更优选2∶25
所述短链醇为含有1～6个碳原子、1-3个羟基的脂肪醇，优选乙醇、正丙醇、异丙醇、正丁醇、异丁醇或丁二醇、丙二醇中的一种或几种，更优选乙醇、丙二醇中的一种或组 合，最优选为乙醇。
在某些实施方案中，本公开的透皮制剂中含有以重量计为20-70％的短链醇，优选20-50％的短链醇，更优选30-50％的短链醇，最优选为35-45％的短链醇。
本公开中所述的促渗剂可选自膦酯、胆固醇和表面活性剂中的一种或几种。所述的磷脂优选为天然磷脂和/或合成磷脂。
所述天然磷脂可选自蛋黄卵磷脂、氢化蛋黄磷脂、蛋黄磷脂酰甘油、蛋黄磷脂酰丝氨酸、氢化蛋黄脑磷脂-PEG2000、大豆磷脂、氢化大豆磷脂、大豆磷脂酰甘油、大豆磷脂酰丝氨酸和氢化大豆脑磷脂-PEG2000中的一种或多种，优选蛋黄卵磷脂、大豆卵磷脂中的一种或多种，更优选蛋黄卵磷脂。
在某些实施方案中，所述合成磷脂可选自二油酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二油酰磷脂酰甘油、二硬脂酰磷脂酰甘油、二棕榈酰磷脂酰甘油、二肉豆蔻酰磷脂酰甘油、二月桂酰磷脂酰甘油、二硬脂酰磷脂酰乙醇胺-PEG2000、二棕榈酰磷脂酰乙醇胺-PEG2000和二肉豆蔻酰磷脂酰乙醇胺-PEG2000中的一种或多种。
本公开中所述麻醉活性成分与磷脂的重量比为5∶1～1∶5，优选4∶1～1∶4，更优选3∶1～1∶3，更优选2∶1～1∶2，更优选1∶1。
本公开中所述麻醉活性成分与蛋黄卵磷脂的重量比为5∶1～1∶5，优选4∶1～1∶4，更优选3∶1～1∶3，更优选2∶1～1∶2，更优选1∶1。
本公开中所述麻醉活性成分与胆固醇的重量比为100∶1～1∶10，优选50∶1～1∶1，更优选30∶1～10∶1。
在某些实施方案中，所述表面活性剂可以选自两性表面活性剂、阴离子表面活性剂、阳离子表面活性剂以及非离子表面活性剂中的一种或几种。所述表面活性剂可选自十二烷基硫酸钠(SDS)、脱氧胆酸钠、戊烷磺酸钠、吐温、司盘、泊洛沙姆、聚氧乙烯月桂醚、十六烷基三甲基溴化铵、十二烷基乙基二甲基溴化铵、十六烷基氯化吡啶鎓(CPC)、苯扎氯铵(benzalkoniumchloride，BAC)和苄索氯铵(benzethoniumchloride，BZT)中的一种或几种，优选十二烷基硫酸钠、吐温(例如吐温80)、司盘(例如司盘85、司盘80)和聚氧乙烯月桂醚中的一种或多种。所述表面活性剂含量的重量比为0.01％～5％，优选0.1％～2.5％，更优选0.5％～1.0％(例如0.6％)。当表面活性剂的种类为两种以上时，不同种类的表面活性剂之间的用量可根据实际需要选择，一般为等量。
在某些实施方案中，所述的促渗剂优选天然卵磷脂、胆固醇和表面活性剂中的一种或几种，优选选自表面活性剂或者天然卵磷脂、胆固醇和表面活性剂的混合物。
在某些实施方案中，本公开中所述的促渗剂可选自表面活性剂，例如十二烷基硫酸钠。
在某些实施方案中，本公开的所述促渗剂可为蛋黄卵磷脂、胆固醇、十二烷基硫酸钠、吐温和司盘的混合物。
在某些实施方案中，本公开的所述促渗剂可为蛋黄卵磷脂、胆固醇和十二烷基硫酸钠的混合物。
在某些实施方案中，本公开的所述促渗剂可为蛋黄卵磷脂、胆固醇、吐温、司盘和聚氧乙烯月桂醚的混合物。在某些实施方案中，本公开的透皮制剂包含以重量计1％～30％的麻醉活性成分，优选1％～20％的麻醉活性成分，更优选1％～10％的麻醉活性成分，更优选2％～5％的麻醉活性成分(例如3％～5％的麻醉活性成分)。
本公开中的麻醉活性成分可选自酰胺类局部麻醉药。所述酰胺类局部麻醉药物可以为利多卡因、布比卡因、左旋布比卡因、罗哌卡因、甲哌卡因、依替杜卡因、丙胺卡因和它们的可药用盐中的一种或几种，优选为布比卡因、左旋布比卡因、罗哌卡因、利多卡因和它们的可药用的盐中的一种或几种，更优选为利多卡因或其可药用的盐。
在某些实施方案中，麻醉活性成分还可选自非甾体类抗炎药，例如塞来昔布、双氯芬酸钠、氟比洛芬、布洛芬、吲哚美辛、美洛昔康等，又可选自对乙酰氨基酚、曲马多、芬太尼、可待因等。
本公开所述的透皮制剂还可包含增稠剂。所述增稠剂可选自卡波姆、黄原胶、聚丙烯酸钠、甲基纤维素和羟丙基甲基纤维素中的一种或多种；优选增稠剂为卡波姆(例如卡波姆974)。
在某些实施方案中，本公开所述的透皮制剂还可包含水性介质、抗氧化剂、抑菌剂和pH调节剂中的一种或多种。
所述水性介质可选自水、缓冲盐溶液或氯化钠溶液等。其中所述水性介质的含量可为以重量计30％～80％，优选40％～70％，更优选45～60％，最优选40％～50％(例如42％-50％，如42.4％、45.8％、47.1％、49.8％)。
所述抗氧化剂可选自硫代甘油、抗坏血酸、抗坏血酸钠、丁基羟基茴香醚(BHA)、2，6-二叔丁基-4-甲基苯酚(BHT)、生育酚、亚硫酸氢钠和焦亚硫酸钠等中的一种或多种，优选丁基羟基茴香醚、2，6-二叔丁基-4-甲基苯酚和硫代甘油中的一种或多种。其中所述抗氧化剂的含量以重量计可为0.01％～10％，优选0.01％～5％，更优选0.1％～2％，最优选0.1％～1％(例如0.5％)。
在某些实施方案中，所述抗氧化剂可为丁基羟基茴香醚(BHA)。
在另外一些实施方案中，所述抗氧化剂可为2，6-二叔丁基-4-甲基苯酚(BHT)。
在又一些实施方案中，所述抗氧化剂可为硫代甘油。
所述抑菌剂可选自尼泊金丙酯、癸酸、月桂酸、壳聚糖、苯甲酸钠、富马酸、山梨酸钾、三氯叔丁醇、苯甲醇和苯酚等中的一种或多种，优选尼泊金丙酯。其中所述抑菌剂剂的含量以重量计可为0.01％～10％，优选0.01％～5％，更优选0.1％～2％，最优选0.1％～1％(例如0.5％)。
所述pH调节剂可选自维生素C(又称抗坏血酸)、乳酸、苹果酸、富马酸、枸橼酸、酒石酸、琥珀酸、盐酸、三乙醇胺、磷酸和醋酸中的一种或多种；优选盐酸(如50％盐酸水溶液，v/v)或三乙醇胺(如50％三乙醇胺水溶液，v/v)。使用pH调节剂调节所述透皮制剂的pH值为6.0～8.0，优选7.0～8.0。
在某些实施方案中，本公开的透皮制剂包含所述麻醉活性成分、所述有机硅弹性体油性基质、所述亲脂性载体、所述短链醇、所述促渗剂、所述增稠剂和所述水性介质。
在某些实施方案中，本公开的透皮制剂包含所述麻醉活性成分、所述有机硅弹性体油性基质、所述亲脂性载体、所述短链醇、所述促渗剂、所述增稠剂、所述水性介质和所述pH调节剂。
在某些实施方案中，本公开的透皮制剂包含所述麻醉活性成分、所述有机硅弹性体油性基质、所述亲脂性载体、所述短链醇、所述促渗剂、所述增稠剂、所述水性介质、所述抗氧化剂和所述抗菌剂。
在某些实施方案中，本公开的透皮制剂包含所述麻醉活性成分、所述有机硅弹性体油性基质、所述亲脂性载体、所述短链醇、所述促渗剂、所述增稠剂、所述水性介质、所述pH调节剂、所述抗氧化剂和所述抗菌剂。
在某些实施方案中，本公开的透皮制剂包含以重量计1％～30％的麻醉活性成分、1％～10％的有机硅弹性体油性基质、1％～5％的亲脂性载体、30％～50％的短链醇、0.1％～1％的表面活性剂、0.1％～1％的增稠剂、30％～65％的水性介质。优选包含以重量计1％～30％的利多卡因、1％～10％的包含环戊硅氧烷和聚二甲基硅氧烷交联聚合物的混合物、1％～5％的肉豆蔻酸异丙酯、30％～50％的乙醇、0.1％～1％的表面活性剂、0.1％～1％的卡波姆、30％～65％的水。更优选包含以重量计10％～30％的利多卡因、1％～10％的Dow
Figure PCTCN2021105366-appb-000007
ST-Elastomer 10、1％～5％的肉豆蔻酸异丙酯、30％～50％的乙醇、0.1％～1％的表面活性剂、0.1％～1％的卡波姆、30％～65％的水。
在某些实施方案中，本公开的透皮制剂包含以重量计1％～10％的麻醉活性成分、1％～10％的有机硅弹性体油性基质、1％～5％的亲脂性载体、30％～50％的短链醇、1％～10％ 的蛋黄卵磷脂、0.01％～1％的胆固醇、0.1％～1％的表面活性剂、0.1％～1％的增稠剂、30％～65％的水性介质。优选包含以重量计1％～10％的利多卡因、1％～10％的包含环戊硅氧烷和聚二甲基硅氧烷交联聚合物的混合物、1％～5％的肉豆蔻酸异丙酯、30％～50％的乙醇、1％～10％的蛋黄卵磷脂、0.01％～1％的胆固醇、0.1％～1％的表面活性剂、0.1％～1％的卡波姆、30％～65％的水。优选包含以重量计1％～10％的利多卡因、1％～10％的Dow
Figure PCTCN2021105366-appb-000008
ST-Elastomer 10、1％～5％的肉豆蔻酸异丙酯、30％～50％的乙醇、1％～10％的蛋黄卵磷脂、0.01％～1％的胆固醇、0.1％～1％的表面活性剂、0.1％～1％的卡波姆、30％～65％的水。
在某些实施方案中，本公开的透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基磺酸钠、0.2％的吐温80、0.2％的司盘85、0.8％的卡波姆(例如卡波姆974)、0.6％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
Figure PCTCN2021105366-appb-000009
ST-Elastomer 10、0.5％的丁基羟基茴香醚、0.5％的尼泊金丙酯、35％的乙醇和49.8％的水(处方1)。
在某些实施方案中，本公开的透皮制剂包含以重量计5％的利多卡因、5％的蛋黄卵磷脂、0.2％的胆固醇、0.6％的十二烷基磺酸钠、0.5％的卡波姆(例如卡波姆974)、0.6％的三乙醇胺、1.6％的液体石蜡、4.4％的Dow
Figure PCTCN2021105366-appb-000010
ST-Elastomer 10、35％的乙醇和47.1％的水(处方2)。
在某些实施方案中，本公开的透皮制剂包含以重量计5％的利多卡因、5％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基磺酸钠、0.2％的吐温80、0.2％的司盘85、0.5％的卡波姆(例如卡波姆974)、0.6％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
Figure PCTCN2021105366-appb-000011
ST-Elastomer 10、35％的乙醇和47.1％的水(处方3)。
在某些实施方案中，本公开的透皮制剂包含以重量计5％的利多卡因、5％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的吐温80、0.2％的司盘85、0.2％的聚氧乙烯月桂醚、0.5％的卡波姆(例如卡波姆974)、0.6％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
Figure PCTCN2021105366-appb-000012
ST-Elastomer 10、35％的乙醇和47.1％的水(处方4)。
在某些实施方案中，本公开的透皮制剂包含以重量计5％的利多卡因、5％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基磺酸钠、0.2％的吐温80、0.2％的司盘85、0.8％的卡波姆(例如卡波姆974)、0.6％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
Figure PCTCN2021105366-appb-000013
ST-Elastomer 10、0.5％的丁基羟基茴香醚、0.5％的尼泊金丙酯、35％的乙醇和45.8％的水(处方5)。
在某些实施方案中，本公开的透皮制剂包含以重量计5％的利多卡因、0.6％的十二烷基磺酸钠、0.8％的卡波姆、0.2％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
Figure PCTCN2021105366-appb-000014
ST-Elastomer 10、45％的乙醇和42.4％的水(处方6)。
在某些实施方案中，本公开的透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、50.75％的水、0.85％的卡波姆、4.4％的Dow
Figure PCTCN2021105366-appb-000015
ST-Elastomer 10、1.6％的肉豆蔻酸异丙酯、0.2％的硫代甘油、0.2％的尼泊金丙酯和0.2％的盐酸(处方7)。
在某些实施方案中，本公开的透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、50.65％的水、0.85％的卡波姆、4.4％的Dow
Figure PCTCN2021105366-appb-000016
ST-Elastomer 10、1.6％的肉豆蔻酸异丙酯、0.1％的BHT、0.2％硫代甘油、0.2％尼泊金丙酯和0.2％盐酸(处方8)。
在某些实施方案中，本公开的透皮制剂包含以重量计20％的利多卡因、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、45％的乙醇、26.2％的水、1.5％的卡波姆、4.4％的E10、1.6％的肉豆蔻酸异丙酯、0.2％的尼泊金丙酯和0.5％的盐酸(处方9)。
在某些实施方案中，本公开的透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、54％的水、0.8％的卡波姆、1％的Dow
Figure PCTCN2021105366-appb-000017
ST-Elastomer 10、2％的肉豆蔻酸异丙酯、0.2％的硫代甘油和0.2％的尼泊金丙酯(处方10)。
在某些实施方案中，本公开的透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、51％的水、0.8％的卡波姆、5％的Dow
Figure PCTCN2021105366-appb-000018
ST-Elastomer 10、1％的肉豆蔻酸异丙酯、0.2％的硫代甘油和0.2％的尼泊金丙酯(处方11)。
在某些实施方案中，本公开的透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、51％的水、0.8％的卡波姆、4.4％的Dow
Figure PCTCN2021105366-appb-000019
TI-3021、1.6％的肉豆蔻酸异丙酯、0.2％的硫代甘油和0.2％的尼泊金丙酯(处方12)。
本公开的一些实施方案中，将本公开所述的透皮制剂经体外经皮渗透试验测定，所述透皮制剂提供了一个或多个下述皮肤暴露量特征：a)给药10min后皮肤暴露量不低于30μg/cm 2，优选不低于50μg/cm 2，更优选不低于80μg/cm 2；b)给药30min后皮肤暴露量不低于30μg/cm 2，优选不低于50μg/cm 2，更优选不低于80μg/cm 2。其中体外经皮渗透试验受试皮肤给药量为0.34mg/cm 2～1.2mg/cm 2，受试皮肤优选猪耳背皮，电阻值高于3000Ω，具体实验操作参照实施例2中记载的操作步骤，未详述内容参照“Ueda，C.T.，Shah，V.P.，Derdzinski，K.，Ewing，G.，Flynn，G.，Maibach，H.，...&Yacobi，A.(2009).Topical and  Transdermal Drug Products.”或“Transdermal and Topical Delivery Systems-Product Development and Quality Considerations Guidance for Industry DRAFT GUIDANCE 2019年11月”中记载，其中皮肤暴露量为皮肤萃取液样品中利多卡因的含量。
本公开的一些实施方案中，将本公开所述的透皮制剂采用动物进行疼痛阈值检测时，所述透皮制剂提供了一个或多个下述疼痛阈值上升百分率特征：a)给药10min后，疼痛阈值上升百分率不低于200％，优选不低于300％，更优选不低于400％；b)给药20min后，疼痛阈值上升百分率不低于200％，优选不低于300％，更优选不低于400％；c)
给药30min后，疼痛阈值上升百分率不低于300％，优选不低于400％，更优选不低于500％；d)给药10min后，给药结束后30min，疼痛阈值上升百分率不低于100％，优选不低于200％，更优选不低于300％；e)给药10min后，给药结束后60min，疼痛阈值上升百分率不高于200％，优选不高于150％，更优选不高于100％；f)给药10min后，给药结束后120min，疼痛阈值上升百分率不高于100％，优选不高于50％，更优选不高于30％；其中痛阈值测定值为用IITC电子测痛仪检测的豚鼠给药后的痛阈值，动物优选为豚鼠，给药量为1.2mg/cm 2的直径2cm的圆，以豚鼠出现躲避反应为阳性标志，记录豚鼠疼痛阈值。其中给药10min后通常为在皮肤表面施药10min后除去皮肤表面药剂，即刻测定痛阈值，约为擦去给药样品后0～10min测定疼痛阈值，优选0～5min。更优选0～2min，最优选0～1min。给药结束后30min通常为在皮肤表面施药一段时间后除去皮肤表面药剂，除去药剂后30min，即刻测定疼痛阈值。具体操作参照实施例4记载的内容。
本公开提供了一种所述透皮制剂的制备方法，包括下列步骤：将所述的麻醉活性成分和所述有机硅弹性体油性基质混合，可选地与所述亲脂性载体、所述短链醇、所述促渗剂、所述增稠剂、所述水性介质、所述pH调节剂、所述抗氧化剂和所述抗菌剂中的一种或多种混合；优选包括下列步骤：
i)将所述麻醉活性成分所述短链醇混合，可选地加入除十二烷基磺酸钠以外的促渗剂，得到一醇相；
ii)将十二烷基磺酸钠与所述水性介质混合，得到一水相；
iii)将所述醇相和所述水相混合，得一混合液；
iv)将所述的有机硅弹性体油性基质与所述的混合液混合，可选地加入所述抗氧化剂、所述抑菌剂、所述增稠剂、所述的亲脂性载体和所述pH调节剂中的一种或多种。
本公开所述的透皮制剂的制备方法，包括1)将含有麻醉活性成分的醇相和水相混合；2)将增稠剂、亲脂性载体和有机硅弹性体油性基质混合；3)将1)和2)所得混合 物进行混合。
其中所述醇相为将麻醉活性成分溶于短链醇中形成的醇溶液，醇相中还可包含溶于短链醇中的促渗剂，例如蛋黄卵磷脂、胆固醇和吐温、司盘等表面活性剂。其中所述水相为包含促渗剂的水性介质，促渗剂优选十二烷基硫酸钠等表面活性剂。
本公开中所述的“以重量计”为相应成分占透皮制剂总重的百分比，例如“本公开的透皮制剂中含有以重量计为20-70％的短链醇。”即短链醇的重量占透皮制剂重量的20-70％。
本公开中所述的“痛阈”为开始知觉到痛的最小刺激强度；所述的“疼痛阈值”为用IITC电子测痛仪针头分别针刺豚鼠给药部位，以豚鼠出现躲避反应为阳性标志，以测痛仪显示为痛阈值。本公开所述的“疼痛阈值上升百分率”为给药后疼痛阈值较正常疼痛阈值的上升百分率。
本公开中所述的“皮肤暴露量”为皮肤表面施用包含活性成分的药剂后一段时间后，将受试皮肤表面清洗后，检测受试皮肤中活性成分的含量，即皮肤萃取液中活性成分的含量。
本公开的“混入”、“混合”表示的意思是不限定组分的加入顺序，例如将A混入B，可以表达A加入B的意思，也可以表达B加入A的意思，将A和B混合，可以表达A加入B混合的意思，也可以表达B加入A混合的意思。
发明的有益效果
本公开的透皮制剂可在10～30min内快速起效，皮肤暴露量高，刺激性小，可用于医学处置前的局部麻醉，尤其是静脉置留针前的穿刺。
本公开的透皮制剂在长期放置下稳定性良好，放置一个月后，有关物质含量均及含量均匀度符合药学标准。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
以下实施例中杂质的含量通过HPLC检测，其检测条件为使用Thermo U3000型号的HPLC，DAD检测器，采用ACE Excel 3 Super C18柱(4.6*150mm，3μm)色谱柱，流动相为乙腈/磷酸缓冲溶液，检测波长230nm。
以下实施例中进行体外经皮渗透实验(IVPT)的测定使用的多功能透皮扩散仪为沈阳药科大学&延边大学研制，型号为SYT102。
Figure PCTCN2021105366-appb-000020
贴剂为日东电工购入。
实施例5中所用IITC电子测痛仪的厂家为IITC Life Science，型号为2450，机械痛阈测试范围为0～200g，测试精确度为0.01g。
Dow
Figure PCTCN2021105366-appb-000021
ST-Elastomer 10购入厂家为杜邦，下述实施例中简称ST-Elastomer 10、Elastomer 10或E 10。
Dow
Figure PCTCN2021105366-appb-000022
TI-3021购入厂家为杜邦，下述实施例中简称TI-3021。
下述实施例的处方中，如未做特别说明，API是指利多卡因，磷脂是指蛋黄卵磷脂。
实施例1利多卡因透皮制剂的制备
处方1-5及对比例1-3的制备方法：称取处方量的利多卡因(API-麻醉活性成分)、蛋黄卵磷脂(促渗剂)、胆固醇(促渗剂)和表面活性剂(促渗剂除SDS外)溶于无水乙醇(短链醇)中，得到一醇相。同时称取处方量的SDS(十二烷基苯磺酸钠，表面活性剂)溶于水(水性介质)中，得到一水相。后将醇相缓慢注入水相中，并同时开启搅拌。注入完毕后，继续搅拌，加入抗氧化剂(丁基羟基茴香醚(BHA))和抑菌剂(尼泊金丙酯)，搅拌溶解，再加入处方量的卡波姆974(增稠剂)，充分搅拌均匀，根据处方不同分别加入处方量的肉豆蔻酸异丙酯(IPM-亲脂性载体)和ST-Elastomer 10(E10，有机硅弹性体油性基质)、液体石蜡(亲脂性载体)和ST-Elastomer 10(E10)并搅拌均匀，最后可选地用pH调节剂调节pH至适宜范围(7.0～8.0)。
处方6、对比例4的制备方法：称取处方量的利多卡因(API-麻醉活性成分)溶于无水乙醇(短链醇)中，得到一醇相。同时称取处方量的SDS(十二烷基苯磺酸钠，表面活性剂)溶于超纯水(水性介质)中，得到一水相。将醇相与水相中混合，并搅拌均匀，向处方6中加入卡波姆(增稠剂)，搅拌至溶胀完全，继续加入IPM(亲脂性载体)和E10，搅拌混匀，最后用盐酸调节pH至适宜范围(7.0～8.0)。
Figure PCTCN2021105366-appb-000023
实施例2利多卡因透皮制剂体外经皮渗透实验
对处方实施例1中的处方、对比例及Penles进行体外经皮渗透实验(IVPT)来测定10min和30min的皮肤暴露量，将采购的猪耳背皮用刀具将其裁成若干个面积为1.48cm 2的圆形，手术剪刀脱毛，使用PBS缓冲液(pH7.4)洗净，检测猪皮电阻值，选用电阻值高于3000Ω的猪皮用于实验。将裁剪后的圆形猪皮分为每4片一组，安装于弗朗兹流通池的供给池及接收池中间并密封，接收池中加入定量PBS缓冲液(pH7.4)后将流通池置于水浴或干热加热装置中，使皮肤温度升至32±1℃后平衡30分钟，根据表2中给药剂量分别上样，每个处方使用两组猪皮，一组测定给药10min后的结果，另一组测定给药30min后的结果，给药结束后从取样臂中取样200微升，取样结束后立即移除接收池中的接收介质，用经验证的回收介质乙醇清洗猪皮表面(1ml×5)，后将猪皮剪碎加甲醇提取回收其中的利多卡因。接收液、清洗液及猪皮萃取液样品分别经HPLC方法定量，测定利多卡因的渗透量、皮肤表面残留量以及皮肤中的暴露量，其中皮肤暴露量为猪皮萃取液样品中利多卡因的含量。经在体药效试验验证，局麻药效与利多卡因在皮肤中的暴露量正相关。
表2实施例1中处方皮肤暴露量
Figure PCTCN2021105366-appb-000024
Figure PCTCN2021105366-appb-000025
从表2的数据可以看出，处方1中的皮肤暴露量高于未加Elastomer 10的对比例1和对比例2，其给药10min后皮肤暴露量也高于Penles给药30min后的数据结果。处方2-4与对比例3的皮肤暴露量相比，加入IPM和E10、液体石蜡和E10的皮肤暴露量远高于对比例3，从上表中也可以看出，使用不同种类的表面活性剂、不添加蛋黄卵磷脂和胆固醇的其他处方也可以达到较高的皮肤暴露量。
实施例3利多卡因透皮制剂稳定性考察
表3利多卡因透皮制剂信息
Figure PCTCN2021105366-appb-000026
根据实施例1中记载的制备方法进行制备处方7。将制备所得制剂分装至20ml西林瓶中，进行压盖密封，置于长期条件(25℃，60％RH)和加速条件(40℃，75％RH)，其中长期条件(25℃，60％RH)下于第0d、1M进行稳定性检测，加速条件(40℃，75％RH)下于第0d、7d和1M进行稳定性检测，具体稳定性数据详见表6，放置1个月时稳定性良好，单杂、总杂的含量及含量均匀度均符合药典标准。
表4制剂的稳定性结果
Figure PCTCN2021105366-appb-000027
表5制剂的含量均匀度结果
Figure PCTCN2021105366-appb-000028
Figure PCTCN2021105366-appb-000029
根据实施例1中记载的体外经皮渗透实验(IVPT)进行检测，给药剂量为1.2mg/cm2，将处方7放置在长期条件下7d时，10min和30min的皮肤暴露量均高于Penles 30min时的皮肤暴露量，放置时间1M时，检测皮肤暴露量无明显下降。
表6处方7长期试验的皮肤暴露量
Figure PCTCN2021105366-appb-000030
实施例4利多卡因透皮制剂动物实验
根据上述实施例中的制备方法制备空白制剂、处方8、处方9。
表7透皮制剂处方信息
Figure PCTCN2021105366-appb-000031
将Penles、空白制剂、处方8、处方9根据表8中的给药信息进行给药，根据试验各阶段给药前和给药后豚鼠痛阈测定时间，用IITC电子测痛仪针头分别针刺豚鼠给药部位，以豚鼠出现躲避反应为阳性标志，记录豚鼠疼痛阈值，每组10只豚鼠，给药后10/20/30min后分别检测，制剂去除后即刻，0.5h，1h，2h分别检测给药部位的痛阈，每次测定3次， 计算3次平均值，分别统计疼痛阈值及疼痛阈值上升百分率(较给药前动物自身的疼痛阈值)。
痛阈增加值计算：痛阈增加值(g)＝给药后痛阈值-给药前痛阈值
痛阈上升百分率计算公式：痛阈上升百分率＝(疼痛阈值[给药后]-疼痛阈值[给药前])/(疼痛阈值[给药前])×100％
表8给药方法信息
Figure PCTCN2021105366-appb-000032
表9豚鼠针刺模型药效筛选结果
制剂豚鼠皮肤涂抹10min后不同时间点痛阈上升百分率(％，平均±SEM)
Figure PCTCN2021105366-appb-000033
与空白制剂组比较：*P＜0.05，**P＜0.01，***P＜0.001。与Penles组比较：#P＜0.05，###P＜0.001。
表10豚鼠针刺模型药效筛选结果
制剂不同给药涂抹时间对痛阈上升百分率的影响(％，平均±SEM)
Figure PCTCN2021105366-appb-000034
与涂抹10min比较，*P＜0.05，**P＜0.01，***P＜0.001；与涂抹20min比较，#P＜0.05，##P＜0.01，###P＜0.001
根据表9、10中记载的数据，可以看出，当处方8、9在给药1.2mg/cm 2时，给药10min后，痛阈值上升百分率远高于空白制剂和Penles，在给药后30min时痛阈值仍保持较高水平。当给药20min和30min后测量痛阈值时，痛阈上升百分率上升显著。
实施例5利多卡因透皮制剂的制备及体外经皮渗透试验
表11利多卡因透皮制剂处方信息
Figure PCTCN2021105366-appb-000035
根据实施例1中记载的制备方法制备处方10-12，将制备所得的处方10-12按照实施例2中使用的操作方法进行体外经皮渗透实验的测定，给药剂量为0.47mg/cm 2。
表12处方10-12的皮肤暴露量
Figure PCTCN2021105366-appb-000036
从表12的数据可以看出，处方10-12的皮肤暴露量高于未加Elastomer 10的对比例1和对比例2，其给药10min后皮肤暴露量也高于Penles给药30min后的数据结果。制剂形态为半固体，具有良好的稳定性。

Claims (28)

  1. 一种透皮制剂，包含麻醉活性成分和有机硅弹性体油性基质。
  2. 根据权利要求1中所述的透皮制剂，其中所述的有机硅弹性体油性基质为包含有机硅交联共聚物和载液的混合物。
  3. 根据权利要求2中所述的透皮制剂，其中所述的有机硅交联共聚物选自聚二甲基硅氧烷交联聚合物、聚二甲基硅氧烷和乙烯基聚二甲基硅氧烷交联聚合物和聚二甲基硅氧烷和双-异丁基PPG-20交联聚合物中的一种或几种，优选聚二甲基硅氧烷交联聚合物。
  4. 根据权利要求2中所述的透皮制剂，其中所述的载液选自聚二甲基硅氧烷、六甲基二硅氧烷、三硅氧烷、环戊硅氧烷、辛基聚甲基硅氧烷、异十二烷、矿脂、新戊酸异癸酯、聚二甲基硅氧烷醇、异十六烷、蜂蜡、硅石和甲硅烷基化硅石的一种或几种，优选聚二甲基硅氧烷和/或环戊硅氧烷。
  5. 根据权利要求4中所述的透皮制剂，其中所述的有机硅弹性体油性基质为包含聚二甲基硅氧烷交联聚合物和环戊硅氧烷的混合物和/或包含聚二甲基硅氧烷交联聚合物和聚二甲基硅氧烷的混合物。
  6. 根据权利要求1-5中任一项所述的透皮制剂，其中所述的有机硅弹性体油性基质选自Dow
    Figure PCTCN2021105366-appb-100001
    ST-Elastomer 10和Dow
    Figure PCTCN2021105366-appb-100002
    TI-3021中的一种或组合。
  7. 根据权利要求1-6中任一项所述的透皮制剂，其中所述的有机硅弹性体油性基质与麻醉活性成分的重量比为10∶1～1∶10、8∶1～1∶8、6∶1～1∶6、5∶1～1∶5、4∶1～1∶5、3∶1～1∶5、2∶1～1∶5、1.5∶1～1∶5、1.5∶1～1∶3、1.5∶1～1∶1.5或1.5∶1～1∶1。
  8. 根据权利要求1-7中任一项所述的透皮制剂，还包含亲脂性载体、至少一种促渗剂和短链醇。
  9. 根据权利要求8中所述的透皮制剂，其中所述的亲脂性载体选自合成油、植物油、矿物油、挥发性硅油、非挥发性硅油中的一种或几种，优选合成油，更优选肉豆蔻酸异丙酯、棕榈酸异丙酯、液体石蜡中的一种或几种，例如肉豆蔻酸异丙酯。
  10. 根据权利要求8-9中任一项所述的透皮制剂，其中所述的有机硅弹性体油性基质与亲脂性载体的重量比为10∶1～1∶10、8∶1～1∶8、6∶1～1∶6、5∶1～1∶5、5∶1～1∶2、5∶1～1∶1、4∶1～1∶1、3∶1～1∶1或3∶1～2∶1。
  11. 根据权利要求8-10中任一项所述的透皮制剂，其中所述的亲脂性载体的与麻醉活性成分的重量比为10∶1～1∶30、10∶1～1∶20、10∶1～1∶15、5∶1～1∶15、4∶1～1∶15、3∶1～1∶15、2∶1～1∶15、1∶1～1∶15或1∶1.5～1∶13。
  12. 根据权利要求8-11中任一项所述的透皮制剂，其中含有以重量计为20-70％的短链醇， 优选20-50％的短链醇，更优选30-50％的短链醇，最优选为35-45％的短链醇。
  13. 根据权利要求8-12中任一项所述的透皮制剂，其中所述的短链醇选自乙醇、正丙醇、异丙醇、正丁醇、异丁醇、丁二醇、丙二醇中的一种或几种，更优选乙醇、丙二醇中的一种或组合，最优选为乙醇。
  14. 根据权利要求8-13中任一项所述的透皮制剂，其中所述的促渗剂选自磷脂、胆固醇和表面活性剂中的一种或几种，所述的膦酯优选天然卵磷脂，更优选蛋黄卵磷脂或大豆卵磷脂，例如蛋黄卵磷脂。
  15. 根据权利要求14中所述的透皮制剂，其中所述麻醉活性成分与磷脂的重量比为5∶1～1∶5、4∶1～1∶4、3∶1～1∶3、2∶1～1∶2或1∶1；优选地，所述的麻醉活性成分与蛋黄卵磷脂的重量比为5∶1～1∶5、4∶1～1∶4、3∶1～1∶3、2∶1～1∶2或1∶1。
  16. 根据权利要求14中所述的透皮制剂，其中所述麻醉活性成分与胆固醇的重量比为100∶1～1∶10、50∶1～1∶1或30∶1～10∶1。
  17. 根据权利要求1-16中任一项所述的透皮制剂，其中包含以重量计1％～30％的麻醉活性成分、1％～20％的麻醉活性成分，优选1％～10％的麻醉活性成分，更优选2％～5％的麻醉活性成分。
  18. 根据权利要求1-17中所述的透皮制剂，其中所述的麻醉活性成分选自酰胺类局部麻醉药，所述酰胺类局部麻醉药物选自利多卡因、布比卡因、左旋布比卡因、罗哌卡因、甲哌卡因、依替杜卡因、丙胺卡因或它们的可药用盐中的一种或几种，优选为布比卡因、左旋布比卡因、罗哌卡因、利多卡因或其可药用的盐中的一种或几种，更优选为利多卡因或其可药用的盐。
  19. 根据权利要求14-18中任一项所述的透皮制剂，其中所述的表面活性剂选自十二烷基硫酸钠、吐温、司盘、聚氧乙烯月桂醚中的一种或几种，优选表面活性剂含量的以重量计为0.01％～5％、0.1％～2.5％或0.5％～1.0％。
  20. 根据权利要求1-19中任一项所述的透皮制剂，还包含增稠剂，增稠剂选自卡波姆、黄原胶、聚丙烯酸钠、甲基纤维素、羟丙基甲基纤维素中的一种或多种，优选卡波姆。
  21. 根据权利要求1-20中任一项所述的透皮制剂，包含以重量计1％～30％的利多卡因或其可药用盐、1％～10％的有机硅弹性体油性基质、1％～5％的亲脂性载体、30％～50％的短链醇、0.1％～1％的表面活性剂、0.1％～1％的增稠剂、30％～65％的水性介质，其中所述的有机硅弹性体油性基质优选包含环戊硅氧烷和聚二甲基硅氧烷交联聚合物的混合物，优选Dow
    Figure PCTCN2021105366-appb-100003
    ST-Elastomer 10，其中所述的亲脂性载体优选肉豆蔻酸异 丙酯，其中所述的短链醇优选乙醇，其中所述增稠剂优选卡波姆，其中所述的水性基质优选水。
  22. 根据权利要求1-20中任一项所述的透皮制剂，其中包含以重量计1％～10％的利多卡因或其可药用盐、1％～10％的有机硅弹性体油性基质、1％～5％的亲脂性载体、30％～50％的短链醇、1％～10％的蛋黄卵磷脂、0.01％～1％的胆固醇、0.1％～1％的表面活性剂、0.1％～1％的增稠剂、30％～65％的水性介质，其中所述的有机硅弹性体油性基质优选包含环戊硅氧烷和聚二甲基硅氧烷交联聚合物的混合物，优选Dow
    Figure PCTCN2021105366-appb-100004
    ST-Elastomer 10，其中所述的亲脂性载体优选肉豆蔻酸异丙酯，其中所述的短链醇优选乙醇，其中所述增稠剂优选卡波姆，其中所述的水性基质优选水。
  23. 根据权利要求1-22中任一项所述的透皮制剂，其中还包含抗氧化剂、抑菌剂和pH调节剂中的一种或多种；
    所述抗氧化剂可选自硫代甘油、抗坏血酸、抗坏血酸钠、丁基羟基茴香醚、2，6-二叔丁基-4-甲基苯酚、生育酚、亚硫酸氢钠和焦亚硫酸钠等中的一种或多种，优选丁基羟基茴香醚、2，6-二叔丁基-4-甲基苯酚和硫代甘油中的一种或多种；其中所述抗氧化剂的含量以重量计可为0.01％～10％、0.01％～5％、0.1％～2％或0.1％～1％；
    所述抑菌剂可选自尼泊金丙酯、癸酸、月桂酸、壳聚糖、苯甲酸钠、富马酸、山梨酸钾、三氯叔丁醇、苯甲醇和苯酚等中的一种或多种，优选尼泊金丙酯；其中所述抑菌剂剂的含量以重量计可为0.01％～10％、0.01％～5％、0.1％～2％或0.1％～1％；
    使用pH调节剂调节所述透皮制剂的pH值可为6.0～8.0或7.0～8.0。
  24. 根据权利要求1-23中任一项所述的透皮制剂，其为下列任一组合：
    所述透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基磺酸钠、0.2％的吐温80、0.2％的司盘85、0.8％的卡波姆、0.6％的盐酸、
    1.6％的肉豆蔻酸异丙酯、4.4％的Dow
    Figure PCTCN2021105366-appb-100005
    ST-Elastomer 10、0.5％的丁基羟基茴香醚、0.5％的尼泊金丙酯、35％的乙醇和49.8％的水；
    所述透皮制剂包含以重量计5％的利多卡因、5％的蛋黄卵磷脂、0.2％的胆固醇、0.6％的十二烷基磺酸钠、0.5％的卡波姆、0.6％的三乙醇胺、1.6％的液体石蜡、4.4％的Dow
    Figure PCTCN2021105366-appb-100006
    ST-Elastomer 10、35％的乙醇和47.1％的水；
    所述透皮制剂包含以重量计5％的利多卡因、5％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基磺酸钠、0.2％的吐温80、0.2％的司盘85、0.5％的卡波姆、0.6％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
    Figure PCTCN2021105366-appb-100007
    ST-Elastomer 10、35％的乙醇和47.1％ 的水；
    所述透皮制剂包含以重量计5％的利多卡因、5％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的吐温80、0.2％的司盘85、0.2％的聚氧乙烯月桂醚、0.5％的卡波姆、0.6％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
    Figure PCTCN2021105366-appb-100008
    ST-Elastomer 10、35％的乙醇和47.1％的水；
    所述透皮制剂包含以重量计5％的利多卡因、5％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基磺酸钠、0.2％的吐温80、0.2％的司盘85、0.8％的卡波姆、0.6％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
    Figure PCTCN2021105366-appb-100009
    ST-Elastomer 10、0.5％的丁基羟基茴香醚、0.5％的尼泊金丙酯、35％的乙醇和45.8％的水；
    所述透皮制剂包含以重量计5％的利多卡因、0.6％的十二烷基磺酸钠、0.8％的卡波姆、0.2％的盐酸、1.6％的肉豆蔻酸异丙酯、4.4％的Dow
    Figure PCTCN2021105366-appb-100010
    ST-Elastomer 10、45％的乙醇和42.4％的水；
    所述透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、50.75％的水、0.85％的卡波姆、4.4％的Dow
    Figure PCTCN2021105366-appb-100011
    ST-Elastomer 10、1.6％的肉豆蔻酸异丙酯、0.2％的硫代甘油、0.2％的尼泊金丙酯和0.2％的盐酸；
    所述透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、50.65％的水、0.85％的卡波姆、4.4％的Dow
    Figure PCTCN2021105366-appb-100012
    ST-Elastomer 10、1.6％的肉豆蔻酸异丙酯、0.1％的BHT、0.2％硫代甘油、0.2％尼泊金丙酯和0.2％盐酸；
    所述透皮制剂包含以重量计20％的利多卡因、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、45％的乙醇、26.2％的水、1.5％的卡波姆、4.4％的E10、1.6％的肉豆蔻酸异丙酯、0.2％的尼泊金丙酯和0.5％的盐酸；
    所述透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、54％的水、0.8％的卡波姆、1％的Dow
    Figure PCTCN2021105366-appb-100013
    ST-Elastomer 10、2％的肉豆蔻酸异丙酯、0.2％的硫代甘油和0.2％的尼泊金丙酯；
    所述透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、51％的水、0.8％的卡波姆、5％的Dow
    Figure PCTCN2021105366-appb-100014
    ST-Elastomer 10、1％的肉豆蔻酸异丙酯、0.2％的硫代甘 油和0.2％的尼泊金丙酯；
    所述透皮制剂包含以重量计3％的利多卡因、3％的蛋黄卵磷脂、0.2％的胆固醇、0.2％的十二烷基硫酸钠、0.2％的吐温80、0.2％的司盘80、35％的乙醇、51％的水、0.8％的卡波姆、4.4％的Dow
    Figure PCTCN2021105366-appb-100015
    TI-3021、1.6％的肉豆蔻酸异丙酯、0.2％的硫代甘油和0.2％的尼泊金丙酯。
  25. 根据权利要求1-24中任一项所述的透皮制剂，其中当采用猪皮进行体外经皮渗透试验测定，所述透皮制剂提供了一个或多个下述皮肤暴露量特征：
    a)给药10min后皮肤暴露量为不低于30μg/cm 2，优选不低于50μg/cm 2，更优选不低于80μg/cm 2；
    b)给药30min后皮肤暴露量不低于30μg/cm 2，优选不低于50μg/cm 2，更优选不低于80μg/cm 2。
  26. 根据权利要求1-25中任一项所述的透皮制剂，其中当采用动物进行疼痛阈值检测时，所述透皮制剂提供了一个或多个下述疼痛阈值上升百分率特征：
    a)给药10min后，疼痛阈值上升百分率不低于200％，优选不低于300％，更优选不低于400％；
    b)给药20min后，疼痛阈值上升百分率不低于200％，优选不低于300％，更优选不低于400％；
    c)给药30min后，疼痛阈值上升百分率不低于300％，优选不低于400％，更优选不低于500％；
    d)给药10min后，给药结束后30min，疼痛阈值上升百分率不低于100％，优选不低于200％，更优选不低于300％；
    e)给药10min后，给药结束后60min，疼痛阈值上升百分率不高于200％，优选不高于150％，更优选不高于100％；
    f)给药10min后，给药结束后120min，疼痛阈值上升百分率不高于100％，优选不高于50％，更优选不高于30％。
  27. 一种如权利要求1所述的透皮制剂的制备方法，包括将所述的麻醉活性成分和所述有机硅弹性体油性基质混合的步骤。
  28. 权利要求1-26任一项所述的透皮制剂在制备用于镇痛或麻醉的药物中的用途。
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Publication number Priority date Publication date Assignee Title
CN114939103A (zh) * 2022-05-27 2022-08-26 辽宁方诺生物科技有限公司 吲哚美辛凝胶剂及其制备方法和应用
CN114939103B (zh) * 2022-05-27 2023-11-17 辽宁方诺生物科技有限公司 吲哚美辛凝胶剂及其制备方法和应用

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