WO2012048455A1 - 一种抗病毒透皮吸收贴片及其制备方法 - Google Patents

一种抗病毒透皮吸收贴片及其制备方法 Download PDF

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Publication number
WO2012048455A1
WO2012048455A1 PCT/CN2010/077636 CN2010077636W WO2012048455A1 WO 2012048455 A1 WO2012048455 A1 WO 2012048455A1 CN 2010077636 W CN2010077636 W CN 2010077636W WO 2012048455 A1 WO2012048455 A1 WO 2012048455A1
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Prior art keywords
antiviral
transdermal patch
layer
viscous polymer
group
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PCT/CN2010/077636
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English (en)
French (fr)
Inventor
王业富
李卫
周晓舟
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武汉大学
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Priority to PCT/CN2010/077636 priority Critical patent/WO2012048455A1/zh
Priority to EP10838390.2A priority patent/EP2606895A4/en
Priority to US13/108,967 priority patent/US20120089104A1/en
Publication of WO2012048455A1 publication Critical patent/WO2012048455A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • 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
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a patch for transdermal administration, in particular to an antiviral transdermal patch, and to a process for the preparation of such an antiviral transdermal patch.
  • nucleoside antiviral drugs including entecavir, adefovir, lamivudine, acyclovir, ribavirin, and Zidov.
  • entecavir adefovir
  • lamivudine acyclovir
  • ribavirin avirin
  • Zidov Zidov.
  • it is used in the treatment of viral diseases such as hepatitis B, AIDS, viral influenza, and herpes. Book
  • Nucleoside antiviral drugs are generally administered orally or by injection.
  • oral or injectable administration has a problem that the concentration of the drug in the blood may fluctuate significantly with time. That is to say, when the concentration of the drug in the blood is too low, it is difficult to fully exert the therapeutic effect; and when the concentration of the drug in the blood is too high, toxicity is caused by the overdose, which increases the burden on the body.
  • oral or injectable administration methods also have problems such as enzymatic hydrolysis of the gastrointestinal tract and liver first-pass effects, thereby reducing the drug efficacy. Summary of the invention
  • the technical solution to be solved by the present invention is to provide an antiviral transdermal patch which can be continuously and stably administered, and can also avoid gastrointestinal tract enzymatic hydrolysis and liver first pass effect, and reduce drug side effects.
  • the following technical solutions are adopted:
  • the present invention provides an antiviral transdermal patch comprising a backing layer, an adhesive polymer layer and a protective film layer, wherein the adhesive polymer layer comprises an antiviral drug, a viscous polymer and Promoting agent.
  • the antiviral drug is a nucleoside antiviral drug having a daily content of less than 100 mg.
  • the nucleoside antiviral drug having a daily content of less than 100 mg is selected from at least one of entecavir, adefovir dipivoxil, lamivudine or stavudine.
  • the anti-viral transdermal patch has an antiviral drug content per square centimeter of antiviral drug-containing patch of 0. lmg-50mg; preferably 1.5 mg_40mg; more preferably 5 mg-30 mg; 10 mg-25 mg; most preferred It is 15 mg_20 mg.
  • the viscous polymer is selected from the group consisting of polyacrylate pressure sensitive adhesives, polyisobutylene, polyisoprene or silicone copolymers.
  • the polyacrylate pressure sensitive adhesive is selected from the group consisting of polyacrylic resin II, polyacrylic resin III, polyacrylic resin IV, ammonium polymethacrylate I, ammonium polymethacrylate II, acrylic resin EUDRAGIT E100;
  • the resin EUDRAGIT E100 is a butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate (1:2:1) copolymer. 0% ⁇
  • said penetration enhancer is selected from the group consisting of lauric acid, essential oil, dimethyl sulfoxide, thymol, eucalyptus oil, a traditional Chinese medicine containing terpenes or containing At least one of the traditional Chinese medicine ingredients of phenols.
  • a preferred penetration enhancer is selected from the group consisting of lauric acid
  • the penetration enhancer may be selected from the group consisting of lauric acid: the ratio of the essential oil is a weight ratio of 1: 0.5-2.
  • the permeation agent may be selected from the group consisting of lauric acid: dimethyl sulfoxide in a weight ratio of 1: 0.5-2.
  • the viscous polymer layer also contains the balance of an organic solvent.
  • an organic solvent for example: propylene glycol, ethyl lactate.
  • the material of the adhesive layer is selected from the group consisting of polyacrylate pressure sensitive adhesives, polyisobutylene or silicone copolymers.
  • the backing layer of the antiviral transdermal absorption patch of the present invention is selected from the group consisting of high density polyethylene, low density polyethylene, polypropylene, polyvinyl chloride, ethylene-vinyl acetate copolymer, polyester, polyvinylpyrrolidone, polyvinyl alcohol, At least one of a polyurethane and a metal aluminum foil.
  • the backing layer may also be selected from the group consisting of metal aluminum foil and high density polyethylene, low density polyethylene, polypropylene, polyvinyl chloride, ethylene-vinyl acetate copolymer, polyester, polyvinylpyrrolidone, polyvinyl alcohol or polyamino group.
  • the backing layer may also be selected from the group consisting of three composite layers, the intermediate layer being a metal aluminum foil; and the two side layers being selected from at least one of a low density polyethylene polyethylene film and a polyurethane film.
  • the present invention also provides a method for preparing the above-mentioned antiviral transdermal patch, comprising the following steps: After the polymer, the antiviral drug, the penetration enhancer and the solvent are uniformly mixed, the above mixture is coated on the backing layer to obtain a viscous polymer layer, which is then dried, and then cooled, and then covered on the other side of the viscous polymer layer. The anti-viral transdermal patch is obtained by applying a protective film layer.
  • the invention also provides the use of the above anti-viral transdermal absorption patch for preparing antiviral drugs. Advantageous technical effects of the present invention:
  • the viscous polymer layer of the present invention is a controlled release matrix material, and a certain dose of the antiviral drug is dissolved in a laurel azide penetration enhancer or a mixed penetration enhancer containing laurel. It is evenly distributed in the skeleton in the form of a liquid micro-library. The rate of release of the antiviral drug in the patch is then adjusted by varying the amount of drug in the polymer, the density of the liquid micro-library, and the ratio of the penetration enhancer.
  • the invention adopts an antiviral drug transdermal patch prepared by using a lauro azide (i.e., 1-dodecylazepane-2-one) permeation enhancer or a traditional Chinese medicine mixture containing lauryl ketone. It effectively promotes the penetration of nucleoside antiviral drugs into the skin, and is absorbed into the circulation of the human body through capillaries, thereby inhibiting the replication of related viruses and reducing the level of serum viral DNA. At the same time, gastrointestinal tract digestion and liver first-pass effects can be avoided by dermal administration, and toxic side effects are reduced.
  • a lauro azide i.e., 1-dodecylazepane-2-one
  • the invention adopts a mixture of traditional Chinese medicine containing azoxystrobin or laurozolone as a penetration enhancer, so that the antiviral drug can penetrate into the skin better, and the antiviral patch effect of the invention is maintained for 3-5 days. , can continue to be administered stably.
  • the raw material of the invention is simple and easy to obtain, low in cost and strong in practicality.
  • the patch of the present invention was subjected to pharmacological and toxicological studies, and an allergic test and a skin irritation test were conducted. No positive results were observed in the above experimental tests, indicating that the antiviral transdermal patch has no irritating effect on the skin, no hemolysis, and an allergic reaction is negative, indicating that the drug is safe.
  • the patch of the invention can effectively promote the penetration of a plurality of nucleoside antiviral drugs into the skin and the function of the hair can be stably maintained for 3-5 days, thereby reducing the number of administrations. Therefore, the patch of the present invention is a safe, effective, long-acting, and convenient transdermal absorption preparation, which can be used for the treatment of various viral diseases.
  • the viscous polymer polyacrylate pressure sensitive adhesive brand EUDRAGIT E100, produced in Germany, pre-dissolved with ethyl acetate, EUDRAGIT E100 solids weight ratio of 40%
  • 185g antiviral drug entecavir 0. 5g
  • penetration enhancer 9 g of laurel azone 6 g of eucalyptus oil and 8.9 g of propylene glycol, and 100 g of ethyl acetate as a solvent, placed in a jar, bottle The mouth was sealed, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared.
  • the above mixture was coated on a polyethylene-aluminum-polyethylene composite film backing layer, and then dried at 40 ° C for 4 minutes, at 60 ° C for 2 minutes, at 90 ° C for 2 minutes, after cooling, and then
  • the anti-viral transdermal patch 1 is obtained by coating the other side of the viscous polymer layer with a non-stick paper, and then cutting into a patch of a size of 2 cm 2 so that the patch per square centimeter contains entecavir 2.5 mg.
  • the viscous polymer layer containing a polyacrylate pressure sensitive adhesive 75. 2%, entecavir 0. 5%, laurel azide 9.1%, eucalyptus oil 6. 1%, propylene glycol 9%.
  • the permeation rate was 15 g/cm7h measured by a modified Franz diffusion cell device, and the time of the whole process of drug release was greater than 72 h.
  • the patch was recommended to be applied for 3 days.
  • Viscous polymer polyacrylate pressure sensitive adhesive brand EUDRAGIT E100, produced in Germany, pre-dissolved with ethyl acetate, EUDRAGIT E100 solids weight ratio of 40%
  • 225g antiviral drug adefovir dipivoxil 10g
  • promote The penetrant azoxystrobin 9g, thymol 3g mixture, and solvent dichloromethane 150g were placed in a jar, sealed at the mouth of the bottle, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared.
  • the above mixture was coated on a low density polyethylene film backing layer, then dried at 40 ° C for 4 minutes, dried at 60 ° C for 2 minutes, dried at 90 ° C for 2 minutes, cooled, and then in a viscous polymer.
  • the other side of the layer is covered with non-stick paper, and then cut into a patch of 20 cm 2 (4 cm ⁇ 5 cm), so that the patch per square centimeter contains 35 mg of adefovir dipivoxil, that is, the antiviral transdermal patch 2 is obtained.
  • 6% The viscous polymer layer containing polyacrylate pressure sensitive adhesive 80. 4%, adefovir dipivoxil 9%, laurel azone 8%, thymol 2.6%.
  • the permeation rate was measured by a modified Franz diffusion cell device ( ⁇ g/cm7h, and the time of the whole process of drug release was greater than 72h.
  • the patch was recommended to be applied for 3 days.
  • the bottle mouth was sealed, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared.
  • the above mixture was coated on a polyurethane backing layer, then dried at 40 ° C for 4 minutes, dried at 60 ° C for 2 minutes, dried at 90 ° C for 2 minutes, cooled, and then viscous polymer.
  • the other side of the layer is covered with a release paper, and then cut into a patch of 200 cm 2 size, so that the patch per square centimeter contains lamivudine 15 mg, that is, the antiviral transdermal absorption patch 3 is obtained, wherein the adhesive polymer
  • the layer contains 64% polyisobutylene, 7% lamivudine, 3% laurel, 5% essential oil, and 21% ethyl lactate.
  • the permeation rate was 55 g/cm7h measured by a modified Franz diffusion cell device, and the time of the whole process of drug release was greater than 96 h.
  • the patch was recommended to be applied for 4 days.
  • the viscous polymer polyisoprene 87. 5g, the antiviral drug stavudine 15g, the penetration enhancer laurel azalea 6g, two 6 g of methyl sulfoxide and 147 g of ethyl acetate were placed in a jar, sealed at the mouth of the bottle, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared.
  • the above mixture was coated on a polyurethane backing layer, then dried at 40 ° C for 4 minutes, dried at 60 ° C for 2 minutes, dried at 90 ° C for 2 minutes, cooled, and then viscous polymer.
  • the other side of the layer is covered with a release paper, and then cut into a patch of a size of 100 cm 2 so that the patch per square centimeter contains 10 mg of stavudine, that is, the antiviral transdermal patch 4 is obtained, wherein the adhesive polymer 2%, dimethyl sulfoxide 5. 2%.
  • the permeation rate was 34 g/cm7h measured by a modified Franz diffusion cell device, and the time of the whole release process was greater than 72 h. The patch was recommended to be applied for 3 days.
  • the other side of the layer is covered with non-stick paper, and then cut into a patch of 30 cm 2 size, so that the patch per square centimeter contains 40 mg of adefovir dipivoxil, that is, the antiviral transdermal absorption patch 5 is obtained, wherein the adhesive polymerization is carried out.
  • the silicone layer of the silicone copolymer was 83. 5%, adefovir dipivoxil 5. 7%, laurel azide 6.6%, menthol 4. 2%.
  • the permeation rate was 18 g/cm7h measured by a modified Franz diffusion cell device, and the time of the whole process of drug release was greater than 72 h.
  • the patch was recommended to be applied for 3 days.
  • the viscous polymer polyacrylate pressure sensitive adhesive brand EUDRAGIT E100, produced in Germany, pre-dissolved with ethyl acetate, EUDRAGIT E100 solids weight ratio of 40%
  • 225g antiviral drug entecavir 0. 5g
  • penetration enhancer The laurel azide 3.77 g and the solvent ethyl acetate 147 g were placed in a jar, the mouth of the bottle was sealed, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared.
  • the above mixture was coated on a polyurethane backing layer, then dried at 40 ° C for 4 minutes, dried at 60 ° C for 2 minutes, dried at 90 ° C for 2 minutes, cooled, and then dried.
  • the surface of the viscous polymer is coated with a layer of polyacrylate. After drying and cooling in the same manner, it is covered with non-stick paper and cut into 4 cm 2 (2 cm X 2 cm) patches so that each square centimeter patch contains entecavir 3 The 5%, entecavir 0. 5%, laurel azide 4%.
  • the viscous polymer layer comprises a polyacrylate pressure sensitive adhesive 95.5%, entecavir 0.5%.
  • the permeation rate l ( ⁇ g/cm7h) was measured by a modified Franz diffusion cell device, and the time of the whole process of drug release was greater than 48 h. The patch was recommended to be applied for 2 days.
  • Example ⁇ The viscous polymer polyacrylate pressure sensitive adhesive (brand EUDRAGIT E100, produced in Germany, pre-dissolved with ethyl acetate, EUDRAGIT E100 solids weight ratio of 40%) 225g, antiviral drug entecavir 0. 2g, penetration enhancer 9 g of laurel, 9.38 g of propylene glycol and 160 g of ethyl acetate were placed in a jar, sealed at the mouth of the bottle, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared.
  • brand EUDRAGIT E100 brand EUDRAGIT E100, produced in Germany, pre-dissolved with ethyl acetate, EUDRAGIT E100 solids weight ratio of 40%
  • the above mixture was coated on a polyethylene-aluminum-polyethylene composite film backing layer, and then dried at 40 ° C for 4 minutes, at 60 ° C for 2 minutes, at 90 ° C for 2 minutes, after cooling, and then A layer of silicone copolymer is coated on the surface of the dried viscous polymer, dried and cooled in the same manner, and then covered with non-stick paper, and then cut into 4 cm 2 (2 cm ⁇ 2 cm) size patches to make per square centimeter.
  • the viscous polymer layer comprising a polyacrylate pressure sensitive adhesive 84.6%, entecavir 0.19%, lauric acid azide. 9.
  • the viscous polymer layer comprises a polyacrylate pressure sensitive adhesive. 21%, propylene glycol 6%.
  • the permeation rate was 12 g/cm7h measured by a modified Franz diffusion cell device, and the whole process of drug release was greater than 72 h.
  • the patch was recommended to be applied for 3 days.
  • the viscous polymer polyacrylate pressure sensitive adhesive brand EUDRAGIT E100, produced in Germany, pre-dissolved with ethyl acetate, EUDRAGIT E100 solids weight ratio of 40%
  • 170g antiviral drug entecavir 0. 8g
  • penetration enhancer A mixture of 4 g of laurel, 4 g of eucalyptus oil and 5 g of propylene glycol, and 100 g of ethyl acetate in a solvent were placed in a jar, sealed at the mouth of the bottle, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared. .
  • the above mixture was coated on a polyurethane backing layer, then dried at 40 ° C for 4 minutes, dried at 60 ° C for 2 minutes, dried at 90 ° C for 2 minutes, cooled, and then viscous polymer.
  • the other side of the layer was covered with a release paper, and then cut into a patch of 2 cm 2 (1 cm ⁇ 2 cm), so that the patch per square centimeter contained 6 mg of entecavir, that is, the antiviral transdermal patch 8 was obtained, wherein the adhesive polymerization was carried out.
  • the layer contains 82% polyacrylate pressure sensitive adhesive, entecavir 1%, laurel azide 4.5%, eucalyptus oil 6.5%, propylene glycol 6%.
  • the permeation rate was 15 g/cm7h measured by a modified Franz diffusion cell device, and the time of the whole process of drug release was greater than 72 h.
  • the patch was recommended to be applied for 3 days.
  • Viscous polymer polyacrylate pressure sensitive adhesive brand EUDRAGIT E100, produced in Germany, pre-dissolved with ethyl acetate, EUDRAGIT E100 solids weight ratio 40%
  • 200g, antiviral drug entecavir lg, penetration enhancer laurel nitrogen 8 g of ketone, 8.5 g of eucalyptus oil and 100 g of ethyl acetate were placed in a jar, sealed at the mouth of the bottle, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared.
  • the above mixture was coated on a polyethylene-aluminum-polyethylene composite film backing layer, and then dried at 40 ° C for 4 minutes, at 60 ° C for 2 minutes, at 90 ° C for 2 minutes, after cooling, and then Covering the release paper, and then cutting into a patch of 2 cm 2 (1 cm ⁇ 2 cm), so that the patch per square centimeter contains 7 mg of entecavir, that is, the antiviral transdermal patch 9 is obtained, wherein the adhesive polymer layer contains Polyacrylate pressure sensitive adhesive 82%, entecavir 1. 5%, 5% of azoxystrobin and 8.5% of eucalyptus oil.
  • the permeation rate was 12 g/cm7h measured by a modified Franz diffusion cell device, and the time of the whole process of drug release was greater than 96 h.
  • the patch was recommended to be applied for 4 days.
  • the viscous polymer polyacrylate pressure sensitive adhesive brand EUDRAGIT E100, produced in Germany, pre-dissolved with ethyl acetate, EUDRAGIT E100 solids weight ratio of 40%
  • 150g antiviral drug entecavir 0. 5g
  • penetration enhancer 10 g of laurel azide, 10 g of eucalyptus oil and 9.5 g of propylene glycol, and 100 g of solvent ethyl acetate were placed in a jar, sealed at the mouth of the bottle, shaken on a shaker for 15 hours, and allowed to stand until the bubbles disappeared. .
  • the above mixture was coated on a low density polyethylene film backing layer, then dried at 40 ° C for 4 minutes, dried at 60 ° C for 2 minutes, dried at 90 ° C for 2 minutes, cooled, and then dried.
  • the surface of the viscous polymer is coated with a layer of polyisobutylene. After drying and cooling in the same manner, the release paper is covered, and then cut into pieces of 1 cm 2 ( l C mX l C m) to make the patch per square centimeter.
  • Test Example 1 Entecavir transdermal patch stimulating test
  • Test drug entecavir
  • Test drug patch The patch prepared in Example 7
  • Control patch an excipient prepared by coating a blank matrix without the addition of entecavir and a penetration enhancer according to the method of Example 7; Test method:
  • the administration area was depilated 24 hours before the test.
  • the hair removal range is 3cmX 3cm left and right.
  • One patch was applied to one side; the other side was coated with a vehicle as a control.
  • the application time was 8 hours, once a day, and continuous administration for 3 weeks.
  • the test article is removed and the administration site is cleaned with warm water or no stimulating solvent.
  • the erythema and edema, the pigmentation site, the bleeding site, the rough skin or the thin skin were observed 1 hour after each drug removal and before reapplied.
  • the application site was visually observed for erythema and edema at 30, 60, and 72 hours after removal of the drug.
  • Test drug patch the patch prepared in Example 3.
  • Control patch The excipient prepared by coating the blank matrix without lamivudine and penetration enhancer according to the prescription of Example 3; Test method:
  • the administration area was depilated 24 hours before the test.
  • the hair removal range is 4cm X 4cm left and right.
  • One patch was applied to one side; the other side was coated with an excipient as a control.
  • the application time was 8 hours, once a day, and continuous administration for 3 weeks.
  • the test article is removed and the administration site is cleaned with warm water or no stimulating solvent. Observe erythema and edema 1 hour after each drug removal and before reapplied, whether there is hyperpigmentation, bleeding spots, rough skin or thin skin. After the last application, the application site was visually observed for erythema and edema at 30, 60, and 72 hours after removal of the drug.
  • Test Example 3 Stavudine transdermal patch stimuli test
  • Test drug stavudine
  • Test drug patch the patch prepared in Example 4.
  • Control patch The excipient prepared by coating the blank matrix without adding stavudine and penetration enhancer according to the prescription of Example 4; Test method:
  • the administration area was depilated 24 hours before the test.
  • the hair removal range is 4cm X 4cm left and right.
  • One patch was applied to one side; the other side was coated with an excipient as a control.
  • the application time was 8 hours, and the administration was performed once a day for 3 weeks.
  • the test article is removed and the administration site is cleaned with warm water or no stimulating solvent. Observe erythema and edema, staining spots, bleeding spots, rough skin or thin skin at 1 hour after each drug removal and before re-applied. After the last application, the application site was visually observed for erythema and edema at 30, 60, and 72 hours after removal of the drug. happening.
  • Test Example 4 Entecavir transdermal patch allergy test
  • Test drug patch The preparation method of Example 7 prepares a patch having a concentration of entecavir of 4 times the original concentration as a sensitizer, and a patch having a concentration of 8 times the original concentration is an excitation dose;
  • Negative control group the excipient prepared by coating the blank matrix without adding entecavir and penetration enhancer according to the prescription of Example 7;
  • Positive control group 1% thiobenzothiazole sensitized, 2% mercaptobenzothiazole challenged.
  • This Buehler test was induced by topical administration of entecavir transdermal patches on days 0, 6, and 13 and localized on day 27 in unadministered ribs for 6 hours. Skin erythema, edema, and other abnormalities were observed at 1 and 24 hours after sensitization and 24 and 48 hours after challenge, and erythema and edema were scored.

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Description

一种抗病毒透皮吸收贴片及其制备方法 技术领域
本发明涉及一种通过透皮给药的贴剂， 具体是指一种抗病毒透皮吸收贴片， 本发明还 涉及这种抗病毒透皮吸收贴片的制备方法。 说
背景技术
目前， 应用最广泛、 种类最多的抗病毒类药物为核苷类抗病毒药物， 它包括有恩替卡 韦， 阿德福韦酯， 拉米夫定， 阿昔洛韦， 利巴韦林， 齐多夫定等， 多应用于如乙肝、 艾滋 病、 病毒性感冒、 疱疹等病毒性疾病的治疗。 书
核苷类抗病毒药物的给药方式一般为口服或注射。 但是， 口服或注射的给药方式存在 着血液中药物浓度会随着时间曲线出现明显的波动的问题。 也就是说， 当血液中药物的浓 度过低时，难以充分发挥疗效； 而血液中药物的浓度过高时又会由于超剂量而产生毒性， 对 身体增加负担。 同时， 口服或注射的给药方式还存在胃肠道对药物的酶解和肝脏首过效应 等问题， 从而使得药效降低。 发明内容
本发明要解决的技术方案是提供一种可以持续稳定给药， 同时也可以避免胃肠道酶解 和肝脏首过效应， 以及降低药物毒副作用的抗病毒透皮吸收贴片。 为解决本发明的技术问题， 采用如下技术方案：
本发明提供了一种抗病毒透皮吸收贴片， 由背衬层、 粘性聚合物层和保护膜层组成， 其特征在于， 所述的粘性聚合物层包括有抗病毒药物、 粘性聚合物和促透剂。
所述的抗病毒药物为日用含量低于 lOOmg的核苷类抗病毒药物。
所述的日用含量低于 lOOmg的核苷类抗病毒药物选自恩替卡韦、 阿德福韦酯、 拉米夫 定或司他夫定中至少一种。
上述抗病毒透皮吸收贴片每平方厘米抗病毒透皮吸收贴片中含有抗病毒药物含量为 0. lmg-50mg; 优选为 1. 5 mg_40mg; 更优选为 5 mg-30 mg; 再优选为 10 mg-25 mg; 最优选 为 15 mg_20mg。
抗病毒透皮吸收贴片中所述抗病毒药物占粘性聚合物层的重量分数为 0. 1%_15. 0%； 优 选为 0. 5%-13. 0%, 更优选为 1. 0%-9. 0%、 最优选为 5. 0%-7. 0%。
所述的粘性聚合物选自聚丙烯酸酯压敏胶、 聚异丁烯、 聚异戊二烯或硅酮共聚物。 所述的聚丙烯酸酯压敏胶选自聚丙烯酸树脂 II、 聚丙烯酸树脂 III、 聚丙烯酸树脂 IV、 聚甲丙烯酸铵酯 I、 聚甲丙烯酸铵酯 II、 丙烯酸树脂 EUDRAGIT E100 ; 所述的烯酸树脂 EUDRAGIT E100是甲基丙烯酸丁酯-甲基丙烯酸二甲胺基乙酯-甲基丙烯酸甲酯 （1 : 2 : 1 ) 共 聚物。 粘性聚合物占粘性聚合物层的重量分数为 50. 0%-96. 0%， 优选 65. 0%-90. 0%， 更优选
75. 0%-85% ， 最优选为 78. 0-82. 0%。
根据权利要求 1 抗病毒透皮吸收贴片， 所述促透剂选自月桂氮卓酮、 香精油、 二甲基 亚砜、 百里酚、 桉叶油、 含有萜烯类的中药成份或含有酚类的中药成份中至少一种。
优选的促透剂选自月桂氮卓酮；
所述促透剂可以选自月桂氮卓酮： 香精油的比例为重量比 1 : 0. 5-2。
所述促透剂可以选自月桂氮卓酮： 二甲基亚砜的比例为重量比 1 : 0. 5-2。
所述促透剂占粘性聚合物层的重量分数为 2. 0%-12. 0%； 优选 4. 0%-11. 0%； 更优选为 6. 0%-10. 0%； 最优选为 8. 0%-9. 0%。
所述粘性聚合物层还含有余量的有机溶剂。 例如： 丙二醇、 乳酸乙酯。
所述粘性聚合物层表面和保护膜层之间还有粘合剂层。
所述粘合剂层的材料选自： 聚丙烯酸酯压敏胶、 聚异丁烯或硅酮共聚物。
本发明抗病毒透皮吸收贴片的背衬层选自高密度聚乙烯、 低密度聚乙烯、 聚丙烯、 聚 氯乙烯、 乙烯 -醋酸乙烯共聚物、 聚酯、 聚乙烯吡咯烷酮、 聚乙烯醇、 聚氨基甲酯、 金属铝 箔中至少一种。
所述的背衬层还可以选自金属铝箔与高密度聚乙烯、 低密度聚乙烯、 聚丙烯、 聚氯乙 烯、 乙烯 -醋酸乙烯共聚物、 聚酯、 聚乙烯吡咯烷酮、 聚乙烯醇或聚氨基甲酯中至少一种形 成的复合膜。
所述背衬层还可以选自有三层复合层， 中间层为金属铝箔； 两侧层选自低密度聚乙烯 聚乙烯膜、 聚氨基甲酯膜中至少一种。 本发明还提供了一种制备上述的抗病毒透皮吸收贴片的方法， 包括如下步骤： 将粘性 聚合物、 抗病毒药物、 促透剂和溶剂混合均匀后， 将上述混合物涂布在背衬层上得到粘性 聚合物层， 然后进行干燥处理， 并冷却后， 再在粘性聚合物层另一面覆盖上保护膜层即得 到所述抗病毒透皮吸收贴片。 本发明还提供了上述抗病毒透皮吸收贴片在制备抗病毒药物中的应用。 本发明的有益技术效果：
本发明粘性聚合物层是以聚合物为控释骨架材料， 将一定剂量的抗病毒药物溶解于月 桂氮卓酮促透剂或含有月桂氮卓酮的混合促透剂后， 通过溶剂挥发法使以液体微库的形式 均匀分布于骨架中。 再通过改变聚合物中药物含量、 液体微库密度、 促透剂的比例来调节 贴片中的抗病毒药物释放速率。
本发明采用月桂氮卓酮（即 1-十二烷基氮杂环庚烷 -2-酮）促透剂或含有月桂氮卓酮的 中药混合剂制成的抗病毒药物透皮贴片， 可以有效促进核苷类抗病毒药物渗透皮肤， 经毛 细血管吸收进入人体循环中， 从而抑制相关病毒复制， 起到降低血清病毒 DNA水平的作用。 同时， 通过皮肤给药也可以避免胃肠道酶解和肝脏首过效应， 降低毒副作用。 本发明采用 月桂氮卓酮或含有月桂氮卓酮的中药混合剂作为促透剂， 使抗病毒药物可以更好的渗透进 皮肤， 促使本发明的抗病毒贴片药效维持 3-5天时间， 可以持续稳定给药。 本发明的原料 简单易得， 成本低廉， 具有很强的实用性。
本发明贴片经药理毒理研究， 进行了过敏性试验和皮肤剌激性试验。 上述实验检测均 未出现阳性结果， 说明该抗病毒透皮吸收贴剂对皮肤无剌激性， 无溶血作用， 过敏反应为 阴性， 表明药物安全性好。
同时临床验证结果表明， 本发明贴片可有效促进多种核苷类抗病毒药物渗透皮肤并发 挥功能， 药效可以稳定维持 3-5天， 因此可以减少给药次数。 因此本发明贴片是一种安全、 有效、 长效、 使用方便的透皮吸收制剂， 可用于多种病毒性疾病的治疗。 具体实施方式
以下通过具体实施例进一步说明本发明：
实施例 1
将粘性聚合物聚丙烯酸酯压敏胶 （品牌 EUDRAGIT E100，产自德国， 用乙酸乙酯预先溶 解， EUDRAGIT E100固物投料重量比为 40%) 185g、 抗病毒药物恩替卡韦 0. 5g、 促透剂月桂 氮卓酮 9g、 桉叶油 6g和丙二醇 8. 9g混合物， 和溶剂乙酸乙酯 100g—起放入广口瓶中， 瓶 口密封， 在振荡器上振荡 15小时， 再静置直至气泡消失。 将上述混合物涂布在聚乙烯-铝- 聚乙烯复合膜背衬层上， 然后在 40°C下干燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分 钟， 冷却后， 再在粘性聚合物层另一面覆盖上不粘纸， 再切成 2cm2大小的贴片， 使每平方 厘米的贴片含有恩替卡韦 2. 5mg， 即得到所述抗病毒透皮吸收贴片 1， 其中粘性聚合物层含 聚丙烯酸酯压敏胶 75. 2%， 恩替卡韦 0. 5%， 月桂氮卓酮 9. 1%， 桉叶油 6. 1%， 丙二醇 9%。 采 用改进的 Franz扩散池装置测得渗透速率 15 g/cm7h， 释药全过程的时间大于 72h， 该贴剂 建议可贴 3天。 实施例 2
将粘性聚合物聚丙烯酸酯压敏胶 （品牌 EUDRAGIT E100，产自德国， 用乙酸乙酯预先溶 解， EUDRAGIT E100固物投料重量比为 40%) 225g、 抗病毒药物阿德福韦酯 10g、 促透剂月 桂氮卓酮 9g、 百里酚 3g混合物， 和溶剂二氯甲烷 150g—起放入广口瓶中， 瓶口密封， 在 振荡器上振荡 15小时， 再静置直至气泡消失。 将上述混合物涂布在低密度聚乙烯膜背衬层 上， 然后在 40°C下干燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷却后， 再在粘 性聚合物层另一面覆盖不粘纸， 再切成 20cm2 ( 4cmX 5cm) 大小的贴片， 使每平方厘米的贴 片含有阿德福韦酯 35mg， 即得到所述抗病毒透皮吸收贴片 2， 其中粘性聚合物层含聚丙烯 酸酯压敏胶 80. 4%， 阿德福韦酯 9%， 月桂氮卓酮 8%， 百里酚 2. 6%。 采用改进的 Franz扩散 池装置测得渗透速率 2(^g/cm7h， 释药全过程的时间大于 72h， 该贴剂建议可贴 3天。 实施例 3
将粘性聚合物聚异丁烯 128g、 抗病毒药物拉米夫定 14g、 促透剂月桂氮卓酮 6g、 香精 油 10g和乳酸乙酯 42g混合物， 和溶剂乙酸乙酯 134g—起放入广口瓶中， 瓶口密封， 在振 荡器上振荡 15小时， 再静置直至气泡消失。 将上述混合物涂布在聚氨基甲酯膜背衬层上， 然后在 40°C下干燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷却后， 再在粘性聚 合物层另一面覆盖上防粘纸， 再切成 200cm2大小的贴片， 使每平方厘米的贴片含有拉米夫 定 15mg， 即得到所述抗病毒透皮吸收贴片 3， 其中粘性聚合物层含聚异丁烯 64%， 拉米夫定 7%, 月桂氮卓酮 3%， 香精油 5%， 乳酸乙酯 21%。 采用改进的 Franz扩散池装置测得渗透速 率 55 g/cm7h， 释药全过程的时间大于 96h， 该贴剂建议可贴 4天。 实施例 4
将粘性聚合物聚异戊二烯 87. 5g、 抗病毒药物司他夫定 15g、 促透剂月桂氮卓酮 6g、 二 甲基亚砜 6g， 和溶剂乙酸乙酯 147g—起放入广口瓶中， 瓶口密封， 在振荡器上振荡 15小 时， 再静置直至气泡消失。 将上述混合物涂布在聚氨基甲酯膜背衬层上， 然后在 40°C下干 燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷却后， 再在粘性聚合物层另一面覆 盖上防粘纸， 再切成 100cm2大小的贴片， 使每平方厘米的贴片含有司他夫定 10mg， 即得到 所述抗病毒透皮吸收贴片 4， 其中粘性聚合物层含聚异戊二烯 76. 5%， 司他夫定 13. 1%， 月 桂氮卓酮 5. 2%，二甲基亚砜 5. 2%。采用改进的 Franz扩散池装置测得渗透速率 34 g/cm7h， 释药全过程的时间大于 72h， 该贴剂建议可贴 3天。 实施例 5
将粘性聚合物硅酮共聚物 88g、 抗病毒药物阿德福韦酯 6g、 促透剂月桂氮卓酮 7g、 薄 荷醇 4. 4g， 和溶剂乙酸乙酯 147g—起放入广口瓶中， 瓶口密封， 在振荡器上振荡 15小时， 再静置直至气泡消失。 将上述混合物涂布在聚氨基甲酯膜背衬层上， 然后在 40°C下干燥 4 分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷却后， 再在粘性聚合物层另一面覆盖上 不粘纸， 再切成 30cm2大小的贴片， 使每平方厘米的贴片含有阿德福韦酯 40mg， 即得到所述 抗病毒透皮吸收贴片 5， 其中粘性聚合物层含硅酮共聚物 83. 5%， 阿德福韦酯 5. 7%， 月桂氮 卓酮 6. 6%， 薄荷醇 4. 2%。 采用改进的 Franz扩散池装置测得渗透速率 18 g/cm7h， 释药全 过程的时间大于 72h， 该贴剂建议可贴 3天。 实施例 6
将粘性聚合物聚丙烯酸酯压敏胶 （品牌 EUDRAGIT E100，产自德国， 用乙酸乙酯预先溶 解， EUDRAGIT E100固物投料重量比为 40%) 225g、 抗病毒药物恩替卡韦 0. 5g、 促透剂月桂 氮卓酮 3. 77g和溶剂乙酸乙酯 147g—起放入广口瓶中， 瓶口密封， 在振荡器上振荡 15小 时， 再静置直至气泡消失。 将上述混合物涂布在聚氨基甲酯膜背衬层上， 然后在 40°C下干 燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷却后， 再在已干燥的粘性聚合物表 面涂布一层聚丙烯酸酯， 同样方式干燥并冷却后，再覆盖上不粘纸，再切成 4cm2 ( 2cmX 2cm) 大小的贴片， 使每平方厘米的贴片含有恩替卡韦 3. 25mg， 即得到所述抗病毒透皮吸收贴片 6， 其中粘性聚合物层含聚丙烯酸酯压敏胶 95. 5%， 恩替卡韦 0. 5%， 月桂氮卓酮 4%。 采用改 进的 Franz扩散池装置测得渗透速率 l(^g/cm7h， 释药全过程的时间大于 48h， 该贴剂建议 可贴 2天。 实施例 Ί 将粘性聚合物聚丙烯酸酯压敏胶 （品牌 EUDRAGIT E100，产自德国， 用乙酸乙酯预先溶 解， EUDRAGIT E100固物投料重量比为 40%) 225g、 抗病毒药物恩替卡韦 0. 2g、 促透剂月桂 氮卓酮 9. 8g、 丙二醇 6. 38g和溶剂乙酸乙酯 160g—起放入广口瓶中， 瓶口密封， 在振荡器 上振荡 15小时， 再静置直至气泡消失。 将上述混合物涂布在聚乙烯-铝 -聚乙烯复合膜背衬 层上， 然后在 40°C下干燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷却后， 再在 已干燥的粘性聚合物表面涂布一层硅酮共聚物， 同样方式干燥并冷却后， 再覆盖上不粘纸， 再切成 4cm2 ( 2cmX 2cm)大小的贴片， 使每平方厘米的贴片含有恩替卡韦 2. 2mg， 即得到所 述抗病毒透皮吸收贴片 7， 其中粘性聚合物层含聚丙烯酸酯压敏胶 84. 6%， 恩替卡韦 0. 19%, 月桂氮卓酮 9. 21%, 丙二醇 6%。 采用改进的 Franz扩散池装置测得渗透速率 12 g/cm7h， 释药全过程的时间大于 72h， 该贴剂建议可贴 3天。 实施例 8
将粘性聚合物聚丙烯酸酯压敏胶 （品牌 EUDRAGIT E100，产自德国， 用乙酸乙酯预先溶 解， EUDRAGIT E100固物投料重量比为 40%) 170g、 抗病毒药物恩替卡韦 0. 8g、 促透剂月桂 氮卓酮 4g、 桉叶油 5. 4g和丙二醇 5g混合物， 和溶剂乙酸乙酯 100g—起放入广口瓶中， 瓶 口密封， 在振荡器上振荡 15小时， 再静置直至气泡消失。 将上述混合物涂布在聚氨基甲酯 膜背衬层上， 然后在 40°C下干燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷却后， 再在粘性聚合物层另一面覆盖上防粘纸， 再切成 2cm2 ( lcmX 2cm) 大小的贴片， 使每平方 厘米的贴片含有恩替卡韦 6mg， 即得到所述抗病毒透皮吸收贴片 8， 其中粘性聚合物层含聚 丙烯酸酯压敏胶 82%， 恩替卡韦 1%， 月桂氮卓酮 4. 5%， 桉叶油 6. 5%， 丙二醇 6 %。 采用改 进的 Franz扩散池装置测得渗透速率 15 g/cm7h， 释药全过程的时间大于 72h， 该贴剂建议 可贴 3天。 实施例 9
将粘性聚合物聚丙烯酸酯压敏胶 （品牌 EUDRAGIT E100，产自德国， 用乙酸乙酯预先溶 解， EUDRAGIT E100固物投料重量比为 40%) 200g、 抗病毒药物恩替卡韦 lg、 促透剂月桂氮 卓酮 8g、 桉叶油 8. 5g和溶剂乙酸乙酯 100g—起放入广口瓶中， 瓶口密封， 在振荡器上振 荡 15小时，再静置直至气泡消失。将上述混合物涂布在聚乙烯-铝 -聚乙烯复合膜背衬层上， 然后在 40°C下干燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷却后， 再覆盖上防 粘纸， 再切成 2cm2 ( lcmX 2cm)大小的贴片， 使每平方厘米的贴片含有恩替卡韦 7mg， 即得 到所述抗病毒透皮吸收贴片 9，其中粘性聚合物层含聚丙烯酸酯压敏胶 82%，恩替卡韦 1. 5%， 月桂氮卓酮 8%， 桉叶油 8. 5%。 采用改进的 Franz扩散池装置测得渗透速率 12 g/cm7h， 释 药全过程的时间大于 96h， 该贴剂建议可贴 4天。 实施例 10
将粘性聚合物聚丙烯酸酯压敏胶 （品牌 EUDRAGIT E100，产自德国， 用乙酸乙酯预先溶 解， EUDRAGIT E100固物投料重量比为 40%) 150g、 抗病毒药物恩替卡韦 0. 5g、 促透剂月桂 氮卓酮 10g、 桉叶油 10g和丙二醇 9. 5g混合物， 和溶剂乙酸乙酯 100g—起放入广口瓶中， 瓶口密封， 在振荡器上振荡 15小时， 再静置直至气泡消失。 将上述混合物涂布在低密度聚 乙烯膜背衬层上， 然后在 40°C下干燥 4分钟， 60°C下干燥 2分钟， 90°C下干燥 2分钟， 冷 却后， 再在已干燥的粘性聚合物表面涂布一层聚异丁烯， 同样方式干燥并冷却后， 再覆盖 上防粘纸， 再切成 lcm2 ( lCmX lCm)大小的贴片， 使每平方厘米的贴片含有恩替卡韦 0. 8mg， 即得到所述抗病毒透皮吸收贴片 10， 其中粘性聚合物层含聚丙烯酸酯压敏胶 66. 4%， 恩替 卡韦 0. 6%， 月桂氮卓酮 11%， 桉叶油 11. %， 丙二醇 11%。 采用改进的 Franz扩散池装置测 得渗透速率 22 g/cm7h， 释药全过程的时间大于 72h。 该贴剂建议可贴 3天。 试验例
试验例 1: 恩替卡韦透皮贴剂剌激性试验
试验药物： 恩替卡韦；
受试药物贴剂： 实施例 7制得的贴剂
对照贴剂： 按实施例 7的处方不添加恩替卡韦及促透剂的空白基质涂布制得的赋形剂； 试验方法：
取健康豚鼠 40只， 体重 180g± 20g， 雌、 雄各半， 采用同体左右侧自身对比法。 试验 前 24小时对给药区 （背部）进行脱毛处理。 去毛范围左、 右各 3cmX 3cm。 取一片贴剂贴于 一侧； 另一侧涂布赋形剂作对照。 贴敷时间 8 小时， 每天给药 1次， 连续给药 3周。 贴敷 结束后， 除去受试物并用温水或无剌激性溶剂清洁给药部位。 在每次去除药物后 1 小时以 及再次贴敷前观察红斑及水肿、 涂敷部位是否有色素沉着、 出血点、 皮肤粗糙或皮肤菲薄 情况。 末次贴敷后， 在去除药物后 30-60 分钟， 24、 48 和 72 小时肉眼观察涂敷部位有 无红斑和水肿等情况。
试验结果：
试验期间各组白豚鼠外观体征、 行为活动、 进食、 排泄均正常。 无异常瘙痒行为， 所 有动物体重增长正常， 受药部位皮肤无红斑、 无水肿、 无色素沉着、 无出血点、 无皮肤粗 糙、 无皮肤菲薄， 从给药至观察期结束， 全部动物一般情况良好， 无一死亡。 说明该贴剂 无明显剌激性作用。 试验例 2: 拉米夫定透皮贴剂剌激性试验
试验药物： 拉米夫定；
受试药物贴剂： 实施例 3制得的贴剂；
对照贴剂： 按实施例 3的处方不添加拉米夫定及促透剂的空白基质涂布制得的赋形剂； 试验方法：
取健康家兔 30只， 雌、 雄各半， 采用同体左右侧自身对比法。 试验前 24小时对给药 区 （背部） 进行脱毛处理。 去毛范围左、 右各 4cm X 4cm。 取一片贴剂贴于一侧； 另一侧涂 布赋形剂作对照。 贴敷时间 8 小时， 每天给药 1次， 连续给药 3周。 贴敷结束后， 除去受 试物并用温水或无剌激性溶剂清洁给药部位。 在每次去除药物后 1 小时以及再次贴敷前观 察红斑及水肿、 涂敷部位是否有色素沉着、 出血点、 皮肤粗糙或皮肤菲薄情况。 末次贴敷 后， 在去除药物后 30-60 分钟， 24、 48 和 72 小时肉眼观察涂敷部位有无红斑和水肿等 情况。
试验结果：
试验期间各组家兔活动均正常。 受药部位皮肤无红斑、 无水肿、 无色素沉着、 无出血 点、 无皮肤粗糙、 无皮肤菲薄， 从给药至观察期结束， 全部动物一般情况良好， 无一死亡。 说明该贴剂无明显剌激性作用。 试验例 3: 司他夫定透皮贴剂剌激性试验
试验药物： 司他夫定；
受试药物贴剂： 实施例 4制得的贴剂；
对照贴剂： 按实施例 4的处方不添加司他夫定及促透剂的空白基质涂布制得的赋形剂； 试验方法：
取健康家兔 30只， 雌、 雄各半， 采用同体左右侧自身对比法。 试验前 24小时对给药 区 （背部） 进行脱毛处理。 去毛范围左、 右各 4cm X 4cm。 取一片贴剂贴于一侧； 另一侧涂 布赋形剂作对照。 贴敷时间 8 小时， 每天给药 1次， 连续给药 3周。 贴敷结束后， 除去受 试物并用温水或无剌激性溶剂清洁给药部位。 在每次去除药物后 1 小时以及再次贴敷前观 察红斑及水肿、 涂敷部位是否有色素沉着、 出血点、 皮肤粗糙或皮肤菲薄情况。 末次贴敷 后， 在去除药物后 30-60 分钟， 24、 48 和 72 小时肉眼观察涂敷部位有无红斑和水肿等 情况。
试验结果：
试验期间各组家兔活动均正常。 受药部位皮肤无红斑、 无水肿、 无色素沉着、 无出血 点、 无皮肤粗糙、 无皮肤菲薄， 从给药至观察期结束， 全部动物一般情况良好， 无一死亡。 说明该贴剂无明显剌激性作用。 试验例 4: 恩替卡韦透皮贴剂过敏性试验
试验药物： 恩替卡韦
受试药物贴剂： 实施例 7的制备方法制备恩替卡韦浓度为原浓度 4倍的贴剂为致敏剂 量， 浓度为原浓度 8倍的贴剂为激发剂量；
阴性对照组： 按实施例 7 的处方不添加恩替卡韦及促透剂的空白基质涂布制得的赋形 剂；
阳性对照组： 1%的巯基苯并噻唑致敏， 2%的巯基苯并噻唑激发。
试验方法：
选择成年豚鼠 30只， 雌雄不拘。 受试物组 20只、 阳性和阴性对照组分别 5只。 试验 前 24小时对给药区进行脱毛处理。 去毛范围左、 右各 4cmX 4cm。 采用 Buehler试验 （BT) 即试验动物表皮给予诱导剂量， 经过 10— 14 天的诱导期， 此时免疫反应发生， 然后给予 激发剂量， 以观察是否出现了过敏反应。 在诱导期和攻击期的皮肤反应及其程度均应进行 对比， 并与赋形剂组进行比较。
本次 Buehler试验在第 0， 6 和 13天用恩替卡韦透皮贴剂局部给药以诱导， 在第 27 天在未给药的肋腹部贴 6小时以局部激发。 在致敏后 1和 24小时及激发后 24和 48小时观 察皮肤红斑、 水肿和其他异常反应， 并对红斑和水肿进行评分。
试验结果：
皮肤过敏发生率％
组别 Oh 24h 48h 72h 致敏性评价
巯基苯并噻唑 60 80 90 80 有致敏性
阴性对照组 0 0 0 0 无致敏性
恩替卡韦 0 0 0 0 无致敏性
结果表明本贴剂没有明显致敏性。

Claims

权 利 要 求 书
I . 一种抗病毒透皮吸收贴片， 由背衬层、 粘性聚合物层和保护膜层组成， 其特征在于， 所述的粘性聚合物层包括有抗病毒药物、 粘性聚合物和促透剂。
2. 根据权利要求 1抗病毒透皮吸收贴片， 其特征在于， 所述的抗病毒药物为日用含量低 于 lOOmg的核苷类抗病毒药物。
3. 根据权利要求 2抗病毒透皮吸收贴片， 其特征在于， 所述的日用含量低于 lOOmg的核 苷类抗病毒药物选自恩替卡韦、 阿德福韦酯、 拉米夫定或司他夫定中至少一种。
4. 根据权利要求 1-3中任一项的的抗病毒透皮吸收贴片， 其特征在于， 每平方厘米抗病 毒透皮吸收贴片中含有抗病毒药物含量为 0. lmg-50mg。
5. 根据权利要求 1-3中任一项的抗病毒透皮吸收贴片， 其特征在于， 所述抗病毒药物占 粘性聚合物层的重量分数为 0. 1%-15. 0%。
6. 根据权利要求 1-3中任一项的抗病毒透皮吸收贴片， 其特征在于， 所述的粘性聚合物 选自聚丙烯酸酯压敏胶、 聚异丁烯、 聚异戊二烯或硅酮共聚物。
7. 根据权利要求 6抗病毒透皮吸收贴片， 其特征在于， 所述的聚丙烯酸酯压敏胶选自聚 丙烯酸树脂 II、 聚丙烯酸树脂 III、 聚丙烯酸树脂 IV、 聚甲丙烯酸铵酯 I、 聚甲丙烯酸铵酯 II。
8. 根据权利要求 6-7中任一项的抗病毒透皮吸收贴片， 其特征在于， 粘性聚合物占粘性 聚合物层的重量分数为 50. 0%-96. 0%。
9. 根据权利要求 1-3中任一项的抗病毒透皮吸收贴片， 所述促透剂选自月桂氮卓酮、 香 精油、 二甲基亚砜、 百里酚、 桉叶油、 含有萜烯类的中药成份或含有酚类的中药成份中至少 一种。
10. 根据权利要求 9抗病毒透皮吸收贴片， 所述促透剂选自月桂氮卓酮。
I I . 根据权利要求 9抗病毒透皮吸收贴片， 所述促透剂选自月桂氮卓酮： 香精油的比例 为重量比 1 : 0. 5-2。
12. 根据权利要求 9抗病毒透皮吸收贴片， 所述促透剂选自月桂氮卓酮： 二甲基亚砜的 比例为重量比 1 : 0. 5-2。
13. 根据权利要求 9的抗病毒透皮吸收贴片， 其特征在于， 所述促透剂占粘性聚合物层 的重量分数为 2. 0%-12. 0%。
14. 根据权利要求 1-3中任一项的抗病毒透皮吸收贴片， 其特征在于， 所述粘性聚合物 层还含有有机溶剂。
15. 根据权利要求 1-3中任一项的抗病毒透皮吸收贴片， 其特征在于， 所述粘性聚合物 层表面和保护膜层之间还有粘合剂层。
16. 根据权利要求 15的抗病毒透皮吸收贴片， 其特征在于， 所述粘合剂层的材料选自： 聚丙烯酸酯压敏胶、 聚异丁烯或硅酮共聚物。
17. 根据权利要求 1-3中任一项的抗病毒透皮吸收贴片， 其特征在于， 所述的背衬层选 自高密度聚乙烯、 低密度聚乙烯、 聚丙烯、 聚氯乙烯、 乙烯 -醋酸乙烯共聚物、 聚酯、 聚乙烯 吡咯烷酮、 聚乙烯醇、 聚氨基甲酯、 金属铝箔中至少一种。
18. 根据权利要求 17的抗病毒透皮吸收贴片， 其特征在于， 所述的背衬层选自金属铝箔 与高密度聚乙烯、 低密度聚乙烯、 聚丙烯、 聚氯乙烯、 乙烯 -醋酸乙烯共聚物、 聚酯、 聚乙烯 吡咯烷酮、 聚乙烯醇或聚氨基甲酯中至少一种形成的复合膜。
19. 根据权利要求 17的抗病毒透皮吸收贴片， 其特征在于： 所述背衬层选自有三层复合 层， 中间层为金属铝箔； 两侧层选自低密度聚乙烯聚乙烯膜、 聚氨基甲酯膜中至少一种。
20. 一种制备权利要求 1-19中任一项的抗病毒透皮吸收贴片的方法， 其特征在于： 将粘 性聚合物、 抗病毒药物、 促透剂和溶剂混合均匀后， 将上述混合物涂布在背衬层上得到粘性 聚合物层， 然后进行干燥处理， 并冷却后， 再在粘性聚合物层另一面覆盖上保护膜层即得到 所述抗病毒透皮吸收贴片。
21、 权利要求 1-19的抗病毒透皮吸收贴片在制备抗病毒药物中的应用。
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