WO2018133010A1 - 经皮吸收制剂及制备经皮吸收制剂的方法 - Google Patents

经皮吸收制剂及制备经皮吸收制剂的方法 Download PDF

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Publication number
WO2018133010A1
WO2018133010A1 PCT/CN2017/071724 CN2017071724W WO2018133010A1 WO 2018133010 A1 WO2018133010 A1 WO 2018133010A1 CN 2017071724 W CN2017071724 W CN 2017071724W WO 2018133010 A1 WO2018133010 A1 WO 2018133010A1
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layer
drug
acid
oseltamivir
percutaneous absorption
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PCT/CN2017/071724
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English (en)
French (fr)
Inventor
戴伟
罗丽娜
赵步文
游劲松
黄芳芳
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广东东阳光药业有限公司
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Priority to PCT/CN2017/071724 priority Critical patent/WO2018133010A1/zh
Publication of WO2018133010A1 publication Critical patent/WO2018133010A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention relates to the field of pharmaceutical and chemical engineering.
  • the invention relates to percutaneous absorption formulations and methods of making transdermal absorption formulations.
  • Oseltamivir has the chemical name ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)cyclohexene-1-carboxylate.
  • the chemical structure is as follows:
  • Oseltamivir has a strong inhibitory activity against neuraminidase and is effective against both influenza A and B viruses, and its properties and preparation methods are disclosed in WO 1998007685 A1 and WO 1996026933 A1.
  • oseltamivir The dosage forms currently marketed for oseltamivir are granules, capsules, and dry suspensions.
  • oseltamivir is a particularly bitter drug, so its orally administered pharmaceutical composition is difficult to swallow.
  • the bitter taste of oseltamivir is usually masked by the addition of a sweetener to the composition or in the form of a capsule formulation.
  • Chinese patent CN 101389323 B discloses a pharmaceutical composition
  • a pharmaceutical composition comprising an excipient and oseltamivir phosphate, wherein the excipient is selected from the group consisting of an equilibrium moisture content of 1% by weight or less at 25 ° C and a relative humidity of 70%.
  • the excipient is selected from the group consisting of an equilibrium moisture content of 1% by weight or less at 25 ° C and a relative humidity of 70%.
  • One or more of a sugar and a sugar alcohol, and the content of glucose and mannose contained in the sugar and the sugar alcohol are each 0.01% by weight or less.
  • a high intensity sweetener such as sucrose or stevioside is also added to the invention to mask bitterness.
  • Chinese patent CN 1820774 B discloses a oseltamivir granule and a preparation method thereof, the granule comprising 1.97 to 19.8% by weight of oseltamivir phosphate, 75.0 to 97.5% by weight of a diluent, 0.1 to 5.0. % by weight of binder, and 1.0 to 5.0% by weight of food flavor, sweetener and/or food coloring.
  • Chinese patent application CN 104367558 A1 provides an oseltamivir freeze-dried orally disintegrating tablet and a preparation method thereof, wherein the oseltamivir freeze-dried orally disintegrating tablet is composed of oseltamivir phosphate or oseltamivir and a matrix.
  • the active ingredient is 10 to 75 parts by weight based on oseltamivir
  • the matrix contains 1 to 60 parts by weight of the skeleton proppant, 1 to 50 parts by weight of the binder, 0 to 10 parts by weight of the lyoprotectant, and flavoring agent 0.
  • the base may further contain 0 to 10 parts by weight of the flavoring agent and 0 to 69 parts by weight of the inorganic base to 10 parts by weight.
  • the present invention aims to solve at least one of the technical problems existing in the prior art.
  • the present invention provides a transdermal absorption preparation containing oseltamivir or a pharmaceutically acceptable salt thereof and a process for the preparation thereof.
  • the percutaneous absorption preparation can achieve a prophylactic or therapeutic blood concentration in a short time after administration, and release the drug at a constant rate to avoid the peak-to-valley phenomenon of oral administration of oseltamivir, and maintain a constant
  • the optimal blood concentration range avoids the adverse reactions caused by oral administration or the side effects caused by the sharp increase of blood concentration; it can be administered continuously for a long time, prolonging the effective action time and reducing the number of times of administration of the patient;
  • the skin absorption preparation is convenient to be administered, and the patient compliance can be improved, and the administration can be interrupted at any time to improve the safety of administration.
  • the percutaneous absorption preparation can enhance the compliance of the patient, and solve the problem of administration in special cases (such as patients under water shortage,
  • optional pharmaceutically acceptable excipient in the present invention is meant that it may be optionally added or selected without the addition of any pharmaceutically acceptable excipient.
  • oseltamivir preparations In the existing oseltamivir preparations, it is basically an oral preparation, and the taste-masking agent is used to mask the bitterness of oseltamivir, but the addition of a taste-masking agent to the preparation may not completely cover up the oseltamivir. bitterness.
  • oral medications are restricted to specific populations (elderly, infants, and infants) or under certain conditions (water deficit conditions and patients with dysphagia).
  • there is currently no percutaneous absorption preparation of oseltamivir there is currently no percutaneous absorption preparation of oseltamivir, and there is a lack of intensive research on the percutaneous absorption preparation of oseltamivir in the prior art.
  • the right side of the rabbit's right hair removal area was designated as the control area, the left side of the test area, the control area was given a blank vehicle, the test area was given oseltamivir preparation, the dosage volume was 0.5ml / time, 2 times / day, each application
  • the posting time is 4h for 14 consecutive days. Apply a cotton swab to the area of 2.5cm ⁇ 2.5cm, cover with two layers of gauze and a layer of cellophane, and then fix it with non-irritating tape and straps.
  • the inventors have intensively studied and found that the drug is designed into a transdermal drug preparation and functions as a systemic circulation, requiring the drug itself to have no toxic side effects on the skin, and it is expected that the drug can smoothly penetrate the stratum corneum, the active epidermis, and enter. After the dermis layer, it is taken into the blood by capillary blood. Since the transdermal drug delivery system has a low drug loading amount, the candidate drug generally has a short half-life and needs to be administered frequently, and the daily dose is small (the daily dose is less than 20 mg), and the effect is stronger.
  • the daily dose of oseltamivir is high (>60 mg), and the taking period is long (at least 5 days in a row), so it is difficult to achieve a blood drug concentration that is effective after transdermal administration.
  • the current oral dose of oseltamivir for the prevention of influenza in adults and adults over the age of 13 is 75 mg once daily; oral dose is recommended for influenza treatment in adults and adolescents over 13 years old. It is 75mg each time, 2 times a day for 5 days.
  • the body weight is administered, ⁇ 15kg, the recommended oral dose for influenza treatment is 30mg, 2 times a day; >15-23kg, the oral dose is 45mg, 2 times a day; At 23-40 kg, the oral dose is 60 mg twice daily; when >40 kg, the oral dose is 75 mg twice daily, and the pharmaceutically acceptable salts of oseltamivir are mostly water-soluble and poor in fat solubility. Compounds with a high melting point are more difficult to directly exert through the skin into the systemic circulation.
  • the present invention proposes a transdermal absorption preparation containing oseltamivir or a pharmaceutically acceptable salt thereof and a process for the preparation thereof.
  • the percutaneous absorption preparation is convenient to be administered, and the patient compliance can be improved, and the drug loading amount of the drug in the preparation is high (for example, up to 7 mg/cm 2 ), and the transdermal permeation amount of the drug is high (for example, the total release after 24 hours)
  • the amount of blood exceeds 40%), thereby achieving the blood concentration of the preventive or therapeutic effect, and effectively solving the blood drug concentration and the water-soluble drug which are difficult to achieve the efficacy after the daily administration of the drug with high daily dose is difficult to directly penetrate.
  • the adverse reactions of the digestive system during oral administration can be avoided, and a feasible administration method for the treatment of influenza is brought about.
  • the invention provides a transdermal absorption preparation comprising oseltamivir or a pharmaceutically acceptable salt thereof.
  • the percutaneous absorption preparation comprises: a backing layer; a protective layer; and a pharmaceutical preparation layer, the pharmaceutical preparation layer being located between the backing layer and the protective layer, wherein the pharmaceutical preparation layer Contains oseltamivir or a pharmaceutically acceptable salt thereof.
  • the percutaneous absorption preparation of the present invention is convenient to be administered, and can improve patient compliance, and the drug-loading amount of the drug in the preparation is high, and the transdermal permeation amount of the drug is high, thereby achieving a blood concentration which is a preventive or therapeutic effect. In addition, adverse reactions of the digestive system at the time of oral administration can also be avoided.
  • the above percutaneous absorption preparation containing oseltamivir or a pharmaceutically acceptable salt thereof may further have the following additional technical features:
  • the weight of the oseltamivir or a pharmaceutically acceptable salt thereof, based on the weight of the drug formulation layer is not less than 1.0%, or 10.0, based on oseltamivir free base. % ⁇ 80.0%, or 30.0% ⁇ 75.0%.
  • the inventors have obtained the above-mentioned oseltamivir or a pharmaceutically acceptable salt thereof by a large amount of experiments, under which conditions the properties of the drug preparation layer can be further effectively improved, for example, the solubility of the drug is improved, the stability of the drug is improved, and the drug is promoted. Release of the drug in the patch, enhance the percutaneous penetration ability of the drug, and improve the drug preparation layer and the protective layer Or interaction between the backing layers to improve the cohesion of the drug formulation layer.
  • the pharmaceutical formulation layer further comprises at least one of the following: a pressure sensitive adhesive, a matrix material, and a crosslinking agent.
  • a pressure sensitive adhesive a matrix material
  • a crosslinking agent a crosslinking agent
  • the pharmaceutical formulation layer is composed of: the oseltamivir or a pharmaceutically acceptable salt thereof; and a pressure sensitive adhesive, wherein the pressure sensitive adhesive comprises a weight of the pharmaceutical formulation layer
  • the ratio is: no more than 90.0%, or 20.0% to 70.0%, or 30.0% to 50.0%.
  • the inventors have optimized the composition of the above-mentioned pharmaceutical preparation layer by a large number of experiments, under which conditions the properties of the drug preparation layer can be further effectively improved, for example, the solubility of the drug is improved, the stability of the drug is improved, and the release of the drug in the patch is promoted.
  • the percutaneous penetration ability of the drug is enhanced, the interaction between the drug preparation layer and the protective layer or the backing layer is improved, and the cohesive force of the drug preparation layer is improved.
  • the pharmaceutical formulation layer is composed of: the oseltamivir or a pharmaceutically acceptable salt thereof; a matrix material; and a crosslinking agent, wherein the weight of the matrix material accounts for the pharmaceutical preparation
  • the ratio of the layer weight is: not more than 25.0%, or 1.0% to 15.0%, or 5.0% to 12.0%, and the ratio of the weight of the crosslinking agent to the weight of the pharmaceutical preparation layer is not higher than 3.0%, or 0.1% to 2.5%, or 0.2% to 2.0%.
  • the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, and enhancing the drug.
  • the percutaneous penetration ability improves the interaction between the drug preparation layer and the protective layer or the backing layer, and improves the cohesive force of the drug preparation layer.
  • the pharmaceutical formulation layer is composed of: the oseltamivir or a pharmaceutically acceptable salt thereof; a pressure sensitive adhesive; and a matrix material, wherein the pressure sensitive adhesive comprises the drug
  • the ratio of the weight of the preparation layer is: not more than 90.0%, or 20.0% to 70.0%, or 30.0% to 50.0%, and the ratio of the weight of the skeleton material to the weight of the pharmaceutical preparation layer is not higher than 10.0%, or 0.5% to 8.0%, or 1.0% to 6.0%.
  • the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, and enhancing the drug.
  • the percutaneous penetration ability improves the interaction between the drug preparation layer and the protective layer or the backing layer, and improves the cohesive force of the drug preparation layer.
  • the pharmaceutical formulation layer further comprises a pharmaceutically acceptable excipient, the excipient comprising at least one of the following: a transdermal absorption enhancer, a plasticizer, a solvent, a humectant, a crosslinking regulator, Acids, fillers, preservatives, bacteriostats, antioxidants and chelating agents.
  • a pharmaceutically acceptable excipient comprising at least one of the following: a transdermal absorption enhancer, a plasticizer, a solvent, a humectant, a crosslinking regulator, Acids, fillers, preservatives, bacteriostats, antioxidants and chelating agents.
  • the pharmaceutically acceptable salt comprises: hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, lactate, ascorbate, maleate , tartrate, malate or succinate.
  • the inventors have found that under such conditions, the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, and promoting the drug in the patch.
  • the release enhances the transdermal penetration ability of the drug, improves the interaction between the drug preparation layer and the protective layer or the backing layer, and improves the cohesive force of the drug preparation layer.
  • the pressure sensitive adhesive includes, but is not limited to, an acrylic polymer (eg, DURO-TAK 87-2194, DURO-TAK 387-2287, DURO-TAK 87-2852), methacrylic polymer , polyisobutylene polymers, rubbers (eg, natural rubber, synthetic rubber - SIS) and silicones (eg, Dow) BIO-PSAQ7-2920, BIO-PSAQ7-2675, BIO-PSA4301, BIO-PSA4302, BIO-PSA4201, BIO-PSA4202, BIO-PSA4101, BIO-PSA4102, BIO-PSA4601, BIO-PSA4602, BIO-PSA4501, BIO- PSA4502, BIO-PSA4401, BIO-PSA4402) or mixtures thereof.
  • an acrylic polymer eg, DURO-TAK 87-2194, DURO-TAK 387-2287, DURO-TAK 87-2852
  • methacrylic polymer eg, polyisobutylene polymers,
  • the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, enhancing the percutaneous penetration ability of the drug, and improving the drug preparation layer and the protective layer. Or interaction between the backing layers to improve the cohesion of the drug formulation layer.
  • the framework material including but not limited to polyvinyl alcohol, polyacrylic acid, sodium polyacrylate, partially neutralized sodium polyacrylate (eg, NP-600/700/800), acrylic acid copolymer, methylene Acid copolymer, acrylic acid and methacrylate copolymer, acrylate, phthalate, gelatin, tragacanth, agar, carbomer, hydroxypropyl methylcellulose, povidone (XL, K90) , sodium carboxymethyl cellulose, polyethylene glycol or a mixture thereof) and a crosslinking agent (including but not limited to aluminum sulphate, aluminum hydroxide, aluminum hydroxide gel, magnesium aluminum silicate, calcium hydroxide, aluminum aluminate A matrix formed by crosslinking after magnesium, aluminum chloride, potassium aluminum sulfate, aluminum nitrate, calcium chloride, calcium nitrate, aluminum glycinate, magnesium aluminum silicate, magnesium aluminum carbonate or a mixture thereof.
  • a crosslinking agent including but not limited to
  • the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, enhancing the percutaneous penetration ability of the drug, and improving the drug preparation layer and the protective layer. Or interaction between the backing layers to improve the cohesion of the drug formulation layer.
  • the transdermal absorption enhancers include, but are not limited to, pyrrolidone (eg, 2-pyrrolidone, N-methyl-pyrrolidone), azone, and the like (eg, Azone, HPE-101) ), fatty acids and their esters (eg, oleic acid, lauric acid, esters of oleic acid or lauric acid, isopropyl myristate, propylene glycol fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters, Oleic acid polyethylene glycol glyceride, polyglyceryl-3 diisostearate, polyglyceryl oleate, polyglycolic acid decanoate, sodium lauryl sulfate, ethers (eg, Poloxa M, polyoxypropylene stearyl ether), alcohols (eg, ethanol, isopropanol), polyols (eg, propylene
  • the ratio of the transdermal absorption enhancer to the weight of the drug formulation layer is from 0.5% to 15%, or from 1.0% to 10.0%, or from 2.0% to 8.0%.
  • the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, enhancing the percutaneous penetration ability of the drug, and improving the drug preparation layer and the protective layer. Or interaction between the backing layers to improve the cohesion of the drug formulation layer.
  • the plasticizer includes, but is not limited to, petroleum oil, squalane, squalene, vegetable oil, silicone oil, dibasic acid ester, liquid rubber, liquid fatty acid ester, diethylene glycol. , polyethylene glycol, propylene glycol, glycerin or a mixture thereof.
  • the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, enhancing the percutaneous penetration ability of the drug, and improving the drug preparation layer and the protective layer. Or interaction between the backing layers to improve the cohesion of the drug formulation layer.
  • the solvent includes, but is not limited to, water, ethanol, propylene glycol, heptane, acetone, methanol, ethyl acetate, or a mixture thereof.
  • solubility of oseltamivir can be improved, the coating property of the drug preparation layer can be improved, the percutaneous penetration ability of the drug can be enhanced, the interaction between the drug preparation layer and the protective layer or the backing layer can be improved, and the drug preparation layer can be improved. Cohesion.
  • the filler includes, but is not limited to, kaolin, zinc oxide, micronized silica gel, calcium carbonate, kaolin, bentonite, titanium dioxide, or a mixture thereof.
  • the properties of the drug preparation layer can be further effectively improved, for example, the stability of the drug is improved, the interaction between the drug preparation layer and the protective layer or the backing layer is improved, and the cohesive force of the drug preparation layer is improved.
  • the humectant includes, but is not limited to, glycerin, propylene glycol, polyethylene glycol, hyaluronic acid, or a mixture thereof.
  • the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, enhancing the percutaneous penetration ability of the drug, and improving the drug preparation layer and the protective layer. Or interaction between the backing layers to improve the cohesion of the drug formulation layer.
  • the acid includes, but is not limited to, tartaric acid, lactic acid, oleic acid, succinic acid, acetic acid, malic acid, citric acid, hydrochloric acid, phosphoric acid, ascorbic acid, maleic acid, or mixtures thereof.
  • the properties of the drug preparation layer can be further effectively improved, for example, improving the solubility of the drug, improving the stability of the drug, promoting the release of the drug in the patch, enhancing the percutaneous penetration ability of the drug, and improving the drug preparation layer and the protective layer. Or interaction between the backing layers to improve the cohesion of the drug formulation layer.
  • the preservative or bacteriostatic agent includes, but is not limited to, methylparaben, propylparaben, butylparaben, sorbic acid, benzoic acid, benzyl alcohol, imidate , benzyl alcohol or a mixture thereof.
  • the antioxidant includes, but is not limited to, propyl gallate, BHA (butylhydroxyanisole), BHT (dibutylhydroxytoluene), citric acid, EDTA and salts thereof, tocopherol or mixture.
  • BHA butylhydroxyanisole
  • BHT dibutylhydroxytoluene
  • citric acid EDTA and salts thereof, tocopherol or mixture.
  • the thickness of the drug preparation layer is not strictly limited, and those skilled in the art can determine the appropriate amount by factors such as the dose.
  • the drug preparation layer has a thickness of 10 to 4000 ⁇ m, or 20 to 3000 ⁇ m. Thereby, the properties of the drug preparation layer can be further effectively improved, for example, the release of the drug in the patch is promoted, and the transdermal penetration ability of the drug is enhanced.
  • the protective layer in the present invention is a release material for protecting the drug-containing layer of the preparation.
  • the protective layer of the best material according to the properties of the specific pharmaceutical preparation layer or the backing layer.
  • the material should have good compatibility with the drug preparation layer or the backing layer, and should be an inert, opaque or light-shielding metallized polyester film, which may be made of polyethylene terephthalate.
  • the surface of the protective layer that is in contact with the drug formulation layer may be coated with a layer of a polymer that prevents pressure sensitive adhesives from sticking, such as silicone, fluorosilicone or perfluorocarbon polymers.
  • the protective layer can be firmly adhered to the surface of the drug preparation layer or the backing layer before use, and is easily peeled off from the drug preparation layer or the backing layer at the time of use.
  • the thickness of the protective layer can be appropriately determined by those skilled in the art.
  • the backing layer described in the present invention is a film supporting a drug preparation layer, and the backing layer may be, but not limited to, an organic polymer film, a metal foil or an organic polymer film, a laminated film of a metal foil, and a non-woven fabric. Cloth and so on.
  • the organic polymer film described therein may be, but not limited to, cellulose acetate, ethyl cellulose, polyester, nylon, polyvinyl chloride, polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-propylene copolymer. a film made of vinyl acetate-vinyl chloride copolymer, polyethylene terephthalate, polytetrafluoroethylene or ionomer resin.
  • the ideal backing material requirements are: good compatibility with drugs and excipients; thickness of about 75 ⁇ m; low moisture transmission rate ( ⁇ 20g/m 2 /24h); high oxygen transmission rate, improving skin water At the same time, it can ensure the normal breathing of the skin; no toxicity; there is acceptable color or transparent or translucent; the halo is less than 10%; it feels good on the skin; the texture is firm and smooth, and the touch is Dry feel; good tear strength and heat seal.
  • it is necessary to select the backing layer of the best material according to the nature of the drug preparation layer or the protective layer and the length of the adhesion time, and the thickness thereof can be appropriately determined by those skilled in the art.
  • the backing layer may be a 3M CoTran TM 9700,3M CoTran TM 9701,3M CoTran TM 9718,3M CoTran TM 9719,3M CoTran TM 9720,3M CoTran TM 9722,3M CoTran TM 9726.
  • the percutaneous absorption preparation may be a patch or a patch, but is not limited to the two types of percutaneous absorption preparations.
  • the percutaneous absorption preparation of the present invention comprises: a backing layer; a protective layer; and a pharmaceutical preparation layer, the pharmaceutical preparation layer comprising:
  • the ratio of the weight of oseltamivir or a pharmaceutically acceptable salt thereof to the weight of the drug preparation layer is from 10.0% to 78.0%, based on the oseltamivir free base;
  • the ratio of the pressure-sensitive adhesive to the weight of the drug preparation layer is 22.0% to 90.0%.
  • the percutaneous absorption preparation of the present invention is convenient to be administered, and can improve patient compliance, and the drug-loading amount of the drug in the preparation is high, and the transdermal permeation amount of the drug is high, thereby achieving a blood concentration which is a preventive or therapeutic effect. In addition, adverse reactions of the digestive system at the time of oral administration can also be avoided.
  • the percutaneous absorption preparation of the present invention comprises: a backing layer; a protective layer; and a pharmaceutical preparation layer in which the pharmaceutical preparation layer:
  • the ratio of oseltamivir or a pharmaceutically acceptable salt thereof to the weight of the drug formulation layer, based on oseltamivir free base, is 48.6%;
  • the ratio of the pressure sensitive adhesive to the weight of the drug preparation layer is 46.60%
  • the ratio of the transdermal absorption enhancer weight to the weight of the drug preparation layer was 4.8%.
  • the percutaneous absorption preparation of the present invention is convenient to be administered, and can improve patient compliance, and the drug-loading amount of the drug in the preparation is high, and the transdermal permeation amount of the drug is high, thereby achieving a blood concentration which is a preventive or therapeutic effect. In addition, adverse reactions of the digestive system at the time of oral administration can also be avoided.
  • the percutaneous absorption preparation of the present invention comprises: a backing layer; a protective layer; and a pharmaceutical preparation layer in which the pharmaceutical preparation layer:
  • the ratio of the weight of oseltamivir or a pharmaceutically acceptable salt thereof to the weight of the drug preparation layer is 53.89% to 59.3% based on the oseltamivir free base;
  • the ratio of the pressure sensitive adhesive to the weight of the drug preparation layer is 36.2% to 41.6%;
  • the ratio of the transdermal absorption enhancer weight to the weight of the drug preparation layer was 4.5%.
  • the percutaneous absorption preparation of the present invention is convenient to be administered, and can improve patient compliance, and the drug-loading amount of the drug in the preparation is high, and the transdermal permeation amount of the drug is high, thereby achieving a blood concentration which is a preventive or therapeutic effect. In addition, adverse reactions of the digestive system at the time of oral administration can also be avoided.
  • the percutaneous absorption preparation of the present invention comprises: a backing layer; a protective layer; and a pharmaceutical preparation layer in which the pharmaceutical preparation layer:
  • the ratio of the weight of oseltamivir or a pharmaceutically acceptable salt thereof to the weight of the drug preparation layer is from 10.0% to 50.2%, based on the oseltamivir free base;
  • the ratio of the pressure-sensitive adhesive to the weight of the drug preparation layer is 49.8% to 90.0%.
  • the percutaneous absorption preparation of the present invention is convenient to be administered, and can improve patient compliance, and the drug-loading amount of the drug in the preparation is high, and the transdermal permeation amount of the drug is high, thereby achieving a blood concentration which is a preventive or therapeutic effect. In addition, adverse reactions of the digestive system at the time of oral administration can also be avoided.
  • the percutaneous absorption preparation of the present invention comprises: a backing layer; a protective layer; and a pharmaceutical preparation layer in which the pharmaceutical preparation layer:
  • the ratio of the weight of oseltamivir or a pharmaceutically acceptable salt thereof to the weight of the drug preparation layer is 7.76% to 25.20% based on the oseltamivir free base;
  • the ratio of the pressure sensitive adhesive to the weight of the drug preparation layer is 48.3% to 69.4%;
  • the ratio of the weight of the plasticizer to the weight of the layer of the pharmaceutical preparation is 9.3% to 10.2%;
  • the ratio of the weight of the solvent to the weight of the drug preparation layer is 9.3% to 10.2%.
  • the percutaneous absorption preparation of the present invention is convenient to be administered, and can improve patient compliance, and the drug-loading amount of the drug in the preparation is high, and the transdermal permeation amount of the drug is high, thereby achieving a blood concentration which is a preventive or therapeutic effect. In addition, adverse reactions of the digestive system at the time of oral administration can also be avoided.
  • the percutaneous absorption preparation of the present invention comprises: a backing layer; a protective layer; and a pharmaceutical preparation layer in which the pharmaceutical preparation layer:
  • the ratio of oseltamivir or a pharmaceutically acceptable salt thereof to the weight of the drug formulation layer is from 1.52% to 3.81%, based on the oseltamivir free base;
  • the ratio of the weight of the humectant to the weight of the drug preparation layer is 30.0%;
  • the ratio of the weight of the skeleton material to the weight of the drug preparation layer is 6.2% to 10.0%;
  • the ratio of the weight of the crosslinking agent to the weight of the drug preparation layer is 0.15% to 0.2%;
  • the ratio of the weight of the solvent to the weight of the drug preparation layer is 55.39% to 61.2%;
  • the ratio of the weight of the acid to the weight of the layer of the pharmaceutical preparation is 0.18% to 0.2%;
  • the ratio of the weight of the chelating agent to the weight of the drug preparation layer is from 0.18% to 0.2%.
  • the percutaneous absorption preparation of the present invention is convenient to be administered, and can improve patient compliance, and the drug-loading amount of the drug in the preparation is high, and the transdermal permeation amount of the drug is high, thereby achieving a blood concentration which is a preventive or therapeutic effect. In addition, adverse reactions of the digestive system at the time of oral administration can also be avoided.
  • the invention provides a process for the preparation of the aforementioned oseltamivir or a pharmaceutically acceptable salt thereof A method of skin absorption preparation.
  • the method comprises: (1) providing a backing layer and a protective layer; (2) applying a pharmaceutical formulation solution containing oseltamivir or an acceptable salt thereof to the backing layer Or the protective layer is allowed to stand or dry; and (3) laminating the backing layer and the protective layer to obtain the percutaneous absorption preparation, wherein the oseltamivir or the pharmaceutical thereof is contained
  • a pharmaceutical preparation solution of an acceptable salt is obtained by mixing the following: oseltamivir or a pharmaceutically acceptable salt thereof; at least one of a pressure sensitive adhesive, a matrix material, and a crosslinking agent; and an optional pharmaceutically acceptable Acceptable excipients.
  • the method according to an embodiment of the invention is simple to operate and is suitable for industrial production.
  • the obtained percutaneous absorption preparation is convenient to be administered, and the patient compliance can be improved, and the drug loading amount of the drug in the preparation is high, and the transdermal permeation amount of the drug is high, thereby achieving a blood concentration which is a preventive or therapeutic effect.
  • adverse reactions of the digestive system at the time of oral administration can also be avoided.
  • transdermal absorption formulations containing oseltamivir or a pharmaceutically acceptable salt thereof are equally applicable to the preparation of oseltamivir or its pharmaceutically acceptable form.
  • the method of percutaneous absorption of an acceptable salt is not described herein.
  • Figure 1 shows a Franz diffusion cell used in a transdermal experimental investigation in accordance with an embodiment of the present invention
  • FIG. 2 is a graph showing the cumulative amount of permeation per unit area of oseltamivir in a percutaneous absorption preparation of different formulations according to an embodiment of the present invention
  • Fig. 3 is a graph showing the relationship between the cumulative permeation amount per unit area of oseltamivir and the time in a percutaneous absorption preparation containing different kinds of transdermal absorption enhancers according to an embodiment of the present invention.
  • reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
  • Oseltamivir phosphate and purified water mixed uniformly, followed by adding glycerol, silicone pressure-sensitive adhesive (BIO-PSA4301), after mixing, it was coated on 3M Scotchpak TM 1022 release film, dried, and 3M CoTran TM 9726 backing is laminated to give a percutaneous absorption preparation 22 and 23 a prescription.
  • phase two Dispersing galaluminate and EDTA-Na 2 in glycerin, and then adding NP-700 to disperse uniformly to obtain phase two;
  • phase three Dissolve povidone K90, D-tartaric acid in an appropriate amount of water, swell evenly, add oseltamivir phosphate, stir and dissolve to obtain phase three;
  • the osvitavir percutaneous absorption patch obtained according to the prescriptions 1, 4, 7, and 8 was examined for skin irritation after a single administration.
  • Each test preparation was attached to healthy skin and damaged skin on the back of the rabbit for 24 hours, and the skin symptoms after 1 hour, 24 hours, and 48 hours of peeling were visually judged according to the scoring standard of Table 1, and the stimulation index of each test preparation was calculated.
  • the skin irritation intensity was determined according to Table 2.
  • the Franz diffusion cell where 100 is the supply chamber, 200 is the drug delivery system, 300 is the constant temperature water bath, 400 is the skin, 500 is the sampling port, 600 is the receiving chamber, 700 is the star stirring, the receiving chamber volume It was 7 ml and the water bath temperature was 37 ⁇ 0.5 °C.
  • the skin is fixed between the supply chamber and the receiving chamber, the stratum corneum is facing upward, the receiving liquid is a phosphate buffer solution of pH 7.4, the protective layer of the oseltamivir percutaneous absorption patch is peeled off, and the adhesive layer is adhered and fixed to the supply.
  • HPLC chromatographic conditions are as follows:
  • Diluent phosphate buffer pH 7.4 (0.05 M potassium dihydrogen phosphate solution + NaOH);
  • FIG. 2 shows a graph of cumulative skin permeation per unit area versus time for oseltraside patches (other prescription ratios of oseltamivir) prepared according to prescription 14, prescription 15, and prescription 16 in accordance with an embodiment of the invention;
  • the obtained patch has the highest content of oseltamivir, and the patch obtained in the prescription 14 has the lowest content of oseltamivir.
  • the cumulative amount of permeation per unit area of the patch obtained in the prescription 16 was the highest within 24 hours, and the cumulative permeation amount per unit area of the patch obtained in the prescription 14 was the lowest, indicating that the content of the drug in the patch was improved.
  • Formulation 9 contains a transdermal absorption enhancer N-methylpyrrolidone; prescription 10 contains a transdermal absorption enhancer diethylene glycol monoethyl ether; prescription 14 contains a transdermal absorption enhancer oleic acid; prescription 4 does not contain The transdermal absorption enhancer was used as a control group.
  • the patch obtained from prescription 14 had the highest cumulative permeation per unit area of skin, which significantly increased the cumulative permeation per unit area of oseltamivir in the patch compared with prescription 4; prescription 9 (including N -Methylpyrrolidone)
  • prescription 9 including N -Methylpyrrolidone
  • the patch obtained can increase the permeation amount per unit area of oseltamivir in the patch compared with the prescription 4; and the patch obtained from the prescription 10 (containing diethylene glycol monoethyl ether) Compared with the prescription 4, the cumulative permeation amount per unit area of oseltamivir in the patch is decreased.
  • the experimental results show that the selection of a suitable transdermal absorption enhancer can significantly increase the skin penetration of the drug in the patch, and the selection of an inappropriate transdermal absorption enhancer may not increase the skin penetration of the drug in the patch, and may even reduce the patch. The amount of skin penetration of the drug.
  • the active ingredient oseltamivir can be efficiently absorbed into the circulating blood through the skin.
  • the description of the terms “one embodiment”, “some embodiments”, or “specific embodiments” and the like means that the specific features, structures, materials or characteristics described in connection with the embodiments or examples are included in In at least one embodiment or example of the invention.
  • the schematic representation of the above terms is not necessarily directed to the same embodiment or example.
  • the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples.
  • those skilled in the art can combine various embodiments or examples described in the specification and features of different embodiments or examples, and combination.

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Abstract

本发明公开了含有奥司他韦或其药学上可接受的盐的经皮吸收制剂，所述经皮吸收制剂包括：背衬层；保护层；以及药物制剂层，所述药物制剂层位于所述背衬层及保护层之间，其中所述药物制剂层含有奥司他韦或其药学上可接受的盐。

Description

经皮吸收制剂及制备经皮吸收制剂的方法 技术领域
本发明涉及医药化工领域。具体地，本发明涉及经皮吸收制剂及制备经皮吸收制剂的方法。
背景技术
奥司他韦，化学名为(3R,4R,5S)-4-乙酰胺基-5-氨基-3-(1-乙基丙氧基)环己烯-1-羧酸乙酯。化学结构式如下：
Figure PCTCN2017071724-appb-000001
奥司他韦具有很强的抑制神经氨酸酶的活性，对A、B型流感病毒均有效，其性质和制备方法等信息公开于WO 1998007685 A1和WO 1996026933 A1中。
奥司他韦目前上市的剂型有颗粒剂、胶囊剂、和干混悬剂等。然而，奥司他韦是一种苦味特别大的药物，因此其经口服的药物组合物难以下咽。在现有技术中，通常通过在组合物中加入甜味剂或者采用胶囊制剂形式掩盖奥司他韦的苦味。
中国专利CN 101389323 B公开了一种药物组合物，其含有赋形剂以及磷酸奥司他韦，其中该赋形剂选自在25℃、相对湿度70％下平衡水分含量为1重量％以下的糖和糖醇的一种以上，且该糖和糖醇中所含的葡萄糖和甘露糖的含量分别为0.01重量％以下。为了抑制该药物组合物的苦味，所述发明中还加入了高度甜味剂(如蔗糖或甜菊素)以掩盖苦味。
中国专利CN 1820774 B公开了一种磷酸奥司他韦颗粒剂及其制备方法，所述颗粒剂包含1.97～19.8重量％的磷酸奥司他韦、75.0～97.5重量％的稀释剂、0.1～5.0重量％的粘合剂、以及1.0～5.0重量％的食用香精、甜味剂和/或食用色素。
中国专利申请CN 104367558 A1提供了一种奥司他韦冻干口崩片及其制备方法，该奥司他韦冻干口崩片是由磷酸奥司他韦或奥司他韦与基质组成，其中有效成分以奥司他韦计为10～75重量份，基质含有骨架支撑剂1～60重量份、粘合剂1～50重量份、冻干保护剂0～10重量份、矫味剂0～10重量份，基质还可以含有矫味剂0～10重量份、无机碱0～69重量份。
然而，目前的奥司他韦制剂仍有待改进。
发明内容
发明概述
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明提供了一种含有奥司他韦或其药学上可接受的盐的经皮吸收制剂及其制备方法。所述经皮吸收制剂能够在给药后的较短时间内达到起预防作用或治疗作用的血药浓度，并且恒速释放药物，避免奥司他韦口服给药的峰谷现象，维持恒定的最佳血药浓度范围，避免口服给药引起的消化系统不良反应或伴随血药浓度的急剧升高而引起的副作用；可长时间持续地给药，延长有效作用时间，减少患者用药次数；经皮吸收制剂给药便利，可改善患者依从性，可随时中断给药，提高用药安全性。此外，经皮吸收制剂可以增强患者用药的顺应性，解决了特殊情况下(如缺水条件下、吞咽困难的患者、婴幼儿和儿童)的给药难题，避免口服带来的不良口感，同时减少口服给药引起的不良反应。
术语定义
本发明中“％”，除另有说明外均指质量百分比。
本发明中所涉及的具体数值是指该数值±5％。
本发明中“任选的药学上可接受的辅料”是指可以选择加入或选择不加入任意药学上可接受的辅料。
发明详述
需要说明的是，本发明是基于发明人的下列发现而完成的：
在现有的奥司他韦制剂中基本都是口服制剂，且多采用掩味剂掩盖奥司他韦的苦味，但在制剂中加入掩味剂也不一定能完全掩盖住奥司他韦的苦味。同时，口服药物对特定的人群(老人、儿童和婴幼儿)或在特定条件下(缺水条件和吞咽困难的患者)用药都受到限制。而当前没有奥司他韦的经皮吸收制剂上市，且现有技术中缺乏对奥司他韦的经皮吸收制剂的深入研究。
为开发奥司他韦经皮给药制剂进行可行性研究，为奥司他韦能够进行经皮给药提供数据支持，发明人考察了奥司他韦原料药对家兔的皮肤刺激性。具体方法如下：家兔4只，雌雄各半，在给药前24h，用电推剪在所有实验兔背部脊柱两侧进行脱毛，脱毛面积左右各3cm×3cm。将兔子背部右侧脱毛区定为对照区，左侧定位试验区，对照区给予空白溶媒，试验区给予奥司他韦制剂，给药体积为0.5ml/次，2次/天，每次敷贴时间为4h，连续14天。用棉棒涂药面积2.5cm×2.5cm，涂药后用两层纱布和一层玻璃纸覆盖，再用无刺激胶布和绑带固定。在每次去除药物后1h以及每次给药前，以及末次敷贴去除药物后1h、24h、48h、72h肉眼观察及记录涂贴部位有无红斑、水肿、色素沉着、出血点、皮肤粗糙情况及发生时间及消退时间，并对红斑及水肿进行评分。存在持久性损伤的，延长观察期限以评价上述变化的恢复 情况和时间。结果和结论：整个实验过程中，未见动物死亡，动物体重未见明显异常；实验期间未出现刺激性以外的其他毒性作用；经积分计算，给药区每天每只动物刺激反应积分为0.11，根据刺激强度标准，表明该奥司他韦API对家兔皮肤无刺激性。
进一步地，发明人经过深入研究发现，将药物设计成经皮给药制剂，且起全身循环作用，要求药物本身对皮肤无毒副作用，并且期望药物可以顺利透过角质层、活性表皮层，进入真皮层后经毛细血管摄取入血发挥作用。经皮给药系统由于载药量低，因此其候选药物一般以半衰期短需频繁给药、日剂量较小(日剂量低于20mg)、作用较强者为理想。
但是奥司他韦的日剂量高(>60mg)，服用周期长(至少连续服用5天)，因此经皮给药后难达到发挥药效的血药浓度。目前市场上的奥司他韦口服制剂，用于成人和13岁以上青少年流感季节时预防流感的推荐剂量为75mg，每日1次；用于成人和13岁以上青少年的流感治疗时推荐口服剂量是每次75mg，每日2次，共5天。对于1岁以上的儿童，按体重给药，<15kg时，用于流感治疗时推荐的口服剂量为30mg，每日2次；＞15-23kg时，口服剂量为45mg，每日2次；＞23-40kg时，口服剂量为60mg，每日2次；＞40kg时，口服剂量为75mg，每日2次，且奥司他韦药学上可接受的盐大都为水溶性良好、脂溶性差，且熔点高的化合物，较难直接透过皮肤进入体循环发挥药效。
有鉴于此，本发明提出了一种含有奥司他韦或其药学上可接受的盐的经皮吸收制剂及其制备方法。该经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量较高(例如可达7mg/cm2)，药物的经皮渗透量较高(例如24h后的释放总量超过40％)，从而达到起预防作用或治疗作用的血药浓度，有效地解决日剂量高的药物经皮给药后较难达到发挥药效的血药浓度和水溶性药物较难直接透过皮肤进入体循环发挥药效的难题。另外，还可避免口服给药时的消化系统的不良反应，为流感的治疗带来了一种可行的给药方式。
为此，在本发明的一个方面，本发明提出了一种含有奥司他韦或其药学上可接受的盐的经皮吸收制剂。根据本发明的实施例，所述经皮吸收制剂包括：背衬层；保护层；以及药物制剂层，所述药物制剂层位于所述背衬层及保护层之间，其中所述药物制剂层含有奥司他韦或其药学上可接受的盐。本发明的经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量高，药物的经皮渗透量高，从而达到起预防作用或治疗作用的血药浓度。另外，还可避免口服给药时的消化系统的不良反应。
根据本发明的实施例，上述含有奥司他韦或其药学上可接受的盐的经皮吸收制剂还可以具有下列附加技术特征：
在一些实施例中，所述奥司他韦或其药学上可接受的盐重量占所述药物制剂层重量的比例，按奥司他韦游离碱计，为：不低于1.0％，或10.0％～80.0％，或30.0％～75.0％。发明人经过大量实验得到上述奥司他韦或其药学上可接受的盐含量，在此条件下能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层 或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述药物制剂层进一步包括下列的至少之一：压敏胶、骨架材料和交联剂。发明人发现，通过在制剂中加入压敏胶、骨架材料和/或交联剂，显著提高了经皮给药制剂中药物的载药量和制剂中药物的释放速度，提高了奥司他韦的经皮渗透量，从而达到起预防作用或治疗作用的血药浓度，有效地解决日剂量高的药物经过经皮给药后较难达到发挥药效的血药浓度和水溶性药物较难直接透过皮肤进入体循环发挥药效的难题。
在一些实施例中，所述药物制剂层由下列构成：所述奥司他韦或其药学上可接受的盐；及压敏胶，其中，所述压敏胶重量占所述药物制剂层重量的比例为：不高于90.0％，或20.0％～70.0％，或30.0％～50.0％。发明人经过大量实验优化得到上述药物制剂层组分，在此条件下能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述药物制剂层由下列构成：所述奥司他韦或其药学上可接受的盐；骨架材料；以及交联剂，其中，所述骨架材料重量占所述药物制剂层重量的比例为：不高于25.0％，或1.0％～15.0％，或5.0％～12.0％，所述交联剂重量占所述药物制剂层重量的比例为：不高于3.0％，或0.1％～2.5％，或0.2％～2.0％。发明人发现，在上述最优药物制剂层组分下，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述药物制剂层由下列构成：所述奥司他韦或其药学上可接受的盐；压敏胶；以及骨架材料，其中，所述压敏胶重量占所述药物制剂层重量的比例为：不高于90.0％，或20.0％～70.0％，或30.0％～50.0％，所述骨架材料重量占所述药物制剂层重量的比例为：不高于10.0％，或0.5％～8.0％，或1.0％～6.0％。发明人发现，在上述最优药物制剂层组分下，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述药物制剂层进一步包括药学上可接受的辅料，所述辅料包括下列的至少之一：透皮吸收促进剂、增塑剂、溶剂、保湿剂、交联调节剂、酸、填充剂、防腐剂、抑菌剂、抗氧剂及螯合剂。发明人发现，通过添加辅料，提高了制剂中药物的载药量及药物的经皮渗透量，从而达到起预防作用或治疗作用的血药浓度，有效地解决日剂量高的药物经过经皮给药后较难达到发挥药效的血药浓度和水溶性药物较难直接透过皮肤进入体循环发挥药效的难题。
在一些实施例中，所述药学上可接受的盐包括：盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、柠檬酸盐、乳酸盐、抗坏血酸盐、马来酸盐、酒石酸盐、苹果酸盐或琥珀酸盐。发明人发现，在此条件下，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的 释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述压敏胶包括但不限于丙烯酸类聚合物(如，DURO-TAK 87-2194、DURO-TAK 387-2287、DURO-TAK 87-2852)、甲基丙烯酸类聚合物、聚异丁烯类聚合物、橡胶类(如，天然橡胶、合成橡胶-SIS)以及硅酮类(如，Dow
Figure PCTCN2017071724-appb-000002
BIO-PSAQ7-2920、BIO-PSAQ7-2675、BIO-PSA4301、BIO-PSA4302、BIO-PSA4201、BIO-PSA4202、BIO-PSA4101、BIO-PSA4102、BIO-PSA4601、BIO-PSA4602、BIO-PSA4501、BIO-PSA4502、BIO-PSA4401、BIO-PSA4402)或其混合物。由此，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述骨架材料(包括但不限于聚乙烯醇、聚丙烯酸、聚丙烯酸钠、部分中和的聚丙烯酸钠(如NP-600/700/800)、丙烯酸共聚物、甲烯酸共聚物、丙烯酸和甲烯酸共聚物、丙烯酸酯、邻苯二甲酸酯、明胶、西黄芪胶、琼脂、卡波姆、羟丙基甲基纤维素、聚维酮(XL、K90)、羧甲基纤维素钠、聚乙二醇或其混合物)与交联剂(包括但不限于甘羟铝、氢氧化铝、氢氧化铝凝胶、硅酸镁铝、氢氧化钙、铝酸镁、氯化铝、硫酸铝钾、硝酸铝、氯化钙、硝酸钙、甘氨酸铝、硅酸镁铝、铝碳酸镁或其混合物)交联后形成的基质。由此，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述透皮吸收促进剂包括但不限于吡咯酮类(如，2-吡咯酮、N-甲基-吡咯烷酮)、氮酮及其类似物(如，Azone、HPE-101)、脂肪酸及其酯类(如，油酸、月桂酸、油酸或月桂酸的酯类、肉豆蔻酸异丙酯、丙二醇脂肪酸酯、甘油脂肪酸酯、脱水山梨糖醇脂肪酸酯、油酸聚乙二醇甘油酯、聚甘油-3双异硬脂酸酯、聚甘油油酸酯、辛酸癸酸聚乙二醇甘油酯、月桂醇硫酸钠)、醚类(如，泊洛沙姆、聚氧丙烯硬脂醇醚)、醇类(如，乙醇、异丙醇)、多元醇类(如，丙二醇、甘油、1,3-丁二醇)、萜烯类(如，薄荷醇、桉叶油)、胺类(如，尿素、十二烷基-N,N-二甲氨基乙酯)、酰胺类(如，二甲基甲酰胺、二甲基乙酰胺)、磷脂类(如，卵磷脂、磷脂酰甘油)或其混合物。根据本发明的具体实施例，所述透皮吸收促进剂占药物制剂层重量的比例是0.5％～15％，或1.0％～10.0％，或2.0％～8.0％。由此，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述增塑剂包括但不限于石油系油、角鲨烷、角鲨烯、植物系油、硅油、二元酸酯、液状橡胶、液状脂肪酸酯类、二乙二醇、聚乙二醇、丙二醇、甘油或其混合物。由此，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述溶剂包括但不限于水、乙醇、丙二醇、庚烷、丙酮、甲醇、乙酸乙酯或其混合物。由此，可以提高奥司他韦的溶解度，改善药物制剂层的涂布性能，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述填充剂包括但不限于白陶土、氧化锌、微粉硅胶、碳酸钙、高岭土、皂土、二氧化钛或其混合物。由此，能够进一步有效地改善药物制剂层的性质，例如提高药物的稳定性，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述保湿剂包括但不限于甘油、丙二醇、聚乙二醇、透明质酸或其混合物。由此，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述酸包括但不限于酒石酸、乳酸、油酸、琥珀酸、醋酸、苹果酸、柠檬酸、盐酸、磷酸、抗坏血酸、马来酸或其混合物。由此，能够进一步有效地改善药物制剂层的性质，例如改善药物的溶解性，提高药物的稳定性，促进贴剂中药物的释放，增强药物的经皮渗透能力，改善药物制剂层与保护层或背衬层之间的相互作用，改善药物制剂层的内聚力。
在一些实施例中，所述防腐剂或抑菌剂包括但不限于对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、山梨酸、苯甲酸、苯甲醇、咪脲、苄醇或其混合物。由此，能够进一步有效地改善药物制剂层的性质，例如提高药物的稳定性。
在一些实施例中，所述抗氧化剂包括但不限于没食子酸丙酯、BHA(丁基羟基茴香醚)、BHT(二丁基羟基甲苯)、柠檬酸、EDTA及其盐类、生育酚或其混合物。由此，能够进一步有效地改善药物制剂层的性质，例如提高药物的稳定性。此外，EDTA及其盐类等物质还可以起到螯合剂的作用。
需要说明的是，对药物制剂层的厚度不作严格限定，本领域技术人员可以通过药量等因素适量决定。根据本发明的具体实施例，所述药物制剂层的厚度为10～4000μm，或20～3000μm。由此，能够进一步有效地改善药物制剂层的性质，例如促进贴剂中药物的释放，增强药物的经皮渗透能力。
本发明中的保护层是防粘材料，用于保护制剂含药层，在实际应用中，本领域技术人员可以依据具体的药物制剂层或背衬层的性质筛选最佳材质的保护层。具体地，其材料应该与药物制剂层或背衬层有良好的相容性，应该为惰性的、不透明的或者遮光的镀金属的聚酯薄膜，其材质可以是聚对苯二甲酸乙二酯、铝箔、聚乙烯-铝复合膜、聚乙烯-格拉辛纸-聚乙烯复合膜中的一种或几种。保护层的与药物制剂层接触的表面上可以涂有一层防止压敏胶粘贴的聚合物如硅酮化、氟硅酮或者全氟碳聚合物。在使用之前，保护层能够牢牢黏附在药物制剂层或背衬层表面上，在使用时容易与药物制剂层或背衬层剥离。保护层的厚度可以由本领域的技术人员适当决定。
本发明中所述的背衬层采用支持药物制剂层的薄膜，所述的背衬层可以是但不限于有机聚合物膜、金 属箔或有机聚合物膜、金属箔的层压膜和无纺布等。其中所述的有机聚合物膜可以是由但不限于醋酸纤维素、乙基纤维素、聚酯、尼龙、聚氯乙烯、聚乙烯、聚丙烯、乙烯-醋酸乙烯共聚物、乙烯-丙烯共聚物、醋酸乙烯-氯乙烯共聚物、聚对苯二甲酸乙二酯、聚四氟乙烯或离聚体树脂制成的膜。理想的背衬材料要求为：与药物和辅料有良好的相容性；厚度大约在75μm；低的水分透过速率(<20g/m2/24h)；高氧气透过率，在提高皮肤水化作用的同时，能够保证皮肤正常呼吸；无毒性；有患者可以接受的色泽或者透明的或半透明的；晕光度低<10％；贴在皮肤上感觉有良好；质地结实而且光滑，触摸有干的感觉；良好的撕裂强度以及可以热封。在实际应用过程中，需要依据药物制剂层或保护层的性质以及粘附时间的长短选择最佳材质的背衬层，其厚度可以由本领域的技术人员适当决定。具体地，背衬层可以为3M CoTranTM9700、3M CoTranTM9701、3M CoTranTM9718、3M CoTranTM9719、3M CoTranTM9720、3M CoTranTM9722、3M CoTranTM9726。
需要说明的是，经皮吸收制剂可以是贴剂，也可以贴膏剂，但并不局限于这两种经皮吸收制剂。
在一些实施例中，本发明所述的经皮吸收制剂包括：背衬层；保护层；以及药物制剂层，所述的药物制剂层含有：
奥司他韦或其药学上可接受的盐重量占药物制剂层重量的比例，按奥司他韦游离碱计，是10.0％～78.0％；
压敏胶重量占药物制剂层重量的比例是22.0％～90.0％。
本发明的经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量高，药物的经皮渗透量高，从而达到起预防作用或治疗作用的血药浓度。另外，还可避免口服给药时的消化系统的不良反应。
在一些实施例中，本发明所述的经皮吸收制剂包括：背衬层；保护层；以及药物制剂层，所述的药物制剂层中：
奥司他韦或其药学上可接受的盐重量占药物制剂层重量的比例，按奥司他韦游离碱计，是48.6％；
压敏胶重量占药物制剂层重量的比例是46.60％；
透皮吸收促进剂重量占药物制剂层重量的比例是4.8％。
本发明的经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量高，药物的经皮渗透量高，从而达到起预防作用或治疗作用的血药浓度。另外，还可避免口服给药时的消化系统的不良反应。
在一些实施例中，本发明所述的经皮吸收制剂包括：背衬层；保护层；以及药物制剂层，所述的药物制剂层中：
奥司他韦或其药学上可接受的盐重量占药物制剂层重量的比例，按奥司他韦游离碱计，是53.89％～59.3％；
压敏胶重量占药物制剂层重量的比例是36.2％～41.6％；
透皮吸收促进剂重量占药物制剂层重量的比例是4.5％。
本发明的经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量高，药物的经皮渗透量高，从而达到起预防作用或治疗作用的血药浓度。另外，还可避免口服给药时的消化系统的不良反应。
在一些实施例中，本发明所述的经皮吸收制剂包括：背衬层；保护层；以及药物制剂层，所述的药物制剂层中：
奥司他韦或其药学上可接受的盐重量占药物制剂层重量的比例，按奥司他韦游离碱计，是10.0％～50.2％；
压敏胶重量占药物制剂层重量的比例是49.8％～90.0％。
本发明的经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量高，药物的经皮渗透量高，从而达到起预防作用或治疗作用的血药浓度。另外，还可避免口服给药时的消化系统的不良反应。
在一些实施例中，本发明所述的经皮吸收制剂包括：背衬层；保护层；以及药物制剂层，所述的药物制剂层中：
奥司他韦或其药学上可接受的盐重量占药物制剂层重量的比例，按奥司他韦游离碱计，是7.76％～25.20％；
压敏胶重量占药物制剂层重量的比例是48.3％～69.4％；
增塑剂重量占药物制剂层重量的比例是9.3％～10.2％；
溶剂重量占药物制剂层重量的比例为9.3％～10.2％。
本发明的经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量高，药物的经皮渗透量高，从而达到起预防作用或治疗作用的血药浓度。另外，还可避免口服给药时的消化系统的不良反应。
在一些实施例中，本发明所述的经皮吸收制剂包括：背衬层；保护层；以及药物制剂层，所述的药物制剂层中：
奥司他韦或其药学上可接受的盐重量占药物制剂层重量的比例，按奥司他韦游离碱计，是1.52％～3.81％；
保湿剂重量占药物制剂层重量的比例为30.0％；
骨架材料重量占药物制剂层重量的比例为6.2％～10.0％；
交联剂重量占药物制剂层重量的比例为0.15％～0.2％；
溶剂重量占药物制剂层重量的比例为55.39％～61.2％；
酸重量占药物制剂层重量的比例为0.18％～0.2％；
螯合剂重量占药物制剂层重量的比例为0.18％～0.2％。
本发明的经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量高，药物的经皮渗透量高，从而达到起预防作用或治疗作用的血药浓度。另外，还可避免口服给药时的消化系统的不良反应。
在本发明的另一方面，本发明提出了一种制备前面所描述的含有奥司他韦或其药学上可接受的盐的经 皮吸收制剂的方法。根据本发明的实施例，所述方法包括：(1)提供背衬层和保护层；(2)将含有奥司他韦或其可接受的盐的药物制剂溶液涂布于所述背衬层或保护层上，进行静置或干燥；以及(3)将所述背衬层与所述保护层层合，获得所述经皮吸收制剂，其中，所述含有奥司他韦或其药学上可接受的盐的药物制剂溶液是通过将下列混合而得到的：奥司他韦或其药学上可接受的盐；压敏胶、骨架材料和交联剂的至少一种；和任选的药学上可接受的辅料。由此，根据本发明实施例的方法操作简便，适于工业化生产。所得到的经皮吸收制剂给药便利，可改善患者依从性，且制剂中药物的载药量高，药物的经皮渗透量高，从而达到起预防作用或治疗作用的血药浓度。另外，还可避免口服给药时的消化系统的不良反应。
需要说明的是，本领域技术人员可以根据实际需要选定混合方式，既可以将所有药物制剂同时进行混合，也可以按照各组分的物化性质分类混合，再将各类的混合物全部混合在一起。
本领域技术人员能够理解的是，前面针对含有奥司他韦或其药学上可接受的盐的经皮吸收制剂所描述的特征和优点，同样适用于该制备含有奥司他韦或其药学上可接受的盐的经皮吸收制剂的方法，在此不再赘述。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
图1显示了根据本发明实施例透皮实验考察过程中用到的Franz扩散池；
图2显示了根据本发明实施例考察得到的不同处方的经皮吸收制剂中奥司他韦的单位面积皮肤累积渗透量与时间的关系图；以及
图3显示了根据本发明实施例考察得到的含不同种类的透皮吸收促进剂的经皮吸收制剂中奥司他韦的单位面积皮肤累积渗透量与时间的关系图。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
实施例1
药物制剂层处方：
Figure PCTCN2017071724-appb-000003
Figure PCTCN2017071724-appb-000004
制备方法：
将奥司他韦与乙酸乙酯混合均匀后，依次加入丙烯酸酯压敏胶(LOCTITE DURO-TAK 2852)，搅拌均匀后，将其涂布于3M CoTranTM9748离型膜(即保护层)上，干燥后(乙酸乙酯挥发除去，未计入处方中)，与3M ScotchpakTM9735背衬层层合即可，得到处方1～8的经皮吸收制剂。
实施例2
药物制剂层处方：
Figure PCTCN2017071724-appb-000005
制备方法：
将奥司他韦与乙酸乙酯混合均匀后，加入压敏胶(LOCTITE DURO-TAK2852)，搅拌后加入N-甲基吡咯烷酮/二乙二醇单乙基醚/PEG4000/柠檬酸/PVP K90/油酸，搅拌均匀后，将其涂布于3M CoTranTM9748离型膜(即保护层)上，干燥后(乙酸乙酯挥发除去，未计入处方中)，与3M ScotchpakTM9735背衬层层合即可，得到处方9～14的经皮吸收制剂。
实施例3
药物制剂层处方：
Figure PCTCN2017071724-appb-000006
制备方法：
将奥司他韦与乙酸乙酯混合均匀后，加入压敏胶(LOCTITE DURO-TAK2852)，搅拌后加入油酸，搅拌均匀后，将其涂布于3M CoTranTM9748离型膜(即保护层)上，干燥后(乙酸乙酯挥发除去，未计入处方中)，与3M ScotchpakTM9735背衬层层合即可，得到处方15、16的经皮吸收制剂。
实施例4
药物制剂层处方：
Figure PCTCN2017071724-appb-000007
制备方法：
将奥司他韦与乙酸乙酯混合均匀后，加入压敏胶，搅拌均匀后，将其涂布于3M CoTranTM9748离型膜(即保护层)上，干燥后(乙酸乙酯挥发除去，未计入处方中)，与3M ScotchpakTM9735背衬层层合即可，得到处方17～21的经皮吸收制剂。
实施例5
药物制剂层处方：
Figure PCTCN2017071724-appb-000008
制备方法：
将磷酸奥司他韦与纯化水混合均匀后，依次加入甘油、硅酮压敏胶(BIO-PSA4301)，搅拌均匀后，将其涂布于3M ScotchpakTM1022离型膜上，干燥后，与3M CoTranTM 9726背衬层层合即可，得到处方22、23的经皮吸收制剂。
实施例6
药物制剂层处方：
Figure PCTCN2017071724-appb-000009
制备方法：
1)将卡波姆980加入到水中，充分溶胀后，得相一；
2)将甘羟铝、EDTA-Na2分散于甘油中，再加入NP-700分散均匀，得相二；
3)将聚维酮K90、D-酒石酸溶于适量水中，溶胀均匀后加入磷酸奥司他韦，搅拌溶解得相三；
4)将相一分批加入相二中，搅拌均匀后，得混合物，再将相三加入其中，搅拌均后，涂布在水刺无
纺布上，盖上3M ScotchpakTM1022离型膜即可，得到处方24、25的经皮吸收制剂。
实施例7
兔皮肤刺激性实验
考察根据处方1、4、7、8所获得奥司他韦经皮吸收贴剂，单次给药后的皮肤刺激性。
实验动物：健康家兔。
实验目的：考察高、中、低载药量的贴剂和不含药物的贴剂(赋形剂组)对家兔皮肤刺激性的影响。
实验方法：
将各试验制剂贴附在兔背部的健康皮肤和损伤皮肤上24h，根据表1的评分标准对剥离1h、24h、48h后的皮肤症状进行目测判定，计算各试验制剂的刺激指数。根据表2判定皮肤刺激强度。
刺激指数计算方法：皮肤刺激性指数＝总刺激性值/观察次数；
1、对于每只家兔，将移除贴剂后1h、24h、48h后观察到的值相加，以确定红斑或焦痂形成部分合计的刺激性值。
2、对于每只家兔，将移除贴剂后1h、24h、48h后观察到的值相加，以确定水肿形成部分合计的刺激性值。
3、对于每只家兔，将红斑或焦痂形成部分合计的刺激性值与水肿形成部分合计的刺激性值相加，计算每只家兔的总刺激性值。
表1皮肤刺激反应评分标准
Figure PCTCN2017071724-appb-000010
Figure PCTCN2017071724-appb-000011
表2皮肤刺激强度评价标准
分值 评价
0～0.49 无刺激性
0.5～2.99 轻度刺激性
3.0～5.99 中度刺激性
6.0～8.0 强刺激性
实验结果：
实验制剂 处方1 处方4 处方7 处方8(赋形剂组)
刺激指数 0.48 0.42 0.33 0.21
由上述结果，可以确认本发明中高、中、低载药量的制剂和赋形剂组制剂对家兔皮肤均无刺激性，说明压敏胶和不同载药量的含药压敏胶均具有良好的安全性。
实施例8
体外经皮渗透行为考察
考察根据处方4、处方9、处方10、处方14、处方15和处方16所获得奥司他韦经皮吸收贴剂，将其冲裁成合适大小的形状(如1.4×1.4cm2)，贴附于离体皮肤上，考察不同处方比例的奥司他韦和不同种类透皮吸收促进剂对贴剂体外经皮渗透的影响。
实验动物：巴马香猪侧腹部皮肤
实验装置及条件：
如图1所示Franz扩散池，其中100为供给室、200为给药系统、300为恒温水浴、400为皮肤、500为取样口、600为接收室、700为星形搅拌子，接收室体积为7ml，水浴温度为37±0.5℃。将皮肤固定于供给室和接收室之间，角质层朝上，接收液为pH7.4的磷酸盐缓冲液，将奥司他韦经皮吸收贴剂的保护层剥离后，粘附固定于供给室中皮肤上，开启磁力搅拌200rpm，分别于30min、1h、2h、4h、6h、8h、12h和24h取接收液2.0ml，同时补充等量的pH7.4的磷酸盐缓冲液，样本分析采用HPLC。
HPLC色谱条件如下：
仪器：Agilent 1260 HPLC-DAD；
色谱柱：Agilent ZORBAX Eclipse XDB-C18，4.6*150mm，5μm；
流动相：甲醇-乙腈-磷酸二氢钾缓冲液(pH＝6.0)＝245:135:620；
稀释剂：pH7.4的磷酸盐缓冲液(0.05M磷酸二氢钾溶液+NaOH)；
流速：1.2ml/min；
柱温：50℃；
进样量：15μl
检测波长：207nm；
样品盘温度：4℃；
运行时间：12min；
洗脱方式：等度洗脱。
实验结果：
图2显示依据发明实施例中处方14、处方15和处方16制备的奥司他韦贴剂(不同处方比例的奥司他韦)的单位面积皮肤累积渗透量与时间的关系图；其中处方16所得的贴剂中奥司他韦的含量最高，处方14所得的贴剂中奥司他韦的含量最低。如图2所示，在24h内，处方16所得贴剂的单位面积皮肤累积渗透量最高，处方14所得的贴剂的单位面积皮肤累积渗透量最低，说明提高贴剂中药物的含量，能够明显提高奥司他韦的单位面积皮肤累积渗透量。
图3显示依据发明实施例中处方4、处方9、处方10和处方14制备的奥司他韦贴剂的单位面积皮肤累积渗透量与时间的关系图，考察了不同种类的透皮吸收促进剂对奥司他韦贴剂的皮肤渗透性能的影响。处方9中含透皮吸收促进剂N-甲基吡咯烷酮；处方10中含透皮吸收促进剂二乙二醇单乙基醚；处方14中含透皮吸收促进剂油酸；处方4中不含透皮吸收促进剂，为对照组。结果显示，处方14(含油酸)所得的贴剂的单位面积皮肤累积渗透量最高，较处方4相比能够显著提高贴剂中奥司他韦的单位面积皮肤累积渗透量；处方9(含N-甲基吡咯烷酮)所得的贴剂较处方4相比能够提高贴剂中奥司他韦的单位面积皮肤累积渗透量；而处方10(含二乙二醇单乙基醚)所得的贴剂较处方4相比，贴剂中奥司他韦的单位面积皮肤累积渗透量反而降低。实验结果说明选择合适的透皮吸收促进剂能够明显提高贴剂中药物的皮肤渗透量，而选择不合适的透皮吸收促进剂可能不能提高贴剂中药物的皮肤渗透量，甚至可能降低贴剂中药物的皮肤渗透量。
综上实施例所述，根据本发明提供的经皮吸收型制剂，有效成分奥司他韦能够通过皮肤在循环血液中高效吸收。另外，还可避免口服给药时的消化系统的不良反应，避免伴随血药浓度的急剧升高而引起的副作用，为流感的治疗带来了一种可行的给药方式。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、或“具体实施例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和 组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (21)

  1. 一种含有奥司他韦或其药学上可接受的盐的经皮吸收制剂，其特征在于，包括：
    背衬层；
    保护层；以及
    药物制剂层，所述药物制剂层位于所述背衬层及保护层之间，其中所述药物制剂层含有奥司他韦或其药学上可接受的盐。
  2. 根据权利要求1所述的经皮吸收制剂，其特征在于，所述奥司他韦或其药学上可接受的盐重量占所述药物制剂层重量的比例，按奥司他韦游离碱计，为：不低于1.0％，或10.0％～80.0％，或30.0％～75.0％。
  3. 根据权利要求1所述的经皮吸收制剂，其特征在于，所述药物制剂层进一步包括下列的至少之一：
    压敏胶、骨架材料和交联剂。
  4. 根据权利要求1所述的经皮吸收制剂，其特征在于，所述药物制剂层由下列构成：
    所述奥司他韦或其药学上可接受的盐；以及
    压敏胶，
    其中，所述压敏胶重量占所述药物制剂层重量的比例为：不高于90.0％，或20.0％～70.0％，或30.0％～50.0％。
  5. 根据权利要求1所述的经皮吸收制剂，其特征在于，所述药物制剂层由下列构成：
    所述奥司他韦或其药学上可接受的盐；
    骨架材料；以及
    交联剂，
    其中，所述骨架材料重量占所述药物制剂层重量的比例为：不高于25.0％，或1.0％～15.0％，或5.0％～12.0％，
    所述交联剂重量占所述药物制剂层重量的比例为：不高于3.0％，或0.1％～2.5％，或0.2％～2.0％。
  6. 根据权利要求1所述的经皮吸收制剂，其特征在于，所述药物制剂层由下列构成：
    所述奥司他韦或其药学上可接受的盐；
    压敏胶；以及
    骨架材料，
    其中，所述压敏胶重量占所述药物制剂层重量的比例为：不高于90.0％，或20.0％～70.0％，或30.0％～50.0％，
    所述骨架材料重量占所述药物制剂层重量的比例为：不高于10.0％，或0.5％～8.0％，或1.0％～6.0％。
  7. 根据权利要求1所述的经皮吸收制剂，其特征在于，所述药物制剂层进一步包括药学上可接受的辅料，
    所述辅料包括下列的至少之一：
    透皮吸收促进剂、增塑剂、溶剂、保湿剂、酸、填充剂、防腐剂、抑菌剂、抗氧剂及螯合剂。
  8. 根据权利要求1所述的经皮吸收制剂，其特征在于，所述药学上可接受的盐包括：
    盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、柠檬酸盐、乳酸盐、抗坏血酸盐、马来酸盐、酒石酸盐、苹果酸盐或琥珀酸盐。
  9. 根据权利要求3所述的经皮吸收制剂，其特征在于，所述的压敏胶包括下列的至少一种：
    丙烯酸类聚合物、甲基丙烯酸类聚合物、聚异丁烯类聚合物、橡胶类以及硅酮类。
  10. 根据权利要求3所述的经皮吸收制剂，其特征在于，所述骨架材料包括下列的至少一种：
    聚乙烯醇、聚丙烯酸、聚丙烯酸钠、部分中和的聚丙烯酸钠、丙烯酸共聚物、甲烯酸共聚物、丙烯酸和甲烯酸共聚物、丙烯酸酯、邻苯二甲酸酯、明胶、西黄芪胶、琼脂、卡波姆、羟丙基甲基纤维素、聚维酮、羧甲基纤维素钠以及聚乙二醇。
  11. 根据权利要求3所述的经皮吸收制剂，其特征在于，所述交联剂包括下列的至少之一：
    甘羟铝、氢氧化铝、氢氧化铝凝胶、硅酸镁铝、氢氧化钙、铝酸镁、氯化铝、硫酸铝钾、硝酸铝、氯化钙、硝酸钙、甘氨酸铝、硅酸镁铝和铝碳酸镁。
  12. 根据权利要求7所述的经皮吸收制剂，其特征在于，所述透皮吸收促进剂包括下列的至少之一：
    吡咯酮类、氮酮及其类似物、脂肪酸及其酯类、醇类、多元醇类、萜烯类、胺类、醚类、酰胺类及磷脂类。
  13. 根据权利要求7所述的经皮吸收制剂，其特征在于，所述增塑剂包含下列的至少之一：
    石油系油、角鲨烷、角鲨烯、植物系油、硅油、二元酸酯、液状橡胶、液状脂肪酸酯类、二乙二醇、聚乙二醇、丙二醇及甘油。
  14. 根据权利要求7所述的经皮吸收制剂，其特征在于，所述溶剂包括下列的至少之一：
    水、乙醇、丙二醇、庚烷、丙酮、甲醇及乙酸乙酯。
  15. 根据权利要求7所述的经皮吸收制剂，其特征在于，所述填充剂包括下列的至少之一：
    白陶土、氧化锌、微粉硅胶、碳酸钙、高岭土、皂土及二氧化钛。
  16. 根据权利要求7所述的经皮吸收制剂，其特征在于，所述保湿剂包括下列的至少之一：
    甘油、丙二醇、聚乙二醇及透明质酸。
  17. 根据权利要求7所述的经皮吸收制剂，其特征在于，所述酸包括下列的至少之一：
    酒石酸、乳酸、油酸、琥珀酸、醋酸、苹果酸、柠檬酸、盐酸、磷酸、抗坏血酸及马来酸。
  18. 根据权利要求7所述的经皮吸收制剂，其特征在于，所述防腐剂或抑菌剂包括下列的至少之一：
    对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、山梨酸、苯甲酸、苯甲醇、咪脲及苄醇。
  19. 根据权利要求7所述的经皮吸收制剂，其特征在于，所述抗氧剂包括下列的至少之一：没食子酸 丙酯、丁基羟基茴香醚、二丁基羟基甲苯、柠檬酸、EDTA及其盐类以及生育酚。
  20. 根据权利要求1所述的经皮吸收制剂，其特征在于，所述药物制剂层的厚度为10～4000μm，或20～3000μm。
  21. 一种制备权利要求1～20任一项所述含有奥司他韦或其药学上可接受的盐的经皮吸收制剂的方法，其特征在于，包括：
    (1)提供背衬层和保护层；
    (2)将含有奥司他韦或其可接受的盐的药物制剂溶液涂布于所述背衬层或保护层上，进行静置或干燥；以及
    (3)将所述背衬层与所述保护层层合，获得所述经皮吸收制剂，
    其中，所述含有奥司他韦或其药学上可接受的盐的药物制剂溶液是通过将下列混合而得到的：
    奥司他韦或其药学上可接受的盐；
    压敏胶、骨架材料和交联剂的至少一种；和
    任选的药学上可接受的辅料。
PCT/CN2017/071724 2017-01-19 2017-01-19 经皮吸收制剂及制备经皮吸收制剂的方法 WO2018133010A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101378729A (zh) * 2005-12-14 2009-03-04 扎尔斯制药公司 治疗皮肤症状的制剂和方法
CN102573886A (zh) * 2009-09-17 2012-07-11 相互制药公司 用抗病毒剂治疗哮喘的方法
CN106361728A (zh) * 2015-07-22 2017-02-01 广东东阳光药业有限公司 经皮吸收制剂及制备经皮吸收制剂的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101378729A (zh) * 2005-12-14 2009-03-04 扎尔斯制药公司 治疗皮肤症状的制剂和方法
CN102573886A (zh) * 2009-09-17 2012-07-11 相互制药公司 用抗病毒剂治疗哮喘的方法
CN106361728A (zh) * 2015-07-22 2017-02-01 广东东阳光药业有限公司 经皮吸收制剂及制备经皮吸收制剂的方法

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