WO2015051763A1 - 一种含埃克替尼的皮肤外用药物组合物及其应用 - Google Patents

一种含埃克替尼的皮肤外用药物组合物及其应用 Download PDF

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Publication number
WO2015051763A1
WO2015051763A1 PCT/CN2014/088344 CN2014088344W WO2015051763A1 WO 2015051763 A1 WO2015051763 A1 WO 2015051763A1 CN 2014088344 W CN2014088344 W CN 2014088344W WO 2015051763 A1 WO2015051763 A1 WO 2015051763A1
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Prior art keywords
pharmaceutical composition
composition according
mass
group
amount
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PCT/CN2014/088344
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English (en)
French (fr)
Inventor
王印祥
袁树军
王燕萍
胡邵京
胡云雁
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贝达药业股份有限公司
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Priority to CA2926874A priority Critical patent/CA2926874C/en
Priority to KR1020167012110A priority patent/KR20160061425A/ko
Priority to RU2016118063A priority patent/RU2698796C2/ru
Priority to BR112016007627A priority patent/BR112016007627A2/pt
Application filed by 贝达药业股份有限公司 filed Critical 贝达药业股份有限公司
Priority to CN201480001225.7A priority patent/CN105101966A/zh
Priority to NZ718802A priority patent/NZ718802A/en
Priority to EP14851908.5A priority patent/EP3056206A4/en
Priority to AU2014334222A priority patent/AU2014334222B2/en
Priority to JP2016521612A priority patent/JP6463745B2/ja
Priority to US15/028,118 priority patent/US20160235757A1/en
Priority to SG11201602826VA priority patent/SG11201602826VA/en
Publication of WO2015051763A1 publication Critical patent/WO2015051763A1/zh
Priority to HK16101922.3A priority patent/HK1213813A1/zh
Priority to IL245015A priority patent/IL245015A0/en
Priority to US16/398,827 priority patent/US20190321369A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to an external pharmaceutical composition for skin containing ectinib or a pharmaceutically acceptable salt thereof and use thereof.
  • Skin diseases are diseases related to the skin, and are one of the common and frequently-occurring diseases that seriously affect people's health, such as leprosy, acne, fungal diseases, psoriasis, and skin bacterial infections.
  • Skin disease is the change of morphology, structure and function of skin (including hair and nail) after internal and external factors, resulting in pathological processes, and correspondingly produced various clinical manifestations.
  • the incidence of skin diseases is very high, most of them are light, and often do not affect health (but a few are heavier or even life-threatening), but seriously affect the appearance of patients, which brings a heavy psychological burden to patients, which in turn affects patients' daily work. With life.
  • psoriasis is a common chronic inflammatory skin disease, the incidence rate is about 2% in the West, about 0.3% in Asia, but it has grown rapidly in recent years.
  • the typical skin manifestations of psoriasis are red plaques with clear boundaries and silvery white scales that severely affect the appearance of the patient. Therefore, although psoriasis is not life-threatening, it brings a heavy psychological burden to the patient's spirit, which in turn affects the patient's daily work and life. Improper treatment can also exacerbate the condition and increase the mental and financial burden on the patient.
  • the erythrodermic and pustular psoriasis can cause systemic metabolic disorders, complications such as cardiovascular and lung diseases, and infections, which are life-threatening. The occurrence and aggravation of erythrodermic and pustular psoriasis, except for some unknown causes, is due to improper treatment.
  • psoriasis is mainly the abnormality of epidermal hyperplasia and the activation of the immune system.
  • the guidelines for the treatment of psoriasis in China included tazarotene (retinoic acid), intermediate-effect and potent glucocorticoids, and calcipotriol (VitD3 derivatives) as the recommended drugs for topical treatment.
  • corticosteroids can cause side effects such as skin atrophy, telangiectasia, folliculitis, hyperpigmentation or regression.
  • Vitamin A acid has skin mucous membrane irritation, especially in patients with allergies.
  • the more common side effects of calcipotriol are pruritus, skin irritation, burning sensation, tingling, dry skin, erythema and rash, and have a certain effect on calcium metabolism. Therefore, the effect is remarkable and the side effects are small, and the products available for the patient are very limited.
  • EGFR epidermal growth factor receptor
  • Tyrosine kinase receptors are transmembrane proteins involved in signal transduction, and they will have growth factor signals that control important functions such as growth, mutation, angiogenesis, and inhibition of apoptosis, from cell surface to cell.
  • One such class of tyrosine kinase receptors is the epidermal growth factor receptor (EGFR) tyrosine kinase.
  • EGFR epidermal growth factor receptor
  • the present invention provides a pharmaceutical composition for external use for inhibiting tyrosine kinase and a preparation method thereof.
  • the present invention firstly provides a pharmaceutical composition for external use on skin, comprising an active ingredient for inhibiting tyrosine kinase and an excipient for external preparation, characterized in that the active ingredient is ectinib or a pharmaceutically acceptable salt thereof.
  • the excipients include one or more of a dispersion medium, an emulsifier, and/or an excipient of other pharmaceutically acceptable external preparations.
  • the active ingredient is ectinib free base, ectinib hydrochloride, ectinib maleate or ectinib phosphate.
  • the content of the active ingredient is from 0.1 to 11% by mass, more preferably from 0.3 to 5% by mass, still more preferably from 0.9 to 4.3% by mass, particularly preferably from 1 to 1.5% by mass.
  • the dispersion medium is divided into a water-soluble base and/or an oily base.
  • the water soluble matrix comprises water, glycerin, gelatin, ethanol, polyethylene glycol, propylene glycol, DMSO and/or a cellulose derivative.
  • the water-soluble matrix is contained in an amount of from 40 to 100% by mass, more preferably from 65 to 85% by mass.
  • the oily matrix comprises a hydrocarbon matrix, a lipid based matrix, a lipid based matrix and/or a silicone oxide polymer.
  • the hydrocarbon matrix comprises cetyl alcohol, stearyl alcohol and/or liquid paraffin;
  • the oily and fat base comprises soybean oil, castor oil, glyceryl mono, distearate and/or petrolatum;
  • the matrix comprises lanolin and/or beeswax;
  • the polymer of the organosilicon oxide is a polymer of dimethylsiloxane.
  • the oily base is contained in an amount of from 0 to 25% by mass, more preferably from 9 to 11% by mass.
  • the emulsifier is an anionic emulsifier and/or a nonionic emulsifier, more preferably a nonionic emulsifier.
  • the anionic emulsifier is a monovalent soap and/or a fatty alcohol sulfate; the nonionic emulsifier is a higher fatty acid polyol ester, a polyethylene glycol fatty acid ester and/or a polyoxyethylene Ether derivatives.
  • the monovalent soap is sodium stearate; the fatty alcohol sulfate is sodium lauryl sulfate and/or sodium cetyl sulfate; and the higher fatty acid polyol ester is cetyl alcohol. , octadecyl alcohol, stearic acid monoglyceride, poloxamer, polysorbate-80, polysorbate-60 and / or polysorbate-85; the polyoxyethylene ether derivative is flat plus O;
  • the polyethylene glycol fatty acid ester is polyethylene glycol-7-stearate and/or oleic acid polyethylene glycol glyceride.
  • the emulsifier is contained in an amount of 0 to 23% by mass, more preferably 10 to 15% by mass.
  • the excipient of the other pharmaceutically acceptable external preparation is a suspending agent.
  • the suspending agent is a polymeric suspending agent.
  • the polymer suspending agent is carbomer, polyvinylpyrrolidone (PVP-K30), dextran, sodium carboxymethylcellulose (CMC-Na), hydroxypropylmethylcellulose (hydroxypropyl) Methylcellulose, HPMC) and/or methylcellulose.
  • PVP-K30 polyvinylpyrrolidone
  • CMC-Na sodium carboxymethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • the suspending agent is contained in an amount of from 0 to 8.5% by mass, more preferably from 0 to 0.1% by mass.
  • the excipient of the other pharmaceutically acceptable external preparation is a pH adjuster.
  • the pH adjusting agent is a base, an acid and/or a buffer solution.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide and/or ammonium hydroxide;
  • the buffer solution is selected from the group consisting of a weak base and a weak acid.
  • the weak acid is selected from the group consisting of citric acid (tannic acid), potassium hydrogen phthalate and/or acetic acid;
  • the weak base is selected from the group consisting of triethanolamine, diethanolamine, disodium hydrogen phosphate, sodium dihydrogen phosphate, lemon Sodium and/or sodium acetate.
  • the content of the pH adjusting agent is 0-12.8% by mass, more preferably 0.2-1.5% by mass.
  • the excipient of the other pharmaceutically acceptable external preparation is a preservative.
  • the preservative is selected from the group consisting of p-hydroxybenzoic acid esters and/or sorbic acid and salts thereof.
  • the preservative is selected from the group consisting of ethylparaben (hydroxyphenylethyl ester), methylparaben, hydroxypropylpropyl ester, sorbic acid, potassium sorbate, chlorocresol and/or chlorobutanol.
  • the preservative is contained in an amount of from 0 to 0.3% by mass.
  • the excipient of the other pharmaceutically acceptable external preparation is a transdermal absorption enhancer.
  • the transdermal absorption enhancer is selected from the group consisting of Transcutol P and/or Labrasol.
  • the transdermal absorption enhancer is contained in an amount of from 0 to 45% by mass, more preferably from 15 to 30% by mass.
  • the present invention also provides the use of the above-mentioned external pharmaceutical composition for the preparation of an ointment.
  • the ointment is a cream.
  • the present invention also provides the use of the above-mentioned external pharmaceutical composition for preparing a gelling agent.
  • the gelling agent is a clear gelling agent.
  • the present invention also provides the use of the above-mentioned external pharmaceutical composition for the preparation of a medicament for treating a non-malignant hyperproliferative disorder or a tumor and a complication thereof.
  • the non-malignant hyperproliferative disorder is benign skin hyperplasia.
  • the non-malignant hyperproliferative disorder is a skin disorder.
  • the skin condition comprises a skin disease caused by psoriasis, scleroderma and/or diabetes.
  • the skin disease is psoriasis.
  • the tumor and its complications are skin tumors and complications thereof
  • the invention also provides a method of treating a tissue hyperproliferative disorder in a mammal comprising administering to a patient suffering from a tissue hyperproliferative disorder a therapeutically effective amount of the above pharmaceutical composition.
  • the tissue hyperproliferative disease is a skin disease or a skin tumor and a complication thereof.
  • the skin disease is a skin disease caused by psoriasis, scleroderma and/or diabetes.
  • the skin disease is psoriasis.
  • the active ingredient in the external pharmaceutical composition for skin provided by the present invention may be ectinib free base prepared by dissolving ectinib hydrochloride in a mixture of ethanol and water.
  • a solution prepared by dissolving sodium hydroxide in water is added dropwise to a solution of ectinib hydrochloride at a certain temperature until the pH of the reaction mixture is ⁇ 13.
  • the reaction solution was stirred and cooled to room temperature to give a precipitate.
  • the precipitate was filtered off and washed with pure water, and dried under vacuum at a certain temperature to obtain ectinib free base.
  • ectinib free base is not limited to the above preparation method.
  • the structure of ectinib free base is as follows:
  • the active ingredient in the external pharmaceutical composition provided by the present invention uses ectinib hydrochloride, ie, ectinib hydrochloride, preferably using ectinib hydrochloride Form I, which can pass
  • ectinib hydrochloride ie, ectinib hydrochloride, preferably using ectinib hydrochloride Form I, which can pass
  • the preparation method disclosed in the international application WO2010/003313A1 is not limited to the above production method.
  • the structure of ectinib hydrochloride is as follows:
  • the active ingredient in the external pharmaceutical composition provided by the present invention uses ectinib maleate
  • ectinib maleate can be prepared by the following method: ectotinib free base is first dissolved An ectinib solution was obtained in acetone. In addition, maleic acid is dissolved in acetone to obtain a maleic acid solution. The maleic acid solution was added to the ectinib solution, and the resulting reaction mixture was stirred and reacted to obtain ectinib maleate.
  • the ectinib maleate is not limited to the above preparation method.
  • the structure of ectinib maleate is as follows:
  • the active ingredient in the external pharmaceutical composition provided by the present invention uses ectinib phosphate
  • ectinib phosphate can be prepared by the method of: ectinib free base is dissolved in isopropyl alcohol. Ekertini solution. Further, a phosphoric acid solution was added to isopropyl alcohol to prepare a phosphoric acid solution. The phosphoric acid solution was added to the ectinib solution, and the resulting reaction mixture was stirred to separate ectinib phosphate.
  • the ectinib phosphate is not limited to the above preparation method.
  • the structure of ectinib phosphate is as follows:
  • the ectinib or a pharmaceutically acceptable salt thereof according to the present invention refers to any pharmaceutically acceptable substance comprising an ectinib structure, including but not limited to: ectinib free base, Etctinib hydrochloride, ectinib maleate, ectinib phosphate, ectinib solvate, chelate containing ectinib, hydrate of ectinib and the above Various crystal forms of matter, etc.
  • the ectinib or a pharmaceutically acceptable salt thereof according to the invention may contain asymmetric centers, chiral axes and chiral surfaces (see John Wiley & Sons, New York City, 1994). "Stereochemistry of Carbon Compounds" (pp. 1119-1190 in the book edited by EX. Eliel and SHwilen), may exist as racemates, racemic mixtures, individual diastereomers , all possible isomers and mixtures thereof, including optical isomers as well as all such stereoisomers included in the present invention. Furthermore, ectinib or a pharmaceutically acceptable salt thereof described herein may exist as a tautomer, and all tautomers are also included in the scope of the present invention.
  • the ectinib or a pharmaceutically acceptable salt thereof of the present invention may exist in a number of different polymorphic forms.
  • any drug When any drug is supplied for clinical use, it must be in a form suitable for different medical and prophylactic applications, and these forms are referred to as dosage forms, and various dosage forms are generally referred to as pharmaceutical preparations.
  • dosage forms When any drug is supplied for clinical use, it must be in a form suitable for different medical and prophylactic applications, and these forms are referred to as dosage forms, and various dosage forms are generally referred to as pharmaceutical preparations.
  • the purpose of the pharmaceutical dosage form and preparation which is convenient to take, convenient to store and transport, and stable in quality, although related to production technology, production equipment, preparation process, quality management, etc., depends mainly on the pharmaceutical auxiliary materials. Since any of the preparations, except for the active ingredient (the main drug), all of them are pharmaceutical excipients. Therefore, the quality of the pharmaceutical excipients, the scientific and rationality of the selected excipient formulas, directly affect the quality of the preparation.
  • the external pharmaceutical composition of ectinib or a pharmaceutically acceptable salt thereof must release the drug, pass through the epidermis, and then exert a therapeutic effect in the skin.
  • the skin covers the whole body, prevents the loss of water, electrolytes and other substances in the body, and is a barrier against the invasion of external substances, which plays an important role in protecting the human body.
  • the function of the skin barrier is mainly borne by the stratum corneum, which is a film layer with a certain mechanical strength, which is a major obstacle to the transdermal absorption of drugs. It is generally believed that the stratum corneum can contain a suitable concentration of water-soluble and fat-soluble substances, and a drug having a small molecular weight can diffuse into the inner layer through the intercellular space.
  • the stratum corneum is penetrated by hair follicles and ducts to provide another way of absorbing drugs.
  • Ektorinib chemical name 4-[(3-ethynylphenyl)amino]-quinazoline[6,7-b]-12-crown-4) or a pharmaceutically acceptable salt thereof
  • the active ingredient of the formulation
  • Transcutol P chemical name diethylene glycol monoethyl ether, English chemical name diethylene glycol monoethyl ether.
  • Formulations are solvents and transdermal absorption enhancers for active pharmaceuticals.
  • Labrasol a Chinese chemical called bismuth citrate polyglycol glyceride, English name Caprylocaproyl macrogol-8glycerides, is a mixture of a defined ratio of mono-, di-, tri-glycerides and mono- and di-fatty acid polyethylene glycol esters. It is commonly used in emulsifiers and transdermal absorption enhancers.
  • Carbopol also known as carbomer, is called carbomer in Chinese. It is a white, "fluffy", acidic, water-absorbing, slightly light odor, which is high in acrylic acid-bonded allyl sucrose or pentaerythritol allyl ether. Molecular polymers are commonly used gel skeletons.
  • polyethylene glycol-7 stearate which is polyethylene glycol-6 stearate (PEG-6 stearate), ethylene glycol palmitostearate and polyethylene.
  • PEG-6 stearate polyethylene glycol-6 stearate
  • ethylene glycol palmitostearate polyethylene.
  • a mixture of alcohol-32 stearate PEG-32stearate).
  • Labrafil M The chemical name is oleic acid polyethylene glycol glyceride (EP), which is a mixture of a defined ratio of mono-, di-, tri-glycerides and mono- and di-fatty acid polyethylene glycol esters.
  • EP oleic acid polyethylene glycol glyceride
  • DMSO dimethyl sulfoxide
  • the present invention provides an external preparation containing ectinib or a pharmaceutically acceptable salt thereof and a process for the preparation thereof.
  • the external preparation provided by the invention has small skin irritation, no pruritus, burning sensation, tingling sensation, dry skin, erythema and rash, and the like, and long-term use does not cause hormone atrophy such as skin atrophy, pigmentation or hypothyroidism. Side effects, no related skin disease symptoms after stopping the drug.
  • the preparation method has the advantages of simple, easy operation and control, and easy industrialization.
  • the present invention provides a specific embodiment of the external preparation.
  • the numerical values in the examples indicate "% by mass” unless otherwise specified.
  • step (3) The mixture obtained in the step (2) is added to the swollen carbomer solution obtained in the step (1), and stirred at room temperature until it is transparent.
  • Tefose 63 Labrafil M 1944, petrolatum, stearyl alcohol, cetyl alcohol, ethyl paraben and/or liquid paraffin, mix and stir, and heat to 75-80 ° C until melting;
  • step (3) The mixture obtained in the step (2) is added to the mixture obtained in the step (1), emulsified for 20 minutes, and cooled to room temperature in a water bath to obtain.
  • step (3) separately weigh the prescribed amount of citric acid and / or the remaining triethanolamine, dissolved in water, added dropwise to the solution obtained in the step (2), and added to the carbomer solution obtained in the step (1), emulsified for 5 minutes, Then heated to 60-70 ° C;
  • Tefose 63 Labrafil M 1944, sodium lauryl sulfate, stearyl alcohol, cetyl alcohol, liquid paraffin, ethylparaben and/or glycerin, mix and stir, and heat to 75-80 ° C, until it is melted, added to the solution obtained in the step (3), emulsified for 15 minutes, and stirred in a water bath to cool to room temperature, that is, obtained.
  • Tefose 63 Labrafil M 1944, petrolatum, stearyl alcohol, cetyl alcohol, soybean oil, stearic acid, ethyl paraben and/or liquid paraffin, mix and stir, heat to 75 -80 ° C until molten;
  • step (3) The mixture obtained in the step (2) is added to the mixture obtained in the step (1), emulsified for 20 minutes, and cooled in a water bath. But to the room temperature, that is.
  • Tefose 63 Labrafil M 1944, beeswax, dimethicone, stearyl alcohol, liquid paraffin, ethyl paraben, benzoic acid, chlorobutanol and/or chlorocresol, respectively. Mix and stir, heat to 75-80 ° C until melting;
  • step (3) The mixture obtained in the step (2) is added to the mixture obtained in the step (1), emulsified for 20 minutes, and cooled to room temperature to obtain.
  • ectinib hydrochloride 100 g was dissolved in a mixed solvent of 300 ml of ethanol and 200 ml of water, and an aqueous solution of sodium hydroxide (NaOH, 11.2 g; water, 100 ml) was added dropwise at 60 ° C until the reaction mixture was measured. The pH is 13. After stirring for 1 hour, cooling to room temperature, filtering, washing the precipitate with pure water, and drying under vacuum at 60 ° C for 8 hours, to obtain 90 g of ectinib free base.
  • NaOH sodium hydroxide
  • Example A Effect of ectinib hydrochloride cream on the formation of granule layer of rat tail epidermis
  • Test drug ectinib hydrochloride cream preparation, specification 1g/100ml (1%);
  • Blank cream matrix group no active component (Ectinini hydrochloride), the other components are the same as the test drug;
  • Positive control drug Halemisone cream, size 15g: 7.5mg, Hong Kong Aomei Pharmaceutical Factory, batch number 0911551;
  • Test animals ICR mice, male, 30;
  • Test instrument OLYMPUS biological microscope.
  • mice Thirty ICR mice, all male, were randomly divided into 3 groups, 10 in each group, divided into blank cream matrix group, positive drug halomethasone ointment group and 1% ectibrinide hydrochloride cream group, tail skin application drugs . Wipe the tail with a cotton swab and water before each dose, and apply a thin layer to the tail of different groups of mice twice a day for 14 consecutive days. After the drug was over, the mice were sacrificed, and the skin was about 1.5 cm ⁇ 0.2 cm from the tail of the mouse, and the skin was fixed in 4% formaldehyde, embedded in paraffin, sectioned, and stained with HE.
  • the ectinib hydrochloride cream formulation can significantly promote the formation of the granule layer of the tail scale of the mouse compared with the blank matrix group, and the effect is stronger than that of the positive control halomethasone group.
  • Example B Effect of ectinib hydrochloride gel formulation on the formation of rat tail epidermal granular layer
  • Test drug ectinib hydrochloride gel preparation: size 1g / 100ml (1%); specification 1.5g / 100ml (1.5%);
  • Blank gel matrix group no active component (Ectinib hydrochloride), the other components are the same as the test drug;
  • Positive control drug clobetasol propionate cream, size 10g: 2mg (0.02%), Guangdong Shunfeng Pharmaceutical Co., Ltd., batch number 20110304;
  • Test animals ICR mice, male, 40;
  • Test instrument Biological microscope.
  • mice Forty ICR mice, all male, were randomly divided into 4 groups. Among them, blank gel matrix group, 1% ectinib hydrochloride gel group, 1.5% ectinib hydrochloride gel group, and positive drug clobetasol propionate cream group, 10 in each group. Apply the drug to the skin of the tail. Gently wipe the tail with a cotton swab and water before each dose, and apply a thin layer to the tail of the different groups of mice each time. The drug was administered twice a day for 14 consecutive days. After the drug was over, the mice were sacrificed, and the skin was about 1.5 cm ⁇ 0.2 cm from the tail of the mouse, and the skin was fixed in 4% neutral formaldehyde, embedded in paraffin, sectioned, and stained with HE.
  • Both the 1% ectinib hydrochloride gel group and the 1.5% ectibrinide hydrochloride gel group increased the number of scales in the tail layer of mice.
  • Example C Effect of octatinib hydrochloride cream on propofolol-induced scalloped skin lesions in guinea pig ears
  • Test drug ectinib hydrochloride cream preparation: size 1g / 100ml (1%); size 2g / 100ml (2%); size 4g / 100ml (4%);
  • Blank cream matrix group no active component (Ectinini hydrochloride), the other components are the same as the test drug;
  • Positive control drug calcipotriol ointment, batch number EH4129, Leo, Ireland;
  • Test animals guinea pigs, 250-300 g, half male and half, 70;
  • Test instrument Biological microscope.
  • Penelopeol 5 g of propranolol hydrochloride is dissolved in 50% ethanol, 5 ml of Azone-propylene glycol is added as a composite accelerator, and polyvinylpyrrolidone (PVP-K30) is added. 5g is a film-forming material, and finally 50% ethanol solution is added to make 100ml, and it is evenly stirred.
  • guinea pigs Seventy healthy adult guinea pigs were randomly selected from 10 (male and female) as normal control group, and the remaining guinea pigs were treated with 5% propranolol hydrochloride sputum on both sides of the auricle (80 ⁇ l/ear), once a day in the morning and evening. , for 2 consecutive weeks.
  • the model group guinea pigs were randomly divided into 6 groups, namely model group, blank matrix group, 1% ectinib hydrochloride cream group, bid., 2% ectinib hydrochloride cream group. Bid., 4% ectinib hydrochloride cream group, bid.
  • the left and right ears of the model group were not applied, and the blank matrix was applied to the left and right ears of the blank group.
  • the animals were sacrificed by CO 2 anesthesia, and the tissues of the left and right auricle skins of each group were 10 mm ⁇ 5 mm in the middle, 4% neutral formaldehyde was fixed, embedded in paraffin, and HE stained.
  • the changes of keratinized layer, granular layer, spinous cell layer, basal cell layer and dermis of guinea pig auricle were observed under light microscope.
  • the cuticle of the epidermis of the normal control group was intact, the granule layer was linear, and the basal layer was a single-layer columnar cell.
  • the true epidermal junction was wavy, the capillaries were not congested, and the structure was normal.
  • the model group was keratinized. Incomplete or excessive keratinization, the spine cell layer becomes thicker, the epidermal process is extended in a rod shape, the dermal papilla extends upward and becomes a rod-like change, and the epidermis thickness of the ear is compared with normal.
  • the group increased significantly (P ⁇ 0.01).

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Abstract

一种抑制酪氨酸激酶的外用制剂及其制备方法，特别是一种抑制酪氨酸激酶的外用药物组合物及其制备方法。外用制剂活性成分为埃克替尼或其药学上可接受的盐。该制剂适用于局部用药，具有对皮肤刺激小，无瘙痒症、灼烧感、刺痛感、皮肤干燥、红斑和皮疹等不良反应，长期使用不会产生皮肤萎缩、色素沉着或减退等类激素样副作用，停药后无相关皮肤病症状。该制备方法具有简单、易操作控制，易于工业化等优点。

Description

一种含埃克替尼的皮肤外用药物组合物及其应用 技术领域
本发明涉及一种含埃克替尼或其药学上可接受的盐的皮肤外用药物组合物及其应用。
背景技术
皮肤病是有关皮肤的疾病，是严重影响人民健康的常见病、多发病之一，如麻风、疥疮、真菌病、银屑病、皮肤细菌感染等。皮肤病是皮肤(包括毛发和甲)受到内外因素的影响后，其形态、结构和功能均发生变化，产生病理过程，并相应的产生各种临床先后表现。皮肤病的发病率很高，多数较轻，常不影响健康(但少数较重甚至可以危及生命)，但严重影响患者外观相貌，给患者带来了沉重的心理负担，进而影响患者的日常工作与生活。
其中，银屑病是一种常见的慢性炎症性皮肤病，其发病率在西方约为2％，亚洲大概0.3％，但近年来增长迅速。银屑病典型的皮肤表现是边界清楚的具有银白色鳞屑的红色斑块，严重影响患者外观相貌。因此，虽然银屑病不会危及生命，但是给患者精神带来了沉重的心理负担，进而影响患者的日常工作与生活。不当的治疗亦可使病情加重，同时增加了患者的精神与经济负担。红皮病型和脓疱型银屑病可引起全身的代谢紊乱，出现心血管和肺等多脏器的并发症以及感染等，威胁生命。红皮病型和脓疱型银屑病的发生和加重，除一部分病因不明者外，相当部分是治疗不当所致。
早期研究认为，银屑病的病理机制主要为表皮增生分化的异常和免疫系统的激活。2008年中国银屑病治疗指南将他扎罗汀(维A酸类)、中效与强效的糖皮质激素、卡泊三醇(VitD3衍生物)做为局部治疗的推荐药物。然而皮质类固醇激素长期使用可引起皮肤萎缩、毛细血管扩张、毛囊炎、色素沉着或减退等副反应。大面积长期应用强效糖皮质激素制剂可引起全身反应，停药后甚至诱发脓疱型或红皮病型银屑病。维A酸类存在皮肤黏膜刺激症状，尤其过敏体质患者容易发生。卡泊三醇较常见的副作用为瘙痒症、皮肤刺激、灼烧感、刺痛感、皮肤干燥、红斑和皮疹，并对钙代谢有一定的影响。因此，效果显著且副作用小的，可供患者选择的产品非常有限。
有新的研究发现，在正常人表皮各层中，EGFR(表皮生长因子受体)的表达不一致，分裂活跃的基底层及靠近基底层的部分棘细胞层中存在大量的EGFR；而在寻常性银屑病 中，各层均呈现阳性表达，在棘细胞层以上的各层中，其表达可比正常人高8倍以上。EGFR在寻常型银屑病皮损中过度表达，提示其与银屑病的表皮细胞过度增殖、分化异常有关。纠正其异常表达可为银屑病治疗开辟新途径，提供新药物。
酪氨酸激酶受体是参与信号转化的跨膜蛋白，它们将拥有控制诸如生长、变异、血管生成和抑制凋亡等重要功能的生长因子信号，从细胞表面传导到细胞内。其中一类这样的酪氨酸激酶受体是表皮生长因子受体(EGFR)酪氨酸激酶。现在市场上还没有成熟的银屑病治疗药物采用酪氨酸激酶抑制剂。
发明内容
针对现有技术中存在的空白，本发明提供了一种抑制酪氨酸激酶的外用药物组合物及其制备方法。
本发明首先提供了一种皮肤外用药物组合物，包括抑制酪氨酸激酶的活性成分和外用制剂的辅料，其特征在于，所述活性成分为埃克替尼或其药学上可接受的盐，所述辅料包括分散介质、乳化剂和/或其他药学上可接受的外用制剂的辅料中的一种或几种。
本发明还提供了上述技术方案的优选技术方案：
作为优选，所述活性成分为埃克替尼游离碱、埃克替尼盐酸盐、埃克替尼马来酸盐或埃克替尼磷酸盐。
作为优选，所述活性成分的含量为0.1-11质量％，更优选为0.3-5质量％，进一步优选为0.9-4.3质量％，特别优选为1-1.5质量％。
作为优选，所述分散介质分为水溶性基质和/或油性基质。
作为优选，所述水溶性基质包括水、甘油、明胶、乙醇、聚乙二醇、丙二醇、DMSO和/或纤维素衍生物。
作为优选，所述水溶性基质的含量为40-100质量％，更优选为65-85质量％。
作为优选，所述油性基质包括烃类基质、油脂类基质、类脂类基质和/或有机硅氧化物的聚合物。
作为优选，所述烃类基质包括十六醇、十八醇和/或液状石蜡；所述油脂类基质包括大豆油、蓖麻油、单、双硬脂酸甘油酯和/或凡士林；所述类脂类基质包括羊毛脂和/或蜂蜡；所述有机硅氧化物的聚合物为二甲基硅氧烷的聚合物。
作为优选，所述油性基质的含量为0-25质量％，更优选为9-11质量％。
作为优选，所述乳化剂为阴离子型乳化剂和/或非离子型乳化剂，更优选为非离子型乳化剂。
作为优选，所述阴离子型乳化剂为一价皂类和/或脂肪醇硫酸酯类；所述非离子型乳化剂为高级脂肪酸多元醇酯、聚乙二醇脂肪酸酯和/或聚氧乙烯醚衍生物。
作为优选，所述一价皂类为硬脂酸钠；所述脂肪醇硫酸酯类为十二烷基硫酸钠和/或十六烷基硫酸钠；所述高级脂肪酸多元醇酯为十六醇、十八醇、硬脂酸单甘脂、泊洛沙姆、聚山梨酯-80、聚山梨酯-60和/或聚山梨酯-85；所述聚氧乙烯醚衍生物为平平加O；所述聚乙二醇脂肪酸酯为聚乙二醇-7-硬脂酸酯和/或油酸聚乙二醇甘油酯。
作为优选，所述乳化剂的含量为0-23质量％，更优选为10-15质量％。
作为优选，所述其他药学上可接受的外用制剂的辅料为助悬剂。
作为优选，所述助悬剂为高分子助悬剂。
作为优选，所述高分子助悬剂为卡波姆、聚乙烯吡咯烷酮(PVP-K30)、葡聚糖、羧甲基纤维素钠(CMC-Na)、羟丙基甲基纤维素(羟丙甲纤维素，HPMC)和/或甲基纤维素。
作为优选，所述助悬剂的含量为0-8.5质量％，更优选为0-0.1质量％。
作为优选，所述其他药学上可接受的外用制剂的辅料为pH调节剂。
作为优选，所述pH调节剂为碱、酸和/或缓冲溶液。
作为优选，所述碱选自氢氧化钠、氢氧化钾和/或氢氧化铵；所述缓冲溶液选自由弱碱和弱酸组成的缓冲对。
作为优选，所述弱酸选自柠檬酸(枸橼酸)、邻苯二甲酸氢钾和/或醋酸；所述弱碱选自三乙醇胺、二乙醇胺、磷酸氢二钠、磷酸二氢钠、柠檬酸钠和/或醋酸钠。
作为优选，所述PH调节剂的含量为0-12.8质量％，更优选为0.2-1.5质量％。
作为优选，所述其他药学上可接受的外用制剂的辅料为防腐剂。
作为优选，所述防腐剂选自对羟基苯甲酸脂类和/或山梨酸及其盐类。
作为优选，所述防腐剂选自尼泊金乙酯(羟苯乙酯)、羟苯甲酯、羟苯丙酯、山梨酸、山梨酸钾、氯甲酚和/或三氯叔丁醇。
作为优选，所述防腐剂的含量为0-0.3质量％。
作为优选，所述其他药学上可接受的外用制剂的辅料为透皮吸收促进剂。
作为优选，所述透皮吸收促进剂选自Transcutol P和/或Labrasol。
作为优选，所述透皮吸收促进剂的含量为0-45质量％，更优选为15-30质量％。
本发明还提供了上述外用药物组合物用于制备软膏剂的用途。
作为优选，所述软膏剂为乳膏。
本发明还提供了上述外用药物组合物用于制备凝胶剂的用途。
作为优选，所述凝胶剂为透明凝胶剂。
本发明还提供了上述外用药物组合物用于制备治疗非恶性过度性增生病症或肿瘤及其并发症的药物的应用。
本发明还提供了上述技术方案的优选技术方案：
作为优选，所述非恶性过度性增生病症是良性皮肤增生。
作为优选，所述非恶性过度性增生病症为皮肤病。
作为优选，所述皮肤病包括银屑病、硬皮病和/或糖尿病所致的皮肤病。
作为优选，所述皮肤病为银屑病。
作为优选，所述肿瘤及其并发症为皮肤肿瘤及其并发症
本发明还提供了一种治疗哺乳动物的组织过度增生疾病的方法，包括对患有组织过度增生疾病的患者施用治疗有效量的上述药物组合物。
本发明还提供了上述技术方案的优选技术方案：
作为优选，所述组织过度增生疾病为皮肤病或皮肤肿瘤及其并发症。
作为优选，所述皮肤病为银屑病、硬皮病和/或糖尿病所致的皮肤病。
作为优选，所述皮肤病为银屑病。
特别地，本发明提供的皮肤外用药物组合物中的活性组分，可以为埃克替尼游离碱，通过如下方法制备：将埃克替尼盐酸盐溶于乙醇和水的混合物中。将氢氧化钠溶于水制得的溶液在一定温度下逐滴加入到埃克替尼盐酸盐的溶液中，直到反应混合液的pH值≥13。搅拌反应溶液，冷却至室温产生沉淀。滤出沉淀并用纯水洗涤，低于一定温度下真空干燥，即得到埃克替尼游离碱。但埃克替尼游离碱不限于上述制备方法制得。埃克替尼游离碱的结构如下：
Figure PCTCN2014088344-appb-000001
特别地，本发明提供的外用药物组合物中的活性组分，采用埃克替尼盐酸盐，即盐酸埃克替尼，优选使用盐酸埃克替尼晶型I，该晶型I可以通过国际申请WO2010/003313A1公开的制备方法，且并不限于上述制备方法制得。盐酸埃克替尼的结构如下：
Figure PCTCN2014088344-appb-000002
特别地，本发明提供的外用药物组合物中的活性组分，采用埃克替尼马来酸盐，埃克替尼马来酸盐可以通过如下方法制备：埃克替尼游离碱首先溶于丙酮中得到埃克替尼溶液。另外，马来酸溶于丙酮中得到马来酸溶液。马来酸溶液加入到埃克替尼溶液，得到的反应混合物搅拌反应，分离得到埃克替尼马来酸盐。埃克替尼马来酸盐并不限于上述制备方法制得。埃克替尼马来酸盐的结构如下：
Figure PCTCN2014088344-appb-000003
特别地，本发明提供的外用药物组合物中的活性组分，采用埃克替尼磷酸盐，埃克替尼磷酸盐可以通过如下方法制备：埃克替尼游离碱溶于异丙醇中形成埃克替尼溶液。另外，磷酸溶液加入到异丙醇制成磷酸溶液。磷酸溶液加入到埃克替尼溶液，所得反应混合物搅拌，分离得到埃克替尼磷酸盐。埃克替尼磷酸盐并不限于上述制备方法制得。埃克替尼磷酸盐的结构如下：
Figure PCTCN2014088344-appb-000004
特别地，本发明所述的埃克替尼或其药学上可接受的盐是指任何药学上可接受的包含有埃克替尼结构的物质，包括但不限于：埃克替尼自由碱、埃克替尼盐酸盐、埃克替尼马来酸盐、埃克替尼磷酸盐、埃克替尼溶剂化物、含埃克替尼的螯合物、埃克替尼的水合物及上述物质的各种晶型等。
本发明所述的埃克替尼或其药学上可接受的盐可以含有不对称中心、手性轴和手性面(参见约翰·威利父子出版公司(John Wiley&Sons，纽约市)于1994年出版的《碳化合物的立体化学(Stereochemistry of Carbon Compounds)》(EX.Eliel和S.H.wilen编)一书的第1119-1190页)，可以存在外消旋体、外消旋混合物、个别非对映体，所有可能的异构体及其混合物，包括光学异构体以及本发明中包括的所有这类立体异构体。此外，本文中所述的埃克替尼或其药学上可接受的盐可以存在互变异构体，所有互变异构体也均包括在本发明的保护范围内。
本发明所述的埃克替尼或其药学上可接受的盐可以存在大量不同的多晶态形式。
任何一种药物供给临床使用时，必须制成适宜于不同的医疗和预防应用的形式，这些形式均称为剂型，而各种剂型通称为药物制剂。为了开发和生产出疗效高、毒副作用小、 便于服用、贮运方便、质量稳定的药物剂型和制剂这一目的，虽然与生产技术、生产设备、制备工艺、质量管理等有关，但主要取决于药剂辅料。因为任何一种制剂，除了活性组分(主药)外，其余全是药剂辅料。所以，药剂辅料质量的优劣，所选用辅料配方的科学性和合理性等，直接影响着制剂的质量。
埃克替尼或其药学上可接受的盐的外用药物组合物必须使药物释放，透过表皮，然后在皮肤内发挥治疗作用。皮肤覆蔽全身，防止体内水分、电解质和其他物质丧失，并且是抵御外部物质入侵的屏障，对人体起着重要的保护作用。皮肤屏障的功能主要由角质层承担，这是有一定机械强度的薄膜层，是药物透皮吸收的重大障碍。一般认为，角质层能容纳适当浓度的水溶性和脂溶性物质，分子量小的药物可以通过细胞间隙扩散进入内层。角质层被毛囊和腺管所穿透而提供了吸收药物的另一途径。
影响药物透皮吸收的因素很多，如生理因素、药物的理化性质和基质的类型及其组成，虽然药物本身固有的活性是决定其治疗用途的最重要的因素，但是药物的释放与透皮吸收在很大程度上受到基质的影响。
埃克替尼(化学名为4-[(3-乙炔基苯基)氨基]-喹唑啉并[6,7-b]-12-冠-4)或其药学上可接受的盐为本制剂的活性成分。
Transcutol P，化学名为二乙二醇单乙基醚，英文化学名为diethylene glycol monoethyl ether。制剂学用于活性药物的溶剂和透皮吸收促进剂。
Labrasol，中文化学名为辛酸癸酸聚乙二醇甘油酯，英文名Caprylocaproyl macrogol-8glycerides，是由确定比例的单、双、三甘油酯和单、双脂肪酸聚乙二醇酯组成的混合物，制剂学上常用于乳化剂和透皮吸收促进剂。
Carbopol又称carbomer，中文名为卡波姆，是一种白色、“绒毛状”、酸性、吸水性、微具轻微特殊气味的粉末，为丙烯酸键合烯丙基蔗糖或季戊四醇烯丙醚的高分子聚合物，是常用凝胶骨架。
Figure PCTCN2014088344-appb-000005
化学名为聚乙二醇-7硬脂酸酯，为聚乙二醇-6硬脂酸酯(PEG-6 stearate)、硬脂酸棕榈酸乙二醇酯(ethylene glycol palmitostearate)和聚乙二醇-32硬脂酸酯(PEG-32stearate)的混合物。
Labrafil M
Figure PCTCN2014088344-appb-000006
化学名为油酸聚乙二醇甘油酯(EP)，是由确定比例的单、双、三甘油酯和单、双脂肪酸聚乙二醇酯组成的混合物。
DMSO化学名为二甲基亚砜，无色液体。可与许多有机溶剂及水互溶。
在制备本发明提供的制剂时，需要注意辅料间的配伍禁忌，如卡波姆遇间二苯酚变色， 且和苯酚、阳离子聚合物、强酸及高浓度的电解质不相容。痕量的铁或其他过渡金属能够催化降解卡波姆分散液。卡波姆与强碱性物质如氨、氢氧化钾、氢氧化钠或强碱性有机胺接触时，能够产生大量的热。某些含氨基官能团药物与卡波姆能形成水溶性的络合物，一般来说，用适当的醇或多元酸调节液体的溶解度参数，可以防止这类情况发生。
本制剂应用的辅料及其配伍禁忌均是本领域的公知常识，可查《药用辅料手册》([英]R.C.罗，[美]P.J.舍斯基，[英]P.J.韦勒编，郑俊民主译，化学工业出版社出版)、《常用药物辅料手册》(李捷玮、刘吉祥主编，第二军医大学出版社出版)及《药剂辅料大全》(罗明生、高天惠主编，四川科学技术出版社出版)等，在此不一一说明。
本发明提供了一种含有埃克替尼或其药学上可接受的盐的外用制剂及其制备方法。本发明提供的外用制剂具有对皮肤刺激小，无瘙痒症、灼烧感、刺痛感、皮肤干燥、红斑和皮疹等不良反应，长期使用不会产生皮肤萎缩、色素沉着或减退等类激素样副作用，停药后无相关皮肤病症状。该制备方法具有简单、易操作控制，易于工业化等优点。
具体实施方式
下述实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够实施本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本技术领域的常规技术手段或方法等。
本发明提供外用制剂的具体实施例如下，需要说明的是，实施例中数值在无特别说明时，表示“质量％”。
实施例1-10
1.配方(见表1)
表1
Figure PCTCN2014088344-appb-000007
2.实施例1-10的制备方法
(1)称取处方量的卡波姆，在丙二醇中完全溶胀；
(2)分别称取处方量的埃克替尼盐酸盐、Transcutol P和/或Labrasol，混合均匀；
(3)将步骤(2)所得混合物加入到步骤(1)所得的溶胀好的卡波姆溶液中；
(4)将步骤(3)所得混合物室温搅拌至透明。
实施例11-14
1.配方(见表2)
表2
Figure PCTCN2014088344-appb-000008
2.实施例11-14的制备方法
(1)分别称取处方量的埃克替尼盐酸盐、Transcutol P和Labrasol，混合均匀；
(2)将步骤(1)所得混合物加入到丙二醇溶液中；
(3)将步骤(2)所得混合物室温搅拌至透明。
实施例15-20
1.配方(见表3)
表3
Figure PCTCN2014088344-appb-000009
2.实施例15-20的制备方法
(1)分别称取处方量的卡波姆和尼泊金乙酯，在丙二醇中完全溶胀；
(2)分别称取处方量的埃克替尼盐酸盐、Transcutol P和Labrasol，混合均匀；
(3)将步骤(2)所得混合物加入到步骤(1)所得溶胀好的卡波姆溶液中；
(4)将步骤(3)所得混合物室温搅拌至透明，即得。
实施例21-24
1.配方(见表4)
表4
Figure PCTCN2014088344-appb-000010
2.实施例21-24的制备方法
(1)称取处方量的卡波姆，在丙二醇中完全溶胀；
(2)分别称取处方量的埃克替尼盐酸盐、Transcutol P和Labrasol，混合均匀；
(3)将步骤(2)所得混合物加入到步骤(1)所得溶胀好的卡波姆溶液中；
(4)按处方量，向步骤(3)所得混合物中加入甘油或乙醇，室温搅拌至透明，即得。
实施例25-29
1.配方(见表5)
表5
Figure PCTCN2014088344-appb-000011
2.实施例25-29的制备方法
(1)分别称取处方量的PVP-K30、卡波姆、CMC-Na和/或HPMC在丙二醇中完全溶胀；
(2)分别称取处方量的埃克替尼盐酸盐、Transcutol P和Labrasol，混合均匀；
(3)将步骤(2)所得混合物加入到步骤(1)所得溶胀好的卡波姆溶液中，室温搅拌至透明，即得。
实施例30-36
1.配方(见表6)
表6
Figure PCTCN2014088344-appb-000012
2.制备方法
A、实施例30-32的制备方法
(1)分别称取处方量的Tefose 63、Labrafil M 1944、凡士林、十八醇、十六醇、尼泊金乙酯和/或液状石蜡，混合搅拌，加热至75-80℃，直至熔融；
(2)另分别称取处方量的埃克替尼盐酸盐、水和/或甘油，混合搅拌，加热至60-70℃，搅拌均匀；
(3)将步骤(2)所得混合物加入到步骤(1)所得混合物中，乳化20分钟，水浴冷却至室温，即得。
B、实施例33-36的制备方法
(1)分别称取处方量的凡士林、十八醇、液状石蜡和尼泊金乙酯，混合搅拌，加热至75-80℃，直至熔融；
(2)另分别称取处方量的甘油、十二烷基硫酸钠、水、DMSO和/或丙二醇，混合搅拌，加热至60-70℃，搅拌均匀；
(3)将步骤(2)所得混合物加入到步骤(1)所得混合物中，乳化10-30分钟；
(4)在步骤(3)所得混合物中加入处方量的埃克替尼盐酸盐，继续乳化10分钟，冷却至室温，即得。
实施例37-43
1.配方(见表7)
表7
Figure PCTCN2014088344-appb-000013
2.实施例37-43的制备方法
(1)称取处方量的卡波姆，用水溶解，加入三乙醇胺，搅拌至溶胀完全；
(2)另称取处方量的埃克替尼盐酸盐，加水，40℃下搅拌，加入称取的处方量氢氧化钠，搅拌均匀；
(3)另分别称取处方量的柠檬酸和/或剩余的三乙醇胺，用水溶解，滴加到步骤(2)所得溶液中，并加入步骤(1)所得卡波姆溶液，乳化5分钟，然后加热至60-70℃；
(4)另分别称取处方量的Tefose 63、Labrafil M 1944、十二烷基硫酸钠、十八醇、十六醇、液状石蜡、尼泊金乙酯和/或甘油，混合搅拌，加热至75-80℃，直至熔融，将其加入到步骤(3)所得溶液中，乳化15分钟，水浴中搅拌冷却至室温，即得。
实施例44-50
1.配方(见表8)
表8
Figure PCTCN2014088344-appb-000014
2.A、实施例44-47的制备方法
(1)分别称取处方量的Tefose 63、Labrafil M 1944、凡士林、十八醇、十六醇、大豆油、硬脂酸、尼泊金乙酯和/或液状石蜡，混合搅拌，加热至75-80℃，直至熔融；
(2)另分别称取处方量的埃克替尼游离碱、三乙醇胺、柠檬酸、柠檬酸钠、水和/或卡波姆，混合搅拌，加热至60-70℃；
(3)将步骤(2)所得混合物加入到步骤(1)所得混合物中，乳化20分钟，水浴冷 却至室温，即得。
B、实施例48-50的制备方法
(1)分别称取处方量的凡士林、十八醇、液状石蜡和尼泊金乙酯，混合搅拌，加热至75-80℃，直至熔融；
(2)另分别称取处方量的柠檬酸、卡波姆、水和/或三乙醇胺，混合搅拌，加热至60-70℃；
(3)将步骤(2)所得混合物加入到步骤1所得混合物中，乳化10分钟；
(4)在步骤(3)所得混合物中加入处方量的埃克替尼游离碱，继续乳化10分钟，冷却至室温，即得。
实施例51-56
1.配方(见表9)
表9
Figure PCTCN2014088344-appb-000015
2.实施例51-56的制备方法
(1)分别称取处方量的Tefose 63、Labrafil M 1944、蜂蜡、二甲基硅油、十八醇、液状石蜡、尼泊金乙酯、苯甲酸、三氯叔丁醇和/或氯甲酚，混合搅拌，加热至75-80℃，直至熔融；
(2)另分别称取处方量的埃克替尼盐酸盐、埃克替尼马来酸盐、埃克替尼磷酸盐、三乙醇胺、柠檬酸、柠檬酸钠、水和/或十二烷基硫酸钠，混合搅拌，加热至60-70℃；
(3)将步骤(2)所得混合物加入到步骤(1)所得混合物中，乳化20分钟，冷却至室温，即得。
实施例57.埃克替尼游离碱的制备
将100g埃克替尼盐酸盐溶解在300ml乙醇和200ml水的混合溶剂中，60℃下，逐滴滴加氢氧化钠的水溶液(NaOH，11.2g；水，100ml)至测得反应混合物的pH值为13。搅拌1小时，冷却至室温，过滤，纯水洗涤沉淀，低于60℃真空干燥8小时，即得90g埃克替尼游离碱。
实施例58.埃克替尼马来酸盐的制备
10mg埃克替尼游离碱首先溶于1ml丙酮中得到埃克替尼溶液。另外，34.82mg马来酸溶于3ml丙酮中得到0.1mol/L马来酸溶液。0.26ml的0.1mol/L马来酸溶液加入到埃克替尼溶液，得到的反应混合物搅拌反应24小时，分离得到埃克替尼马来酸盐。
实施例59.埃克替尼磷酸盐的制备
10mg埃克替尼游离碱溶于1ml异丙醇中形成埃克替尼溶液。另外，18.9μL磷酸溶液加入到3ml异丙醇制成0.1mol/L磷酸溶液。0.26ml的0.1mol/L磷酸溶液加入到埃克替尼溶液，所得反应混合物搅拌24小时，分离得到埃克替尼磷酸盐。
实施例A.埃克替尼盐酸盐乳膏对鼠尾表皮颗粒层形成的影响试验
试验材料：
试验药物：埃克替尼盐酸盐乳膏制剂，规格1g/100ml(1％)；
空白乳膏基质组：取不含活性组分(埃克替尼盐酸盐)，其他各成分同试验药物；
阳性对照药：卤米松乳膏，规格15g:7.5mg，香港澳美制药厂，批号0911501；
试验动物：ICR小鼠，雄性，30只；
试验仪器：OLYMPUS生物显微镜。
试验方法：
30只ICR小鼠，全雄，随机分3组，每组10只，分空白乳膏基质组、阳性药卤米松软膏组和1％埃克替尼盐酸盐乳膏组，尾部皮肤涂抹药物。每次给药前用棉签和清水轻轻擦净鼠尾，每次涂抹一薄层于不同组别的小鼠尾部，每日2次，连续14天。用药结束后处死小鼠，取距鼠尾根1～2cm处大小约1.5cm×0.2cm的皮肤，4％甲醛固定、石蜡包埋、切片、HE染色。
光镜下观察鼠尾皮肤角化层、颗粒层、棘细胞层、基底细胞层、真皮层和毛囊等变化。凡是两个相邻的毛囊间表皮(即鳞片表皮)具有连续的颗粒层细胞者称为有颗粒层的鳞片，每只动物观察50个鳞片，并计算有颗粒层形成的鳞片数(SG)，数据见表A。
表A：不同药物对小鼠尾表皮分化(颗粒层形成)的影响
组别 N SG/50
空白乳膏基质组 10 2.2±1.4
卤米松软膏组 10 3.6±2.0
1％埃克替尼盐酸盐乳膏制剂组 10 7.8±4.1**
注：与空白基质组比较，**P<0.01
由表A可以看出：与空白基质组相比较，埃克替尼盐酸盐乳膏制剂能够显著促进小鼠尾部鳞片颗粒层形成，并且作用强于阳性对照卤米松组。
实施例B.埃克替尼盐酸盐凝胶制剂对鼠尾表皮颗粒层形成的影响试验
试验材料：
试验药物：埃克替尼盐酸盐凝胶制剂：规格1g/100ml(1％)；规格1.5g/100ml(1.5％)；
空白凝胶基质组：取不含活性组分(埃克替尼盐酸盐)，其他各成分同试验药物；
阳性对照药：丙酸氯倍他索乳膏，规格10g：2mg(0.02％)，广东顺峰药业有限公司，批号20110304；
试验动物：ICR小鼠，雄性，40只；
试验仪器：生物显微镜。
试验方法：
40只ICR小鼠，全雄，随机分4组。其中空白凝胶基质组、1％埃克替尼盐酸盐凝胶组、1.5％埃克替尼盐酸盐凝胶组、阳性药丙酸氯倍他索乳膏组，每组10只。尾部皮肤涂抹药物，每次给药前用棉签和清水轻轻擦净鼠尾，每次涂抹一薄层于不同组别的小鼠尾部。每日给药2次，连续14天。用药结束后处死小鼠，取距鼠尾根1～2cm处大小约1.5cm×0.2cm的皮肤，4％中性甲醛固定、石蜡包埋、切片、HE染色。
光镜下观察鼠尾皮肤角化层、颗粒层、棘细胞层、基底细胞层、真皮层和毛囊等变化。凡是两个相邻的毛囊间表皮(即鳞片表皮)具有连续的颗粒层细胞者称为有颗粒层的鳞片，每只动物观察并计算有颗粒层形成的鳞片数占总鳞片数的比值，数据见表B。
表B不同药物对小鼠尾表皮分化(颗粒层形成)的影响
组别 N 比值％
空白凝胶基质组 10 4.8±3.2
1％埃克替尼盐酸盐凝胶组 10 11.1±3.9**
1.5％埃克替尼盐酸盐凝胶组 10 13.2±4.2**
丙酸氯倍他索乳膏 10 10.1±4.0**
注：与空白基质组比较，**P<0.01
1％埃克替尼盐酸盐凝胶组及1.5％埃克替尼盐酸盐凝胶组均有增加小鼠尾颗粒层鳞片数的作用。
实施例C.埃克替尼盐酸盐乳膏对盐酸普萘洛尔所致豚鼠耳部皮肤银屑样皮损模型的影响试验
试验材料：
试验药物：埃克替尼盐酸盐乳膏制剂：规格1g/100ml(1％)；规格2g/100ml(2％)；规格4g/100ml(4％)；
空白乳膏基质组：取不含活性组分(埃克替尼盐酸盐)，其他各成分同试验药物；
阳性对照药：卡泊三醇软膏，批号EH4129，爱尔兰利奥；
试验动物：豚鼠，250-300g，雌雄各半，70只；
试验仪器：生物显微镜。
试验方法：
5％普奈洛尔搽剂：取盐酸普萘洛尔5g溶于适量50％的乙醇中，加入月桂氮卓酮(Azone-丙二醇)5ml作为复合促进剂，加入聚乙烯吡咯烷酮(PVP-K30)5g为成膜材料，最后加入50％的乙醇液使成100ml，搅匀即得。
健康成年豚鼠70只，随机选取10只(雌雄各半)作为正常对照组，其余豚鼠用5％盐酸普萘洛尔乳搽剂涂抹两侧耳廓背部皮肤(80μl/耳)，每日早晚各一次，连续2周。造模结束后将模型组豚鼠随机分成6组，即模型组、空白基质组、1％埃克替尼盐酸盐乳膏组，bid.、2％埃克替尼盐酸盐乳膏组，bid.、4％埃克替尼盐酸盐乳膏组，bid.和卡泊三醇软膏组，bid.。模型组左右耳均不抹药，空白基质组左右耳均抹空白基质，给药组动物左右耳均抹 药。用药2周后，CO2麻醉处死动物，取各组别动物左右两侧耳廓皮肤中间10mm×5mm的组织，4％中性甲醛固定，石蜡包埋，HE染色。光镜下观察豚鼠耳廓皮肤角化层、颗粒层、棘细胞层、基底细胞层、真皮层等变化，100倍光镜下测量表皮层厚度，计数25×25格测微尺格数，格数×0.0212＝厚度(mm)。
光镜下观察豚鼠耳廓皮肤角化层、颗粒层、棘细胞层、基底细胞层、真皮层等变化，100倍光镜下测量表皮层厚度，计数25×25格测微尺格数，格数×0.0212＝厚度/mm，数据见表C。(注：正常对照组和2％埃克替尼盐酸盐乳膏组有一只动物死亡，模型组和卡泊三醇组有一只动物切片做得不好)
表C.埃克替尼盐酸盐乳膏对豚鼠耳廓表皮厚度的影响
组别 组别 N 表皮厚度/mm
1 正常对照组 9 0.0538±0.0050ΔΔ
2 模型组 9 0.1457±0.0076**
3 空白基质组 10 0.1505±0.0179**
4 1％埃克替尼盐酸盐乳膏组,bid 10 0.0969±0.0130**ΔΔ
5 2％埃克替尼盐酸盐乳膏组,bid 9 0.0904±0.0151**ΔΔ
6 4％埃克替尼盐酸盐乳膏组,bid 10 0.0802±0.0199**ΔΔ
7 卡泊三醇软膏组,bid 9 0.1266±0.0256**ΔΔ
注：**P<0.01，vs.正常对照组，ΔΔP<0.01，vs.空白基质组，所有数据(Mean±SD)采用SPSS17.0进行单因素方差分析。
P值：
组2 vs.组3＝0.560；组2 vs.组4＝0.000；组2 vs.组5＝0.000；组2 vs.组6＝0.000；组2 vs.组7＝0.008；
组3 vs.组4＝0.000；组3 vs.组5＝0.000；组3 vs.组6＝0.000；组3 vs.组7＝0.001；
组4 vs.组5＝0.250；组4 vs.组6＝0.003；组4 vs.组7＝0.000；
组5 vs.组6＝0.075；组5 vs.组7＝0.000。
造模1周后，耳部毛发脱落，局部皮肤红肿，并覆有少量细小银白色鳞屑，造模1-2周期间，豚鼠耳廓出现糜烂及结痂，脱皮，而对照组动物双耳正常。给药2周后，模型组与给药组动物双耳皮肤糜烂脱皮等改善，埃克替尼盐酸盐乳膏给药组耳表面见新生毛发，而模型组未见新生毛发。
光镜下观察，正常对照组表皮角质层完整匀质，颗粒层单层线状，基底层为单层柱状细胞，真表皮交界呈波浪形，毛细血管无充血，结构正常；模型组角化层角化不全或过度，棘细胞层变厚，表皮突延伸呈棒状，真皮乳头向上伸呈杆状变，耳部表皮厚度较正常对照 组明显增加(P<0.01)。
1％，2％和4％埃克替尼盐酸盐乳膏给药后，角化过度或不全减轻，棘层变薄，表皮突延伸、乳头上伸明显减轻，表皮厚度较模型组明显减小(P<0.01)，
2％的乳膏组与1％的乳膏组比较，表皮厚度的减小未见显著性差异(P＝0.250)，4％的乳膏组与1％的乳膏组比较，表皮厚度明显减小(P<0.01)。
上述实施例仅为充分说明本发明而列举的具体实施例，本发明的保护范围以权利要求书的内容为准，而不限于上述具体实施方式。本领域的技术人员在本发明基础上所作的不脱离本发明实质内容的等同替代或变换，亦均在本发明的保护范围之内。

Claims (51)

  1. 一种皮肤外用药物组合物，包括抑制酪氨酸激酶的活性成分和外用制剂的辅料，其特征在于，所述活性成分为埃克替尼或其药学上可接受的盐，所述辅料包括分散介质、乳化剂和/或其他药学上可接受的外用制剂的辅料中的一种或几种。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述活性成分为埃克替尼游离碱、埃克替尼盐酸盐、埃克替尼马来酸盐或埃克替尼磷酸盐。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，所述活性成分的含量为0.1-11质量％。
  4. 根据权利要求1-3任一项所述的药物组合物，其特征在于，所述活性成分的含量为0.3-5质量％。
  5. 根据权利要求1-4任一项所述的药物组合物，其特征在于，所述活性成分的含量为0.9-4.3质量％。
  6. 根据权利要求1-5任一项所述的药物组合物，其特征在于，所述分散介质分为水溶性基质和/或油性基质。
  7. 根据权利要求6所述的药物组合物，其特征在于，所述水溶性基质包括水、甘油、明胶、乙醇、聚乙二醇、丙二醇、DMSO和/或纤维素衍生物。
  8. 根据权利要求6或7所述的药物组合物，其特征在于，所述水溶性基质的含量为40-100质量％。
  9. 根据权利要求6-8任一项所述的药物组合物，其特征在于，所述水溶性基质的含量为65-85质量％。
  10. 根据权利要求6所述的药物组合物，其特征在于，所述油性基质包括烃类基质、油脂类基质、类脂类基质和/或有机硅氧化物的聚合物。
  11. 根据权利要求10所述的药物组合物，其特征在于，所述烃类基质包括十六醇、十八醇和/或液状石蜡；所述油脂类基质包括大豆油、蓖麻油、单、双硬脂酸甘油酯和/或凡士林；所述类脂类基质包括羊毛脂和/或蜂蜡；所述有机硅氧化物的聚合物为二甲基硅氧烷的聚合物。
  12. 根据权利要求10或11所述的药物组合物，其特征在于，所述油性基质的含量为0-25质量％。
  13. 根据权利要求10-12任一项所述的药物组合物，其特征在于，所述油性基质的含量为9-11质量％。
  14. 根据权利要求1-13任一项所述的药物组合物，其特征在于，所述乳化剂为阴离子型乳化剂和/或非离子型乳化剂。
  15. 根据权利要求14所述的药物组合物，其特征在于，所述阴离子型乳化剂为一价皂类和/或脂肪醇硫酸酯类；所述非离子型乳化剂为高级脂肪酸多元醇酯、聚乙二醇脂肪酸酯和/或聚氧乙烯醚衍生物。
  16. 根据权利要求15所述的药物组合物，其特征在于，所述一价皂类为硬脂酸钠；所述脂肪醇硫酸酯类为十二烷基硫酸钠和/或十六烷基硫酸钠；所述高级脂肪酸多元醇酯为十六醇、十八醇、硬脂酸单甘脂、泊洛沙姆、聚山梨酯-80、聚山梨酯-60和/或聚山梨酯-85；所述聚氧乙烯醚衍生物为平平加O；所述聚乙二醇脂肪酸酯为聚乙二醇-7-硬脂酸酯和/或油酸聚乙二醇甘油酯。
  17. 根据权利要求1-16任一项所述的药物组合物，其特征在于，所述乳化剂的含量为0-23质量％。
  18. 根据权利要求1-17任一项所述的药物组合物，其特征在于，所述乳化剂的含量为10-15质量％
  19. 根据权利要求1-18任一项所述的药物组合物，其特征在于，所述其他药学上可接受的外用制剂的辅料为助悬剂。
  20. 根据权利要求19所述的药物组合物，其特征在于，所述助悬剂为高分子助悬剂。
  21. 根据权利要求20所述的药物组合物，其特征在于，所述高分子助悬剂为卡波姆、聚乙烯吡咯烷酮、葡聚糖、羧甲基纤维素钠、羟丙基甲基纤维素和/或甲基纤维素。
  22. 根据权利要求19-21任一项所述的药物组合物，其特征在于，所述助悬剂的含量为0-8.5质量％。
  23. 根据权利要求19-22任一项所述的药物组合物，其特征在于，所述助悬剂的含量为0-0.1质量％。
  24. 根据权利要求1-23任一项所述的药物组合物，其特征在于，所述其他药学上可接受的外用制剂的辅料为pH调节剂。
  25. 根据权利要求24所述的药物组合物，其特征在于，所述pH调节剂为碱、酸和/或缓冲溶液。
  26. 根据权利要求25所述的药物组合物，其特征在于，所述碱选自氢氧化钠、氢氧化钾和/或氢氧化铵；所述缓冲溶液选自由弱碱和弱酸组成的缓冲对。
  27. 根据权利要求26所述的药物组合物，其特征在于，所述弱酸选自柠檬酸、邻苯二 甲酸氢钾和/或醋酸；所述弱碱选自三乙醇胺、二乙醇胺、磷酸氢二钠、磷酸二氢钠、柠檬酸钠和/或醋酸钠。
  28. 根据权利要求24-27任一项所述的药物组合物，其特征在于，所述pH调节剂的含量为0-12.8质量％。
  29. 根据权利要求24-28任一项所述的药物组合物，其特征在于，所述pH调节剂的含量为0.2-1.5质量％。
  30. 根据权利要求1-29任一项所述的药物组合物，其特征在于，所述其他药学上可接受的外用制剂的辅料为防腐剂。
  31. 根据权利要求30所述的药物组合物，其特征在于，所述防腐剂选自对羟基苯甲酸脂类和/或山梨酸及其盐类。
  32. 根据权利要求30或31所述的药物组合物，其特征在于，所述防腐剂选自尼泊金乙酯、羟苯甲酯、羟苯丙酯、山梨酸、山梨酸钾、氯甲酚和/或三氯叔丁醇。
  33. 根据权利要求30-32任一项所述的药物组合物，其特征在于，所述防腐剂的含量为0-0.3质量％.
  34. 根据权利要求1-33任一项所述的药物组合物，其特征在于，所述其他药学上可接受的外用制剂的辅料为透皮吸收促进剂。
  35. 根据权利要求34所述的药物组合物，其特征在于，所述透皮吸收促进剂选自Transcutol P和/或Labrasol。
  36. 根据权利要求34或35所述的药物组合物，其特征在于，所述透皮吸收促进剂的含量为0-45质量％.
  37. 根据权利要求34-36任一项所述的药物组合物，其特征在于，所述透皮吸收促进剂的含量为15-30质量％.
  38. 根据权利要求1-37任一项所述的药物组合物，其特征在于，所述药物组合物为软膏剂。
  39. 根据权利要求38所述的药物组合物，其特征在于，所述软膏剂为乳膏。
  40. 根据权利要求1-37任一项所述的药物组合物，其特征在于，所述药物组合物为凝胶剂。
  41. 根据权利要求40所述的药物组合物，其特征在于，所述凝胶剂为透明凝胶剂。
  42. 权利要求1-41任一项所述的药物组合物用于制备治疗非恶性过度性增生病症或肿瘤及其并发症的药物的应用。
  43. 根据权利要求42所述的应用，其特征在于，所述非恶性过度性增生病症是良性皮肤增生。
  44. 根据权利要求42或43所述的应用，其特征在于，所述非恶性过度性增生病症是皮肤病。
  45. 根据权利要求44所述的应用，其特征在于，所述皮肤病包括银屑病、硬皮病和/或糖尿病所致的皮肤病。
  46. 根据权利要求44或45所述的应用，其特征在于，所述皮肤病为银屑病。
  47. 根据权利要求42所述的应用，其特征在于，所述肿瘤及其并发症为皮肤肿瘤及其并发症。
  48. 一种治疗哺乳动物的组织过度增生疾病的方法，包括对患有组织过度增生疾病的患者施用治疗有效量的权利要求1-41任一项所述的药物组合物。
  49. 根据权利要求48所述的治疗哺乳动物的组织过度增生疾病的方法，其特征在于，所述组织过度增生疾病为皮肤病或皮肤肿瘤及其并发症。
  50. 根据权利要求49所述的治疗哺乳动物的组织过度增生疾病的方法，其特征在于，所述皮肤病为银屑病、硬皮病和/或糖尿病所致的皮肤病。
  51. 根据权利要求49或50所述的治疗哺乳动物的组织过度增生疾病的方法，其特征在于，所述皮肤病为银屑病。
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