WO2022022434A1 - Composition pharmaceutique et préparation contenant un sel pharmaceutiquement acceptable de tofacitinib et son utilisation - Google Patents

Composition pharmaceutique et préparation contenant un sel pharmaceutiquement acceptable de tofacitinib et son utilisation Download PDF

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WO2022022434A1
WO2022022434A1 PCT/CN2021/108320 CN2021108320W WO2022022434A1 WO 2022022434 A1 WO2022022434 A1 WO 2022022434A1 CN 2021108320 W CN2021108320 W CN 2021108320W WO 2022022434 A1 WO2022022434 A1 WO 2022022434A1
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tofacitinib
pharmaceutical composition
composition according
pharmaceutically acceptable
tartrate
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PCT/CN2021/108320
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English (en)
Chinese (zh)
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周星露
钟诗春
朱建荣
胡苗
罗文华
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杭州和正医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the invention belongs to the technical field of research and development of pharmaceutical compositions, in particular to a pharmaceutical composition, preparation and application containing a pharmaceutically acceptable salt of tofacitinib.
  • Tofacitinib chemical name is 3- ⁇ (3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino] Piperidin-1-yl ⁇ -3-oxopropionitrile:
  • Tofacitinib is a JAK inhibitor indicated for organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, type 1 diabetes and other types of diabetes, cancer, Asthma, Atopic Dermatitis (also known as atopic dermatitis), autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications requiring immunosuppression of immunosuppressive therapy.
  • Tofacitinib citrate is currently approved in the United States. Sold in tablet form, each tablet contains 8 mg of tofacitinib citrate twice daily for the treatment of rheumatoid arthritis, among others. Current studies have shown that oral tofacitinib citrate has many side effects. Such as upper respiratory tract infection, cold, headache and other symptoms. At present, the academic community has proposed to use topical preparations to avoid the side effects caused by oral administration. For example, patent document CN103459394B discloses that an ointment made from free state tofacitinib is used for the treatment of psoriasis.
  • Patent document TW201940174A discloses a topical formulation made of tofacitinib citrate for the treatment of vitiligo and atopic dermatitis.
  • Patent document CN103459394B proposes to use free state tofacitinib to make ointment.
  • free state tofacitinib has poor stability, and the purity is only 97.3% when stored at 40° C. for 4 weeks.
  • dimethyl sulfoxide is used as the solvent of its bulk drug, and the usage amount is 45%, which is relatively large.
  • dimethyl sulfoxide has local toxicity and low systemic toxicity. Dimethyl sulfoxide mainly stimulates the skin, causing redness, burning, itching, scaling, urticaria, etc. (RC Luo, PJ Shesky, PJ Weller. Handbook of Pharmaceutical Excipients [M]. Beijing: Chemical Industry Press , 2005: 256).
  • the present invention provides a pharmaceutical composition containing a pharmaceutically acceptable salt of tofacitinib.
  • the composition has high stability, good safety, good solubility and significant anti-inflammatory effect.
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt of tofacitinib and one or more penetration enhancers comprising diethylene glycol monoethyl ether, polyglycerol fatty acid ester, lauryl nitrogen One or more or more of ketone, oleic acid, oleyl alcohol, and polyethylene glycol.
  • the pharmaceutical composition does not contain dimethyl sulfoxide.
  • the content of the penetration enhancer is 1% to 80% by weight.
  • the weight percentage of the penetration enhancer is less than 40%.
  • the weight percentage of the penetration enhancer is 1-39%; as a further preference, in the pharmaceutical composition, the weight percentage of the penetration enhancer is 1-35%;
  • the weight percent content of the penetration enhancer is 5-30%; as an optimal technical solution, in the pharmaceutical composition, the weight percent content of the penetration enhancer is 5%. ⁇ 20%; as a specific preferred solution, in the pharmaceutical composition, the content of the penetration enhancer is 5-15% by weight.
  • the penetration enhancer is diethylene glycol monoethyl ether (Transcutol). That is, preferably, the pharmaceutical composition includes a pharmaceutically acceptable salt of tofacitinib and diethylene glycol monoethyl ether.
  • the penetration enhancer is a combination of diethylene glycol monoethyl ether and one or more of lauryl azone, polyglycerol fatty acid ester, oleic acid, oleyl alcohol, and polyethylene glycol .
  • the composition includes a pharmaceutically acceptable salt of tofacitinib as well as diethylene glycol monoethyl ether and other penetration enhancers (i.e., lauryl azone, polyglycerol fatty acid esters, oleic acid, oleyl alcohol, polyethylene glycol one or more of the diols) in combination.
  • the pharmaceutically acceptable salt of tofacitinib is selected from tofacitinib tartrate, tofacitinib sulfate, and tofacitinib phosphate.
  • the pharmaceutically acceptable salt including tofacitinib is tofacitinib tartrate.
  • the pharmaceutical composition includes tofacitinib tartrate and diethylene glycol monoethyl ether; or includes tofacitinib tartrate and diethylene glycol monoethyl ether and other penetration enhancers (ie lauryl nitrogen ketone, polyglycerol fatty acid ester, oleic acid, oleyl alcohol, one or more of polyethylene glycol).
  • the weight percentage of the pharmaceutically acceptable salt of tofacitinib is 0.1% to 10%.
  • the pharmaceutical composition in terms of weight percentage, comprises 0.1%-10% of a pharmaceutically acceptable salt of tofacitinib and 1%-80% of diethylene glycol monoethyl ether.
  • the pharmaceutical composition in terms of weight percentage, comprises 0.1%-10% of a pharmaceutically acceptable salt of tofacitinib and 1%-35% of diethylene glycol monoethyl ether.
  • the weight percent content of the pharmaceutically acceptable salt of tofacitinib is 0.5% to 5%.
  • the pharmaceutical composition in terms of weight percentage, comprises 0.5%-5% tofacitinib tartrate and 1%-80% diethylene glycol monoethyl ether.
  • the pharmaceutical composition in terms of percentage by weight, comprises 0.5% to 5% of tofacitinib tartrate and 1% to 35% of diethylene glycol monoethyl ether.
  • the pharmaceutical composition in terms of percentage by weight, comprises 0.5% to 5% of tofacitinib tartrate and 5% to 30% of diethylene glycol monoethyl ether.
  • the pharmaceutical composition in terms of percentage by weight, comprises 0.5%-5% of tofacitinib tartrate and 5%-20% of diethylene glycol monoethyl ether.
  • the pharmaceutical composition in terms of weight percentage, comprises 0.5%-3% of tofacitinib tartrate and 5%-15% of diethylene glycol monoethyl ether.
  • the pharmaceutical composition further includes excipients.
  • the weight percentage of the excipients is 70% to 98.5%; the excipients at least include preservatives and emulsifiers.
  • the weight percent content of the preservative is 0.1-5%; the weight percent content of the emulsifier is 0.5-20%.
  • the emulsifier is more preferably 5 to 15%.
  • the pharmaceutical composition is made up of the following components by weight:
  • Tofacitinib pharmaceutically acceptable salt 0.1% to 10%
  • the weight percentage of the excipient is 50-98.9%; more preferably 55-98.9%; still more preferably 60-98.9%; or preferably 70-98.9%; or preferably 75 to 98.5%.
  • the excipients include solvents, diluents, antioxidants, chelating agents, emulsifiers, preservatives, antibacterial agents, opacifiers, colorants, gelling agents, flavoring agents, pH adjusters and other suitable oils One or more of substances and water-based substances.
  • the antioxidant is selected from 2,6-di-tert-butyl-4-methylphenol, butylated hydroxyanisole, butylated hydroxytoluene (BHT, 2,6-di-tert-butyl-p-cresol), Ascorbic acid (vitamin C), ascorbic acid derivatives, polyphenols, tocopherols, tocopherol derivatives, vitamin A, lutein, lycopene, sodium sulfoxylate, sodium thiosulfate, propyl gallate, lipoic acid , one or more of sulfites.
  • the mass percentage content of the antioxidant is 0.05% to 5%.
  • the pharmaceutical composition by weight percentage, comprises:
  • the stabilizer is an antioxidant-containing stabilizer or other forms of stabilizer.
  • the pharmaceutical composition comprises:
  • the balance is other penetration enhancers or/and excipients.
  • compositions of the present invention comprise: (a) a therapeutically effective amount of a pharmaceutically acceptable salt of tofacitinib; (b) diethylene glycol monoethyl ether; ( c) optionally, other penetration enhancers; (d) optionally, an emulsifier; (e) optionally, a preservative; (f) optionally, an antioxidant; (g) optionally, a or various other pharmaceutically acceptable excipients.
  • the stabilizers include, but are not limited to, antibacterial agents, preservatives, or other antioxidants.
  • compositions of the present invention comprise: (a) a therapeutically effective amount of a pharmaceutically acceptable salt of tofacitinib; (b) diethylene glycol monoethyl ether; (c) purified water ; (d) dimethicone, polyethylene glycol-7 stearate, cetyl alcohol, liquid paraffin, polyglycerol fatty acid ester; (e) optional, one or more antioxidants; (f) Optionally, one or more preservatives.
  • the composition comprises:
  • the composition comprises:
  • Stabilizers including antioxidants or other stabilizers
  • the composition comprises:
  • Dimethicone polyethylene glycol-7 stearate, cetyl alcohol, glycerin, propylene glycol, stearyl alcohol, petrolatum, sodium lauryl sulfate, liquid paraffin, polyglycerol fatty acid ester, One or more of glycerol monostearate, glyceryl distearate, triethanolamine, stearic acid, lanolin, one or more of petrolatum.
  • it includes 0.1-2% of one or more of methylparaben, propylparaben and ethylparaben.
  • the composition includes:
  • compositions of methylparaben, ethylparaben, and propylparaben 0.1 to 2% of one or more of the compositions of methylparaben, ethylparaben, and propylparaben;
  • the present invention also provides a preparation prepared from the above-mentioned pharmaceutical composition.
  • the formulations are creams, lotions, solutions (eg, liquid sprays), gels, pastes, plasters, paints.
  • the preparation is an external preparation.
  • topical formulations which may be used in the form of compositions suitable for topical application to the body surface.
  • the external preparation is a cream.
  • the present invention also provides a preparation method of the above-mentioned cream preparation, comprising:
  • Oil phase mix and dissolve the oil-soluble substances in the formulation
  • Water phase dissolve the water-soluble substances in the formulation
  • the external phase is a pharmaceutically acceptable salt of tofacitinib, a penetration enhancer (such as diethylene glycol monoethyl ether) or a combined solution of the two;
  • the composition of the external and aqueous phases may be adjusted; for example, when the pharmaceutically acceptable salt of tofacitinib is Phosphate or sulfate, which are more soluble in water, can be added as part of the aqueous phase.
  • the pharmaceutically acceptable salt of tofacitinib is tartrate, it can be directly dissolved in the penetration enhancer, and at this time, the pharmaceutically acceptable salt of tofacitinib is prepared as an external phase.
  • the present invention also provides the application of the composition of the present invention in preparing a medicine for treating and/or preventing autoimmune diseases.
  • the present invention also provides an application of the composition of the present invention in the treatment and/or prevention of autoimmune diseases.
  • the autoimmune diseases include vitiligo, alopecia areata, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, Crohn's disease, colitis, autoimmune hemolytic anemia , Ankylosing spondylitis, pemphigus, urticaria, asthma, optic neuritis, psoriasis, chronic obstructive airway disease, skin inflammation, scleroderma.
  • the autoimmune disease is preferably vitiligo, atopic dermatitis, alopecia areata, psoriasis, skin inflammation, scleroderma.
  • tofacitinib refers to tofacitinib free base or a stereoisomer or a mixture of stereoisomers thereof.
  • the tartaric acid can be L-tartaric acid, D-tartaric acid, or a racemate, or a mixture of L-tartaric acid and D-tartaric acid in any ratio.
  • the pharmaceutically acceptable salt of tofacitinib of the present invention can be obtained by reacting tofacitinib with a corresponding acid.
  • terapéuticaally effective amount refers to an amount that reduces symptoms of one or more diseases.
  • degradation product refers to harmful chemical substances or impurities that can affect the efficacy of the drug during the production or transportation and storage of the drug. It will change due to factors such as temperature, pH, humidity, light, excipients, etc.
  • the excipient When the excipient is actually used, it may have the function of a single excipient, or it may also serve as the function of other excipients. For example, for a certain emulsifier, it may only have the function of emulsifying, or it may have both The emulsifying function also has the function of dissolving or diluting at the same time, and may even have the function of antioxidant or antibacterial agent.
  • the penetration enhancer of the present invention may also function as an excipient, for example, as a solvent.
  • aqueous substances can also be used as stabilizers, and penetration enhancers can also be used as solvents or diluents.
  • the aqueous substances are preferably diethylene glycol monoethyl ether, propylene glycol, glycerin, polyethylene glycol, isopropanol, methanol, sodium pyrrolidone carboxylate, 2-hydroxypropyl- ⁇ -cyclodextrin, acetone, purified water , ethanol, propanol, butanediol, or a combination of two or more of the above compounds.
  • other excipients can also play the role of solvent reagents at the same time.
  • the chelating agent is preferably tetraacetic acid diaminoethane, succinic acid, trin's base, nitrilotriacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), diethylenetriaminepentaacetic acid, bis- (Aminoacetyl) glycol ether - one or more of N,N,N',N'-tetraacetic acid, iminodiacetic acid, citric acid, tartaric acid, and fumaric acid.
  • the emulsifier is preferably one of sodium lauryl sulfate, polyethylene glycol-7-stearate, glycerol monostearate, glyceryl distearate, triethanolamine, polyglycerol fatty acid ester or variety.
  • the added amount of the emulsifier can be adjusted according to the different types of the emulsifier, and the general added amount is between 0.5% and 20%.
  • the antimicrobial agent is preferably methylparaben, ethylparaben, propylparaben, ethylene oxide, phenol, and benzoic acid.
  • the oily bases are preferably petrolatum, lanolin, fatty alcohols, mineral oils, triglycerides and silicone oils.
  • the diluent is preferably glycerin, propylene glycol, purified water, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium lauryl sulfate, cetyl alcohol, stearyl alcohol, white petrolatum, liquid paraffin, lanolin, beeswax, Alcohol wax, stearic acid, dimethicone, polysorbate, fatty acid, oleyl alcohol, polyethylene glycol-7 stearate, water, etc. 50%w/w ⁇ 85%w/w of the total weight of the formula.
  • the above-mentioned sodium hydroxide, potassium hydroxide, and sodium bicarbonate can also serve as pH adjusters at the same time.
  • the preservatives are preferably methylparaben, ethylparaben, propylparaben, butylparaben, ethylene oxide, phenol, and benzoic acid.
  • the preservative concentration is preferably from 0.5% w/w to 5% w/w, preferably from 0.1% w/w to 1.0% w/w based on the total formulation weight.
  • the antioxidants are preferably butylated hydroxyanisole (tert-butyl-4-hydroxyanisole, BHA (including 3-BHA or 2-BHA)) and butylated hydroxytoluene (BHT) and vitamin E derivatives (such as vitamin E acetate) and vitamin C derivatives (such as vitamin C sodium). It is preferably from 0.1% w/w to 5.0% w/w based on the total weight of the formulation.
  • the pH adjusting agent is preferably a pH adjusting agent commonly used in medicine, including inorganic acids or inorganic bases, such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, and the like.
  • the added amount of the pH adjuster is to maintain the pH of the composition preferably at 6-8.
  • the salt form of tofacitinib selected in the present invention has better solubility, simplifies the preparation processing difficulty, and increases its permeability in the skin; the present invention ensures that by screening different salt forms and solvents of tofacitinib On the premise of its complete solubility, it is found that the ionic form has higher stability than free tofacitinib, which ensures the safety and good efficacy of the drug; the present invention screened out diethylene glycol monoethyl ether. Ether acts as a solvent and penetration enhancer, and is not irritating to the skin; meanwhile, the preparation prepared from the pharmaceutical composition of the present invention shows better drug exposure in the skin in the transdermal experiment, and does not increase the drug in the transdermal diffusion pool.
  • the preparation has an anti-inflammatory effect in the delayed-type hypersensitivity reaction model induced by dinitrofluorobenzene, and the preparation of the present invention can also reduce the vitiligo patient's leukoplakia area, It can be used to treat and prevent autoimmune diseases including vitiligo, alopecia areata, scleroderma, psoriasis, atopic dermatitis, etc.
  • Figure 1 Difference in mouse ear thickness
  • Embodiment 3 Tofacitinib dissolution property test of different salt forms
  • Xiaoxiang pig skin was selected as the transdermal skin to test the penetration of different formulations of tofacitinib in the skin.
  • the permeation cell is a vertical diffusion cell
  • the volume of the permeation cell is 6.5 cm
  • the area of the cell mouth is 2.2 cm 2
  • the skin is the back skin of an 8-month-old pig, and the hair is removed.
  • skins with a thickness of 1400 ⁇ m were taken for experiments. Take about 0.2g of the cream and place it on the skin of Xiaoxiang pig.
  • the sampling points are 1, 2, 4, and 6 hours. After 6 hours, the skin is removed and cut into pieces and extracted with organic solvent ultrasonic for 1 hour. After the sample is filtered, the content is determined by liquid chromatography. .
  • tofacitinib sulfate (formulation D1) and tofacitinib phosphate (formulation D2) have significantly improved skin retention/penetration, and their safety is also significantly improved compared to E1.
  • Example 1 (2) of the present invention Three batches of tofacitinib tartrate were prepared according to the method in Example 1 (2) of the present invention, and were placed under accelerated conditions (temperature: 40° C., humidity: 75%) and long-term conditions (temperature: 25° C., humidity: 65° C.) %) to measure its stability.
  • the tofacitinib tartrate prepared by the invention has an average degradation of 0.5% after 1 month under accelerated conditions, and an average degradation of 0.1% in 1 month under long-term conditions, indicating that it has good stability.
  • the samples (“Tofacitinib polyethylene glycol 400 solution in free state”, “Tofacitinib tartrate diethylene glycol monoethyl ether solution”, “Tofacitinib sulfate solution” and “Tofacitinib phosphate solution”) configuration: take 0.2 g of each of the raw materials (tofacitinib and tofacitinib tartrate), put them in a 10ml volumetric flask, and add 10ml of the corresponding dissolution medium (corresponding to tofacitinib tartrate) In diethylene glycol monoethyl ether, tofacitinib corresponds to PEG400, tofacitinib phosphate and tofacitinib sulfate correspond to purified water), heat and dissolve at 60°C.
  • Example 15 in the CN 103459394 B patent document as a comparative example, and compare the cream samples B3, B4, B5, B13, D1, D2, E2 (see Example 2) of the present invention with the comparative example at 40 ° C, 75% Percentage reduction in formulation purity after 2 and 4 weeks of exposure.
  • the stability of the pharmaceutically acceptable salt of tofacitinib of the present invention is significantly higher than that of the free state.
  • the formulation prepared from the pharmaceutically acceptable salt of tofacitinib is placed at 40°C for 1 month, The stability is high, no obvious degradation occurs, and the purity is above 99.2%.
  • the purity of free body tofacitinib cream (formulation B5) is only 95.4%, and the comparative proportion in patent CN103459394B is only 97.3%. (refer to CN103459394B embodiment).
  • Tofacitinib tartrate prepared in Example 5 was selected, and the cream was prepared according to the C1 prescription and batch 1kg. The finished creams were taken and placed under long-term conditions (25° C., 65%) to measure their stability.
  • mice Fifteen 6-8 week old female BALB/c mice were divided into three groups, A, B and C, with 5 mice in each group. Among them, group A is the control group, group B is the administration group, and group C is the modeling positive group
  • Groups B and C were uniformly coated with 20 ⁇ L of 5g/L DNFB (2,4-dinitrofluorobenzene) solution (solvent is acetone-olive oil with a volume ratio of 4:1) 10 ⁇ L within a range of 1 cm ⁇ 1 cm, once a day, For 2 consecutive days, group A only applied acetone-olive oil.
  • group B received topical tofacitinib tartrate cream (prescription B3 in Example 2) every day since the first DNFB sensitization.
  • Example 12 Clinical trial of topical formulation of tofacitinib tartrate in the treatment of vitiligo
  • a randomized, double-blind, placebo-controlled clinical trial was conducted to determine the efficacy of topical tofacitinib tartrate formulations of the present invention for 8 weeks in vitiligo patients.
  • the trial recruited 20 patients, and after randomization, they were respectively given a placebo (blank cream without tofacitinib tartrate) and the prescription B3 of the present invention at a dosage of about 3 mg/cm 2 twice a day. All patients were assessed for clinical improvement at baseline and monthly and photographed.
  • Fig. 3 shows the curative effect of smearing the cream of the present invention at the neck of a female patient A for 4 weeks, 8 weeks and 12 weeks, compared with the benchmark, the vanished area of leukoplakia accounted for 80% of the original leukoplakia area at 8 weeks, and at 12 weeks, Vitiligo basically disappeared.
  • Figure 4 shows the curative effect of a male patient B smearing the cream of the present invention on the forehead after 5 months. Compared with the benchmark, the vanishing area of leukoplakia accounts for 90% of the original leukoplakia area.
  • Figure 5 shows the curative effect of a male patient C smearing the cream of the present invention on the lower jaw of the face for 4 weeks and 8 weeks. Compared with the benchmark, the leukoplakia completely disappeared after 8 weeks.
  • Example 13 Clinical trial of topical formulation of tofacitinib tartrate in the treatment of atopic dermatitis
  • a clinical trial was conducted to determine the efficacy of topical tofacitinib tartrate formulations of the present invention in patients with atopic dermatitis.
  • the trial recruited 6 patients and was given prescription B3 of the present invention at a dose of about 3 mg/cm 2 twice daily. All patients were assessed for clinical improvement at baseline and every 2 weeks.
  • Figure 6 shows a male patient with atopic dermatitis, D, with a systemic rash with itching and skin lesions.
  • the disease course lasted for more than 3 months and gradually worsened.
  • the skin lesions faded, scabs began to form in an all-round way, and recovered.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique, comprenant un sel pharmaceutiquement acceptable de tofacitinib et un activateur de pénétration, et son utilisation dans la préparation d'un médicament pour le traitement et/ou la prévention de maladies auto-immunes. L'activateur de pénétration peut être l'éther monoéthylique de diéthylèneglycol et les maladies auto-immunes comprennent le vitiligo, la pelade, la sclérodermie, le psoriasis, la dermatite atopique, etc.
PCT/CN2021/108320 2020-07-27 2021-07-26 Composition pharmaceutique et préparation contenant un sel pharmaceutiquement acceptable de tofacitinib et son utilisation WO2022022434A1 (fr)

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CN115192522A (zh) * 2022-08-24 2022-10-18 烟台慧暄医药科技有限公司 一种含有伊布替尼的组合物及其制备方法和应用
CN116019762A (zh) * 2022-09-19 2023-04-28 厦门大学 一种用于治疗银屑病的药物组合物、制备方法和用途
CN115887464B (zh) * 2022-10-25 2024-02-02 湖北工业大学 枸橼酸托法替尼碳酸钙脂质纳米喷雾剂及其制备方法与应用
CN116983312A (zh) * 2023-05-24 2023-11-03 凌科药业(杭州)有限公司 一种药物组合物、外用制剂及其制备方法、应用
CN116942602B (zh) * 2023-09-20 2023-12-22 北京普祺医药科技股份有限公司 一种枸橼酸托法替布药物组合物

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