WO2019096303A1 - 一种局部给药的药物组合物及其制备方法 - Google Patents

一种局部给药的药物组合物及其制备方法 Download PDF

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WO2019096303A1
WO2019096303A1 PCT/CN2018/116197 CN2018116197W WO2019096303A1 WO 2019096303 A1 WO2019096303 A1 WO 2019096303A1 CN 2018116197 W CN2018116197 W CN 2018116197W WO 2019096303 A1 WO2019096303 A1 WO 2019096303A1
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pharmaceutical composition
weight
polyethylene glycol
composition according
active ingredient
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PCT/CN2018/116197
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English (en)
French (fr)
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奚宏磊
蒋秋冬
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江苏恒瑞医药股份有限公司
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Priority to JP2020545425A priority Critical patent/JP2021503505A/ja
Priority to US16/765,227 priority patent/US11241378B2/en
Priority to EP18878378.1A priority patent/EP3714887A4/en
Priority to CN201880047607.1A priority patent/CN110913862B/zh
Publication of WO2019096303A1 publication Critical patent/WO2019096303A1/zh

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    • 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
    • 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
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrole) And [2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, and a pharmaceutical combination of diethylene glycol monoethyl ether Things.
  • Psoriasis is a common, persistent and recurrent chronic non-infectious inflammatory skin disease characterized by hyperproliferation of the epidermis.
  • the total prevalence rate in China is about 0.4%, and the incidence rate in European and American countries is as high as 2% to 3%.
  • There is no gender difference in the disease and about one-third of patients have a family history.
  • the incidence of psoriasis vulgaris accounts for more than 95% of psoriasis.
  • the main purpose of traditional therapeutic drugs is to inhibit epidermal hyperplasia and anti-inflammatory, and the therapeutic drugs include methotrexate and hydroxyurea.
  • TNF- ⁇ tumor necrosis factor alpha
  • PDE4 phosphodiesterase 4
  • Janus kinase JAK and interleukin. Its receptor (IL & ILR) and so on.
  • Janus kinase JAK is a non-receptor tyrosine kinase involved in the signaling of a variety of cytokines and is critical for the cytokine-mediated JAK-signaling and transcriptional activator (JAK/ATART) pathway.
  • a variety of cytokines, including hematopoiesis, inflammatory responses, and other cytokines play a key role in biological processes. Therefore, inhibition of JAK may have a therapeutic effect on psoriasis.
  • the external JAK inhibitors studied at home and abroad include: Ruxolitinib phosphate cream and tofacitinib ointment.
  • CN104470927B discloses a JAK inhibitor compound (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrole) And [2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, has good activity and has the following structure:
  • the key to the success of local treatment of skin diseases is not only that the drug reaches the lesion through the stratum corneum, but also needs to maintain a period of efficacy.
  • (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d] Pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof is not potent in the skin barrier and retained in the skin, and is prepared as a pharmaceutical combination There is a risk of uneven content.
  • the present invention provides a pharmaceutical composition containing a JAK inhibitor and a preparation process thereof, which solve the above problems.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the active ingredient (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(A (7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, and diethylene glycol Monoethyl ether.
  • the diethylene glycol monoethyl ether content is from 0.5 to 20% by weight based on the total weight of the pharmaceutical composition, and may be 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5. %, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0% 18.5%, 19.0%, 19.5% or 20.0%, preferably 1 to 10%.
  • the pharmaceutical composition of the present invention may further comprise a matrix, which may be a water-soluble matrix, preferably a polyethylene glycol-based polymer compound, and the polyethylene glycol-based polymer compound may have an average molecular weight of 100 to 6000.
  • the average molecular weight may be 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900 or 6000.
  • the substrate may be polyethylene glycol 400 and polyethylene glycol 4000, and the weight ratio of the polyethylene glycol 400 to the polyethylene glycol 4000 is 1:10 to 10:1, preferably 1:5 ⁇ 5:1, to adjust the ointment to achieve the appropriate viscosity and spreadability, and to ensure the content uniformity of the active ingredients.
  • the matrix content is 40 to 90%, based on the total weight of the pharmaceutical composition, and may be 40.0%, 40.5%, 41.0%, 41.5%, 42.0%, 42.5%, 43.0%. , 43.5%, 44.0%, 44.5%, 45.0%, 45.5%, 46.0%, 46.5%, 47.0%, 47.5%, 48.0%, 48.5%, 49.0%, 49.5%, 50.0%, 50.5%, 51.0%, 51.5 %, 52.0%, 52.5%, 53.0%, 53.5%, 54.0%, 54.5%, 55.0%, 55.5%, 56.0%, 56.5%, 57.0%, 57.5%, 58.0%, 58.5%, 59.0%, 59.5%, 60.0%, 60.5%, 61.0%, 61.5%, 62.0%, 62.5%, 63.0%, 63.0%, 63.5%, 64.0%, 64.5%, 65.0%, 65.5%, 66.
  • the active ingredient of the present invention is present in an amount of from about 0.1% to about 20%, based on the total weight of the pharmaceutical composition, and may be 0.10%, 0.16%, 0.21%, 0.26%, 0.31%, 0.36%, 0.41.
  • At least one of phenylmercury, phenol, cresol and benzalkonium chloride preferably the preservative is 0.05 to 0.5% by weight based on the total weight of the pharmaceutical composition, and may be 0.05%, 0.06%, 0.07%, 0.08% , 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25 %, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49% or 0.50%.
  • the antioxidant of the present invention is known or identifiable by those skilled in the art, and is selected from, but not limited to, at least one of butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate and tocopherol, preferably
  • the anti-oxygen content is 0.05 to 0.5% by weight based on the total weight of the pharmaceutical composition, and may be 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14.
  • the pharmaceutical composition comprises:
  • a water-soluble substrate preferably polyethylene glycol 400 and polyethylene glycol 4000.
  • the pharmaceutical composition comprises:
  • a water-soluble substrate preferably a polyethylene glycol 400 and a polyethylene glycol 4000
  • a humectant preferably hydroxybenzyl ester, hydroxyphenylethyl ester, benzoic acid, sorbic acid, phenoxyethanol, chlorobutanol, phenylmercuric acetate, phenol, A At least one of phenol and benzalkonium chloride.
  • the active ingredient has a particle diameter of not more than 50 ⁇ m, and may be 50, 48, 46, 44, 42, 40, 38, 36, 34, 32, 30, 28, 26, 24, 22 20, 18, 16, 14, 12, 10, 8, 6, 4 or 2 ⁇ m, preferably not more than 30 ⁇ m, more preferably not more than 20 ⁇ m.
  • the invention also provides a method of preparing the aforementioned pharmaceutical composition, the method comprising:
  • the invention also provides the use of a pharmaceutical composition as described above for the manufacture of a medicament for the treatment or prevention of a disorder or disease of the immune system.
  • a pharmaceutical composition as described above for the manufacture of a medicament for treating a skin disorder.
  • W i is the molar mass M i is the mass fraction accounted fraction
  • N i M i is the molar mass fraction mole fraction
  • the pharmaceutical adjuvant or reagent of the present invention may be derived from a commercial route such as diethylene glycol monoethyl ether; the compound (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazole- 5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide can be referred to CN103415520B Medium method preparation.
  • the active ingredient (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide was slowly added to propylene glycol, respectively, with polyethylene glycol glyceride caprylate, diethylene glycol monoethyl ether Mixing with isopropyl myristate; adding polyethylene glycol 400 (PEG400), polyethylene glycol 4000 (PEG4000), glycerin, dibutylhydroxytoluene (BHT), stirring and dissolving, and quenching.
  • PEG400 polyethylene glycol 400
  • PEG4000 polyethylene glycol 4000
  • BHT dibutylhydroxytoluene
  • Preparation of isolated skin The skin of the same part of Bama pig was selected as the experimental model, the pig hair was shaved, the excess fat under the skin was peeled off, washed with PBS, and stored at -70 ° C for use.
  • the residual active ingredient in the supply chamber is collected by a cotton swab wiping method, the active ingredient in the stratum corneum is collected by a tape stripping method, and the remaining skin is chopped to collect the active ingredient, and the above three active ingredient samples are dissolved and fixed in a suitable solvent.
  • the active ingredient content was determined by HPLC and the recovery was calculated.
  • the content of the active ingredient in the supply chamber is referred to as the residual amount, and the content of the active ingredient in the stratum corneum and the skin is referred to as the retention of the stratum corneum and the retention of the epidermis, respectively, and the cumulative permeation of the active ingredient in the receiving chamber is referred to as the permeate amount.
  • the above test was carried out in parallel with 12 parts, and the results are shown in Table 2.
  • total skin retention stratum corneum retention + epidermal retention
  • promotion ratio refers to the ratio of the total skin retention of the skin containing the penetration enhancer to the total skin retention without the penetration enhancer.
  • Example 2 The above data shows that the total retention of the active ingredient in the skin in Example 2 is the largest, and the promotion ratio is optimal, indicating that diethylene glycol monoethyl ether can better promote the transdermal absorption of the active ingredient.
  • Example 2 The stability of the sample obtained in Example 2 was investigated under accelerated conditions (30 ° C ⁇ 2 ° C / RH 65% ⁇ 5%) and long-term conditions (25 ° C ⁇ 2 ° C / RH 60% ⁇ 5%). Evaluation of traits, content, viscosity, and related substances, wherein the viscosity measurement method was determined by the Chinese Pharmacopoeia 2015 edition four general rules 0893 cone penetration measurement method. The results are shown in Table 5.

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Abstract

本发明涉及一种局部给药的药物组合物及其制备方法。具体而言，本发明涉及一种含有(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，和二乙二醇单乙醚的药物组合物。

Description

一种局部给药的药物组合物及其制备方法
本申请要求申请日为2017年11月20日的中国专利申请CN201711160777.4的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物制剂领域，具体涉及(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，和二乙二醇单乙醚的药物组合物。
背景技术
银屑病是一种常见的以表皮过度增生为特征的顽固且易复发的慢性非感染性炎症性皮肤病。在我国总患病率约为0.4％，在欧美国家的发病率高达2％～3％，该病无性别差异，且约1/3的患者具有家族遗传史。其中，寻常型银屑病的发病率占银屑病的95％以上。由于银屑病早起临床主要表现为表皮的过度增生，传统治疗药物主要目的是抑制表皮增生和抗炎，治疗药物包括甲氨蝶呤和羟基脲等。随着银屑病分子机制研究的不断深入，银屑病新药研发的靶点多样化，包括了肿瘤坏死因子α(TNF-α)、磷酸二酯酶4(PDE4)、Janus激酶JAK和白介素及其受体(IL&ILR)等。
Janus激酶JAK是一种非受体型酪氨酸激酶，参与多种细胞因子的信号传导，是细胞因子介导生物效应的JAK-信号传导及转录激活因子(JAK/ATART)通路的关键，在包括造血、炎症反应等多种细胞因子介导生物进程中均发挥关键作用。因此，抑制JAK可能对银屑病起到治疗作用。目前国内外在研的外用JAK抑制剂包括：Ruxolitinib磷酸盐乳膏、托法替尼软膏。
CN104470927B公开了一种JAK抑制剂化合物(3aR,5s,6aS)-N-(3-甲氧基 -1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，具有良好的活性，具有如下结构：
Figure PCTCN2018116197-appb-000001
通过局部给药方式治疗皮肤疾病成功的关键不仅在于药物透过角质层达到病变部位，而且需要维持一段药效时间。而(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐透过皮肤屏障并滞留于皮肤中的能力不强，且制备成药物组合物存在含量不均匀的风险。本发明提供一种含有JAK抑制剂的药物组合物及其制备工艺，解决上述问题。
发明内容
本发明提供了一种药物组合物，其含有活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，和二乙二醇单乙醚。
在可选实施方案中，所述二乙二醇单乙醚含量以药物组合物总重量计为0.5～20％，可以为0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.5％、2.0％、2.5％、3.0％、3.5％、4.0％、4.5％、5.0％、5.5％、6.0％、6.5％、7.0％、7.5％、8.0％、8.5％、9.0％、9.5％、10.0％、10.5％、11.0％、11.5％、12.0％、12.5％、13.0％、13.5％、14.0％、14.5％、15.0％、15.5％、16.0％、16.5％、17.0％、17.5％、18.0％、18.5％、19.0％、19.5％或20.0％，优选为1～10％。
本发明所述药物组合物还可以含有基质，所述基质可以为水溶性基质，优选为聚乙二醇类高分子化合物，所述聚乙二醇类高分子化合物的平均分子 量可以为100～6000，在可选实施例中，平均分子量可以为100、200、300、400、500、600、700、800、900、1000、1100、1200、1300、1400、1500、1600、1700、1800、1900、2000、2100、2200、2300、2400、2500、2600、2700、2800、2900、3000、3100、3200、3300、3400、3500、3600、3700、3800、3900、4000、4100、4200、4300、4400、4500、4600、4700、4800、4900、5000、5100、5200、5300、5400、5500、5600、5700、5800、5900或6000。
在优选实施方案中，所述基质可以为聚乙二醇400和聚乙二醇4000，所述聚乙二醇400与聚乙二醇4000的重量比为1:10～10:1，优选为1:5～5:1，以调节软膏达到适宜粘度和涂展性，以及保证活性成分的含量均匀度。
进一步地，在可选实施方案中，基于药物组合物总重量计，所述基质含量为40～90％，可以为40.0％、40.5％、41.0％、41.5％、42.0％、42.5％、43.0％、43.5％、44.0％、44.5％、45.0％、45.5％、46.0％、46.5％、47.0％、47.5％、48.0％、48.5％、49.0％、49.5％、50.0％、50.5％、51.0％、51.5％、52.0％、52.5％、53.0％、53.5％、54.0％、54.5％、55.0％、55.5％、56.0％、56.5％、57.0％、57.5％、58.0％、58.5％、59.0％、59.5％、60.0％、60.5％、61.0％、61.5％、62.0％、62.5％、63.0％、63.5％、64.0％、64.5％、65.0％、65.5％、66.0％、66.5％、67.0％、67.5％、68.0％、68.5％、69.0％、69.5％、70.0％、70.5％、71.0％、71.5％、72.0％、72.5％、73.0％、73.5％、74.0％、74.5％、75.0％、75.5％、76.0％、76.5％、77.0％、77.5％、78.0％、78.5％、79.0％、79.5％、80.0％、80.5％、81.0％、81.5％、82.0％、82.5％、83.0％、83.5％、84.0％、84.5％、85.0％、85.5％、86.0％、86.5％、87.0％、87.5％、88.0％、88.5％、89.0％、89.5％或90.0％、优选为50～80％。
在可选实施方案中，基于药物组合物总重量计，本发明所述活性成分的含量约0.1～20％，可以为0.10％、0.16％、0.21％、0.26％、0.31％、0.36％、0.41％、0.46％、0.51％、0.56％、0.61％、0.66％、0.71％、0.76％、0.81％、0.86％、0.91％、0.96％、0.41％、0.43％、0.45％、0.47％、0.49％、0.51％、0.53％、0.55％、 0.57％、0.59％、0.61％、0.63％、0.65％、0.67％、0.69％、0.71％、0.73％、0.75％、0.77％、0.79％、0.81％、0.83％、0.85％、0.87％、0.89％、0.91％、0.93％、0.95％、0.97％、0.99％、1.0％、1.5％、2.0％、2.5％、3.0％、3.5％、4.0％、4.5％、5.0％、5.5％、6.0％、6.5％、7.0％、7.5％、8.0％、8.5％、9.0％、9.5％、10.0％、10.5％、11.0％、11.5％、12.0％、12.5％、13.0％、13.5％、14.0％、14.5％、15.0％、15.5％、16.0％、16.5％、17.0％、17.5％、18.0％、18.5％、19.0％、19.5％或20.0％，优选约为0.1至10％。
进一步地，本发明所述药物组合物还含有附加剂。所述附加剂为本领域技术人员所熟知的，选自但不限于防腐剂、保湿剂和抗氧剂中的至少一种。
本发明所述防腐剂为本领域技术人员所知或可以确认的，选自但不限于羟苯甲酯、羟苯乙酯、苯甲酸、山梨酸、苯氧乙醇、三氯叔丁醇、醋酸苯汞、苯酚、甲酚和苯扎氯铵中的至少一种，优选所述防腐剂含量以药物组合物总重量计为0.05～0.5％，可以为0.05％、0.06％、0.07％、0.08％、0.09％、0.10％、0.11％、0.12％、0.13％、0.14％、0.15％、0.16％、0.17％、0.18％、0.19％、0.20％、0.21％、0.22％、0.23％、0.24％、0.25％、0.26％、0.27％、0.28％、0.29％、0.30％、0.31％、0.32％、0.33％、0.34％、0.35％、0.36％、0.37％、0.38％、0.39％、0.40％、0.41％、0.42％、0.43％、0.44％、0.45％、0.46％、0.47％、0.48％、0.49％或0.50％。
本发明所述保湿剂为本领域技术人员所知或可以确认的，可以选自但不限于甘油、丙二醇、1,3-丁二醇、山梨醇、木糖醇、透明质酸和海藻糖中的至少一种，优选地，所述保湿剂含量以药物组合物总重量计为20～60％，可以为20.0％、20.5％、21.0％、21.5％、22.0％、22.5％、23.0％、23.5％、24.0％、24.5％、25.0％、25.5％、26.0％、26.5％、27.0％、27.5％、28.0％、28.5％、29.0％、29.5％、30.0％、30.5％、31.0％、31.5％、32.0％、32.5％、33.0％、33.5％、34.0％、34.5％、35.0％、35.5％、36.0％、36.5％、37.0％、37.5％、38.0％、38.5％、39.0％、39.5％、40.0％、40.5％、41.0％、41.5％、42.0％、42.5％、43.0％、43.5％、44.0％、 44.5％、45.0％、45.5％、46.0％、46.5％、47.0％、47.5％、48.0％、48.5％、49.0％、49.5％、50.0％、50.5％、51.0％、51.5％、52.0％、52.5％、53.0％、53.5％、54.0％、54.5％、55.0％、55.5％、56.0％、56.5％、57.0％、57.5％、58.0％、58.5％、59.0％、59.5％或60.0％。
本发明所述抗氧剂为本领域技术人员所知或可以确认的，选自但不限于丁羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯和生育酚中的至少一种，优选地，所述抗氧基含量以药物组合物总重量计为0.05～0.5％，可以为0.05％、0.06％、0.07％、0.08％、0.09％、0.10％、0.11％、0.12％、0.13％、0.14％、0.15％、0.16％、0.17％、0.18％、0.19％、0.20％、0.21％、0.22％、0.23％、0.24％、0.25％、0.26％、0.27％、0.28％、0.29％、0.30％、0.31％、0.32％、0.33％、0.34％、0.35％、0.36％、0.37％、0.38％、0.39％、0.40％、0.41％、0.42％、0.43％、0.44％、0.45％、0.46％、0.47％、0.48％、0.49％或0.50％。
可选实施方案中，所述药物组合物含有：
1)0.1～20％重量的活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，
2)0.5～20％重量的二乙二醇单乙醚。
可选实施方案中，所述药物组合物含有：
1)0.1～20％重量的活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，
2)0.5～20％重量的二乙二醇单乙醚，
3)40～90％重量的水溶性基质，所述水溶性基质优选聚乙二醇400和聚乙二醇4000。
可选实施方案中，所述药物组合物含有：
1)0.1～20％重量的活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5- 基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，
2)0.5～20％重量的二乙二醇单乙醚，
3)40～90％重量的水溶性基质，所述水溶性基质优选聚乙二醇400和聚乙二醇4000，
4)20～60％重量的保湿剂，所述保湿剂优选自羟苯甲酯、羟苯乙酯、苯甲酸、山梨酸、苯氧乙醇、三氯叔丁醇、醋酸苯汞、苯酚、甲酚和苯扎氯铵中的至少一种。
进一步地，本发明所述药物组合物中活性成分粒径不大于50μm，可以为50、48、46、44、42、40、38、36、34、32、30、28、26、24、22、20、18、16、14、12、10、8、6、4或2μm，优选不大于30μm，更优选不大于20μm。
本发明还提供一种制备前述药物组合物的方法，该方法包括：
1)将活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐、二乙二醇单乙醚、和任选自基质、抗氧剂和防腐剂中的至少一种药用辅料相混合，
2)将从1)步骤所获得的混合物灌装。
本发明还提供了一种前述药物组合物在制备治疗或预防免疫系统障碍或疾病的药物中的用途。
其中，所述的免疫系统障碍或疾病可以选自免疫系统的疾病，包括例如器官移植排斥(如异体抑制排斥和移植物抗宿主疾病)；自身免疫性疾病，包括例如狼疮、多发性硬化、类风湿性关节炎、青少年关节炎、银屑病、溃疡性结肠炎、克罗恩氏病、自体免疫性甲状腺疾病等；皮肤病，包括例如牛皮癣、皮疹、特应性皮炎等；变应性病症，包括例如哮喘、鼻炎等；病毒性疾病，包括例如乙型肝炎、丙型肝炎、水痘-带状疱疹病毒等；I型糖尿病与糖尿病并发症；阿尔茨海默病、干眼病、骨髓纤维化、血小板增多症、红细胞 增多症或白血病；癌症，包括例如实体瘤(如前列腺癌、肾癌、肝癌、胰腺癌、胃癌、乳腺癌、肺癌、头颈部癌、甲状腺癌、胶质母细胞瘤、黑素瘤等)、血液癌(如淋巴瘤、白血病等)、皮肤癌(如皮肤T-细胞淋巴瘤、皮肤B-细胞淋巴瘤)等。
在一些实施方案中，前述药物组合物在制备治疗皮肤疾病的药物中的用途。
本发明所述(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺可药用盐可选自但不限于盐酸盐、马来酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐。
本发明中“平均分子量”采用聚合物的重均分子量，是按聚合物中各级分的质量分数进行的统计平均值。可由下式计算获得：
Figure PCTCN2018116197-appb-000002
式中：W i是摩尔质量为M i级分占的质量分数，N i是摩尔质量为M i级分的摩尔分数。
本发明所述药物辅料或试剂均可来自商业途径，如二乙二醇单乙醚；化合物(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺可以参照CN103415520B中方法制备。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实施例1～4
将活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺缓慢加入丙二醇中，分别与辛酸癸酸聚乙二醇甘油酯、二乙二醇单乙醚、肉豆蔻酸异丙酯混合；再加入聚乙二醇400(PEG400)、聚乙二醇4000(PEG4000)、甘油、二丁基羟基甲苯(BHT)搅拌溶解，骤冷即得。具体数据见表1。
表1
Figure PCTCN2018116197-appb-000003
将实施例1～4制得的软膏进行离体透皮试验，考察不同处方的活性成分透过皮肤屏障并滞留于皮肤中的能力。
离体皮肤制备：选取巴马猪同一部位的皮肤为试验模型，剃除猪毛，剥离皮下多余脂肪，PBS洗净，储存于-70℃备用。
离体透皮试验：将猪皮恢复至室温，装于Franz扩散池上，取软膏约0.300g，精密称定，置于供给室，涂匀。接收室加入转子及磷酸盐缓冲液(pH＝7.4)4ml。采用多功能透皮扩散仪，设置温度32.0℃，转速500rpm。 于2、4、6、8、10、12h取样2ml，同时加入等体积等温磷酸盐缓冲液。取出样品以LC-MS检测药物含量，计算药物累积透过量。试验结束后以棉签擦拭法收集供给室中残余活性成分，以胶带剥离法收集角质层中活性成分，以及剩余皮肤剪碎收集活性成分，上述三份含活性成分样品以适宜溶剂溶解并定容，通过HPLC法测定活性成分含量，并计算回收率。其中供给室中活性成分含量称为残余量，角质层和皮肤中的活性成分含量分别称为角质层滞留量和表皮滞留量，接受室中活性成分的累积透过量称为透过量。上述试验平行12份，结果见表2。
表2
Figure PCTCN2018116197-appb-000004
注：皮肤总滞留量＝角质层滞留量+表皮滞留量；促进比是指含促渗剂处方皮肤总滞留量与不含促渗剂处方皮肤总滞留量的比值。
以上数据可知，实施例2中活性成分在皮肤中总滞留量最大，促进比最优，表明二乙二醇单乙醚能够较好地促进活性成分的经皮吸收。
实施例5～6
将活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺缓慢加入丙二醇中，再加入二乙二醇单乙醚混合；随后加入PEG400、PEG4000、甘油、BHT搅拌溶解，骤冷即得。具体数据见表3。
表3
Figure PCTCN2018116197-appb-000005
离体透皮试验：具体方法同实施例1，结果见表4。
表4
Figure PCTCN2018116197-appb-000006
结论：
实施例5与实施例2相比，PEG 400与PEG 4000的比例为2:1时，活性成分成分在皮肤表层的滞留量更高，有利于药物组合物中活性成分在皮肤中发挥药效。
实施例6与实施例2相比可见，甘油与丙二醇的比例为1:1时，活性成分皮肤表层滞留量更高，有利于药物组合物中活性成分在皮肤中发挥药效。
实施例7稳定性研究
将实施例2所得样品放置加速条件(30℃±2℃/RH65％±5％)和长期条件(25℃±2℃/RH60％±5％)下研究其稳定性。评价性状、含量、黏度、有关物质，其中黏度测定方法采用中国药典2015年版四部通则0983锥入度测定法测定。结果见表5。
表5稳定性研究结果
Figure PCTCN2018116197-appb-000007
结果表明，实施例2制备的产品在加速条件(30℃±2℃/RH65％±5％)和长期条件(25℃±2℃/RH60％±5％)下，表现出良好的物理和化学稳定性。

Claims (14)

  1. 一种药物组合物，其含有活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，和二乙二醇单乙醚，优选所述二乙二醇单乙醚含量以药物组合物总重量计为0.5～20％，优选为1％～10％。
  2. 根据权利要求1所述的药物组合物，其特征在于，其还含有基质，所述基质为水溶性基质，优选为聚乙二醇类高分子化合物，更优选平均分子量在100～6000的聚乙二醇类高分子化合物。
  3. 根据权利要求2所述的药物组合物，其特征在于，其中所述基质为聚乙二醇400和聚乙二醇4000，优选所述聚乙二醇400与聚乙二醇4000的重量比为1:10～10:1，更优选为1:5～5:1。
  4. 根据权利要求2或3所述的药物组合物，其特征在于，其中所述基质含量以药物组合物总重量计为40～90％，优选为50～80％。
  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，其中所述活性成分含量以药物组合物总重量计为0.1～20％，优选为1％～10％。
  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，其还含有选自防腐剂、保湿剂和抗氧剂中的至少一种附加剂。
  7. 根据权利要求6所述的药物组合物，其特征在于，其中所述防腐剂选自羟苯甲酯、羟苯乙酯、苯甲酸、山梨酸、苯氧乙醇、三氯叔丁醇、醋酸苯汞、苯酚、甲酚和苯扎氯铵中的至少一种，优选所述防腐剂含量以药物组合物总重量计为0.05～0.5％。
  8. 根据权利要求6所述的药物组合物，其特征在于，其中所述保湿剂选自甘油、丙二醇、1,3-丁二醇、山梨醇、木糖醇、透明质酸和海藻糖中的至少一种，优选所述保湿剂含量以药物组合物总重量计为20～60％，更优选为30～50％。
  9. 根据权利要求6所述的药物组合物，其特征在于，其中所述抗氧剂选 自丁羟基茴香醚、二丁基羟基甲苯、没食子酸丙酯和生育酚中的至少一种，优选所述抗氧剂含量以药物组合物总重量计为0.05～0.5％。
  10. 根据权利要求1-9任一项所述的药物组合物，其特征在于，其含有：
    1)0.1～20％重量的活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，
    2)0.5～20％重量的二乙二醇单乙醚，
    3)40～90％重量的水溶性基质，所述水溶性基质优选聚乙二醇400和聚乙二醇4000，
    4)20～60％重量的保湿剂，所述保湿剂优选自甘油、丙二醇、1,3-丁二醇、山梨醇、木糖醇、透明质酸和海藻糖中的至少一种。
  11. 一种药物组合物，其含有：
    1)0.1～20％重量的活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐，2)0.5～20％重量的二乙二醇单乙醚，3)40～90％重量的水溶性基质，所述水溶性基质优选聚乙二醇400和聚乙二醇4000。
  12. 根据权利要求1-11任一项所述的药物组合物，其特征在于，其中所述活性成分粒径不大于50μm，优选不大于30μm，更优选不大于20μm。
  13. 一种制备权利要求1-12任一项所述的药物组合物的方法，其包括：
    1)将活性成分(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺或其可药用盐、二乙二醇单乙醚和任选自基质、抗氧剂或防腐剂中的至少一种药用辅料相混合，
    2)将从1)步骤所获得的混合物灌装。
  14. 一种如权利要求1-12任一项所述的药物组合物在制备治疗或预防免疫系统障碍或疾病的药物中的用途。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113577013A (zh) * 2020-10-23 2021-11-02 南京欣通瑞亿医药科技有限公司 一种含有氨苯砜类化合物的经皮给药组合物及其制备方法
WO2023016583A1 (zh) * 2021-08-13 2023-02-16 杭州中美华东制药有限公司 一种芦可替尼组合物及其用途

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112023001283A2 (pt) * 2020-07-28 2023-02-14 Arcutis Biotherapeutics Inc Composição farmacêutica tópica; método para tratar uma doença, distúrbio ou afecção inflamatória de pele em um indivíduo que necessita do mesmo; e método para intensificar a penetração em pele em um indivíduo de uma formulação farmacêutica tópica
MX2023005763A (es) * 2020-11-17 2023-05-29 Arcutis Biotherapeutics Inc Composiciones y metodos para la administracion dermica profunda de farmacos.
TW202320788A (zh) * 2021-08-12 2023-06-01 大陸商江蘇恒瑞醫藥股份有限公司 用於治療或預防抗宿主病的吡咯并六元雜芳物
US20230181591A1 (en) * 2021-12-15 2023-06-15 Arcutis Biotherapeutics, Inc. Stable formulations of shr0302
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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103415520A (zh) 2011-12-21 2013-11-27 江苏恒瑞医药股份有限公司 吡咯并六元杂芳环类衍生物、其制备方法及其在医药上的应用
WO2014194741A1 (zh) * 2013-06-07 2014-12-11 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的硫酸氢盐及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101687819B (zh) * 2007-08-17 2013-03-20 卫材R&D管理有限公司 外用剂
EP2574168B9 (en) * 2010-05-21 2016-10-05 Incyte Holdings Corporation Topical formulation for a jak inhibitor
WO2012061428A2 (en) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Nicotinamides as jak kinase modulators
EP3185852A1 (en) * 2014-08-27 2017-07-05 AbbVie Inc. Topical formulation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103415520A (zh) 2011-12-21 2013-11-27 江苏恒瑞医药股份有限公司 吡咯并六元杂芳环类衍生物、其制备方法及其在医药上的应用
WO2014194741A1 (zh) * 2013-06-07 2014-12-11 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的硫酸氢盐及其制备方法
CN104470927A (zh) 2013-06-07 2015-03-25 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的硫酸氢盐及其制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"Chinese Pharmacopoeia", vol. IV, 2015
LUO YANGUO: "Clinical Research Progress of JAK Inhibitor", STRAIT PHARMACEUTICAL JOURNAL, vol. 24, no. 1, 31 December 2012 (2012-12-31), pages 199 - 200, XP009520569, ISSN: 1006-3765 *
See also references of EP3714887A4
WU YING ET AL.: "Application and Mechanism of Transcutol as Enhancer for Percutaneous Absorption", CHINSES JOURNAL OF MODERN APPLIED PHARMACY, vol. 21, no. 1, 29 February 2004 (2004-02-29), pages 23 - 25, XP009520567, DOI: 10.13748/j.cnki.issn1007-7693.2004.01.010 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113577013A (zh) * 2020-10-23 2021-11-02 南京欣通瑞亿医药科技有限公司 一种含有氨苯砜类化合物的经皮给药组合物及其制备方法
CN113577013B (zh) * 2020-10-23 2023-12-22 南京欣通瑞亿医药科技有限公司 一种含有氨苯砜类化合物的经皮给药组合物及其制备方法
WO2023016583A1 (zh) * 2021-08-13 2023-02-16 杭州中美华东制药有限公司 一种芦可替尼组合物及其用途

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