WO2023202580A1 - 一种jak抑制剂的微乳泡沫剂及其应用 - Google Patents

一种jak抑制剂的微乳泡沫剂及其应用 Download PDF

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WO2023202580A1
WO2023202580A1 PCT/CN2023/089004 CN2023089004W WO2023202580A1 WO 2023202580 A1 WO2023202580 A1 WO 2023202580A1 CN 2023089004 W CN2023089004 W CN 2023089004W WO 2023202580 A1 WO2023202580 A1 WO 2023202580A1
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jak inhibitor
microemulsion
foam
accounts
surfactant
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English (en)
French (fr)
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华丽
谢军
姜春阳
李惠
舒海英
黄利明
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上海博悦生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/02—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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or 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
    • A61K9/0012—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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/122—Foams; Dry foams
    • 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
    • A61P17/14—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]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of pharmaceutical preparations and relates to a microemulsion foam agent of a JAK inhibitor, a preparation method and an application thereof.
  • JAK inhibitors can selectively inhibit JAK kinase and block the JAK/STAT signaling pathway.
  • JAK inhibitors are mainly used to screen therapeutic drugs for hematological diseases, tumors, rheumatoid arthritis, psoriasis and other diseases.
  • Janus kinases are a family of intracellular non-receptor tyrosine kinases that can transduce cytokine-mediated signals through the JAK-STAT pathway. Since members of the type I and type II cytokine receptor families do not have catalytic kinase activity, they rely on the JAK tyrosine kinase family to phosphorylate and activate downstream proteins involved in their signal transduction pathways.
  • Receptors exist as paired polypeptides and thus exhibit two intracellular signaling domains.
  • JAKs associate with a proline-rich region in each intracellular domain adjacent to the cell membrane, termed the box1/box2 region. After the receptor binds to its respective cytokine/ligand, it undergoes a conformational change that brings the two JAKs into close enough proximity to phosphorylate each other. JAK autophosphorylation induces its own conformational changes, allowing it to transduce intracellular signals by further phosphorylating and activating transcription factors called STATs. Activated STATs dissociate from receptors and form dimers before translocating to the nucleus, where they regulate the transcription of selected genes.
  • JAK inhibitors include abuxitinib, upapatinib, ruxolitinib, baricitinib, tofacitinib, SHR0302, Jactinib hydrochloride, etc.
  • Ruxolitinib is a small molecule and an orally available specific inhibitor of Janus kinase isoforms 1 and 2 (JAK1 and JAK2) that was approved in the United States in 2011 for the treatment of intermediate- and high-risk myelofibrosis. Subsequently, indications were expanded to include polycythemia vera that is resistant or intolerant to conventional treatments and acute graft-versus-host disease that is resistant to corticosteroids.
  • Abxitinib is a once-daily oral JAK1 inhibitor and a member of Pfizer's global pipeline of JAK inhibitors. It regulates interleukins including IL-4, IL-13, IL-31, IL Various cytokines related to atopic dermatitis, such as -22 and thymic stromal lymphopoietin (TSLP), play a role.
  • TSLP thymic stromal lymphopoietin
  • JAK1 JAK1 thymic stromal lymphopoietin
  • MHRA UK's Medicines and Healthcare products Regulatory Agency
  • AD moderate to severe atopic dermatitis
  • Pfizer is also developing the drug for multiple indications such as psoriasis, systemic lupus erythematosus and arthritis. Research. Currently only available in tablet form.
  • AD is a chronic skin disease that affects more than 21 million people ages 12 and older in the United States and is characterized by inflammation and itching. Signs and symptoms include irritated and itchy skin, which causes redness that may ooze and crust. lesions, patients are also more susceptible to bacterial, viral, and fungal infections. Ruxolitinib cream can also be used to treat atopic dermatitis, vitiligo and other diseases.
  • microemulsion foams Compared with creams, which have less skin retention and can give patients a greasy feeling, microemulsion foams have good stability, spreadability, and are easy to apply. Especially for skin with hair, they are easier to use and do not stick to the skin. On the hair, and has greater skin penetration and skin retention than soft creams, it can provide patients with a non-greasy feeling after use, and will not stain clothes, making clinical use simple and convenient. Therefore, it is necessary to develop a new type of JAK inhibitor microemulsion foam.
  • the purpose of the embodiments of the present invention is to overcome the shortcomings of the above-mentioned JAK inhibitor cream and provide a JAK inhibitor microemulsion foam, a preparation method and its application.
  • the present invention relates to a microemulsion foam of a JAK inhibitor, which is characterized in that the microemulsion foam is composed of a therapeutically effective amount of a JAK inhibitor and auxiliary materials, and the auxiliary materials include an oil-in-water surfactant (foaming type). ), co-surfactants, oily phases, humectants or solvents, emollients, chelating agents and preservatives.
  • auxiliary materials include an oil-in-water surfactant (foaming type). ), co-surfactants, oily phases, humectants or solvents, emollients, chelating agents and preservatives.
  • the present invention relates to a microemulsion foam of a JAK inhibitor.
  • the active ingredient of the JAK inhibitor is an effective therapeutic dose of the JAK inhibitor, preferably 0.5%-3% of the JAK inhibitor active ingredient.
  • the active ingredient is selected from the group consisting of: Any one or more of abuxitinib, upapatinib, ruxolitinib, baricitinib, tofacitinib, SHR0302, molotinib, and coxitinib hydrochloride.
  • JAK inhibitor microemulsion foam is a solution or suspension oil-in-water preparation, containing 2-25% of oil-in-water surfactant, preferably 15-25%, and 1-10% of co-surfactant, preferably 2-8 %.
  • the oil phase contains 0.2-1%, preferably 0.5-0.9%, chelating agent 0.01-1%, preferably 0.5-0.8%, humectant or solvent 4-25%, preferably 5-20%, and emollient 0.5-2 %, preferably 0.5-1%, containing preservative 0.1-1.0%, preferably 0.2-0.9%.
  • the ratio of oil-in-water surfactant to co-surfactant is 6:1 to 3:1.
  • the oil-in-water surfactant is selected from any one or more of octanoic acid decanoic acid polyethylene glycol glyceride, cetearyl alcohol polyoxyethylene ether-20, and lauryl alcohol polyoxyethylene ether, preferably caprylic acid decanoic acid polyoxyethylene ether.
  • octanoic acid decanoic acid polyethylene glycol glyceride cetearyl alcohol polyoxyethylene ether-20
  • lauryl alcohol polyoxyethylene ether preferably caprylic acid decanoic acid polyoxyethylene ether.
  • ethylene glycol glyceride or cetearyl alcohol polyoxyethylene ether-20 One or both of ethylene glycol glyceride or cetearyl alcohol polyoxyethylene ether-20.
  • a co-surfactant is a type of surfactant that works by further reducing the interfacial energy in addition to the surfactant, but does not work effectively as a surfactant alone.
  • the co-surfactant is selected from any one or more of polyglycerol fatty acid esters, propylene glycol fatty acid esters, glyceryl monostearate, diethylene glycol monoethyl ether, polyglycerol 3-oleate, etc., One or two of polyglycerol fatty acid ester, propylene glycol fatty acid ester and diethylene glycol monoethyl ether are preferred.
  • the oil phase is selected from medium chain triglycerides, cyclomethicone, isopropyl palmitate, triacetin light liquid paraffin, etc., preferably medium chain triglycerides, cyclomethicone, and isopropyl palmitate. Any one or more.
  • the chelate is selected from disodium ethylenediaminetetraacetate, calcium sodium ethylenediaminetetraacetate, etc., with disodium ethylenediaminetetraacetate being preferred.
  • the humectant or solvent is selected from any one or more of propylene glycol, glycerin, polyethylene glycol-200, etc., preferably one or both of propylene glycol and polyethylene glycol-200.
  • the emollient is selected from any one or more of propylene glycol dinonanoate, polydimethylsiloxane 350, and polyethylene glycol-7 coconut glyceride, preferably propylene glycol dinonanoate, polydimethylsiloxane One or two types of siloxane 350.
  • the preservative is any one or more of phenoxyethanol, propylparaben, methylparaben, ethylparaben, etc., preferably phenoxyethanol, propylparaben, p-hydroxybenzoate, etc. Methyl Hydroxybenzoate.
  • the microemulsion foam of the JAK inhibitor involved in the present invention is as follows:
  • the invention also relates to a method for preparing a JAK inhibitor microemulsion foam, which method includes the following steps:
  • Oil phase preparation Stir and dissolve the prescribed amount of O/W emulsifier, oil phase, chelating agent, preservatives, and emollient at 30-80°C, and cool to room temperature.
  • the present invention also relates to the application of a JAK inhibitor microemulsion foam as an external medicine for treating alopecia areata, atopic dermatitis, vitiligo and the like.
  • Figure 4 Foaming situation of microemulsion foam in Example 4.
  • the preparation method of the JAK inhibitor microemulsion foam of the present invention includes the following steps:
  • Example 1-4 relates to the preparation of a ruxolitinib microemulsion foam. Its raw and auxiliary materials and proportions are as follows in Table 1:
  • This embodiment relates to the preparation of an aboxitinib microemulsion foam.
  • This comparative example involves the preparation of a ruxolitinib microemulsion foam. Its raw materials and excipients and their proportions are as shown in Table 4 below. The preparation method is the same as in Example 2, but the surfactants used are different.
  • Examples 1-5 and Comparative Examples 1-2 were tested for viscosity, centrifugation, properties, emulsion droplet size, pH, content, related substances and content uniformity. The results are as follows in Table 5.
  • the ruxolitinib microemulsion foam prepared according to Examples 1-4 of this patent and the abuxitinib microemulsion foam prepared in Example 5 have good stability and spreadability compared with the cream in Comparative Example 1. Sexy, easy to apply, especially for skin with hair, easier to use and does not stick to hair.
  • Example 7 From the long-term stability comparative data of Example 7, it can be seen that the microemulsion foam prepared in Examples 1-5 has good stability. During the long-term three-month period, the properties, viscosity, pH value, content, and related material indicators have no differences. Significant changes. It shows that the microemulsion foam prepared according to Examples 1-5 can basically meet the stability requirements during use.
  • Receiving fluid physiological saline
  • Samples Coat preparations with different prescriptions evenly on experimental pigskin.
  • the sample size of each preparation is about 200mg.
  • the pigskin without cream is used as blank pigskin.
  • Example 8 It can be seen from the in vitro transdermal test of Example 8 that the ruxolitinib microemulsion foam prepared in Examples 1-4 has greater skin penetration and skin retention than the soft cream. The in vitro penetration test shows that it has greater skin penetration than the soft cream. Comparative Example 1 and Comparative Example 2 have better clinical effects.
  • the microemulsion foam is an oil-in-water microemulsion foam that provides patients with a non-greasy feel after use and does not stain clothes. It is simple and convenient for clinical use.
  • the present invention has the following beneficial effects:
  • Microemulsion foam containing JAK inhibitor is a composition of microemulsion foam without propellant, used as water phase/oil-in-water surfactant/auxiliary surfactant, oil phase, humectant or solvent, and emollient
  • water phase/oil-in-water surfactant/auxiliary surfactant oil phase, humectant or solvent, and emollient
  • chelating agents, and preservatives are mixed together at appropriate concentrations, an oil-in-water microemulsion will spontaneously form.
  • the microemulsions formed are clear to opalescent, optically isotropic, and thermodynamically stable.
  • the microemulsion can improve drug solubility, reduce skin irritation, maintain the concentration difference between the internal and external phases of the drug, and promote the continuous penetration of the drug through the stratum corneum.
  • the microemulsion foam passes microemulsion through a specific delivery device and can spray foam without a booster. It has good spreadability, is easy to apply, and has good patient compliance,

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Abstract

一种治疗斑秃、特应性皮炎、白癜风的微乳泡沫剂的组合物及其制备方法，活性成分为JAK抑制剂及其药学上可接受的盐，该制剂适用于局部用药。该微乳泡沫剂无助推剂、容易生产和易于涂抹，具有润肤、保湿的功能，对皮肤无刺激，无瘙痒、灼烧感和刺痛感等副作用，停药后无相关皮肤病症状。

Description

一种JAK抑制剂的微乳泡沫剂及其应用 技术领域
本发明属于药物制剂领域，涉及一种JAK抑制剂的微乳泡沫剂、制备方法及其应用。
背景技术
JAK抑制剂可选择性抑制JAK激酶，阻断JAK/STAT信号通路，临床上JAK抑制剂主要用于筛选血液***疾病、肿瘤、类风湿性关节炎及银屑病等治疗药物。Janus激酶(JAK)是一个细胞内非受体酪氨酸激酶家族，可通过JAK-STAT通路转导细胞因子介导的信号。由于I型和II型细胞因子受体家族的成员不具有催化激酶活性，它们依赖JAK酪氨酸激酶家族来磷酸化和激活参与其信号转导途径的下游蛋白。受体以配对多肽的形式存在，因此表现出两个细胞内信号转导结构域。JAK与每个细胞内结构域中的富含脯氨酸的区域相关联，该区域与细胞膜相邻，称为box1/box2区域。在受体与其各自的细胞因子/配体结合后，它会发生构象变化，使两个JAK足够接近以相互磷酸化。JAK自身磷酸化诱导其自身的构象变化，使其能够通过进一步磷酸化和激活称为STAT的转录因子来转导细胞内信号。激活的STAT在转移到细胞核之前与受体分离并形成二聚体，在那里它们调节选定基因的转录。JAK抑制剂包括阿布昔替尼、乌帕替尼、芦可替尼、巴瑞替尼、托法替布、SHR0302、盐酸杰克替尼等。
芦可替尼是一种小分子，是一种口服可用的Janus激酶亚型1和2(JAK1和JAK2)特异性抑制剂，于2011年在美国获批用于治疗中高危骨髓纤维化。随后，适应症扩大到包括对常规治疗耐药或不耐受的真性红细胞增多症以及对皮质类固醇耐药的急性移植物抗宿主病。
阿布昔替尼是一种每日一次的口服JAK1抑制剂，也是辉瑞JAK抑制剂全球管线中的成员之一，通过调节包括白细胞介素IL-4,、IL-13,、IL-31、IL-22和胸腺基质淋巴细胞生成素(TSLP)等多种与特应性皮炎相关细胞因子发挥作用。抑制JAK1被认为可以调节参与特应性皮炎病理生理学的多种细胞因子，包括白细胞介素IL-4、IL-13、IL-31、IL-22和胸腺基质淋巴细胞生成素(TSLP)2021年9月，该药获得英国药品和保健品监管局(MHRA)批准，用于治疗成人和12岁及以上青少年的中度至重度特应性皮炎(AD)。这是阿布昔替尼在全球首次获得药监机构批准。随后，阿布昔替尼片陆续在日本、韩国、欧盟和美国获批上市。除此之外，辉瑞还对该药品开展针对银屑病、***性红斑狼疮和关节炎等多项适应症的 研究。目前只有片剂剂型。
2021年9月21日FDA批准INCYTE CORP的商品名为OPZELURA的芦可替尼乳膏上市，被批准用于对12岁及以上的非免疫功能低下患者的轻度至中度AD的短期和非连续慢性治疗。AD是一种慢性皮肤病，在美国影响超过2100万12岁及以上的人，其特征是炎症和瘙痒,体征和症状包括刺激和发痒的皮肤，这会导致可能渗出和结痂的红色病变,患者也更容易受到细菌、病毒和真菌感染。芦可替尼乳膏还可以用于特应性皮炎、白癜风等疾病的治疗。
相比较乳膏皮肤滞留量少，同时会带给患者油腻感的缺点，微乳泡沫剂具有良好的稳定性、铺展性、易于涂抹，特别是针对有毛发的皮肤，更易于使用且不黏附在毛发上，且具有比软乳膏剂更大的皮肤渗透和皮肤滞留量，在使用后可为患者提供不油腻的感觉，并且不会弄脏衣服，临床使用简洁方便。所以有必要开发一种新型的JAK抑制剂微乳泡沫剂。
发明内容
本发明的实施例目的在于克服上述JAK抑制剂乳膏存在的不足，提供一种JAK抑制剂的微乳泡沫剂、制备方法及其应用。
本发明的实施例目的是通过以下技术方案来实现的：
本发明涉及一种JAK抑制剂的微乳泡沫剂，其特征在于所述微乳泡沫剂由治疗有效量的JAK抑制剂的和辅料组成，所述辅料包括水包油表面活性剂(发泡型)、辅助表面活性剂、油相、保湿剂或溶剂、润肤剂、螯合剂和防腐剂。
作为一个实施方案，本发明涉及JAK抑制剂的微乳泡沫剂，所述JAK抑制剂活性成分为有效治疗剂量的JAK抑制剂，优选0.5％-3％的JAK抑制剂活性成分，活性成分选自阿布昔替尼、乌帕替尼、芦可替尼、巴瑞替尼、托法替布、SHR0302、莫洛替尼、盐酸杰克替尼中的任意一种或者多种。
JAK抑制剂微乳泡沫剂为溶液型或混悬型水包油制剂，含水包油表面活性剂2-25％，优选15-25％，含助表面活性剂1-10％，优选2-8％。含油相0.2-1％，优选0.5-0.9％，含螯合剂0.01-1％，优选0.5-0.8％，含保湿剂或溶剂4-25％，优选5-20％，含润肤剂0.5-2％，优选0.5-1％，含防腐剂0.1-1.0％，优选0.2-0.9％。
作为一个实施方案，水包油表面活性剂与助表面活性剂的比例为6：1至3：1。
水包油表面活性剂选自辛酸癸酸聚乙二醇甘油酯、鲸蜡硬脂醇聚氧乙烯醚-20、月桂醇聚氧乙烯醚中的任意一种或者多种，优选辛酸癸酸聚乙二醇甘油酯或鲸蜡硬脂醇聚氧乙烯醚-20一种或者两种。
助表面活性剂是一种表面活性剂，除了表面活性剂外，还通过进一步降低界面能而发挥作用，但单独作为表面活性剂并不能有效发挥作用。助表面活性剂选自聚甘油脂肪酸酯、丙二醇脂肪酸酯、单硬脂酸甘油酯、二乙二醇单乙基醚、聚甘油3-油酸酯等中的任一种或者多种，优选聚甘油脂肪酸酯、丙二醇脂肪酸酯、二乙二醇单乙基醚中的一种或者两种。
油相选自中链甘油三酯、环甲基硅油、棕榈酸异丙酯、三乙酸甘油酯轻质液体石蜡等，优选中链甘油三酯、环甲基硅油和棕榈酸异丙酯中的任意一种或者多种。
螯合选自为乙二胺四乙酸二钠、乙二胺四乙酸钙钠等任意一种，优选乙二胺四乙酸二钠。
保湿剂或溶剂选自丙二醇、甘油、聚乙二醇-200等中的任一种或者多种，优选丙二醇和聚乙二醇-200中的一种或者两种。
润肤剂选自丙二醇二壬酸酯、聚二甲基硅氧烷350、聚乙二醇-7椰油甘油酯中的任一种或者多种，优选丙二醇二壬酸酯、聚二甲基硅氧烷350中的一种或者两种。
防腐剂为苯氧乙醇、对羟基苯甲酸丙酯、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯等中的任一种或者多种，优选苯氧乙醇、对羟基苯甲酸丙酯、对羟基苯甲酸甲酯。
作为一个实施方案，本发明涉及的JAK抑制剂的微乳泡沫剂，其原辅料以及处方占比(以占JAK抑制剂的微乳泡沫剂总重的质量百分比计)如下：
本发明还涉及一种JAK抑制剂的微乳泡沫剂的制备方法，所述方法包含如下步骤：
(1)活性相的配制，在30-80℃下，将处方量的活性成分溶解在保湿剂或溶剂中，并加入助表面活性剂，降温至室温。
(2)油相配制：在30-80℃条件下，将处方量的O/W乳化剂、油相、螯合剂、防腐剂、润肤剂搅拌溶解，降温至室温。
(3)将活性相加入油相，搅拌均匀。
(4)室温条件下，将(3)加入水中，搅拌均匀，用盐酸/氢氧化钠调节pH，得微乳泡沫剂。
本发明还涉及一种JAK抑制剂的微乳泡沫剂在作为治疗斑秃、特应性皮炎、白癜风等外用药中的应用。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1实施例1微乳泡沫剂的发泡情况；
图2实施例2微乳泡沫剂的发泡情况；
图3实施例3微乳泡沫剂的发泡情况；
图4实施例4微乳泡沫剂的发泡情况；
图5实施例5微乳泡沫剂的发泡情况
图6对照例2微乳泡沫剂的发泡情况。
具体实施方式
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干调整和改进。这些都属于本发明的保护范围。
本发明的JAK抑制剂的微乳泡沫剂的制备方法包括如下步骤：
(1)活性相的制备：将处方量的活性成分溶解在溶剂丙二醇中，加入助表面活性剂，30-50℃搅拌溶解并降温至室温。
(2)油相的制备：将O/W乳化剂、油相、螯合剂、防腐剂、润肤剂搅拌，加热到30-50℃，溶解、混合均匀，并降温至室温。
(3)将混合好的油相加入水相，搅拌均匀后，用盐酸/氢氧化钠调节pH至2.8-5.0，得微乳泡沫剂。
具体应用示例如下：
实施例1-4
本实施例1-4涉及一种芦可替尼微乳泡沫剂的制备，其原辅料以及占比如下表1：
表1
实施例5
本实施例涉及一种阿布昔替尼微乳泡沫剂的制备。
按照表2的处方和实施例1-4制备方法，，制备含1％阿布昔替尼微乳泡沫剂。
表2
对比例1对照制剂的制备
按照CN105853356A专利说明书第19页的0274段表5中的处方和说明书0277-0286段的制备工艺，制备含芦可替尼的乳膏，作为对照制剂。其原辅料以及占比如下表3.
表3

对比例2
本对比例涉及一种芦可替尼微乳泡沫剂的制备，其原辅料以及占比如下表4，制备方法同实施例2，但是所采用的表面活性剂不同。
表4
实施例6 质量对比研究
对实施例1-5以及对比例1-2进行了黏度、离心、性状、乳滴粒径、pH、含量、有关物质和含量均匀度等检测，结果如下表5。
表5
结论：实施例1-5和对比例2制备得到的替尼微乳泡沫剂发泡情况见附图1-6。按照实施例1至5制备得微乳泡沫剂具有良好的发泡能力，对比例2的发泡能力较差，临床使用中容易未涂抹均匀即变成溶液而导致微乳从皮肤表面流淌或者滴落。
按照本专利实施例1-4制备芦可替尼微乳泡沫剂和实施例5制备得到的阿布昔替尼微乳泡沫剂，相比较对比例1中的乳膏，具有良好的稳定性、铺展性、易于涂抹，特别是针对有毛发的皮肤，更易于使用且不黏附在毛发上。
实施例7 长期稳定性对比研究结果
将实施例1-4以及对比例1和2制备出来的样品，放置于温度为30±2℃、湿度为RH60％±5％的条件下，分别于1月、3月取样检测性状、黏度、pH值、含量、有关物质，具体检测结果见下表6。
表6

从实施例7长期稳定性对比数据可知，实施例1-5制备的微乳泡沫剂，具有良好的稳定性，在长期三个月期间，性状、黏度、pH值、含量、有关物质指标均无显著性变化。说明按照实施例1-5制备的微乳泡沫剂基本可以满足使用期间的稳定性要求。
实施例8 体外透皮试验对比研究：
1)方法：Franz扩散池法；
2)仪器：禄亘药物透皮扩散试验仪,LOGAN 918-12***
3)皮肤：实验用猪皮，厚度0.8-1mm，接触直径2cm；
4)接收液：生理盐水；
5)接收液温度：32±0.5℃；
6)转速：600rpm；
7)样本：分别将不同处方的制剂均匀涂布在实验用猪皮上，每个制剂的样本量分别为200mg左右，同时将未涂抹乳膏的猪皮作为空白猪皮。
8)扩散池容积：12ml；
9)采样方式：全部取样；
10)采样时间点：2h、4h、6h、10h、21h、24h；
11)样本分析：LC/MS测定，检测结果见表7。
表7
从实施例8体外透皮试验可以看到，实施例1-4制备得到的芦可替尼微乳泡沫剂具有比软乳膏剂更大的皮肤渗透和皮肤滞留量，体外渗透实验表明其具有比对比例1和对比例2更好的临床效果。该微乳泡沫剂是水包油型微乳泡沫剂，在使用后可为患者提供不油腻的感觉，并且不会弄脏衣服。临床使用简洁方便。
与现有技术相比，本发明具有如下有益效果：
含JAK抑制剂的微乳泡沫剂即微乳泡沫剂的组合物，无助推剂，当水相/水包油表面活性剂/辅助表面活性剂、油相、保湿剂或溶剂、润肤剂、螯合剂、防腐剂以适当的浓度混合在一起时，会自发形成水包油微乳液。形成的微乳液是透明的至乳白色、光学各向同性的和热力学稳定的。该微乳可提高药物溶解度、降低皮肤刺激性、保持药物的内相外相浓度差而促进药物持续透过角质层。该微乳泡沫剂将微乳通过特定的给药装置，无需助推剂即可喷出泡沫，具有良好的铺展性，易于涂抹，患者的顺应性良好，特别是针对含有毛发的皮肤的使用，更方便和具有较高的皮肤滞留和渗透。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。

Claims (10)

  1. 一种JAK抑制剂的微乳泡沫剂，其特征在于所述微乳泡沫剂由JAK抑制剂的活性成分和辅料组成，所述辅料包括水包油表面活性剂、助表面活性剂、油相、保湿剂或溶剂、润肤剂、螯合剂和防腐剂。
  2. 根据权利要求1所述的JAK抑制剂的微乳泡沫剂，其特征在于，所述JAK抑制剂选自芦可替尼磷酸盐、芦可替尼、阿布昔替尼、莫洛替尼中的一种或者多种，所述JAK抑制剂的活性成分为质量占比0.5％-3％。
  3. 根据权利要求1所述的JAK抑制剂的微乳泡沫剂，其特征在于，所述辅料以JAK抑制剂的微乳泡沫剂总重的质量百分比计，含水包油表面活性剂2-25％，含助表面活性剂1-10％，含油相0.2-1％，含螯合剂0.01-1％，含保湿剂或溶剂4-25％，含润肤剂0.5-2％，含防腐剂0.1-1.0％。
  4. 根据权利要求3所述的JAK抑制剂的微乳泡沫剂，其特征在于，所述辅料以JAK抑制剂的微乳泡沫剂总重的质量百分比计，含水包油表面活性剂15-25％，含助表面活性剂2-8％，含油相0.5-0.9％，含螯合剂0.5-0.8％，含保湿剂或溶剂5-20％，含润肤剂比例0.5-1％，含防腐剂0.2-0.9％。
  5. 根据权利要求2或者4任意一项所述的JAK抑制剂的微乳泡沫剂，其特征在于，所述JAK抑制剂的活性成分和辅料以JAK抑制剂的微乳泡沫剂总重的质量百分比计，占比如下：芦可替尼磷酸盐或芦可替尼或阿布昔替尼或者莫洛替尼占0.5-3％，辛酸癸酸聚乙二醇甘油酯占比15-25％，聚甘油脂肪酸酯或者丙二醇脂肪酸酯占比2-8％，中链甘油三酯占比0.5-0.9％，聚二甲基硅氧烷350占比0.5-1％，丙二醇占比5-20％，EDTA-2Na占比0.5-0.8％，苯氧乙醇占比0.2-0.8％，对羟基苯甲酸甲酯占比0.05-0.15％，对羟基苯甲酸丙酯占比0.01-0.1％，盐酸或氢氧化钠适量，水定重至100。
  6. 根据权利要求1所述的JAK抑制剂的微乳泡沫剂，其特征在于，所述水包油表面活性剂为辛酸癸酸聚乙二醇甘油酯、鲸蜡硬脂醇聚氧乙烯醚-20、月桂醇聚氧乙烯醚的任意一种；所述助表面活性剂为聚甘油脂肪酸酯、丙二醇脂肪酸酯、单硬脂酸甘油酯、二乙二醇单乙基醚、聚甘油3-油酸酯中的一种或者多种。
  7. 根据权利要求7所述的JAK抑制剂的微乳泡沫剂，其水包油表面活性剂与助表面活性剂的比例为6：1至3：1。
  8. 根据权利要求1所述的JAK抑制剂的微乳泡沫剂，其特征在于，所述油相选自中链甘油三酯、环甲基硅油、棕榈酸异丙酯、三乙酸甘油酯轻质液体石蜡中的任意一种，
    所述保湿剂或溶剂选自丙二醇、甘油、聚乙二醇-200中的任意一种，
    所述润肤剂选自丙二醇二壬酸酯、聚二甲基硅氧烷350、聚乙二醇-7椰油甘油酯中的任意一种。
  9. 如权利要求1所述的JAK抑制剂的微乳泡沫剂的制备方法，其步骤包括：
    a活性相的配制：在30-80℃下，将处方量的活性成分溶解在保湿剂或溶剂中，并加入助表面活性剂，降温至室温；
    b油相配制：在30-80℃条件下，将处方量的O/W乳化剂、油相、螯合剂、防腐剂、润肤剂搅拌溶解，降温至室温；
    c将活性相加入油相，搅拌均匀；
    d室温条件下，将含有活性相的油相加入水中，搅拌均匀，并调节pH值，得微乳泡沫剂。
  10. 如权利要求1所述的JAK抑制剂的微乳泡沫剂在制备治疗斑秃、特应性皮炎、白癜风等外用药物制剂中的应用。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230181591A1 (en) * 2021-12-15 2023-06-15 Arcutis Biotherapeutics, Inc. Stable formulations of shr0302
CN114870016B (zh) * 2022-04-21 2023-05-26 上海博悦生物科技有限公司 一种jak抑制剂的微乳泡沫剂及其应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060217283A1 (en) * 2005-03-25 2006-09-28 L'oreal Foaming O/W emulsion and use thereof in cosmetics
WO2008110872A2 (en) * 2006-06-23 2008-09-18 Foamix Ltd. Foamable compositions and kits comprising one or more of a channel agent, a cholinergic agent, a nitric oxide donor, and related agents and their uses
CN102639098A (zh) * 2009-07-31 2012-08-15 赢创斯托豪森有限公司 能发泡的水包油乳液
CN103002875A (zh) * 2010-05-21 2013-03-27 因塞特公司 Jak 抑制剂的局部用制剂
CN112402615A (zh) * 2020-11-11 2021-02-26 长沙晶易医药科技有限公司 一种用于治疗斑秃的复方外用制剂及其制备方法
US20210213021A1 (en) * 2018-06-04 2021-07-15 Lars BRICHTA Topical compositions for stimulating hair growth
WO2021229578A1 (en) * 2020-05-13 2021-11-18 Follicle Pharma Ltd Compositions for delivery of bioactive agents into hair follicles
CN114870016A (zh) * 2022-04-21 2022-08-09 上海博悦生物科技有限公司 一种jak抑制剂的微乳泡沫剂及其应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2830662T3 (da) * 2012-03-29 2019-01-02 Univ Columbia Fremgangsmåder til behandlng af hårtabsforstyrrelser
WO2021059281A1 (en) * 2019-09-26 2021-04-01 Sol-Gel Technologies Ltd. Treatment of skin disorders with topical combination compositions comprising tapinarof and an additional ahr activator
EP4061332A4 (en) * 2019-11-24 2023-11-29 Sol-Gel Technologies Ltd. TREATMENT OF SKIN DISEASES USING TOPICAL COMPOSITIONS CONTAINING TAPINAROF AND A PDE4 INHIBITOR

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060217283A1 (en) * 2005-03-25 2006-09-28 L'oreal Foaming O/W emulsion and use thereof in cosmetics
WO2008110872A2 (en) * 2006-06-23 2008-09-18 Foamix Ltd. Foamable compositions and kits comprising one or more of a channel agent, a cholinergic agent, a nitric oxide donor, and related agents and their uses
CN102639098A (zh) * 2009-07-31 2012-08-15 赢创斯托豪森有限公司 能发泡的水包油乳液
CN103002875A (zh) * 2010-05-21 2013-03-27 因塞特公司 Jak 抑制剂的局部用制剂
US20210213021A1 (en) * 2018-06-04 2021-07-15 Lars BRICHTA Topical compositions for stimulating hair growth
WO2021229578A1 (en) * 2020-05-13 2021-11-18 Follicle Pharma Ltd Compositions for delivery of bioactive agents into hair follicles
CN112402615A (zh) * 2020-11-11 2021-02-26 长沙晶易医药科技有限公司 一种用于治疗斑秃的复方外用制剂及其制备方法
CN114870016A (zh) * 2022-04-21 2022-08-09 上海博悦生物科技有限公司 一种jak抑制剂的微乳泡沫剂及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HAJJAR,B. ET AL.: "In Vitro Evaluation of a Foamable Microemulsion Towards an Improved Topical Delivery of Diclofenac Sodium", AAPS PHARMSCITECH, vol. 23, 4 April 2022 (2022-04-04), pages 1 - 9, XP037792755, DOI: 10.1208/s12249-022-02258-0 *
JONG STEPHEN YIN-CHYUAN, NGUYEN QUOC PHUC: "Effect of microemulsion on foam stability", APPLIED NANOSCIENCE, vol. 8, no. 3, 1 March 2018 (2018-03-01), pages 231 - 239, XP093100614, ISSN: 2190-5509, DOI: 10.1007/s13204-018-0808-7 *

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