WO2023051833A1 - 一种芦可替尼组合物及其制备方法 - Google Patents

一种芦可替尼组合物及其制备方法 Download PDF

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WO2023051833A1
WO2023051833A1 PCT/CN2022/126399 CN2022126399W WO2023051833A1 WO 2023051833 A1 WO2023051833 A1 WO 2023051833A1 CN 2022126399 W CN2022126399 W CN 2022126399W WO 2023051833 A1 WO2023051833 A1 WO 2023051833A1
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Prior art keywords
ruxolitinib
emulsifier
gel
polyoxyethylene
castor oil
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PCT/CN2022/126399
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English (en)
French (fr)
Inventor
喻进
罗艳华
戚卫蕊
吴笑笑
严婷婷
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Priority to JP2024518979A priority Critical patent/JP2024535105A/ja
Priority to EP22875213.5A priority patent/EP4509124A4/en
Priority to US18/695,839 priority patent/US20240390276A1/en
Priority to CN202280065210.1A priority patent/CN118043052A/zh
Publication of WO2023051833A1 publication Critical patent/WO2023051833A1/zh
Anticipated expiration legal-status Critical
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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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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, in particular to a composition of ruxolitinib or a pharmaceutically acceptable salt thereof and a preparation method thereof.
  • Ruxolitinib (also known as Ruxolitinib, Ruxolitinib, Ruxolitinib) has a chemical name of (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile, a JAK1 and JAK2 tyrosine kinase inhibitor, for intermediate-risk or high-risk primary myelofibrosis (primary myelofibrosis, PMF) (also known as chronic idiopathic myelofibrosis), myelofibrosis secondary to polycythemia vera (PPV-MF) or myelofibrosis secondary to essential thrombocythemia ( Myelofibrosis secondary to primary thrombocytosis (PET-MF) in adult patients, can be treated for splenomegaly or other symptoms associated with the above diseases.
  • the Chinese invention patent application whose publication number is CN103002875B discloses a cream for the formation of an oil-in-water emulsion for topical skin application.
  • the oil phase is selected from One or more substances of petrolatum, fatty alcohol, mineral oil, triglyceride and dimethylsiloxane
  • the emulsifier component contains one or more substances independently selected from glycerin fatty esters and sorbitan fatty esters
  • the substance and the solvent component contain one or more substances independently selected from alkylene glycols and polyalkylene glycols
  • the stabilizer component contains one or more substances independently selected from polysaccharides
  • general external preparations The pH value is required to be between 4.5-7, while the pH value of the preparation sample in this patent is about 3.1-3.6, which has certain skin irritation to patients when used, and is not suitable for parts with certain damaged skin.
  • the U.S. invention patent with the publication number US20200405627A1 discloses a method for treating vitiligo using 1.5% w/w ruxolitinib oil-in-water emulsion
  • the oil component of the ruxolitinib oil-in-water emulsion is selected from petrolatum, fatty alcohol, mineral oil , substances of triglycerides and polydimethylsiloxanes, substances of emulsifier components glycerol fatty acid esters and sorbitan fatty acid esters, solvent components of alkylene glycols and polyalkylene glycols
  • the substance, the stabilizer component is selected from polysaccharide substances such as xanthan gum.
  • the in vitro release test is a recognized and effective method for evaluating semi-solid preparations (such as creams, ointments, gels, etc.) at present, and it is an in vitro embodiment of the drug efficacy of the preparation in vivo.
  • In vitro release has the characteristics of strong operability, good reproducibility and high sensitivity. Therefore, appropriate in vitro release test methods will be helpful for the development of transdermal formulations.
  • the Chinese invention patent with publication number CN111337640A discloses a method for rapidly evaluating the in vitro release of external preparations. At present, the Franz diffusion cell method is mainly used to evaluate the in vitro release and permeation of external preparations.
  • In vitro release uses artificial membranes, and permeation uses isolated rat abdominal skin or isolated Panama pig skin or artificial biomimetic membranes ( Membrane) to examine the skin penetration rate of drugs.
  • One aspect of the present invention is to provide a ruxolitinib composition comprising a therapeutic agent and an emulsifier.
  • the therapeutic agent is ruxolitinib and/or a pharmaceutically acceptable salt thereof, the content of which is 0.5%-2.0% by weight of the composition based on free base.
  • the emulsifier is polyoxyethylene alkyl aryl ether, polyoxyethylene monolaurate, polyoxyethylene monolaurate, polyoxyethylene lauryl ether, polyoxyethylene hydrogenated castor oil , one or more of polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene monooleate, polyoxyethylene monolaurate, vitamin E succinic acid, preferably polyoxyethylene hydrogenated castor oil, polyoxyethylene One or more of castor oil, polyoxyethylene monooleate, polyoxyethylene monolaurate, vitamin E succinic acid, more preferably polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E succinic acid one or more species.
  • the emulsifier is one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E succinic acid, and the polyoxyethylene hydrogenated castor oil is selected from RH20, RH30 , one or more of RH40, RH50, RH60, preferably one of RH40 and RH60, more preferably RH40; polyoxyethylene castor oil is selected from one or more of EL20, EL25, EL30, EL35, EL40, EL60, Preferably one or more of EL30, EL35, EL40, more preferably EL35; the vitamin E succinic acid is selected from one or more of VE-TPGS 400, VE-TPGS1000, VE-TPGS1500, preferably VE-TPGS 1000 ;
  • the emulsifier content is 2%-30% by weight of the composition, more preferably 3%-12%.
  • the ruxolitinib composition comprises a therapeutic agent, an emulsifier, and a co-emulsifier.
  • the co-emulsifier comprises propylene glycol monocaprylate (Capryol-90), the content of which is 0-10% by weight of the composition, preferably 0-7%;
  • the ruxolitinib composition comprises a therapeutic agent, an emulsifier, a co-emulsifier, and a solvent.
  • the solvent is propylene glycol, diethylene glycol monoethyl ether (HP), one or more of ethanol, and its content is 0-60% by weight of the composition, preferably 0-50% %;
  • the ruxolitinib composition comprises a therapeutic agent, an emulsifier, a co-emulsifier, a solvent, and an aqueous phase.
  • the aqueous phase includes water and optional auxiliary materials.
  • a pH regulator, an osmotic pressure regulator, a preservative, an antioxidant and a sunscreen can be added to the water to further improve the preparation of the ruxolitinib composition to meet the needs of different clinical administration routes, and its content is calculated in weight percent
  • the sum of therapeutic agent, emulsifier, co-emulsifier and solvent is 100%.
  • the ruxolitinib composition comprises:
  • Therapeutic agent ruxolitinib or a pharmaceutically acceptable salt thereof
  • Emulsifier one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E succinic acid;
  • Co-emulsifier propylene glycol monocaprylate
  • Solvent one or more of propylene glycol, diethylene glycol monoethyl ether, ethanol;
  • the ruxolitinib composition comprises:
  • Therapeutic agent 0.5% to 2.0% of ruxolitinib or its pharmaceutically acceptable salt (calculated as free base);
  • Emulsifier one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E succinic acid, 2%-30%, further preferably 3%-12%;
  • Co-emulsifier propylene glycol monocaprylate 0-10%, preferably 0-7%;
  • Solvent one or more of propylene glycol, diethylene glycol monoethyl ether, ethanol, 0-60%, preferably 0-50%;
  • the preparation method of the ruxolitinib composition is as follows: 1) heating the therapeutic agent, emulsifier, and co-emulsifier to 30-70°C, preferably 35-60°C, and adding the water phase after stirring to obtain or 2) Therapeutic agent, co-emulsifier, mixed and heated to 30-70°C and stirred to dissolve, then add emulsifier, preferably at 35-60°C, add water phase after stirring.
  • the preparation method of the ruxolitinib composition is as follows: 1) heating the therapeutic agent, emulsifier, solvent, and co-emulsifier to 30-70°C, preferably 35-60°C, adding water after stirring or 2) Therapeutic agent, co-emulsifier, and solvent are mixed and heated to 30-70°C, stirred and dissolved, and then the emulsifier is added, preferably at 35-60°C, and the water phase is added after stirring.
  • the present invention provides a use of the aforementioned ruxolitinib composition, which can be used for the preparation of pharmaceutical preparations, including but not limited to tablets, granules, Pills, ointments, creams, gels.
  • the present invention provides a use of the aforementioned ruxolitinib composition, specifically ruxolitinib gel, which contains the aforementioned ruxolitinib combination In addition to the material, it also contains a gel material.
  • the gel material is selected from one of carbomer, methyl cellulose, sodium carboxymethyl cellulose, chitosan, gellan gum, guar gum, sodium carboxymethyl cellulose, and hydroxypropyl cellulose
  • carbomer methyl cellulose, sodium carboxymethyl cellulose, chitosan, gellan gum, guar gum, sodium carboxymethyl cellulose, and hydroxypropyl cellulose
  • the ruxolitinib gel comprises:
  • Therapeutic agent ruxolitinib, or a pharmaceutically acceptable salt thereof;
  • Emulsifier one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E succinic acid;
  • Co-emulsifier propylene glycol monocaprylate
  • Solvent one or more of propylene glycol, diethylene glycol monoethyl ether, ethanol;
  • Gel material one or more of carbomer, methyl cellulose, sodium carboxymethyl cellulose, chitosan, gellan gum, guar gum, sodium carboxymethyl cellulose, hydroxypropyl cellulose kind;
  • the ruxolitinib gel comprises:
  • Therapeutic agent 0.5% to 2.0% of ruxolitinib or its pharmaceutically acceptable salt (calculated as free base);
  • Emulsifier one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E succinic acid, 2%-30%, preferably 3%-12%;
  • Co-emulsifier propylene glycol monocaprylate 0-10%, preferably 0-7%;
  • Solvent one or more of propylene glycol, diethylene glycol monoethyl ether, ethanol 0-60%, preferably 0-50%, more preferably 2-50%;
  • Gel material one or more of carbomer, methyl cellulose, sodium carboxymethyl cellulose, chitosan, gellan gum, guar gum, sodium carboxymethyl cellulose, hydroxypropyl cellulose 0.10% to 2.0%, preferably 0.25% to 1.0%;
  • the ruxolitinib gel comprises:
  • Therapeutic agent 0.5% to 2.0% of ruxolitinib or its pharmaceutically acceptable salt (calculated as free base);
  • Emulsifier polyoxyethylene hydrogenated castor oil 1-10%, polyoxyethylene castor oil 1-20%, vitamin E succinic acid 0-20%;
  • Co-emulsifier Propylene Glycol Monocaprylate 0-20%;
  • Solvent propylene glycol 1-50%, diethylene glycol monoethyl ether 1-10%, ethanol 0-50%;
  • Gel material Carbomer 0.10% ⁇ 10.0%;
  • the ruxolitinib gel comprises:
  • Therapeutic agent 0.5% to 2.0% of ruxolitinib or its pharmaceutically acceptable salt (calculated as free base);
  • Emulsifier polyoxyethylene hydrogenated castor oil 1.0-5.0%, polyoxyethylene castor oil 1-10%, vitamin E succinic acid 0-10%;
  • Co-emulsifier Propylene Glycol Monocaprylate 0-10%;
  • Solvent propylene glycol 1-45%, diethylene glycol monoethyl ether 1-5.0%, ethanol 0-40%;
  • Gel material Carbomer 0.10% ⁇ 5.0%;
  • the ruxolitinib gel comprises:
  • Therapeutic agent 0.5% to 2.0% of ruxolitinib or its pharmaceutically acceptable salt (calculated as free base);
  • Emulsifier polyoxyethylene hydrogenated castor oil 1-2%, polyoxyethylene castor oil 4-10%, vitamin E succinic acid 0-5%;
  • Co-emulsifier Propylene Glycol Monocaprylate 0-7%;
  • Solvent propylene glycol 5-45%, diethylene glycol monoethyl ether 2-5%, ethanol 0-15%;
  • the preparation method of the ruxolitinib composition gel comprises the following steps: mixing and heating the above ruxolitinib composition except the water phase to 30-70°C, preferably 35-60°C, Stir to completely melt the excipients and dissolve the therapeutic agent, then stir evenly with the swollen carbomer, then add the water phase to obtain the ruxolitinib gel.
  • Another aspect of the present invention is to provide a ruxolitinib composition and the use of ruxolitinib gel for treating diseases as described above, and the diseases are dermatitis, psoriasis, vitiligo, hidradenitis, One or more of urticaria and alopecia areata.
  • the beneficial effect of the present invention is: the average particle diameter range of the ruxolitinib composition provided by the present invention is 10-200nm, the PDI value is 0.05-0.40, and further can reach the average particle diameter range of 10-100nm, the PDI value is 0.05- 0.20, and good stability, not easy to produce aggregation, flocculation, etc.
  • the gel made from the composition of the present invention has improved membrane penetration efficiency and can meet the stability of topical skin administration at a pH value of 5-7.
  • the gel made from the composition of the present invention has better efficacy in treating psoriasis than ruxolitinib cream, and commercially available calcipotriol and phenvimod.
  • Fig. 2 PASI appearance score curve chart in embodiment 6
  • Diethylene glycol monoalkyl ether should be understood as more than one diethylene glycol substituted by C1 to C6 alkyl ethers.
  • Diethylene glycol monoalkyl ether is one or both of diethylene glycol monoethyl ether (DGME) and diethylene glycol monomethyl ether (DGMM).
  • DGME diethylene glycol monoethyl ether
  • DGMM diethylene glycol monomethyl ether
  • HP in the embodiment of the present invention refers to diethylene glycol monoalkyl ether, further diethylene glycol monoethyl ether.
  • PPI polydispersity index
  • polydispersity index polydispersity index
  • its physical meaning is the uniformity of particle size distribution, and the smaller the value distribution range, the more uniform the particle size dispersion.
  • the detection instrument for the average particle size and PDI value of the ruxolitinib composition is: Malvern Nano S90.
  • Embodiment 1 ruxolitinib composition and preparation method thereof
  • the ruxolitinib composition of the present invention contains the following ingredients:
  • Therapeutic agent ruxolitinib (content is calculated as free base)
  • Emulsifier one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E succinic acid
  • Co-emulsifier Propylene Glycol Monocaprylate (Capryol-90)
  • Solvent one or more of propylene glycol, diethylene glycol monoethyl ether (HP), ethanol
  • Water phase contains water and pharmaceutically acceptable auxiliary materials, which include but not limited to pH regulators, osmotic pressure regulators, preservatives, antioxidants, and sunscreens.
  • Prescription 1-Prescription 7 are prepared by method 1: mix the therapeutic agent, emulsifier, co-emulsifier, and solvent and heat to 50°C, stir to completely melt the excipients and dissolve the therapeutic agent, then add the water phase to obtain the product.
  • Prescription 8-Prescription 14 are prepared by method 2: mix the therapeutic agent, co-emulsifier, and solvent and heat to 50°C, stir to completely melt the excipients and dissolve the therapeutic agent, then add the emulsifier, stir and then add the water phase.
  • the emulsifier can be one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E succinic acid, and its content is 3-12% w/w; co-emulsifier content is 0-7% w/w; solvent content is 2-50% w/w; water phase content is related to therapeutic agent, emulsifier, co-emulsifier, solvent content The sum is 100%, and the obtained ruxolitinib compositions have average particle diameters below 100 nm and PDI values below 0.2.
  • Embodiment 2 investigation of different emulsifiers
  • Embodiment 3 Stability investigation of ruxolitinib composition prescription
  • ruxolitinib composition prescription 12 in Example 1 was selected to investigate the pH stability of the ruxolitinib composition prescription of the present invention.
  • Recipe 12 was adjusted to different pH values using triethanolamine, and room temperature and accelerated experiments were conducted to investigate the content of ruxolitinib in the prescription. The specific results are shown in Table 5.
  • Embodiment 4 ruxolitinib gel and its stability
  • Prescription 9, prescription 10, and prescription 12 in Example 2 are selected to make gel prescription 1, gel prescription 2, and gel prescription 3 respectively, and the total weight of the gel is 100g.
  • the preparation method is as follows: mix the above-mentioned ruxolitinib composition except the water phase and heat to 45°C, stir to completely melt the auxiliary materials and dissolve the therapeutic agent, stir evenly with the swollen carbomer, and then add the water phase to obtain Ruxolitinib composition gel.
  • Embodiment 5 In vitro osmotic release study of ruxolitinib gel
  • Qn cumulative drug penetration per unit area at the nth time point (unit: mg/cm 2 );
  • Cn the drug concentration at the nth time point (unit: mg/mL);
  • C i-1 the drug concentration at the i-1th time point (unit: mg/mL);
  • V the volume of the receiving pool (unit: mL);
  • the comparative example was prepared with reference to the prescription shown in Table 4 in Example 3 of Inset Holding Company's Chinese invention patent CN103002875B specification (ruxolitinib free base concentration 1.0%). .
  • Table 7 In vitro cumulative release of the formulation of the present invention (unit: mg/cm 2 )
  • Example 6 Drug efficacy research of ruxolitinib gel for psoriasis
  • the medicament of the present invention can effectively improve the symptoms of psoriasis, and the therapeutic effect of the medicament of the present invention on psoriasis can be further confirmed through the following experimental studies.
  • Table 8 The prescription composition of gel 1 and gel 2 (based on total weight 100g)
  • Experimental grouping The experiment was divided into 8 groups, 6 rats in each group, and 48 rats were used in the experiment.
  • mice were adaptively fed for 7 days to make a psoriasis vulgaris (PSO) mouse model.
  • the modeling method is as follows: the skin area on the back of the mouse was cleaned to about 2cm*3cm, and 50mg of 5% imiquimod cream was applied topically on the exposed skin every morning for 3 consecutive days for model preparation, and modeling drugs were continued in the later stage.
  • Model verification This model already has a mature SOP standard, and there is no need to use another mouse for model verification.
  • Treatment (3 days after modeling), the corresponding drug treatment was carried out on the 4th day, and 5% IMQ was continued to be given during the administration treatment to maintain the modeling, and the modeling drugs were maintained according to the number of days of administration.
  • Group 1) blank control group (no treatment) without any treatment
  • Group 2 the model group was smeared with 5% imiquimod ointment 62.5mg/only to maintain the model, without any treatment;
  • the model group was smeared with 5% imiquimod ointment 62.5mg/only to maintain the model, and smeared with blank gel every day, the frequency was 2 times/day, and the treatment continued for 7 days;
  • the model group was smeared with 5% imiquimod ointment 62.5mg/only to maintain the model, and in addition, the positive drug A (calcipotriol ointment) was smeared every day, the frequency was 2 times/day, and the treatment continued for 7 days;
  • the model group was smeared with 5% imiquimod ointment 62.5mg/only to maintain the model, and in addition, the positive drug B (Benvimod cream) was smeared every day, the frequency was 2 times/day, and the treatment continued for 7 days;
  • the 6th) group the model group was smeared with 5% imiquimod ointment 62.5mg/only to maintain the model, and in addition, smeared the test drug (gel 1 of this embodiment) every day, the frequency was 2 times/day, and treated continuously for 7 days;
  • the 7th) group the model group is smeared 5% imiquimod ointment 62.5mg/only to maintain modeling, additionally smears test drug (commercially available ruxolitinib phosphate cream) every day, frequency 2 times/day, continuous Dosing sequence for 7 days of treatment: 1 dose of therapeutic drug in the morning, 1 dose of modeling drug at noon, and 1 dose of therapeutic drug in the evening.
  • the 8th) group the model group smears 5% imiquimod ointment 62.5mg/only to maintain modeling, and daubs test drug (gel 2 of this embodiment) every day in addition, frequency 2 times/day, continuous treatment for 7 days
  • the PASI score was scored. From the score trend chart of 7 days after drug administration, after 4 days of drug administration, compared with the model group, the PASI score decreased significantly. On the 4th day, compared with the model group, the benzodiazepines and the gel group of the present invention all decreased significantly, and compared with the blank gel group, they also decreased significantly (p ⁇ 0.05 or p ⁇ 0.01). On the 5th day of administration, compared with the model group, the PASI score of the gel group of the present invention decreased significantly, and compared with the blank gel group, the gel group decreased significantly. On the 6th day and the 7th day of administration, compared with the model group and the blank gel group, the scores of the gel group of the present invention decreased significantly (p ⁇ 0.01), see Figure 1 and Figure 2 for details.

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Abstract

本发明公开了一种芦可替尼组合物，所述组合物包含：芦可替尼或其药学上可接受的盐、乳化剂、助乳化剂、溶剂和水相。所述的乳化剂包含聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种，助乳化剂包含丙二醇单辛酸酯，溶剂包含丙二醇、二乙二醇单乙醚、乙醇一种或多种。本发明的芦可替尼组合物具有理想的粒径和PDI。进一步的本发明提供一种芦可替尼凝胶，相比于芦可替尼乳膏，提高了透膜效率、可满足外用皮肤在pH值5-7条件下给药的稳定性，且相比于芦可替尼乳膏、以及市售的卡泊三醇和苯维莫德，在银屑病治疗方面具有更好的药效。

Description

一种芦可替尼组合物及其制备方法 技术领域
本发明属于药物制剂领域，具体涉及一种芦可替尼或其药学上可接受的盐的组合物及其制备方法。
背景技术
芦可替尼(又称鲁索替尼，鲁索利替尼，Ruxolitinib)其化学名为(R)-3-环戊基-3-[4-(7H-吡咯并[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈，是一种JAK1和JAK2酪氨酸激酶抑制剂，用于中危或高危的原发性骨髓纤维化(primary myelofibrosis，PMF)(亦称为慢性特发性骨髓纤维化)、真性红细胞增多症继发的骨髓纤维化(Myelofibrosis secondary to polycythemia vera，PPV-MF)或原发性血小板增多症继发的骨髓纤维化(Myelofibrosis secondary to primary thrombocytosis，PET-MF)的成年患者，可以治疗与上述疾病相关的脾肿大或其他症状。
Figure PCTCN2022126399-appb-000001
公开号为CN103002875B的中国发明专利申请公开了一种用于局部皮肤施用的水包油乳液形成的霜剂，该霜剂所用的治疗剂(R)-3-环戊基-3-[4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基]丙腈(即芦可替尼)或其药学上可接受的盐，油相选自凡士林、脂肪醇、矿物油、甘油三酯和二甲基硅氧烷的一种或多种物质、乳化剂组分包含独立地选自甘油脂肪酯和山梨醇酐脂肪酯的一种或多种物质、溶剂组分包含独立地选自亚烷基二醇和聚亚烷基二醇的一种或多种物质、稳定剂组分包含独立地选自多糖的一种或多种物质，一般外用制剂pH值要求在4.5-7之间，而该专利中的制剂样品pH值在3.1-3.6左右，使用时对患者具有一定的皮肤刺激性，且不适用于皮肤有一定破损的部位。
公开号US20200405627A1的美国发明专利公开了使用1.5％w/w芦可替尼水包油乳液治疗白癜风的方法，所述芦可替尼水包油乳液油组分选自凡士林,脂肪醇,矿物油,甘油三酸酯和聚二甲基硅氧烷的物质，乳化剂组分甘油脂肪酸酯和脱水山梨糖醇脂肪酸酯的物质，溶剂组分亚烷基二醇和聚亚烷基二醇的物质，稳定剂组分选自多糖的物质如黄原胶。
体外释放试验是目前评价半固体制剂(如乳膏剂、软膏剂、凝胶剂等)的公认的有效方法，是制剂体内药效的体外体现。体外释放具有可操作性强、重现性好、灵敏度高的特点。因此，合适的体外释放试验方法将有助于透皮吸收制剂的开发。公开号CN111337640A的中国发明专利公开了一种快速评价外用制剂体外释放的方法。目前主要使用Franz扩散池法评价外用制剂体外释放和渗透，体外释放则使用人工膜，渗透则使用离体大鼠腹部皮肤或离体巴拿马香猪的皮肤或人工仿生膜(
Figure PCTCN2022126399-appb-000002
Membrane)考察药物的皮肤透过率。
发明内容
本发明的一方面是提供一种芦可替尼组合物，所述组合物含有治疗剂和乳化剂。
根据本发明的一些实施例，所述治疗剂为芦可替尼和/或其药学上可接受的盐，其含量以基于游离碱按所述组合物重量计的0.5％～2.0％。
根据本发明的一些实施例，所述乳化剂为聚氧乙烯烷基芳基醚、聚氧乙烯单月桂酸酯、聚氧乙烯单月桂酸酯、聚氧乙烯月桂醚、聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、聚氧乙烯植物油、聚氧乙烯单油酸酯、聚氧乙烯单月桂酸酯、维生素E琥珀酸的一种或多种，优选聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、聚氧乙烯单油酸酯、聚氧乙烯单月桂酸酯、维生素E琥珀酸的一种或多种，进一步优选聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种。
根据本发明的一些实施例，所述乳化剂为聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种，所述的聚氧乙烯氢化蓖麻油选自RH20、RH30、RH40、RH50、RH60的一种或多种，优选RH40和RH60的一种，更优选RH40；聚氧乙烯蓖麻油选自EL20、EL25、EL30、EL35、EL40、EL60的一种或多种，优选EL30、EL35、EL40的一种或多种，更优选EL35；所述的维生素E琥珀酸选自VE-TPGS 400、VE-TPGS1000、VE-TPGS1500的一种或多种，优选VE-TPGS 1000；乳化剂含量按所述组合物重量计的2％-30％，进一步的优选3％-12％。
根据本发明的一些实施例，所述的芦可替尼组合物包含治疗剂、乳化剂、助乳化剂。
根据本发明的一些实施例，所述助乳化剂包含丙二醇单辛酸酯(Capryol-90)，其含量按所述组合物重量计0～10％，优选0～7％；
根据本发明的一些实施例，所述的芦可替尼组合物包含治疗剂、乳化剂、助乳化剂、溶剂。
根据本发明的一些实施例，所述溶剂为丙二醇，二乙二醇单乙醚(HP)，乙醇的一种或多种，其含量按所述组合物重量计0～60％，优选0～50％；
根据本发明的一些实施例，所述的芦可替尼组合物包含治疗剂、乳化剂、助乳化剂、溶剂、水相。
根据本发明的一些实施例，所述水相包括水和任选的辅料。可以在水中添加pH调节剂、渗透压调节剂、防腐剂、抗氧剂及遮光剂等，进一步提高所述芦可替尼组合物制剂满足临床不同给药途径的需求，其含量以重量百分比计为与治疗剂、乳化剂、助乳化剂、溶剂之和为100％。
在一些实施例中，所述芦可替尼组合物包含：
治疗剂：芦可替尼或其药学上可接受的盐；
乳化剂：聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种；
助乳化剂：丙二醇单辛酸酯；
溶剂：丙二醇、二乙二醇单乙醚、乙醇一种或多种；
以及至100wt％的水；
在一些实施例中，以所述组合物的总重量计，所述芦可替尼组合物包含：
治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
乳化剂：聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种，2％-30％，进一步的优选3％-12％；
助乳化剂：丙二醇单辛酸酯0～10％，优选0～7％；
溶剂：丙二醇、二乙二醇单乙醚、乙醇一种或多种，0～60％，优选0～50％；
以及至100wt％的水；
根据本发明的实施例，所述芦可替尼组合物的制备方法为：1)将治疗剂、乳化剂、助乳化剂加热至30-70℃，优选35-60℃，搅拌后加水相即得；或2)治疗剂、助乳化剂、混合加热至30-70℃搅拌溶解，再加入乳化剂，优选35-60℃，搅拌后加水相即得。
根据本发明的实施例，所述芦可替尼组合物的制备方法为：1)将治疗剂、乳化剂、溶剂、助乳化剂加热至30-70℃，优选35-60℃，搅拌后加水相即得；或2)治疗剂、助乳化剂、溶剂混合加热至30-70℃搅拌溶解，再加入乳化剂，优选35-60℃，搅拌后加水相即得。
在本发明的又一方面，本发明提供了一种前面所述芦可替尼组合物的用途，所述组合物可用于制备药物制剂，所述制剂包括但不限于片剂、颗粒剂、微丸剂、软膏剂、乳膏剂、凝胶剂。
在本发明的又一方面，本发明提供了一种前面所述芦可替尼组合物的用途，具体的为芦可替尼凝胶，所述凝胶除含有前面所述芦可替尼组合物外，还含有凝胶材料。所述凝胶材料选自卡波姆、甲基纤维素、羧甲基纤维素钠、壳聚糖、结冷胶、瓜尔胶、羧甲基纤维素钠、羟丙基纤维素中的一种或多种，优选卡波姆，其含量以重量百分比计为0.10％～2.0％，进一步的优选0.25％～1.0％。
在一些实施例中，所述芦可替尼凝胶包含：
治疗剂：芦可替尼，或其药学上可接受的盐；
乳化剂：聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种；
助乳化剂：丙二醇单辛酸酯；
溶剂：丙二醇、二乙二醇单乙醚、乙醇一种或多种；
凝胶材料：卡波姆、甲基纤维素、羧甲基纤维素钠、壳聚糖、结冷胶、瓜尔胶、羧甲基纤维素钠、羟丙基纤维素中的一种或多种；
以及至100wt％的水；
在一些实施例中，以所述凝胶的总重量计，所述芦可替尼凝胶包含：
治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
乳化剂：聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种，2％-30％、优选3％-12％；
助乳化剂：丙二醇单辛酸酯0～10％、优选0～7％；
溶剂：丙二醇、二乙二醇单乙醚、乙醇一种或多种0～60％，优选0～50％、更优选2～50％；
凝胶材料：卡波姆、甲基纤维素、羧甲基纤维素钠、壳聚糖、结冷胶、瓜尔胶、羧 甲基纤维素钠、羟丙基纤维素中的一种或多种0.10％～2.0％，优选0.25％～1.0％；
以及至100wt％的水；
在一些实施例中，以所述凝胶的总重量计，所述芦可替尼凝胶包含：
治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
乳化剂：聚氧乙烯氢化蓖麻油1～10％、聚氧乙烯蓖麻油1～20％、维生素E琥珀酸0～20％；
助乳化剂：丙二醇单辛酸酯0～20％；
溶剂：丙二醇1～50％、二乙二醇单乙醚1～10％、乙醇0～50％；
凝胶材料：卡波姆0.10％～10.0％；
以及至100wt％的水；
在一些实施例中，以所述凝胶的总重量计，所述芦可替尼凝胶包含：
治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
乳化剂：聚氧乙烯氢化蓖麻油1.0～5.0％、聚氧乙烯蓖麻油1～10％、维生素E琥珀酸0～10％；
助乳化剂：丙二醇单辛酸酯0～10％；
溶剂：丙二醇1～45％、二乙二醇单乙醚1～5.0％、乙醇0～40％；
凝胶材料：卡波姆0.10％～5.0％；
以及至100wt％的水；
在一些实施例中，以所述凝胶的总重量计，所述芦可替尼凝胶包含：
治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
乳化剂：聚氧乙烯氢化蓖麻油1～2％、聚氧乙烯蓖麻油4～10％、维生素E琥珀酸0～5％；
助乳化剂：丙二醇单辛酸酯0～7％；
溶剂：丙二醇5～45％、二乙二醇单乙醚2～5％、乙醇0～15％；
凝胶材料：卡波姆0.25％～1.0％；
以及至100wt％的水；
根据本发明的实施例，所述芦可替尼组合物凝胶的制备方法包括如下步骤：将上述芦可替尼组合物除水相外混合加热至30-70℃，优选35-60℃，搅拌使辅料完全融化及 治疗剂溶解后，再与溶胀好的卡波姆搅拌均匀后加入水相，即得芦可替尼凝胶。
本发明的又一方面是提供一种如前所述芦可替尼组合物和芦可替尼凝胶用于治疗疾病的用途，所述的疾病为皮炎、银屑病、白癜风、汗腺炎、荨麻疹、斑秃的一种或多种。
本发明的有益效果为：本发明提供的芦可替尼组合物的平均粒径范围为10～200nm，PDI值0.05～0.40，进一步的可以达到平均粒径范围为10-100nm，PDI值0.05-0.20，且稳定性好、不易产生聚集、絮凝等。更进一步的，以本发明组合物制成的凝胶相比于芦可替尼乳膏，提高了透膜效率、可满足外用皮肤在pH值5-7条件下给药的稳定性。更进一步的，以本发明组合物制成的凝胶相比于芦可替尼乳膏、以及市售的卡泊三醇和苯维莫德，在银屑病治疗方面具有更好的药效。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
附图说明
图1：实施例6中给药后7天PASI评分
图2：实施例6中PASI外观评分曲线图
具体实施方式
以下实施例中所用试剂和原料均可通过商购获得。
“二乙二醇单烷基醚”应该被理解为一种以上被C1至C6烷基醚取代的二乙二醇。二乙二醇单烷基醚是二乙二醇单乙醚(DGME)和二乙二醇单甲醚(DGMM)中的一种或两种。
本发明实施例中的HP代指二乙二醇单烷基醚，进一步的是二乙二醇单乙醚。
本发明中“PDI”是多分散性指数(polydispersity index)的简称，其物理含义是粒径分布的均匀性，其值分布范围越小则粒径分散越均匀。
芦可替尼组合物的平均粒径和PDI值的检测仪器为：马尔文Nano S90。
实施例1：芦可替尼组合物及其制备方法
一、处方组成
本发明的芦可替尼组合物含有以下成分：
治疗剂：芦可替尼(含量以游离碱计)
乳化剂：聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种
助乳化剂：丙二醇单辛酸酯(Capryol-90)
溶剂：丙二醇、二乙二醇单乙醚(HP)、乙醇一种或多种
水相：包含水和药学上可接受的辅料，所述辅料包括但不限于pH调节剂、渗透压调节剂、防腐剂、抗氧剂、遮光剂。
二、芦可替尼组合物的制备
处方1-处方7以方法1制备：将治疗剂、乳化剂、助乳化剂、溶剂混合加热至50℃，搅拌使辅料完全融化及治疗剂溶解后，加入水相，即得。
处方8-处方14以方法2制备：将治疗剂、助乳化剂、溶剂混合加热至50℃，搅拌使辅料完全融化及治疗剂溶解后，再加入乳化剂，搅拌后加水相即得。
表1：组分比例考察
Figure PCTCN2022126399-appb-000003
表2：组分比例考察
Figure PCTCN2022126399-appb-000004
由表1、表2可知，当治疗剂含量为0.5％～2.0％时，乳化剂可以为聚氧乙烯氢化蓖 麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种，其含量为3～12％w/w；助乳化剂含量则为0～7％w/w；溶剂含量则为2～50％w/w；水相含量与治疗剂、乳化剂、助乳化剂、溶剂含量之和为100％，所得的芦可替尼组合物具有平均粒径均在100nm以下、PDI值均在0.2以下。
实施例2：不同乳化剂考察
实施例2与实施例1的制备方法相同，不同之处仅在于所使用乳化剂种类、用量，具体如下表所示：
表3：对比例考察
Figure PCTCN2022126399-appb-000005
由表3可知，乳化剂选择Kolliphor hs15、甘油脂肪酯、泊洛沙姆407、吐温80、聚氧乙烯十六烷基醚、聚氧乙烯失水山梨醇单月桂酸酯，均不能形成理想粒径和PDI的芦可替尼组合物。
实施例3：芦可替尼组合物处方的稳定性考察
选取实施例1中芦可替尼组合物处方2、处方8、处方9、处方12，根据本发明芦可替尼组合物处方在25℃和40℃下，一个月和两个月平均粒径和PDI的变化，以考察本发明芦可替尼组合物处方的稳定性，具体结果如表4所示。
表4：芦可替尼组合物的稳定性
Figure PCTCN2022126399-appb-000006
结果可知，本发明提供的芦可替尼组合物平均粒径和PDI在室温和40℃下均没有发生显著性的变化，稳定性良好。
另外选取实施例1中芦可替尼组合物处方12，考察本发明芦可替尼组合物处方的pH稳定性。将处方12使用三乙醇胺调节至不同的pH值，进行室温和加速实验考察处方中芦可替尼的含量，具体结果如表5所示。
表5：芦可替尼组合物处方的pH稳定性
Figure PCTCN2022126399-appb-000007
结果表明，本发明芦可替尼组合物处方在不同pH值3-7条件下芦可替尼的含量均未发生明显变化，稳定性良好。
实施例4：芦可替尼凝胶及其稳定性
选取实施例2中的处方9、处方10、处方12分别制成凝胶处方1、凝胶处方2、凝胶处方3，凝胶总重为100g。
制备方法为：将上述芦可替尼组合物除水相外混合加热至45℃，搅拌使辅料完全融化及治疗剂溶解后，与溶胀好的卡波姆搅拌均匀后再加入水相，即得芦可替尼组合物凝胶。
根据凝胶处方1、凝胶处方2、凝胶处方3芦可替尼的含量考察本发明提供的凝胶 处方的稳定性，具体结果如表6所示。
表6：芦可替尼凝胶处方稳定性
Figure PCTCN2022126399-appb-000008
结果表明，凝胶处方1、凝胶处方2、凝胶处方3的pH值均在5-7之间，且含量在25℃及40℃条件下没有发生显著性的变化，温度稳定性良好。
实施例5：芦可替尼凝胶的体外渗透释放研究
实验方法：采用Franz扩散池(天津博宇伟业科技有限公司，型号TP-6)，将人工透皮膜(
Figure PCTCN2022126399-appb-000009
Membrane)固定于扩散池与接收池之间，扩散池直径为1.5cm，接收池体积为15mL，扩散池装入约300mg芦可替尼凝胶样品，接收池注入接收液(0.05M的pH 7.2-7.4的磷酸盐缓冲液)。水浴温度为32±1℃，恒温磁力搅拌转速为300rpm/min。分别于1h、2h、4h、6h、8h从接收池中取出1.5mL，同时及时补加相同量同温度的接收液至接收池，将取出的接收液样品经高速离心(18000rpm/min，离心10min)，取上清液HPLC法测定不同时间点溶液的浓度(C n)。
单位面积累积药物渗透量，计算公式如下:
Figure PCTCN2022126399-appb-000010
其中，
Qn：为第n个时间点单位面积的累积药物渗透量(单位：mg/cm 2)；
Cn：为第n个时间点的药物浓度(单位：mg/mL)；
C i-1：为第i-1个时间点的药物浓度(单位：mg/mL)；
V：为接收池体积(单位：mL)；
S：为有效渗透面积，本试验中为1.76625cm 2；
对比例参照因塞特控股公司中国发明专利CN103002875B说明书实施例3中表4所示的处方(芦可替尼游离碱浓度1.0％)制备而成。。
表7：本发明处方体外累积释放量(单位：mg/cm 2)
  凝胶处方1 凝胶处方2 凝胶处方3 对比乳膏处方
30min 0.0010 0.0005 0.0081 0.0000
1h 0.0044 0.0016 0.0256 0.0003
2h 0.0181 0.0104 0.0652 0.0068
4h 0.0662 0.0354 0.1430 0.0294
6h 0.1119 0.0689 0.2101 0.0508
8h 0.1521 0.1086 0.2767 0.0694
根据表8：凝胶处方1、凝胶处方2、凝胶处方3相比对比乳膏均具有更快的释放结果，体外释放量显著高于对比乳膏。
实施例6：芦可替尼凝胶银屑病药效研究
本发明药物能有效改善银屑病症状，本发明药物对银屑病的治疗效果，可通过下述实验研究得到进一步证实。
动物实验：寻常型银屑病(PSO)小鼠模型的建立和药物处理
1药物与试剂
实验材料：健康SPF级C57BL/6J小鼠(雌雄各半，8-9周龄，体重20-25g)48只，造模药物(5％咪喹莫特乳膏，四川明欣药业)；阳性对照药物(市售卡泊三醇软膏、市售本维莫德乳膏)；空白凝胶制剂；市售芦可替尼磷酸盐乳膏(简称原研乳膏，芦可替尼游离碱1.5％)；凝胶1；凝胶2；其中凝胶1和凝胶2的处方组成见表8。
表8：凝胶1和凝胶2的处方组成(以总重量100g计)
Figure PCTCN2022126399-appb-000011
2实验方法
2.1实验分组
实验分组：实验分8组，每组6只，实验共用48只。
1)空白对照组(除剃毛外不做任何处理)(N＝6只)；
2)PSO模型组(除涂抹咪喹莫特造模外不做任何处理)(N＝6只)；
3)PSO模型+空白凝胶制剂组(外用涂抹，频率2次/日，15mg/cm 2，连续治疗7天)(N＝6只)；
4)PSO模型+阳性药物A组(0.005％卡泊三醇软膏处理，外用涂抹，频率2次/日，15mg/cm 2，连续治疗7天)(N＝6只)；
5)PSO模型+阳性药物B组(1％本维莫德乳膏处理，外用涂抹，频率2次/日，15mg/cm 2，暂定连续治疗7天)(N＝6只)；
6)PSO模型+凝胶样品1(外用涂抹，频率2次/日，15mg/cm 2，连续治疗7天)(N＝6只)；
7)PSO模型+市售芦可替尼乳膏(外用涂抹，频率2次/日，15mg/cm 2，连续治疗7天)(N＝6只)；
8)PSO模型+凝胶样品2(外用涂抹，频率2次/日，15mg/cm 2，连续治疗7天)(N＝6只)。
实验步骤：
造模：小鼠适应性饲养7天，制作寻常型银屑病(PSO)小鼠模型。造模方式如下：清理小鼠背部皮肤面积约2cm*3cm，暴露皮肤处每天上午局部外用5％咪喹莫特乳膏50mg，连续使用3天，用于模型制备，后期继续给予造模药物。
模型验证：此模型已具备成熟的SOP标准，不再另设老鼠进行模型验证。
治疗：(造模3天后)，于第4天进行相应药物治疗，在给药治疗期间继续给予5％IMQ维持造模，根据给药天数情况维持给予造模药物。
第1)组：空白对照组(不治疗)不做任何处理；
第2)组：模型组涂抹5％咪喹莫特软膏62.5mg/只维持造模，不做任何治疗处理；
第3)组：模型组涂抹5％咪喹莫特软膏62.5mg/只维持造模，另外每日涂抹空白凝胶，频率2次/日，连续治疗7天；
第4)组：模型组涂抹5％咪喹莫特软膏62.5mg/只维持造模，另外每日涂抹阳性 药物A(卡泊三醇软膏)，频率2次/日，连续治疗7天；
第5)组：模型组涂抹5％咪喹莫特软膏62.5mg/只维持造模，另外每日涂抹阳性药物B(本维莫德乳膏)，频率2次/日，连续治疗7天；
第6)组：模型组涂抹5％咪喹莫特软膏62.5mg/只维持造模，另外每日涂抹供试药物(本实施例凝胶1)，频率2次/日，连续治疗7天；
第7)组：模型组涂抹5％咪喹莫特软膏62.5mg/只维持造模，另外每日涂抹供试药物(市售芦可替尼磷酸盐乳膏)，频率2次/日，连续治疗7天给药顺序：早上给予1次治疗药物、中午给予1次造模药物、晚上给予1次治疗药物。
第8)组：模型组涂抹5％咪喹莫特软膏62.5mg/只维持造模，另外每日涂抹供试药物(本实施例凝胶2)，频率2次/日，连续治疗7天
注：为了防止动物之间有舔舐药物的现象。动物背部涂完凝胶后，单独放置在无垫料的独立笼内活动一段时间，让凝胶自然风干(预计1小时内)，然后再放入饲养笼正常喂养。禁单独喂养，容易出现抑郁；禁用纱布包裹涂抹部位，会吸附走药剂。
2.2实验结果：PSO动物模型药物处理后的病理检测
实验步骤：
各组小鼠银屑病样皮损面积和疾病严重程度(PASI)评分：每天观察各组小鼠的体重和皮损变化情况(体重测定：从适应性饲养至给药结束，每只每天1次，共计17次；皮损评分：造模期间至给药期间每天进行评分，每只每天1次，共计10次)，采用数码照相的方法每日记录，并依据PASI评分标准，给予小鼠皮损处红斑、鳞屑及浸润增厚程度0～4的积分，将三者评分相加得到总的皮损严重程度评分，对各组小鼠积分取平均值后绘制皮损积分趋势线，观察各组小鼠皮损的变化情况。
2.3统计方法：
结果以均数±标准误(Mean±S.E.M.)表示，并采用SPSS 17.0统计软件进行分析，各组间差异比较用单因素方差分析(One-way ANOVA)(不假定方差齐性Dunnett's T3)。P<0.05表示差异具有统计学意义。
3结果：
本发明凝胶和阳性药物以及市售芦可替尼磷酸盐乳膏对咪喹莫特诱导小鼠银屑病模型皮损外观(PASI)情况的影响
根据小鼠皮损处红斑、鳞屑及浸润增厚程度进行PASI评分，从给药7天评分趋势图观察，在给予药物4天后，药物与模型组比较，PASI评分下降趋势明显。在第4天， 与模型组比较，苯维莫德，本发明凝胶组均有显著性下降，与空白凝胶组比较，也显著性下降(p<0.05或p<0.01)。在给药第5天，与模型组比较，本发明凝胶组的PASI评分显著下降，与空白凝胶比较，凝胶组显著下降。给药第6天和给药第7天，与模型组和空白凝胶组比较，本发明凝胶组评分显著性下降(p<0.01)，具体详见图1和图2。
4结论
本研究采用咪喹莫特诱导银屑病小鼠模型评价专利方和阳性药物及市售对比方芦克替尼乳膏的保护作用，结果显示，本发明凝胶和阳性药物及市售芦克替尼乳膏均能够显著性降低小鼠PASI评分，本发明凝胶与阳性药物及市售芦克替尼乳膏相比，本发明凝胶效果更优，说明本发明凝胶和阳性药物及市售芦克替尼乳膏均有治疗银屑病作用，而在同浓度下本发明凝胶外用治疗银屑病疗效优于阳性药物及市售芦克替尼乳膏。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含本发明的至少一个实施例或示例中。在本发明说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外在不互相矛盾的情况下，本领域技术人员可以将本说明书中描述的不同实施例或示例的特征进行结合或组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (15)

  1. 一种芦可替尼组合物，其特征在于，所述芦可替尼组合物含有治疗剂和乳化剂，所述治疗剂为芦可替尼或其药学上可接受的盐，其含量为以基于游离碱按所述组合物重量计的0.5％～2.0％，乳化剂为聚氧乙烯烷基芳基醚、聚氧乙烯单月桂酸酯、聚氧乙烯单月桂酸酯、聚氧乙烯月桂醚、聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、聚氧乙烯植物油、聚氧乙烯单油酸酯、聚氧乙烯单月桂酸酯、维生素E琥珀酸的一种或多种，优选聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、聚氧乙烯单油酸酯、聚氧乙烯单月桂酸酯、维生素E琥珀酸的一种或多种，更优选聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种。
  2. 如权利要求1所述的组合物，其特征在于，所述的乳化剂选自聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油和维生素E琥珀酸的一种或多种，所述的聚氧乙烯氢化蓖麻油选自RH20、RH30、RH40、RH50、RH60的一种或多种，优选RH40和RH60的一种，更优选RH40；聚氧乙烯蓖麻油选自EL20、EL25、EL30、EL35、EL40、EL60的一种或多种，优选EL30、EL35、EL40的一种或多种，更优选EL35；所述的维生素E琥珀酸选自VE-TPGS 400、VE-TPGS 1000、VE-TPGS1500的一种或多种，优选VE-TPGS 1000；所述的乳化剂含量为按所述组合物重量计的2％-30％，进一步的优选3％-12％。
  3. 如权利要求2所述的芦可替尼组合物，其特征在于，所述组合物包含助乳化剂，所述助乳化剂为丙二醇单辛酸酯，其含量为按所述组合物重量计0～10％，优选0～7％。
  4. 如权利要求3所述的芦可替尼组合物，其特征在于，所述组合物包含溶剂，所述溶剂选自丙二醇、二乙二醇单乙醚、乙醇一种或多种，其含量为按所述组合物重量计的0～60％，优选0～50％。
  5. 如权利要求4所述的芦可替尼组合物，其特征在于，所述组合物包含水相，所述水相包含水和任选的辅料，所述辅料选自pH调节剂、渗透压调节剂、防腐剂、遮光剂的一种或多种，其含量与治疗剂、乳化剂、助乳化剂、溶剂之和为按所述组合物重量 计的100％。
  6. 一种制备如权利要求1～5之一所述芦可替尼组合物的方法，其特征在于，所述方法包括如下步骤：将治疗剂、乳化剂、助乳化剂和/或溶剂加热至30-70℃，优选35-60℃，搅拌后加水相即得。
  7. 一种制备如权利要求1～5之一所述芦可替尼组合物的方法，其特征在于所述方法包括如下步骤：治疗剂、助乳化剂和/或溶剂混合加热至30-70℃搅拌溶解，优选35-60℃，再加入乳化剂，搅拌后加水相即得。
  8. 一种如权利要求1～5之一所述芦可替尼组合物在制备药物制剂中的用途，所述药物制剂选自胶囊剂、片剂、颗粒剂、微丸剂、软膏剂、乳膏剂、凝胶剂。
  9. 一种芦可替尼凝胶，其特征在于所述凝胶剂包含如权利要求1～5之一所述的组合物和凝胶材料。
  10. 如权利要求9所述的芦可替尼凝胶，所述凝胶材料选自卡波姆、结冷胶、瓜尔胶、羧甲基纤维素钠、羟丙基纤维素中的一种或多种，优选卡波姆，其含量为按所述凝胶重量计的0.10％～2.0％，进一步的优选0.25％～1.0％。
  11. 一种芦可替尼凝胶，其特征在于，所述芦可替尼凝胶包含：
    治疗剂：芦可替尼，或其药学上可接受的盐；
    乳化剂：聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种；
    助乳化剂：丙二醇单辛酸酯；
    溶剂：丙二醇、二乙二醇单乙醚、乙醇一种或多种；
    凝胶材料：卡波姆、甲基纤维素、羧甲基纤维素钠、壳聚糖、结冷胶、瓜尔胶、羧甲基纤维素钠、羟丙基纤维素中的一种或多种；
    以及至100wt％的水。
  12. 如权利要求11所述的芦可替尼凝胶，其特征在于，以所述凝胶的总重量计，所述芦可替尼凝胶包含：
    治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
    乳化剂：聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E琥珀酸一种或多种，2％-30％；
    助乳化剂：丙二醇单辛酸酯，0～20％；
    溶剂：丙二醇、二乙二醇单乙醚、乙醇一种或多种，0～60％，优选0～50％，更优选2～50％；
    凝胶材料：卡波姆、甲基纤维素、羧甲基纤维素钠、壳聚糖、结冷胶、瓜尔胶、羧甲基纤维素钠、羟丙基纤维素中的一种或多种，0.10％～2.0％；
    以及至100wt％的水；
    优选的，其特征在于，以所述凝胶的总重量计，所述芦可替尼凝胶包含：
    治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
    乳化剂：聚氧乙烯氢化蓖麻油1～10％、聚氧乙烯蓖麻油1～20％、维生素E琥珀酸0～20％；
    助乳化剂：丙二醇单辛酸酯0～20％；
    溶剂：丙二醇1～50％、二乙二醇单乙醚1～10％、乙醇0～50％；
    凝胶材料：卡波姆0.10％～2.0％；
    以及至100wt％的水；
    更优选的，其特征在于，以所述凝胶的总重量计，所述芦可替尼凝胶包含：
    治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
    乳化剂：聚氧乙烯氢化蓖麻油1.0～5.0％、聚氧乙烯蓖麻油1～10％、维生素E琥珀酸0～10％；
    助乳化剂：丙二醇单辛酸酯0～10％；
    溶剂：丙二醇1～45％、二乙二醇单乙醚1～5.0％、乙醇0～40％；
    凝胶材料：卡波姆0.10％～2.0％；
    以及至100wt％的水；
    进一步优选的，其特征在于，以所述凝胶的总重量计，所述芦可替尼凝胶包含：
    治疗剂：芦可替尼或其药学上可接受的盐0.5％～2.0％(以游离碱计)；
    乳化剂：聚氧乙烯氢化蓖麻油1～2％、聚氧乙烯蓖麻油4～10％、维生素E琥珀酸0～5％；
    助乳化剂：丙二醇单辛酸酯0～7％；
    溶剂：丙二醇5～45％、二乙二醇单乙醚2～5％、乙醇0～15％；
    凝胶材料：卡波姆0.25％～1.0％；
    以及至100wt％的水。
  13. 一种制备如权利要求9～12所述芦可替尼凝胶的方法，其中所述方法包括如下步骤：
    将上述芦可替尼组合物除水相外混合加热至30-70℃，优选35-60℃，搅拌使辅料完全融化及治疗剂溶解后，再与溶胀好的卡波姆搅拌均匀后加入水相，即得。
  14. 一种如权利要求1～5之一所述芦可替尼组合物用于治疗疾病的用途，所述的疾病为皮炎、银屑病、白癜风、汗腺炎、荨麻疹、斑秃的一种或多种。
  15. 一种如权利要求9～12所述芦可替尼凝胶用于治疗疾病的用途，所述的疾病为皮炎、银屑病、白癜风、汗腺炎、荨麻疹、斑秃的一种或多种。
PCT/CN2022/126399 2021-09-28 2022-10-20 一种芦可替尼组合物及其制备方法 Ceased WO2023051833A1 (zh)

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