WO2023016583A1 - Composition de ruxolitinib et utilisation associée - Google Patents

Composition de ruxolitinib et utilisation associée Download PDF

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WO2023016583A1
WO2023016583A1 PCT/CN2022/125162 CN2022125162W WO2023016583A1 WO 2023016583 A1 WO2023016583 A1 WO 2023016583A1 CN 2022125162 W CN2022125162 W CN 2022125162W WO 2023016583 A1 WO2023016583 A1 WO 2023016583A1
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ruxolitinib
gel
composition
diethylene glycol
ethanol
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PCT/CN2022/125162
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English (en)
Chinese (zh)
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喻进
罗艳华
戚卫蕊
严婷婷
吴笑笑
王剑
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杭州中美华东制药有限公司
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Priority to CN202280054196.5A priority Critical patent/CN117813117A/zh
Publication of WO2023016583A1 publication Critical patent/WO2023016583A1/fr

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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
    • A61K47/30—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
    • 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
    • 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]

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a composition of ruxolitinib and/or a pharmaceutically acceptable salt thereof and an application 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.
  • Ruxolitinib cream was approved by the US FDA in September 2021, under the trade name Opzelura, for short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis.
  • CN103002875B discloses a cream formed from an oil-in-water emulsion containing ruxolitinib or a pharmaceutically acceptable salt thereof, which comprises water, an oil component, an emulsifier component and a solvent component.
  • penetration enhancers can be divided into hydrophilic penetration enhancers, lipophilic penetration enhancers, and amphiphilic penetration enhancers.
  • Common hydrophilic penetration enhancers include carvone and menthol; common lipophilic penetration enhancers include lemon essential oil; amphiphilic penetration enhancers mainly include azone, pyrrolone, terpenes, fatty acids, etc. Among them, azone, pyrrolone, and unsaturated fatty acids have relatively good penetration-promoting effects on water-soluble drugs.
  • the structure of the penetration enhancer it can be divided into sulfoxides, fatty acids, terpenes, hydrocarbons, amides, alcohols, amines, etc.
  • Diethylene glycol monoethyl ether was first approved by the FDA for use in topical preparations in 2005.
  • the trade name is Transcutol, abbreviated as DEGEE, which can be used as a solubilizer, penetration enhancer, surfactant, etc.
  • the first aspect of the present invention is to provide a ruxolitinib composition, which comprises the active ingredient ruxolitinib or a pharmaceutically acceptable salt thereof, diethylene glycol monoalkyl ether, ethanol and/or propylene glycol.
  • 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
  • Transcutol in the embodiments of the present invention refers to diethylene glycol monoalkyl ether, further diethylene glycol monoethyl ether.
  • the content of the active ingredient is 0.1 to 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%, 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.
  • the content of the diethylene glycol monoalkyl ether is 10 to 50% based on the total weight of the pharmaceutical composition, and may be 10.0%, 10.5%, 10.6%, 10.7%, 10.8%, 10.9% , 20.0%, 20.5%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 20 to 50%, more preferably 20 to 45%.
  • the ethanol and/or propylene glycol content is 1 to 50% based on the total weight of the pharmaceutical composition, and may be 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%, 10.6%, 10.7%, 10.8%, 10.9% , 20.0%, 20.5%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 5 to 50%, more preferably 5 to 40%.
  • the ruxolitinib composition provided by the present invention also includes water, and the content of the water is up to 100% based on the total weight of the pharmaceutical composition, which can be 20.0%, 20.5%, 30.0%, 30.5%, 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%, 60.0%, 60.5%, 61.0%, 61.5%, 62.0%, 62.
  • the ruxolitinib composition provided by the present invention may further comprise one or more additional dermatologically acceptable excipients.
  • additional dermatologically acceptable excipients include, but are not limited to, pH adjusters, chelating agents, preservatives, humectants, thickeners or viscosity builders, fragrances, colorants, and mixtures thereof.
  • the ruxolitinib composition provided by the present invention may further comprise a pH regulator.
  • the pH adjusting agent is an acid, an acid salt, or a mixture thereof.
  • the acid is selected from the group consisting of lactic acid, acetic acid, maleic acid, succinic acid, citric acid, benzoic acid, boric acid, sorbic acid, tartaric acid, edetic acid, phosphoric acid, nitric acid, sulfuric acid and hydrochloric acid, and mixture.
  • the pH adjusting agent is a buffer.
  • the buffer is selected from the group consisting of triethanolamine, citrate/citric acid, acetate/acetic acid, phosphate/phosphoric acid, propionate/propionic acid, lactate/lactic acid, ammonium salt/ammonia, and Dietate/Edetate.
  • the pH adjusting agent is a buffer which is citrate/citric acid.
  • the ruxolitinib composition provided by the present invention may further comprise a chelating agent.
  • the chelating agent is a mixture of two or more chelating agents.
  • the compositions of the present invention may comprise a mixture of chelating agents and antioxidants, where both excipients serve to prevent or minimize oxidative degradation reactions in the composition.
  • Exemplary chelating agents include, but are not limited to, citric acid, glucuronic acid, sodium hexametaphosphate, zinc hexametaphosphate, ethylenediaminetetraacetic acid (EDTA), phosphonates, salts thereof, and mixtures thereof.
  • EDTA is also known as edetic acid.
  • the chelating agent is EDTA or a salt thereof, such as potassium, sodium or calcium salt of EDTA. In one embodiment, the EDTA or salt thereof is disodium EDTA. In another embodiment, the chelating agent is citric acid. In yet another embodiment, the composition of the present invention comprises a chelating agent and an antioxidant mixture which is a mixture of EDTA or a salt thereof and propyl gallate. In a further embodiment, the composition of the present invention comprises a mixture of chelating agent and antioxidant which is a mixture of EDTA or a salt thereof and BHT. In one embodiment, the composition of the present invention comprises a mixture of chelating agent and antioxidant which is a mixture of disodium EDTA and BHT.
  • the composition comprises a mixture of chelating agent and antioxidant which is a mixture of citric acid and propyl gallate.
  • the composition of the present invention comprises a mixture of chelating agent and antioxidant, which is a mixture of citric acid and BHT.
  • the ruxolitinib composition provided by the present invention may further contain a preservative.
  • the preservative is a mixture of two or more preservatives.
  • Exemplary preservatives include, but are not limited to, benzyl alcohol, imidazolidinyl urea, diazolidinyl urea, dichlorobenzyl alcohol, chloroxylenol, methylparaben, ethylparaben, propylparaben, Butylparaben, phenoxyethanol, sorbic acid, benzoic acid, their salts, and mixtures thereof.
  • the preservative is selected from benzyl alcohol, phenoxyethanol, and benzoic acid, and mixtures thereof.
  • the ruxolitinib composition provided by the present invention may further comprise an antioxidant selected from butylated hydroxytoluene, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone , 4-hydroxymethyl-2,6-di-tert-butylphenol, isoascorbic acid, guaiac resin, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butyl p-phenyl Diphenols and tocopherols or pharmaceutically acceptable salts or esters or combinations thereof.
  • an antioxidant selected from butylated hydroxytoluene, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone , 4-hydroxymethyl-2,6-di-tert-butylphenol, isoascorbic acid, guaiac resin, propyl
  • the ruxolitinib composition of the present invention comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.1 to 20%
  • Diethylene glycol monoalkyl ether 10 to 50%
  • Ethanol and/or propylene glycol 1 to 50%
  • the ruxolitinib composition of the present invention comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.1 to 10%
  • Diethylene glycol monoalkyl ether 20 to 50%
  • Ethanol and/or propylene glycol 5 to 50%
  • the ruxolitinib composition of the present invention comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.5-2%
  • Ethanol and/or propylene glycol 5 to 40%
  • composition provided by the present invention has good stability, or ruxolitinib or a pharmaceutically acceptable salt thereof has good stability in the composition of diethylene glycol monoalkyl ether, ethanol and/or propylene glycol.
  • Another aspect of the present invention is to provide an external preparation based on the ruxolitinib composition provided by the present invention, which can be emulsion, cream, ointment, gel, lotion, spray, aerosol, foam or suspension liquid.
  • the present invention provides a ruxolitinib gel, which comprises the active ingredient ruxolitinib or a pharmaceutically acceptable salt thereof, diethylene glycol monoalkyl ether, ethanol and/or propylene glycol, and a gel matrix .
  • the present invention provides a ruxolitinib gel, which comprises the active ingredient ruxolitinib or a pharmaceutically acceptable salt thereof, diethylene glycol monoalkyl ether, ethanol and/or propylene glycol, and a gel matrix
  • the gel matrix is one or one of carbomer, cellulose derivatives, xanthan gum, gum arabic, tragacanth gum, carrageenan, gelatin, sodium alginate, poloxamer
  • carbomer methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate and poloxamer.
  • the active ingredient content is 0.1 to 20% based on the total weight of the ruxolitinib gel, and can be 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%, 5.0%
  • the diethylene glycol monoalkyl ether content is 10 to 50% based on the total weight of the ruxolitinib gel, and can be 10.0%, 10.5%, 10.6%, 10.7%, 10.8% , 10.9%, 20.0%, 20.5%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 20 to 50%, more preferably 20 to 45%.
  • the ethanol and/or propylene glycol content is 1 to 50% based on the total weight of the ruxolitinib gel, which can be 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%, 10.6%, 10.7%, 10.8% , 10.9%, 20.0%, 20.5%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 5 to 50%, more preferably 5 to 40%.
  • the gel matrix is carbomer, and its content is 0.1 to 20% based on the total weight of the ruxolitinib gel, which can be 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 %
  • the gel matrix is poloxamer, and its content is 1 to 50% based on the total weight of the ruxolitinib gel, which can be 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%, 10.6% , 10.7%, 10.8%, 10.9%, 20.0%, 20.5%, 20.5%, 30.0%, 30.5%, 40.0%, 40.5% or 50.0%, preferably 5 to 40%, more preferably 10 to 30%.
  • the ruxolitinib gel provided by the present invention also contains water, and the content of the water is up to 100% based on the total weight of the pharmaceutical composition, and can be 20.0%, 20.5%, 30.0%, 30.5%, 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%, 60.0%, 60.5%, 61.0%, 61.5%, 62.0%, 62.
  • the ruxolitinib gel comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.1 to 20%
  • Diethylene glycol monoalkyl ether 10 to 50%
  • Ethanol and/or propylene glycol 1 to 50%
  • the ruxolitinib gel comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.1 to 10%
  • Diethylene glycol monoalkyl ether 20 to 50%
  • Ethanol and/or propylene glycol 5 to 50%
  • the ruxolitinib gel comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.5-2%
  • Ethanol and/or propylene glycol 5 to 40%
  • the ruxolitinib gel comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.1 to 20%
  • Diethylene glycol monoalkyl ether 10 to 50%
  • Ethanol and/or propylene glycol 1 to 50%
  • the ruxolitinib gel comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.1 to 10%
  • Diethylene glycol monoalkyl ether 20 to 50%
  • Ethanol and/or propylene glycol 5 to 50%
  • the ruxolitinib gel comprises:
  • Ruxolitinib or a pharmaceutically acceptable salt thereof: 0.5-2%
  • Ethanol and/or propylene glycol 5 to 40%
  • 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.
  • FIG. 3 Slices of skin tissue from different sample groups
  • Embodiment 1 investigation of impurity stability
  • Detection conditions The above-mentioned method is used for liquid phase analysis, and it is determined according to high-performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512).
  • Embodiment 2 Composition content stability research
  • Sample preparation Take 10g as the basis, weigh 0.1g (1%) of ruxolitinib phosphate, add the corresponding penetration enhancer and/or water, and ultrasonically dissolve to obtain the sample solution, which is divided into vials , sealed storage.
  • Sampling points were carried out at 25°C for 0 days, 25°C for 1 month, 25°C for 2 months, 40°C for 14 days, and 40°C for 2 months;
  • Embodiment 3 Gel prescription composition
  • step 1) drug phase with step 2) carbomer gel phase or poloxamer 407 water phase, then add corresponding water to 100% of the prescription amount, stir well and mix well to get ready Ruxolitinib Gel.
  • Embodiment 4 the in vitro release test of gel
  • Example 3 Take prescription 6, prescription 8, and prescription 10 in Example 3 to investigate the in vitro release effect of the gel.
  • 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%).
  • Experimental method using an improved vertical Franz diffusion cell (Tianjin Boyu Weiye Technology Co., Ltd., model TP-6), artificial transdermal membrane (Strat- Membrane) is fixed between the diffusion cell and the receiving cell, the diffusion cell diameter is 1.5cm, the receiving cell volume is 15mL, the diffusion cell is filled with 300mg ruxolitinib gel preparation sample, and the receiving cell is injected with receiving solution (15% ethanol solution).
  • the temperature of the water bath is 32 ⁇ 1°C, and the constant temperature magnetic stirring speed is 300rpm/min.
  • Qn cumulative drug penetration per unit area at the nth time point (unit: ⁇ g/cm 2 );
  • Cn drug concentration at the nth time point (unit: ⁇ g/mL);
  • C i-1 the drug concentration at the i-1th time point (unit: ⁇ g/mL);
  • V the volume of the receiving pool (unit: mL);
  • Embodiment 5 Psoriasis drug efficacy investigation
  • 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.
  • Experimental grouping The experiment was divided into 7 groups, 6 rats in each group, and 42 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;
  • Group 4 The model group was smeared with 5% imiquimod ointment 62.5mg/body 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 smears 5% imiquimod ointment 62.5mg/ only to maintain modeling, in addition smears test medicine (prescription 14 samples of the embodiment of the present invention 4) every day, frequency 2 times/day, continuous treatment 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.
  • Psoriasis-like skin lesion area and disease severity (PASI) scores of mice in each group observe the body weight and skin lesion changes of mice in each group every day (body weight measurement: from adaptive feeding to the end of administration, every day Only once a day, a total of 17 times; skin lesion scoring: scoring every day from the modeling period to the administration period, each animal once a day, a total of 10 times), using digital photography to record daily, and according to the PASI scoring standard.
  • the scores of erythema, scale, and infiltration and thickening in the skin lesions of the mice were given 0-4 points, and the three scores were added to obtain the total severity score of the skin lesions, and the scores of the mice in each group were averaged to draw the trend of the scores of the skin lesions Lines were used to observe the changes of the skin lesions of the mice in each group.
  • 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 had a significant decrease, and compared with the blank gel group, it 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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  • General Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

La présente invention concerne une composition de ruxolitinib et/ou un sel pharmaceutiquement acceptable de celui-ci, ainsi qu'une utilisation associée. La composition de ruxolitinib comprend un principe actif de ruxolitinib ou un sel pharmaceutiquement acceptable de celui-ci, du monoalkyléther de diéthylène glycol, de l'éthanol et/ou du propylène glycol. La composition présente une bonne stabilité et une bonne perméabilité. L'invention concerne en outre un gel de ruxolitinib comprenant une composition de ruxolitinib et une matrice de gel. La composition de ruxolitinib et le gel de ruxolitinib ont des effets de traitement de maladies significativement meilleurs que les préparations disponibles dans le commerce et la maladie est une ou plusieurs parmi la dermatite, le psoriasis, le vitiligo, l'hidradénite, l'urticaire et la pelade.
PCT/CN2022/125162 2021-08-13 2022-10-13 Composition de ruxolitinib et utilisation associée WO2023016583A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103002875A (zh) * 2010-05-21 2013-03-27 因塞特公司 Jak 抑制剂的局部用制剂
US20140296191A1 (en) * 2013-04-02 2014-10-02 Themis Medicare Limited Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives
WO2019096303A1 (fr) * 2017-11-20 2019-05-23 江苏恒瑞医药股份有限公司 Composition pharmaceutique pour administration topique et procédé de préparation associé

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103002875A (zh) * 2010-05-21 2013-03-27 因塞特公司 Jak 抑制剂的局部用制剂
US20140296191A1 (en) * 2013-04-02 2014-10-02 Themis Medicare Limited Compositions of pharmaceutical actives containing diethylene glycol monoethyl ether or other alkyl derivatives
WO2019096303A1 (fr) * 2017-11-20 2019-05-23 江苏恒瑞医药股份有限公司 Composition pharmaceutique pour administration topique et procédé de préparation associé

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FEIZPOUR AMIN, MARSTRAND TROELS, BASTHOLM LOUISE, EIREFELT STEFAN, EVANS CONOR L.: "Label-Free Quantification of Pharmacokinetics in Skin with Stimulated Raman Scattering Microscopy and Deep Learning", JOURNAL OF INVESTIGATIVE DERMATOLOGY, ELSEVIER, NL, vol. 141, no. 2, 1 February 2021 (2021-02-01), NL , pages 395 - 403, XP093034233, ISSN: 0022-202X, DOI: 10.1016/j.jid.2020.06.027 *

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