WO2024051687A1 - 一种含有吡非尼酮的局部外用制剂及其用途 - Google Patents

一种含有吡非尼酮的局部外用制剂及其用途 Download PDF

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WO2024051687A1
WO2024051687A1 PCT/CN2023/116997 CN2023116997W WO2024051687A1 WO 2024051687 A1 WO2024051687 A1 WO 2024051687A1 CN 2023116997 W CN2023116997 W CN 2023116997W WO 2024051687 A1 WO2024051687 A1 WO 2024051687A1
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preparation
pirfenidone
dmso
topical
ethanol
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PCT/CN2023/116997
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English (en)
French (fr)
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刘飞
姜伟化
石莉
李培冉
曹晓琴
杜子蝶
王婕
张翠霞
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南京迈诺威医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and specifically relates to a topical preparation containing pirfenidone and its use.
  • Pirfenidone chemically named 5-methyl-1-phenyl-2-(1H)pyridone, is a compound with broad-spectrum anti-fibrotic effects that can prevent and reverse fibrosis and scarring
  • the formation of its chemical structure is as follows:
  • pirfenidone was approved by the U.S. Food and Drug Administration (FDA) for marketing under the trade name Pirfenidone has become the first drug approved in multiple countries for the treatment of idiopathic pulmonary fibrosis (IPF).
  • FDA U.S. Food and Drug Administration
  • pirfenidone has been extensively studied for other uses.
  • WO00/16775 discloses the use of pirfenidone for the treatment and prevention of skin lesions, especially lesions of a fibrotic nature, such as fibrotic damaged tissue, contact infectious warts, contact dermatitis, burns and scars.
  • WO99/47140 discloses the use of 2-1H-pyridone compounds, especially pirfenidone, as a local disinfection treatment, which can be used to treat fungi, bacteria, etc. on the skin surface.
  • WO01/62253 discloses the use of pirfenidone in the treatment of epilepsy.
  • pirfenidone discloses the use of pirfenidone as an anti-inflammatory agent.
  • Mexican Patent 182,266 discloses that pirfenidone has antifibrotic activity.
  • Chinese patent document CN111246840A discloses that pirfenidone can be used to prevent or treat chronic skin injuries and injuries caused by neuropathic ulcers, especially for the treatment of diabetic foot syndrome and the treatment of vascular ulcers.
  • pirfenidone Nicotine has poor solubility in water, making it difficult to prepare stable external preparations.
  • CN10808641A discloses a gel composition containing pirfenidone.
  • This application discloses the use of solubilizers such as NMP, ethanol and propylene glycol to prepare the gel preparation, which can be used for tissue recovery with fibrotic lesions and for fibrosis. Prevention of lesions, but its stability, transdermal effect and in vivo effect have not been studied.
  • One object of the present invention is to provide a topical preparation of pirfenidone, which has high skin permeability, good stability, low irritation, can efficiently penetrate the skin and take effect safely.
  • the present invention provides a pirfenidone topical formulation, which includes a therapeutically effective amount of pirfenidone, water and at least one co-solvent.
  • the co-solvent is selected from dimethyl sulfoxide (DMSO) and an alcoholic solvent
  • the alcoholic solvent is selected from one of ethanol, propylene glycol, isopropyl alcohol, 1-propanol, and butylene glycol. species, two or more species.
  • the co-solvent is a combination of DMSO and ethanol, or a combination of DMSO and propylene glycol, or a combination of DMSO, ethanol and propylene glycol.
  • the amount of water used in the formulation is 10 wt% to 55 wt%, preferably 15 wt% to 50 wt%, such as 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt% or 45 wt%.
  • the formulation when the co-solvent is a combination of DMSO and ethanol, contains 15 to 35 wt% DMSO, 15 to 30 wt% ethanol, based on the total weight of the topical formulation; preferably, the formulation The formulation contains 15 to 25 wt% DMSO, 15 to 25 wt% ethanol, for example 20 wt% DMSO and 20 wt% ethanol, or 20 wt% DMSO and 25 wt% ethanol.
  • the formulation when the co-solvent is a combination of DMSO, ethanol, and propylene glycol, the formulation includes 15 to 35 wt% DMSO, 15 to 30 wt% ethanol, 15 wt% based on the total weight of the topical formulation. to 25 wt% propylene glycol; preferably, the formulation contains 15 to 25 wt% DMSO, 15 to 25 wt% ethanol, and 20 to 25 wt% propylene glycol.
  • pirfenidone is present in an amount of 1 to 14 wt%; preferably, 4 to 12 wt%, based on the total weight of the pirfenidone topical formulation; For example, it exists in an amount of 6 to 12 wt%, for example, it exists in an amount of 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11% wt, or any interval range thereof.
  • the topical pirfenidone formulations of the present invention can be formulated into different dosage forms, such as solutions, suspensions, creams, ointments, lotions, and gels.
  • the topical pirfenidone preparation of the present invention is a solution or gel. More preferably, the topical pirfenidone preparation of the present invention is a gel.
  • the pirfenidone topical formulation further comprises a gelling agent.
  • the gelling agent may be one known in the art for use in topical formulations, including but not limited to: cellulose derivatives, polyvinylpyrrolidone, carbomer polymers, carbomer derivatives, malt One, two or more of dextrin, polydextrose, glucose binding agent, polyacrylamide gelling agent, carboxypolymethylene, polyvinyl alcohol, poloxamer, and polyethylene glycol; preferably Preferably, the gelling agent is selected from one, two or more types of cellulose derivatives, carbomer polymers, and carbomer derivatives.
  • the gelling agent is HPC, carbomer 980, carbomer 981, etc.
  • the gelling agent is present in an amount from 0.05% to 5% by weight, preferably from 0.1% to 2% by weight, such as from 0.3% to 1% by weight, based on the total weight of the pirfenidone topical formulation. Quantity exists.
  • the pirfenidone topical formulation further includes a humectant, which may be a humectant known in the art for topical formulations, including but not limited to: One, two or more of glycerin, urea, allantoin, sodium hyaluronate, polyethylene glycol, squalane, cyclomethicone.
  • a humectant known in the art for topical formulations, including but not limited to: One, two or more of glycerin, urea, allantoin, sodium hyaluronate, polyethylene glycol, squalane, cyclomethicone.
  • the moisturizing agent is selected from one, two or three types of glycerin, allantoin, and sodium hyaluronate.
  • the humectant is present in an amount from 0.5 to 10 wt%, preferably from 2 to 8 wt%, such as from 3 to 6 wt%, based on the total weight of the pirfenidone topical formulation.
  • the pirfenidone topical formulation includes a pH adjuster, which may be a pH adjuster known in the art for topical formulations, particularly a base.
  • the pH adjuster is, for example, one, two or three types selected from triethanolamine, sodium hydroxide, and triethylamine; preferably, the pH adjuster is triethanolamine.
  • the pH adjuster is used in an appropriate amount, and it is appropriate to adjust the pH of the topical preparation to a range of 5.0 to 7.5, and more preferably to a pH of 5.5 to 7.5.
  • the pirfenidone topical formulation further includes a preservative, which may be a preservative known in the art for topical formulations, for example, selected from p-hydroxyl One, two or more of methyl benzoate (methyl hydroxybenzoate), propyl parahydroxybenzoate (propyl parahydroxybenzoate), benzyl alcohol, benzoic acid, and phenol.
  • a preservative which may be a preservative known in the art for topical formulations, for example, selected from p-hydroxyl One, two or more of methyl benzoate (methyl hydroxybenzoate), propyl parahydroxybenzoate (propyl parahydroxybenzoate), benzyl alcohol, benzoic acid, and phenol.
  • the preservative is present in an amount from 0.01% to 2% by weight, such as from 0.05% to 1% by weight, based on the total weight of the pirfenidone topical formulation.
  • the pirfenidone topical preparation of the present invention further includes one, two or more other pharmaceutically acceptable auxiliary materials, including but not limited to: antioxidants, thickeners , stabilizers, chelating agents, oily materials, emulsifiers, penetration accelerators, antimicrobial agents, sunscreen agents, fragrances, colorants, surfactants, etc.
  • auxiliary materials including but not limited to: antioxidants, thickeners , stabilizers, chelating agents, oily materials, emulsifiers, penetration accelerators, antimicrobial agents, sunscreen agents, fragrances, colorants, surfactants, etc.
  • the excipients can be used in conventional amounts known in the art.
  • the antioxidant may be one known in the art for use in topical formulations, such as selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene, vitamin C, vitamin E, vitamin A, phylloside Vitamin, lycopene, retinyl palmitate, potassium metabisulfite, sodium metabisulfite, sodium thiosulfate pentahydrate, 3,4-dihydroxybenzoic acid, propyl gallate, alpha-lipoic acid , one, two or more of ascorbyl palmitate, sodium metabisulfite, ubiquinone, and selenium.
  • BHA butylated hydroxyanisole
  • the antioxidant may be present in an amount from 0.05% to 5% by weight, for example from 0.1% to 3% by weight, based on the total weight of the pirfenidone topical formulation.
  • the thickening agent may be, for example, cellulose derivatives, polyvinylpyrrolidone, carbomer polymers, carbomer derivatives, maltodextrin, polydextrose, dextrate, carboxypolymethylene , one, two or more of polyvinyl alcohol, poloxamer and polyethylene glycol; more preferably, the thickener is hydroxypropyl cellulose.
  • the thickening agent may be present in an amount of 0.05 to 5 wt%, preferably 0.1 to 4 wt%, such as 1 to 3 wt%, based on the total weight of the pirfenidone topical formulation.
  • the pirfenidone topical formulation of the present invention comprises a therapeutically effective amount of pirfenidone, water and at least one co-solvent comprising DMSO and ethanol, wherein Based on the total weight of the formulation, the formulation includes 4 to 12 wt% pirfenidone, 15 to 30 wt% DMSO, and 15 to 30 wt% ethanol.
  • the formulation further contains 0.05wt% to 5wt% gelling agent (for example, selected from carbomer 980, carbomer 981 one or two).
  • the preparation further contains 0.05 wt% to 8 wt% of a moisturizing agent (for example, one, two or three selected from the group consisting of glycerin, allantoin, and sodium hyaluronate).
  • a moisturizing agent for example, one, two or three selected from the group consisting of glycerin, allantoin, and sodium hyaluronate.
  • the formulation further contains 0.05% to 2% by weight of a preservative.
  • the preparation further contains a pH adjuster (for example, one or two selected from triethanolamine and NaOH) to adjust the pH range of the preparation to 5.0-7.5.
  • the preparation further contains other pharmaceutically acceptable auxiliary materials.
  • the pirfenidone topical formulation of the present invention comprises a therapeutically effective amount of pirfenidone, water and at least one co-solvent comprising DMSO and ethanol, wherein Based on the total weight of the formulation, the formulation includes 6 to 12 wt% pirfenidone, 20 to 30 wt% DMSO, and 20 to 30 wt% ethanol.
  • the preparation further contains 0.4 wt% to 1 wt% of a gelling agent (for example, one or two selected from carbomer 980, carbomer 981).
  • the preparation further contains 3 to 6 wt% of a moisturizing agent (for example, one, two or three selected from the group consisting of glycerol, allantoin, and sodium hyaluronate).
  • a moisturizing agent for example, one, two or three selected from the group consisting of glycerol, allantoin, and sodium hyaluronate.
  • the formulation further contains 0.05 to 0.5 wt% of a preservative.
  • the preparation further contains a pH adjuster (for example, one or two selected from triethanolamine and NaOH) to adjust the pH range of the preparation to 5.0-7.5.
  • the preparation further contains other pharmaceutically acceptable auxiliary materials.
  • the formulation includes 4 to 12 wt% pirfenidone, 15 to 35 wt% DMSO, 15 to 30 wt% ethanol, 20 to 50 wt% water, 0.3 wt % to 1wt% gelling agent, 2wt% to 8wt% humectant, and an appropriate amount of pH adjuster to adjust the pH range of the preparation to 5.0-7.5.
  • the formulation includes 4 to 12 wt% pirfenidone, 20 to 25 wt% DMSO, 20 to 25 wt% ethanol, 30 to 45 wt% water, 0.3 wt % to 1wt% gelling agent, 2wt% to 8wt% humectant, 0.05wt% to 1wt% preservative, and an appropriate amount of pH adjuster to adjust the pH range of the preparation to 5.0-7.5.
  • the present invention also provides the use of the above-mentioned pirfenidone topical preparation in the preparation of medicaments for preventing or treating diseases related to skin or connective tissue hyperproliferation and chronic skin damage.
  • the present invention provides a method for preventing or treating skin or connective tissue hyperproliferation-related diseases and chronic skin damage in a mammal (e.g., a human), the method comprising administering a therapeutically effective amount to the mammal (e.g., a human).
  • a mammal e.g., a human
  • the topical pirfenidone preparation of the present invention is administered to a mammal (e.g., a human).
  • the diseases related to skin or connective tissue hyperproliferation include, but are not limited to, pathological scars (such as keloids, hypertrophic scars), acne scars, skin neoplastic fibrosis and cicatricial alopecia;
  • the Chronic skin lesions include, but are not limited to, vasculitis, burn healing, diabetic foot syndrome, vascular ulcers, scleroderma, Peyronie's syndrome, Deutsch syndrome, or bursitis.
  • the inventor of the present invention unexpectedly discovered that when DMSO and alcohol solvents are used as co-solvents in pirfenidone topical preparations, its medicinal properties can be significantly improved.
  • the resulting preparation overcomes the problem of low solubility of pirfenidone in water and skin problems.
  • Technical problems such as low transmittance and sensitivity to skin irritation.
  • the preparation has high skin permeability, good stability, non-irritation, good skin tolerance, and is easy to use. It can significantly improve the compliance of patients with keloids, pathological scars or hypertrophic scars, and can be developed into a very Promising topical agents.
  • Figures 1 to 4 respectively show the HE stained pathological sections of four different groups of rabbit ear surface scar areas 28 days after administration in the pirfenidone in vivo efficacy test of Test Example 4 of the present invention.
  • the small figures in each figure Figures 1, 2, 3, and 4 respectively show the HE stained pathological sections of 4 samples in each group.
  • prevention or treatment means the administration of a formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with said disease, and includes: (i) prevention of a disease or disease state in lactation occur in animals, especially when such mammals are susceptible to the disease state but have not been diagnosed as suffering from the disease state; (ii) inhibit the disease or disease state, that is, arrest its progression; (iii) alleviate the disease or disease state, even if the disease or disease state resolves.
  • terapéuticaally effective amount means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a formulation of the invention that is associated with the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a formulation of the invention that constitutes a "therapeutically effective amount” will vary depending on the formulation, the disease state and its severity, the mode of administration and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, water, other solvents, etc.
  • solvent is water
  • co-solvent refers to a substance that acts as a co-solvent in combination with other substances, such as solvent water.
  • chronic skin injury refers to exuberant activity during various stages of wound healing that results in abnormal fibrotic tissue formation (eg, scarring).
  • Diabetic foot syndrome As used herein, the term “diabetic foot syndrome.” Diabetic foot is a clinical entity that refers to the presence of chronic hyperglycemia in patients with diabetes due to extrinsic and intrinsic factors such as trauma, local hygiene, and skeletal deformities. A syndrome resulting from the interaction of predisposing factors such as vasculopathy, neuropathy, and infection. Common typical clinical symptoms include lower limb ulcers and foot ulcers (also known as diabetic foot ulcers).
  • polyacrylamide gelling agent primarily refers to the polyacrylamide gelling agent produced by SEPPIC under the name Sepineo (or Simulgel 600 ) sold as a mixture Sodium Acryldimethyl Taurate Copolymer/Isohexadecane/Polysorbate 80, a mixture Polyacrylamide/Isoparaffin C13-14/Laureth-7 (as sold by SEPPIC by name Products sold by 305.
  • DMSO dimethyl sulfoxide
  • NMP represents N-methylpyrrolidone
  • Solutol HS 15 represents polyethylene glycol (PEG)-15 hydroxystearate
  • Transcutol represents diethylene glycol Monoethyl ether
  • HPC stands for hydroxypropyl cellulose
  • BHA stands for butyl hydroxyanisole.
  • This example examines the solubility of pirfenidone in water/DMSO/alcohol solvents.
  • pirfenidone in water The solubility is low. Even if DMSO is added for solubilization, the solubility is difficult to reach the desired concentration (80 mg/mL) in topical preparations. However, if ethanol or propylene glycol is further added for solubilization, the solubility of pirfenidone in water can be significantly improved. For example, pirfenidone has good solubility in water/DMSO/ethanol or water/DMSO/propylene glycol, and can reach the desired concentration of pirfenidone in topical formulations (80 mg/mL).
  • a compatibility test of raw materials and excipients was conducted to examine the effects of excipients such as cosolvents, gelling agents, and moisturizers on the stability of pirfenidone topical preparations.
  • Gelling agents eg, carbomer
  • humectants eg, glycerin, allantoin, sodium hyaluronate
  • pirfenidone has excellent properties among the co-solvents (DMSO, ethanol), commonly used gelling agents (carbopol), and humectants (glycerin, allantoin, sodium hyaluronate) tested in Example 1. Therefore, these excipients have good compatibility with pirfenidone and can be used in the pirfenidone topical preparation of the present invention.
  • co-solvents DMSO, ethanol
  • carbopol commonly used gelling agents
  • humectants glycerin, allantoin, sodium hyaluronate
  • this application also tested the stability of pirfenidone in the presence of Transcuto.
  • Transcutol can also solubilize pirfenidone in a DMSO + water system
  • the use of Transcutol results in product instability.
  • a preparation containing pirfenidone/Transcutol/water at a ratio of 1%:23.5%:75.5% will produce obvious degradation impurities after being placed under high temperature (60°C, dry) conditions for 30 days. It is speculated that Transcutol may induce pirfenidone. Degradation of nitone.
  • DMSO+alcohol solvent used in the present invention not only can solubilize, but also does not affect the stability of pirfenidone and is a good co-solvent.
  • a topical preparation of pirfenidone was prepared according to the prescription shown in Table 3.
  • Preparation method According to the prescription, 1) mix pirfenidone and co-solvent; 2) mix the gelling agent with an appropriate amount of purified water; 3) mix the humectant with the remaining amount of purified water; 4) mix step 1) , 2), 3) The mixture obtained is mixed evenly, and a pH adjuster is added to adjust the pH to 5.5-7.5, and stirred until uniform.
  • a topical preparation of pirfenidone was prepared according to the prescription shown in Table 4.
  • Preparation method According to the prescription, 1) mix pirfenidone and cosolvent, add preservative and mix; 2) mix gelling agent and Mix an appropriate amount of purified water; 3) Mix the moisturizer with the remaining amount of purified water; 4) Mix the mixture obtained in steps 1), 2), and 3) evenly, add a pH adjuster to adjust the pH to 5.5 ⁇ 7.5, and stir until Uniform, that's it.
  • a topical preparation of pirfenidone was prepared according to the prescription shown in Table 5.
  • a topical preparation of pirfenidone was prepared according to the prescription shown in Table 6.
  • Preparation method According to the prescription, 1) mix pirfenidone and co-solvent, add antioxidant and mix well; 2) mix gelling agent and purified water; 3) mix the mixture obtained in steps 1) and 2) evenly, Add pH adjuster to adjust pH to 5.5 ⁇ 7.5, stir until uniform, and it is ready.
  • a topical preparation of pirfenidone was prepared according to the prescription shown in Table 7.
  • a topical preparation of pirfenidone was prepared according to the prescription shown in Table 8.
  • the control preparation prescription C1 was prepared with reference to the prescription of KitosCell, a pirfenidone gel preparation marketed in Mexico.
  • Preparation method According to the prescription, 1) mix pirfenidone and co-solvent, add preservatives (if any) and other auxiliary materials to mix; 2) mix the gelling agent with an appropriate amount of purified water; 3) mix step 1) , 2) Mix the resulting mixture evenly, add a pH adjuster to adjust the pH to 5.5-7.5, and stir until uniform.
  • This test example examines the stability of pirfenidone topical preparations.
  • Test method The pirfenidone topical preparations in Examples 3 to 8 were subjected to high temperature (60°C, drying) and accelerated conditions. Stability research experiments were conducted under the conditions of (40°C ⁇ 2°C, 75% RH ⁇ 5% RH) to examine the physical and chemical stability of each preparation at 0 days and 30 days. The experimental results are shown in Table 9 below.
  • topical gel preparations prepared using different gelling agents have different viscosities.
  • different viscosities can produce different feelings, and all can be made into medicines without affecting the stability and efficacy of the preparation.
  • the results show that the addition of humectants, preservatives, antioxidants, etc. of the present invention will not affect the stability of the preparation, which is consistent with the raw material compatibility test results of Example 2.
  • the co-solvent can be a combination of DMSO and alcohol solvents.
  • the control prescription C1 uses polyethylene glycol glyceryl hydroxystearate and NMP as solubilizers or co-solvents.
  • the gel preparation becomes darker and the total degradation products increase after being placed at 60°C for 30 days. to 0.34%, the stability of the preparation is poor.
  • the control prescription C2 uses hydroxystearic acid
  • Polyethylene glycol glyceride and propylene glycol are used as co-solvents, and their stability is better than the control prescription C1.
  • Transcutol and DMSO are used as co-solvents, and the total degradation impurities increased to 0.60% after being left at 60°C for 30 days. It is speculated that Transcutol is The stability of the preparation is affected, and this result is consistent with the raw material compatibility test results in Example 2.
  • the topical pirfenidone preparation of the present invention has better physical and chemical stability.
  • Test Example 2 In vitro transdermal test of pirfenidone topical preparation
  • Test method Use the back skin of Bama Xiang pigs (1.5 months old, Linxi County Jingde Agricultural Products Sales Co., Ltd., No. 20220454, 20220455, 20220456) as the permeability membrane, and use a vertical diffusion cell to conduct skin penetration/retention tests. Take 0.8-1.0mm thick pig skin and cut off the hair on the skin. Confirm skin resistance to ensure skin integrity. The skin was placed on top of a diffusion cell in contact with the receptor, the receiving phase of which was filled with phosphate buffered saline (PBS) (pH 6.8). Approximately 25 mg of pirfenidone topical preparation was added to the skin surface in the donor compartment. After 24 hours, the receiving phase medium was taken, filtered with a 0.45 ⁇ m filter, and analyzed by high-performance liquid chromatography (HPLC) to determine and calculate the average formulation prescription Cumulative penetration amount, the results are shown in Table 10.
  • PBS phosphate buffered saline
  • the experimental results show that the 24h cumulative penetration amount of control prescription C1 is 405.7 ⁇ g/cm 2 , the 24h cumulative penetration amount of control prescription C2 is only 173.0 ⁇ g/cm 2 , and the 24h cumulative penetration amount of control preparation C3 is higher than that of control prescriptions C1 and C2.
  • the 24-hour cumulative penetration amount of the pirfenidone topical preparation on the skin is about 800-1300 ⁇ g/cm 2 , which is about 2-7 times that of the control prescription.
  • the preparation of the present invention has a higher cumulative skin penetration, which may be the result of DMSO, ethanol and propylene glycol acting as co-solvents to promote the penetration of active pharmaceutical ingredients.
  • experimental results show that the addition of humectants, preservatives and antioxidants will not affect the cumulative permeability of the preparation.
  • This test example examines the skin irritation of pirfenidone topical preparations through an acute skin irritation test (i.e., a single application test).
  • Test method Select 15 volunteers as subjects and try different formulations shown in Table 14 in sequence. under test Test the drug on the back of the hand and the inside of the arm. After cleaning the back of the hand and the inside of the arm, select an area of about 2cmx2cm (not covered by heavy body hair), apply about 0.1g of the sample to the selected area, smooth it to a thin layer, 2- Carry out skin irritation score within 3 minutes. The higher the skin irritation score, the stronger the irritation of the corresponding preparation.
  • control preparation prescription C1 which may be caused by the large dosage of NMP
  • preparation of the present invention does not contain NMP, but uses Using an appropriate amount of DMSO with ethanol and/or propylene glycol as a co-solvent, the subjects basically felt no pain or irritation after application.
  • prescriptions 5, 6 and 16 had the best experience.
  • adding a humectant to the topical formulation of pirfenidone can also keep the skin moist and reduce irritation, especially when subjects need to apply the drug for a long time, helping to improve skin comfort.
  • Test materials 4 groups of experimental preparations, of which group G1: preparation prescription 6 of the present invention; group G2: the matrix of preparation prescription 6 of the present invention, excluding pirfenidone; group G3: control prescription C1; group G4: model group , without applying any preparation).
  • Test instruments dehydrator (DIAPATH, Donatello), embedding machine (Wuhan Junjie Electronics Co., Ltd., JB-P5), freezing table (Wuhan Junjie Electronics Co., Ltd., JB-L5), pathology microtome (Shanghai Leica Instruments Co., Ltd., RM2016), tissue spreader (Jinhua Kedi Instrument Equipment Co., Ltd., Zhejiang province, KD-P), oven (Tianjin Lai Bo Rui Instrument Equipment Co., Ltd., GFL-230), anti-falling slides (Servicebio), Upright optical microscope (NIKON ECLIPSE E100, Nikon, Japan), imaging system (NIKON DS-U3, Nikon, Japan), xylene (Sinopharm Chemical Reagent Co., Ltd., 10023418), absolute ethanol (Sinopharm Chemical Reagent Co., Ltd., 100092683 ), HE dye solution set (Servicebio; G1003), central gum (Sinopharm
  • Test method 16 rabbit ears of 8 male New Zealand rabbits (1.7 ⁇ 2.0kg) were randomly divided into 4 groups, each group had 4 rabbit ears. After marking, they were adaptively raised for 1 week, and then the rabbits were anesthetized and shaved with a razor. Shave the ventral hair of rabbit ears and perform routine disinfection. Use a wound punch with a diameter of 1cm to measure the area on the ventral side of the rabbit ear. After touching the surface of the rabbit ear, press it tightly. Use a heavy object to tap the wound punch gently and turn it three or four times. Each rabbit ear will cause 4 full-thickness skin wounds of 1cm ⁇ 1cm, with an interval of approximately 1.5cm between each wound. The skin in the wound area is removed together with the underlying perichondrium, leaving the cartilage intact. After the operation, the wound was disinfected with iodophor, and administration was started the next day. The administration method is shown in Table 15 below.
  • a dressing needs to be used to cover the administration site of the rabbit ear.
  • a cotton swab dipped in physiological saline should be used to wipe the administration site.
  • 28 days after administration the rabbits were euthanized. The scar and surrounding normal tissue within 3 mm are cut and removed together with the cartilage.
  • a normal rabbit ear tissue was selected as a blank control.
  • a landmark wound of each rabbit ear was selected and fixed with 10% formalin, sectioned and stained with HE.
  • the slicing steps are: fresh tissue is fixed in fixative for more than 24 hours. Remove the tissue from the fixative and use a scalpel to smooth the tissue at the target site in the fume hood. Place the trimmed tissue and corresponding labels in the dehydration box.
  • the tissue Before the wax solidifies, take the tissue out of the dehydration box and put it into the embedding frame according to the requirements of the embedding surface and attach the corresponding label. Cool on a -20°C freezing platform. After the wax solidifies, remove the wax block from the embedding frame and trim the wax block. Place the trimmed wax block into a -20°C freezer to cool, and then place the cooled wax block into paraffin microtome slices with a thickness of 4 ⁇ m. The slices were floated on warm water at 40°C in a spreading machine to flatten the tissue. The tissue was picked up by a glass slide and baked in a 60°C oven. After the water-baked dry wax is baked, take it out and store it at room temperature for later use.
  • HE staining The steps of HE staining are: stain the sections with hematoxylin dye for 3 to 5 minutes, wash with tap water, differentiate with differentiation solution, wash with tap water, return to blue with blue-returning solution, and rinse with running water. Then add 85% and 95% gradient alcohol for dehydration for 5 minutes each, and then add eosin staining solution for 5 minutes. Finally, add absolute ethanol I for 5 minutes, absolute ethanol II for 5 minutes, absolute ethanol III for 5 minutes, xylene I for 5 minutes, and xylene II for 5 minutes to make it transparent. The slides are sealed with neutral gum for microscopy and image acquisition and analysis.
  • Tissue damage was evaluated through pathological sections, and scar tissue was pathologically analyzed. Observe fibroblasts, capillaries, collagen fibers, etc. under a microscope and score them. The scoring criteria are:
  • Score 4-6 thin, immature granulation tissue, mainly inflammatory cells, with a small amount of fibroblasts, capillaries or collagen deposition. minimal epithelial cell migration;
  • Score 7-9 medium-thick granulation tissue, which is mainly composed of inflammatory cells and converted to fibroblasts and collagen deposition. Extensive neovascularization. Moderate degree of epithelialization and migration;
  • This test case aims to study a single topical application of pirfenidone topical preparation in mini pigs, detect the concentration of active ingredients in plasma, and evaluate the pharmacokinetics (PK) characteristics, systemic exposure and safety of mini pigs after topical administration. sex.
  • PK pharmacokinetics
  • mice male Bama Miniature Swine (3-5 months old, weight 9-10kg, purchased from Shanghai Jiaqian Biotechnology Co., Ltd.), experimental preparation (preparation prescription 6 of the present invention).
  • Blood samples were collected at 0min before administration and at 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 24h after administration into K2EDTA anticoagulant tubes, stored on wet ice, and centrifuged within 1h. (1500 ⁇ 1600g, 4°C) for 10 minutes, separate the plasma, store the obtained plasma sample in an environment of -90 ⁇ -60°C, and place it on dry ice for transportation.

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Abstract

一种吡非尼酮局部外用制剂，其包含治疗有效量的吡非尼酮、水和至少一种助溶剂，所述助溶剂选自二甲亚砜与醇类溶剂的组合。该制剂皮肤透过性高、稳定性好、无刺激性，皮肤耐受性好，使用方便，可用于制备预防或治疗皮肤或结缔组织过度增生相关疾病、慢性皮肤损伤的药物。

Description

一种含有吡非尼酮的局部外用制剂及其用途
本申请要求以下在先申请的优先权：2022年09月06日向中国国家知识产权局提交的专利申请号为202211086265.9，发明名称为“一种含有吡非尼酮的局部外用制剂及其用途”的在先申请。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于药物制剂领域，具体涉及一种含有吡非尼酮的局部外用制剂及其用途。
背景技术
吡非尼酮(pirfenidone)，化学名为5-甲基-1-苯基-2-(1H)吡啶酮，是一种具有广谱抗纤维化作用的化合物，能够防止和逆转纤维化和瘢痕的形成，其化学结构如下所示：
2014年，吡非尼酮获美国食品和药物管理局(FDA)批准上市，商品名称目前，吡非尼酮已成为第一个在多个国家获得批准用于治疗特发性肺纤维化(IPF)的药物。
近年来，人们对吡非尼酮在其他方面的用途也有广泛的研究。例如，WO00/16775中公开将吡非尼酮用于治疗和预防皮肤病变，特别是纤维化性质病变，如纤维化损伤组织，接触传染的疣，接触性皮炎，烧伤和瘢痕等。WO99/47140公开了应用2-1H-吡啶酮类化合物，特别是吡非尼酮作为局部消毒处理，可用于皮肤表面对真菌、细菌等进行处理。WO01/62253公开了将吡非尼酮用于治疗癫痫。美国专利US4,052,509中公开了吡非尼酮具有作为抗炎剂的用途。墨西哥专利182,266中公开了吡非尼酮具有抗纤维化活性。中国专利文献CN111246840A中公开了吡非尼酮可以用于预防或治疗慢性皮肤损伤和由神经性溃疡引起的损伤，特别是治疗糖尿病足综合症和治疗血管性溃疡。
综上，许多研究表明吡非尼酮可用于治疗和预防皮肤病变，如手术伤口、烧伤、事故、紫外线、怀孕或化学制剂引起的纤维化或炎症性的皮肤异常疤痕和其他缺陷，但吡非尼酮在水中的溶解性差，较难制备成稳定的外用制剂。
CN10808641A公开了一种含吡非尼酮的凝胶组合物，该申请公开了选用增溶剂如NMP、乙醇和丙二醇来制备凝胶制剂，可用于带有纤维化病变的组织恢复和用于纤维化病变的预防，但未对其稳定性、透皮效果及体内效果等进行研究。
因此，需要进一步提供一种稳定性高的、具有良好透皮效果和疗效的吡非尼酮药物组合 物。
发明内容
本发明的一个目的是提供一种吡非尼酮局部外用制剂，该制剂皮肤渗透性高、稳定性好、刺激性低，能够高效地透过皮肤并安全起效。
为实现上述目的，本发明提供以下技术方案：
第一方面，本发明提供一种吡非尼酮局部外用制剂，其包含治疗有效量的吡非尼酮、水和至少一种助溶剂。
在一些实施方案中，所述助溶剂选自二甲亚砜(DMSO)和醇类溶剂，所述醇类溶剂选自乙醇、丙二醇、异丙醇、1-丙醇、丁二醇中的一种，两种或更多种。优选地，所述助溶剂为DMSO和乙醇的组合，或DMSO和丙二醇的组合，或DMSO、乙醇和丙二醇三者的组合。
在一些实施方案中，所述制剂中水的用量为10wt％至55wt％，优选15wt％至50wt％，例如20wt％，25wt％，30wt％，35wt％，40wt％或45wt％。
在一些实施方案中，当助溶剂为DMSO和乙醇的组合时，按局部外用制剂的总重量计，所述制剂包含15wt％至35wt％的DMSO、15wt％至30wt％的乙醇；优选地，所述制剂包含15wt％至25wt％的DMSO、15wt％至25wt％的乙醇，例如含有20wt％的DMSO和20wt％的乙醇，或者含有20wt％的DMSO和25wt％的乙醇。
在一些实施方案中，当助溶剂为DMSO、乙醇和丙二醇的组合时，按局部外用制剂的总重量计，所述制剂包含15wt％至35wt％的DMSO、15wt％至30wt％的乙醇，15wt％至25wt％的丙二醇；优选地，所述制剂包含15wt％至25wt％的DMSO、15wt％至25wt％的乙醇和20wt％至25wt％的丙二醇。
在一些实施方案中，按吡非尼酮局部外用制剂的总重量计，所述制剂中的吡非尼酮以1wt％至14wt％的量存在；优选地，4wt％至12wt％的量存在；例如以6wt％至12wt％的量存在，例如以7wt％、8wt％、9wt％、10wt％、11％wt的量或其任意区间范围存在。
在一些实施方案中，本发明的吡非尼酮局部外用制剂可调配成不同剂型，例如溶液、悬浮液、乳膏、软膏、洗剂和凝胶。优选地，本发明的吡非尼酮局部外用制剂为溶液或凝胶。更优选地，本发明的吡非尼酮局部外用制剂为凝胶。
在一些实施方案中，可选地，所述吡非尼酮局部外用制剂进一步包含胶凝剂。所述胶凝剂可以是本领域中已知的用于局部外用制剂的胶凝剂，包括但不限于：纤维素衍生物、聚乙烯吡咯烷酮、卡波姆聚合物、卡波姆衍生物、麦芽糊精、聚葡萄糖、葡萄糖结合剂、聚丙烯酰胺类胶凝剂、羧基聚亚甲基、聚乙烯醇、泊洛沙姆、聚乙二醇中的一种，两种或更多种；优选地，所述胶凝剂选自纤维素衍生物、卡波姆聚合物、卡波姆衍生物中的一种，两种或更多种。例如，所述胶凝剂为HPC、卡波姆980、卡波姆981等。
在一些实施方案中，按吡非尼酮局部外用制剂的总重量计，胶凝剂以0.05wt％至5wt％的量存在，优选以0.1wt％至2wt％，例如0.3wt％至1wt％的量存在。
在一些实施方案中，可选地，所述吡非尼酮局部外用制剂进一步包含保湿剂，所述保湿剂可以是本领域中已知的用于局部外用制剂的保湿剂，包括但不限于：甘油、尿素、尿囊素、透明质酸钠、聚乙二醇、角鲨烷、环甲基硅酮中的一种，两种或更多种。优选地，所述保湿剂选自甘油、尿囊素、透明质酸钠中的一种，两种或三种。
在一些实施方案中，按吡非尼酮局部外用制剂的总重量计，保湿剂以0.5wt％到10wt％，优选以2wt％到8wt％，例如3wt％到6wt％的量存在。
在一些实施方案中，可选地，所述吡非尼酮局部外用制剂包含pH调节剂，所述pH调节剂可以是本领域中已知的用于局部外用制剂的pH调节剂，特别是碱性pH调节剂，例如选自三乙醇胺、氢氧化钠、三乙胺中的一种，两种或三种；优选地，pH调节剂为三乙醇胺。所述pH调节剂的用量为适量，以调节该局部外用制剂的pH为5.0～7.5范围为宜，更优选pH为5.5～7.5。
在一些实施方案中，可选地，所述吡非尼酮局部外用制剂还包含防腐剂，所述防腐剂可以是本领域中已知的用于局部外用制剂的防腐剂，例如选自对羟基苯甲酸甲酯(羟苯甲酯)、对羟基苯甲酸丙酯(羟苯丙酯)、苯甲醇、苯甲酸、苯酚中的一种，两种或更多种。
在一些实施方案中，按吡非尼酮局部外用制剂的总重量计，防腐剂以0.01wt％至2wt％的量存在，例如0.05wt％至1wt％的量存在。
在一些实施方案中，可选地，本发明的吡非尼酮局部外用制剂进一步包括一种，两种或更多种药学上可接受的其他辅料，包括但不限于：抗氧化剂、增稠剂、稳定剂、螯合剂、油性材料、乳化剂、渗透促进剂、抗微生物剂、遮光剂、芳香剂、着色剂、表面活性剂等。所述辅料可以以本领域已知的常规用量使用。
例如，抗氧化剂可以是本领域中已知的用于局部外用制剂的抗氧化剂，例如选自丁基羟基茴香醚(BHA)、丁基化羟基甲苯、维生素C、维生素E、维生素A、叶黄素、番茄红素、棕榈酸视黄酯、偏亚硫酸氢钾、偏亚硫酸氢钠、硫代硫酸钠五水合物、3，4-二羟基苯甲酸、没食子酸丙酯、α-硫辛酸、棕榈酸抗坏血酸酯、焦亚硫酸钠、泛醌、硒中的一种，两种或更多种。例如，抗氧化剂为丁基羟基茴香醚(BHA)。按吡非尼酮局部外用制剂的总重量计，抗氧化剂可以0.05wt％至5wt％，例如0.1wt％到3wt％的量存在。
例如，所述增稠剂可以是例如纤维素衍生物、聚乙烯吡咯烷酮、卡波姆聚合物、卡波姆衍生物、麦芽糊精、聚葡萄糖、葡萄糖结合剂(dextrate)、羧基聚亚甲基、聚乙烯醇、泊洛沙姆、聚乙二醇中的一种，两种或更多种；更优选地，增稠剂为羟丙基纤维素。按吡非尼酮局部外用制剂的总重量计，增稠剂可以以0.05wt％到5wt％，优选0.1wt％到4wt％，例如1wt％到3wt％的量存在。
在一种示范性实施方案中，本发明的吡非尼酮局部外用制剂包含治疗有效量的吡非尼酮、水和至少一种助溶剂，所述助溶剂包含DMSO和乙醇，其中按局部外用制剂的总重量计，所述制剂包含4wt％至12wt％的吡非尼酮、15wt％至30wt％的DMSO、15wt％至30wt％的乙醇。可选地，该制剂进一步包含0.05wt％至5wt％的胶凝剂(例如选自卡波姆980、卡波姆981中 的一种或两种)。可选地，该制剂进一步包含0.05wt％至8wt％的保湿剂(例如选自甘油、尿囊素、透明质酸钠中的一种，两种或三种)。可选地，该制剂进一步包含0.05wt％至2wt％的防腐剂。可选地，该制剂进一步包含pH调节剂(例如选自三乙醇胺、NaOH中的一种或两种)，使该制剂的pH范围调节至5.0～7.5。可选地，该制剂进一步包含药学上可接受的其他辅料。
在一种示范性实施方案中，本发明的吡非尼酮局部外用制剂包含治疗有效量的吡非尼酮、水和至少一种助溶剂，所述助溶剂包含DMSO和乙醇，其中按局部外用制剂的总重量计，所述制剂包含6wt％至12wt％的吡非尼酮、20wt％至30wt％的DMSO、20wt％至30wt％的乙醇。可选地，该制剂进一步包含0.4wt％至1wt％的胶凝剂(例如选自卡波姆980、卡波姆981中的一种或两种)。可选地，该制剂进一步包含3wt％至6wt％的保湿剂(例如选自甘油、尿囊素、透明质酸钠中的一种，两种或三种)。可选地，该制剂进一步包含0.05wt％至0.5wt％的防腐剂。可选地，该制剂进一步包含pH调节剂(例如选自三乙醇胺、NaOH中的一种或两种)，使该制剂的pH范围调节至5.0～7.5。可选地，该制剂进一步包含药学上可接受的其他辅料。
在一种示范性实施方案中，所述制剂包含4wt％至12wt％的吡非尼酮、15wt％至35wt％的DMSO、15wt％至30wt％的乙醇、20wt％至50wt％的水、0.3wt％至1wt％的胶凝剂、2wt％至8wt％的保湿剂，以及适量pH调节剂使该制剂的pH范围调节至5.0～7.5。
在一种示范性实施方案中，所述制剂包含4wt％至12wt％的吡非尼酮、20wt％至25wt％的DMSO、20wt％至25wt％的乙醇、30wt％至45wt％的水、0.3wt％至1wt％的胶凝剂、2wt％至8wt％的保湿剂、0.05wt％至1wt％的防腐剂，以及适量pH调节剂使该制剂的pH范围调节至5.0～7.5。
第二方面，本发明还提供上述吡非尼酮局部外用制剂在制备用于预防或治疗皮肤或结缔组织过度增生相关疾病、慢性皮肤损伤的药物中的用途。
第三方面，本发明提供了一种预防或治疗哺乳动物(例如人)的皮肤或结缔组织过度增生相关疾病、慢性皮肤损伤的方法，所述方法包括向哺乳动物(例如人)给予治疗有效量的本发明所述的吡非尼酮局部外用制剂。
本发明的一些实施方案中，所述皮肤或结缔组织过度增生相关疾病包括但不限于病理性瘢痕(例如疤痕疙瘩、增生性疤痕)、痤疮瘢痕、皮肤肿瘤性纤维化和瘢痕性脱发；所述慢性皮肤损伤包括但不限于血管炎、烧伤愈合、糖尿病足综合征、血管性溃疡、硬皮病、阴茎硬结症、杜伊氏综合征或粘性囊炎。
本发明的发明人意外地发现当吡非尼酮局部外用制剂中使用DMSO和醇类溶剂作为助溶剂时，可以显著改善其药用性能，所得制剂克服了吡非尼酮在水中溶解度低、皮肤透过率低、对皮肤刺激敏感等技术问题。所述制剂皮肤透过性高、稳定性好、无刺激性，皮肤耐受性好，使用方便，能够显著提高疤痕疙瘩、病理性瘢痕或增生性疤痕患者的顺应性，可开发成为一种非常有前景的局部外用药物。
附图说明
图1～4分别为本发明测试例4的吡非尼酮体内药效试验中，四个不同组别的家兔耳表面瘢痕区给药28天后HE染色病理切片图，每个图中的小图1、2、3、4分别表示每组中的4个样本的HE染色病理切片图。
术语定义和说明
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
本文所用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
术语“预防或治疗”意为将本发明所述制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；(ii)抑制疾病或疾病状态，即遏制其发展；(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本发明制剂的用量。构成“治疗有效量”的本发明制剂的量取决于该制剂、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、水、其他溶剂等。
如本文所用，术语“溶剂”是水。
如本文所用，术语“助溶剂”是指与其它物质结合，例如溶剂水充当辅助的物质。
如本文所用，术语“慢性皮肤损伤”是指伤口愈合的各个阶段中会导致异常纤维化组织形成(例如瘢痕形成)的旺盛活性。
如本文所用，术语“糖尿病足综合征”糖尿病足是一种临床实体，糖尿病足综合征是指由于在糖尿病患者中存在慢性高血糖，外部因素和内在因素(诸如创伤、局部卫生和骨骼畸形)所引起的由诱发因素(诸如血管病、神经病和感染)相互作用而产生的综合征。常见的典型临床症状有患者下肢溃疡、足溃疡(也称糖尿病足溃疡)等。
如本文所用，术语“聚丙烯酰胺类胶凝剂”，主要是指由SEPPIC公司以名称Sepineo (或Simulgel 600)销售的混合物丙烯酰基二甲基牛磺酸钠共聚物/异十六烷/聚山梨醇酯80，混合物聚丙烯酰胺/异链烷烃C13-14/月桂醇聚醚-7(如由SEPPIC公司以名称 305销售的产品。
具体实施方式
以下结合具体实施例对本发明的技术方案做进一步的详细说明。应当理解，下列实施例仅为示例性地解释说明的目的，而不应理解为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件操作。除非另有说明，实施例中所用的百分比和份数均为重量计，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
本发明采用下述缩略词：DMSO代表二甲基亚砜；NMP代表N-甲基吡咯烷酮；Solutol HS 15代表聚乙二醇(PEG)-15羟基硬脂酸酯；Transcutol代表二乙二醇单乙醚；HPC代表羟丙基纤维素，BHA代表丁基羟基茴香醚。下表中“-”表示不含或未添加对应的成分。
实施例1吡非尼酮的溶解性测试
本实施例考察吡非尼酮在水/DMSO/醇类溶剂中的溶解性能。
实验方法：将过量吡非尼酮添加到表1中所列的溶剂体系中。将所得悬浮液搅拌过夜，通过0.22μm滤膜过滤。将滤液稀释到合适的浓度。通过HPLC方法测定每一溶液中吡非尼酮的浓度。吡非尼酮在不同溶剂体系中的溶解度结果如表1所示。
表1.吡非尼酮在不同溶剂体系中的溶解度
从实验结果可以看出，虽然纯化水是局部外用制剂中的常用溶剂，然而吡非尼酮在水中 的溶解度较低，即便加入DMSO进行增溶，溶解度也难以达到在局部外用制剂中期望达到的浓度(80mg/mL)。然而，若进一步加入乙醇或者丙二醇进行增溶，则能显著提高吡非尼酮在水中的溶解度。例如，吡非尼酮在水/DMSO/乙醇或水/DMSO/丙二醇中均具有较好的溶解度，可达到吡非尼酮在局部外用制剂中期望达到的浓度(80mg/mL)。
实施例2吡非尼酮局部外用制剂的原辅料相容性实验
本实施例进行原辅料相容性实验，以考察助溶剂、胶凝剂、保湿剂等辅料对吡非尼酮局部外用制剂稳定性的影响。胶凝剂(例如卡波姆)和保湿剂(例如甘油、尿囊素、透明质酸钠)是局部外用制剂中常用的辅料。
实验方法：将吡非尼酮与辅料(包括助溶剂、胶凝剂、保湿剂等)以重量比1∶99的比例混合(API吡非尼酮占重量份为1％，其他各辅料总重量份为99％)，在高温(60℃，干燥)条件下放置30天，测试其总降解杂质含量和最大单杂含量。实验结果如表2所示。
表2.原辅料相容性实验

实验结果显示，吡非尼酮在实施例1测试的助溶剂(DMSO、乙醇)、常用的胶凝剂(卡波姆)、保湿剂(甘油、尿囊素、透明质酸钠)中均具有良好的稳定性，因此，这些辅料与吡非尼酮的相容性良好，可用于本发明的吡非尼酮局部外用制剂中。
此外，本申请还测试了吡非尼酮在Transcuto存在下的稳定性。尽管Transcutol也可以对吡非尼酮在DMSO+水的体系中起到增溶作用，但使用Transcutol导致产品不稳定。例如，含吡非尼酮/Transcutol/水为1％∶23.5％∶75.5％的制剂在高温(60℃，干燥)条件下放置30天后，会产生明显的降解杂质，推测Transcutol可能会诱导吡非尼酮的降解。
综上可知，并非任意的有机溶剂都可以作为增容剂用于本申请的吡非尼酮局部外用制剂中。本发明使用的DMSO+醇类溶剂，不仅可以增溶，还不会对吡非尼酮的稳定性等产生影响，是良好的助溶剂。
实施例3吡非尼酮局部外用制剂的制备
本实施例按表3所示处方制备吡非尼酮的局部外用制剂。
制备方法：根据处方，1)将吡非尼酮与助溶剂混合；2)将胶凝剂与适量的纯化水混合；3)将保湿剂与剩余量的纯化水混合；4)将步骤1)、2)、3)所得的混合物混合均匀，加入pH调节剂调节pH至5.5～7.5，搅拌至均一，即得。
表3.吡非尼酮的局部外用制剂
实施例4吡非尼酮局部外用制剂的制备
本实施例按表4所示处方制备吡非尼酮的局部外用制剂。
制备方法：根据处方，1)将吡非尼酮与助溶剂混合，加入防腐剂混匀；2)将胶凝剂与 适量的纯化水混合；3)将保湿剂与剩余量的纯化水混合；4)将步骤1)、2)、3)所得的混合物混合均匀，加入pH调节剂调节pH至5.5～7.5，搅拌至均一，即得。
表4.吡非尼酮的局部外用制剂
实施例5吡非尼酮局部外用制剂的制备
本实施例按表5所示处方制备吡非尼酮的局部外用制剂。
制备方法：参考实施例4。
表5.吡非尼酮的局部外用制剂

实施例6吡非尼酮局部外用制剂的制备
本实施例按表6所示处方制备吡非尼酮的局部外用制剂。
制备方法：根据处方，1)将吡非尼酮与助溶剂混合，加入抗氧化剂混匀；2)将胶凝剂与纯化水混合；3)将步骤1)、2)所得的混合物混合均匀，加入pH调节剂调节pH至5.5～7.5，搅拌至均一，即得。
表6.吡非尼酮局部外用制剂
实施例7吡非尼酮局部外用制剂的制备
本实施例按表7所示处方制备吡非尼酮的局部外用制剂。
制备方法：参考实施例3。
表7.吡非尼酮局部外用制剂

实施例8吡非尼酮局部外用制剂的制备
本实施例按表8所示处方制备吡非尼酮的局部外用制剂。其中对照制剂处方C1参照墨西哥上市的吡非尼酮凝胶制剂KitosCell的处方来制备。
制备方法：根据处方，1)将吡非尼酮与助溶剂混合，加入防腐剂(如果有的话)等辅料混合；2)将胶凝剂与适量的纯化水混合；3)将步骤1)、2)所得的混合物混合均匀，加入pH调节剂调节pH至5.5～7.5，搅拌至均一，即得。
表8.吡非尼酮局部外用制剂
测试例1吡非尼酮局部外用制剂的稳定性
本测试例考察吡非尼酮局部外用制剂的稳定性。
试验方法：将实施例3～8中的吡非尼酮局部外用制剂在高温(60℃，干燥)和加速条件 (40℃±2℃、75％RH±5％RH)条件下进行稳定性研究实验，考察0天、30天时各制剂的物理和化学稳定性。实验结果如下表9所示。
表9.吡非尼酮局部外用制剂的稳定性研究



注：0天测定数据是样品制备完成后检测获得的测定值。
实验结果显示，本发明的吡非尼酮局部外用制剂在高温和加速条件下放置30天，颜色性状没有改变，杂质含量无明显增加，均保持良好的稳定性。其中，不同制剂处方的黏度差异较大，是由于胶凝剂的黏度不同导致的。举例说明，例如浓度为0.5％w/w的卡波姆980在pH7.5时的粘度为40000～60000厘泊，性状粘稠，流动性弱；而0.5％w/w的卡波姆981在pH7.5时的粘度为4000～10000厘泊，流动性相对较强，因此使用不同胶凝剂制备的局部外用凝胶类制剂具有不同的黏度。在制剂施用时，不同的黏度可产生不同的感受，均可成药，不影响制剂的稳定性和药效。此外，结果显示，本发明的保湿剂、防腐剂和抗氧化剂等的加入不会影响制剂的稳定性，与实施例2的原辅料相容性实验结果一致。
本发明的制剂处方中，助溶剂可以为DMSO和醇类溶剂的组合。相比之下，对照处方C1中以羟基硬脂酸聚乙二醇甘油酯和NMP作为增溶剂或助溶剂，该凝胶制剂在60℃放置30天制剂颜色变深，且总降解产物增大至0.34％，制剂稳定性较差，这可能是NMP和防腐剂重氮烷基咪唑脲、丁基氨基甲酸碘代丙炔酯对制剂的稳定性有影响；对照处方C2中以羟基硬脂酸聚乙二醇甘油酯和丙二醇作为助溶剂，稳定性优于对照处方C1；对照处方C3中以Transcutol和DMSO为助溶剂，高温60℃放置30天，总降解杂质增加至0.60％，推测Transcutol对制剂的稳定性产生影响，该结果与实施例2中的原辅料相容性实验结果相一致。综上可知，本发明的吡非尼酮局部外用制剂具有更好的物理和化学稳定性。
测试例2吡非尼酮局部外用制剂的体外透皮试验
本测试例对实施例3～8中的吡非尼酮局部外用制剂进行体外透皮试验，评估各吡非尼酮局部外用制剂的透过皮肤层的能力。一般地，无毛发天竺鼠或猪是用于预测人类皮肤吸收率的公认模型。相比之下，使用具有毛发的实验动物(如大鼠、兔和天竺鼠)的其他模型通常导致高估人类皮肤吸收率。
试验方法：使用巴马香猪(1.5月龄，临西县敬德农产品销售有限公司，编号20220454、20220455、20220456)的背部皮肤作为渗透膜，采用垂直扩散池进行皮肤渗透/保留测试。取0.8-1.0mm厚度的猪皮，并剪去皮肤上的毛发。确认皮肤的电阻以确保皮肤完整性。将皮肤放在与受体相接触的扩散池的顶部上，所述扩散池的接收相填充有磷酸盐缓冲液(PBS)(pH 6.8)。将约25mg吡非尼酮局部外用制剂添加到供体隔室中的皮肤表面上，24小时后，取接收相介质，用0.45μm滤膜过滤后，通过高效液相色谱(HPLC)分析，测定并计算制剂处方的平均 累积渗透量，结果见表10。
表10.不同制剂处方的24h累积渗透量
实验结果显示，对照处方C1的24h累积渗透量为405.7μg/cm2，对照处方C2的24h累积渗透量也仅为173.0μg/cm2，对照制剂C3的24h累积渗透量高于对照处方C1和C2。而本发明所述的吡非尼酮局部外用制剂在皮肤上的24h累积渗透量约在800～1300μg/cm2，是对照处方的约2～7倍。综上，本发明的制剂具有更高的皮肤累积透过量，这可能是DMSO及乙醇和丙二醇作为助溶剂促进药物活性成分渗透的结果。此外，实验结果显示，保湿剂、防腐剂和抗氧化剂的加入基本不会影响制剂的累积渗透性。
测试例3皮肤刺激性试验
除上述的渗透量外，局部外用制剂的刺激性也是一个重要考虑因素。本测试例通过急性皮肤刺激实验(即一次涂抹实验)考察吡非尼酮局部外用制剂对皮肤的刺激性。
试验方法：选择15名志愿者作为受试者，依次试用表14所示的不同制剂处方。在受试 者手背及手臂内侧试药，手背和手臂内侧清洗干净后，选取约2cmx2cm的面积(无厚重体毛覆盖)，将约0.1g样品涂抹在选定区域内，抹平至薄薄一层，2-3min内进行皮肤刺激性评分。皮肤刺激评分越高说明相应制剂的刺激性越强。
评分方法：参考《化妆品安全技术规范》(2015年版)皮肤刺激性/腐蚀性试验方法，设置以下评分方法。根据公式1[皮肤疼痛积分＝(∑手部疼痛积分×0.4+∑手臂内侧疼痛积分×0.6)/受试人数]计算疼痛积分，根据表11的皮肤疼痛反应评分标准来进行疼痛评分；有疼痛感受的样品涂抹2-3分钟后立即擦去受试药，无明显刺痛样品等待30min后擦去受试药，擦去受试药后观察皮肤刺激反应；并根据公式2[皮肤刺激积分＝(∑手部红斑和水肿积分×0.4+∑手臂内侧红斑和水肿积分×0.6)/受试人数]计算皮肤刺激积分，根据表12的皮肤刺激反应评分标准来进行皮肤刺激评分；并根据公式3(皮肤刺激总分＝皮肤疼痛积分+皮肤刺激积分)计算皮肤刺激总分，根据表13来评价皮肤刺激强度。实验结果见表14。
表11皮肤疼痛反应评分标准
表12皮肤刺激反应评分标准
表13皮肤刺激强度评价表

表14不同处方制剂的皮肤刺激性评价结果
实验结果显示，受试者在对照制剂处方C1施用过程中有明显轻微疼痛感觉，且有明显轻刺激性，这可能是NMP用量较大导致的；而本发明的制剂不含NMP，而是使用适量的DMSO与乙醇和/或丙二醇作为助溶剂，受试者施用后基本无疼痛感和刺激性，其中处方5、6和16的施用体验最佳。此外，在吡非尼酮局部外用制剂中加入保湿剂也可以保持皮肤湿润，减少刺激性，特别是当受试者需要长期施用药物时，有助于提高皮肤的舒适感。
测试例4吡非尼酮体内药效试验
病理性瘢痕常常发生于真皮深层受损后，造成患者美学及功能的损毁，严重影响患者的生活质量。由于人的瘢痕组织在临床取材常常受到限制，因此大部分药效研究需要使用实验动物模型。在家兔耳朵上建立创面，并去除软骨膜，可以使创面收缩变缓、愈合缓慢，最终导致瘢痕的发生。该模型常常用于瘢痕类药物的体内药效研究。本实验通过模拟临床使用方法，在已形成创面的兔耳上涂抹外用制剂来治疗瘢痕，通过HE病理切片观察瘢痕愈合等情况。
试验材料：实验制剂4组，其中G1组：本发明的制剂处方6；G2组：本发明的制剂处方6的基质，不含吡非尼酮；G3组：对照处方C1；G4组：模型组，不施用任何制剂)。
试验仪器：脱水机(DIAPATH，Donatello)、包埋机(武汉俊杰电子有限公司，JB-P5)、冻台(武汉俊杰电子有限公司，JB-L5)、病理切片机(上海徕卡仪器有限公司，RM2016)、组织摊片机(浙江省金华市科迪仪器设备有限公司，KD-P)、烤箱(天津市莱玻瑞仪器设备有限公司，GFL-230)、防脱载玻片(Servicebio)、正置光学显微镜(日本尼康，NIKON ECLIPSE E100)、成像系统(日本尼康，NIKON DS-U3)、二甲苯(国药集团化学试剂有限公司，10023418)、无水乙醇(国药集团化学试剂有限公司，100092683)、HE染液套装(Servicebio；G1003)、中心树胶(国药集团化学试剂有限公司，10004160)、新西兰兔(南京市浦口区莱芙养殖场，许可证号：SCXK(苏)2019-0005)。
试验方法：将8只雄性新西兰兔(1.7～2.0kg)的16只兔耳随机分成4组，每组4只兔耳，标记后，适应性饲养1周，然后将兔子麻醉，用剃毛刀将兔子耳腹侧毛发剃去并进行常规消毒。用直径为1cm的创面打孔器，在兔耳腹侧测量好的区域，接触兔耳表面后压紧，用重物轻打创面打孔器，并轻转三四圈，每只兔耳造成4个1cm×1cm的全层皮肤创口，每个创口间隔约1.5cm。创口区内皮肤连同其下软骨膜一并去除，保留软骨。手术后对创口进行碘伏消毒，并于次日开始给药，给药方式如下表15所示。
表15
每次给药后，需用敷贴覆盖于兔耳给药部位，每次给药前，需用棉签蘸取生理盐水擦拭给药部位。给药后28天后，对兔子进行安乐死。将瘢痕及周围3mm以内的正常组织，连同软骨一起切割取下。同时选取一只正常家兔耳朵组织作为空白对照。每只兔耳选取一个标志性的创口用10％福尔马林固定，并进行切片和HE染色。
切片步骤为：新鲜组织用固定液固定24h以上。将组织从固定液取出在通风橱内用手术刀将目的部位组织修平整，将修切好的组织和对应的标签放于脱水盒内。将脱水盒放进脱水机内依次梯度进行脱水：75％酒精4h，85％酒精2h，90％酒精2h，95％酒精1h，无水乙醇I 30min，无水乙醇II 30min，醇苯(乙醇、二甲苯混合溶剂，V乙醇∶V二甲苯＝1∶1)5～10min，二甲苯I 5～10min，二甲苯II 5～10min，65℃融化石蜡I 1h，65℃融化石蜡II 1h，65℃融化石蜡III 1h。将浸好蜡的组织于包埋机内进行包埋。先将融化的蜡放入包埋框，待蜡凝固之前将组织从脱水盒内取出按照包埋面的要求放入包埋框并贴上对应的标签。于-20℃冻台冷却，蜡凝固后将蜡块从包埋框中取出并修整蜡块。将修整好的蜡块，放入-20℃冻台冷却，再将冷却的蜡块置于石蜡切片机切片，厚4μm。切片漂浮于摊片机40℃温水上将组织展平，载玻片将组织捞起，60℃烘箱内烤片。水烤干蜡烤化后取出常温保存备用。
HE染色步骤为：切片入苏木素染液染3～5min，自来水洗，分化液分化，自来水洗，返蓝液返蓝，流水冲洗。再依次入85％、95％的梯度酒精脱水各5min，入伊红染液中染色5min。最后依次放入无水乙醇I 5min，无水乙醇II 5min，无水乙醇III 5min，二甲苯I 5min，二甲苯II 5min透明，中性树胶封片用于显微镜镜检和图像采集分析。
通过病理切片评价组织损伤情况，对瘢痕组织进行病理分析。显微镜下观察成纤维细胞、微血管、胶原纤维等情况并进行打分，评分标准为：
1-3分，无～最小的细胞聚集。无肉芽组织或上皮移行；
4-6分，薄、不成熟的肉芽组织，以炎症细胞为主，少量的成纤维细胞、毛细血管或胶原 沉积。最小的上皮细胞迁移；
7-9分，中等厚度的肉芽组织，以由炎症细胞为主转换为以成纤维细胞与胶原沉积为主。广泛的新生血管。中等程度的上皮化迁移；
10-12分，较厚的血管肉芽组织，以成纤维细胞与广泛胶原沉积为主。上皮部分或完全覆盖创面。根据该标准，对16张病理切片打分如下表16。四个不同组别的家兔耳表面瘢痕区给药28天后的HE染色病理切片图分别见图1～4。
表16.HE病理切片评分
实验结果显示，本发明的吡非尼酮局部外用制剂组(G1)纤维修复作用最明显，其次是对照处方C1(G3)，空白基质组(G2)与模型组(G4)的评分无差异。表明本发明的吡非尼酮局部外用制剂对瘢痕具有非常良好的治疗效果，且效果优于对照处方C1(G3)。
测试例5药代动力学性质研究
本测试例旨在研究小型猪单次局部涂抹吡非尼酮局部外用制剂，检测血浆中活性成分浓度，并评估局部给药后小型猪体内药物代谢动力学(PK)特性、系统暴露量及安全性。
实验材料：雄性巴马小型猪(Bama Miniature Swine)(3-5月龄，体重9-10kg，购自上海甲干生物科技有限公司)、实验制剂(本发明的制剂处方6)。
实验方法：实验前一天，2只小型猪禁食过夜。实验当天，称量体重并计算给药面积后，按10％体表面积在小型猪背部选取标记相应面积的区域，剔除毛发、清洁，按给药量20mg/cm2分别吸取制剂均匀涂抹给药，纱布覆盖给药区域并使用马甲固定。
给药前0min，给药后15min、30min、1h、2h、3h、4h、6h、8h、10h和24h各采集血样至K2EDTA抗凝管中，存放于湿冰上，并于1h之内，离心(1500～1600g，4℃)10min，分离血浆，将所得血浆样品保存于-90～-60℃环境中，放置在干冰条件下运输。
采用LC-MS/MS生物分析方法检测小型猪血浆中的药物浓度，采用非房室模型，使用WinNonlinTM(Version8.3，Certara，USA)对血药浓度-时间数据进行分析，评估其在小型猪体内药物代谢动力学特性。表17显示局部涂抹给予吡非尼酮局部外用制剂后雄性小型猪血浆中吡非尼酮的药代动力学参数。
表17.吡非尼酮局部外用制剂的药代动力学参数


注：NR表示无法计算。
实验结果显示，以20mg/cm2的剂量局部涂抹给予吡非尼酮局部外用制剂后雄性小型猪血浆中最大血药浓度(Cmax)为150ng/mL，AUC(可以用于表示暴露量)为2.695h*μg/mL，说明本发明的吡非尼酮局部外用制剂具有良好的长期使用的安全性。
通过以上实施例和测试例，本领域技术人员可以更好地了解本发明的特点和优势。然而本发明的技术方案并不限于上述实施例，凡在本发明的精神和原则之内，对制剂处方尤其是助溶剂体系所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种吡非尼酮局部外用制剂，其特征在于，包含治疗有效量的吡非尼酮、水和至少一种助溶剂，所述助溶剂选自二甲亚砜(DMSO)和醇类溶剂。
  2. 如权利要求1所述的制剂，其中，所述醇类溶剂选自乙醇、丙二醇、异丙醇、1-丙醇、丁二醇中的一种，两种或更多种。
    优选地，所述助溶剂为DMSO和乙醇的组合，或DMSO和丙二醇的组合，或DMSO、乙醇和丙二醇三者的组合。
  3. 如权利要求2所述的制剂，其中，所述制剂中水的用量为10wt％至55wt％。
  4. 如权利要求1-3任一项所述的制剂，其中，所述助溶剂为DMSO和乙醇的组合时，按局部外用制剂的总重量计，所述制剂包含15wt％至35wt％的DMSO、15wt％至30wt％的乙醇；或者
    所述助溶剂为DMSO、乙醇和丙二醇的组合时，按局部外用制剂的总重量计，所述制剂包含15wt％至35wt％的DMSO、15wt％至30wt％的乙醇，15wt％至25wt％的丙二醇。
  5. 如权利要求1-4任一项所述的制剂，其中，按吡非尼酮局部外用制剂的总重量计，吡非尼酮以1wt％至14wt％的量存在。
  6. 如权利要求1-5任一项所述的制剂，其中，所述制剂进一步包括药学上可接受的其他辅料，所述辅料选自胶凝剂、保湿剂、防腐剂、抗氧化剂、pH调节剂、增稠剂、稳定剂、螯合剂、油性材料、乳化剂、渗透促进剂、抗微生物剂、遮光剂、芳香剂、着色剂、表面活性剂中的一种，两种或更多种。
  7. 如权利要求1所述的制剂，其中，所述制剂的剂型选自溶液、悬浮液、乳膏、软膏、洗剂和凝胶。
  8. 如权利要求1-7任一项所述的制剂，其中，所述制剂包含4wt％至12wt％的吡非尼酮、20wt％至35wt％的DMSO、20wt％至25wt％的乙醇、20wt％至50wt％的水、0.3wt％至1wt％的胶凝剂、2wt％至8wt％的保湿剂，以及适量pH调节剂使该制剂的pH范围调节至5.0～7.5。
  9. 如权利要求1-8任一项所述的制剂，其中，所述制剂包含4wt％至12wt％的吡非尼酮、20wt％至25wt％的DMSO、20wt％至25wt％的乙醇、30wt％至45wt％的水、0.3wt％至1wt％的胶凝剂、2wt％至8wt％的保湿剂、0.05wt％至1wt％的防腐剂，以及适量pH调节剂使该制剂的pH范围调节至5.0～7.5。
  10. 权利要求1-9任一项所述的吡非尼酮局部外用制剂在制备用于预防或治疗皮肤或结缔组织过度增生相关疾病、慢性皮肤损伤的药物中的用途。
PCT/CN2023/116997 2022-09-06 2023-09-05 一种含有吡非尼酮的局部外用制剂及其用途 WO2024051687A1 (zh)

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