WO2021204223A1 - Composition pharmaceutique comprenant du nicotinamide - Google Patents

Composition pharmaceutique comprenant du nicotinamide Download PDF

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Publication number
WO2021204223A1
WO2021204223A1 PCT/CN2021/086035 CN2021086035W WO2021204223A1 WO 2021204223 A1 WO2021204223 A1 WO 2021204223A1 CN 2021086035 W CN2021086035 W CN 2021086035W WO 2021204223 A1 WO2021204223 A1 WO 2021204223A1
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Prior art keywords
nicotinamide
composition
skin
preparation
pharmaceutically acceptable
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PCT/CN2021/086035
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English (en)
Chinese (zh)
Inventor
李晨
齐倩
苏叶青
吴炎
陈令武
季世春
Original Assignee
扬子江药业集团南京海陵药业有限公司
南京海陵中药制药工艺技术研究有限公司
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Publication of WO2021204223A1 publication Critical patent/WO2021204223A1/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
    • A61K31/435—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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K47/44—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
    • A61P17/04—Antipruritics
    • 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
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a pharmaceutical composition containing nicotinamide, a preparation method and application thereof.
  • Nicotinamide is a member of the vitamin B family.
  • the chemical name of nicotinamide is 3-pyridine carboxamide, also known as nicotinamide, with a molecular formula of C 6 H 6 N 2 O and a molecular weight of 122.13. It is a common SIRT1 inhibitor. Nicotinamide is clinically mainly used to prevent and treat pellagra, stomatitis and glossitis. It can also be used to treat coronary heart disease, viral myocarditis, rheumatic heart disease, hand and foot skin reactions, etc.
  • the present invention provides a composition comprising nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt.
  • the composition comprises nicotinamide, its hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable salt of nicotinamide is selected from the following categories, for example, acid addition salts derived from inorganic or organic acids, such as hydrochloride, hydrobromide, and p-toluenesulfonate Acid salt, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, lactate, oxalate, tartaric acid Salt and benzoate.
  • acid addition salts derived from inorganic or organic acids such as hydrochloride, hydrobromide, and p-toluenesulfonate Acid salt, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, lactate, oxalate, tartaric acid Salt and benzoate.
  • the composition may be in any suitable preparation form, such as a solid preparation, a liquid preparation, a semi-solid preparation or a gas preparation.
  • the formulation can be administered by oral, intravenous, intramuscular, subcutaneous, topical application, additional routes including sublingual, rectal, intranasal, or pulmonary inhalation; suitable forms such as aqueous or non-aqueous Solution or suspension, dispersible powder or granule, cream, gel, dispersion, emulsion, foam, mist, mouthwash, lotion, ointment, ointment, spray, aerosol, oil, hard Ointment, patch, suspension or suppository, etc.
  • suitable forms such as aqueous or non-aqueous Solution or suspension, dispersible powder or granule, cream, gel, dispersion, emulsion, foam, mist, mouthwash, lotion, ointment, ointment, spray, aerosol, oil, hard Ointment, patch, suspension or suppository, etc.
  • the preparation may be in the form of a sterile injectable aqueous or non-aqueous (e.g., oily) solution or suspension.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension dissolved in a non-toxic and parenteral diluent or solvent.
  • Acceptable carriers and solvents that can be used are water, phosphate buffer solution, Ringer's solution, glucose, and isotonic sodium chloride solution.
  • sterile fixed oil is usually used as a solvent or suspension medium.
  • any bland fixed oil can be used, including synthetic monoglycerides or diglycerides.
  • fatty acids such as oleic acid
  • Suspensions can be prepared according to the prior art using those suitable dispersing or wetting agents and suspending agents mentioned elsewhere.
  • fast-dissolving tablets can be used, as well as several forms described above.
  • the oral administration can be administered in the form of tablets, capsules or liquids
  • a pharmaceutically acceptable carrier for topical use may be included, and the matrix used in any topical formulation according to the present invention and described herein is any pharmaceutically acceptable carrier capable of transdermal delivery of the active compound contained in the pharmaceutical composition.
  • the matrix used in any topical formulation according to the present invention and described herein is any pharmaceutically acceptable carrier capable of transdermal delivery of the active compound contained in the pharmaceutical composition.
  • it is cream, gel, dispersion, emulsion, foam, mist, mouthwash, lotion, ointment, ointment, oil, spray, aerosol, suppository, suspension , Plasters, patches, and various passive and active local devices absorbed through the skin and mucous membranes.
  • the pharmaceutical preparations of the present invention may also be in the form of oil-in-water emulsions.
  • the oil phase can be vegetable oil, such as olive oil or peanut oil; or mineral oil, such as liquid paraffin; or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybeans and lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono Oleate and the condensation product of the partial ester and ethylene oxide, such as polyoxyethylene sorbitan monooleate; sodium lauryl sulfate, polysorbate 60, polysorbate 80, polyethylene Glycol hydroxystearate, polyethoxylated castor oil, ethylene oxide or propylene oxide copolymer, stearoyl polyethylene glycol-32 glyceride, lauroyl polyethylene glycol-32 glyceride
  • the topical formulation base is preferably used for general application to the skin.
  • the base preferably includes conventional emulsifiers and emollients (humectants) including alginate, glyceryl stearate, PEG-100 stearate, cetyl alcohol, propyl paraben, butyl paraben Ester, propylene glycol, sorbitol, polyethoxylated sorbitan monostearate, glycerin, white petrolatum, triethanolamine, lanolin, cocoa butter, shea butter, cetyl alcohol, stearyl alcohol, liquid Paraffin wax, polyoxyl 40 stearate, polysorbate 80, etc.
  • emulsifiers and emollients including alginate, glyceryl stearate, PEG-100 stearate, cetyl alcohol, propyl paraben, butyl paraben Ester, propylene glycol, sorbitol, polyethoxylated
  • Aqueous suspensions contain active ingredients mixed with excipients suitable for the preparation of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing agent or wetting agent Agents such as naturally occurring phospholipids, such as lecithin, or condensation products of alkylene oxide and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as seventeen ethyleneoxy Heptadecaethyleneoxycetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as condensation products of polyoxyethylene and partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene dehydration Sorbitol monooleate.
  • suspending agents such as sodium carboxymethyl
  • the aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more Various sweeteners, such as sucrose or saccharin.
  • Non-aqueous (i.e. oily) suspensions can be prepared by suspending the active ingredient in vegetable oil (for example, peanut oil, olive oil, sesame oil, or coconut oil) or mineral oil (for example, liquid paraffin).
  • the oily suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. These compositions can be preserved by adding antioxidants such as ascorbic acid.
  • Dispersible powders or granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredients mixed with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are known.
  • the active ingredient may also be administered in the form of suppositories for rectal administration of the drug.
  • suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at normal temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at normal temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • Such substances are cocoa butter and polyethylene glycol.
  • the formulation may be administered in a dose of four times a day, three times a day, twice a day, once a day, or once every other day.
  • the appropriate mode of administration and dosage can be selected according to the severity of different levels. However, it should be understood that the specific dosage level for any particular patient will depend on many factors, including age, weight, general health, gender, diet, time of administration, drug combination, and the severity of the specific condition being treated.
  • the formulation of the present invention is applied for at least one year or longer, preferably at least one month, more preferably at least one week, and most preferably at least one day, to achieve continuous relief of hand and foot skin reactions.
  • the preparation can be prepared as an external preparation by a conventional method in the art, and in addition to the active ingredient, it further includes, but is not limited to, a base, a pH adjuster, a wetting agent, a stabilizer, a thickener, and a cosolvent. , One or more of absorption promoters, preservatives, solvents, etc.
  • the matrix is selected from carbomer, hydroxymethyl cellulose, chitosan derivatives, polycarbophil, xyloglucan, alginate, glyceryl stearate, PEG -100 stearate, cetyl alcohol, propyl paraben, butyl paraben, sorbitol, polyethoxylated sorbitan monostearate, white petrolatum, lanolin, cocoa
  • One or more of fat and shea butter may also include one or more of other conventional emulsifiers, wetting agents, thickeners, and absorption enhancers;
  • the base may be selected from one or more of emulsifiers, wetting agents, and thickeners.
  • the emulsifier may be a naturally occurring gum, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybeans and lecithin; and esters or partials derived from fatty acids and hexitol anhydrides.
  • Esters such as sorbitan monooleate and condensation products of the partial ester and ethylene oxide, such as polyoxyethylene sorbitan monooleate; sodium lauryl sulfate, polysorbate 60, poly Sorbitol ester 80, polyethylene glycol hydroxystearate, polyethoxylated castor oil, ethylene oxide or propylene oxide copolymer, stearoyl polyethylene glycol-32 glyceride, lauroyl polyethylene Glycerol-32 glyceride, propylene glycol monocaprylate and caprylyl acetyl polyethylene glycol-8 glyceride, polyoxy 40 stearate.
  • the pH adjusting agent is selected from one or more of citric acid, sodium citrate, lactic acid, sodium lactate, dihydrogen phosphate, dihydrogen phosphate, Tris (tris(hydroxymethyl)aminomethane), and triethanolamine;
  • the wetting agent is selected from polysorbate-20, polysorbate-80, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, bile salt, lecithin, polyethylene glycol, ethanol, propylene glycol, glycerin, ten One or more of six alcohols;
  • the absorption enhancer is selected from one or more of propylene glycol, azone, and menthol;
  • the preservative is selected from one or more of ethyl paraben, sodium benzoate and potassium sorbate;
  • the stabilizer is selected from one or more of EDTA, butylated hydroxyanisole (BHA), dibutylhydroxytoluene (BHT), propyl gallate (PG), glyceryl monostearate, and tocopherol.
  • the thickener is selected from one or a combination of two or more of petrolatum, fatty acid glycerides, xanthan gum, carrageenan and Brunei gum;
  • the co-solvent is selected from one or a combination of two or more of propylene glycol, glycerin, and polyethylene glycol.
  • the formulation may include, in addition to the active ingredients, a base, pH adjusters, wetting agents, emulsifiers, stabilizers, thickeners, solubilizers, absorption promoters, preservatives, solvents, etc.
  • a base pH adjusters, wetting agents, emulsifiers, stabilizers, thickeners, solubilizers, absorption promoters, preservatives, solvents, etc.
  • the formulation comprises 1 part of nicotinamide, its hydrate, solvate or pharmaceutically acceptable salt thereof, 0.01-1 part of base, 0.01-1 part of pH adjusting agent, 0.2-3 part Wetting agent, 0.2-3 parts absorption enhancer, 0.001-0.03 parts preservative, and the balance is solvent.
  • the matrix is, for example, 0.025 part, 0.05 part, 0.08 part, 0.1 part, 0.125 part, 0.2 part, 0.25 part, 0.3 part, 0.35 part, 0.4 part, 0.45 part, 0.5 part, 0.55 part , 0.6 part, 0.65 part, 0.7 part, 0.75 part, 0.8 part, 0.85 part, 0.9 part;
  • the pH adjusting agent is, for example, 0.025 part, 0.05 part, 0.08 part, 0.1 part, 0.125 part, 0.2 part, 0.25 part, 0.3 part, 0.35 part, 0.4 part, 0.45 part, 0.5 part, 0.55 part, 0.6 part, 0.65 part, 0.7 part, 0.75 part, 0.8 part, 0.85 part, 0.9 part
  • the wetting agent is for example 0.5 part, 1 part , 1.5 parts, 2 parts, 2.5 parts;
  • the absorption enhancer is, for example, 0.5 part, 1 part, 1.5 parts, 2 parts, 2.5 parts;
  • the preservative is, for example, 0.005 part, 0.01 part
  • the mass percentage of the matrix in the formulation is 0.1%-50%, for example, selected from 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%.
  • the preparation comprises 1 part of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt, 0.05-1 part of carbomer, 0.05-1 part of pH regulator, 0.2-3 part of propylene glycol , 0.2-3 parts glycerin, 0.001-0.03 parts preservative, and the balance is water;
  • the mass ratio of the base to the pH adjuster is 1:0.5-2.0, and the preferred mass ratio is 1:0.9-1.5, for example, 1:1, 1:1.1, 1:1.2, 1:1.3;
  • the pH of the formulation is 4-8, preferably 5.5-750, for example selected from 6.0, 6.5, 7.0.
  • the carbomer may be selected from 980NF, 974P, 940NF, 934NF.
  • the formulation comprises 1 part of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt, 0.01-2 parts of base, 0.05-2 parts of emulsifier, 0.2-3 parts Wetting agent, 0.001-0.3 parts preservative, the balance is solvent.
  • the base is selected from one or more of white petrolatum and glyceryl monostearate
  • the emulsifier is selected from polyoxyl 40 stearate, polysorbate 80, and glyceryl monostearate.
  • the base is, for example, 0.05 part, 0.1 part, 0.35 part, 0.5 part, 1 part, 1.4 part, 1.5 part
  • the emulsifier is, for example, 0.1 part, 0.35 part, 0.5 part, 1 part , 1.4 parts, 1.5 parts, 2 parts
  • the wetting agent is, for example, 0.5 part, 1 part, 1.5 parts, 2 parts, 2.5 parts
  • the preservative is, for example, 0.005 part, 0.01 part, 0.02 part.
  • the formulation comprises 1 part of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt, 0.1-2 parts of base, 0.05-2 parts of emulsifier, 0.5-3 parts Wetting agent, 0.005-0.03 parts preservative, the balance is solvent.
  • the formulation comprises 1 part of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt, 0.1-1.5 part of white petrolatum, and 0.1-0.5 part of glyceryl monostearate , 0.05-0.5 parts polyoxy 40 stearate, 0.05-0.5 parts polysorbate 80, 0.5-2.5 parts glycerin, 0.1-0.5 parts cetyl alcohol, 0.005-0.03 parts preservative, and the balance is water.
  • the composition/preparation comprises 0.5%-40% by weight of nicotinamide, its hydrates, solvates or their pharmaceutically acceptable salts, preferably 4%-30% by weight, More preferably 10%-20% by weight, for example, selected from 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17 %, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%.
  • the dosage of the preparation for a single application is 0.5g-3.5g, preferably 0.5g-3.0g; the dosage of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt in the preparation for a single application is 0.015mg-0.5mg; the dosage of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt in a single administration formulation is preferably 0.05mg/kg-10mg/kg, more preferably 0.1mg/kg -8mg/kg.
  • the preparation process of the composition/formulation includes the following steps:
  • step (3) of the preparation process further includes adding a pH regulator and the remaining amount of water, stirring to make the formulation uniformly mixed, and filling after sterilization.
  • the preparation process includes:
  • the preparation process includes:
  • the preparation process of the composition/preparation includes the following steps:
  • the oil phase component in the step (1), can be heated to 70-80°C; in the step (2), the water phase component can be heated to 70-80°C.
  • the oil phase component is selected from white petrolatum, cetyl alcohol, glyceryl monostearate, polyoxy(40) stearate, and the water phase component is selected from polysorbate 80, Glycerin, ethyl paraben.
  • the present invention provides preparations comprising nicotinamide, its hydrates, solvates, derivatives, prodrugs, or their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers for the prevention and/or treatment of skin-related diseases or disorders Application in preparations.
  • the skin-related diseases or conditions include skin rash, pruritus, erythema, dry skin, hair loss, folliculitis, paronychia, pigmentation disorders, hand-foot syndrome (increase explanation), hand-foot skin reaction (increase Explanation), peeling, skin atrophy, acne, paresthesia, telangiectasia, hyperesthesia, maculopapular skin reaction, urticaria, angioedema, fixed drug eruption, erythema multiforme, DRESS (with eosinophilia) Drug reaction with systemic symptoms; also known as drug hypersensitivity syndrome), Stevens Johnson syndrome, toxic epidermal necrolysis, blisters.
  • the nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt is the sole active ingredient in the formulation; in some embodiments, the The preparation also contains other drugs, such as anti-inflammatory and anti-infective drugs, vitamin B, vitamin E, and glucocorticoids.
  • the pharmaceutical composition containing nicotinamide, its hydrates, solvates or their pharmaceutically acceptable salts prepared by the present invention has small side effects, moderate prices, good druggability, and high clinical feasibility. Especially when it is used as an external preparation (for example, gel, cream), the patient can self-administer the drug, the patient has good compliance and the clinical medication effect is excellent, and it is widely used.
  • an external preparation for example, gel, cream
  • the present invention has been further verified by clinical trials that the nicotinamide preparation is beneficial to alleviate and inhibit skin-related diseases or disorders, especially beneficial to further use with drugs that produce adverse reactions, reduce the generation of adverse reactions, and alleviate or inhibit skin-related diseases Or illness.
  • Figure 1 is a graph of the treatment effect of patient No. 1 in the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect of patient on day D14)
  • Figure 2 is a graph of the treatment effect of patient No. 2 in the experiment of Example 8 (the left graph shows the patient's symptoms on day 0, and the right graph shows the treatment effect of patient on day D14)
  • FIG. 3 Example 8 experiment is a graph of the treatment effect of patient No. 5 (the left graph shows the patient's symptoms on day 0, and the right graph shows the treatment effect of patient on day D14)
  • Figure 4 is a graph showing the treatment effect of patient No. 6 in the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect of patient on day D14)
  • Figure 5 is a graph of the treatment effect of patient No. 7 in the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect of patient on day D14)
  • Figure 6 is a graph showing the treatment effect of the left foot of patient 9 in the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect of patient on day D14)
  • Figure 7 is a graph showing the treatment effect of patient No. 9 on the right foot of the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect of patient on day D14)
  • Fig. 8 is a treatment effect diagram of the left foot of patient No. 10 in the experiment of Example 8 (the left picture shows the patient's symptoms at day 0, and the right picture shows the treatment effect of the patient on day D14)
  • Figure 9 is a graph showing the treatment effect of patient No. 10 on the right foot of the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect on day D14 of the patient)
  • Figure 10 is a graph showing the treatment effect of patient No. 11 in the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect of patient on day D14)
  • Figure 11 is a graph showing the treatment effect of patient No. 11 with left foot hand-foot syndrome in the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect of patient on day D14)
  • Figure 12 is a graph showing the treatment effect of patient No. 11 with right foot hand-foot syndrome in the experiment of Example 8 (the left graph shows the patient's symptoms at day 0, and the right graph shows the treatment effect of patient at day D14)
  • Figure 13 is a graph showing the treatment effect of patient No. 12 with hand-foot syndrome in the experiment of Example 8.
  • Figure 14 is a graph of the treatment effect of patient No. 13 with hand-foot syndrome (the first line shows the symptoms of each part of the patient on day 0, and the second line shows the treatment effect of each part of the patient on day D14)
  • Figure 15 is a graph showing the treatment effect of patient No. 14 with hand-foot syndrome in the experiment of Example 8. treatment effect
  • Figure 16 is the treatment effect diagram of patient No. 15 in the experiment of Example 8 (the first line shows the symptoms of each part of the patient on day 0, and the second line shows the treatment effect of each part of the patient on day D14)
  • Figure 17 is a graph showing the treatment effect of patient No. 16 with hand-foot syndrome in the experiment of Example 8 (the first and second rows show the symptoms of each part of the patient on day 0, the third row shows the treatment effect of the patient on day D11, and the fourth row shows the treatment effect of patient on day D14. treatment effect)
  • Figure 18 is a graph showing the treatment effect of patient No. 17 in the experiment of Example 8. Treatment effect; the second line shows the treatment effect of each part of the patient on D14)
  • Figure 19 is a graph of the treatment effect of patient 003 in the experiment of Example 7 (the drug concentration is 20%, the arrow indicates the state change before and after treatment)
  • Figure 20 is a graph of the treatment effect of patient 005 in the experiment of Example 7 (the drug concentration is 20%, the arrow indicates the state change before and after treatment)
  • Figure 21 is a graph of the treatment effect of patient No. 011 in the experiment of Example 7 (the drug concentration is 10%, and the arrow indicates the state change before and after treatment)
  • Figure 22 is a graph showing the treatment effect of patient No. 015 in the experiment of Example 7 (the drug concentration is 10%, the arrow indicates the state change before and after treatment)
  • Figure 23 is a graph of the treatment effect of patient No. 018 in the experiment of Example 7 (the drug concentration is 10%, the arrow indicates the state change before and after treatment)
  • Figure 24 is a graph showing the treatment effect of patient No. 010 in the experiment of Example 7 (the drug concentration is 4%, the arrow indicates the state change before and after treatment)
  • Dosage/g Dosage/g Dosage/g Nicotinamide 150 150 150 Carbomer 20 20 20 Triethanolamine 20 20 20 20 glycerin 50 50 50 50 Propylene Glycol 50 50 50 50 Peppermint oil / 50 / Borneol / / 50 Ethyl paraben 1 1 1 purified water Right amount Right amount Right amount Batch/g 1000 1000 1000 1000
  • the gel prescription does not contain propylene glycol, or when only propylene glycol is added as a moisturizer and scalp absorption enhancer, the properties are colorless and transparent, and the properties are good; the gel prescription is based on propylene glycol Further adding 5% peppermint oil, the character is oily, and the viscosity is reduced; in the gel formulation, 5% borneol is further added on the basis of propylene glycol, the character is milky white, and it has a gritty feeling after application.
  • a Brookfield viscometer was selected, the rotation speed was 20 revolutions per minute, and the temperature was 25 ⁇ 1°C to determine the viscosity of the composition of different specifications.
  • the results show that the viscosity of the composition prepared with different amounts of matrix is different, and the viscosity of the gel is positively related to the amount of carbomer. The greater the amount of carbomer, the greater the viscosity, but when the amount is 50g (5%), Carbomer does not swell sufficiently, is a viscous gel-like, and has poor fluidity.
  • triethanolamine is mainly used as a carbomer pH neutralizer, and its dosage affects the pH of the gel.
  • the pH value of the preparation of the present invention is preferably 4-8. Therefore, the dosage of triethanolamine needs to be investigated.
  • the results show that triethanolamine/cal It is better when the perme weight ratio is in the range of 0.5 to 2.0, the product properties are good, and the pH value meets the requirements.
  • Dosage/g Dosage/g Dosage/g Dosage/g Nicotinamide 50 100 150 200 300 Carbomer 20 20 20 20 20 20 Triethanolamine 20 20 20 20 20 glycerin 100 100 100 100 100 100 100 Propylene Glycol 100 100 100 100 100 100 100 Ethyl paraben 1 1 1 1 purified water Right amount Right amount Right amount Right amount Right amount Batch/g 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000
  • nicotinamide gel (5%, 20%) accelerated in 3 months compared with 0 day, and the traits and content did not change significantly; nicotinamide gel (15%) accelerated in January compared with 0 day, the traits, The content and related substances have not changed significantly.
  • Preparation process take the oil phase ingredients white petrolatum, cetyl alcohol, glyceryl monostearate, polyoxy(40) stearate and heat to 70 ⁇ 80°C in a water bath; take the water phase ingredients polysorbate 80, glycerin , Ethyl hydroxyphenate is dissolved in purified water, heated to 70 ⁇ 80°C, when the two phases are at the same temperature, slowly add the oil phase to the water phase, stirring while adding, to emulsify and add when the temperature drops below 60°C Use an appropriate amount of purified water to dissolve the nicotinamide solution, continue to stir until it condenses, and it is ready.
  • Steps for using ointment First step: Wash your hands and apply appropriate amount of ointment on your fingertips. Second step: Apply evenly on both palms and soles. The third step: continue to massage until the cream is completely absorbed by the skin.
  • the internationally used method for estimating the amount of ointment used Fingertip Unit Measurement (FTU), one FTU corresponds to 0.5g ointment, which can meet the skin area the size of two palms of one's own, which is equivalent to 2% of the surface area of the human body.
  • FTU Fingertip Unit Measurement
  • Subjects receive treatment evaluation according to CTCAE standard (V4.03), and complete remission (grade 2/3 to grade 0) or partial remission (grade 2 to 0-1, grade 3 to 0-2) according to HSFR Effectiveness is recorded and evaluated for the quality of life of hand, foot and skin; at the same time, the adverse reactions of nicotinamide are observed.
  • Hand-foot skin reaction remission rate according to the CTCAE standard (V4.03) adverse reaction standard to evaluate the level of hand-foot skin reaction before and after treatment, referring to HFSR from grade 3 to 0-2, 2 to 0-1, and 2 to 0 Number of subjects / total number of subjects enrolled in the group (level 0 is normal);
  • Hand-foot skin reaction complete remission rate According to the CTCAE standard (4.03) adverse reaction standard to evaluate the level of hand-foot skin reaction before and after treatment, it refers to the number of subjects with HFSR from grade 2/3 to grade 0/total number of subjects enrolled in the group ;
  • the initial set use cycle is 14 days (the use cycle can be extended or shortened according to the remission of the disease), and a total of 20 patients completed the trial.
  • the 20 patients enrolled this time all reported severe pain when they were enrolled in the screening, which may affect severe cases. Normal life. In this experiment, 10 patients used 20% medicine, 8 patients took 10% medicine, 1 patient took 5% medicine, and 1 patient took 4% medicine.
  • Table 2 The experimental results are shown in Table 2 below:
  • Partial alleviation of skin-related diseases or disorders according to the CTCAE standard (V4.03) adverse reaction criteria to evaluate the level of hand and foot skin reactions before and after treatment, referring to skin-related diseases or disorders from grade 3 to grade 1-2, and grade 2 to grade 1; skin Complete remission of related diseases or conditions: according to the CTCAE standard (4.03) adverse reaction standard to evaluate the level of hand and foot skin reaction before and after treatment, referring to HFSR from 2/3 to 0;
  • the use period of the preparation is 14 days or more (the experiment period can be increased as appropriate according to the patient's condition).
  • the patients selected for the group experiment have skin-related diseases or diseases, and feedback severe pain, which affects normal life in severe cases.
  • the results of the patient's experiment are shown in Table 4 and Table 5 below.
  • D is the abbreviation for Day, which means the number of days of treatment.

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Abstract

L'invention concerne une composition pharmaceutique et son procédé de préparation. La composition pharmaceutique comprend du nicotinamide, un hydrate, un solvate, ou un sel pharmaceutiquement acceptable de celui-ci, et un support pharmaceutiquement acceptable. L'invention concerne également une application de la composition pharmaceutique dans des préparations pour prévenir et traiter des maladies ou des troubles liés à la peau.
PCT/CN2021/086035 2020-04-08 2021-04-08 Composition pharmaceutique comprenant du nicotinamide WO2021204223A1 (fr)

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WO2022171064A1 (fr) * 2021-02-09 2022-08-18 扬子江药业集团南京海陵药业有限公司 Utilisation pharmaceutique de nicotinamide et composition le contenant

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FR2823671B1 (fr) * 2001-04-23 2004-01-09 Dermaconcept Jmc Composition dermatologique comprenant l'acide nicotinique ou un amide, et une base sphingoide
GB201112657D0 (en) * 2011-07-22 2011-09-07 Lowe Nicholas J Compositions for treatment of skin disorders

Non-Patent Citations (3)

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Title
DAI LIUJUN, SHAO ZHIWEIZHU JIANYONG: "Development of Nicotinamide Gel and Clinical Application Thereof", CAPITAL MEDICINE, vol. 6, no. 6, 15 June 1999 (1999-06-15), pages 32 - 32, XP055855862, ISSN: 2096-8213 *
LI ZHIPING, LIN ZUWEN, WU TIEQIANG: "Preparation and Quality Control of Nicotinamide Cream", CHINESE JOURNAL OF HOSPITAL PHARMACY, ZHONGGUO YAO XUEHUI WUHAN FENHUI, WUHAN, CN, vol. 29, no. 14, 30 July 2009 (2009-07-30), CN , pages 1231 - 1232, XP055855856, ISSN: 1001-5213 *
WEI WEI: "Preparation of Nicotinamide Gel", CHINESE JOURNAL OF HOSPITAL PHARMACY, ZHONGGUO YAO XUEHUI WUHAN FENHUI, WUHAN, CN, vol. 25, no. 10, 28 October 2005 (2005-10-28), CN , XP055855860, ISSN: 1001-5213 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022171064A1 (fr) * 2021-02-09 2022-08-18 扬子江药业集团南京海陵药业有限公司 Utilisation pharmaceutique de nicotinamide et composition le contenant

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