WO2021204223A1 - Pharmaceutical composition including nicotinamide - Google Patents

Abstract

Provided is a pharmaceutical composition and a preparation method thereof. The pharmaceutical composition includes nicotinamide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also provided is an application of the pharmaceutical composition in preparations for preventing and treating skin-related diseases or disorders.

Description

A pharmaceutical composition containing nicotinamide

The present invention claims the priority of the prior application filed with the State Intellectual Property Office of China on April 8, 2020, with a patent application number of 202010271265.0 and the title of the invention "Application of Nicotinamide in the Preparation of Preparations for the Treatment of Hand and Foot Skin Reactions". The full text of this application is incorporated into the present invention by reference.

Technical field

The invention belongs to the field of medicine, and specifically relates to a pharmaceutical composition containing nicotinamide, a preparation method and application thereof.

Background technique

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.

Summary of the invention

The present invention provides a composition comprising nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt.

According to an embodiment of the present invention, the composition comprises nicotinamide, its hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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. In addition, sterile fixed oil is usually used as a solvent or suspension medium. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) can be used in the preparation of injections. Suspensions can be prepared according to the prior art using those suitable dispersing or wetting agents and suspending agents mentioned elsewhere.

For sublingual delivery, 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

For local delivery, 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. By way of example, according to the present invention, 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, Propylene glycol monocaprylate, caprylyl acetyl polyethylene glycol-8 glyceride, polyoxyl 40 stearate.

The topical formulation base provided 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. For example, after dissolving nicotinamide or its pharmaceutically acceptable salt in the base of cetomacrogol cream, a stable formulation is obtained.

Aqueous suspensions contain active ingredients mixed with excipients suitable for the preparation of aqueous suspensions. Such 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. 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. 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. Such substances are cocoa butter and polyethylene glycol.

According to an embodiment of the present invention, 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. According to the present invention, 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.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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;

According to an embodiment of the present invention, the base may be selected from one or more of emulsifiers, wetting agents, and thickeners.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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. One or more of.

In some embodiments, 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.

According to an embodiment of the present invention, 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, 0.015 part, 0.02 part, 0.025 parts.

According to an embodiment of the present invention, 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%.

Preferably, 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;

According to an embodiment of the present invention, in the formulation, 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;

According to an embodiment of the present invention, the pH of the formulation is 4-8, preferably 5.5-750, for example selected from 6.0, 6.5, 7.0.

According to an embodiment of the present invention, the carbomer may be selected from 980NF, 974P, 940NF, 934NF.

In other embodiments, 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. Preferably, the base is selected from one or more of white petrolatum and glyceryl monostearate, and the emulsifier is selected from polyoxyl 40 stearate, polysorbate 80, and glyceryl monostearate. One or more of esters and cetyl alcohol, the wetting agent is selected from one or more of glycerol and cetyl alcohol, and the preservative is selected from ethyl paraben, sodium benzoate, potassium sorbate One or more of. According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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.

In some embodiments, the preparation process of the composition/formulation includes the following steps:

(1) Mix the prescription amount of the base with the prescription amount of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt dissolved in water;

(2) Add one or more of the prescribed amount of wetting agent, emulsifier, stabilizer, thickener, cosolvent, and absorption enhancer under stirring;

(3) Add a prescription amount of pH regulator to adjust the pH value, and add the remaining amount of water.

According to an embodiment of the present invention, 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.

Or include the following steps:

(1) Add the base to an appropriate amount of water; (2) Add the pH adjuster to (1) and stir evenly to obtain solution 1; (3) Add the prescription amount of nicotinamide, its hydrate, solvate or their pharmacy The above-acceptable salt is dissolved in one or more of the prescribed amount of wetting agent, emulsifier, stabilizer, thickener, co-solvent, and absorption enhancer, stirred evenly, and adjusted the pH to 4-8; 4) Add (3) to solution 1 and stir evenly.

According to an embodiment of the present invention, the preparation process includes:

Mix the prescription amount of carbomer with the prescription amount of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt in water solution, and after it is completely swelled, add the prescription under stirring The amount of glycerin, propylene glycol and ethyl paraben, and finally the prescription amount of triethanolamine is added to adjust the pH value, and the remaining amount of water is added.

According to an embodiment of the present invention, the preparation process includes:

(1) Add carbomer to an appropriate amount of water to swell;

(2) Add triethanolamine to (1) and stir evenly to obtain solution 1;

(3) Dissolve nicotinamide in a solution of glycerin, propylene glycol, and ethyl paraben, add or not add peppermint oil, borneol, stir evenly, and adjust the pH to 4-8;

(4) Add (3) to solution 1 and stir evenly.

In other embodiments, the preparation process of the composition/preparation includes the following steps:

(1) Heat the oil phase ingredients in the composition/preparation to 50～90℃;

(2) Take the water phase ingredients in the composition/preparation and dissolve it with water, and heat to 50～90℃;

(3) When the two phases are at the same temperature, slowly add the oil phase to the water phase, stirring while adding, and when the temperature drops below 60°C, add an appropriate amount of water-dissolved nicotinamide solution, and continue to stir until it condenses.

According to an embodiment of the present invention, in the step (1), the oil phase component can be heated to 70-80°C; in the step (2), the water phase component can be heated to 70-80°C.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, 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.

According to an embodiment of the present invention, in some embodiments, 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.

Beneficial effect

1) 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.

2) 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.

Description of the drawings

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)

Figure 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)

Detailed ways

The technical solution of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only illustrative and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the foregoing contents of the present invention are covered by the scope of the present invention.

Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

Example 1

Specification	15%	15%	15%
Ingredient name	Dosage/g	Dosage/g	Dosage/g
Nicotinamide	150	150	150
Carbomer	20	20	20
Triethanolamine	20	20	20
glycerin	50	50	50
Propylene Glycol	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

Process: (1) Add carbomer into appropriate amount of purified water to swell; (2) Add triethanolamine to (1) and stir evenly to obtain solution 1; (3) Dissolve nicotinamide in glycerin, propylene glycol, and hydroxyl In the phenethyl solution, add or not add peppermint oil and borneol, stir evenly, and adjust the pH to 4-8; (4) add (3) to solution 1 and stir evenly to obtain a colorless transparent gel.

Result analysis: when the drug loading is 15%, 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.

Example 2

Process: Refer to Example 1.

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.

Example 3

Specification	15%	15%	15%	15%	15%	15%
Ingredient name	Dosage/g	Dosage/g	Dosage/g	Dosage/g	Dosage/g	Dosage/g
Nicotinamide	150	150	150	150	150	150
Carbomer	10	10	10	10	10	10
Triethanolamine	0.25	5	10	15	20	25
glycerin	100	100	100	100	100	100
Propylene Glycol	100	100	100	100	100	100
Ethyl paraben	1	1	1	1	1	1
purified water	Right amount	Right amount	Right amount	Right amount	Right amount	Right amount
Batch/g	1000	1000	1000	1000	1000	1000
pH	3.0	4.0	6.0	7.0	8.0	11
Traits	turbid	Colorless and transparent	Colorless and transparent	Colorless and transparent	Colorless and transparent	Colorless and transparent

Process: Mix the prescription amount of carbomer with the prescription amount of nicotinamide in water to make it completely swell, add the prescription amount of glycerin, propylene glycol and ethyl paraben under stirring, and finally add the three slowly Ethanolamine, adjust the pH to 4-8, add the remaining amount of water, stir to make the gel evenly mixed, and fill after sterilization.

The results show that: 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.

Example 4

concentration	5%	10%	15%	20%	30%
Ingredient name	Dosage/g	Dosage/g	Dosage/g	Dosage/g	Dosage/g
Nicotinamide	50	100	150	200	300
Carbomer	20	20	20	20	20
Triethanolamine	20	20	20	20	20
glycerin	100	100	100	100	100
Propylene Glycol	100	100	100	100	100
Ethyl paraben	1	1	1	1	1
purified water	Right amount	Right amount	Right amount	Right amount	Right amount
Batch/g	1000	1000	1000	1000	1000

Process: Refer to Example 1.

The results show that when the drug loading is 30%, a little crude drug will precipitate after the gel is placed at room temperature, and the stability is slightly reduced. The stability of the drug loading range below 30% is better.

Example 5

Specification	4%	5%	10%	15%	20%
Ingredient name	Dosage/g	Dosage/g	Dosage/g	Dosage/g	Dosage/g
Nicotinamide	40	50	100	150	200
Carbomer	10	10	10	10	10
Triethanolamine	10	10	10	10	10
Propylene Glycol	100	100	100	100	100
glycerin	100	100	100	100	100
Ethyl paraben	1	1	1	1	1
purified water	Right amount	Right amount	Right amount	Right amount	Right amount
Total	1000	1000	1000	1000	1000

Process: Refer to Example 1.

5.1 Influencing factors test

The following influencing factor experiments were carried out for the formulations of each specification in Example 5

5.1.1 Influencing factors test sample information

Table Influencing factors test sample information table 1

Table Influencing factors test sample information table 2

5.1.2 Test results of influencing factors

Influencing factor test results (5% specification)

Note: (1) "/" means that this test has not been carried out

The results showed that the content of niacinamide gel (5% specification) lofted for 30 days, compared with 0 days, the content has no significant change; niacinamide gel (5% specification) unpackaged lighting for 30 days, the color changed, but the same specification There is no change in the properties of the tube-packed nicotinamide gel (5% specification).

Influencing factor test results (20% specification)

Note: (1) "/" means that this test has not been carried out

The results showed that the color of the unpackaged nicotinamide gel (20%) changed after 30 days of lighting and the increase of impurities was obvious; the impurity content of the tube-packaged nicotinamide gel (20%) was lower than that of the unpackaged nicotinamide gel (20%) There is no significant change in the content of impurities compared with 0 days.

Influencing factor test results (15% specification)

Note: (1) "/" means that this test has not been carried out

Result analysis: The color of unpackaged nicotinamide gel (15%) was set up for 30 days, and the impurity increased obviously; the nicotinamide gel (15%) in tube was put out at high temperature for 30 days, and the impurity tended to increase. The content has no significant change compared with 0 days.

5.2 Accelerated test (30℃±2℃, 65%RH±5%RH)

Accelerated test results

Note: (1) "/" means that this test has not been carried out

The result analysis showed that 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.

Example 6 Preparation of nicotinamide cream formulation

Specification	5%	20%
Nicotinamide	50	200
White Vaseline	70	70
Cetyl Alcohol	20	20
Glyceryl Monostearate	20	20
Polyoxy 40 stearate	20	20
Polysorbate 80	11	11
glycerin	100	100
Ethyl paraben	1	1
purified water	Right amount	Right amount
batch	1000	1000

Preparation process: take the oil phase ingredients white petrolatum, cetyl alcohol, glyceryl monostearate, polyoxy(40) stearate and heat to 70～80℃ in a water bath; take the water phase ingredients polysorbate 80, glycerin , Ethyl hydroxyphenate is dissolved in purified water, heated to 70～80℃, 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℃ Use an appropriate amount of purified water to dissolve the nicotinamide solution, continue to stir until it condenses, and it is ready.

Influencing factor test retention sample test:

Example 7 External application effect test of nicotinamide preparation

7.1 Purpose of the experiment: To evaluate the effectiveness and safety of niacinamide topical preparations for treating VEGFR inhibitors causing hand-foot skin reactions.

7.2 Experimental method: According to the V4.03CTCAE standard (see Table 1), patients with advanced solid tumors treated with sorafenib and other VEGFR inhibitors and those with HSFR level 2 or above will be rubbed with the preparation of Example 5, daily 3 times, the daily dosage is about 5g, each time for the best supportive care treatment (such as foot skin care, wear thick cotton gloves and/or socks, avoid contact with hot water, tight shoes and excessive friction, etc.).

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.

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.

Table 1 Hand-foot adverse reaction (HFRS) CTCAE classification

7.3 Patient efficacy evaluation and experimental results

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. The experimental results are shown in Table 2 below:

Table 2 Hand-foot adverse reaction (HFRS) CTCAE classification of patients before and after treatment

The results of the experiment showed that patients with 10% and 20% concentration of the drug could feel significant changes within one week after taking the drug. Most patients had pain relief on the 2-3 days after taking the drug; 7 days after taking the drug, the hardened joints of the hand softened. The scab falls off and the pain is significantly reduced; the new affected area is treated in time, the pain is alleviated, and the disease progresses slowly, and the course of the disease is short; after 12-14 days of treatment, the patient has new skin on the hands, which is no different from normal skin. In patients with 10% and 20% medication concentrations, the pain was relieved on the first 2-3 days after the medication; 7-9 days after the medication, the scabs fell off, fresh skin grew, and the pain was significantly reduced; the first 10-14 medications Today, new skin grows on the soles of the feet, just like normal skin. Patients with a 4% concentration of medication have less changes, and the therapeutic effect is less obvious than that of high concentrations. After the end of the experimental medication cycle, the remission rate of the hand-foot skin reaction of the patients using 10% and 20% concentration of the drug was 100% (18/18), and the complete remission rate of the hand-foot skin reaction was 33% (6/18); using 4% The improvement of patients with 5% concentration of the drug was relatively small, and the burning sensation was slightly reduced when walking after the drug.

Example 8 External application effect test of nicotinamide preparation

Experimental purpose: To evaluate the effectiveness and safety of the application of nicotinamide in the preparation of preparations for the prevention and/or treatment of skin-related diseases or disorders.

Experimental method: According to the V4.03 CTCAE standard (see Table 3), tumor patients receiving anti-tumor drug treatment and those with skin-related diseases or disorders were rubbed with the preparation with a nicotinamide concentration of 15% in Example 5. 3 times a day, the daily dosage is about 5g, each time for the best supportive care treatment (such as foot skin care, wear thick cotton gloves and/or socks, avoid contact with hot water, tight shoes and excessive friction, etc.).

Subjects were evaluated for treatment according to the CTCAE standard (V4.03). According to the skin-related diseases or conditions, complete remission (grade 2/3 to grade 0) or partial remission (grade 2 to 0-1, and grade 3 to 0- Level 2,) To record the effectiveness and evaluate the quality of life; at the same time observe the adverse effects of nicotinamide.

Table 3 CTCAE classification of skin-related diseases or disorders

Patient efficacy evaluation and experimental results:

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.

Table 4. Information of enrolled patients:

Table 5. Patient treatment effect:

Note: D is the abbreviation for Day, which means the number of days of treatment.

In the foregoing, the embodiments of the present invention have been described. However, the present invention is not limited to the above-mentioned embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A pharmaceutical composition comprising nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.
2. The composition according to claim 1, wherein the composition contains at least one matrix in addition to the active ingredient.
3. The composition according to any one of claims 1-2, characterized in that it is selected from a solid preparation, a liquid preparation, a semi-solid preparation or a gas preparation.
4. The composition according to any one of claims 1-3, wherein the composition comprises 0.5%-40% by weight of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt , Preferably 4%-30% by weight, preferably, a single application of 0.5g-3.5g of the composition, more preferably, a single application of 0.5g-3.0g of the composition; smoke in a single application of the composition The dosage of amide, its hydrate, solvate or their pharmaceutically acceptable salt is 0.015mg-0.5mg, preferably 0.05mg/kg-10mg/kg, preferably 0.1mg/kg-8mg/kg .
5. The composition according to any one of claims 1 to 4, characterized in that in addition to the active ingredients, the composition also includes a base, a pH adjuster, a wetting agent, an emulsifier, a stabilizer, a thickener, and an auxiliary One or more of solvents, absorption enhancers, preservatives, solvents, etc.
6. The composition according to any one of claims 1-5, characterized in that the composition comprises 1 part of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt, and 0.01-1 part of base , 0.01-1 part of pH regulator, 0.2-3 part of wetting agent, 0.2-3 part of absorption enhancer, 0.001-0.03 part of preservative, and the balance is solvent.
7. The composition according to any one of claims 1 to 6, characterized in that the composition comprises 1 part of nicotinamide, its hydrate, solvate or their pharmaceutically acceptable salt, and 0.01-2 part of base , 0.05-2 parts emulsifier, 0.2-3 parts wetting agent, 0.001-0.03 parts preservative, and the balance is solvent.
8. A method for preparing the composition according to any one of claims 1-7, the method comprising the following steps:

   (1) Add the base to an appropriate amount of water; (2) Add the pH adjuster to (1) and stir evenly to obtain solution 1; (3) Add the prescribed amount of nicotinamide, its hydrates, solvates or their pharmaceuticals The above-acceptable salt is dissolved in one or more of the prescribed amount of wetting agent, emulsifier, stabilizer, thickener, co-solvent, and absorption enhancer, stirred evenly, and adjusted the pH to 4-8; 4) Add (3) to solution 1 and stir evenly;

   Or include the following steps:

   (1) Heat the oil phase ingredients in the composition/preparation to 50～90℃;

   (2) Take the water phase ingredients in the composition/preparation and dissolve it with water, and heat to 50～90℃;

   (3) When the two phases are at the same temperature, slowly add the oil phase to the water phase, stirring while adding, and when the temperature drops below 60°C, add an appropriate amount of water-dissolved nicotinamide solution, and continue to stir until it condenses.
9. An application of the composition according to any one of claims 1 to 8 for preparing a preparation for preventing and/or treating skin-related diseases or disorders.
10. The use according to claim 9, characterized in that the skin-related diseases or conditions include skin rash, itching, erythema, dry skin, hair loss, folliculitis, paronychia, pigmentation disorders, hand-foot syndrome, hand-foot skin reactions, peeling , Skin atrophy, acne, paresthesia, telangiectasia, hyperesthesia, maculopapular skin reactions, urticaria, angioedema, fixed drug eruption, erythema multiforme, DRESS (with eosinophilia and systemic symptoms) Drug reaction; also known as drug hypersensitivity syndrome), Stevens Johnson syndrome, toxic epidermal necrolysis, blisters.

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