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CN113101289A - Application of nicotinamide in preparation of preparation for treating hand-foot skin reaction - Google Patents

Application of nicotinamide in preparation of preparation for treating hand-foot skin reaction Download PDF

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Publication number
CN113101289A
CN113101289A CN202010271271.6A CN202010271271A CN113101289A CN 113101289 A CN113101289 A CN 113101289A CN 202010271271 A CN202010271271 A CN 202010271271A CN 113101289 A CN113101289 A CN 113101289A
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nicotinamide
preparation
kinase inhibitor
foot skin
vegfr
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何俏军
杨波
罗沛华
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NANJING HAILING PHARMACEUTICAL CO Ltd OF YANGTZE RIVER PHARMACEUTICAL GROUP
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Zhejiang University ZJU
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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
    • 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
    • A61P35/00—Antineoplastic agents

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  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides an application of nicotinamide, a hydrate and a solvate thereof or pharmaceutically acceptable salts thereof in preparing a preparation for treating hand-foot skin reaction. Proved by animal in vivo experimental study, the SIRT1 inhibitor nicotinamide has a remarkable protection effect on hand-foot skin reaction caused by a VEGFR small molecular kinase inhibitor. The VEGFR small-molecule kinase inhibitor can effectively treat HFSR induced by the VEGFR small-molecule kinase inhibitor, reduces hand-foot skin reaction of tumor patients caused by the VEGFR small-molecule kinase inhibitor, and greatly expands clinical application of the VEGFR small-molecule kinase inhibitor; the nicotinamide used has small toxic and side effects and moderate price, can be prepared into proper dosage forms according to requirements, and has high clinical feasibility, thereby expanding the clinical application of the VEGFR small-molecule kinase inhibitor.

Description

Application of nicotinamide in preparation of preparation for treating hand-foot skin reaction
Technical Field
The invention belongs to the field of medicines, relates to a new application of a SIRT1 inhibitor nicotinamide, and particularly relates to an application of nicotinamide in preparation of a preparation for treating hand-foot skin reactions.
Background
The concept that tumor growth is dependent on angiogenesis began in the early 70's of the 20 th century, angiogenesis has a significant impact on tumor growth, invasion and metastasis, and anti-angiogenesis has become one of the important strategies for anti-tumor. Vascular Endothelial Growth Factor Receptors (VEGFR) play a crucial role in angiogenesis. The VEGFR small-molecule kinase inhibitor is a kinase inhibitor aiming at VEGFR family, and can remarkably improve the progression-free survival time of tumor patients. However, the toxic and side effect of hand-foot skin reaction (HFSR) is generated in the using process of various VEGFR small-molecule kinase inhibitors, the clinical characteristics are represented by excessive keratinization, and the incidence rate is as high as 40% -60%. This side effect seriously affects the quality of life of the patient and may also lead to down-regulation of the dosage or interruption of the treatment, ultimately threatening the life of the patient.
Because the molecular mechanism of the VEGFR small-molecule kinase inhibitor for inducing HFSR is unknown, no effective strategy for solving the toxic and side effects exists in the clinic at present. For mild HFSR patients can be relieved with keratolytic agents or lubricants, while for patients with moderate or severe HFSR during administration, the dosage of the drug needs to be reduced or even the treatment interrupted. The above methods provide only very limited relief from these symptoms and do not achieve the desired goals of reducing or curing HFSR. Therefore, there is a great need to find a common molecular mechanism for VEGFR small molecule kinase inhibitors to induce HFSR and to find a suitable intervention strategy based on this mechanism.
Nicotinamide is a member of the vitamin B group and is known by the chemical name 3-pyridinecarboxamideCalled nicolinamide, molecular formula C6H6N2O, molecular weight 122.13, which is a common SIRT1 inhibitor. Nicotinamide is mainly used for preventing and treating pellagra, stomatitis, glossitis and the like in clinic, and can also be used for treating coronary heart disease, viral myocarditis, rheumatic heart disease and the like, but no report of using nicotinamide as HFSR for treating is available.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides an application of nicotinamide, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof in preparing a preparation for treating hand-foot skin reaction.
According to an embodiment of the invention, said niacinamide may alleviate and treat Hand and Foot Skin Reactions (HFSR).
According to an embodiment of the invention, the clinical symptoms of HFSR include heat, pain, erythema swelling of the fingers/toes, and severe persons may develop desquamation, ulceration and severe pain.
According to an embodiment of the present invention, the HFSR includes 1 stage, 2 stages, and 3 stages.
The HFSR rating (according to CTCAE4.03 standard) is as follows:
level 1: mild skin changes or dermatitis (erythema, edema, hyperkeratosis, painlessness).
And 2, stage: skin changes (flaking, blisters, bleeding, swelling, hyperkeratosis), pain; affecting the tool's activities of daily living.
And 3, level: severe skin changes (flaking, blisters, bleeding, edema, hyperkeratosis) pain, and limited ability of an individual to self-care.
According to an embodiment of the invention, the hand-foot skin reaction is a skin toxicity reaction induced by a VEGFR small molecule kinase inhibitor.
According to embodiments of the invention, the nicotinamide may alleviate VEGFR small molecule kinase inhibitor induced HFSR.
According to an embodiment of the invention, said pharmaceutically acceptable salt of nicotinamide is selected from the class of, for example, acid addition salts derived from inorganic or organic acids, such as hydrochloride, hydrobromide, p-toluenesulfonate, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, lactate, oxalate, tartrate and benzoate.
According to an embodiment of the present invention, the preparation for treating hand-foot skin reaction using nicotinamide, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient may be in any suitable form, such as a solid preparation, a liquid preparation, a semi-solid preparation, or a gas preparation.
According to embodiments of the invention, the formulation may be administered orally, intravenously, intramuscularly, subcutaneously, topically, additional routes include sublingual, rectal, intranasal, or pulmonary inhalation; suitable forms are, for example, aqueous or non-aqueous solutions or suspensions, dispersible powders or granules, creams, gels, dispersions, emulsions, foams, mists, mouthwashes, lotions, ointments, sprays, aerosols, oils, plasters, patches, suspensions or suppositories, and the like.
According to an embodiment of the invention, the formulation may be in the form of a sterile injectable aqueous or non-aqueous (e.g. oleaginous) solution or suspension. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be used are water, phosphate buffered saline, Ringer's solution, and dextrose, isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids (e.g., oleic acid) may be used in the preparation of injectables. Suspensions may be prepared according to the prior art using those suitable dispersing or wetting agents and suspending agents which have been mentioned elsewhere.
For sublingual delivery, rapidly dissolving tablets may be used, as well as several forms described above. The oral administration may be in the form of tablets, capsules or liquids
For topical 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 transdermally delivering the active compound included in the pharmaceutical composition. By way of example, according to the invention, it is creams, gels, dispersions, emulsions, foams, mists, mouthwashes, lotions, salves, ointments, oils, sprays, aerosols, suppositories, suspensions, plasters, patches and various passive and active topical devices that are absorbed through the skin and mucous membranes.
The pharmaceutical formulation of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil; or mineral oils, such as liquid paraffin; or mixtures thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth; naturally occurring phospholipids, such as soy, lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
The topical formulation base is preferably provided for general application on the skin. The base preferably comprises conventional emulsifiers and emollients including alginates, glyceryl stearate, PEG-100 stearate, cetyl alcohol, propyl paraben, butyl paraben, propylene glycol, sorbitol, polyethoxylated sorbitan monostearate, glycerin, white petrolatum, triethanolamine, lanolin, cocoa butter, shea butter, and the like. For example, upon dissolution of nicotinamide or a pharmaceutically acceptable salt thereof in the base of a cetomacrogol cream, a stable formulation results.
Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents are, for example, naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol (heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as condensation products of polyethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Non-aqueous (i.e., oily) suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders or granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent 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 ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
According to an embodiment of the invention, the formulation comprises 0.5-40% by weight of nicotinamide, hydrate, solvate or a pharmaceutically acceptable salt thereof, preferably 1-30% by weight; the single application amount of the preparation is 0.5g-3.5g, preferably 0.5g-3.0 g; the amount of nicotinamide, its hydrate, solvate or a pharmaceutically acceptable salt thereof administered in a single administration formulation is 0.015mg-0.5 mg; the amount of nicotinamide, its hydrate, solvate or a pharmaceutically acceptable salt thereof administered in a single administration formulation is preferably 0.05mg/kg-10mg/kg, more preferably 0.1mg/kg-8 mg/kg.
According to embodiments of the 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. Suitable modes of administration and dosages may be selected according to the severity of the various levels. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, drug combination and the severity of the particular condition being treated. According to the present invention, the formulation of the present invention is applied for at least one year or more, preferably at least one month, more preferably at least one week, most preferably at least one day, to achieve continuous relief of the hand and foot skin reactions.
According to embodiments of the present invention, in some embodiments, the nicotinamide, hydrate, solvate or pharmaceutically acceptable salt thereof is used as the sole active ingredient in the formulation; in some embodiments, the formulation further comprises other drugs, such as anti-inflammatory, anti-infective drugs, vitamin B, vitamin E, glucocorticoids, and the like.
According to embodiments of the invention, in some embodiments, the nicotinamide, hydrate, solvate or pharmaceutically acceptable salt thereof may be administered separately from the HFSR-inducing VEGFR small molecule kinase inhibitor, e.g., prior to or after administration of the VEGFR small molecule kinase inhibitor. In some embodiments, the nicotinamide, hydrate, solvate, or pharmaceutically acceptable salt thereof may be administered concurrently with the HFSR-inducing VEGFR small molecule kinase inhibitor.
According to embodiments of the invention, in some embodiments, the nicotinamide, hydrate, solvate or pharmaceutically acceptable salt thereof and the VEGFR small molecule kinase inhibitor are administered as a combined preparation. The combined preparation is further used for relieving and inhibiting hand-foot skin reaction in chemotherapy treatment.
According to embodiments of the invention, the VEGFR small molecule kinase inhibitor is in a variety of forms, including, but not limited to: PAN-90806, Foretinib, Tafinitib (Tafetinib), canertinib (Kanitinib), Apatinib (Apatinib), Tanibirumab, Anlotinib (Anlotinib), Delitinib (Lucitinib), Vatalaniib, Cediranib (Cediraniib), Sevoranib (Chiuranib), Dovirtinib (Dovitinib), Donafenib (Donafenib), Famitatinib (Famitininib), Sinatinib, Teratinib (Telatinib), L-21649, TAS-115, Cabovatinib (Cabozantinib), Thielanib (Thiophenib), Fruentinib (Fruetinib), Blertinib (Brivaniib), Vevatinib (Vetivib), Thiertinib (Fabertinib), Thielanib (Thiampinib), Sufanib (Thiampinib), Thiampinib (Thiampinib), Thielanib (Thielanib), Neissimanib (Fabrinib, Glutinoib, Glutinonib (Glutinonib), Glutinonib (Glutinoib, Glutinonib), Glutinonib (Glutinonib), Glutinonib (Glutinonib ), Glutinonib (Glutinonib), Glutinonib (Glutinonib), Glutinonib (Glutinonib), Glutinonib, Glutino, And the like or pharmaceutically acceptable salts of the medicaments of Lenvatinib (Lenvatinib).
Advantageous effects
(1) The invention discovers, through animal in vivo experimental study, that the SIRT1 inhibitor nicotinamide can be used for treating HFSR induced by the VEGFR small-molecular kinase inhibitor, thereby providing a drug capable of effectively treating HFSR induced by the VEGFR small-molecular kinase inhibitor, relieving the hand-foot skin reaction of tumor patients caused by the use of the VEGFR small-molecular kinase inhibitor, and greatly improving the safety of clinical use of the VEGFR small-molecular kinase inhibitor, thereby expanding the clinical use of the VEGFR small-molecular kinase inhibitor and simultaneously providing a brand-new strategy for treating HFSR;
(2) the nicotinamide has small toxic and side effects and moderate price, can be prepared into proper dosage forms according to requirements, and has high clinical feasibility.
Drawings
Figure 1 is a graph demonstrating that regorafenib causes mice to develop HFSR in a mouse model, and that SIRT1 inhibitor nicotinamide can reverse regorafenib induced thickening of the horny layer of ICR mouse paw, i.e., regorafenib induced HFSR.
Figure 2 is a graph demonstrating that the SIRT1 inhibitor nicotinamide can reverse the ICR mouse paw stratum corneum thickening induced by anitinib, i.e. reverse the anitinib induced HFSR, in a mouse model that results in the development of HFSR in mice.
Figure 3 is a demonstration that apatinib causes HFSR in mice in a mouse model, and that SIRT1 inhibitor nicotinamide can reverse apatinib-induced thickening of the horny layer of ICR mouse paw, i.e. reverse apatinib-induced HFSR.
FIG. 4 shows the effect on keratinization progression after the administration of VEGRF small molecule inhibitor and nicotinamide treated HUVEC cell culture broth as conditioned medium on HaCat cells (FIG. 4 a: SUNI + NAM; FIG. 4 b: CABO + NAM; FIG. 4 c: AXI + NAM; FIG. 4 d: PONA + NAM).
Figure 5 illustrates nicotinamide treatment sorafenib: clinical effects of hand-foot skin reactions caused by regorafenib, aritinib and apatinib.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1
20 female ICR mice, randomly divided into 4 groups, each group was a placebo group, regorafenib group, nicotinamide group, regorafenib + nicotinamide combination group, and 5 mice per group were administered by intragastric gavage. Regorafenib is administered at a dose of 25mg/kg/day and niacinamide at a dose of 20mg/kg/day for 4 weeks. After 4 weeks, the mice were sacrificed and the claws were removed. The H & E staining results showed that the horny layer of the mouse paw in regorafenib group was significantly thickened compared to the blank control group, indicating that regorafenib can cause HFSR in mice. Niacinamide reverses the thickening of the stratum corneum of the claw caused by regorafenib, i.e., reverses the HFSR they cause. The results are shown in FIG. 1.
Example 2
20 female ICR mice, randomly divided into 4 groups, each group was a placebo group, an Arotinib group, a nicotinamide group, and a combination of Arotinib and nicotinamide, and 5 mice per group were administered by intragastric gavage. Arotinib was administered at a dose of 2mg/kg/day and niacinamide at a dose of 20mg/kg/day for 4 weeks. After 4 weeks, the mice were sacrificed and the claws were removed. The H & E staining results showed that the horny layer of the mouse paw of the anitinib group was significantly thickened compared to the placebo group, indicating that anitinib can cause HFSR in mice. Niacinamide can reverse the thickening of the stratum corneum of the claw caused by antrotinib, i.e. reverse their induced HFSR. The results are shown in FIG. 2.
Example 3
20 female ICR mice, randomly divided into 4 groups, respectively blank control group, apatinib group, nicotinamide group, apatinib + nicotinamide combination group, each group of 5 mice, administered by intragastric administration. Apatinib was administered at a dose of 100mg/kg/day and nicotinamide at a dose of 20mg/kg/day for 4 weeks. After 4 weeks, the mice were sacrificed and the claws were removed. The H & E staining results showed that the horny layer of the mouse paw of the apatinib group was significantly thickened compared to the placebo group, indicating that apatinib can cause HFSR in mice. Niacinamide reverses the thickening of the stratum corneum of the claw caused by apatinib, i.e. their induced HFSR. The results are shown in FIG. 3.
Example 4
The influence of sunitinib, cabozantinib, axitinib and panatinib on HaCaT cell differentiation indexes and the potential therapeutic effect of Nicotinamide (NAM) are researched. HUVEC cells were stimulated with 250nM sunitinib (sunitinib, labeled SUNI), 2.5. mu.M cabozantinib (Cabozanib, labeled CABO), 70nM axitinib (axitinib, labeled AXI) and 140nM pinatinib (Ponatinib, labeled PONA) for 24h, respectively, and the supernatants were collected as conditioned medium (CdM); HUVEC cells were treated with DMSO for 24h in the control group, and cell culture broth was collected as control conditioned medium (CdM)CTRL). Thereafter CdMCTRL、CdM、CdMCTRL+ NAM (10mM) and CdM + NAM (10mM)) HaCaT cells were used for 24h, after which the cells were harvested for RT-PCR experiments to examine the changes in the differentiation indices keratin 1(KRT1) and Loicrin (LORICRIN). The results are shown in FIGS. 4a, 4b, 4c, 4d, and the NAM was able to reverse CdMSUNI、CdMCABOAnd CdMAXIThe up-regulation function on differentiation indexes of HaCaT cells. And CdMPONAHas no obvious influence on HaCaT differentiation indexes, and has no obvious change when being used with NAM.
The results show that NAM inhibits CdM at the in vitro levelSUNI、CdMCABOAnd CdMAXIAccelerated keratinization processes thus inhibit their induced hand-foot skin reactions (HFSR).
Example 5: testing the clinical efficacy of Nicotinamide against cancer patients who develop severe HFSR following treatment with VEGFR inhibitors
The clinical test subjects were advanced liver cancer patients taking sorafenib (800 mg/day), metastatic colorectal cancer patients taking regorafenib (160 mg/day), advanced non-small cell lung cancer patients taking antrotinib (12 mg/day) and advanced gastric cancer patients taking apatinib (500 mg/day), respectively. With informed consent and ethical approval, patients were graded for HFSR after taking niacin tablets (100mg, three times per day, niacin enters the body and converts to nicotinamide to work) continuously for two weeks. The results show (see fig. 5) that HFSR was completely alleviated in all patients. Thus, nicotinamide may be a potential drug against HFSR induced by various VEGFR inhibitors.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (5)

1.烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐在制备治疗手足皮肤反应制剂中的应用。1. Use of nicotinamide, its hydrates, solvates or their pharmaceutically acceptable salts in the preparation of preparations for treating hand-foot skin reactions. 2.根据权利要求1的应用，其特征在于，所述手足皮肤反应是一种VEGFR小分子激酶抑制剂诱导引起的皮肤毒性反应。2. The application according to claim 1, wherein the hand-foot skin reaction is a skin toxicity reaction induced by a VEGFR small molecule kinase inhibitor. 3.根据权利要求1-2任一项所述的应用，其特征在于，所述烟酰胺的药学上可接受的盐选自如下类别，例如衍生自无机酸或有机酸的酸加成盐，例如盐酸盐、氢溴酸盐、对甲苯磺酸盐、磷酸盐、硫酸盐、高氯酸盐、乙酸盐、三氟乙酸盐、丙酸盐、柠檬酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐和苯甲酸盐。3. The use according to any one of claims 1-2, wherein the pharmaceutically acceptable salt of nicotinamide is selected from the following categories, such as acid addition salts derived from inorganic or organic acids, such as hydrochloride, hydrobromide, p-toluenesulfonate, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, Succinate, lactate, oxalate, tartrate and benzoate. 4.根据权利要求1-3任一项所述的应用，其特征在于，所述治疗手足皮肤反应制剂选自固体制剂、液体制剂、半固体制剂或气体制剂。The application according to any one of claims 1-3, wherein the preparation for treating hand-foot skin reaction is selected from a solid preparation, a liquid preparation, a semi-solid preparation or a gas preparation. 5.根据权利要求1-4任一项所述的应用，其特征在于，所述制剂包含0.5％-40％重量的烟酰胺、其水合物、溶剂合物或它们的药学上可接受的盐，优选为1％-30％重量，优选的，单次施用0.5g-3.5g所述制剂，更优选的，单次施用0.5g-3.0g所述制剂；单次施用制剂中烟酰胺、其水合物、溶剂合物或它们的药学上可接受的盐的给药量为0.015mg-0.5mg，优选为0.05mg/kg-10mg/kg，优选为0.1mg/kg-8mg/kg。5. The use according to any one of claims 1-4, wherein the preparation comprises 0.5%-40% by weight of nicotinamide, its hydrate, solvate or its pharmaceutically acceptable salt , preferably 1%-30% by weight, preferably, a single application of 0.5g-3.5g of the preparation, more preferably, a single application of 0.5g-3.0g of the preparation; nicotinamide, its The hydrate, solvate or their pharmaceutically acceptable salts are administered in an amount of 0.015 mg-0.5 mg, preferably 0.05 mg/kg-10 mg/kg, preferably 0.1 mg/kg-8 mg/kg.
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