Application of Zhongwinning in preparation of medicine for preventing and treating sarcopenia

Abstract

The invention belongs to the field of medicines, and provides application of Zhongwinning in preparation of a medicine for preventing and treating sarcopenia. The invention provides application of Zhongwinning or acceptable salts, esters or solvates thereof in preparation of drugs for preventing and treating sarcopenia. Tests prove that Zhongwinning has a remarkable effect of preventing and treating sarcopenia. The application of the invention provides a new thought and strategy for clinical treatment of sarcopenia.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and in particular relates to the application of Zhongwuning in preparing medicines for preventing and treating sarcopenia. Background Art

[0002] Sarcopenia, also known as age-related muscle wasting, is a degenerative disease that occurs mainly with age, characterized by reduced skeletal muscle mass, strength and dysfunction. In addition to age factors, multiple factors such as skeletal muscle cell denervation, mitochondrial dysfunction, inflammatory response, nutrient absorption and utilization disorders, disuse, obesity, fat infiltration and endocrine changes can consume skeletal muscle and lead to the occurrence of sarcopenia. The main clinical symptoms are fatigue, weakness, falls, disability and incapacity, which seriously affect the quality of life.

[0003] Epidemiological studies have shown that the number of people suffering from sarcopenia in the world is as high as 50 million, and it is estimated that the number of people suffering from this disease will reach 500 million by 2050. A study of elderly people in the British community showed that the prevalence of sarcopenia in men was 4.6% and that in women was 7.9%; DXA testing of 465 elderly people in Canada showed that the prevalence of sarcopenia in men was 38.9% and that in women was 17.8%; the prevalence of sarcopenia in Asian elderly people was about 4.1%-11.5%, which was lower than that in Europe and the United States; the prevalence of sarcopenia in urban men and women in China was 12.3% and 4.8% respectively, while the prevalence of sarcopenia in elderly men in rural areas was 6.4% and that in women was 11.5%. With the increase of the aging population in society, the high incidence of sarcopenia will impose a huge burden on the society and the medical system.

[0004] Currently, there are no drugs approved clinically for sarcopenia. The role of nutritional support, sex hormones and other drugs in the prevention and treatment of sarcopenia still needs to be evaluated. There is a huge gap in drug development for sarcopenia.

[0005] Mesaconine (Cas No.: 6792-09-2; Molecular formula: C 24 H 39 NO9) has the effect of treating heart failure. Zhongwu Ning was found in previous studies to remove damaged mitochondria, balance mitochondrial homeostasis, and restore cellular energy supply. Zhongwu Ning has abundant raw material sources and a clear chemical structure, which can be synthesized. It overcomes the problem that the complex and difficult to clarify Chinese medicine compound substances, and is expected to become an innovative drug through research and development in accordance with the laws of modern medicine.

[0006] At present, there is no literature or patent indicating that mesaconine (Cas No.: 6792-09-2; molecular formula: C 24 H 39NO9) has the effect of preventing and treating sarcopenia. Summary of the invention

[0007] The purpose of the present invention is to provide a new medicine and method for preventing and treating sarcopenia. The use of Zhongwuning in the preparation of medicine for preventing and treating sarcopenia is disclosed for the first time.

[0008] The present invention provides a use of Zhonguning or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a medicine or health product for preventing and treating sarcopenia, wherein the structural formula of the Zhonguning is as follows.

[0009]

[0010] In the present invention, the drug for preventing and treating sarcopenia is a preparation prepared by using Zhongwuning or its pharmaceutically acceptable salt, ester or solvate as an active ingredient and adding excipients or auxiliary ingredients commonly used in medicine.

[0011] Wherein, the pharmaceutically acceptable salt is an inorganic salt or an organic salt; the dosage form of the preparation is a liquid preparation, a solid preparation or a semi-solid preparation.

[0012] Experimental data show that Zhongwu Ning has a significant effect in improving sarcopenia.

[0013] The present invention studies the prevention and treatment of sarcopenia with Zhongwu Ning through pharmacological experiments. The results show that the Zhongwu Ning described in the present invention can effectively improve relevant symptoms and indicators, has an improving effect on sarcopenia, and can be used to prepare health products and medicines for the prevention and treatment of sarcopenia. The use of Zhongwu Ning in the preparation of medicines for the prevention and treatment of sarcopenia involved in the present invention is disclosed for the first time.

[0014] The term "prevention" refers to preventing or reducing the occurrence of sarcopenia after use in the presence of possible sarcopenia factors. The term "treatment" refers to alleviating the degree of the disease, or delaying the progression of sarcopenia, or curing sarcopenia and normalizing it.

[0015] As used herein, the term "pharmaceutically acceptable" means having no long-term adverse effects on the general health of the subject being treated.

[0016] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy of the free base of Zhongwu Ning and has no adverse effects in biology or other aspects. Pharmaceutically acceptable salts refer to the conversion of the base group in the parent compound into a salt form, such as inorganic or organic acid salts of the base group (such as amine), which are generally prepared by reacting the parent compound with conventional acids in a solvent system. Inorganic acids generally include sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, or phosphoric acid; organic acids generally include acetic acid, propionic acid, maleic acid, oxalic acid, malic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, citric acid, benzoic acid, fumaric acid, tartaric acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid or salicylic acid. In the present invention, the term "pharmaceutically acceptable solvate" refers to a combination of Zhongwu Ning and solvent molecules formed by solvation, which may include stoichiometric or non-stoichiometric solvents, and the solvent molecules in the solvent may exist in an ordered or non-ordered arrangement.

[0017] In the present invention, the term "pharmaceutically acceptable ester" refers to a pharmaceutically acceptable ester of Zhonguning. Generally, under in vitro or in vivo biological conditions, the ester bond can be cleaved from the compound or reacted in other ways to provide Zhonguning. The ester may be inactive, or less active than Zhonguning itself, so that Zhonguning can not exert its activity until it is cleaved from the ester. After the Zhonguning is esterified, it can generally improve the properties of the parent compound (i.e., Zhonguning) in terms of tissue compatibility or pharmacokinetic properties.

[0018] In the present invention, the "drug for preventing and treating sarcopenia" may include Zhonguning or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable excipient, which can be prepared according to conventional methods in the art, generally by mixing Zhonguning or a pharmaceutically acceptable salt, ester or solvate thereof with one or more conventional pharmaceutical excipients (which may be solid excipients or liquid excipients) and / or excipients to prepare a dosage form suitable for human or animal use, such as ordinary preparations (such as capsules, tablets, granules or injections, etc.), sustained-release preparations, controlled-release preparations, targeted preparations and various particulate delivery systems.

[0019] The "medicine for preventing and treating sarcopenia" can be administered by any known administration method, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, lung and respiratory tract, skin, vagina, rectum, eye, etc. The dosage form can be a solid dosage form, a semi-solid dosage form or a liquid dosage form. The liquid dosage form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), an eye drop, a nasal drop, a lotion and an ointment, etc.; the solid dosage form can be a tablet (including ordinary tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets, enteric-coated tablets, lozenges), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dripping pills, aerosols (powders), sprays, suppositories, films, patches, etc.; the semi-solid dosage form can be an ointment, a gel, a paste, etc.

[0020] When the "medicine for preventing and treating sarcopenia" is a tablet, various excipients conventional in the art can be used, including diluents, disintegrants, binders, wetting agents, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, calcium carbonate, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the disintegrant may be pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the binder may be starch slurry, dextrin, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. The above tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0021] When the "medicine for preventing and treating sarcopenia" is a capsule, the active ingredient (Zhongwu Ning) can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient can also be first made into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. The diluents, binders, wetting agents, disintegrants and glidants of the above-mentioned tablets can also be used to prepare the capsule.

[0022] When the "medicine for preventing and treating sarcopenia" is an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent to prepare the compound of the present invention into an injection, and an appropriate amount of a solubilizer, a cosolvent, a pH regulator or an osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If a lyophilized powder injection is prepared, mannitol, glucose, lactose, etc. can also be added as a support agent.

[0023] The dosage of the "drug for preventing and treating sarcopenia" may vary depending on the nature and severity of the disease to be prevented and / or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc.

[0024] The "medicine or health product for preventing and treating sarcopenia" can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, the dosage should be adjusted according to the actual situation.

[0025] In the application of the present invention, the products include but are not limited to medicines and health products. Without violating the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily to obtain the preferred embodiments of the present invention.

[0026] The raw material of the present invention, unetin, is synthesized by itself (the synthesis process has been patented), and the reagents used are all commercially available. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a statistical graph of the forced swimming time of each group of mice provided in Experimental Example 1 of the present invention (N=9). DETAILED DESCRIPTION

[0028] The present invention is further described in detail by way of examples below, but the protection scope of the present invention is not limited by any specific examples, but is defined by the claims. Experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions.

[0029] Evaluation of the therapeutic efficacy of Wuning on dexamethasone-induced sarcopenia mice in Example 1

[0030] Materials and Methods

[0031] Grouping: Thirty-six 8-week-old C57BL / 6J mice were randomly divided into 4 groups: normal control group, model group, low-dose Zhongwuning group, and high-dose Zhongwuning group, with 9 mice in each group.

[0032] Model replication: Except for the normal control group, the other groups were given multiple intraperitoneal injections of dexamethasone sodium phosphate (16.5 mg / kg) to establish the sarcopenia mouse model. The normal control group was given an equal amount of normal saline intraperitoneally.

[0033] Drug treatment: 6 hours after the injection of dexamethasone sodium phosphate, the low-dose (3 mg / kg) and high-dose (15 mg / kg) Zhonguning groups were gavaged with the corresponding low-dose (3 mg / kg) and high-dose (15 mg / kg) Zhonguning, and the model group and the normal control group were gavaged with an equal amount of solvent (normal saline) once a day.

[0034] Exercise endurance test: The swimming time of each group of mice was tested by forced swimming on the 7th and 14th days after administration to evaluate the rescue effect of the drug on strength attenuation.

[0035] Results and Conclusions:

[0036] See also Figure 1 (Note: Compared with the model group, *P<0.05, **P<0.01, result = mean±SEM), compared with the normal control group, the swimming time of the mice in the model group was significantly shortened on the 7th day (p<0.01), and there was a trend on the 14th day. Compared with the model group, the swimming time of the mice in each Zhongwuning group on the 7th and 14th days showed an increasing trend, with significant differences (p<0.05).

[0037] The experimental results show that Zhongwu Ning can enhance the muscle strength of mice with sarcopenia, suggesting that Zhongwu Ning has a certain therapeutic effect on sarcopenia.

[0038] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Use of Zhonguning or its pharmaceutically acceptable salt, ester or solvate in the preparation of drugs for preventing and treating sarcopenia, wherein the structural formula of Zhonguning is shown below.

2. The use according to claim 1, characterized in that The drug for preventing and treating sarcopenia is a preparation prepared by using Zhongwuning or its pharmaceutically acceptable salt, ester or solvate as an active ingredient and adding auxiliary materials or auxiliary ingredients commonly used in medicine.

3. The use according to claim 1, characterized in that The pharmaceutically acceptable salt is an inorganic salt or an organic salt.

4. The use according to claim 2, characterized in that The dosage form of the preparation is a liquid preparation, a solid preparation or a semisolid preparation.

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