WO2020253835A1 - Composition contenant des nitrates et des vitamines, son procédé de préparation, formulation associée et utilisation associée - Google Patents

Composition contenant des nitrates et des vitamines, son procédé de préparation, formulation associée et utilisation associée Download PDF

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WO2020253835A1
WO2020253835A1 PCT/CN2020/097156 CN2020097156W WO2020253835A1 WO 2020253835 A1 WO2020253835 A1 WO 2020253835A1 CN 2020097156 W CN2020097156 W CN 2020097156W WO 2020253835 A1 WO2020253835 A1 WO 2020253835A1
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nitrate
vitamin
composition
preparation
combination
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PCT/CN2020/097156
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Chinese (zh)
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王松灵
王玉记
李国情
秦力峥
胡亮
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爱希（北京）国际咨询有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • the present invention relates to the technical field of medicine, in particular, to a composition containing nitrate and vitamins, its preparation (Naruit), its preparation method, and its use in the preparation of drugs for increasing blood nitrate content or treating tumors and/ Or use in drugs that inhibit tumor cell proliferation.
  • Nitrate and nitrite are widely found in water, soil, air and plants.
  • the main source of nitrate absorption by the human body is food, and green vegetables account for the main part.
  • Nitrate plays a physiological function in various system activities, including blood pressure reduction, platelet aggregation inhibition and vascular protection (Lundberg JO et al., Cardiovasc Res, 2011; Kapil V et al, Nitric Oxide, 2014).
  • Rat skeletal muscle cells can take up nitrate from peripheral blood, and then reduce nitrate to nitric oxide through the xanthine oxidoreductase pathway, thereby increasing the body’s blood flow and promoting metabolism (Weitzberg E et al., Annu Rev Nutr, 2013).
  • Nitrate prevents ischemic heart disease by increasing vasodilatory epicardial blood flow, reducing vascular resistance, reducing coronary blood stealing and reducing preload (Pragani MA et al., Rev Cardiovasc Med, 2017). Nitrate in the diet can reduce endogenous nitric oxide production by inhibiting NADPH oxidase and regulating the expression of angiotensin (Ang) II receptors, thereby partially improving age-related hypertension and metabolic activity in mice (Hezel M et al., Free Radic Biol Med, 2016).
  • Ang angiotensin
  • inorganic nitrates inhibit acute and chronic inflammation by increasing neutrophil counts, which may reduce the occurrence of atherosclerotic plaques (Khambata RS et al., Proc Natl Acad Sci USA, 2017).
  • a long-term dietary nitrate deficiency experiment showed that after 22 months of a low-nitrate diet, mice will experience metabolic syndrome, endothelial dysfunction, and cardiovascular death (Kina-Tanada M et al., Diabatologia, 2017) .
  • Inorganic nitrates can reduce blood pressure and improve myocardial ischemia by enhancing the activity of epithelial cells and relaxing blood vessels, reducing platelet aggregation (Machha A et al., Eur J Nutr, 2011).
  • nitrates were considered harmful because under certain conditions, such as acidic gastric environment, carcinogenic nitrosamines may be produced, and nitrosamines are related to esophageal cancer, gastric cancer, colon cancer and other tumors (Bedale W et al., Meat Sci, 2016, Park JE et al, Toxicol Res, 2015). Therefore, the World Health Organization (WHO) recommends that the upper limit of daily intake of nitrate and nitrite is 3.7mg/kg and 0.06-0.07mg/kg respectively (Weitzberg E et al., Annu Rev Nutr, 2013) .
  • WHO World Health Organization
  • nitrate plays an important physiological regulation role in the body, and dietary nitrate can basically meet the amount of nitrate required by healthy people.
  • cardiovascular function damage gastrointestinal stress damage, liver degeneration, liver steatosis, systemic radiation damage and tumors
  • the intake of dietary nitrates simply cannot reach the therapeutic dose ( ⁇ 13mg /kg). So far, the prior art has not provided nitrate preparations that are suitable for direct use as drugs and produce good absorption effects and excellent therapeutic effects.
  • An object of the present invention is to provide a composition containing nitrates, said composition comprising nitrates and vitamins, wherein the ratio of the amount of nitrates and vitamins is 10:1 to 1:10, preferably 5:1 -1:5, more preferably 3:1-1:1, most preferably 2:1-1:1.
  • the nitrate is sodium nitrate, potassium nitrate or a combination thereof, preferably sodium nitrate or potassium nitrate, and most preferably sodium nitrate.
  • the vitamin is vitamin C, vitamin B6 or a combination thereof, preferably vitamin C or vitamin B6, most preferably vitamin C.
  • the ratio of the amount of the nitrate and the vitamin may be 10:1, 5:1, 2:1, 1:1, 1:2, 1:3, 1:5, 1:10, more preferably In particular, the ratio is 2:1, 1:1.
  • Another object of the present invention is to provide a preparation method of the composition comprising nitrate and vitamins according to the present invention, which includes dissolving nitrate and vitamins separately, filtering and sterilizing with a 0.22 ⁇ m microporous filter membrane, according to the above nitrate and vitamin
  • the ratio of the amount of the vitamin substance is mixed, the mixed solution is divided into sterile vials, sealed, frozen at -20 ⁇ -60°C for 2 ⁇ 18h, freeze-dried with a lyophilizer: set -20 ⁇ - Sublimation once at 20°C for 4-20h, and sublimation twice at 20-40°C for 1-30h, then take it out.
  • Another object of the present invention is to provide a preparation comprising the composition of the present invention including nitrate and vitamins and one or more pharmaceutically acceptable excipients.
  • the preparation can be any pharmaceutically acceptable preparation form, such as solid form or liquid form, such as tablet, capsule, granule, oral liquid, injection, liposome, lipid microemulsion, freeze-dried Powder preparations and so on.
  • pharmaceutically acceptable preparation form such as solid form or liquid form, such as tablet, capsule, granule, oral liquid, injection, liposome, lipid microemulsion, freeze-dried Powder preparations and so on.
  • the preparation method of the formulation can be prepared according to conventional methods known in the art.
  • the specific preparation form of the present invention preferably, it can be prepared according to the specific preparation method described in the embodiment of the present application.
  • the pharmaceutically acceptable excipients can be any suitable excipients suitable for the preparation of different formulations, such as fillers, diluents, binders, disintegrants, glidants Agents, lubricants, flavoring agents, inclusion materials, freeze-dried stabilizers.
  • a preferred form of preparation is liposome, with a nanometer particle size of 150-200nm, and the formula composition is as follows: sodium nitrate 0.2-2.0g, vitamin C 0.2-0.9g, lecithin 0.5-3.5g, cholesterol 0.1-0.5g, Lauryl alcohol 0.05 ⁇ 0.4g, phosphate buffered saline (PBS) 100 ⁇ 200mL.
  • PBS phosphate buffered saline
  • a preferred liposome includes 0.2 g of sodium nitrate, 0.2-0.83 g of vitamin C, 0.5-2.0 g of lecithin, 0.1-0.4 g of cholesterol, 0.05-0.2 g of lauryl alcohol, and an appropriate amount of phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • Another object of the present invention is to provide the use of the composition comprising nitrate and vitamin or its preparation in the preparation of a medicine for increasing the nitrate content in blood.
  • nitrate can relax blood vessels. When the body is injured by ischemia, the pH of the damaged part often drops below 7. By quickly replenishing nitrate and increasing the content of nitrate in the blood, it can relax the aortic ring and produce regulation. The role of cardiovascular function. Moreover, studies have shown that increasing the nitrate content in the blood can regulate gastrointestinal function, improve and/or treat gastrointestinal stress damage, prevent liver degeneration and liver steatosis, and reduce damage caused by systemic radiation.
  • Still another object of the present invention is to provide the use of the composition comprising nitrate and vitamins or preparations thereof in the preparation of drugs for treating tumors and/or inhibiting the proliferation of tumor cells.
  • the tumor is oral cancer.
  • nitrate preparations that are suitable for direct use as drugs and produce better absorption effects and excellent therapeutic effects.
  • nitrate and vitamin are prepared into a composition (especially preferably, nanoliposome preparation composition) according to a specific ratio, which can significantly increase the nitrate content in the blood, increase the bioavailability, and can be used to regulate cardiovascular function , Improve and/or treat gastrointestinal stress damage, prevent liver degeneration and liver steatosis, or reduce damage caused by whole body radiation without any adverse side effects.
  • composition 5 in rats in 2 hours is 2.1 times that of the nitrate group alone, which is equivalent to that of composition 5 when the dose is reduced by one time and the effect of nitrate alone is still equivalent
  • composition 5 of nitrate and vitamins can produce a significant effect of treating tumors; the composition of the present invention is confirmed by animal experiments, without any toxicity, safe and effective. Therefore, the technical solution of the present invention produces unexpected technical effects, and has important clinical significance.
  • the dose of the composition of the present invention or the pharmaceutical composition administered to the patient may depend on, for example, the type of disease to be treated or the level of nitrate content in the blood that needs to be reached, and may be based on a dose-selection method known to those skilled in the art Make a selection.
  • the dosage of the composition administered to the patient is about 13 mg/kg or higher based on the nitrate content of the composition, such as about 15 mg/kg to 30 mg/kg.
  • the ratio of the nitrate to the vitamin is the ratio of the amount of the substance (ie, the molar ratio). If not specifically stated, the materials, devices or equipment, the preparation methods of the materials or compositions, etc., are all conventional or well-known in the art, or those skilled in the art can obtain them according to the description of this specification according to conventional technical means. of.
  • Fig. 1 is a graph of nitrate content in blood after gavage of 5 kinds of compositions of the present invention and sodium nitrate alone according to test example 1, according to body weight.
  • the combinations 1, 2, 3, 4 and 5 are the amount ratios of the substances prepared according to Example 1 of 5:1, 1:5, 1:1, 1:2, 2:1 sodium nitrate and vitamin C. combination.
  • Figure 2 is a graph showing the effect of a nitrate composition diet on the volume of transplanted tumors of oral cancer CAL27 cells in nude mice.
  • Figure 3 is a graph showing the effect of nitrate nanocomposites on the body weight of nude mice transplanted with oral cancer CAL27. Note: The results show that the application of nitrate has no significant change in the body weight of nude mice.
  • Figure 4 is a graph showing the effect of nitrate composition on the morphology of oral cancer CAL27 cells.
  • Figure 5 is a graph showing the effect of nitrate composition on the proliferation of oral cancer CAL27 cells.
  • Figure 6 is a graph showing the effect of nitrate composition on the scratch width of oral cancer CAL27 cells.
  • Figure 7 is a graph showing the anti-migration activity of a nitrate composition on oral cancer CAL27 cells.
  • Example 1 Composition of nitrate and vitamin
  • Composition 1 Sodium nitrate 0.85g, vitamin C 0.176g (substance ratio 10:1)
  • Composition 2 Sodium nitrate 0.85g, vitamin C 0.352g (substance ratio 5:1)
  • Composition 3 Sodium nitrate 0.85g, vitamin C 0.88g (substance ratio 2:1)
  • Composition 4 Sodium nitrate 0.85g, vitamin C 1.76g (substance ratio 1:1)
  • Composition 5 0.85g of sodium nitrate, 3.52g of vitamin C (substance ratio 1:2)
  • Composition 6 sodium nitrate 0.85g, vitamin C 5.28g (substance ratio 1:3)
  • Composition 7 0.85g of sodium nitrate, 8.8g of vitamin C (substance ratio 1:5)
  • Composition 8 0.85g of sodium nitrate, 17.6g of vitamin C (substance ratio 1:10)
  • Preparation method Weigh the corresponding amount of sodium nitrate or vitamin C according to the above ratio, dissolve the nitrate and vitamin C separately, filter and sterilize with a 0.22 ⁇ m microporous filter, mix separately according to different proportions, and pack the mixed solution.
  • a sterile vial sealed, frozen at -20 ⁇ -60°C for 2 ⁇ 18h, freeze-dried with a freeze dryer: set at -20 ⁇ 20°C for 4 ⁇ 20h once sublimation, 20 ⁇ 40°C for second sublimation 1 ⁇ 30h, take it out and get the composition.
  • Example 2 Tablets containing nitrate and vitamins
  • composition of tablets 1000 tablets:
  • Each tablet of this product contains about 1.76 ⁇ 176mg of vitamin C, 8.5mg of nitrate, and the tablet weight is about 250mg.
  • composition of microemulsion is composition of microemulsion:
  • Step 1 Under the protection of nitrogen, add 1000g soybean oil to 8g lecithin and 20g polyethylene glycol PEG2000, and heat to 30 ⁇ 70°C to form an oil phase mixture;
  • Step 2 Mix the composition of 0.176g ⁇ 17.6g vitamin C and 0.85g sodium nitrate, 200g poloxamer 188 and 8L water for injection in different proportions at 20 ⁇ 70°C to form an aqueous mixture;
  • Step 3 Under the protection of nitrogen, mix the water phase mixture obtained in step 2 with the mixture obtained in step 1, and then disperse at a high speed for 5 to 30 minutes under the conditions of 30 to 80°C and 5000 to 50000 r/min, then use 0.1 mol/L NaOH or HCl adjust the pH to 6.0-8.5, homogenize for 5-15 times under the pressure of 90-210MPa, until the mixed phase is in a uniform and transparent state, and the obtained uniform and transparent mixed phase is detected, Divide the packaging to obtain nano microemulsion.
  • Step 1 Weigh lecithin, cholesterol and lauryl alcohol, put them in an eggplant-shaped bottle, and dissolve them with chloroform. Make dry film by rotary evaporation for use;
  • Step 2 Prepare phosphate buffer solution, dissolve vitamin C in an appropriate amount of phosphate buffer solution (PBS) 100-200mL, and then add sodium nitrate to obtain a solution;
  • PBS phosphate buffer solution
  • Step 3 Slowly inject the solution of step 2 into the eggplant-shaped bottle of step 1, agitate slowly, and form liposomes after ultrasonic treatment.
  • the nanometer properties were characterized by a laser nanoparticle sizer, and the particle size was measured to be 150-200nm.
  • the encapsulation efficiency of the liposome composition of combinations 3, 4, and 5 is 92.5%, 94.3%, and 95.2%, respectively, as determined by the HPLC method.”
  • Example 5 Granules containing nitrate and vitamins
  • Sodium nitrate and 8.5g vitamin B 6 41.0g, and HPMC (HT-K80000S) 2.0g mixed with 20% ethanol solution 20mL obtain a soft material, extrusion and spheronization into particles, dried to a moisture less than 3%, Sodium nitrate and vitamin B6 composition granules are obtained.
  • Test Example 1 Detection of nitrate content in blood after administration of the composition of the present invention
  • C57BL6 mice male, 30 ⁇ 5 g (70 in total, 10 in each group) were anesthetized by intraperitoneal injection of pentobarbital physiological saline solution at a dose of 50 mg/kg.
  • the sodium nitrate and five nitrate-containing reagent compositions prepared in accordance with Example 1 respectively, and the ratio of the amount of substances is 5:1 (combination 1), 1:5 (combination 2), 1:1 ( Combination 3), 1:2 (combination 4), 2:1 (combination 5) sodium nitrate and vitamin C composition) (in the six groups of experiments, the nitrate content is the same) by intragastric administration at 0.2 mmol/kg, respectively At 0h, blood was taken from the tail vein at 2, 4, 6, 12 h after intragastric administration.
  • nitrate reductase Reconstitute nitrate reductase with 1.0 ml of nitrate reductase stock solution, vortex vigorously, let stand at room temperature for 15 minutes, vortex and let stand at room temperature for another 15 minutes, vortex again and immediately use.
  • reaction diluent (1 ⁇ ) step a ⁇ 4 times the volume
  • NADH reagent-Use 5.0 ml deionized water or distilled water to reconstitute NADH, let it stand for 3 minutes and gently stir before use, use within 15 minutes or place it on ice.
  • reaction diluent (1 ⁇ ) is blank (0 ⁇ mol/L).
  • mice Female nude mice aged 4 weeks were selected as experimental animals (female, 20 ⁇ 5g), human oral squamous cell carcinoma cell line CAL27 was routinely cultured, and the concentration was 2.5 ⁇ 10 7 /mL, and 0.2mL/mouse was injected into the right hind limb of nude mice subcutaneously . When the tumor body enters the rapid growth phase, give each group of compounds:.
  • the experimental animals were divided into 2 control groups (physiological saline group and sodium nitrate group) and 2 composition groups (combination 5 solid group and combination 5 liposome group, where the combination 5 solid was the amount of the substance prepared according to Example 1.
  • Two composition groups (combination 5 solid group and combination 5 liposome group) and 1 control group (sodium nitrate group) were given sodium nitrate composition (combination 5 solid or combination 5 liposome) or sodium nitrate drinking water, respectively.
  • the concentration is 2.5mmo1/L
  • the daily nitrate content of each rat is about 0.5mmo1/Kgbw
  • the nitrate drinking water is continuous for 1 month
  • a control group physiological saline group
  • the volume of the transplanted tumor and the weight of the nude mice were recorded regularly. The results are shown in Figure 2 and Figure 3.
  • composition of the present invention can significantly inhibit the growth of tumor cells without affecting the body weight of nude mice.
  • mice Female nude mice aged 4 weeks were selected as experimental animals (female, 20 ⁇ 5g), human oral squamous cell carcinoma cell line CAL27 was cultured routinely, and transferred to a 96-well plate at a concentration of 50,000 cells/mL, and the negative control physiological saline was detected by the CCK8 method
  • the anti-tumor cell proliferation activity of the composition of the present invention (the liposome of combination 5 prepared according to Example 4) in vitro.
  • the specific experimental method is as follows: inoculate 100 ⁇ L of cell suspension in a 96-well plate, pre-culture the plate in an incubator for 24 hours (at 37°C, 5% CO 2 ), and add test compound (physiological saline) after the cells adhere to the wall. Or the composition of the present invention), each well is administered with a volume of 25 ⁇ L, and then the culture plate is incubated in an incubator for 72 hours, each well is replaced with 100 ⁇ L of new medium, and 10 ⁇ L of CCK-8 solution is added to each well. After 2 hours, the absorbance at 450nm was measured with a microplate reader.
  • Figure 4 shows the effect of the composition of the present invention on the morphology of oral cancer CAL27 cells: under an inverted microscope, the control group cells grow adherently, the cells are fusiform or polygonal, the cytoplasm is rich, the growth is vigorous, and the adjacent cells grow and fuse into sheet. After adding 100mM sodium nitrate, CAL27 cells began to become smaller, rounded, increased refractive index, decreased cell adhesion, and showed typical apoptotic morphology. The morphology of chromatin aggregation, nuclear pyknosis, and nuclear fragmentation can be seen under the microscope. change.
  • Figure 5 shows the effect of different concentrations of the nitrate composition of the present invention on the proliferation of oral cancer CAL27 cells: nitrate (at a concentration of more than 30 mM) can significantly inhibit the proliferation of tumor cells.
  • SPSS 17.0 statistical software was used for statistical analysis. The measurement data of multiple groups were compared by ANOVA analysis, and P ⁇ 0.05 was statistically significant.
  • mice (30 in each group, half male and female) were given water (control group) and 2 compositions (combination 5 solid group and combination 5 liposome group) once within 24 hours.
  • the amount ratio of the substance prepared in Example 1 is a composition of sodium nitrate and vitamin C in a ratio of 2:1 (combination 5), and the combination 5 liposomes are the combination 5 liposomes prepared according to Example 4) (each, 380 mg/ kg, which is 9 times the daily dose under normal circumstances), the control group, the combination 5 solid group and the combination 5 liposome group on the day of administration and the observation period of 14 days after administration of animal movement, eyelid finger There were no abnormalities in symptoms, breathing, fur, excreta and secretions; no animal died during the experiment. It is shown that the composition of the present invention is non-toxic to animals at a certain dose and is safe and usable.

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Abstract

L'invention concerne une composition contenant des nitrates et des vitamines, une formulation associée, son procédé de préparation, une utilisation associée pour la préparation d'un médicament pour améliorer la concentration de nitrates dans le sang, et une utilisation associée dans le traitement de tumeurs.
PCT/CN2020/097156 2019-06-21 2020-06-19 Composition contenant des nitrates et des vitamines, son procédé de préparation, formulation associée et utilisation associée WO2020253835A1 (fr)

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CN110327367A (zh) * 2019-06-21 2019-10-15 北京爱希国际贸易有限公司 含有硝酸盐和维生素的组合物、其制备方法、制剂及其用途
CN112472714B (zh) * 2020-12-03 2022-09-16 爱希（北京）国际咨询有限公司 一种含硝酸盐的组合物及其应用
CN112516159B (zh) * 2020-12-03 2022-06-17 爱希（北京）国际咨询有限公司 一种含有硝酸盐的组合物、胃漂浮剂及制备方法和应用
CN112472713A (zh) * 2020-12-03 2021-03-12 爱希（北京）国际咨询有限公司 一种防治骨质疏松的组合物及其应用
CN113398093B (zh) * 2021-08-19 2021-11-02 首都医科大学附属北京口腔医院 一种硝酸盐和维生素c微囊在治疗干燥综合征中的应用
CN113398098B (zh) * 2021-08-19 2021-11-02 首都医科大学附属北京口腔医院 一种微囊及其制备方法和在预防和/或治疗放射治疗引起的唾液腺损伤中的应用

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