CN114469962A - Preparation method of L-arginine aspirin and L-arginine aspirin capsule - Google Patents
Preparation method of L-arginine aspirin and L-arginine aspirin capsule Download PDFInfo
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- CN114469962A CN114469962A CN202111544815.2A CN202111544815A CN114469962A CN 114469962 A CN114469962 A CN 114469962A CN 202111544815 A CN202111544815 A CN 202111544815A CN 114469962 A CN114469962 A CN 114469962A
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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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention provides a preparation method of L-arginine aspirin and an L-arginine aspirin capsule, belonging to the technical field of medicine preparation, wherein the L-arginine aspirin is obtained by dissolving aspirin in an ether-ethanol mixed solution to obtain an aspirin solution; dissolving L-arginine in water to obtain an arginine solution; slowly dripping the arginine solution into the aspirin solution, and reacting at room temperature to obtain the aspirin compound preparation; the raw materials of the L-arginine aspirin capsule comprise L-arginine aspirin, a diluent, an adhesive, a disintegrating agent and a lubricant. The aspirin is dissolved by using the ether-ethanol mixed solution, so that the hydrolysis of the aspirin is effectively inhibited; meanwhile, the L-arginine aqueous solution is dripped into the aspirin solution, so that the contact between the L-arginine and the aspirin can be increased, the reaction efficiency is accelerated, and in the reaction process, the hydrolysis of the aspirin can be effectively inhibited due to the fact that the ether-ethanol mixed solution is used as a main solvent.
Description
Technical Field
The invention relates to a double salt of aspirin, in particular to a preparation method of L-arginine aspirin and an L-arginine aspirin capsule.
Background
The L-arginine aspirin is prepared by using the alkalinity of L-arginine and the acidity of aspirin, the L-arginine aspirin is easily dissolved in water and is hydrolyzed into aspirin and L-arginine in vivo after entering a human body, and the aspirin is further hydrolyzed to generate salicylic acid, so that cyclooxygenase is inhibited, prostaglandin synthesis is reduced, and the effects of relieving fever, easing pain and resisting inflammation are achieved. L-arginine aspirin is mainly used for fever and moderate and mild pain, and is forbidden to be used for treating pain after coronary artery bypass surgery and the like. The L-arginine aspirin is prepared into a medicament for clinical application, can reduce the stimulation of aspirin to gastrointestinal tracts, reduce the blood viscosity, and is favorable for improving the absorbability, thereby improving the bioavailability.
At present, there are two main methods for producing arginine aspirin: firstly, dissolving arginine in water, adding aspirin to react at 60-80 ℃, and adding an organic solvent to crystallize, wherein the reaction temperature is too high, aspirin is rapidly hydrolyzed, and industrial production is not facilitated (patent of invention with publication number of CN 101380329B); the second method is that aspirin is dissolved in ethanol, arginine is added to react at room temperature, and then cooling and crystallization are carried out to obtain the aspirin-aspirin sustained release tablet, the aspirin is directly dissolved in the ethanol, hydroxyl contained in the ethanol can also cause rapid hydrolysis of the aspirin, and arginine is slightly dissolved in the ethanol in the method and is not beneficial to contact between the aspirin and the arginine, so that the reaction time is prolonged, and the hydrolysis amount of the aspirin is further increased (the invention patent with the publication number of CN 101704766B).
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of L-arginine aspirin and an L-arginine aspirin capsule.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a preparation method of L-arginine aspirin, which comprises the following steps:
dissolving aspirin in diethyl ether-ethanol mixed solution to obtain aspirin solution;
dissolving L-arginine in water to obtain an arginine solution;
slowly dripping an arginine solution into the aspirin solution, reacting at room temperature (the arginine solution is dripped, the precipitate is locally generated and then quickly disappears, the amount of the product L-arginine aspirin is gradually increased along with the increase of the dosage of the arginine solution, the product is insoluble in the solvent system and is separated out in a precipitation mode, and the precipitate is the L-arginine aspirin), filtering and drying to obtain the L-arginine aspirin.
Further, the volume ratio of the diethyl ether to the ethanol in the diethyl ether-ethanol mixed solution is 1.5-2: 1.
further, the weight volume ratio of aspirin to ether-ethanol mixed liquor is 1 kg: 7.2-7.5L;
the weight volume ratio of the L-arginine to the water is 1 kg: 1.5-2L.
Further, the molar ratio of aspirin to L-arginine is 1: 1 to 1.1.
Further, the reaction time at room temperature is 10-15 min.
An L-arginine aspirin capsule, wherein the raw materials for preparing the effective components of the L-arginine aspirin capsule comprise, by weight: 5-7 parts of L-arginine aspirin, 1-2 parts of a diluent, 1.4-1.8 parts of an adhesive, 0.5-1 part of a disintegrating agent and 0.1-0.2 part of a lubricant.
Further, the diluent is microcrystalline cellulose; the adhesive is a mixture of lactose and beta-cyclodextrin; the disintegrating agent is sodium carboxymethyl starch; the lubricant is magnesium stearate.
Further, the weight ratio of lactose to beta-cyclodextrin in the binder is 1: 2.3 to 2.4.
Furthermore, the L-arginine aspirin capsule is prepared by uniformly mixing all the raw materials, granulating by a dry method, and filling the obtained particles into capsules.
Furthermore, all the raw materials are uniformly mixed by uniformly mixing the L-arginine aspirin, the diluent, the adhesive and the disintegrant, and then adding the lubricant for uniform mixing.
The preparation method of the L-arginine aspirin and the L-arginine aspirin capsule have the beneficial effects that:
according to the method, the aspirin is dissolved by the ether-ethanol mixed solution, and the ether in the system can effectively inhibit the hydrolysis of the aspirin; meanwhile, the L-arginine aqueous solution is dripped into the aspirin solution, so that the contact between the L-arginine and the aspirin can be increased, the reaction efficiency is accelerated, and in the reaction process, as the ether-ethanol mixed solution is used as a main solvent, the hydrolysis of the aspirin can be effectively inhibited;
the invention can effectively inhibit aspirin from hydrolyzing by adopting the diethyl ether-ethanol mixed solution with a specific proportion;
according to the invention, by adopting the diethyl ether-ethanol mixed solution and water with specific dosage, the system is always homogeneous and does not delaminate in the reaction process, so that the contact between L-arginine and aspirin is increased and the hydrolysis of aspirin is reduced;
the invention adds a new medicament form by preparing the L-arginine aspirin into the capsule, can avoid the stimulation of the L-arginine aspirin which is orally taken into the stomach and hydrolyzed to the stomach, protects the gastric mucosa, can cover the bitter taste of the medicament, and improves the medicament stability and bioavailability.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
EXAMPLE 1A method for preparing L-arginine aspirin
The embodiment is a preparation method of L-arginine aspirin, and the specific preparation process comprises the following steps in sequence:
mixing 8.1L diethyl ether with 5.4L ethanol to obtain diethyl ether-ethanol mixture;
dissolving 1.8kg of aspirin in 13.5L of diethyl ether-ethanol mixed solution to obtain aspirin solution;
dissolving 1.92kg of L-arginine in 3.84L of water to obtain an arginine solution;
slowly dripping an arginine solution into an aspirin solution (the dripping time is 1h), stirring at room temperature for reaction for 10min, beginning to drip an arginine solution, locally generating precipitate, then quickly disappearing, gradually increasing the amount of a product L-arginine aspirin along with the increase of the dosage of the arginine solution, and insolubilizing the product in a solvent system, wherein the precipitate is the L-arginine aspirin, cooling to 0 ℃ for crystallization for 1h, filtering, and drying in vacuum to obtain 3.12kg of L-arginine aspirin (a mark), wherein the yield is 88.05%, and the content of free salicylic acid is 0.17% (the content of the free salicylic acid is determined by a high performance liquid chromatography for determining aspirin in pharmacopoeia).
Example 2-6 preparation of L-arginine Aspirin
Embodiments 2 to 6 are respectively a method for preparing L-arginine aspirin, the steps of which are substantially the same as those of embodiment 1, and the differences are only in the amount of raw materials and process parameters, and the details are shown in table 1:
TABLE 1 summary of the process parameters of examples 2 to 6
The contents of the other portions of examples 2 to 6 are the same as those of example 1.
Example 7A method for preparing L-arginine aspirin capsules
The embodiment is a preparation method of an L-arginine aspirin capsule, and the specific preparation process comprises the following steps in sequence:
taking 0.085kg of lactose and 0.195kg of beta-cyclodextrin as adhesives;
1kg of L-arginine aspirin M1 prepared in example 1, 0.2kg of microcrystalline cellulose, 0.28kg of a binder and 0.1kg of sodium carboxymethyl starch were uniformly mixed, then 0.02kg of magnesium stearate was added and uniformly mixed, and then the mixture was subjected to dry granulation and then placed into enteric capsules to obtain L-arginine aspirin capsules, which were labeled as N1.
Example 8-12 preparation method of L-arginine Aspirin Capsule
Examples 8 to 12 are methods of preparing L-arginine aspirin capsules, respectively, which are substantially the same as example 7 except for the difference in the amount of raw materials, and are specifically shown in table 2:
TABLE 2 summary of the process parameters of examples 8 to 12
The contents of the other portions of examples 8 to 12 are the same as those of example 7.
Experimental example 1 Performance measurement of L-arginine Aspirin
Comparative example 1L-arginine aspirin was prepared in 74.73% overall yield and 0.54% free salicylic acid content according to the method disclosed in the patent publication CN 101380329B.
Comparative example 2L-arginine aspirin was prepared in a total yield of 75.2% and a free salicylic acid content of 0.31% according to the method disclosed in the patent publication No. CN 101704766B.
Compared with the free salicylic acid in the comparative example, the free salicylic acid content in the L-arginine aspirin prepared by the invention is obviously reduced, which shows that the reaction system of the invention can effectively inhibit aspirin from hydrolyzing, and further improves the yield of the L-arginine aspirin.
Experimental example 2 Performance measurement of L-arginine aspirin Capsule
Comparative examples 3 to 4 are comparative experiments of the preparation process of L-arginine aspirin [ specification 40mg (in terms of L-arginine aspirin) ] of example 6, the differences being only:
in comparative example 3 0.28kg of lactose was used as binder;
in comparative example 4 0.28kg of beta-cyclodextrin was used as binder.
a1) Accelerated test
The L-arginine aspirin capsules prepared in examples 7-12 and comparative examples 3-4 were placed at 40 + -2 deg.C and RH75 + -5% for 6 months, during which samples (powder in capsule) were taken at 1 st, 3 rd and 6 th months, respectively, and compared with the data for 0 days, the specific test results are shown in the following table:
TABLE 3 summary of test results of accelerated test
As can be seen from Table 3, the L-arginine aspirin capsules prepared in examples 7 to 12 of the present invention have good powder stability.
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (10)
1. A preparation method of L-arginine aspirin is characterized by comprising the following steps:
dissolving aspirin in diethyl ether-ethanol mixed solution to obtain aspirin solution;
dissolving L-arginine in water to obtain an arginine solution;
and (3) slowly dripping the arginine solution into the aspirin solution, reacting at room temperature, filtering and drying to obtain the L-arginine aspirin.
2. The method for preparing L-arginine aspirin according to claim 1, wherein a volume ratio of ethyl ether to ethanol in the ethyl ether-ethanol mixed solution is 1.5-2: 1.
3. the method for producing L-arginine aspirin according to claim 1 or 2, wherein a weight-to-volume ratio of aspirin to the ether-ethanol mixed solution is 1 kg: 7.2-7.5L;
the weight volume ratio of the L-arginine to the water is 1 kg: 1.5-2L.
4. The process for producing L-arginine aspirin according to claim 1 or 2, wherein the molar ratio of aspirin to L-arginine is 1: 1 to 1.1.
5. The method for producing L-arginine aspirin according to claim 1 or 2, wherein the reaction time at room temperature is 10 to 15 min.
6. The L-arginine aspirin capsule is characterized in that the effective components of the L-arginine aspirin capsule are prepared from the following raw materials in parts by weight: 5-7 parts of L-arginine aspirin, 1-2 parts of a diluent, 1.4-1.8 parts of a binder, 0.5-1 part of a disintegrating agent and 0.1-0.2 part of a lubricant, wherein the L-arginine aspirin is prepared by the preparation method of claims 1-5.
7. The L-arginine aspirin capsule of claim 6, wherein the diluent is microcrystalline cellulose; the adhesive is a mixture of lactose and beta-cyclodextrin; the disintegrating agent is sodium carboxymethyl starch; the lubricant is magnesium stearate.
8. The L-arginine aspirin capsule of claim 7, wherein the weight ratio of lactose to β -cyclodextrin in the binder is 1: 2.3 to 2.4.
9. An L-arginine aspirin capsule according to any one of claims 6-8, wherein the L-arginine aspirin capsule is prepared by mixing all the raw materials, granulating by a dry method, and filling the obtained particles into a capsule.
10. The L-arginine aspirin capsule of claim 9, wherein the mixing of all the raw materials is carried out by taking L-arginine aspirin, diluent, adhesive and disintegrating agent, mixing uniformly, adding lubricant, and mixing uniformly.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111544815.2A CN114469962A (en) | 2021-12-16 | 2021-12-16 | Preparation method of L-arginine aspirin and L-arginine aspirin capsule |
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| CN202111544815.2A CN114469962A (en) | 2021-12-16 | 2021-12-16 | Preparation method of L-arginine aspirin and L-arginine aspirin capsule |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704766A (en) * | 2009-11-05 | 2010-05-12 | 蚌埠丰原涂山制药有限公司 | Preparation method of arginine aspirin and powder-injection of arginine aspirin |
| CN104744249A (en) * | 2013-12-31 | 2015-07-01 | 海口天行健药物研究有限公司 | Method for preparing stable salt of aspirin and alkaline amino acid |
| WO2016195153A1 (en) * | 2015-05-29 | 2016-12-08 | 한국유나이티드제약 주식회사 | Pharmaceutical composite preparation |
-
2021
- 2021-12-16 CN CN202111544815.2A patent/CN114469962A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704766A (en) * | 2009-11-05 | 2010-05-12 | 蚌埠丰原涂山制药有限公司 | Preparation method of arginine aspirin and powder-injection of arginine aspirin |
| CN104744249A (en) * | 2013-12-31 | 2015-07-01 | 海口天行健药物研究有限公司 | Method for preparing stable salt of aspirin and alkaline amino acid |
| WO2016195153A1 (en) * | 2015-05-29 | 2016-12-08 | 한국유나이티드제약 주식회사 | Pharmaceutical composite preparation |
Non-Patent Citations (2)
| Title |
|---|
| 张晓云, 倪京满, 王小红, 王荷, 孟庆刚: "阿司匹林精氨酸盐注射液的制备及其稳定性研究", 西北药学杂志, no. 02, pages 71 - 72 * |
| 雷春华;李其华;刘利民;曾立华;李承志;: "乙醚在阿司匹林重结晶中的作用", 化学工程师, no. 02, pages 16 - 17 * |
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