CN117298040A - Vonopraz fumarate injection and preparation method thereof - Google Patents

Vonopraz fumarate injection and preparation method thereof Download PDF

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Publication number
CN117298040A
CN117298040A CN202210722019.1A CN202210722019A CN117298040A CN 117298040 A CN117298040 A CN 117298040A CN 202210722019 A CN202210722019 A CN 202210722019A CN 117298040 A CN117298040 A CN 117298040A
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injection
prescription
fumarate
fumaric acid
nuola
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张贵民
朱鹏
杨艳双
刘忠
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0023Heat
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/20Targets to be treated
    • A61L2202/21Pharmaceuticals, e.g. medicaments, artificial body parts

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a fumarase injection and a preparation method thereof, belonging to the technical field of pharmaceutical preparations, wherein the injection consists of Fu Nuola raw fumaric acid, a pH regulator, sodium chloride and water for injection; the preparation method provided by the invention comprises the steps of dissolving the voronoi fumarate and sodium chloride in water for injection, adjusting a proper pH value, filling the mixture into a brown ampoule bottle, filling inert gas, and sterilizing. The Fu Nuola raw fumaric acid injection prepared by the method has few impurities, good product stability and high sterility assurance level.

Description

Vonopraz fumarate injection and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an injection containing vonolamine fumarate and a preparation method thereof.
Background
Fumaric acid Fu Nuola is a new type of potassium ion (K+) competitive acid blocker (P-CAB) developed by the Wuta-tsai company in Japan, can stop gastric acid secretion in advance by inhibiting the binding action of K+ on H+ -K+ -ATPase (proton pump) in the last step of gastric acid secretion of parietal cells, and has a powerful and durable gastric acid secretion inhibiting effect.
The currently marketed formulation of voronoi fumarate is a tablet, and has a first pass effect of liver in vivo, low oral bioavailability, and can not achieve good effect on patients suffering from severe acute symptoms or dysphagia. Therefore, there is a need to develop a voronoi fumarate injection.
Vonolamine fumarate is poor in stability, sensitive to light, heat and humidity, poor in solubility in acidic aqueous solutions, easy to react with organic acids in acids, and unstable in neutral or alkaline environments, and therefore presents a great challenge in developing injection dosage forms.
The prior art patent CN105640877a discloses a liquid preparation of vonolamine, which comprises Fu Nuola raw active ingredient and its salt, pH regulator, metal ion complexing agent and inorganic salt, but the metal ion complexing agent is easy to hemolyze, and may be twitched due to the decrease of blood calcium concentration, etc.; patent CN106265535a mentions that the vonolamine fumarate is prepared into a freeze-dried powder injection, but the sterility assurance level of the freeze-dried powder injection is lower than that of a finally sterilized injection; the solubility of the voronoi fumarate is improved by adding the beta-cyclodextrin derivative and the amino acid in the patent CN106924179A, but the preparation method is complex, the dosage of auxiliary materials is large, and the beta-cyclodextrin has renal toxicity and hemolysis; CN201610714831 discloses a composition containing vonolamine fumarate and a solubilizing agent, wherein the solubilizing agent is substituted beta-cyclodextrin, tween 80, phospholipid, poloxamer or any combination thereof, but the dosage of the auxiliary material substituted beta-cyclodextrin is larger. In summary, in order to improve the solubility and stability of the active ingredient voronoi fumarate in the prior art, various auxiliary materials are added in the prescription of the preparation, so that the safety risk of medication is increased.
Therefore, it is necessary to provide Fu Nuola raw fumaric acid injection which has simple prescription, good stability and proper solubility and can meet clinical needs.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide Fu Nuola raw fumaric acid injection which has good stability and simple prescription and can meet clinical requirements.
Experiments show that when the Fu Nuola raw fumaric acid is compatible with sodium chloride, no complexation effect and no precipitation are generated, and the stability of Fu Nuola raw fumaric acid injection can be improved while the osmotic pressure is regulated.
The specific technical content of the invention is as follows:
an injection containing vonolamine fumarate is prepared from Fu Nuola raw fumaric acid, pH regulator, inorganic salt and water for injection.
The concentration of the active ingredient, namely, the vonolamine fumarate (calculated by the vonolamine free base) is 0.1 mg/ml-5 mg/ml, preferably 0.5 mg/ml-3 mg/ml; in some embodiments the concentration of voronoi fumarate is 0.5mg/ml,1mg/ml,2mg/ml,3mg/ml,4mg/ml, or 5mg/ml.
The inorganic salt in the injection is sodium chloride; the dosage of the sodium chloride is 0.5% -2.0% according to the ratio (W/V, g/100 mL) of the weight of the sodium chloride to the total volume of the injection; preferably 0.8% to 1.0% sodium chloride is used in some embodiments in an amount of 0.8%,0.9%, or 1.0%.
The pH regulator in the injection is one or more selected from sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, acetic acid and fumaric acid.
The pH of the injection is 2.0-5.0; preferably pH 3.0 to 5.0; further preferably, the pH is 3.0 to 4.0; in some embodiments, the pH of the injection is 2.0,3.0,3.5,4.0,4.5, or 5.0.
The injection containing the vonolamine fumarate consists of Fu Nuola raw fumaric acid, sodium chloride, a pH regulator and water for injection, wherein the concentration of the vonolamine fumarate is 0.1-5 mg/ml, the dosage of the sodium chloride is 0.5-2.0%, and the pH of the injection is 2.0-5.0.
The injection containing the vonolamine fumarate consists of Fu Nuola raw fumaric acid, sodium chloride, a pH regulator and water for injection, wherein the concentration of the vonolamine fumarate is 0.5-3 mg/ml, the dosage of the sodium chloride is 0.8-1.0%, and the pH of the injection is 3.0-5.0.
The invention also provides a preparation method of the injection, which comprises the following steps:
1) Weighing inorganic salt and fumaric acid Fu Nuola with the prescribed amount, dissolving in water for injection, regulating the pH to 2.0-5.0 by using a pH regulator, and fixing the volume to the full volume;
2) Filtering, bottling, and sterilizing by oversterilization.
The sterilization condition is sterilization for 15 min-20 min at 121 ℃.
Preferably, in the preparation method, inert gas selected from one or more of argon, nitrogen and carbon dioxide can be filled in the preparation and filling processes.
Preferably, the injection is filled in a brown ampoule bottle or a brown penicillin bottle.
Compared with the prior art, the invention has the following advantages:
(1) The injection prepared by the invention only contains active ingredients, sodium chloride and pH regulator, does not need to add auxiliary materials such as substituted beta-cyclodextrin, ethylenediamine tetraacetic acid and the like, and improves the safety of the preparation.
(2) Compared with the commercially available tablets, the injection prepared by the invention has quicker effect, is suitable for patients with dysphagia and patients with acute gastritis and gastric ulcer, and can better meet clinical requirements.
(3) The injection prepared by the invention is sterilized by an oversterilization method, and has high sterility assurance level and high preparation safety.
(4) The injection prepared by the invention has good stability, less impurities and simple preparation process.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
EXAMPLE 1 dissolution of Vonoprazol fumarate
Prescription: as shown in table 1.
Table 1.
Prescription of prescription Prescription 1 Prescription 2 Prescription 3 Prescription 4
Concentration of the dispensed medicine 0.1mg/ml 5mg/ml 10mg/ml 20mg/ml
The preparation process comprises the following steps: weighing Fu Nuola raw fumaric acid with a prescription amount, respectively adding water for injection to prepare Vonolamine injection with a prescription concentration, and stirring until the Vonolamine injection is dissolved.
Experimental results:
prescription 1: stirring the water for injection at 40-90 ℃ for rapid dissolution, and standing at room temperature for 24 hours without precipitation.
Prescription 2: stirring with water for injection at 40-90deg.C, dissolving completely, standing at room temperature for 24 hr, and no precipitation.
Prescription 3: ultrasonic stirring and dissolving are carried out on water for injection at 40-90 ℃, and precipitation is carried out after the water for injection is placed at room temperature for 24 hours.
Prescription 4: the water for injection is magnetically stirred for 2 hours to be not completely dissolved.
The proper concentration of the vonolamine fumarate is 0.1-5 mg/ml according to the dissolution condition of the vonolamine fumarate.
Example 2 Effect of osmolality adjusting agent species on injection stability and osmolality
Prescription: as shown in table 2.
Table 2.
The preparation process comprises the following steps: weighing prescription amount of voronoi fumarate, adding prescription amount of sodium chloride, calcium chloride dihydrate and glucose respectively, adding water for injection, stirring and dissolving, adjusting pH after dissolving completely, and fixing volume; filled in brown ampoule and sterilized at 121℃for 15 min.
The prepared samples are respectively placed under high temperature (60 ℃) and strong light for 30 days, related substances, content and osmotic pressure are measured, and the investigation results are shown in table 3.
Table 3.
The result shows that the Fu Nuola raw fumaric acid and the glucose can produce more impurities, and the sodium chloride can reduce the generation of the impurities; the prescription containing calcium chloride has higher osmotic pressure and related substances are slightly larger than sodium chloride.
Example 3 investigation of the Effect of sodium chloride usage on injection stability and osmotic pressure
Prescription: as shown in table 4.
Table 4.
Prescription of prescription Prescription 9 Prescription 10 Prescription 11 Prescription 12 Prescription 13
Fu Nuola raw fumaric acid 0.134g 0.134g 0.134g 0.134g 0.134g
Sodium chloride 0.60g 0.80g 0.90g 1.0g 2.0g
Hydrochloric acid pH3.5 pH3.5 pH3.5 pH3.5 pH3.5
Injection water is added to 100ml 100ml 100ml 100ml 100ml
The preparation process comprises the following steps: weighing prescription amount of voronoi fumarate and sodium chloride, adding water for injection, stirring for dissolving, adjusting pH after dissolving completely, and fixing volume; filled in brown ampoule and sterilized at 121℃for 15 min.
The prepared samples are respectively placed under high temperature (60 ℃) and strong light for 30 days, the osmotic pressure, the substances before and after storage and the content are respectively measured, and the investigation results are shown in table 5.
Table 5.
The results show that: the dosage of sodium chloride is 0.8-1.0%, and the osmotic pressure intravenous injection can be tolerated while the Fu Nuola raw stability of fumaric acid can be effectively improved; when the amount of sodium chloride is 0.6%, the related substances are increased more, and when the amount of sodium chloride is 2.0%, the osmotic pressure is too high to be tolerated.
EXAMPLE 4 stability investigation of different concentrations of Fu Nuola raw fumaric acid injection
Prescription: as shown in table 6.
Table 6.
The preparation process comprises the following steps: weighing prescription amount of voronoi fumarate and sodium chloride, adding water for injection, stirring for dissolving, adjusting pH after dissolving completely, and fixing volume; filled in brown ampoule and sterilized at 121℃for 15 min.
The prepared samples are respectively placed under high temperature (60 ℃) and strong light for 30 days, the osmotic pressure, the substances before and after storage and the content are respectively measured, and the investigation results are shown in Table 7.
Table 7.
The results show that: along with the increase of the Fu Nuola raw concentration of fumaric acid, related substances are gradually increased after the irradiation for 30 days at high temperature, and the proper concentration of Fu Nuola raw fumaric acid (calculated by the vonolamine free alkali) in the prepared injection is 0.5-3 mg/ml.
Example 5 investigation of the influence of pH on stability of injection
Prescription: as shown in table 8.
Table 8.
The preparation process comprises the following steps: weighing prescription amount of voronoi fumarate and sodium chloride, adding water for injection, stirring and dissolving, and adjusting pH and constant volume according to the prescription after the solution is completely dissolved; filled in brown ampoule and sterilized at 121℃for 15 min.
The prepared samples were subjected to high temperature (60 ℃) and intense light for 30 days, and sampled for 0 day, 10 days, 20 days and 30 days, respectively, and the content of the relevant substances was measured, and the results are shown in Table 9.
Table 9.
The result shows that the pH range of the Fu Nuola fumaric acid injection is 3.0-4.0, and the fumaric acid injection has better stability under Wen Huoguang days after sterilization.
EXAMPLE 6 Effect of sterilization conditions on stability of injection
Prescription:
the preparation process comprises the following steps: weighing prescription amount of voronoi fumarate and sodium chloride, adding water for injection, stirring and dissolving, adjusting pH after dissolving completely, and fixing volume; encapsulating in brown ampoule; the prepared split products are divided into 5 parts, respectively, the split products are not sterilized, and are sterilized at 115 ℃ for 15 minutes, 121 ℃ for 12 minutes, 121 ℃ for 15 minutes and 121 ℃ for 20 minutes, the split products are placed for 30 days, and the influence of different sterilization conditions on the stability of injection is examined. The results are shown in Table 10.
Table 10.
The results show that: the residual probability method and the excessive killing method have little change of related substances, so the excessive killing method with higher sterility assurance level is selected for sterilization, and the sterilization condition is 121 ℃ for 15-20 min.
Example 7 formulation, whether filling procedure is inert gas filled or not and the effect of packaging on stability of injection
Prescription: as in table 11.
Table 11.
The preparation process comprises the following steps: weighing prescription amount of voronoi fumarate and sodium chloride, adding water for injection, stirring for dissolving, adjusting pH after dissolving completely, and fixing volume; filling in ampoule, sterilizing at 121deg.C for 15 min; wherein, the prescriptions 27-2 and 28-2 are not filled with nitrogen in the preparation and filling processes; filling the injection into a white ampoule bottle according to prescriptions 27-1 and 28-1; the prescriptions 27-3, 28-3 are filled with nitrogen during the formulation and filling process and the injecta is filled into brown ampoule bottles.
The prepared samples were subjected to high temperature (60 ℃) and intense light for 30 days, sampled for 0 day, 10 days and 30 days, respectively, and the content of the relevant substances was measured, and the results are shown in Table 12.
Table 12.
Prescription of prescription Prescription 27-1 Prescription 27-2 Prescription 27-3 Prescription 28-1 Prescription 28-2 Prescription 28-3
After 0 day sterilization 0.09 0.09 0.08 0.09 0.11 0.09
High temperature of 10 days 0.21 0.16 0.10 0.34 0.22 0.11
10 day illumination 0.32 0.12 0.09 0.53 0.15 0.10
High temperature for 30 days 0.39 0.25 0.18 0.47 0.36 0.20
30 days of illumination 0.71 0.20 0.12 0.93 0.23 0.14
The results show that: the nitrogen is filled in the preparation and filling processes, and the brown ampoule bottle is matched for use, so that the injection can better keep stability, and particularly, the Fu Nuola raw fumaric acid injection with higher concentration (such as 3 mg/ml) can better keep stability.
EXAMPLE 8 stability investigation of Vonoprazol fumarate injection
Prescription: as shown in table 13.
Table 13.
The preparation process comprises the following steps: weighing prescription amount of voronoi fumarate and sodium chloride, adding water for injection, stirring for dissolving, adjusting pH after dissolving completely, and fixing volume; filling in ampoule, sterilizing at 121deg.C for 15 min; wherein nitrogen is filled in the preparation and filling processes.
And (3) placing the sample at 40 ℃ and 75% RH, and detecting the change conditions of related substances and content of the sample in 1, 3 and 6 months respectively. The results are shown in Table 14.
Table 14.
The result shows that the Fu Nuola raw fumaric acid injection prepared by the invention is still in a clear transparent colorless state after being placed for 6 months under the acceleration condition, has no visible foreign matters, has no obvious change of the content and related substances, and has good stability.

Claims (10)

1. An injection containing vonolamine fumarate is characterized by comprising Fu Nuola raw fumaric acid, a pH regulator, inorganic salt and water for injection.
2. Injection according to claim 1, characterized in that the concentration of voronoi fumarate is 0.1mg/ml to 10mg/ml, preferably 0.5mg/ml to 3mg/ml.
3. The injection according to claim 1, wherein the inorganic salt is sodium chloride.
4. Injection according to claim 1, characterized in that the amount of inorganic salt is 0.5-2%, preferably 0.8-1.0% by weight of inorganic salt to the total volume of the injection.
5. The injection according to claim 1, wherein the pH adjuster is selected from one or more of sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, acetic acid, fumaric acid.
6. The injection according to claim 1, wherein the pH of the injection is 2.0-5.0.
7. A method of preparing the injection according to any one of claims 1 to 6, comprising the steps of:
1) Weighing inorganic salt and fumaric acid Fu Nuola with the prescribed amount, dissolving in water for injection, regulating the pH to 2.0-5.0 by using a pH regulator, and fixing the volume to the full volume;
2) Filtering, bottling, and sterilizing by oversterilization.
8. The method according to claim 7, wherein an inert gas is introduced during the preparation and filling process, and the inert gas is one or more selected from the group consisting of argon, nitrogen and carbon dioxide.
9. The method according to claim 7, wherein the sterilization condition is sterilization at 121 ℃ for 15min to 20min.
10. The method of claim 7, wherein the injection is filled in a brown ampoule or a brown penicillin bottle.
CN202210722019.1A 2022-06-17 2022-06-17 Vonopraz fumarate injection and preparation method thereof Pending CN117298040A (en)

Priority Applications (1)

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CN202210722019.1A CN117298040A (en) 2022-06-17 2022-06-17 Vonopraz fumarate injection and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210722019.1A CN117298040A (en) 2022-06-17 2022-06-17 Vonopraz fumarate injection and preparation method thereof

Publications (1)

Publication Number Publication Date
CN117298040A true CN117298040A (en) 2023-12-29

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