CN112294756A - Cisatracurium besilate injection and preparation method thereof - Google Patents
Cisatracurium besilate injection and preparation method thereof Download PDFInfo
- Publication number
- CN112294756A CN112294756A CN202011009522.XA CN202011009522A CN112294756A CN 112294756 A CN112294756 A CN 112294756A CN 202011009522 A CN202011009522 A CN 202011009522A CN 112294756 A CN112294756 A CN 112294756A
- Authority
- CN
- China
- Prior art keywords
- injection
- cisatracurium besilate
- besilate
- cisatracurium
- ethanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Images
Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Anesthesiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses cisatracurium besilate injection and a preparation method thereof. The cisatracurium besilate injection can be prepared, stored and clinically compatible and applied at normal temperature, has high safety and strong administration compliance, and provides a new choice for clinical application. The injection consists of cisatracurium besilate, citric acid and ethanol, and has the advantages of safety, stability, mild preparation process and storage condition, and good clinical compliance.
Description
Technical Field
The invention relates to a skeletal muscle relaxant, in particular to a cisatracurium besilate injection preparation capable of being prepared and stored at normal temperature and a preparation method thereof.
Background
Cisatracurium besilate is a neuromuscular blocking agent with medium/long-term effect, and can be clinically used as an auxiliary means for general anesthesia or Intensive Care Unit (ICU) sedation to relax skeletal muscles, promote tracheal intubation and assist artificial respiration of ICU patients.
The atracurium besilate is an all-cis isomer in 10 isomers of atracurium besilate, has great advantages compared with atracurium besilate, has the drug effect about 3 times that of atracurium besilate, has no obvious histamine release, small muscle relaxation effect, no accumulation effect, small cardiovascular reaction and small dependence on functions of liver, kidney and other organs, and is an ideal medium-aging non-depolarizing muscle relaxant. In recent years, people pay more and more attention to the safety of medication, and the development of chiral drugs is more and more rapid. The drug after chiral resolution can reduce the dosage and adverse reaction, and simultaneously reduce the burden of drug metabolism. Therefore, the clinical application of cisatracurium besilate has incomparable advantages.
The cisatracurium sulfonate is slightly soluble in water, easily soluble in ethanol and hygroscopic. Cisatracurium besilate is a quaternary ammonium salt, and can be subjected to Hofmann degradation under the conditions of physiological pH and body temperature. Is unstable under acid, alkali and high temperature conditions. From the structure of cis-atracurium besilate, ester bonds and quaternary ammonium structures existing in the structure are unstable structures, and the degradation process can be divided into an ester bond breaking process and a quaternary ammonium Hofmann eliminating process: (1) the ester bond cleavage route: the ester bond in the structure of the product is unstable to acid and alkali, and is easy to hydrolyze and chain-open to generate corresponding impurities such as acid, alcohol and the like; (2) hofmann elimination pathway: quaternary ammonium in the structure of the product is unstable to high temperature, and Hofmann elimination reaction can occur in the high temperature and placement process, so that corresponding degradation products are generated. Literature reports also show that the product is unstable to high temperature and has a tendency to increase degradation products during long-term storage.
Cisatracurium besilate injection was first marketed in the United kingdom by Aspen, 8.7.8.1995, under the trade name
The formula comprises 32% w/v benzenesulfonic acid to adjust the pH of the solution to 3.25-3.65, and the headspace residual oxygen of the product is about 20% by analyzing the characteristics of the original product, and the preparation process of the product is presumed not to specially control the dissolved oxygen and the residual oxygen. Cisatracurium is degraded mainly by Hofmnnn elimination (chemical process) at physiological pH and body temperature into labdanine and a mono-quaternary ammonium acrylate metabolite, which forms a mono-quaternary ammonium ethanol metabolite by non-specific enzymatic hydrolysis. Cisatracurium clearance is strongly organ independent, and liver and kidney are the main clearance pathways of metabolites.
Raw grinding product
The specification indicates that the potency of cisatracurium besilate decreases by 5% per year when stored at 5 ℃; when stored at 25 ℃, the titer is reduced by 5% per month; once left from the refrigerator (2-8 ℃) and kept at 25 ℃, the sample liquid must be used up in 21d even if it is returned to the refrigerator. It can be seen that cisatracurium besilate has poor stability in an aqueous solution state.
The prior art of cisatracurium besilate injection adopts a mode of sterile filtration or adding a certain concentration of bacteriostatic agent to ensure the sterility level of a product to a certain extent, and adopts storage at 2-8 ℃ to improve the stability of the product in the storage period; the stability of the product is improved to a certain extent by controlling the dissolved oxygen in the liquid preparation process, the residual oxygen in the filling and sealing process and the low-temperature liquid preparation and storage modes.
The cisatracurium besilate has stable oxidation conditions, and researches show that the control of dissolved oxygen and residual oxygen in the liquid preparation process has no practical and obvious effect on controlling the impurity level. The invention abandons the conventional thinking, and a large number of experiments show that the citric acid and the ethanol are synergistic, so that the sensitivity of API in a certain temperature range can be remarkably reduced, the Hofmann elimination reaction is slowed down, and the stability of the product under a certain temperature condition is improved.
Patent CN 107049936A discloses an enlarged production method of cisatracurium besilate injection containing preservative, the technical scheme is that nitrogen is filled in the solution preparation process to dissolve oxygen and reduce the oxygen content to be lower than 1ppm, the pH value of water for injection is adjusted to be 3.9-4.1, finally cisatracurium besilate and benzyl alcohol are added, and the residual oxygen is controlled to be less than 0.1% in the encapsulation process to reduce the impurity content in the injection.
Patent CN 109125259A discloses cisatracurium besilate injection without preservative, which adopts the main technical scheme that the residual oxygen concentration is controlled to be less than or equal to 5.0 percent by low-temperature liquid preparation at 2-8 ℃, heat preservation, vacuum and nitrogen-filled pressure plug, so as to realize that the impurities of the product do not exceed the standard in the period of validity.
The inventor finds that the stability of the product can be ensured to a certain extent in the prior art, but the production, transportation and clinical application conditions are harsh, the safety cannot be ensured, and great risk exists in clinical use.
The invention provides cisatracurium besilate injection containing citric acid and ethanol, the technical scheme is used for preparing, storing and clinically applying at normal temperature, the compliance is better, and the cisatracurium besilate injection with good compliance and high safety is provided for clinic.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention abandons the conventional thinking, and discovers that the stability of the cisatracurium besilate in a solution system containing citric acid and ethanol is greatly improved through a large number of experimental researches, thereby providing a safe, stable and good clinical compliance cisatracurium besilate injection for clinic.
Citric acid is generally used as pH regulator, masking agent, antioxidant synergist of solution, and can also be used as perfume enhancer. Ethanol is used primarily as a solvent and also often as a dissolved bacteriostat/disinfectant. The citric acid and the ethanol have synergistic effect, so that the sensitivity of the cisatracurium besilate to temperature and the tolerance of pH are obviously reduced, the Hofmann elimination reaction is obviously antagonized, and the stable pH range of the product is improved.
The prior art adopts benzene sulfonic acid as a pH regulator, and the inventor researches the stability of the product of the benzene sulfonic acid, lactic acid, citric acid and ethanol in 4 systems of the benzene sulfonic acid, lactic acid, citric acid and ethanol, wherein the product is preserved for 30 days at 25 ℃. The result shows that the citric acid as the pH regulator improves the stability of the product at 25 ℃ to a certain extent, but the synergistic system stability of the citric acid and the ethanol is optimal, the sensitivity of the cisatracurium besilate to the temperature is remarkably slowed down, and the risk of clinical medication of the product is reduced.
TABLE 1 Effect of using different pH adjusting Agents on product stability
The inventor also investigated the stability of cisatracurium besilate injection prepared by citric acid and ethanol in different weight proportions when the product is stored at 25 ℃ for 30 days.
TABLE 2 Effect of different amounts of citric acid and ethanol on product stability
The result shows that the cisatracurium besilate injection is characterized in that the dosage of citric acid is 0.05-0.20mg/ml, and the dosage of ethanol is 0.05-0.10 mg/ml.
The cisatracurium besilate injection is characterized in that the dosage of citric acid is 0.10-0.15mg/ml, and the dosage of ethanol is 0.08 mg/ml.
Specifically, sodium citrate and sodium hydroxide can be added into the cisatracurium besilate injection to adjust the pH of the product.
The specific inventor also inspects the influence of the cisatracurium besilate injection on related substances under different pH conditions, and the result is shown in Table 3 after the sample is placed at 25 ℃ for 6 months, and the result shows that the product has good stability within the pH range of 2.5-4.5, and particularly, each impurity of the product is stable under the pH condition of 3.0-4.0.
TABLE 3 Effect of different pH on product related substances
| Numbering | Test conditions | BSA-B％ | BSA-D％ | BSA-F％ | BSA-H％ | BSA-M％ | Total miscellaneous% |
| 1 | pH2.5 | 2.58 | 1.52 | 1.64 | 0.04 | 1.47 | 8.81 |
| 2 | pH3.0 | 1.22 | 0.97 | 0.75 | 0.04 | 0.98 | 4.57 |
| 3 | pH3.5 | 1.32 | 1.11 | 0.88 | 0.05 | 1.02 | 4.91 |
| 4 | pH4.0 | 1.29 | 1.05 | 0.78 | 0.04 | 1.07 | 5.01 |
| 5 | pH4.5 | 2.64 | 1.41 | 1.35 | 0.04 | 1.25 | 8.17 |
The preparation method of the cisatracurium besilate liquid preparation comprises the following steps: adding citric acid into injection water and ethanol with the amount of 80-90% of the prescription amount, stirring for dissolving, adding cisatracurium besilate with the prescription amount, stirring for dissolving, measuring the pH value, fixing the volume, performing sterile filtration, filling and sealing an ampoule, performing light inspection, and packaging.
The preparation method of the cisatracurium besilate liquid preparation has the temperature of liquid preparation below 35 ℃.
The invention adopts citric acid and ethanol as a stabilizer in a synergistic manner, provides a cisatracurium besilate injection with good compliance and high safety for clinic, and meets the requirements of clinic and market.
Drawings
FIG. 1 shows the structural formula of cisatracurium besylate (CAS: 96946-42-8).
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
The preparation process comprises the following steps:
(1) adding ethanol into 800ml of water for injection at 30 ℃, and stirring and mixing uniformly;
(2) adding citric acid, stirring for 5min to dissolve, adding cisatracurium besilate, stirring for 5min to dissolve; measuring the pH value to be 4.51;
(3) and (5) fixing the volume. The volume is fixed to 1000ml by water for injection;
(4) and (5) sterile filtration. The medicinal liquid is filtered by a 0.45 μm coarse filter and a 0.22 μm fine filter.
(5) And (6) filling and sealing the ampoule, checking the ampoule by using a lamp, and packaging.
Example 2
The preparation process comprises the following steps:
(1) adding ethanol into 800ml of water for injection at 30 ℃, and stirring and mixing uniformly;
(2) adding citric acid, stirring for 5min to dissolve, adding cisatracurium besilate, stirring for 5min to dissolve; measuring the pH value to be 3.32;
(3) and (5) fixing the volume. The volume is fixed to 1000ml by water for injection;
(4) and (5) sterile filtration. The medicinal liquid is filtered by a 0.45 μm coarse filter and a 0.22 μm fine filter.
(5) And (6) filling and sealing the ampoule, checking the ampoule by using a lamp, and packaging.
Example 3
The preparation process comprises the following steps:
(1) adding ethanol into 800ml of water for injection at 30 ℃, and stirring and mixing uniformly;
(2) adding citric acid, stirring for 5min to dissolve, adding cisatracurium besilate, stirring for 5min to dissolve; measuring the pH value to be 3.01;
(3) and (5) fixing the volume. The volume is fixed to 1000ml by water for injection;
(4) and (5) sterile filtration. The medicinal liquid is filtered by a 0.45 μm coarse filter and a 0.22 μm fine filter.
(5) And (6) filling and sealing the ampoule, checking the ampoule by using a lamp, and packaging.
Example 4
The preparation process comprises the following steps:
(1) adding ethanol into 800ml of water for injection at 30 ℃, and stirring and mixing uniformly;
(2) adding citric acid, stirring for 5min to dissolve, adding cisatracurium besilate, stirring for 5min to dissolve; measuring pH to 3.01, adding 0.1M sodium citrate solution to adjust pH to 3.5;
(3) and (5) fixing the volume. The volume is fixed to 1000ml by water for injection;
(4) and (5) sterile filtration. Filtering the liquid medicine by a 0.45 mu m coarse filter and a 0.22 mu m fine filter;
(5) and (6) filling and sealing the ampoule, checking the ampoule by using a lamp, and packaging.
Example 5
The preparation process comprises the following steps:
(1) adding ethanol into 800ml of water for injection at 30 ℃, and stirring and mixing uniformly;
(2) adding citric acid, stirring for 5min to dissolve, adding cisatracurium besilate, stirring for 5min to dissolve; measuring pH to 3.01, adding 0.1M sodium citrate solution to adjust pH to 3.50;
(3) and (5) fixing the volume. The volume is fixed to 1000ml by water for injection;
(4) and (5) sterile filtration. Filtering the liquid medicine by a 0.45 mu m coarse filter and a 0.22 mu m fine filter;
(5) and (6) filling and sealing the ampoule, checking the ampoule by using a lamp, and packaging.
Example 6
The preparation process comprises the following steps:
(1) adding ethanol into 800ml of water for injection at 30 ℃, and stirring and mixing uniformly;
(2) adding citric acid, stirring for 5min to dissolve, adding cisatracurium besilate, stirring for 5min to dissolve; measuring pH to 2.01, adding 0.1M sodium hydroxide solution to adjust pH to 3.02;
(3) and (5) fixing the volume. The volume is fixed to 1000ml by water for injection;
(4) and (5) sterile filtration. Filtering the liquid medicine by a 0.45 mu m coarse filter and a 0.22 mu m fine filter;
(5) and (6) filling and sealing the ampoule, checking the ampoule by using a lamp, and packaging.
Example 7
For the samples of examples 1 to 6 and
the long-term test stability examination is carried out, the sample is placed in long-term conditions (25 +/-2 ℃ and 60 +/-5% RH) for 6 months, the samples are respectively sampled in 0 month and 6 months, the appearance, the content, the pH value and related substances are compared, the results are shown in the following table, the results show that the samples of each example are stable under the long-term conditions,
the related substances are increased to a certain degree, and the content is reduced to a certain degree.
TABLE 4 stability results of cisatracurium besilate injection under accelerated conditions for 6 months
Claims (8)
1. The cisatracurium besilate injection is characterized by comprising cisatracurium besilate, citric acid and ethanol.
2. The cisatracurium besilate injection according to claim 1, characterized in that citric acid is present in an amount of 0.05-0.2mg/ml and ethanol is present in an amount of 0.05-0.1 mg/ml.
3. The cisatracurium besilate injection according to claim 2, characterized in that citric acid is present in an amount of 0.10-0.15mg/ml and ethanol is present in an amount of 0.08 mg/ml.
4. Cisatracurium besilate injection according to claim 1, characterized by a pH comprised between 2.5 and 4.5.
5. Cisatracurium besilate injection according to claim 1, characterized by a pH comprised between 3.0 and 4.0.
6. The cisatracurium besilate injection according to claim 1, characterized in that sodium citrate and sodium hydroxide pH adjusting agents may be added.
7. The method for preparing cisatracurium besilate liquid preparation according to claim 1, comprising the steps of: adding citric acid into injection water and ethanol with the amount of 80-90% of the prescription amount, stirring for dissolving, adding cisatracurium besilate with the prescription amount, stirring for dissolving, measuring the pH value, fixing the volume, performing sterile filtration, filling and sealing an ampoule, performing light inspection, and packaging.
8. The method for preparing cisatracurium besilate liquid preparation according to claim 1, characterized in that the temperature of the liquid preparation is below 35 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011009522.XA CN112294756A (en) | 2020-09-23 | 2020-09-23 | Cisatracurium besilate injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011009522.XA CN112294756A (en) | 2020-09-23 | 2020-09-23 | Cisatracurium besilate injection and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112294756A true CN112294756A (en) | 2021-02-02 |
Family
ID=74488114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011009522.XA Withdrawn CN112294756A (en) | 2020-09-23 | 2020-09-23 | Cisatracurium besilate injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112294756A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113318074A (en) * | 2021-06-24 | 2021-08-31 | 上药东英（江苏）药业有限公司 | Preparation method of cisatracurium besilate injection |
| CN116421553A (en) * | 2023-03-07 | 2023-07-14 | 长春工业大学 | Preparation method of cisatracurium besilate injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536552A (en) * | 2013-10-15 | 2014-01-29 | 海南卫康制药(潜山)有限公司 | Cisatracurium besilate composition freeze-dried powder for injection |
| CN104434822A (en) * | 2014-12-12 | 2015-03-25 | 海南先通药业有限公司 | Cisatracurium besilate composition for injection and preparation method and application thereof |
| CN109125259A (en) * | 2018-10-25 | 2019-01-04 | 上药东英（江苏）药业有限公司 | A kind of preparation method of the benzene sulphur without preservative along atracurium injection |
-
2020
- 2020-09-23 CN CN202011009522.XA patent/CN112294756A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536552A (en) * | 2013-10-15 | 2014-01-29 | 海南卫康制药(潜山)有限公司 | Cisatracurium besilate composition freeze-dried powder for injection |
| CN104434822A (en) * | 2014-12-12 | 2015-03-25 | 海南先通药业有限公司 | Cisatracurium besilate composition for injection and preparation method and application thereof |
| CN109125259A (en) * | 2018-10-25 | 2019-01-04 | 上药东英（江苏）药业有限公司 | A kind of preparation method of the benzene sulphur without preservative along atracurium injection |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113318074A (en) * | 2021-06-24 | 2021-08-31 | 上药东英（江苏）药业有限公司 | Preparation method of cisatracurium besilate injection |
| CN116421553A (en) * | 2023-03-07 | 2023-07-14 | 长春工业大学 | Preparation method of cisatracurium besilate injection |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH10511364A (en) | Stable budezonide solution, process for its preparation and use of said solution as enema and pharmaceutical foam | |
| AU2001291775B2 (en) | Testosterone ester formulation for human use | |
| CN112294756A (en) | Cisatracurium besilate injection and preparation method thereof | |
| US5164405A (en) | Nicardipine pharmaceutical composition for parenteral administration | |
| CN101167730B (en) | Compound betamethasone suspension injection | |
| CN107412152B (en) | Dexmedetomidine hydrochloride injection composition | |
| US11246851B2 (en) | Pharmaceutical compositions of furosemide and uses thereof | |
| EP2156832B1 (en) | Pharmaceutical composition | |
| CN110269837B (en) | Naloxone hydrochloride injection and preparation method thereof | |
| CN104840418A (en) | Fasudil hydrochloride injection composition and preparation method thereof | |
| Campbell et al. | Stability of amiodarone hydrochloride in admixtures with other injectable drugs | |
| CN110664747A (en) | Injection of abidol hydrochloride and preparation method thereof | |
| US20180177800A1 (en) | Composition for percutaneous absorption | |
| CN107569454B (en) | A kind of Olopatadine hydrochloride nasal spray and preparation method thereof | |
| CN102166185A (en) | Isotonic naloxone injection and preparation method thereof | |
| JPH08231403A (en) | Stable aqueous solution containing arginine vasopressin antagonist | |
| CN114668762B (en) | Pharmaceutical composition | |
| CN109925280B (en) | Lipoic acid injection and preparation method thereof | |
| CN109010268A (en) | A kind of ophthalmic composition and preparation method thereof improving chloramphenicol stability | |
| CN114767628B (en) | Stable ambroxol hydrochloride injection and preparation method thereof | |
| CN114306219B (en) | Stable R-ketamine pharmaceutical composition | |
| CN1973839B (en) | Nizatidine injection | |
| CN118105338A (en) | Nimodipine water-soluble injection and preparation method thereof | |
| CN105997899A (en) | Asarone drug composition for injection or inhalation | |
| TW202345781A (en) | R-ketamine liquid preparation and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20210202 |