Posterior pituitary injection and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a posterior pituitary injection and a preparation method thereof. The posterior pituitary injection comprises the following raw materials in concentration: 6 units / ml of posterior pituitary powder, 1-5 mg / ml of trichlorobutanol and pharmaceutically acceptable acid, wherein the dosage of the pharmaceutically acceptable acid ensures that the pH value of the posterior pituitary injection is adjusted to 3.0-4.0. The invention further provides a preparation method of the posterior pituitary injection. According to the invention, the dissolving capacity of the auxiliary material trichlorobutyl alcohol in water can be improved, so that trichlorobutyl alcohol cannot be separated out under the condition of normal temperature or refrigeration. According to the invention, the quality of a medicinal preparation and the safety of medication can be better ensured, and the method has a good application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a posterior pituitary injection and a preparation method thereof. Background Art

[0002] Posterior pituitary injection is a pharmaceutical preparation, the main ingredients of which are extracts from the posterior pituitary of animals (usually pigs or cattle), and mainly contain oxytocin and vasopressin (also known as antidiuretic hormone, Vasopressin). Posterior pituitary injection is a drug with multiple physiological effects, mainly used for the treatment of obstetrics and gynecology and endocrinology, especially diseases related to reproductive system function regulation and fluid balance.

[0003] Chlorobutanol is an important excipient in the posterior pituitary injection, and its function is to act as a preservative and antibacterial agent. Chlorobutanol is a colorless crystalline organic substance. It exists in two types of crystals: half-molecular crystalline water type and anhydrous type. The type containing half-molecular crystalline water has a melting point of 78°C, is slightly soluble in water (1:250), and is easily soluble in ethanol (1:1), glycerol (1:10), ether, chloroform and volatile oil. Chlorobutanol is a colorless crystalline organic substance. It exists in two types of crystals: half-molecular crystalline water type and anhydrous type. The type containing half-molecular crystalline water has a melting point of 78°C, is slightly soluble in water (1:250), and is easily soluble in ethanol (1:1), glycerol (1:10), ether, chloroform and volatile oil. It is easily soluble (1:1~10ml) in hot water (70-80°C).

[0004] Since the posterior pituitary injection uses water as a solvent, appropriate heating is required in the existing posterior pituitary injection process to promote the dissolution of chlorobutanol. However, it was found during the experiment that after the dissolution was completed, chlorobutanol would precipitate when the solution was cooled, which was not conducive to the control of the drug quality of the posterior pituitary injection. Therefore, it is necessary to optimize the formula and preparation process of the posterior pituitary injection, so as to obtain a posterior pituitary injection that does not precipitate chlorobutanol under normal temperature and refrigerated environment. Summary of the invention

[0005] In view of the problems of the prior art, the present invention provides a posterior pituitary injection and a preparation method thereof.

[0006] A posterior pituitary injection, comprising raw materials of the following concentrations: Posterior pituitary powder 6 units / ml, Chlorobutanol 1-5 mg / ml, A pharmaceutically acceptable acid, wherein the amount of the pharmaceutically acceptable acid is sufficient to adjust the pH of the posterior pituitary injection to 3.0-4.0; The posterior pituitary injection is prepared according to the following method: Step 1, dissolving chlorobutanol in an aqueous solution of a pharmaceutically acceptable acid, then adding it to water for injection, and heating to dissolve it to obtain a chlorobutanol solution; Step 2, adding the posterior pituitary powder to the chlorobutanol solution, heating to dissolve, and adding water for injection to make up the volume according to the formula to obtain a posterior pituitary powder solution; Step 3, adjusting the pH of the posterior pituitary powder solution to 3.0-4.0 using a pharmaceutically acceptable acid solution; Step 4: Filter and you’re done.

[0007] Preferably, the amount of the pharmaceutically acceptable acid is sufficient to adjust the pH of the posterior pituitary injection to 3.4-3.6.

[0008] Preferably, the pharmaceutically acceptable acid is selected from at least one of acetic acid or phosphoric acid.

[0009] Preferably, the pharmaceutically acceptable acid is selected from acetic acid, and the final concentration of acetic acid in the posterior pituitary injection is 0.225-0.275% by mass.

[0010] Preferably, the final concentration of acetic acid in the posterior pituitary injection is 0.25% by mass.

[0011] Preferably, it comprises the following raw materials in parts by weight: Posterior pituitary powder 6 units / ml, Chlorobutanol 5 mg / ml, A pharmaceutically acceptable acid, wherein the amount of the pharmaceutically acceptable acid is sufficient to adjust the pH of the posterior pituitary injection to 3.05-3.14.

[0012] Preferably, in step 1, the heating and dissolving conditions are 25-35° C. and stirring for at least 30 minutes; And / or, in step 2, the heating and dissolving conditions are stirring at 25-35° C. for at least 10 min; And / or, in step 3, adjusting the pH to 3.4-3.6; And / or, in step 3, 1.5-2.4 mol / L acetic acid solution is used to adjust the pH.

[0013] Preferably, in step 1, the heating and dissolving conditions are stirring at 30° C. for 30 min; And / or, in step 2, the heating and dissolving conditions are stirring at 30° C. for 10 min.

[0014] Preferably, in step 3, the pH is adjusted to 3.4-3.6; And / or, in step 3, 1.5-2.4 mol / L acetic acid solution is used to adjust the pH.

[0015] The present invention also provides a method for preparing the posterior pituitary injection, comprising the following steps: Step 1, dissolving chlorobutanol in an aqueous solution of a pharmaceutically acceptable acid, then adding it to water for injection, and heating to dissolve it to obtain a chlorobutanol solution; Step 2, adding the posterior pituitary powder to the chlorobutanol solution, heating to dissolve, and adding water for injection to make up the volume according to the formula to obtain a posterior pituitary powder solution; Step 3, adjusting the pH of the posterior pituitary powder solution to 3.0-4.0 using a pharmaceutically acceptable acid solution; Step 4: Filter and you’re done.

[0016] The present invention optimizes the formula of the posterior pituitary injection and the preparation method thereof. In the posterior pituitary injection of the present invention, no chlorobutanol will be precipitated whether under room temperature or under refrigerated conditions. This effectively ensures the quality of the pharmaceutical preparation and the safety of medication, and has a good application prospect.

[0017] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0018] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0019] In the following examples and experimental examples, reagents and raw materials not specifically described are all commercially available products.

[0020] Example 1 Posterior pituitary injection and preparation method thereof The posterior pituitary injection provided in this embodiment is composed of the following components in the following concentrations: Posterior pituitary powder is measured at a potency of 6 units / ml, Chlorobutanol 5mg / ml, The mass percentage of acetic acid is 0.225-0.275%.

[0021] Among them, the amount of acetic acid ensures that the pH of the posterior pituitary injection is 3.4-3.6. After testing and verification of multiple batches of samples, the mass percentage of acetic acid varies in the range of 0.225-0.275%.

[0022] The preparation method of the posterior pituitary injection in this embodiment is as follows: 1) Set the stirring parameters of the dilution tank: 30% (corresponding frequency is 15Hz); 2) Prepare 0.25% acetic acid aqueous solution and 2 mol / L acetic acid aqueous solution with water for injection respectively.

[0023] 3) Inject 90% (27kg) of the total volume of the preparation liquid into the dilution tank. The injection water below 30°C is closed. Nitrogen is introduced into the liquid until the dissolved oxygen value is ≤1mg / L.

[0024] 4) Open the lid of the dilution tank, dissolve the weighed chlorobutanol with 0.25% acetic acid aqueous solution, add it to the dilution tank, rinse the container containing chlorobutanol with 500ml of injection water below 30℃, add the rinse water into the tank, and start stirring. Stir for no less than 30 minutes until it is completely dissolved visually.

[0025] 5) Add the weighed posterior pituitary powder to the dilution tank, rinse the container containing the posterior pituitary powder with 500ml of injection water below 30℃, add the rinse water into the tank, and start stirring. Stir for no less than 10 minutes until it is completely dissolved visually.

[0026] 6) Add injection water below 30℃ to the full amount (±0.2kg), and stir for at least 10 minutes to mix the drug solution evenly. The pH value of the sampled drug solution should be between 3.0 and 4.0 (target 3.4 to 3.6). If it is not within the specified range, take the prepared 2 mol / L glacial acetic acid solution to adjust the pH value to 3.0 to 4.0 (target 3.4 to 3.6).

[0027] 7) After preparation, take samples of the liquid in the dilution tank for testing.

[0028] 8) After the preparation liquid sampling is completed, the liquid is filtered with nitrogen through a first-level 0.22µm hydrophilic sterilizing filter (PVDF) into a liquid storage tank. Then, it is filtered with nitrogen through a first-level 0.22µm hydrophilic sterilizing filter (PVDF) into a balance tank.

[0029] 9) Fill into 2 ml colorless transparent low-borosilicate glass ampoule, control the filling volume to 1.05~1.10 ml, and seal after filling.

[0030] 10) The filled products are inspected for leaks and packed before being put into storage.

[0031] Example 2 Posterior pituitary injection The posterior pituitary injection provided in this embodiment is substantially the same as that in embodiment 1, except that it is composed of the following components in the following concentrations: Posterior pituitary powder is measured at a potency of 6 units / ml, Chlorobutanol 1mg / ml, The mass percentage of acetic acid is 0.225-0.275%.

[0032] The technical solution of the present invention is further illustrated by experiments below.

[0033] Experimental Example 1 Comparison of the solubility of chlorobutanol under different conditions This experimental example compares the solubility of chlorobutanol under different conditions. The specific experimental groups and results are as follows: (1) Dissolve in room temperature water: Take 50 mg of chlorobutanol and add it to 10 ml of water. Shake to dissolve. Visually observe that more insoluble substances appear. (2) Dissolve in hot water: Take 50 mg of chlorobutanol, add it to 10 ml of water, put it in 30°C hot water, shake it to dissolve, and visually dissolve it completely. After the dissolution is complete, cool the chlorobutanol solution to room temperature. Visually precipitate chlorobutanol. If it does not dissolve after shaking, continue to put it in 30°C hot water, and the chlorobutanol can be redissolved. Place the chlorobutanol in a refrigerator (2-8°C) to precipitate more chlorobutanol. It can be seen that within a certain range, the higher the temperature, the better the solubility of chlorobutanol, but when the temperature is lowered, chlorobutanol will re-precipitate.

[0034] (3) Dissolve using acetic acid solution: 0.05% (0.05g dissolved in 100ml, pH is 3.42) acetic acid solution: Take 50mg of tert-chlorobutanol, add it to 10ml of 0.05% acetic acid solution, shake to dissolve, visually observe that there is a lot of insoluble phenomenon, heat the solution (30℃ hot water), the tert-chlorobutanol will dissolve, and tert-chlorobutanol will precipitate after being left at room temperature.

[0035] 0.10% (0.1g dissolved in 100ml, pH is 3.33) acetic acid solution: Take 50mg of tert-chlorobutanol, add it to 10ml of 0.1% acetic acid solution, shake to dissolve, visually observe that there is a lot of insoluble phenomenon, heat the solution (30℃ hot water), tert-chlorobutanol will dissolve, after leaving it at room temperature, tert-chlorobutanol will precipitate, the amount of precipitation is less than 0.05% (about 50%).

[0036] 0.15% (0.15g dissolved in 100ml, pH 3.24) acetic acid solution: Take 50mg of chlorobutanol, add it to 10ml of 0.15% acetic acid solution, shake to dissolve, visually there is a lot of insoluble phenomenon, heat the solution (30℃ hot water), chlorobutanol dissolves, after leaving it at room temperature, chlorobutanol precipitates, the amount of precipitation is less than 0.10% (about 20% or less) 0.20% (0.20g-100ml, pH 3.14) acetic acid solution: Take 50mg of chlorobutanol, add it to 10ml of 0.20% acetic acid solution, shake to dissolve, and visually there is a lot of insoluble phenomenon. Heat the solution (30℃ hot water) and the chlorobutanol will dissolve. After leaving it at room temperature, no chlorobutanol is precipitated. Refrigerate it in the refrigerator for 2 hours, and visually there is very little chlorobutanol precipitation.

[0037] 0.25% (0.25g-100ml, pH 3.05) acetic acid solution: Take 50mg of chlorobutanol, add it to 10ml of 0.25% acetic acid solution, shake it to dissolve, and visually see more insoluble phenomena. Heat the solution (30℃ hot water), and the chlorobutanol will dissolve. After leaving it at room temperature, no chlorobutanol precipitation is seen. Put it in the refrigerator for 2 hours, and no chlorobutanol precipitation is seen visually. Put it in the refrigerator again and leave it overnight. No chlorobutanol precipitation is detected when it is taken out. It can be seen that 0.25% acetic acid has good solubility for chlorobutanol (5mg / ml), and chlorobutanol will not precipitate after the temperature is lowered.

[0038] The above experimental results show that chlorobutanol has poor solubility in water, and in acetic acid solution, pH affects the solubility of chlorobutanol. In the final pH range of 3.0-4.0 controlled by the posterior pituitary injection, chlorobutanol may precipitate.

[0039] Experimental Example 2 Comparison of the solubility of chlorobutanol under different raw material mixing sequences This experimental example is based on Example 1, and compares the dissolution ability of chlorobutanol under different raw material mixing sequences. The operation of the experimental steps and the use of reagents not specifically described in the comparative experimental group are the same as those in Example 1. The specific experimental groups and results are as follows: Repeated experiments have shown that the preparation of the comparative experimental group may not dissolve chlorobutanol easily during the preparation process, or the prepared preparation may precipitate crystals at room temperature. However, at the same pH, the preparation of Example 1 will not precipitate during the preparation process, and after the preparation is prepared, it can be ensured that no crystals will precipitate under room temperature or refrigerated conditions.

[0040] It can be seen from the above experimental data that the posterior pituitary injection provided by the present invention and its preparation method can improve the solubility of the auxiliary material chlorobutanol in water, so that chlorobutanol will not precipitate under normal temperature or refrigerated conditions. The present invention can better ensure the quality of the pharmaceutical preparation and the safety of medication, and has a good application prospect.

Claims

1. A posterior pituitary injection, characterized in that: It includes the following raw materials in the following concentrations: Posterior pituitary powder 6 units / ml, Chlorobutanol 1-5 mg / ml, A pharmaceutically acceptable acid, wherein the amount of the pharmaceutically acceptable acid is sufficient to adjust the pH of the posterior pituitary injection to 3.0-4.0; The posterior pituitary injection is prepared according to the following method: Step 1, dissolving chlorobutanol in an aqueous solution of a pharmaceutically acceptable acid, then adding it to water for injection, and heating to dissolve it to obtain a chlorobutanol solution; Step 2, adding the posterior pituitary powder to the chlorobutanol solution, heating to dissolve, and adding water for injection to make up the volume according to the formula to obtain a posterior pituitary powder solution; Step 3, adjusting the pH of the posterior pituitary powder solution to 3.0-4.0 using a pharmaceutically acceptable acid solution; Step 4: Filter and you’re done.

2. The posterior pituitary injection according to claim 1, characterized in that: The amount of the pharmaceutically acceptable acid ensures that the pH of the posterior pituitary injection is adjusted to 3.4-3.

6.

3. The posterior pituitary injection according to claim 1, characterized in that: The pharmaceutically acceptable acid is selected from at least one of acetic acid or phosphoric acid.

4. The posterior pituitary injection according to claim 3, characterized in that: The pharmaceutically acceptable acid is selected from acetic acid, and the final concentration of acetic acid in the posterior pituitary injection is 0.225-0.275% by mass.

5. The posterior pituitary injection according to claim 4, characterized in that: The final concentration of acetic acid in the posterior pituitary injection is 0.25% by mass.

6. The posterior pituitary injection according to claim 1, characterized in that: It includes the following raw materials in parts by weight: Posterior pituitary powder 6 units / ml, Chlorobutanol 5 mg / ml, A pharmaceutically acceptable acid, wherein the amount of the pharmaceutically acceptable acid is sufficient to adjust the pH of the posterior pituitary injection to 3.05-3.

14.

7. The posterior pituitary injection according to claim 1, characterized in that: In step 1, the heating and dissolving conditions are 25-35°C and stirring for at least 30 minutes; And / or, in step 2, the heating and dissolving conditions are stirring at 25-35° C. for at least 10 min; And / or, in step 3, adjusting the pH to 3.4-3.6; And / or, in step 3, 1.5-2.4 mol / L acetic acid solution is used to adjust the pH.

8. The posterior pituitary injection according to claim 7, characterized in that: In step 1, the heating and dissolving conditions are stirring at 30°C for 30 minutes; And / or, in step 2, the heating and dissolving conditions are stirring at 30° C. for 10 min.

9. The posterior pituitary injection according to claim 1, characterized in that: In step 3, the pH is adjusted to 3.4-3.6; And / or, in step 3, 1.5-2.4 mol / L acetic acid solution is used to adjust the pH.

10. The method for preparing the posterior pituitary injection according to any one of claims 1 to 9, characterized in that: The steps include: Step 1, dissolving chlorobutanol in an aqueous solution of a pharmaceutically acceptable acid, then adding it to water for injection, and heating to dissolve it to obtain a chlorobutanol solution; Step 2, adding the posterior pituitary powder to the chlorobutanol solution, heating to dissolve, and adding water for injection to make up the volume according to the formula to obtain a posterior pituitary powder solution; Step 3, adjusting the pH of the posterior pituitary powder solution to 3.0-4.0 using a pharmaceutically acceptable acid solution; Step 4: Filter and you’re done.

Images