Preparation method of multivitamin injection

Abstract

The invention belongs to the technical field of medicines, and relates to a preparation method of a multivitamin injection. The preparation method comprises the following steps: preparing sodium glycocholate and sodium hydroxide into a sodium glycocholate solution; preparing a fat-soluble solution from vitamin A palmitate, vitamin D3, vitamin E, ethanol, soybean lecithin and a sodium glycocholate solution; preparing biotin, vitamin B12, dexpanthenol, riboflavin sodium phosphate, vitamin C, vitamin B1, vitamin B6, nicotinamide, a freeze-drying protective additive and folic acid into a water-soluble solution; mixing the fat-soluble solution and the water-soluble solution, and adjusting the pH value to prepare a fat-water mixed solution; and filtering the lipid-water mixed solution, and freeze-drying to obtain the lipid-water mixed solution. According to the multivitamin injection prepared by the invention, fat-soluble vitamins and water-soluble vitamins can be dissolved in the same container, the stability is good, and the injectable characteristic of the multivitamin injection in a final preparation can be maintained while the multivitamin injection is stored, so that different clinical requirements can be better met.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals and relates to a preparation method of a multivitamin injection. Background Art

[0002] Disclosing the information of this background art section is only intended to enhance the overall understanding of the present invention and does not necessarily constitute an admission or imply in any form that this information forms the prior art already known to those of ordinary skill in the art.

[0003] Vitamins are essential nutrients for maintaining normal material metabolism and certain special physiological functions of the human body, and play an important role in regulating metabolism, maintaining physiology, promoting growth and development, etc. Among them, vitamin A has the functions of promoting growth and maintaining the normal functions of epithelial tissues such as the conjunctiva and cornea. At the same time, it also participates in the synthesis of rhodopsin, which is beneficial for the treatment of vitamin deficiency, night blindness, xerophthalmia and other diseases; vitamin B participates in the process of the body's metabolism and usually provides important coenzymes for the body's metabolism, and is used for preventing and treating malnutrition, beriberi and other diseases caused by vitamin B deficiency. Vitamin C participates in the formation of collagen in the body, usually maintains immune function, promotes the absorption of non-heme iron, and is used for treating acute and chronic infectious diseases, purpura, chronic iron poisoning and other diseases. Vitamin D usually maintains the normal growth and development of bones. This component acts on the body, promotes the absorption of calcium and phosphorus by the intestine, and is used for treating vitamin D deficiency rickets, osteoporosis and other diseases. Vitamin E can play an antioxidant role, and at the same time can enhance ovarian function, and has antioxidant, skin-moisturizing and antipruritic effects.

[0004] Multivitamin for injection is a parenteral nutrition preparation. In China, multivitamin injection has been applied to the surgical field since the 1980s. As a total parenteral nutrition preparation, multivitamin injection can be an important component of non-gastrointestinal nutrition for patients who cannot eat, such as those undergoing various major surgeries, suffering from severe infections, various burns, cancers, etc. In injection vitamin preparations, the components of traditional products are relatively single, while malnourished patients generally need to supplement water-soluble and fat-soluble vitamins at the same time. However, due to the different physical and chemical properties of water-soluble vitamins and fat-soluble vitamins, when they are mixed to form a dosage form for injection, it is easy to have the problem of poor stability, thus increasing the safety risk for patients to use. Summary of the Invention

[0005] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a preparation method of a multivitamin injection. The multivitamin injection prepared by the present invention can dissolve fat-soluble vitamins and water-soluble vitamins in the same container, has good stability, and can maintain its injectable characteristics in the final preparation during storage, so as to better meet different clinical needs.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] In a first aspect, a preparation method of a multivitamin injection comprises the following steps:

[0008] Dissolve sodium glycocholate and a portion of sodium hydroxide in water to prepare a sodium glycocholate solution;

[0009] Mix vitamin A palmitate, vitamin D 3 , vitamin E and ethanol by heating until evenly mixed, then add soybean phospholipid, mix until the solution becomes clear, and then mix with the sodium glycocholate solution until clear and transparent to obtain a fat-soluble solution;

[0010] Dissolve biotin, vitamin B 12 , D-panthenol, riboflavin sodium phosphate, vitamin C, vitamin B 1 , vitamin B 6 , nicotinamide and a freeze-drying protectant in water, heat and mix evenly, then add the other portion of sodium hydroxide and folic acid, and mix until completely dissolved to obtain a water-soluble solution;

[0011] Mix the fat-soluble solution and the water-soluble solution evenly, add the remaining sodium hydroxide, and adjust the pH to 5.6 - 6.2 to obtain a fat-water mixed solution;

[0012] Filter and freeze-dry the fat-water mixed solution.

[0013] During the preparation process of the multivitamin injection prepared by the present invention, first, the addition sequence of each raw material is adjusted to make the prepared liquid medicine clear to meet the requirements of the injection (if the liquid medicine cannot be satisfied during the preparation process, it is even more impossible to ensure the clarity of the final injection, thus unable to meet the requirements of the injection). Second, sodium glycocholate is made into a sodium glycocholate solution and added during the preparation process of the fat-soluble solution, which can act as a surfactant to change the surface energy of the oily material, enable the fat-soluble solution to form micelles in water, ensure the clarity and transparency of the fat-soluble solution, and at the same time ensure that it remains clear during the subsequent mixing process with the water-soluble solution to meet the requirements of the injection. Experiments have shown that after reconstitution, the multivitamin injection prepared by the present invention can ensure the clarity of the solution and meet the injection requirements.

[0014] In addition, the present invention has found that after the fat-soluble solution and the water-soluble solution are mixed, the pH value affects the content and stability of vitamins in the prepared injection. When the pH value is 5.6 - 6.2, it can not only ensure that the content of each vitamin is consistent with the added amount and ensure the content stability of each component of the multivitamin injection, but also greatly reduce the content of other single impurities and improve the chemical stability of the multivitamin injection.

[0015] In some embodiments, the raw materials for preparing a multivitamin injection per vial include the following:

[0016] Vitamin A palmitate 2,800 - 4,200 IU, vitamin D 3 0.0044 - 0.0066 mg, vitamin E 8.16 - 12.24 mg, vitamin C 100 - 150 mg, vitamin B 1 4.64 - 6.96 mg, riboflavin sodium phosphate 4.54 - 6.80 mg, vitamin B 6 4.40 - 6.60 mg, vitamin B 12 0.0048 - 0.0072 mg, folic acid

[0017] 0.33 - 0.50 mg, dexpanthenol 12.92 - 19.38 mg, biotin 0.055 - 0.083 mg, nicotinamide 36.80 - 55.20 mg, lyoprotectant 200 - 300 mg, glycocholic acid 112 - 168 mg, soybean phospholipid 90 - 135 mg, sodium hydroxide 32 - 48 mg.

[0018] Specifically, it further includes: ethanol 0.04 - 0.06 ml.

[0019] Specifically, it further includes: water; the added amount of water is: add water until the total volume of the liquid before freeze - drying in each vial is 5.0 ml ± 0.15 ml. More specifically, the water is water for injection. To avoid introducing impurities.

[0020] In some embodiments, the lyoprotectant is glycine or mannitol, preferably glycine.

[0021] In some embodiments, during the preparation process, the dissolved oxygen in the liquid is controlled not to be higher than 0.5 mg / L. The residual oxygen in the headspace is controlled not to be higher than 2.0%.

[0022] Specifically, the dissolved oxygen in the liquid is adjusted by filling nitrogen into the liquid.

[0023] In some embodiments, the temperature for preparing the glycocholic acid sodium solution is 30 - 50 °C.

[0024] In some embodiments, during the preparation of the fat - soluble solution, the temperature for heating and mixing evenly is 30 - 50 °C.

[0025] In some embodiments, during the preparation of the water - soluble solution, the temperature for heating and mixing evenly is 30 - 50 °C.

[0026] In some embodiments, the reagent for mixing the fat - soluble solution and the water - soluble solution to adjust the pH is hydrochloric acid.

[0027] In some embodiments, filtration is carried out using a 0.22 μm PVDF filter element. Specifically, the lipid-water mixed solution is filtered through two 0.22 μm PVDF filter elements.

[0028] In some embodiments, after filtration, it is canned and then freeze-dried. Specifically, filling is carried out using vials. More specifically, the vials are borosilicate vials.

[0029] On the other hand, a multivitamin injection is obtained by the above preparation method.

[0030] In a third aspect, an injection kit includes the above multivitamin injection and a reconstitution solvent.

[0031] The multivitamin injection prepared by the present invention is a freeze-dried preparation. When it is used, the freeze-dried preparation needs to be added to the reconstitution solvent for dissolution, and then injection is carried out using an injector. Therefore, the reconstitution solvent described in the present invention is a solvent that can completely dissolve the multivitamin injection. The solvent is generally water for injection.

[0032] In some embodiments, a syringe is further included.

[0033] The beneficial effects of the present invention are as follows:

[0034] 1. In the multivitamin injection prepared by the present invention, fat-soluble and water-soluble vitamins can be placed in the same container, and the prepared product has good stability, meeting the convenience of clinical use.

[0035] 2. The multivitamin injection prepared by the present invention uses fewer excipients, improving the clinical use safety of the preparation. Specific Embodiments

[0036] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific examples and comparative examples.

[0037] Example 1

[0038] Prescription:

[0039]

[0040]

[0041] Process:

[0042] ① Weighing: Weigh the prescription amount of the raw material drug separately under light-shielded conditions and put it into a light-shielded bag;

[0043] ② Solution preparation (nitrogen filling throughout the process):

[0044] Sodium glycocholate solution: Heat the water for injection to 35°C, add 30% of the prescribed amount of sodium hydroxide while stirring, stir to dissolve, then add the prescribed amount of glycocholic acid and stir to dissolve.

[0045] Fat-soluble solution: Add the prescribed amount of vitamin A palmitate and vitamin D into the preparation tank. 3 , vitamin E, anhydrous ethanol, fill the liquid with nitrogen to a dissolved oxygen content of ≤0.5 mg / L while stirring, heat to 35°C, slowly add the prescribed amount of soybean lecithin, stir to dissolve completely, pour the drug solution into the sodium glycocholate solution, stir to make it clear.

[0046] Water-soluble solution: Add 60% of the injection water in the batch into the preparation tank, heat to 35°C, fill the liquid with nitrogen until the dissolved oxygen content is ≤0.5mg / L, and add the prescribed amount of biotin and vitamin B in sequence. 12 , Dexpanthenol, Riboflavin Sodium Phosphate, Vitamin C, Vitamin B 1 , Vitamin B 6 , niacinamide, and glycine, stir until completely dissolved, add about 40% of the prescribed amount of sodium hydroxide solution, add the prescribed amount of folic acid, and stir until completely dissolved.

[0047] Mixing: Add the fat-soluble solution to the water-soluble solution, stir until mixed, add the remaining amount of sodium hydroxide solution, add hydrochloric acid to adjust the pH to 5.6, and add water for injection to the full amount.

[0048] ③Filtration: Filter the drug solution through two 0.22μm PVDF filter elements for sterilization.

[0049] ④Filling: Fill 5.0ml±0.15ml in brown borosilicate vials, half-stoppered, and freeze-dried.

[0050] ⑤ Freeze-drying.

[0051] ⑥ Cover and package.

[0052] Embodiment 2 prescription:

[0053]

[0054] Process:

[0055] ① Weighing: weigh the prescribed amount of raw materials respectively under light-shielding conditions and put them into light-shielding bags;

[0056] ② Liquid preparation (nitrogen filling throughout the process):

[0057] Sodium glycocholate solution: Heat the water for injection to 40°C, add 30% of the prescribed amount of sodium hydroxide while stirring, stir to dissolve, then add the prescribed amount of glycocholic acid and stir to dissolve.

[0058] Fat-soluble solution: Add the prescribed amount of vitamin A palmitate and vitamin D into the preparation tank. 3 , vitamin E, and anhydrous ethanol. Fill the liquid with nitrogen under stirring until the dissolved oxygen content is ≤0.5 mg / L. Heat to 40°C. Slowly add the prescribed amount of soybean lecithin and stir to dissolve completely. Pour the drug solution into the sodium glycocholate solution to prepare phospholipid / choline micelles and stir until clear.

[0059] Water-soluble solution: Add 60% of the injection water in the batch into the preparation tank, heat to 40°C, fill the liquid with nitrogen until the dissolved oxygen content is ≤0.5mg / L, and add the prescribed amount of biotin and vitamin B in sequence. 12 , Dexpanthenol, Riboflavin Sodium Phosphate, Vitamin C, Vitamin B 1 , Vitamin B 6 , niacinamide, and glycine, stir until completely dissolved, then add 40% of the prescribed amount of sodium hydroxide solution, add the prescribed amount of folic acid (because folic acid dissolves in an alkaline environment), and stir until completely dissolved.

[0060] Mixing: Add the fat-soluble solution to the water-soluble solution, stir until mixed, add the remaining amount of sodium hydroxide solution, add hydrochloric acid to adjust the pH to 5.9, and add water for injection to the full amount.

[0061] ③Filtration: Filter the drug solution through two 0.22μm PVDF filter elements for sterilization.

[0062] ④Filling: Fill 5.0ml±0.15ml in brown borosilicate vials, half-stoppered, and freeze-dried.

[0063] ⑤ Freeze-drying.

[0064] ⑥ Cover and package.

[0065] Example 3

[0066] prescription:

[0067]

[0068]

[0069] Process:

[0070] ① Weighing: weigh the prescribed amount of raw materials under light-shielding conditions and put them into light-shielding bags;

[0071] ② Liquid preparation (nitrogen filling throughout the process):

[0072] Sodium glycocholate solution: Heat the water for injection to 45°C, add 30% of the prescribed amount of sodium hydroxide while stirring, stir to dissolve, then add the prescribed amount of glycocholic acid and stir to dissolve.

[0073] Fat-soluble solution: Add the prescribed amount of vitamin A palmitate and vitamin D into the preparation tank. 3 , vitamin E, anhydrous ethanol, fill the liquid with nitrogen to a dissolved oxygen content of ≤0.5 mg / L while stirring, heat to 45°C, slowly add the prescribed amount of soybean lecithin, stir to dissolve completely, pour the drug solution into the sodium glycocholate solution, stir to make it clear.

[0074] Water-soluble solution: Add 60% of the injection water in batches into the preparation tank, heat to 45°C, fill the liquid with nitrogen until the dissolved oxygen content is ≤0.5mg / L, and add the prescribed amount of biotin and vitamin B in sequence. 12 , Dexpanthenol, Riboflavin Sodium Phosphate, Vitamin C, Vitamin B 1 , Vitamin B 6 , niacinamide, and glycine, stir until completely dissolved, add about 40% of the prescribed amount of sodium hydroxide solution, add the prescribed amount of folic acid, and stir until completely dissolved.

[0075] Mixing: Add the fat-soluble solution to the water-soluble solution, stir until mixed, add the remaining amount of sodium hydroxide solution, add hydrochloric acid to adjust the pH to 6.2, and add water for injection to the full amount.

[0076] ③Filtration: Filter the drug solution through two 0.22μm PVDF filter elements for sterilization.

[0077] ④Filling: Fill 5.0ml±0.15ml in brown borosilicate vials, half-stoppered, and freeze-dried.

[0078] ⑤ Freeze-drying.

[0079] ⑥ Cover and package.

[0080] Comparative Example 1

[0081] Prescription: Compared with Example 2, the composition remains unchanged.

[0082] Process: Adjust the sample pH to 5.0, and keep the rest unchanged.

[0083] Comparative Example 2

[0084] Prescription: Compared with Example 2, the composition remains unchanged.

[0085] Process: Adjust the sample pH to 7.0 and keep the rest unchanged.

[0086] Comparative Example 3

[0087] Prescription: Compared with Example 2, the composition remains unchanged.

[0088] Process: Adjust the preparation order of fat-soluble solution, and keep the rest unchanged.

[0089] Lipid-soluble solution: Add the prescribed amounts of soybean phospholipid, glycocholic acid, vitamin A palmitate, and vitamin D into the solution preparation tank. 3 , vitamin E, and absolute ethanol. While stirring, purge with nitrogen until the dissolved oxygen content is ≤ 0.5 mg / L, heat to 45°C, and stir (Conclusion: After stirring for 3 hours, it could not become clear, did not meet the requirements of an injection, and the stirring time was too long, which was not conducive to commercial production. Therefore, no further investigation was carried out).

[0090] Comparative Example 4

[0091] Prescription: Compared with Example 2, the active ingredients in the prescription remain unchanged, and the metal ion chelating agent disodium edetate is added.

[0092] Process: The same as in Example 2.

[0093] Comparative Example 5

[0094] Prescription: Compared with Example 2, the active ingredients in the prescription remain unchanged, and the freeze-drying protectant glycine is adjusted to mannitol.

[0095] Process: The same as in Example 2.

[0096] Results: The samples prepared in the above examples and comparative examples were respectively detected (or detected after reconstitution with injection water). The summary table of the detections is as follows.

[0097]

[0098]

[0099] Conclusion: 1. When the pH is lower than 5.0, the content of dexpanthenol and folic acid in the sample is relatively low; when the pH is higher than 7.0, the content of vitamin C, vitamin A palmitate, biotin, etc. in the sample is relatively low, and the single impurity content is relatively high; it shows that the pH range of the product should be 5.6 - 6.2. 2. After adding the metal ion chelating agent to the prescription, the product quality has no obvious difference compared with before adding. Since this product is an injection, the types of excipients in the prescription should be as few as possible. Therefore, there is no need to add a metal ion chelating agent.

[0100] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing a multivitamin injection, characterized in that: The steps include: Sodium glycocholate and a portion of sodium hydroxide are added into water and dissolved to prepare a sodium glycocholate solution; Vitamin A palmitate, vitamin D3, vitamin E and ethanol are heated and mixed evenly, and then soybean lecithin is added and mixed until the solution is clear, and then mixed with the sodium glycocholate solution until it is clear and transparent to obtain a fat-soluble solution; Biotin, vitamin B 12 , dexpanthenol, riboflavin sodium phosphate, vitamin C, vitamin B1, vitamin B6, niacinamide, and lyophilization protective agent are added to water, heated and mixed evenly, and then another portion of sodium hydroxide and folic acid are added, mixed until completely dissolved, to obtain a water-soluble solution; The fat-soluble solution and the water-soluble solution are mixed evenly, remaining sodium hydroxide is added, and the pH is adjusted to 5.6-6.2 to obtain a fat-water mixed solution; The lipid-water mixed solution is filtered and freeze-dried.

2. The method for preparing the multivitamin injection according to claim 1, characterized in that: The preparation of multivitamin injection includes the following raw materials per vial: Vitamin A palmitate 2800-4200 IU, vitamin D3 0.0044-0.0066 mg, vitamin E 8.16-12.24 mg, vitamin C 100-150 mg, vitamin B1 4.64-6.96 mg, riboflavin sodium phosphate 4.54-6.80 mg, vitamin B6 4.40-6.60 mg, vitamin B 12 0.0048-0.0072mg, folic acid 0.33-0.50mg, dexpanthenol 12.92-19.38mg, biotin 0.055-0.083mg, niacinamide 36.80-55.20mg, lyophilized protective agent 200-300mg, glycocholic acid 112-168mg, soybean lecithin 90-135mg, sodium hydroxide 32-48mg; Preferably, it also includes: 0.04-0.06 ml of ethanol; Preferably, it also includes: water; the amount of water added is: water is added until the total volume of each vial of pre-lyophilized drug solution is 5.0ml±0.15ml.

3. The method for preparing the multivitamin injection according to claim 1, characterized in that: The lyoprotectant is glycine or mannitol, preferably glycine.

4. The method for preparing the multivitamin injection as claimed in claim 1, characterized in that During the preparation process, the dissolved oxygen content in the liquid is controlled to be no higher than 0.5 mg / L; Preferably, the amount of dissolved oxygen in the liquid is adjusted by injecting nitrogen into the liquid.

5. The method for preparing the multivitamin injection according to claim 1, characterized in that: The temperature for preparing the sodium glycocholate solution is 30-50°C; Alternatively, during the preparation of the fat-soluble solution, the temperature for heating and mixing is 30 to 50°C; Alternatively, during the preparation of the water-soluble solution, the temperature for uniform heating and mixing is 30 to 50°C.

6. The method for preparing the multivitamin injection according to claim 1, characterized in that: The reagent for adjusting the pH of the mixture of the fat-soluble solution and the water-soluble solution is hydrochloric acid or sodium hydroxide solution.

7. The method for preparing the multivitamin injection according to claim 1, characterized in that: After filtering, it is canned and then freeze-dried.

8. A multivitamin injection, characterized in that: Obtained by the preparation method according to any one of claims 1 to 7.

9. An injection kit, characterized in that: The multivitamin injection comprises the multivitamin injection as claimed in claim 8, and a reconstitution solvent.

10. The injection kit according to claim 9, characterized in that: A syringe is also included.

Images