Polyoxyethylene 35 castor oil and HS15 solubilized multivitamin injection and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and discloses a polyoxyethylene 35 castor oil and HS 15 solubilized multi-flower vitamin injection and a preparation method thereof, the polyoxyethylene 35 castor oil and HS 15 solubilized multi-flower vitamin injection comprises a plurality of vitamins, a solubilizer, a buffer agent and a pH value regulator, the plurality of vitamins comprise water-soluble vitamins and fat-soluble vitamins; the solubilizer is polyoxyethylene 35 castor oil and HS 15, the concentration range of the polyoxyethylene 35 castor oil is 0.025%-5% (g / ml), and the concentration range of the HS 15 is 0.025%-5% (g / ml). The problems that an existing solubilizer is insufficient in hemolytic property and stability, complex in production process and the like can be effectively solved, and meanwhile single-bottle packaging can be achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a multivitamin injection solubilized by polyoxyethylene 35 castor oil and HS15 and a preparation method thereof, which are used to improve the solubility of fat-soluble vitamins and the stability of the preparation, and at the same time simplify the production process and the clinical use process. Background Art

[0002] The statements herein only provide background art related to the present invention and do not necessarily constitute prior art.

[0003] Multivitamin injection is a commonly used nutritional supplement in clinical practice for the treatment and prevention of vitamin deficiency disorders. However, the existing multivitamin injections have the following problems:

[0004] First, due to the complex chemical properties of vitamins, some vitamins (such as fat-soluble vitamins A, D, E, and K) have extremely low solubility in water and are difficult to directly prepare into stable injections. Traditional solubilizers (such as polysorbate 80) have limited solubilizing ability. After reaching a certain concentration, increasing their dosage further will not increase the solubility of the drug. At high concentrations, the viscosity increases significantly, affecting the stability of the preparation.

[0005] In addition, polysorbate 80 is prone to foaming and is not easy to accurately measure during preparation; and the viscosity, hemolytic activity, and histamine level of polysorbate 80 increase rapidly at high concentrations, which can easily cause pain, hemolysis, histamine release, etc. The hemolytic activity and histamine release problems of the solubilizing effect of polysorbate 80 may lead to adverse reactions after injection, such as allergic reactions and vascular irritation.

[0006] Second, commercially available products need to be divided into two bottles and need to be separately prepared and packaged during production, with a cumbersome process and high production costs; before clinical use, the two bottles of samples need to be combined for use, increasing the safety risk for patients and the inconvenience of clinical use. Summary of the Invention

[0007] Aiming at the deficiencies of the existing technology, the purpose of the present invention is to provide a multivitamin injection solubilized by polyoxyethylene 35 castor oil and HS15 and a preparation method thereof. It can effectively solve the problems such as insufficient hemolytic and stability of the existing solubilizers and complex production processes, and at the same time can achieve single-bottle packaging.

[0008] To achieve the above purpose, the present invention is realized through the following technical solutions:

[0009] In a first aspect, the present invention provides a multivitamin injection solubilized by polyoxyethylene 35 castor oil and HS15, which includes multivitamins, solubilizers, buffers, and pH regulators. Among them, the multivitamins include water-soluble vitamins and fat-soluble vitamins;

[0010] The solubilizer is polyoxyl 35 castor oil and HS15. The concentration range of polyoxyl 35 castor oil is 0.025% - 5%, g / ml; the concentration range of HS15 is 0.025% - 5%, g / ml.

[0011] In some embodiments, the multiple vitamins include at least two of vitamin C, vitamin A palmitate, vitamin D3, vitamin B1, riboflavin sodium phosphate, vitamin B6, nicotinamide, dexapanthenol, vitamin E, vitamin K1, folic acid, biotin, vitamin B 12 in the formula.

[0012] Preferably, the multiple vitamins include vitamin C, vitamin A palmitate, vitamin D3, vitamin B1, riboflavin sodium phosphate, vitamin B6, nicotinamide, dexapanthenol, vitamin E, vitamin K1, folic acid, biotin, vitamin B 12 .

[0013] More preferably, in the multiple vitamin injection, the single - bottle prescription is: vitamin C 50 - 300 mg, vitamin A palmitate 1000 - 4000 IU, vitamin D3 100 - 600 IU, vitamin B1 0.1 - 10 mg, riboflavin sodium phosphate 0.1 - 10 mg, vitamin B6 0.1 - 10 mg, nicotinamide 5 - 100 mg, dexapanthenol 1 - 50 mg, vitamin E 1 - 50 IU, vitamin K1 0.05 - 5 mg, folic acid 0.05 - 5 mg, biotin 0.005 - 0.5 mg, vitamin B 12 0.0001 - 0.05 mg, polyoxyl 35 castor oil 5 - 100 mg, HS15 5 - 100 mg, propylene glycol / mannitol 0 - 5000 mg, water for injection 2 - 20 ml, and the pH value is 4 - 7.

[0014] In some embodiments, the buffer is citric acid / sodium citrate.

[0015] Preferably, the pH value regulator is sodium hydroxide or hydrochloric acid.

[0016] More preferably, the pH value of the multiple vitamin injection is 4 - 7.

[0017] In some embodiments, the multiple vitamin injection further includes a stabilizer. The concentration range of the stabilizer is 0% - 30%, g / ml; preferably 2% - 20%, g / ml;

[0018] The stabilizer is propylene glycol or mannitol.

[0019] In some embodiments, the solvent of the multiple vitamin injection is water for injection.

[0020] In a second aspect, the present invention provides a method for preparing a multiple vitamin injection solubilized by polyoxyethylene 35 castor oil and HS15, comprising the following steps:

[0021] After mixing polyoxyethylene 35 castor oil and HS15 in proportion, they are mixed with fat-soluble vitamins to obtain a fat-soluble vitamin solution;

[0022] Mix a part of water for injection, sodium hydroxide or sodium citrate, folic acid and biotin to obtain a first water-soluble vitamin solution;

[0023] Mix a part of water for injection with the remaining water-soluble vitamins and excipients evenly to obtain a second water-soluble vitamin solution;

[0024] After mixing the first water-soluble vitamin solution and the second water-soluble vitamin solution, they are further mixed with the fat-soluble vitamin solution, and the pH value is adjusted to 5-7;

[0025] Make up the water for injection, filter, sterilize, and fill with nitrogen for packaging, and that's it.

[0026] When polyoxyethylene 35 castor oil and HS15 are applied simultaneously, the solubilization effect on fat-soluble vitamins can be effectively improved, and the stability of the preparation is significantly enhanced.

[0027] Folic acid and biotin can only dissolve under alkaline conditions.

[0028] In some embodiments, when preparing the fat-soluble vitamin solution, the heating temperature is 30-60°C.

[0029] In some embodiments, the filter membrane used during filtration is a 0.22 μm microporous filter membrane.

[0030] In some embodiments, during the dissolution process of various vitamins, nitrogen is filled for protection.

[0031] The beneficial effects obtained from one or more of the above embodiments of the present invention are as follows:

[0032] Improved solubilization performance: Polyoxyethylene 35 castor oil and HS15 are both non-ionic solubilizers with good biocompatibility. The combined use of the two can reduce the concentration of a single component, reduce the stimulation of cell membranes, and at the same time maintain the solubilization effect. It not only increases the solubility of vitamins to avoid the precipitation of fat-soluble vitamins, but also reduces the hemolytic activity and sensitization activity. The hemolytic activity of HS15 is only 1 / 10 of that of polysorbate 80, and the histamine release amount is significantly reduced, with high safety; at a 20% concentration, the viscosity is only 1 / 3 of that of polysorbate 80, improving the fluidity and stability of the preparation; it has excellent solubilization ability, increasing the solubility of fat-soluble vitamins by 10-100 times and avoiding phase separation or precipitation.

[0033] Promote miscibility: Polyoxyethylene 35 castor oil and HS15 can form clear solutions when dissolved in water. Their aqueous solutions have good stability, which promotes the miscibility of the oil phase and the water phase, resulting in good stability of the miscible solution.

[0034] Simplify the process: The one-pot method is used for solution preparation and sealing, which simplifies the solution preparation and sealing processes and greatly saves production costs.

[0035] Single-bottle packaging: Single-bottle packaging is adopted, and no mixing is required before clinical use, which not only reduces the packaging cost but also improves the convenience of clinical use.

[0036] Excellent stability: After 30 days of accelerated test at 40°C, the appearance, pH value, related substances and content all meet the pharmacopoeia standards. Detailed implementation mode

[0037] It should be noted that the following detailed description is illustrative and aims to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0038] Term explanation:

[0039] Polyoxyethylene 35 castor oil is a polyoxyethylene castor oil derivative, belonging to non-ionic surfactants, and is applied to oral, topical and injectable dosage forms. Polyoxyethylene 35 castor oil can also form a clear and stable solution in water and is stable in low-concentration electrolyte solutions such as acids or salts.

[0040] HS15 is polyethylene glycol 15-hydroxystearate, which has the characteristics of low hemolytic activity, low histamine release and high solubilization ability. It is approved for use in injectables and has been included in the German Pharmacopoeia (DAB), the United States Pharmacopoeia (USP) and the European Pharmacopoeia (Ph.Eur.). HS15 is soluble in water to form a clear solution, and its aqueous solution has good stability. The solubilization ability of HS15 is excellent. HS15 at a concentration of 20% can increase the water solubility of different drugs by 10 - 100 times. At a concentration of 30%, the viscosity of the HS15 solution is 1 / 3 of that of polysorbate 80 (i.e., Tween 80). At a concentration of 10%, the hemolytic property of polysorbate 80 is 10 times that of HS15, and the histamine level is many times that of HS15, indicating that HS15 is a new excipient with high solubilization ability and low toxicity.

[0041] Multivitamin injection is a common nutritional supplement and is widely used in clinical treatment and prevention of vitamin deficiency.

[0042] The prescription composition of single-bottle multivitamin injection is shown in Table 1.

[0043] Table 1

[0044]

[0045] Among them, vitamin C, vitamin A palmitate, vitamin D3, vitamin B1, riboflavin sodium phosphate, vitamin B6, niacinamide, D-panthenol, vitamin E, vitamin K1, folic acid, biotin, vitamin B 12 are bulk drugs, polyoxyl 35 castor oil and HS15 are solubilizers, citric acid / sodium citrate is a buffer and pH regulator, and water for injection is a solvent, which are essential materials; propylene glycol / mannitol is a stabilizer, and sodium hydroxide / hydrochloric acid is a pH regulator, which are optional materials.

[0046] The present invention will be further described below in conjunction with embodiments.

[0047] Example 1

[0048] The prescription composition of the single-vial multivitamin injection is shown in Table 2.

[0049] Table 2

[0050]

[0051] Preparation process:

[0052] ① Weighing: Weigh the prescribed amounts of bulk drugs separately under light-shielded conditions and put them into light-shielded bags;

[0053] ② Solution preparation:

[0054] Weigh 10% of the total amount of water for injection, fill it with nitrogen until the dissolved oxygen content ≤ 1 mg / ml, add sodium hydroxide (about 0.08 g / L), stir to dissolve, then add folic acid and biotin, stir to dissolve, and use it as Solution 1 for standby.

[0055] Weigh the prescribed amounts of polyoxyl 35 castor oil and HS15, heat to 50 °C, add the prescribed amounts of vitamin A palmitate, vitamin D3, vitamin E, and vitamin K1, stir until evenly mixed to obtain a fat-soluble vitamin solution;

[0056] Add 50% of the total amount of water for injection to the solution preparation tank, fill it with nitrogen, control the dissolved oxygen content ≤ 1 mg / ml, add the prescribed amounts of vitamin C, vitamin B1, riboflavin sodium phosphate, vitamin B6, niacinamide, D-panthenol, mannitol, and vitamin B 12 Stir to dissolve under nitrogen protection, add Solution 1, stir evenly, add the fat-soluble vitamin solution, stir evenly, adjust the pH value with citric acid / sodium citrate solution, make up the volume to the full amount with water for injection, and stir evenly under nitrogen protection.

[0057] ③ Filtration: Filter and sterilize with a 0.22 μm microporous membrane filter;

[0058] ④ Sealing: Sealing under nitrogen filling, with the residual oxygen content ≤ 2.0%.

[0059] Example 2

[0060] The prescription composition of the single - bottle multivitamin injection is shown in Table 3.

[0061] Table 3

[0062]

[0063]

[0064] Preparation process:

[0065] ① Weighing: Weigh the prescription amount of the bulk drugs separately under light - shielding conditions and put them into a light - shielding bag;

[0066] ② Solution preparation:

[0067] Weigh 20% of the total amount of injection water for solution preparation, fill it with nitrogen until the dissolved oxygen content ≤ 1 mg / ml, add sodium citrate (dosage 0.8 g / L), stir and dissolve, then add folic acid and biotin, stir and dissolve to obtain Solution 1 for standby.

[0068] Weigh the prescription amount of polyoxyl 35 castor oil and HS15, mix them evenly, heat to 45 °C, add the prescription amount of vitamin A palmitate, vitamin D3, vitamin E, and vitamin K1, stir until evenly mixed to obtain the fat - soluble vitamin solution for standby.

[0069] Fill the solution preparation tank with nitrogen, add 50% of the total amount of injection water, control the dissolved oxygen content ≤ 1 mg / ml, add the prescription amount of vitamin C, vitamin B1, riboflavin sodium phosphate, vitamin B6, nicotinamide, dexpanthenol, propylene glycol, and vitamin B 12 Stir until dissolved under nitrogen protection. Add Solution 1, stir evenly, add the fat - soluble vitamin solution, stir evenly, adjust the pH value with the citric acid / sodium citrate solution regulator, make up the injection water to the full volume, and stir evenly under nitrogen protection.

[0070] ③ Filtration: Filter and sterilize with a 0.22 - μm microporous membrane filter;

[0071] ④ Sealing: Seal under nitrogen filling, with the residual oxygen content ≤ 3.0%.

[0072] Comparative Example 1

[0073] The difference from Example 1 is that polyoxyl 35 castor oil is replaced with an equal amount of HS15, and the others are the same as Example 1.

[0074] Comparative Example 2

[0075] The difference from Example 1 is that HS15 is replaced with an equal amount of polyoxyl 35 castor oil, and the others are the same as Example 1.

[0076] Comparative Example 3

[0077] The difference from Example 1 is that HS15 and polyoxyl 35 castor oil are replaced with an equal amount of polysorbate 80, and the others are the same as in Example 1.

[0078] The test results are shown in Table 4 and Table 5. The commercially available sample in Table 4 is Infuvite purchased from Sandoz Canada Inc., indicated for the prevention of vitamin deficiencies in adults and children 11 years of age and older receiving parenteral nutrition. The package specification is Bottle 1: 5 ml + Bottle 2: 5 ml. The dosage and administration are as follows: After dilution, it is intravenously infused; the recommended daily dose is 10 ml; single dose: once a day, add 10 ml (5 ml from Bottle 1 and 5 ml from Bottle 2) to no less than 500 ml, preferably 1000 ml of intravenous glucose, normal saline or similar infusion solution.

[0079] The sample prepared by the present invention is in single-bottle packaging and only needs to be mixed with the infusion solution during administration.

[0080] Table 4

[0081]

[0082]

[0083] In Table 4, for the samples prepared in Example 1 and Example 2, riboflavin diphosphate, impurity A, and other total impurities in terms of related substances are less than those of the commercially available sample under the conditions of 0 day and 30 days at 40°C. Other impurities are comparable to those of the commercially available sample and all meet the quality standard requirements; the change trends in terms of appearance, content, pH value, etc. are consistent with those of the reference preparation and all meet the quality standard requirements, indicating that the prescription process of the present invention has good stability.

[0084] Table 5

[0085]

[0086]

[0087] In Table 5, for the samples prepared in Comparative Example 1, Comparative Example 2, and Comparative Example 3, free riboflavin and other total impurities in terms of related substances are higher than those of the samples in Example 1 and Example 2 under the conditions of 0 day and 30 days at 40°C. In terms of content, the contents of fat-soluble vitamins D3, K1, vitamin A palmitate, and vitamin E are all lower than those of the samples in Example 1 and Example 2, and the downward trend is more significant during the 30-day investigation at 40°C. It is further proved that polyoxyl 35 castor oil and HS15 can synergistically improve the solubility of fat-soluble vitamins and the stability of the preparation.

[0088] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. 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 multiple vitamin injection solubilized by polyoxyethylene 35 castor oil and HS15, characterized in that: It includes various vitamins, solubilizers, buffers and pH regulators. Among them, the various vitamins include water-soluble vitamins and fat-soluble vitamins; The solubilizers are polyoxyl 35 castor oil and HS15. The concentration range of polyoxyl 35 castor oil is 0.025% - 5%, g / ml; the concentration range of HS15 is 0.025% - 5%, g / ml.

2. The polyoxyethylene 35 castor oil and HS15 solubilized multivitamin injection according to claim 1, characterized in that: The multivitamins include at least two of vitamin C, vitamin A palmitate, vitamin D3, vitamin B1, riboflavin sodium phosphate, vitamin B6, niacinamide, D-panthenol, vitamin E, vitamin K1, folic acid, biotin, vitamin B 12 ; Preferably, the multivitamins include vitamin C, vitamin A palmitate, vitamin D3, vitamin B1, riboflavin sodium phosphate, vitamin B6, niacinamide, dexpanthenol, vitamin E, vitamin K1, folic acid, biotin, vitamin B 12 ; Preferably, in the multivitamin injection, the single-bottle prescription is as follows: 50 - 300 mg of vitamin C, 1000 - 4000 IU of vitamin A palmitate, 100 - 600 IU of vitamin D3, 0.1 - 10 mg of vitamin B1, 0.1 - 10 mg of riboflavin sodium phosphate, 0.1 - 10 mg of vitamin B6, 5 - 100 mg of nicotinamide, 1 - 50 mg of dexpanthenol, 1 - 50 IU of vitamin E, 0.05 - 5 mg of vitamin K1, 0.05 - 5 mg of folic acid, 0.005 - 0.5 mg of biotin, 12 0.0001 - 0.05 mg of vitamin B 12 , 5 - 100 mg of polyoxyl 35 castor oil, 5 - 100 mg of HS15, 0 - 5000 mg of propylene glycol / mannitol, 2 - 20 ml of water for injection, and the pH value is 4 - 7.

3. The polyoxyethylene 35 castor oil and HS15 solubilized multivitamin injection according to claim 1, wherein: The buffer is citric acid / sodium citrate; Preferably, the pH regulator is sodium hydroxide or hydrochloric acid.

4. The polyoxyethylene 35 castor oil and HS15 solubilized multivitamin injection according to claim 3, characterized in that: The pH value of the injection of various vitamins is 4 - 7.

5. The polyoxyethylene 35 castor oil and HS15 solubilized multivitamin injection according to claim 1, characterized in that: The injection of various vitamins also includes a stabilizer, and the concentration range of the stabilizer is 0% - 30%, g / ml; preferably 2% - 20%, g / ml; The stabilizer is propylene glycol or mannitol.

6. The polyoxyethylene 35 castor oil and HS15 solubilized multivitamin injection according to claim 1, characterized in that: The solvent of the injection of various vitamins is water for injection.

7. The preparation method of the polyoxyethylene 35 castor oil and HS15 solubilized multivitamin injection according to any one of claims 1-6, characterized in that: It includes the following steps: Mix polyoxyl 35 castor oil and HS15 in proportion, and then mix with fat-soluble vitamins to obtain a fat-soluble vitamin solution; Mix part of the water for injection, sodium hydroxide or sodium citrate, folic acid and biotin to obtain a first water-soluble vitamin solution; Mix part of the water for injection with the remaining water-soluble vitamins and excipients evenly to obtain a second water-soluble vitamin solution; Mix the first water-soluble vitamin solution and the second water-soluble vitamin solution, and then mix with the fat-soluble vitamin solution, and adjust the pH value to 5 - 7; Make up the water for injection, filter, sterilize, fill with nitrogen and seal, then it is ready.

8. The preparation method of the multiple vitamin injection solubilized by polyoxyethylene 35 castor oil and HS15 according to claim 7, characterized in that: When preparing the fat-soluble vitamin solution, the heating temperature is 30 - 60°C.

9. The preparation method of the multiple vitamin injection solubilized by polyoxyethylene 35 castor oil and HS15 according to claim 7, wherein: The filter membrane used during filtration is a 0.22μm microporous filter membrane.

10. The preparation method of the multiple vitamin injection solubilized by polyoxyethylene 35 castor oil and HS15 according to claim 7, characterized in that: During the dissolution process of various vitamins, nitrogen protection is carried out.

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