CN115554241A - Micelle type vitamin K1 injection and preparation method and application thereof - Google Patents
Micelle type vitamin K1 injection and preparation method and application thereof Download PDFInfo
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- CN115554241A CN115554241A CN202211125151.0A CN202211125151A CN115554241A CN 115554241 A CN115554241 A CN 115554241A CN 202211125151 A CN202211125151 A CN 202211125151A CN 115554241 A CN115554241 A CN 115554241A
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- vitamin
- injection
- micelle type
- poloxamer
- stirring
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- 229940025790 vitamin k 1 injection Drugs 0.000 title claims abstract description 75
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- 235000019175 phylloquinone Nutrition 0.000 claims abstract description 43
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- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 claims abstract description 42
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- ABSPRNADVQNDOU-UHFFFAOYSA-N Menaquinone 1 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(C)C(=O)C2=C1 ABSPRNADVQNDOU-UHFFFAOYSA-N 0.000 claims abstract description 41
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- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 claims description 22
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- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 claims description 20
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides a micelle type vitamin K1 injection and a preparation method and application thereof, relating to the technical field of pharmaceutical preparations. The micelle type vitamin K1 injection is prepared from an active ingredient vitamin K1, auxiliary materials and water for injection, wherein the pH value of the vitamin K1 injection is 4.9-5.1, the solubilizer 15-hydroxystearic acid polyethylene glycol ester and poloxamer are added into the micelle type vitamin K1 injection, the clarity and the granularity of the solution are obviously improved on the basis of reducing the usage amount of the 15-hydroxystearic acid polyethylene glycol ester, the obtained injection is more uniform in granularity distribution, the granularity value can be stabilized in a certain range, the aggregation is not easy in the long-term storage process, and the stability of the medicine is more facilitated.
Description
Technical Field
The application relates to the technical field of pharmaceutical preparations, in particular to a micelle type vitamin K1 injection and a preparation method and application thereof.
Background
Vitamin K1 (Vitamin K1, phytonadione) is a yellow to orange clear viscous liquid, odorless or almost odorless, and easily decomposed by light. Vitamin K1 is easily soluble in chloroform, diethyl ether or vegetable oil, slightly soluble in ethanol, and insoluble in water. The chemical name of vitamin K1 is: a mixture of trans and cis isomers of 2-methyl-3- (3, 7,11, 15-tetramethyl-2-hexadecenyl) -1, 4-naphthalenedione of the formula: c 31 H 46 O 2 Molecular weight: 450.71, structural formula:
at present, the 2020 edition Chinese pharmacopoeia collects raw material medicines and injection liquid of Vitamin K1 (Vitamin K1), and the United states pharmacopoeia USP40 collects raw material medicines, injection emulsion and tablets of Vitamin K1 (Phytonadione).
Vitamin K1 is a fat-soluble vitamin, widely present in green plants, exists in the form of phylloquinone (phylloquinone), and can also be synthesized artificially. Vitamin K1 is the yellow oily liquid which is firstly purified from the alfalfa and is named as vitamin K1, and people use the vitamin K1 as a hemostatic medicament very early. The medical value of hemostasis is discovered in the 30 s of the 20 th century. The Danish biochemist Herrick & Damm studied the bleeding disorder in chickens, and he found that the chickens bleed more and do not coagulate when they are injured until some kind of feed was added to the food, and later found that the feed is rich in a substance that can immediately stop bleeding, which is vitamin K1. Vitamin K1 is then gradually applied to various hemorrhagic diseases. Through years of basic research and clinical use, pharmacological activities of the vitamin K1 except hemostasis are gradually discovered: treating respiratory diseases, relieving spasm and pain, preventing and treating osteoporosis, treating hepatitis, caring skin, and resisting tumor. The vitamin K1 is a clinically common medicament because of definite pharmacological activity and light toxic and side effects.
Vitamin K1 is a vitamin K drug, vitamin K is a substance necessary for liver to synthesize factors II, VII, IX and X, and deficiency of vitamin K can cause synthesis disorder or abnormality of these blood coagulation factors, with clinical bleeding tendency and prolonged prothrombin time. In clinic, vitamin K1 can be used for bleeding caused by vitamin K deficiency, such as bleeding caused by obstructive jaundice, fistulae cum bile, chronic diarrhea and the like, hypoprothrombinemia caused by coumarins, sodium salicylate and the like, neonatal bleeding prevention and in-vivo vitamin K deficiency caused by long-term application of broad-spectrum antibiotics. Through years of basic research and clinical use, vitamin K1 is also found to be capable of preventing and treating respiratory diseases, relieving spasm and pain and treating hepatitis. It is also associated with osteoporosis and cosmetology. The vitamin K1 has definite pharmacological activity and light toxic and side effects, so the vitamin K1 is widely applied to clinic and is a common medicine in clinic.
The 2020 edition Chinese pharmacopoeia collects vitamin K1 injection, which is a sterilized water dispersion liquid of yellow liquid with main drug concentration of 10mg/ml, is allowed to be slightly turbid and needs to be preserved in an antifreezing way, if oil drops are separated out or layered, the yellow liquid can be heated to 70-80 ℃ under the condition of shading, the yellow liquid is shaken to be naturally cooled, and if the clarity is normal, the yellow liquid can be continuously used.
Therefore, how to improve the clarity of the vitamin K1 injection is always the focus of research, for example, as disclosed in the chinese patent application 201410271850.5, a vitamin K1 injection and a preparation method thereof are disclosed, which are prepared by mixing an active ingredient vitamin K1, auxiliary materials and water for injection, and adding anhydrous sodium acetate into 80% of the water for injection according to the formula amount to obtain a solution a; sequentially weighing vitamin K1 and HS15 with formula amount into a clean anhydrous container, and emulsifying uniformly to obtain a solution B; slowly adding the solution A into the solution B, adding sodium metabisulfite, stirring uniformly, and then adjusting the pH value to 5.8-6.2 by using glacial acetic acid; supplementing water for injection to the full amount of the formula, filtering, filling nitrogen, sealing, and rotary sterilizing at 121 deg.C for 12 min or sterilizing. Compared with the existing vitamin K1 injection, the product prepared by the invention not only meets the drug code standard of the vitamin K1 injection, but also greatly improves the clarity of the product, but the clarity still cannot better meet the requirement, and the stability of the injection is not recorded.
For another example, chinese patent application 201910199799.4 discloses a vitamin K1 fat emulsion injection, wherein the emulsion composition comprises vitamin K1, soybean oil, phospholipid, glycerol, and water. The composition is prepared by the processes of preparing water phase, preparing oil phase, preparing coarse emulsion, emulsifying under high pressure, sterilizing under hot pressure and the like. The emulsion composition of the invention exhibits one or more technical effects as described in the specification, for example, the composition can be used at a time of 10mg each time, 1-2 times daily, the total amount within 24 hours does not exceed 40mg, and the administration dose and frequency are adjusted according to prothrombin time response or clinical symptoms; the use mode is intravenous administration, the infusion can be directly injected into a vein without dilution, or the injection is diluted by 5 percent glucose injection and then is instilled into the vein, and the clarity of the vitamin K1 fat emulsion injection prepared by the application can not meet the requirement.
Therefore, it is required to provide a micelle type vitamin K1 injection with uniform particle size, high clarity and good stability and a preparation method thereof.
Disclosure of Invention
The invention aims to provide a micellar vitamin K1 injection and a preparation method thereof, and the micellar vitamin K1 injection with uniform particle size, high clarity and good stability is prepared by selecting auxiliary materials.
In order to achieve the purpose, the invention adopts the following technical scheme:
a micelle type vitamin K1 injection is prepared from an active ingredient vitamin K1, auxiliary materials and water for injection, wherein the pH value of the vitamin K1 injection is 4.9-5.1.
The auxiliary material comprises an auxiliary material composition 1; the auxiliary material composition 1 comprises soybean phosphatidylcholine and glycocholic acid;
the application also provides a preparation method of the auxiliary material composition 1, which comprises the following steps:
(1) Weighing injection water with the total water amount of 80% and adding into a liquid preparation tank, adding sodium hydroxide, stirring to dissolve, adding glycocholic acid, mixing uniformly, adjusting pH to 5.5-6.5 with sodium hydroxide-hydrochloric acid, stirring to clarify, and obtaining sodium glycocholate liquid for later use;
(2) Adding soybean phosphatidylcholine into sodium glycocholate solution, stirring to dissolve to semisolid viscous state, stopping stirring, cooling, drying at 60 deg.C, controlling water content to be less than or equal to 3%, and grading with a swing granulator to obtain adjuvant composition 1.
The preparation method of the micelle type vitamin K1 injection comprises the following steps:
adding 50% of water for injection into the solution preparation tank, adding the adjuvant composition 1, stirring for dissolving, adding vitamin K1, and stirring at 150-180rpm for 2 hr to obtain initial medicinal liquid; adjusting the pH of the initial liquid medicine to 4.9-5.1 by using a sodium hydroxide-hydrochloric acid solution to obtain a micelle type vitamin K1 injection, cooling the micelle type vitamin K1 injection to room temperature, fixing the volume to the full volume, subpackaging the mixture into 1mL brown ampoule bottles with the filling volume of 1.05-1.10mL, and carrying out moist heat sterilization at 121 ℃ for 15 minutes to obtain the micelle type vitamin K1 injection.
In some preferred embodiments, the excipients in the micelle type vitamin K1 injection further comprise 15-hydroxystearic acid polyethylene glycol ester and poloxamer.
The poloxamer is preferably poloxamer 188.
Wherein the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the poloxamer 188 is 3-6;
preferably, the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the poloxamer 188 is 3.75:1.
the preparation method of the micelle type vitamin K1 injection comprises the following steps:
adding 50% of water for injection into a liquid preparation tank, adding the auxiliary material composition 1, stirring for dissolving, adding 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188, heating and stirring at 40 ℃ for dissolving, adding vitamin K1, and stirring at 150-180rpm for 2 hours to obtain an initial liquid medicine; adjusting the pH of the initial liquid medicine to 5.5-6.5 by using a sodium hydroxide-hydrochloric acid solution to obtain a micelle type vitamin K1 injection, cooling the micelle type vitamin K1 injection to room temperature, fixing the volume to the full volume, subpackaging the mixture into 1mL brown ampoule bottles with the filling volume of 1.05-1.1mL, and carrying out moist heat sterilization at 121 ℃ for 15 minutes to obtain the micelle type vitamin K1 injection.
As some preferred embodiments, the micelle type vitamin K1 injection comprises the following active ingredients and auxiliary materials in the following dosage: vitamin K 1 5-20g/L of soybean phosphatidylcholine, 60-90g/L of glycocholic acid, 40-70g/L of glycocholic acid, 3-10g/L of sodium hydroxide, 0.5-5g/L of 1M hydrochloric acid, 1.5-30g/L of 15-hydroxystearic acid polyethylene glycol ester and 1880.5-10g/L of poloxamer;
preferably, the micelle type vitamin K1 injection comprises the following active ingredients and auxiliary materials in percentage by weight: vitamin K 1 10-20g/L of soybean phosphatidylcholine, 70-80g/L of glycocholic acid, 50-65g/L of glycocholic acid, 4-5g/L of sodium hydroxide, 1-3g/L of 1M hydrochloric acid, 3-15g/L of 15-hydroxystearic acid polyethylene glycol ester and 1880.5-7.5g/L of poloxamer;
preferably, the micelle type vitamin K1 injection comprises the following active ingredients and auxiliary materials in percentage by weight: vitamin K 1 10g/L, 80g/L of soybean phosphatidylcholine, 50g/L of glycocholic acid, 4.5g/L of sodium hydroxide, 2g/L of 1M hydrochloric acid, 7.5g/L of 15-hydroxystearic acid polyethylene glycol ester and 2g/L of poloxamer 188.
The application also provides the micelle type vitamin K1 injection for preparing the medicine for treating ischemia and hemorrhage caused by vitamin K deficiency; hypocoagulase hemorrhemia caused by coumarins, sodium salicylate, etc.; the application of the medicine in treating neonatal hemorrhage and vitamin K deficiency in vivo caused by long-term application of broad-spectrum antibiotics.
Compared with the prior art, the beneficial effect of this application lies in:
(1) In the micelle type vitamin K1 injection provided by the application, soybean phosphatidylcholine and glycocholic acid are used as solubilizers, the soybean phosphatidylcholine and the glycocholic acid are firstly mixed to prepare an auxiliary material composition 1, then the auxiliary material composition is mixed with the vitamin K1, and the clarity of the micelle type vitamin K1 injection prepared is improved;
(2) According to the application, the solubilizer 15-hydroxystearic acid polyethylene glycol ester is added into the micelle type vitamin K1 injection, so that the clarity of the micelle type vitamin K1 injection is further improved, but the solubilizer 15-hydroxystearic acid polyethylene glycol ester is known to be expensive in the field, the inventor of the application unexpectedly finds that the clarity and the granularity of the solution can be obviously improved by mixing the 15-hydroxystearic acid polyethylene glycol ester with poloxamer, especially poloxamer 188, on the basis of reducing the using amount of the 15-hydroxystearic acid polyethylene glycol ester, the obtained injection is more uniformly distributed in the granularity, the granularity value can be stabilized in a certain range, the aggregation is not easy to occur in the long-term storage process, and the stability of a medicine is more facilitated.
Drawings
FIG. 1 is an HPLC chromatogram for content detection of example 4;
FIG. 2 example 4 HPLC chromatogram for detection of related substances.
Detailed Description
The present invention will be described in further detail with reference to the following experiments and specific embodiments. It should be understood that the scope of the above-described subject matter of the present invention is not limited to the following examples, and any technique realized based on the contents of the present invention falls within the scope of the present invention.
The raw materials and auxiliary materials used by the invention and the manufacturers and models of the instruments are as follows:
EXAMPLE 1 preparation of micellar vitamin K1 injection
The method comprises the following steps:
1. preparation of adjuvant composition 1:
1.1, weighing injection water accounting for 80% of the total water amount, adding the water into a liquid preparation tank, adding sodium hydroxide, stirring until the water is dissolved, adding glycocholic acid, uniformly mixing, adjusting the pH value to 5.5 by using sodium hydroxide-hydrochloric acid, and stirring until the solution is clear to obtain a sodium glycocholate solution for later use;
1.2, adding soybean phosphatidylcholine into the sodium glycocholate solution, stirring and dissolving to be semisolid viscous, stopping stirring, cooling, drying at 60 ℃, controlling the water content to be less than or equal to 3%, and granulating by a swing granulator to obtain an auxiliary material composition 1;
2. preparing micelle type vitamin K1 injection:
adding 50% of water for injection into the solution preparation tank, adding the adjuvant composition 1, stirring for dissolving, adding vitamin K1, and stirring at 150rpm for 2 hr to obtain initial medicinal liquid; adjusting the pH of the initial liquid medicine to 5.5 by using a sodium hydroxide-hydrochloric acid solution to obtain a micelle type vitamin K1 injection, cooling the temperature of the micelle type vitamin K1 injection to room temperature, then fixing the volume to the full volume, subpackaging the gel type vitamin K1 injection into 1mL brown ampoule bottles with the packaging volume of 1.05-1.1mL, and carrying out moist heat sterilization at the temperature of 121 ℃ for 15 minutes to obtain the micelle type vitamin K1 injection.
The prescription composition is as follows:
| composition (A) | 1000 pieces of Chinese herbal medicine |
| Vitamin K 1 | 10g |
| Glycocholic acid | 50g |
| Soybean phosphatidylcholine | 80g |
| Sodium hydroxide (pH regulator) | 4.5g |
| Hydrochloric acid (pH regulator) | 2g |
| Water for injection | Adding to 1L |
Example 2 preparation of micellar vitamin K1 injection
The method comprises the following steps:
1. preparation of adjuvant composition 1:
1.1, weighing injection water accounting for 80% of the total water amount, adding the water into a liquid preparation tank, adding sodium hydroxide, stirring until the water is dissolved, adding glycocholic acid, uniformly mixing, adjusting the pH value to 6.5 by using sodium hydroxide-hydrochloric acid, and stirring until the solution is clear to obtain a sodium glycocholate solution for later use;
1.2, adding soybean phosphatidylcholine into the sodium glycocholate solution, stirring and dissolving to be semisolid viscous, stopping stirring, cooling, drying at 60 ℃, controlling the water content to be less than or equal to 3%, and granulating by a swing granulator to obtain an auxiliary material composition 1;
2. preparing micelle type vitamin K1 injection:
adding 50% of water for injection into a liquid preparation tank, adding the auxiliary material composition 1, stirring for dissolving, adding 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188, heating and stirring at 40 ℃ for dissolving, finally adding vitamin K1, and stirring at 180rpm for 2 hours to obtain initial liquid medicine; adjusting the pH of the initial liquid medicine to 6.5 by using a sodium hydroxide-hydrochloric acid solution to obtain a micelle type vitamin K1 injection, cooling the temperature of the micelle type vitamin K1 injection to room temperature, fixing the volume to the full volume, subpackaging the mixture into 1mL brown ampoule bottles with the packaging volume of 1.05-1.1mL, and carrying out moist heat sterilization at 121 ℃ for 15 minutes to obtain the micelle type vitamin K1 injection.
The prescription composition is as follows:
| composition (A) | 1000 pieces of Chinese herbal medicine |
| Vitamin K 1 | 10g |
| Glycocholic acid | 55g |
| Soybean phosphatidylcholine | 85g |
| 15-Hydroxystearic acid polyethylene glycol ester | 10g |
| Poloxamer 188 | 3g |
| Sodium hydroxide (pH regulator) | 6g |
| Hydrochloric acid (pH regulator) | 3g |
| Water for injection | Adding to 1L |
Example 3 preparation of micellar vitamin K1 injection
The method comprises the following steps:
1. preparation of adjuvant composition 1:
1.1, weighing injection water accounting for 80 percent of the total water amount, adding the water into a liquid preparation tank, adding sodium hydroxide, stirring to dissolve, adding glycocholic acid, uniformly mixing, adjusting the pH value to 6.0 by using sodium hydroxide-hydrochloric acid, and stirring to clarify to obtain a sodium glycocholate liquid for later use;
1.2, adding soybean phosphatidylcholine into the sodium glycocholate solution, stirring and dissolving to be semisolid viscous, stopping stirring, cooling, drying at 60 ℃, controlling the water content to be less than or equal to 3%, and granulating by a swing granulator to obtain an auxiliary material composition 1;
2. preparing micelle type vitamin K1 injection:
adding 50% of water for injection into a liquid preparation tank, adding the auxiliary material composition 1, stirring for dissolving, adding 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188, heating and stirring at 40 ℃ for dissolving, finally adding vitamin K1, and stirring at 160rpm for 2 hours to obtain initial liquid medicine; adjusting the pH of the initial liquid medicine to 6.0 by using a sodium hydroxide-hydrochloric acid solution to obtain a micelle type vitamin K1 injection, cooling the temperature of the micelle type vitamin K1 injection to room temperature, fixing the volume to the full volume, subpackaging the mixture into 1mL brown ampoule bottles with the packaging volume of 1.05-1.1mL, and carrying out moist heat sterilization at 121 ℃ for 15 minutes to obtain the micelle type vitamin K1 injection.
The prescription composition is as follows:
example 4 preparation of micellar vitamin K1 injection
The method comprises the following steps:
1. preparation of adjuvant composition 1:
1.1, weighing injection water accounting for 80% of the total water amount, adding the water into a liquid preparation tank, adding sodium hydroxide, stirring until the water is dissolved, adding glycocholic acid, uniformly mixing, adjusting the pH value to 6.0 by using sodium hydroxide-hydrochloric acid, and stirring until the solution is clear to obtain a sodium glycocholate solution for later use;
1.2, adding soybean phosphatidylcholine into the sodium glycocholate solution, stirring and dissolving to be semisolid viscous, stopping stirring, cooling, drying at 60 ℃, controlling the water content to be less than or equal to 3%, and granulating by a swing granulator to obtain an auxiliary material composition 1;
2. preparing micelle type vitamin K1 injection:
adding 50% of water for injection into a liquid preparation tank, adding the auxiliary material composition 1, stirring for dissolving, adding 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188, heating and stirring at 40 ℃ for dissolving, finally adding vitamin K1, and stirring at 160rpm for 2 hours to obtain initial liquid medicine; adjusting the pH of the initial liquid medicine to 6.0 by using a sodium hydroxide-hydrochloric acid solution to obtain a micelle type vitamin K1 injection, cooling the temperature of the micelle type vitamin K1 injection to room temperature, fixing the volume to the full volume, subpackaging the mixture into 1mL brown ampoule bottles with the packaging volume of 1.05-1.1mL, and carrying out moist heat sterilization at 121 ℃ for 15 minutes to obtain the micelle type vitamin K1 injection.
The prescription composition is as follows:
comparative example 1
The difference from example 4 is that: only 15-hydroxystearic acid polyethylene glycol ester (the content is the total mass of the 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188) is added into the injection, and other operations and steps are the same as those in example 4.
Namely:
| composition (I) | 1000 pieces of Chinese herbal medicine |
| Vitamin K1 | 10g |
| Glycocholic acid | 50g |
| Soybean phosphatidylcholine | 80g |
| 15-Hydroxystearic acid polyethylene glycol ester | 9.5g |
| Poloxamer 188 | - |
| Sodium hydroxide (pH regulator) | 4.5g |
| Hydrochloric acid (pH regulator) | 2g |
| Water for injection | To add to 1L |
Comparative example 2
The difference from example 4 is that: the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to poloxamer 188 was 1 (the content was the total mass of the 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188), and the other operations and steps were the same as in example 4.
Namely:
comparative example 3
The difference from example 4 is that: the mass ratio of 15-hydroxystearic acid polyethylene glycol ester to poloxamer 188 was 94 (the content was the total mass of 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188), and the other operations and steps were the same as in example 4.
Namely:
| composition (A) | 1000 pieces of Chinese herbal medicine |
| Vitamin K1 | 10g |
| Glycocholic acid | 50g |
| Soybean phosphatidylcholine | 80g |
| 15-Hydroxystearic acid polyethylene glycol ester | 9.4g |
| Poloxamer 188 | 0.1g |
| Sodium hydroxide (pH regulator) | 4.5g |
| Hydrochloric acid (pH regulator) | 2g |
| Water for injection | Adding to 1L |
Comparative example 4
The difference from example 4 is that: poloxamer 188 was replaced with polysorbate 80 and the other procedures and steps were the same as in example 4.
Namely:
| composition (I) | 1000 pieces of Chinese herbal medicine |
| Vitamin K1 | 10g |
| Glycocholic acid | 50g |
| Soybean phosphatidylcholine | 80g |
| 15-Hydroxystearic acid polyethylene glycol ester | 7.5g |
| Poloxamer 188 | - |
| Polysorbate 80 | 2g |
| Sodium hydroxide (pH regulator) | 4.5g |
| Hydrochloric acid (pH regulator) | 2g |
| Water for injection | To add to 1L |
Effect test
1. Clarity and color detection
The detection method comprises the following steps: respectively placing the test solution and an equal amount of turbidity standard solution in paired turbidity-comparing glass tubes, preparing the turbidity standard solution for 5 minutes, vertically placing the turbidity standard solution under an umbrella shed lamp in a dark room, observing and comparing the turbidity standard solution and the turbidity standard solution at an illumination of 1000lx from the horizontal direction (0902 of the general rule of the four parts of the 2020 edition of Chinese pharmacopoeia);
TABLE 1 clarity and color check of the examples
From the test data in table 1, it can be seen that: the micelle type vitamin K1 injection prepared in the embodiments 2-4 is high in clarity, the clarity of the injection prepared by adding 15-hydroxystearic acid polyethylene glycol ester and poloxamer into the components of the injection in the comparative example 1 is not obviously reduced, the clarity of the injection obtained by only adding 15-hydroxystearic acid polyethylene glycol ester as a solubilizer in the comparative example 1 is also obviously reduced, the improvement is not great compared with the embodiment 1, the poloxamer 188 is replaced by polysorbate 80 in the comparative example 4, namely, the poloxamer 188 is replaced by other solubilizers, and the clarity of the obtained injection is not obviously improved compared with the embodiment 1; comparative examples 2 to 3 changing the mass ratio of 15-hydroxystearic acid polyethylene glycol ester to poloxamer 188, which is not within the scope of the present application, affects the clarity of the injection to a certain extent, so that the clarity is reduced.
2. Particle size detection
2.1 detection Instrument
The name of the instrument: a nanometer particle size and Zeta potentiometer; the manufacturer: pearl-sea-true-optics instruments ltd; the model is as follows: nanolin SZ901.
2.2 detection method
The method comprises the steps of turning on a computer and instrument power supply, starting an operation software NanoSizer, selecting nano-particle size detection or Zeta potential detection, pouring a sample to be detected (about 2ml for nano-particle size detection and about 1ml for Zeta potential detection) into a sample cell, putting the sample cell into a detection bin (the Zeta potential detection needs to be inserted and clicked and then put into the detection bin), selecting the type of the sample cell in the operation software, filling optical parameters, test temperature, temperature balance time, measurement time and times, starting to detect the nano-particle size or the Zeta potential, and turning off the operation software, the instrument and the computer power supply after the detection is finished.
TABLE 2 ZATA potential and laser particle size distribution test results for different examples
From the test data in table 2, it can be seen that: the granularity of the injection prepared in the embodiment 2-4 is obviously smaller than that of the embodiment 1, and is consistent with the detection result of the clarity, and the comparative example 1-4 changes the type of the solubilizer and the proportioning ash to influence the granularity of the injection to a certain extent, so that the clarity of the injection is influenced, further, the injection prepared in the embodiment 2-4 is more uniform in granularity distribution, can be stabilized in a certain range, is not easy to aggregate in a long-term storage process, and is more favorable for the stability of medicines.
3. Mass comparison and stability data
3.1 content
3.1.1 detection Instrument
The instrument name: a high performance liquid chromatograph; the manufacturer: shimadzu, japan; the model is as follows: LC-20A
3.1.2 detection method
Chromatographic conditions are as follows:
and (3) chromatographic column: YMC Carotenoid (150X 4.6mm,3 μm); mobile phase: methanol-water (97; flow rate: 1.0ml/min; detection wavelength: 270nm; sample injection volume: 20 mu l of the mixture; column temperature: 30 ℃; diluent agent: anhydrous ethanol
3.2 related substances
3.2.1 detection Instrument
The instrument name: a high performance liquid chromatograph; the manufacturer: shimadzu, japan; the model is as follows: LC-20A
3.2.2 detection method
Chromatographic conditions are as follows:
a chromatographic column: ACE Excel Super C18 (250X 4.6mm,5 μm); mobile phase A: methanol-isopropanol-acetonitrile-water (65; and (3) mobile phase B: methanol-isopropanol (65; flow rate: 1.2ml/min; detection wavelength: 254nm; sample introduction volume: 20 mu l of the mixture; column temperature: 30 ℃; diluent agent: anhydrous ethanol
Gradient program:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 100 | 0 |
| 14 | 100 | 0 |
| 20 | 65 | 35 |
| 55 | 65 | 35 |
| 56 | 0 | 100 |
| 75 | 0 | 100 |
| 76 | 100 | 0 |
| 90 | 100 | 0 |
3.3 test results
TABLE 3 content and related substance testing of different examples
Table 4 example 4 long term stability test results
From the test data in table 3, it can be seen that: the injection prepared by the embodiment 2-4 has the best stability, and the single maximum impurity amount and the total impurity amount are obviously lower than those of the embodiment 1 and the comparative examples 1-4; in conclusion, the micelle type vitamin K1 injection prepared by mixing poloxamer 188 and 15-hydroxystearic acid polyethylene glycol ester as auxiliary materials can obviously improve the clarity and the granularity of the solution on the basis of reducing the dosage of the 15-hydroxystearic acid polyethylene glycol ester, the obtained injection has more uniform granularity distribution, and the granularity value can be stabilized in a certain range.
From the test data in table 4, it can be seen that: the micelle type vitamin K1 injection prepared is not easy to aggregate in the long-term storage process, the key indexes such as properties, pH value, content, related substances and the like have no obvious growth trend, and the prior process is more favorable for the stability of medicines.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A micelle type vitamin K1 injection is characterized in that: the vitamin K injection is prepared from an active ingredient vitamin K1, auxiliary materials and water for injection, wherein the pH value of the vitamin K1 injection is 4.9-5.1;
the auxiliary material comprises an auxiliary material composition 1; the auxiliary material composition 1 comprises soybean phosphatidylcholine and glycocholic acid;
the preparation method of the auxiliary material composition 1 comprises the following steps:
(1) Weighing injection water with the total water amount of 80 percent, adding the injection water into a liquid preparation tank, adding sodium hydroxide, stirring until the injection water is dissolved, then adding glycocholic acid, uniformly mixing, adjusting the pH value to 5.5-6.5 by using sodium hydroxide-hydrochloric acid, and stirring until the mixture is clear to obtain a sodium glycocholate liquid for later use;
(2) Adding soybean phosphatidylcholine into sodium glycocholate solution, stirring and dissolving at 60 deg.C to obtain semisolid viscous state, stopping stirring, cooling, drying, controlling water content to be less than or equal to 3%, and grading with a swing granulator to obtain adjuvant composition 1.
2. A method for preparing the micellar vitamin K1 injection according to claim 1, wherein the method comprises the following steps: the method comprises the following steps:
adding 50% of water for injection into the solution preparation tank, adding the adjuvant composition 1, stirring for dissolving, adding vitamin K1, and stirring at 150-180rpm for 2 hr to obtain initial medicinal liquid; adjusting the pH of the initial liquid medicine to 4.9-5.1 by using a sodium hydroxide-hydrochloric acid solution to obtain a micelle type vitamin K1 injection, cooling the temperature of the micelle type vitamin K1 injection to room temperature, then fixing the volume to the full volume, subpackaging in 1mL brown ampoule bottles with the filling volume of 1.05-1.1mL, and carrying out damp-heat sterilization at 121 ℃ for 15 minutes to obtain the micelle type vitamin K1 injection.
3. The micellar vitamin K1 injection according to claim 1, wherein: the auxiliary materials also comprise 15-hydroxystearic acid polyethylene glycol ester and poloxamer.
4. The micellar vitamin K1 injection according to claim 3, wherein: the poloxamer is preferably poloxamer 188.
5. The micellar vitamin K1 injection according to claim 4, wherein: the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the poloxamer 188 is 3-6.
6. The micellar vitamin K1 injection according to claim 5, wherein: the mass ratio of the 15-hydroxystearic acid polyethylene glycol ester to the poloxamer 188 is 3.75:1.
7. a method for preparing micelle type vitamin K1 injection according to claim 6, which is characterized by comprising the following steps: the method comprises the following steps:
adding 50% of water for injection into a liquid preparation tank, adding the auxiliary material composition 1, stirring for dissolving, adding 15-hydroxystearic acid polyethylene glycol ester and poloxamer 188, heating and stirring at 40 ℃ for dissolving, adding vitamin K1, and stirring at 150-180rpm for 2 hours to obtain an initial liquid medicine; adjusting the pH of the initial liquid medicine to 5.5-6.5 by using a sodium hydroxide-hydrochloric acid solution to obtain a micelle type vitamin K1 injection, cooling the temperature of the micelle type vitamin K1 injection to room temperature, then fixing the volume to the full volume, subpackaging in 1mL brown ampoule bottles with the filling volume of 1.05-1.1mL, and carrying out damp-heat sterilization at 121 ℃ for 15 minutes to obtain the micelle type vitamin K1 injection.
8. The micellar vitamin K1 injection according to claim 6, wherein: the dosage of the active ingredients and the auxiliary materials is as follows: vitamin K 1 5-20g/L, 60-90g/L of soybean phosphatidylcholine, 40-70g/L of glycocholic acid, 3-10g/L of sodium hydroxide, 0.5-5g/L of 1M hydrochloric acid, 1.5-30g/L of 15-hydroxystearic acid polyethylene glycol ester and 1880.5-10g/L of poloxamer.
9. The micellar vitamin K1 injection according to claim 8, wherein: the dosage of the active ingredients and the auxiliary materials is as follows: vitamin K 1 10g/L, 80g/L of soybean phosphatidylcholine, 50g/L of glycocholic acid, 4.5g/L of sodium hydroxide, 2g/L of 1M hydrochloric acid, 7.5g/L of 15-hydroxystearic acid polyethylene glycol ester and 188 g/L of poloxamer.
10. The micelle type vitamin K1 injection according to any one of claims 1 and 3 to 6 is used for preparing a medicament for treating ischemia and hemorrhage caused by vitamin K deficiency; hypocoagulase hemorrhoidosis caused by coumarins, sodium salicylate, etc.; the application of the medicine in treating neonatal hemorrhage and vitamin K deficiency in vivo caused by long-term application of broad-spectrum antibiotics.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117064849A (en) * | 2023-07-10 | 2023-11-17 | 南京臣功制药股份有限公司 | Vitamin K 1 Injection and preparation method thereof |
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| CN1596882A (en) * | 2004-07-22 | 2005-03-23 | 沈阳药科大学 | Vitamin K1 emulsion and its freeze-dried emulsion and preparation method |
| WO2008143380A1 (en) * | 2007-05-17 | 2008-11-27 | Dae Won Pharmaceutical Co., Ltd. | Composition for injection including propofol and method of preparing the same |
| US20100189596A1 (en) * | 2007-07-26 | 2010-07-29 | Shenyang Pharmaceutical University | Composite emulsifier, an emulsion prepared from it and the preparation method thereof |
| CN105997869A (en) * | 2016-06-17 | 2016-10-12 | 合肥华方医药科技有限公司 | Vitamin K1 micelle injection and preparation method thereof |
| CN110876719A (en) * | 2018-09-06 | 2020-03-13 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1596882A (en) * | 2004-07-22 | 2005-03-23 | 沈阳药科大学 | Vitamin K1 emulsion and its freeze-dried emulsion and preparation method |
| WO2008143380A1 (en) * | 2007-05-17 | 2008-11-27 | Dae Won Pharmaceutical Co., Ltd. | Composition for injection including propofol and method of preparing the same |
| US20100189596A1 (en) * | 2007-07-26 | 2010-07-29 | Shenyang Pharmaceutical University | Composite emulsifier, an emulsion prepared from it and the preparation method thereof |
| CN105997869A (en) * | 2016-06-17 | 2016-10-12 | 合肥华方医药科技有限公司 | Vitamin K1 micelle injection and preparation method thereof |
| CN110876719A (en) * | 2018-09-06 | 2020-03-13 | 中国人民解放军军事科学院军事医学研究院 | Vitamin K1 injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117064849A (en) * | 2023-07-10 | 2023-11-17 | 南京臣功制药股份有限公司 | Vitamin K 1 Injection and preparation method thereof |
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Application publication date: 20230103 |