Vitamin B12 preparation composition and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a vitamin B12 preparation composition and a preparation method thereof.The vitamin B12 preparation composition is prepared from vitamin B12, sodium chloride and water for injection, and the pH value is adjusted to 4.0-5.0 through a 0.1 mol / L hydrochloric acid solution; wherein the vitamin B12 preparation composition is subjected to filtration and sterilization treatment; a nanometer titanium dioxide-based hollow fiber membrane is adopted for filtration and sterilization; the vitamin B12 preparation composition prepared by the invention is high in safety and stable in performance, and can meet various injection requirements. After the vitamin B12 preparation composition treated by the nano titanium dioxide-based hollow fiber membrane prepared by the method disclosed by the invention is adopted, a relatively good sterilization effect can be achieved, and the use safety of the vitamin B12 preparation composition is ensured.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a vitamin B 12 The invention relates to a preparation composition and a method for preparing the same. Background Art

[0002] Vitamin B 12 Also known as cobalamin, it is a polycyclic compound containing trivalent cobalt, which can cause rashes, itching, diarrhea and asthma; four reduced pyrrole rings are linked together to form a corrin macrocycle (similar to porphyrin), which is the only vitamin containing metal elements. 12 It is a red crystalline powder, odorless and tasteless, soluble in water, hardly soluble in ethanol, insoluble in acetone, chloroform and ether. It is most stable under weak acid conditions of pH 4.5-5.0, decomposes in strong acid (pH<2) or alkaline solution, and may be destroyed to a certain extent by heat.

[0003] Higher animals and plants cannot produce vitamin B 12 , vitamin B in nature 12 They are all synthesized by microorganisms. 12 It is the only vitamin that requires the help of gastric parietal cell secretions (intrinsic factor) to be absorbed. It is involved in the production of bone marrow red blood cells, preventing pernicious anemia and preventing damage to brain nerves.

[0004] Vitamin B 12 Injection is an important drug, the main ingredient: vitamin B 12 , chemical name is Coα-[α-(5,6-dimethylbenzimidazolyl)]-Coβ cyanocobalamide. Vitamin B 12 The injection is mainly used to treat megaloblastic anemia caused by intrinsic factor deficiency, and can also be used as an adjuvant treatment for subacute combined degenerative nervous system diseases such as neuritis.

[0005] Due to microorganism B 12 The method of administration of the preparation is to directly inject the drug into the human body's blood or subcutaneous parts, so if the product cannot be guaranteed to be sterile, it will cause serious adverse reactions in patients.

[0006] Among all sterilization methods, terminal moist heat sterilization should be the first choice, that is, to sterilize the final product of sterile drugs. When excessive heat sterilization conditions are used, the thermal instability of product components can easily cause product performance degradation, and the sterility assurance level required by regulations cannot be achieved, thus putting the product in a very high-risk position.

[0007] The present invention prepares vitamin B 12The injection solution is filtered using a special filter membrane, which can improve the sterility assurance level, reduce the clinical adverse reactions of the drug, and achieve good commercial production. Summary of the invention

[0008] In view of the problems existing in the prior art, the present invention provides a vitamin B12 preparation composition and a preparation method thereof.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] A B vitamin 12 The preparation composition comprises the following ingredients by weight: vitamin B 12 1-2 parts, 9-11 parts of sodium chloride, 990-1000 parts of water for injection, and use 0.1 mol / L hydrochloric acid solution to adjust the pH value to 4.0-5.0;

[0011] Among them, vitamin B 12 The formulation composition is sterilized by filtration;

[0012] The filtration and sterilization adopts nano-titanium dioxide-based hollow fiber membrane filtration.

[0013] As a further technical solution, the nano-titanium dioxide-based hollow fiber membrane filtration preparation method comprises the following steps:

[0014] (1) First, PSE resin, diluent, and porous nano-titanium dioxide are added to a dissolving tank in sequence, an inert gas is introduced into the dissolving tank, the air in the dissolving tank is exhausted, and then the dissolving tank is heated to 185-188° C. and stirred for 40 minutes to obtain a molten material;

[0015] (2) vacuum degassing the molten material for 40 minutes to obtain a casting solution;

[0016] The vacuum degassing temperature is 170℃;

[0017] (3) The obtained casting liquid and cavity forming fluid are spun out through a spinneret, and then passed through a coagulation bath for phase separation and solidification, and finally passed through water discharge, winding and winding, and then washed and dried to obtain.

[0018] As a further technical solution, in step (1), the mass ratio of the PSE resin, the diluent, and the porous nano-titanium dioxide is 2-3:6-7:0.1-0.15;

[0019] The diluent is dibutyl phthalate or dioctyl phthalate;

[0020] Among them, the mixing mass ratio of dibutyl phthalate and dioctyl phthalate is 1:1.

[0021] As a further technical solution,

[0022] The inert gas in step (1) is nitrogen or neon.

[0023] As a further technical solution, the method for preparing the porous nano-titanium dioxide in step (1) is:

[0024] First, P123 and acetonitrile were added to water in sequence, and stirred at a speed of 1000 r / min for 15 min to obtain a first mixture;

[0025] Put glucose powder and zinc nitrate into a reaction kettle, then add deionized water, stir and mix evenly to obtain a mixed solution;

[0026] The mass ratio of glucose powder to zinc nitrate is 1:3;

[0027] The mass ratio of zinc nitrate and deionized water is 1:10;

[0028] Add urea to the mixed solution, adjust the temperature to 60° C., keep warm and stir for 40 minutes to obtain a composite solution, centrifuge and filter the composite solution to obtain a second mixture;

[0029] The molar ratio of zinc nitrate to urea is 1:1;

[0030] Then, tetrabutyl titanate and the second mixture are added dropwise to the first mixture, and then the second mixture is added, and the mixture is stirred for 30 minutes, and then ultrasonically treated for 10 minutes, and then allowed to stand at room temperature for 1 day to obtain the second mixture;

[0031] The second mixture is centrifuged to collect the precipitate, and then dried to obtain a dry product;

[0032] The dried product was calcined for 3-4 hours and cooled to room temperature to obtain porous nano-titanium dioxide;

[0033] The mass ratio of tetrabutyl titanate to the second mixture is 5:1.

[0034] As a further technical solution, the mass ratio of P123, acetonitrile and water is 0.2-0.3:10:10;

[0035] The mass ratio of tetrabutyl titanate to acetonitrile is 1:8.5-9;

[0036] The centrifugal speed was 5500 r / min and the time was 15 min;

[0037] The calcination was carried out in an air atmosphere at a temperature of 475° C. and a heating rate of 1.5° C. / min.

[0038] As a further technical solution, the cavity forming fluid in step (3) is nitrogen;

[0039] The spinneret temperature was 176°C and the cavity fluid flow rate was 1.75 mL min -1 , kettle pressure 0.3MPa, coagulation bath selected water bath below 55℃, winding speed 1.8m·min -1 .

[0040] As a further technical solution, in step (3), the washing is performed by soaking in anhydrous ethanol for 20 hours, then washing with water for 40 minutes, and then vacuum drying to obtain;

[0041] The vacuum drying temperature was 60°C and the time was 4 hours.

[0042] A B vitamin 12 The preparation method of the formulation composition comprises the following steps:

[0043] S1 preparation

[0044] Prepare 0.1 mol / L hydrochloric acid solution for adjusting pH value;

[0045] The liquid preparation process uses a red light, and 80% of the total amount of injection water is added into the container. The injection water temperature is controlled at 30℃-40℃, and the stirring speed is 70-90r / min. This speed is maintained throughout the process. Add the prescribed amount of sodium chloride and vitamin B 12 , stir for 15 minutes, then add water for injection and make up to the full amount of water for injection; continue stirring for 5 minutes, measure the pH value, adjust the pH value of the system to 4.0-5.0 with 0.1 mol / L hydrochloric acid solution, and then stir and circulate for 15 minutes to obtain vitamin B 12 The preparation composition is transferred into a liquid preparation tank;

[0046] S2 Wash and Dry

[0047] Bottle washing, drying and sterilization, heating section temperature 300±10℃, mesh belt speed: 50Hz;

[0048] S3 Filtration

[0049] Vitamin B 12 The preparation composition is filtered by a sterilizing filter equipped with a nano-titanium dioxide-based hollow fiber membrane; the pressure in the liquid preparation tank during transportation is not greater than 2.0 bar, and vitamin B 12 The pressure difference between the front and rear ends of the sterilizing filter in the sterilizing filtration of the preparation composition should be ≤3 bar to obtain the filtrate;

[0050] S4 filling

[0051] The filling process of glass ampoule is protected from light, and the illumination is ≤500LUX. After the intermediate is tested and qualified, the filtrate is filtered again before filling;

[0052] S5 Sterilization

[0053] After filling, sterilize at 121℃ for 12 minutes.

[0054] Compared with the prior art, the present invention has the following beneficial effects:

[0055] Vitamin B prepared by the present invention 12 The preparation composition has high safety, stable performance, and can be applied to meet various injection needs.

[0056] The nano-titanium dioxide-based hollow fiber membrane prepared in the present invention has a relatively low pore diameter, can be effectively used for filtering and sterilizing liquids, can intercept impurities such as suspended matter, colloids, bacteria, etc. in the liquid, and has a high sterilization efficiency, thereby greatly ensuring the quality of the liquid after filtration. Therefore, the vitamin B12 treated by the nano-titanium dioxide-based hollow fiber membrane prepared in the present invention is 12 After the preparation is combined, it can achieve a better sterilization effect and ensure the vitamin B 12 The preparation composition is safe to use.

[0057] The nano-titanium dioxide-based hollow fiber membrane prepared by the present invention has high porosity and pure water flux, can ensure high pure water flux at low working pressure, has high filtration efficiency, can effectively reduce energy consumption and operating costs, and saves processing time.

[0058] Compared with traditional high-temperature sterilization or antibacterial agent sterilization technology, the nano-titanium dioxide-based hollow fiber membrane filtration sterilization of the present invention does not require the addition of any chemical agents, can avoid the generation of secondary pollution, and at the same time avoids the destructive effect of high temperature on active components, thereby ensuring performance stability.

[0059] The present invention introduces porous nano-titanium dioxide into the nano-titanium dioxide-based hollow fiber membrane, which not only increases the pore structure of the nano-titanium dioxide-based hollow fiber membrane, but also has strong antibacterial properties. The generated free radicals have strong oxidizing ability, which can attack the unsaturated bonds in the bacterial cell wall, inhibit the connection between the polysaccharide chain and the tetrapeptide cross-linking of the bacterial cell wall, and directly destroy the cell wall, which causes the bacteria to lose their protective barrier and are easy to be further killed; the free radicals can also oxidize the polyunsaturated phospholipids of the cell membrane and destroy the integrity of the cell membrane, which causes the intracellular components to flow out, the ions inside and outside the cell are unbalanced, and finally the bacteria lose their biological activity, thereby making vitamin B 12The preparation composition can kill bacteria during the filtration process, preventing bacteria from adhering to the filter membrane and causing the sterilization effect to decrease, thus affecting the vitamin B after filtration. 12 The preparation composition has safe performance.

[0060] The nano-titanium dioxide-based hollow fiber membrane prepared by the present invention has a higher porosity, and a higher porosity means that there are more channels in the nano-titanium dioxide-based hollow fiber membrane material to allow fluid to pass through, thereby improving the permeability of the membrane, which helps to speed up the filtration speed, reduce the processing time, and maintain a higher filtration accuracy. In the filtration and sterilization process, the high permeability can more effectively remove vitamin B 12 Bacteria and other microorganisms in formulation compositions.

[0061] The nano-titanium dioxide-based hollow fiber membrane prepared by the present invention introduces porous nano-titanium dioxide, which is evenly dispersed in the matrix, greatly improving the performance of the hollow fiber membrane, including excellent mechanical properties and acid and alkali resistance, can be better applied to filtration, and can extend its service life. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0063] Figure 1 This is a statistical chart of the porosity of hollow fiber membranes in each test group. DETAILED DESCRIPTION

[0064] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0065] The following are specific embodiments:

[0066] Example 1

[0067] A B vitamin 12 The preparation composition comprises the following ingredients by weight: vitamin B 12 1 part, 9 parts of sodium chloride, 990 parts of water for injection, and adjust the pH value to 4.5 with 0.1 mol / L hydrochloric acid solution;

[0068] Wherein, the vitamin B12 preparation composition is subjected to filtration and sterilization treatment;

[0069] The filtration and sterilization adopts nano-titanium dioxide-based hollow fiber membrane filtration.

[0070] The nano-titanium dioxide-based hollow fiber membrane filtration preparation method comprises the following steps:

[0071] (1) First, PSE resin, diluent, and porous nano-titanium dioxide are added to a dissolving tank in sequence, an inert gas is introduced into the dissolving tank, the air in the dissolving tank is exhausted, and then the mixture is heated to 185° C. and stirred for 40 minutes to obtain a molten material; the mixing mass ratio of PSE resin, diluent, and porous nano-titanium dioxide is 2:6:0.1;

[0072] The diluent is dibutyl phthalate or dioctyl phthalate;

[0073] Among them, the mixing mass ratio of dibutyl phthalate and dioctyl phthalate is 1:1.

[0074] The inert gas is nitrogen.

[0075] The preparation method of porous nano titanium dioxide is as follows:

[0076] First, P123 and acetonitrile were added to water in sequence, and stirred at a speed of 1000 r / min for 15 min to obtain a first mixture;

[0077] Put glucose powder and zinc nitrate into a reaction kettle, then add deionized water, stir and mix evenly to obtain a mixed solution;

[0078] The mass ratio of glucose powder to zinc nitrate is 1:3;

[0079] The mass ratio of zinc nitrate and deionized water is 1:10;

[0080] Add urea to the mixed solution, adjust the temperature to 60° C., keep warm and stir for 40 minutes to obtain a composite solution, centrifuge and filter the composite solution to obtain a second mixture;

[0081] The molar ratio of zinc nitrate to urea is 1:1;

[0082] Then, tetrabutyl titanate and the second mixture are added dropwise to the first mixture, and then the second mixture is added, and the mixture is stirred for 30 minutes, and then ultrasonically treated for 10 minutes, and then allowed to stand at room temperature for 1 day to obtain the second mixture;

[0083] The second mixture is centrifuged to collect the precipitate, and then dried to obtain a dry product;

[0084] The dried product was calcined for 3 hours and cooled to room temperature to obtain porous nano-titanium dioxide;

[0085] The mass ratio of tetrabutyl titanate to the second mixture is 5:1.

[0086] The mass ratio of P123, acetonitrile and water is 0.2:10:10;

[0087] The mass ratio of tetrabutyl titanate to acetonitrile is 1:8.5;

[0088] The centrifugal speed was 5500 r / min and the time was 15 min;

[0089] The calcination was carried out in an air atmosphere at a temperature of 475° C. and a heating rate of 1.5° C. / min.

[0090] (2) vacuum degassing the molten material for 40 minutes to obtain a casting solution;

[0091] The vacuum degassing temperature is 170℃;

[0092] (3) the obtained casting liquid and cavity forming fluid are spun out through a spinneret, and then phase separated and solidified in a coagulation bath, and finally wound and rolled up after water discharge, and then washed and dried to obtain; the cavity forming fluid is nitrogen;

[0093] The spinneret temperature was 176°C and the cavity fluid flow rate was 1.75 mL min -1 , kettle pressure 0.3MPa, coagulation bath selected water bath below 55℃, winding speed 1.8m·min -1 .

[0094] The washing was performed by soaking in anhydrous ethanol for 20 h, then washing with water for 40 min, and then vacuum drying;

[0095] The vacuum drying temperature was 60°C and the time was 4 hours.

[0096] A B vitamin 12 The preparation method of the formulation composition comprises the following steps:

[0097] S1 preparation

[0098] Prepare 0.1 mol / L hydrochloric acid solution for adjusting pH value;

[0099] The liquid preparation process uses a red light, and 80% of the total amount of injection water is added into the container. The injection water temperature is controlled at 30°C, and the stirring speed is 70r / min. This speed is maintained throughout the process. Add the prescribed amount of sodium chloride and vitamin B 12 , stir for 15 minutes, then add water for injection and make up to the full amount of water for injection; continue stirring for 5 minutes, measure the pH value, adjust the pH value of the system to 4.5 with 0.1 mol / L hydrochloric acid solution, and then stir and circulate for 15 minutes to obtain vitamin B 12The preparation composition is transferred into a liquid preparation tank;

[0100] S2 Wash and Dry

[0101] Bottle washing, drying and sterilization, heating section temperature 300±10℃, mesh belt speed: 50Hz;

[0102] S3 Filtration Sterilization

[0103] Vitamin B 12 The preparation composition is filtered by a sterilizing filter equipped with a nano-titanium dioxide-based hollow fiber membrane; during the transportation process, the pressure in the liquid preparation tank is 1.5 bar, and vitamin B 12 The pressure difference between the front and rear ends of the sterilizing filter in the sterilizing filtration of the preparation composition should be 2 bar to obtain the filtrate;

[0104] S4 filling

[0105] The filling process of glass ampoule is protected from light, the illumination is 450LUX, and after the intermediate is tested and qualified, the filtrate is filtered again before filling;

[0106] S5 Sterilization

[0107] After filling, sterilize at 121℃ for 12 minutes.

[0108] Example 2

[0109] A B vitamin 12 The preparation composition comprises the following ingredients by weight: vitamin B 12 1 part, 9 parts of sodium chloride, 990 parts of water for injection, and adjust the pH value to 4.5 with 0.1 mol / L hydrochloric acid solution;

[0110] Among them, vitamin B 12 The formulation composition is sterilized by filtration;

[0111] The filtration and sterilization adopts nano-titanium dioxide-based hollow fiber membrane filtration.

[0112] The nano-titanium dioxide-based hollow fiber membrane filtration preparation method comprises the following steps:

[0113] (1) First, PSE resin, diluent, and porous nano-titanium dioxide are added to a dissolving tank in sequence, an inert gas is introduced into the dissolving tank, the air in the dissolving tank is exhausted, and then the mixture is heated to 186° C. and stirred for 40 minutes to obtain a molten material; the mixing mass ratio of PSE resin, diluent, and porous nano-titanium dioxide is 2.5:6.3:0.12;

[0114] The diluent is dibutyl phthalate or dioctyl phthalate;

[0115] Among them, the mixing mass ratio of dibutyl phthalate and dioctyl phthalate is 1:1.

[0116] The inert gas is nitrogen.

[0117] The preparation method of porous nano titanium dioxide is as follows:

[0118] First, P123 and acetonitrile were added to water in sequence, and stirred at a speed of 1000 r / min for 15 min to obtain a first mixture;

[0119] Put glucose powder and zinc nitrate into a reaction kettle, then add deionized water, stir and mix evenly to obtain a mixed solution;

[0120] The mass ratio of glucose powder to zinc nitrate is 1:3;

[0121] The mass ratio of zinc nitrate and deionized water is 1:10;

[0122] Add urea to the mixed solution, adjust the temperature to 60° C., keep warm and stir for 40 minutes to obtain a composite solution, centrifuge and filter the composite solution to obtain a second mixture;

[0123] The molar ratio of zinc nitrate to urea is 1:1;

[0124] Then, tetrabutyl titanate and the second mixture are added dropwise to the first mixture, and then the second mixture is added, and the mixture is stirred for 30 minutes, and then ultrasonically treated for 10 minutes, and then allowed to stand at room temperature for 1 day to obtain the second mixture;

[0125] The second mixture is centrifuged to collect the precipitate, and then dried to obtain a dry product;

[0126] The dried product was calcined for 3-4 hours and cooled to room temperature to obtain porous nano-titanium dioxide;

[0127] The mass ratio of tetrabutyl titanate to the second mixture is 5:1.

[0128] The mass ratio of P123, acetonitrile and water is 0.25:10:10;

[0129] The mass ratio of tetrabutyl titanate to acetonitrile is 1:8.8;

[0130] The centrifugal speed was 5500 r / min and the time was 15 min;

[0131] The calcination was carried out in an air atmosphere at a temperature of 475° C. and a heating rate of 1.5° C. / min.

[0132] (2) vacuum degassing the molten material for 40 minutes to obtain a casting solution;

[0133] The vacuum degassing temperature is 170℃;

[0134] (3) the obtained casting liquid and cavity forming fluid are spun out through a spinneret, and then phase separated and solidified in a coagulation bath, and finally wound and rolled up after water discharge, and then washed and dried to obtain; the cavity forming fluid is nitrogen;

[0135] The spinneret temperature was 176°C and the cavity fluid flow rate was 1.75 mL min -1 , kettle pressure 0.3MPa, coagulation bath selected water bath below 55℃, winding speed 1.8m·min -1 .

[0136] The washing was performed by soaking in anhydrous ethanol for 20 h, then washing with water for 40 min, and then vacuum drying;

[0137] The vacuum drying temperature was 60°C and the time was 4 hours.

[0138] A B vitamin 12 The preparation method of the formulation composition comprises the following steps:

[0139] S1 preparation

[0140] Prepare 0.1 mol / L hydrochloric acid solution for adjusting pH value;

[0141] The liquid preparation process uses a red light, and 80% of the total amount of injection water is added into the container. The injection water temperature is controlled at 30°C, and the stirring speed is 80r / min. This speed is maintained throughout the process. Add the prescribed amount of sodium chloride and vitamin B 12 , stir for 15 minutes, then add water for injection and make up to the full amount of water for injection; continue stirring for 5 minutes, measure the pH value, adjust the pH value of the system to 4.5 with 0.1 mol / L hydrochloric acid solution, and then stir and circulate for 15 minutes to obtain vitamin B 12 The preparation composition is transferred into a liquid preparation tank;

[0142] S2 Wash and Dry

[0143] Bottle washing, drying and sterilization, heating section temperature 300±10℃, mesh belt speed: 50Hz;

[0144] S3 Filtration Sterilization

[0145] Vitamin B 12 The preparation composition is filtered by a sterilizing filter equipped with a nano-titanium dioxide-based hollow fiber membrane; during the transportation process, the pressure in the liquid preparation tank is 1.5 bar, and vitamin B 12 The pressure difference between the front and rear ends of the sterilizing filter in the sterilizing filtration of the preparation composition should be 2 bar to obtain the filtrate;

[0146] S4 filling

[0147] The filling process of glass ampoule is protected from light, the illumination is 450LUX, and after the intermediate is tested and qualified, the filtrate is filtered again before filling;

[0148] S5 Sterilization

[0149] After filling, sterilize at 121℃ for 12 minutes.

[0150] Example 3

[0151] A B vitamin 12 The preparation composition comprises the following ingredients by weight: vitamin B 12 2 parts, 11 parts of sodium chloride, 1000 parts of water for injection, and adjust the pH value to 4.5 with 0.1 mol / L hydrochloric acid solution;

[0152] Wherein, the vitamin B12 preparation composition is subjected to filtration and sterilization treatment;

[0153] The filtration and sterilization adopts nano-titanium dioxide-based hollow fiber membrane filtration.

[0154] The nano-titanium dioxide-based hollow fiber membrane filtration preparation method comprises the following steps:

[0155] (1) First, PSE resin, diluent, and porous nano-titanium dioxide are added to a dissolving tank in sequence, an inert gas is introduced into the dissolving tank, the air in the dissolving tank is exhausted, and then the mixture is heated to 188° C. and stirred for 40 minutes to obtain a molten material; the mixing mass ratio of PSE resin, diluent, and porous nano-titanium dioxide is 3:7:0.15;

[0156] The diluent is dibutyl phthalate or dioctyl phthalate;

[0157] Among them, the mixing mass ratio of dibutyl phthalate and dioctyl phthalate is 1:1.

[0158] The inert gas is nitrogen.

[0159] The preparation method of porous nano titanium dioxide is as follows:

[0160] First, P123 and acetonitrile were added to water in sequence, and stirred at a speed of 1000 r / min for 15 min to obtain a first mixture;

[0161] Put glucose powder and zinc nitrate into a reaction kettle, then add deionized water, stir and mix evenly to obtain a mixed solution;

[0162] The mass ratio of glucose powder to zinc nitrate is 1:3;

[0163] The mass ratio of zinc nitrate and deionized water is 1:10;

[0164] Add urea to the mixed solution, adjust the temperature to 60° C., keep warm and stir for 40 minutes to obtain a composite solution, centrifuge and filter the composite solution to obtain a second mixture;

[0165] The molar ratio of zinc nitrate to urea is 1:1;

[0166] Then, tetrabutyl titanate and the second mixture are added dropwise to the first mixture, and then the second mixture is added, and the mixture is stirred for 30 minutes, and then ultrasonically treated for 10 minutes, and then allowed to stand at room temperature for 1 day to obtain the second mixture;

[0167] The second mixture is centrifuged to collect the precipitate, and then dried to obtain a dry product;

[0168] The dried product was calcined for 3-4 hours and cooled to room temperature to obtain porous nano-titanium dioxide;

[0169] The mass ratio of tetrabutyl titanate to the second mixture is 5:1.

[0170] The mass ratio of P123, acetonitrile and water is 0.3:10:10;

[0171] The mass ratio of tetrabutyl titanate to acetonitrile is 1:9;

[0172] The centrifugal speed was 5500 r / min and the time was 15 min;

[0173] The calcination was carried out in an air atmosphere at a temperature of 475° C. and a heating rate of 1.5° C. / min.

[0174] (2) vacuum degassing the molten material for 40 minutes to obtain a casting solution;

[0175] The vacuum degassing temperature is 170℃;

[0176] (3) the obtained casting liquid and cavity forming fluid are spun out through a spinneret, and then phase separated and solidified in a coagulation bath, and finally wound and rolled up after water discharge, and then washed and dried to obtain; the cavity forming fluid is nitrogen;

[0177] The spinneret temperature was 176°C and the cavity fluid flow rate was 1.75 mL min -1 , kettle pressure 0.3MPa, coagulation bath selected water bath below 55℃, winding speed 1.8m·min -1 .

[0178] The washing was performed by soaking in anhydrous ethanol for 20 h, then washing with water for 40 min, and then vacuum drying;

[0179] The vacuum drying temperature was 60°C and the time was 4 hours.

[0180] A B vitamin 12 The preparation method of the formulation composition comprises the following steps:

[0181] S1 preparation

[0182] Prepare 0.1 mol / L hydrochloric acid solution for adjusting pH value;

[0183] The liquid preparation process uses a red light, and 80% of the total amount of injection water is added into the container. The injection water temperature is controlled at 40°C, and the stirring speed is 90r / min. This speed is maintained throughout the process. Add the prescribed amount of sodium chloride and vitamin B 12 , stir for 15 minutes, then add water for injection and make up to the full amount of water for injection; continue stirring for 5 minutes, measure the pH value, adjust the pH value of the system to 4.5 with 0.1 mol / L hydrochloric acid solution, and then stir and circulate for 15 minutes to obtain vitamin B 12 The preparation composition is transferred into a liquid preparation tank;

[0184] S2 Wash and Dry

[0185] Bottle washing, drying and sterilization, heating section temperature 300±10℃, mesh belt speed: 50Hz;

[0186] S3 Filtration

[0187] Vitamin B 12 The preparation composition is filtered by a sterilizing filter equipped with a nano-titanium dioxide-based hollow fiber membrane; during the transportation process, the pressure in the liquid preparation tank is 1.5 bar, and vitamin B 12 The pressure difference between the front and rear ends of the sterilizing filter in the sterilizing filtration of the preparation composition should be 2 bar to obtain the filtrate;

[0188] S4 filling

[0189] The filling process of glass ampoule is protected from light, the illumination is 450LUX, and after the intermediate is tested and qualified, the filtrate is filtered again before filling;

[0190] S5 Sterilization

[0191] After filling, sterilize at 121℃ for 12 minutes.

[0192] Comparative Example 1: This comparative example is basically the same as Example 2, except that porous nano-titanium dioxide is not added to the hollow fiber membrane.

[0193] Comparative Example 2: This comparative example is basically the same as Example 2, except that the porous nano-titanium dioxide in the hollow fiber membrane is replaced with commercially available nano-titanium dioxide purchased from Xianfeng Nano, China.

[0194] test:

[0195] Porosity test

[0196] Porosity refers to the ratio of the total volume of the membrane's internal pores to the total volume of the membrane.

[0197] Weigh the wet weight of the membrane fibers (W) on an analytical balance. w ), and then put the membrane into a vacuum oven to dry to constant weight, let the membrane cool to room temperature, and weigh the dry weight of the membrane (W d ), the porosity of the membrane was calculated according to the following formula:

[0198] ε=W w -W d / ρ w V×100%;

[0199] Among them, W w is the wet weight of the membrane, g; W d is the dry weight of the membrane, g; ρ w is the density of ultrapure water, kg / m 3 ; V is the effective volume of the membrane, m 3 ; ε is the porosity of the membrane, %;

[0201] Table 1

[0202] Porosity % Example 1 79.6 Example 2 80.8 Example 3 79.0 Comparative Example 1 70.2 Comparative Example 2 68.7

[0203] It can be seen from Table 1 that the hollow fiber membrane prepared in the present invention has a higher porosity and can improve the filtration efficiency. The use of commercially available nano-titanium dioxide will slightly reduce the porosity.

[0204] The pure water flux of the hollow fiber membranes in the examples and comparative examples was tested using a laboratory-made testing device.

[0205] Test the pure water filtered within 1 minute, calculate the effective area of ​​the membrane assembly, repeat the test 5 times, take the average value, and calculate the pure water flux according to the following formula:

[0206] F = Q / At;

[0207] Where F is the pure water flux of the membrane, L / (m 2 ·h); Q is the pure water permeation, L; A is the membrane area, m 2 ; t is the time used to collect the pure water permeation, h:

[0208] Table 2

[0209] <![CDATA[Pure water flux L / (m 2 ·h)]]> Example 1 220.96 Example 2 223.71 Example 3 219.34 Comparative Example 1 145.27 Comparative Example 2 143.18

[0210] As shown in Table 2, the hollow fiber membrane prepared in the present invention has a higher pure water flux, indicating that the hollow fiber membrane prepared in the present invention can 12The preparation composition has a high filtration efficiency and can save filtration processing time.

[0211] Filtration sterilization test:

[0212] Each group of hollow fiber membranes in the embodiment was subjected to filtration sterilization test, with Escherichia coli and Staphylococcus aureus as the test bacteria, and the concentration of Escherichia coli in the test liquid was 1.3×10 6 cfu / mL, Staphylococcus aureus concentration was 1.0×10 6 cfu / mL, filtered through a sterilizing filter equipped with a nano-titanium dioxide-based hollow fiber membrane in the embodiment, and the contents of Escherichia coli and Staphylococcus aureus in the filtered liquid were detected to calculate the filtration sterilization rate:

[0213] Filtration sterilization rate = 100% × (initial concentration - concentration after filtration) / initial concentration;

[0214] Table 3

[0215]

[0216] From Comparison 3, it can be seen that the hollow fiber membrane prepared by the present invention has a higher filtration and sterilization rate, and can better target vitamin B 12 The preparation composition is filtered and sterilized, thereby avoiding the influence of high temperature sterilization on the performance of the vitamin B12 preparation composition.

[0217] The tensile properties of the hollow fiber membrane were tested using an electronic tensile tester: the sample size of the embodiment and the comparative example was 5 mm × 45 mm, and the tensile speed was set to 0.5 mms -1 , 5 specimens were selected for each sample for tensile testing;

[0218] Table 4

[0219] Tensile stress MPa Example 1 1.31 Example 2 1.36 Example 3 1.33 Comparative Example 1 0.97 Comparative Example 2 1.12

[0220] It can be seen from Table 4 that the hollow fiber membrane prepared in the present invention has excellent tensile properties.

[0221] Acid and alkali resistance test:

[0222] Continuing the above test, each group of samples was immersed in 1mol / L sulfuric acid solution and 5mol / L hydroxide solution for 1h, then cleaned and dried, and the tensile properties were tested to compare the changes in tensile stress:

[0223] Table 5

[0224]

[0225] It can be seen from Table 5 that the hollow fiber membrane prepared in the present invention has excellent acid and alkali resistance.

[0226] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A B vitamin 12 The preparation composition is characterized in that The following ingredients are included by weight: Vitamin B 12 1-2 parts, 9-11 parts of sodium chloride, 990-1000 parts of water for injection, and use 0.1 mol / L hydrochloric acid solution to adjust the pH value to 4.0-5.0; Among them, vitamin B 12 The formulation composition is sterilized by filtration; The filtration and sterilization adopts nano-titanium dioxide-based hollow fiber membrane filtration.

2. A vitamin B according to claim 1 12 The preparation composition is characterized in that The nano-titanium dioxide-based hollow fiber membrane filtration preparation method comprises the following steps: (1) First, PSE resin, diluent, and porous nano-titanium dioxide are added to a dissolving tank in sequence, an inert gas is introduced into the dissolving tank, the air in the dissolving tank is exhausted, and then the dissolving tank is heated to 185-188° C. and stirred for 40 minutes to obtain a molten material; (2) vacuum degassing the molten material for 40 minutes to obtain a casting solution; The vacuum degassing temperature is 170℃; (3) The obtained casting liquid and cavity forming fluid are spun out through a spinneret, and then passed through a coagulation bath for phase separation and solidification, and finally passed through water discharge, winding and winding, and then washed and dried to obtain.

3. A vitamin B according to claim 2 12 The preparation composition is characterized in that In step (1), the mass ratio of PSE resin, diluent and porous nano-titanium dioxide is 2-3:6-7:0.1-0.15; The diluent is dibutyl phthalate or dioctyl phthalate; Among them, the mixing mass ratio of dibutyl phthalate and dioctyl phthalate is 1:

1.

4. A vitamin B according to claim 2 12 The preparation composition is characterized in that The inert gas in step (1) is nitrogen or neon.

5. A vitamin B according to claim 2 12 The preparation composition is characterized in that The method for preparing the porous nano-titanium dioxide in step (1) is: First, P123 and acetonitrile were added to water in sequence, and stirred at a speed of 1000 r / min for 15 min to obtain a first mixture; Put glucose powder and zinc nitrate into a reaction kettle, then add deionized water, stir and mix evenly to obtain a mixed solution; The mass ratio of glucose powder to zinc nitrate is 1:3; The mass ratio of zinc nitrate and deionized water is 1:10; Add urea to the mixed solution, adjust the temperature to 60° C., keep warm and stir for 40 minutes to obtain a composite solution, centrifuge and filter the composite solution to obtain a second mixture; The molar ratio of zinc nitrate to urea is 1:1; Then, tetrabutyl titanate and the second mixture are added dropwise to the first mixture, and then the second mixture is added, and the mixture is stirred for 30 minutes, and then ultrasonically treated for 10 minutes, and then allowed to stand at room temperature for 1 day to obtain the second mixture; The second mixture is centrifuged to collect the precipitate, and then dried to obtain a dry product; The dried product was calcined for 3-4 hours and cooled to room temperature to obtain porous nano-titanium dioxide; The mass ratio of tetrabutyl titanate to the second mixture is 5:

1.

6. Vitamin B according to claim 5 12 The preparation composition is characterized in that The mass ratio of P123, acetonitrile and water is 0.2-0.3:10:10; The mass ratio of tetrabutyl titanate to acetonitrile is 1:8.5-9; The centrifugal speed was 5500 r / min and the time was 15 min; The calcination was carried out in an air atmosphere at a temperature of 475° C. and a heating rate of 1.5° C. / min.

7. A vitamin B according to claim 2 12 The preparation composition is characterized in that The cavity forming fluid in step (3) is nitrogen; The spinneret temperature was 176°C and the cavity fluid flow rate was 1.75 mL min -1 , kettle pressure 0.3MPa, coagulation bath selected water bath below 55℃, winding speed 1.8m·min -1 .

8. A vitamin B according to claim 2 12 The preparation composition is characterized in that In step (3), the washing is performed by soaking in anhydrous ethanol for 20 hours, then washing with water for 40 minutes, and then vacuum drying; The vacuum drying temperature was 60°C and the time was 4 hours.

9. A vitamin B according to claim 1 12 A method for preparing a formulation composition, characterized in that: The steps include: S1 preparation Prepare 0.1 mol / L hydrochloric acid solution for adjusting pH value; The liquid preparation process uses a red light, and 80% of the total amount of injection water is added into the container. The injection water temperature is controlled at 30℃-40℃, and the stirring speed is 70-90r / min. This speed is maintained throughout the process. Add the prescribed amount of sodium chloride and vitamin B 12 , stir for 15 minutes, then add water for injection and make up to the full amount of water for injection; continue stirring for 5 minutes, measure the pH value, adjust the pH value of the system to 4.0-5.0 with 0.1 mol / L hydrochloric acid solution, and then stir and circulate for 15 minutes to obtain vitamin B 12 The preparation composition is transferred into a liquid preparation tank; S2 Wash and Dry Bottle washing, drying and sterilization, heating section temperature 300±10℃, mesh belt speed: 50Hz; S3 Filtration Vitamin B 12 The preparation composition is filtered using a sterilizing filter equipped with a nano-titanium dioxide-based hollow fiber membrane; During the transportation process, the pressure in the liquid mixing tank is not more than 2.0 bar, vitamin B 12 The pressure difference between the front and rear ends of the sterilizing filter in the sterilizing filtration of the preparation composition should be ≤3 bar to obtain the filtrate; S4 filling The filling process of glass ampoule is protected from light, and the illumination is ≤500LUX. After the intermediate is tested and qualified, the filtrate is filtered again before filling; S5 Sterilization After filling, sterilize at 121℃ for 12 minutes.

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