CN104606220A - Multivitamin composition and preparation method thereof - Google Patents
Multivitamin composition and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a multivitamin composition and a preparation method thereof, the multivitamin composition contains vitamin A palmitate, vitamin D3, vitamin E, vitamin K1, vitamin C, vitamin B1, riboflavin sodium phosphate, vitamin B6, vitamin B12, folic acid, dexpanthenol, biotin, nicotinamide, histidine and its salts and polysorbate 80, and compared with the prior art, the multivitamin composition has better solution clarity and can better ensure drug safety and convenient clinical use.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to multivitamin composition and method of making the same, compared with the prior art, there is better stability of solution, also more convenient Clinical practice.
Technical background
Parenteral alimentation plays important supporting function in the treatment of disease, is widely used in as congenital malformation of the alimentary tract, middle severe malnutrition, digestive tract disease (severe diarrhea, necrotizing enterocolitis, short bowel syndrome early stage, intestinal obstruction, intestinal fistula, necrotizing pancreatitis), the treatment of neonate of heavily endangering, the reaction of caused by radiotherapy and chemotherapy serious gastrointestinal, severe infections, larger operation, wound, burn etc. that can not normally ingest.Vitamin maintains the required class trace organic substance of human life activity, generally can not through the assimilation synthesis of self in human body, normal human can obtain the vitamin of needed by human body by food, burn, operation, severe trauma, infection etc. may cause superelevation metabolism etc. that human nutrition will be caused bad, comprise the shortage of vitamin, patient increases vitamin requirement, supplements the outer vitamin of intestinal and is beneficial to Rehabilitation.
Divide by dissolution properties, vitamin can be divided into fatsoluble vitamin and water soluble vitamins, and fatsoluble vitamin is mainly VitAVitE, vitamin K, vitamin D and their analog thereof, and water soluble vitamins is mainly vitamin B
1, vitamin B
2, vitamin B
6, vitamin B
12, folic acid, Dexpanthenol, biotin, nicotiamide, vitamin C and their analog thereof.
Prior art shows, and vitamins composition physicochemical property is complicated, and dissolution properties is different, how unstable, the sensitivities such as multipair light, heat, oxygen, metal ion, acidity, the many requirements of its storage requirement are stricter, as folic acid is unstable to soda acid, vitamin D requires lucifuge, seals, fills nitrogen, the preservation of cold place; Also unstable between each composition of vitamin, as vitamin B
1, vitamin B
12interaction can make content reduce, vitamin B
12vitamin C content can be made to reduce.
Single ingredients Vitamin injection is as vitamin E injection, vitamin D clinically
2injection utilizes it fat-soluble and adopts oil for solvent preparation, and water soluble vitamins is as vitamin B
1injection, vitamin B
2injection, vitamin C injection etc. regulate different pH scope according to its different physicochemical properties etc. and add antioxidant etc. and prepare; The multivitamin ejection preparation of current domestic listing has fat-soluble vitamin for injection, Liposoluble Vitamin Injection, Vitamin H and injection 12 kinds of compound vitamines, the 13 kinds of vitamin injections (Infuvite Adult) as U.S. SabexInc. of external listing.
For preparing reliable and stable multivitamin injection, solve its dissolubility and stability is Main Means, the Liposoluble Vitamin Injection of listing adopts soybean oil, lecithin is that excipient is prepared into stable Emulsion; Injection 12 kinds of compound vitamines (Shi Niweita) of Baxter company import adopt soybean phospholipid, glycocholic acid to be cosolvent and stabilizing agent; " Infuvite Adult " adopts the form of A, B bottle subpackage, and is added with propylene glycol solvent; It is filler with glycine that CN101433547 discloses a kind of, the 12 kinds of vitamin freeze-dried powder injection preparations being cosolvent with soybean phospholipid, glycocholic acid.In addition, CN1989975, CN101491499, CN1843362, CN101073580, CN100361659, CN101181289, JP2006143599, JP4235925, EP0247616, CN1843327 also disclose a series of multivitamin ejection preparation.
The object of the present invention is to provide a kind of stable vitamin combination, and the preparation method of compositions, said composition is single dosage form, and has good quality stability, and composite preparation of the present invention has better clarity of solution.
Summary of the invention
The invention provides a kind of stable vitamin combination, and the preparation method of compositions, all 4 kinds of fatsoluble vitamiies and 9 kinds of water soluble vitamins combine by it, low cost of manufacture, and Clinical practice is convenient, and compositions has good quality stability.
Multivitamin compositions of the present invention, containing vitamin A palmitate, vitamin D
3, vitamin E, vitamin K
1four kinds of fatsoluble vitamiies, and vitamin C, vitamin B
1, riboflavin sodium phosphate, vitamin B
6, vitamin B
12, folic acid, Dexpanthenol, biotin, nicotiamide nine kinds of water soluble vitamins, with medically acceptable adjuvant, its medically acceptable adjuvant that is characterized as of the present invention is containing histidine or its salt, polyoxyethylene sorbitan monoleate, and the consumption of polyoxyethylene sorbitan monoleate and vitamin E mass ratio are 5 ~ 10.
In compositions Chinese medicine, in acceptable adjuvant, histidine or its salt can be histidine, histidine monohydrochloride, and be preferably histidine monohydrochloride, polyoxyethylene sorbitan monoleate, consumption and the vitamin E mass ratio of polyoxyethylene sorbitan monoleate are preferably 6 ~ 8.
Multivitamin compositions of the present invention, its medically acceptable adjuvant is preferably not containing mannitol.
Multivitamin compositions of the present invention, wherein histidine or its salt consumption and vitamin E mass ratio are 4 ~ 14.5, and histidine or its salt consumption and vitamin E mass ratio are preferably 5 ~ 10.
Multivitamin compositions of the present invention, medically acceptable adjuvant is wherein had to contain stabilizing agent, stabilizing agent be selected from disodium edetate, calcium disodium edetate one or more, as the calcium disodium edetate of 0.01% (w/v), the disodium edetate of 0.02% (w/v), or the mixture of above-mentioned 2 kinds or 3 kinds solution, is preferably not containing stabilizing agent.
Described medically acceptable adjuvant is containing being selected from hydrochloric acid, sodium hydroxide, citric acid, one or more pH adjusting agent of sodium citrate, pH value regulator is that its solution is adjusted to suitable pH value, as pH value is adjusted to 4.0 ~ 6.5, for avoiding conciliation too violent, pH value regulator practical application mostly be as described in hydrochloric acid, citric acid, sodium hydroxide, the finite concentration aqueous solution of one or more preparations of sodium citrate, and slowly add, as 0.1mol/L sodium hydroxide solution, saturated sodium hydroxide solution, 0.1mol/ hydrochloric acid solution etc., for improving confecting efficiency, also can get appropriate pH value regulator part material is dissolved in advance, biotin is dissolved as got appropriate 0.1mol/L sodium hydroxide solution, folic acid etc., then mix with other ingredient solution.
Multivitamin compositions of the present invention, the pH value of its composition solution is 4.0 ~ 6.5, and for children thing preparation, preferable ph is 5.0 ~ 6.5.
Multivitamin compositions of the present invention, wherein in compositions, vitamin can meet following proportionate relationship:
The multivitamin compositions of this proportionate relationship, may be used for preparing the daily vitamin supplement parenteral nutrition preparation being applicable to adult or more than 11 years old child, be applicable to accept the adult of parenteral nutrition or the daily vitamin supplement of more than 11 years old child, be particularly useful for the certain situation needing intravenously administrable, comprise the situation that operation, serious burn, fracture or other wounds, serious infectious disease, stupor etc. may cause superelevation metabolism in human body stress and body and then cause histotroph to consume.
Multivitamin compositions of the present invention, wherein in compositions, vitamin can meet proportionate relationship:
The multivitamin compositions of this proportionate relationship, may be used for preparing the daily vitamin supplement parenteral nutrition preparation being applicable to neonate, infant and child below 11 one full year of life, be applicable to accept the daily vitamin supplement of the neonate of parenteral nutrition, infant and child below 11 one full year of life, especially as needed the certain situation of intravenously administrable, the situation that operation, large-area burns, fracture and other wounds, serious infectious disease, stupor etc. may cause superelevation metabolism in human body stress and body and then cause histotroph to consume is comprised.
The general multiplex iu IU of vitamin E indicates, IIU is equivalent to 1mg, polyoxyethylene sorbitan monoleate is mainly used in dissolving fatsoluble vitamin, in the fatsoluble vitamin that the present composition contains, content of vitamin E is the highest, research shows when polyoxyethylene sorbitan monoleate is less than 5 with vitamin E ratio, composition sample easily produces the underproof situation of clarity, as Polysorbate single dose content in embodiment 1 is reduced to 45mg/ prop up time, the finished product clarity that it prepares is close to No. 1 turbidity standard (Chinese Pharmacopoeia 2010 editions two annex IX B).
Compositions of the present invention can by respectively obtaining the method system preparing lyophilized formulations of composition solution provided by the invention by this area routine.
Specifically can operate by the following method, method comprises the following steps:
(1) fatsoluble vitamin preparation: get 4 kinds of fatsoluble vitamiies, respectively or merge be dissolved in polyoxyethylene sorbitan monoleate, for vitamin D
3, because being solid, also can first using a small amount of dissolve with ethanol, adding in polyoxyethylene sorbitan monoleate with the form of dissolve with ethanol thing, after polyoxyethylene sorbitan monoleate dissolves, add water for injection in right amount, mixing, water for injection temperature can be 20-60 DEG C, as 40-50 DEG C; Technique can be: get vitamin A palmitate, vitamin D
3, vitamin E, vitamin K
1, be added in polyoxyethylene sorbitan monoleate and make dissolving, add water for injection in right amount, mixing, obtains fatsoluble vitamin solution, for subsequent use.
(2) water soluble vitamins solution preparation: get all the other each vitamin, and medically acceptable adjuvant, as histidine or its hydrochlorate, respectively or merging water for injection dissolve, by pH value regulator adjust ph 4.0 ~ 6.5, to obtain final product.
Folic acid, biotin water solublity are poor, and method for optimizing is for being added appropriate sodium hydroxide solution or liquor sodii citratis dissolving, for subsequent use, then joins in all the other water soluble vitamins solution.
Riboflavin sodium phosphate is prepared because color is comparatively dark, adds after can dissolving separately.
Compositions adjust ph of the present invention also can regulate after fatsoluble vitamin and water soluble vitamins mixing.
(3) mixing, fill, lyophilization
By above-mentioned fatsoluble vitamin solution and the mixing of water soluble vitamins solution, filter, add to the full amount of water for injection, fine straining, fill, lyophilization, tamponade, roll lid, to obtain final product.
Preparation method of composition of the present invention, after above-mentioned fatsoluble vitamin solution and the mixing of water soluble vitamins solution, activated carbon adsorption impurity can be added, as endotoxin, activated carbon dosage is generally 0.01% ~ 0.1% (g/ml), does not preferably add active carbon.
Due to the unstability of vitamin physicochemical property, preparation process is preferably carried out under lucifuge condition, and as far as possible in process for preparation filling with inert gas to avoid the impact of oxygen, as inflated with nitrogen, each vitamin raw materials is in process for preparation, for raising the efficiency, can to prepare separately according to its different physicochemical property or some properties is similar is combined preparation, as vitamin D
3vitamin A palmitate, vitamin E, vitamin K is added to after dissolving by ethanol in proper amount
1with in the lysate of polyoxyethylene sorbitan monoleate cosolvent; As folic acid, biotin first use appropriate pH value regulator (as sodium hydroxide solution) to dissolve for subsequent use; Vitamin B
12because dosage is very low, also other various vitamin finally can be added to and excipient is all prepared in the solution mixed.
Freeze drying process is general technique, is known to the skilled person technology, can be adjusted accordingly according to different production equipments, different excipient etc.
The preparation method of multivitamin compositions of the present invention, can comprise the following steps:
Method 1
(1) vitamin A palmitate, vitamin D is got
3, vitamin E, vitamin K
1, mix with polyoxyethylene sorbitan monoleate and make dissolving, add water for injection in right amount, obtain fatsoluble vitamin solution, for subsequent use;
(2) all the other each vitamin, histidine or its salt is got, and medically acceptable adjuvant, dissolve with water for injection, mixing, by pH value regulator adjust ph 4.0 ~ 6.5, obtains water soluble vitamins solution, for subsequent use;
(3) by above-mentioned fatsoluble vitamin solution, the mixing of water soluble vitamins solution, filter, add to the full amount of water for injection, fine straining, fill, lyophilization, tamponade, rolls lid, to obtain final product.
Method 2
(1) vitamin A palmitate, vitamin D is got
3, vitamin E, vitamin K
1, mix with polyoxyethylene sorbitan monoleate and make dissolving, add water for injection in right amount, obtain fatsoluble vitamin solution, for subsequent use;
(2) get folic acid, biotin, add appropriate sodium hydroxide solution and dissolve, for subsequent use;
(3) all the other each vitamin, histidine or its salt is got, and medically acceptable adjuvant, dissolve with water for injection, mixing, adds above-mentioned folic acid, biotin solution, mixing, by pH value regulator adjust ph 4.0 ~ 6.5, obtain water soluble vitamins solution, for subsequent use;
(4) by above-mentioned fatsoluble vitamin solution, the mixing of water soluble vitamins solution, filter, add to the full amount of water for injection, fine straining, fill, lyophilization, tamponade, rolls lid, to obtain final product.
In the active component contained in the present composition, each vitamin existence form can be its analog, and the embodiment of the present invention is preferred situation, as:
Vitamin A palmitate and analog thereof can be the esters of vitamin A, retinol, preferred vitamin A cetylate, vitamin A acetate etc.
Vitamin D
3and analog can be vitamin D
2, vitamin D
3and alfacalcidol etc.
Vitamin C and analog thereof can be ascorbic acid and corresponding salt or ester etc.
Vitamin B
1and analog can be thiamine, thiamine hydrochloride, thiamine nitrate, thiamine phosphoric acid, Cocarboxylase tetrahydrate etc.
Riboflavin sodium phosphate and analog thereof can be riboflavin, riboflavin sodium phosphate, riboflavin 5 ' the single sodium salt dihydrate of-(dihydrogen phosphoric acid ester) etc.
Vitamin B
6and analog can be Pyridoxine Hydrochloride, VB6, than many aldehyde, than polyamines etc.
Vitamin B
12and analog can be cobalamine, cyanocobalamin, hydroxocobalamine, mecobalamin element and 5 '-deoxyadenosyl cobalamins etc.
Dexpanthenol and analog thereof can be pantothenic acid, sodium pantothenate, calcium pantothenate, pantothenylol, Dexpanthenol etc.
Nicotiamide and analog thereof can be nicotiamide, nicotinic acid etc.
Vitamin K
1and analog can be vitamin K
1, vitamin K
2.
The multivitamin composition medicine preparation of preparation of the present invention, its key index method of quality control is:
1, acidity gets this product 1 bottle, and the 5ml that adds water makes dissolving, and measure (Chinese Pharmacopoeia version in 2010 two annex VI H), pH value should be 4.0 ~ 6.5 in accordance with the law.
2, the clarity of solution and color get this product, measure (Chinese Pharmacopoeia 2010 editions two annex IX B), often prop up the 5ml that adds water and make dissolving, solution all should be clarified in accordance with the law, displaing yellow, to orange-yellow, must not show muddy (being greater than No. 0.5 turbidity standard).
3, loss on drying gets this product content, accurately weighed, take phosphorus pentoxide as desiccant, and 60 DEG C of drying under reduced pressure 4 hours, less loss weight all must not cross 2.0% (Chinese Pharmacopoeia version in 2010 two annex VIII L).
4, assay
4.1 vitamin A palmitates, vitamin D
3, vitamin E and vitamin K
1measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).(lucifuge operation)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, column temperature 40 DEG C, with methanol/ethanol (15:25) for mobile phase A, with acetonitrile-water (60:5) for Mobile phase B, carry out gradient elution by follow procedure:
Overall flow rate is 1.0ml/min, and determined wavelength is 265nm, and theoretical cam curve presses vitamin K
1peak calculates, and should be not less than 5000, each peak-to-peak separating degree all should meet the requirements.
Vitamin D is got in the preparation of reference substance solution
3reference substance is about 10mg, accurately weighed, puts in 100ml measuring bottle, and add dehydrated alcohol appropriate, jolting makes dissolving and is diluted to scale, shakes up, and precision measures 1ml, puts in 10ml measuring bottle, adds dehydrated alcohol and is diluted to scale, shake up, as vitamin D
3reference substance storing solution; Get vitamin A palmitate reference substance and be about 18mg, accurately weighed, put in 5ml measuring bottle, add dehydrated alcohol appropriate, jolting makes dissolving and is diluted to scale, shakes up, as vitamin A palmitate reference substance storing solution; Get vitamin K
1reference substance is about 15mg, accurately weighed, puts in 50ml measuring bottle, and add dehydrated alcohol appropriate, jolting makes dissolving and is diluted to scale, shakes up, as vitamin K
1reference substance storing solution; Precision measures above-mentioned three kinds of each 1ml of reference substance storing solution, puts in 25ml measuring bottle, separately gets vitamin E reference substance and be about 20mg, accurately weighed, is set up and states in same measuring bottle, and add acetonitrile appropriate, jolting makes dissolving and is diluted to scale, shakes up, in contrast product solution.
This product 7 ~ 15 bottles is got in the preparation of sample solution, and every bottle adds suitable quantity of water respectively and dissolves and be carefully transferred in 50ml measuring bottle, and with moisture time wash-bottle wall, washing liquid is incorporated in volumetric flask, is diluted with water to scale, shakes up, as need testing solution.Get need testing solution, precision measures 10ml, in 250ml separatory funnel, adds the ethanol 40ml of 80%, precision adds normal hexane 25ml, jolting 30 minutes, be placed to upper strata clarification, precision pipettes supernatant liquid 10ml and is placed in conical flask, after drying up with nitrogen, precision adds 10ml acetonitrile makes dissolving, shakes up, as sample solution.
Algoscopy precision measures reference substance solution and each 20 μ l of sample solution injection liquid chromatography respectively, record chromatogram; Calculate by labelled amount with peak area by external standard method, to obtain final product.
4.2 riboflavin sodium phosphate, vitamin B
6, vitamin C, nicotiamide, vitamin B
1, folic acid, Dexpanthenol according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D) measure.(lucifuge operates, face use brand-new)
Chromatographic condition and system suitability Inertsil5 μ ODS2 (4.6 × 250mm) chromatographic column, column temperature 40 DEG C, with 0.1% phosphoric acid solution of 0.005mol/L sodium pentanesulfonate for mobile phase A, with 0.1% phosphoric acid solution of 0.005mol/L sodium pentanesulfonate-acetonitrile (20:80) for Mobile phase B, carry out gradient elution by follow procedure:
Overall flow rate is 0.9ml/min, and determined wavelength is 210nm, and theoretical cam curve calculates should be not less than 15000 by riboflavin sodium phosphate peak, and each peak-to-peak separating degree all should meet the requirements.
Vitamin B is got in the preparation of reference substance solution
1reference substance is about 15mg, accurately weighed, puts in 25ml measuring bottle, and add water appropriate, jolting makes dissolving and is diluted to scale, shakes up, as vitamin B
1reference substance storing solution; Riboflavin sodium phosphate reference substance is about 24.6mg, accurately weighed, puts in 50ml measuring bottle, and add water appropriate, jolting makes dissolving and is diluted to scale, shakes up, as riboflavin sodium phosphate reference substance storing solution; Vitamin B
6reference substance is about 15mg, accurately weighed, puts in 25ml measuring bottle, and add water appropriate, jolting makes dissolving and is diluted to scale, shakes up, as vitamin B
6reference substance storing solution; Get nicotiamide reference substance and be about 20mg, accurately weighed, put in 5ml measuring bottle, add water appropriate, jolting makes dissolving and is diluted with water to scale, shakes up, as nicotiamide reference substance storing solution; Get Dexpanthenol reference substance and be about 15mg, accurately weighed, put in 10ml measuring bottle, add water appropriate, jolting makes dissolving and is diluted to scale, shakes up, as Dexpanthenol reference substance storing solution; Get folic acid reference substance and be about 8mg, accurately weighed, put in 100ml measuring bottle, add water appropriate and sodium hydroxide test solution a little, jolting makes dissolving and is diluted with water to scale, shakes up, as folic acid reference substance storing solution; Precision measures each 1ml of above-mentioned reference substance storing solution, puts in 25ml measuring bottle, separately gets vitamin C reference substance and is about 20mg, accurately weighed, is set up and states in same measuring bottle, and the appropriate jolting that adds water makes dissolving and is diluted to scale, shakes up, in contrast product solution.
This product 6 ~ 15 bottles is got in the preparation of sample solution, and every bottle adds suitable quantity of water respectively and dissolves and be carefully transferred in 50ml measuring bottle, and with moisture time wash-bottle wall, washing liquid is incorporated to volumetric flask, is diluted with water to scale, shakes up, as need testing solution.Get need testing solution, precision measures 2ml, in 100ml measuring bottle, is diluted with water to scale, shakes up, as sample solution.
Algoscopy precision measures reference substance solution and each 20 μ l of sample solution injection liquid chromatography respectively, record chromatogram; Calculate by labelled amount with peak area by external standard method, to obtain final product.
4.3 vitamin B
12measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D) with biotin.(lucifuge operation)
Chromatographic condition and system suitability Inertsil5 μ ODS24.6 × 150mm chromatographic column, column temperature 40 DEG C, with 0.0015mol/L sodium hexanesulfonate-methanol (83:17) (regulating pH to 2.65+0.05 with phosphoric acid solution (1 → 10)) for mobile phase (can suitable resize ratio according to chromatographic column situation), determined wavelength be 210nm.Theoretical cam curve presses vitamin B
12peak calculates should be not less than 1800, biotin peak and vitamin B
12peak-to-peak separating degree should meet the requirements, biotin peak and vitamin B
12the relative retention time at peak is about 0.87.
Vitamin B is got in the preparation of reference substance solution
12reference substance is about 18mg, accurately weighed, puts in 500ml measuring bottle, and add water appropriate, jolting makes dissolving and is diluted to scale, shakes up, as vitamin B
12reference substance storing solution; Get biotin reference substance and be about 20.7mg, accurately weighed, put in 50ml measuring bottle, add water appropriate and sodium hydroxide test solution a little, jolting makes dissolving and is diluted with water to scale, shakes up, as biotin reference substance storing solution; Precision measures above-mentioned two kinds of each 1ml of storing solution in 100ml measuring bottle, adds water and is diluted to scale in right amount, shake up, in contrast product solution.
The preparation of sample solution gets this product content in right amount, and accurately weighed, precision is dissolved in water to 5ml, jolting, and precision measures 3ml, puts in 10ml volumetric flask, is diluted with water to scale, shake up, as sample solution.
Algoscopy precision measures reference substance solution and each 20 μ l of sample solution injection liquid chromatography respectively, record chromatogram; By external standard method with calculated by peak area, to obtain final product.
Detailed description of the invention
Following examples just further illustrate the present invention, and the present invention is not limited in the content of following examples.
According to the prescription of single dose shown in table 1, preparation injection multivitamin compositions, table 1 is single dose prescription, and following embodiment preparation is all according to 10,000 preparation unit preparations.
Embodiment 1
(1) in the operation room of lucifuge, vitamin A palmitate, vitamin D is got
3, vitamin E, vitamin K
1, add in polyoxyethylene sorbitan monoleate, mix and blend makes dissolving, adds water for injection in right amount, obtains fatsoluble vitamin solution, for subsequent use;
(2) get folic acid, biotin, add appropriate sodium hydroxide solution and dissolve, for subsequent use;
(3) get all the other each vitamin, histidine monohydrochlorides, be dissolved in water for injection, mixing, adds above-mentioned folic acid, biotin solution, and mixing, is 5.1 by sodium hydroxide, citric acid adjust ph, obtains water soluble vitamins solution, for subsequent use;
(4) by above-mentioned fatsoluble vitamin solution, the mixing of water soluble vitamins solution, the frit in 0.22 μm of aperture, add to the full amount of water for injection, aseptic filtration is carried out by the filter in two 0.22 μm of apertures of series connection, fill in cillin bottle (4ml/ props up), lyophilization, tamponade, roll lid, to obtain final product.
Embodiment 2
Except adjust ph be 4.3 and fill amount be except 3.5ml/ props up, other as embodiment 1 technique preparation, to obtain final product.
Embodiment 3
Add mannitol together and adjust ph is except 5.6 except in water soluble vitamins preparation, other, as the preparation of embodiment 1 technique, to obtain final product.
Embodiment 4
Except changing histidine monohydrochloride into mannitol in water soluble vitamins preparation and adjust ph is except 5.6, other, as the preparation of embodiment 1 technique, to obtain final product.
Embodiment 5
Except adjust ph is except 6.3, other, as the preparation of embodiment 1 technique, to obtain final product.
Embodiment 6
Except adjust ph be 4.8 and fill amount be except 5ml/ props up, other as embodiment 1 technique preparation, to obtain final product.
Embodiment 7
Except changing histidine monohydrochloride into glycine in water soluble vitamins preparation and adjust ph is except 5.0, other, as the preparation of embodiment 1 technique, to obtain final product.
Embodiment 8
(1) in the operation room of lucifuge, vitamin A palmitate, vitamin D is got
3, vitamin E, vitamin K
1, add in polyoxyethylene sorbitan monoleate, mix and blend makes dissolving, adds water for injection in right amount, obtains fatsoluble vitamin solution, for subsequent use;
(2) get all the other each vitamin, histidine monohydrochlorides, be dissolved in water for injection, mixing, is 4.3 by sodium hydroxide, citric acid adjust ph, obtains water soluble vitamins solution, for subsequent use;
(3) by above-mentioned fatsoluble vitamin solution, the mixing of water soluble vitamins solution, the frit in 0.22 μm of aperture, add to the full amount of water for injection, aseptic filtration is carried out by the filter in two 0.22 μm of apertures of series connection, fill in cillin bottle (3ml/ props up), lyophilization, tamponade, roll lid, to obtain final product.
Embodiment 9
Except water soluble vitamins preparation in change histidine monohydrochloride into histidine, adjust ph be 5.7 and fill amount be except 2.5ml/ props up, other as embodiment 8 technique preparation, to obtain final product.
Embodiment 10
Except adjustment fill amount is except 3ml/ props up, other, as the preparation of embodiment 1 technique, to obtain final product.
Embodiment 11
Be 6.3 except adjust ph and regulate fill amount to be except 2.5ml/ props up, other, as the preparation of embodiment 1 technique, to obtain final product.
Embodiment 12
Except histidine monohydrochloride being changed in water soluble vitamins preparation into mannitol and regulating fill amount to be except 3ml/ props up, other, as the preparation of embodiment 1 technique, to obtain final product.
Embodiment 13
Except changing histidine monohydrochloride into histidine in water soluble vitamins preparation, adjust ph is 4.8 and regulates fill amount to be except 3ml/ props up, and other, as the preparation of embodiment 1 technique, to obtain final product.
Embodiment 14
Except changing histidine monohydrochloride into Dextran 40 in water soluble vitamins preparation, adjust ph is 5.5 and regulates fill amount to be except 2.5ml/ props up, and other, as the preparation of embodiment 1 technique, to obtain final product.
The sample of embodiment 1 ~ embodiment 14 is detected according to related request under Chinese Pharmacopoeia 2010 editions annex injection items, result all meets every regulation, according to above-mentioned key index quality testing, it is basically identical that acidity and this product produce obtain solution pH, and clarity of solution and color, loss on drying, each vitamin content all conform with the regulations.
Stability test
By the sample of embodiment 1 ~ embodiment 14, place according to stability study condition, and measure its place after each Key Quality Indicator of different time points, each vitamin content is 100% as reference using the testing result of initial 0 day, calculates the content of sample after placing.
1) 40 DEG C of influence factor's tests
Sample is placed 10 days under the condition of 40 DEG C, and in 5,10 days sampling investigate, and with initial 0 day results contrast.
Assay result shows, in each vitamin content, each embodiment sample is 0 day result vitamin D comparatively
3all have reduction, reduction amplitude is 4.1% ~ 5.2% (5 days) and 7.7% ~ 8.9% (10 days), vitamin B
12all slightly reduce, reduction amplitude is 1.4% ~ 1.6% (5 days) and 2.7% ~ 3.2% (10 days), other 11 kinds of vitamin contents 5 days and 10 days all substantially unchanged (stability 10 days changes of contents percentage range are between ± 0.1 ~ 1.2).
Acidity and loss on drying detect and show, each embodiment sample 5 days, 10 days results are substantially unchanged compared with 0 day result.
Clarity of solution and color detection result show, the sample of embodiment 4, embodiment 7, embodiment 12, embodiment 14 40 degree 5 days and 10 days clarity all defective, and aobvious muddy, be more richer than No. 1 turbidity standard (Chinese Pharmacopoeia 2010 editions two annex IX B); And other embodiment samples all conform with the regulations.
Above-mentioned further 40 DEG C of each embodiment sample except embodiment 4, embodiment 7, embodiment 12, embodiment 14 is placed to 30 days, clarity of solution and color detection result show, the sample of embodiment 3 is aobvious muddy, compare with No. 1 turbidity standard (Chinese Pharmacopoeia 2010 editions two annex IX B), turbidity is similar to; And other embodiment samples all conform with the regulations.
2) accelerated stability test
Sample thief, places 6 months under the condition of temperature 25 DEG C ± 2 DEG C, respectively at the 1st, 2,3, sampling in June, investigate indices.
Assay result shows, in each vitamin content, each embodiment sample is 0 day result vitamin D comparatively
3all there is reduction, reduce amplitude between each embodiment similar, no significant difference; Vitamin B
12also slightly reduce, reduce amplitude similar, no significant difference between each embodiment, the data of embodiment 1 are in table 2.
Acidity and loss on drying detect and show, each embodiment sample result is substantially unchanged compared with 0 day result.
Clarity of solution and color detection result show, the sample of embodiment 4, embodiment 7, embodiment 12, embodiment 14 is in acceleration clarity in January and defective, and it is aobvious muddy, close to No. 1 turbidity standard (Chinese Pharmacopoeia 2010 editions two annex IX B), acceleration its clarity of solution of sample in June is close to No. 2 turbidity standards (Chinese Pharmacopoeia 2010 editions two annex IX B); The sample of embodiment 3 accelerates to start its clarity of solution aobvious muddiness March, and close to No. 1 turbidity standard (Chinese Pharmacopoeia 2010 editions two annex IX B), acceleration sample in June is obviously greater than No. 1 turbidity standard (Chinese Pharmacopoeia 2010 editions two annex IX B).
Table 2 embodiment 1 accelerated stability test result (content: %)
Influence factor's test and accelerated test result show, the quality control index result such as multivitamin content, acidity, loss on drying of each embodiment sample is similar, no significant difference; Clarity of solution and color detection result show, compare with conventional frozen-dried supporting agent (mannitol, Dextran 40, glycine), histidine or its salt significantly can improve the quality stability of product, especially the clarity of solution, this is to the better safe significance ensureing medication.
Claims (14)
1. multivitamin compositions, containing vitamin A palmitate, vitamin D
3, vitamin E, vitamin K
1four kinds of fatsoluble vitamiies, and vitamin C, vitamin B
1, riboflavin sodium phosphate, vitamin B
6, vitamin B
12, folic acid, Dexpanthenol, biotin, nicotiamide nine kinds of water soluble vitamins, with medically acceptable adjuvant, it is characterized in that: medically acceptable adjuvant is containing histidine or its salt, polyoxyethylene sorbitan monoleate, and the consumption of polyoxyethylene sorbitan monoleate and vitamin E mass ratio are 5 ~ 10.
2. multivitamin compositions according to claim 1, is characterized in that: in said composition Chinese medicine, acceptable adjuvant is histidine monohydrochloride, polyoxyethylene sorbitan monoleate, and the consumption of polyoxyethylene sorbitan monoleate and vitamin E mass ratio are 6 ~ 8.
3. multivitamin compositions according to claim 1, is characterized in that: described medically acceptable adjuvant is not containing mannitol.
4. multivitamin compositions according to claim 1, is characterized in that: histidine or its salt consumption and vitamin E mass ratio are 4 ~ 14.5.
5. multivitamin compositions according to claim 4, is characterized in that: histidine or its salt consumption and vitamin E mass ratio are 5 ~ 10.
6. multivitamin compositions according to claim 1, is characterized in that: described medically acceptable adjuvant is containing one or more the pH adjusting agent being selected from hydrochloric acid, sodium hydroxide, citric acid, sodium citrate.
7. multivitamin compositions according to claim 1, is characterized in that: the pH value of composition solution is 4.0 ~ 6.5.
8. multivitamin compositions according to claim 7, is characterized in that: the pH value of composition solution is 5.0 ~ 6.5.
9. according to the multivitamin compositions one of claim 1-8 Suo Shu, it is characterized in that, in described compositions, vitamin meets following proportionate relationship:
10. multivitamin compositions according to claim 9, the application in the daily vitamin supplement parenteral nutrition preparation that preparation is applicable to adult or more than 11 years old child.
11., according to the multivitamin compositions one of claim 1-8 Suo Shu, is characterized in that, in described compositions, vitamin meets following proportionate relationship:
12. multivitamin compositionss according to claim 11, are applicable to the application in the daily vitamin supplement parenteral nutrition preparation of neonate, infant and child below 11 one full year of life in preparation.
The preparation method of 13. multivitamin compositionss according to claim 1, comprises the following steps:
(1) vitamin A palmitate, vitamin D is got
3, vitamin E, vitamin K
1, mix with polyoxyethylene sorbitan monoleate and make dissolving, add water for injection in right amount, obtain fatsoluble vitamin solution, for subsequent use;
(2) all the other each vitamin, histidine or its salt is got, and medically acceptable adjuvant, dissolve with water for injection, mixing, by pH value regulator adjust ph 4.0 ~ 6.5, obtains water soluble vitamins solution, for subsequent use;
(3) by above-mentioned fatsoluble vitamin solution, the mixing of water soluble vitamins solution, filter, add to the full amount of water for injection, fine straining, fill, lyophilization, tamponade, rolls lid, to obtain final product.
The preparation method of 14. multivitamin compositionss according to claim 1, comprises the following steps:
(1) vitamin A palmitate, vitamin D is got
3, vitamin E, vitamin K
1, mix with polyoxyethylene sorbitan monoleate and make dissolving, add water for injection in right amount, obtain fatsoluble vitamin solution, for subsequent use;
(2) get folic acid, biotin, add appropriate sodium hydroxide solution and dissolve, for subsequent use;
(3) all the other each vitamin, histidine or its salt is got, and medically acceptable adjuvant, dissolve with water for injection, mixing, adds above-mentioned folic acid, biotin solution, mixing, by pH value regulator adjust ph 4.0 ~ 6.5, obtain water soluble vitamins solution, for subsequent use;
(4) by above-mentioned fatsoluble vitamin solution, the mixing of water soluble vitamins solution, filter, add to the full amount of water for injection, fine straining, fill, lyophilization, tamponade, rolls lid, to obtain final product.
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| CN106420793A (en) * | 2016-09-20 | 2017-02-22 | 上海应用技术大学 | Compound vitamin injection and preparation method thereof |
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| CN112336731A (en) * | 2020-11-02 | 2021-02-09 | 北京诺康达医药科技股份有限公司 | Vitamin oral liquid and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106420793A (en) * | 2016-09-20 | 2017-02-22 | 上海应用技术大学 | Compound vitamin injection and preparation method thereof |
| CN109464430A (en) * | 2018-11-23 | 2019-03-15 | 南京协同生物科学研究院有限公司 | A kind of non-human primate's vitamin supplement preparation and its preparation method and application |
| CN112336731A (en) * | 2020-11-02 | 2021-02-09 | 北京诺康达医药科技股份有限公司 | Vitamin oral liquid and preparation method and application thereof |
| CN112336731B (en) * | 2020-11-02 | 2021-12-14 | 北京诺康达医药科技股份有限公司 | Vitamin oral liquid and preparation method and application thereof |
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