CN104415041B - 13 kinds of Compsoite vitamin injection pharmaceutical compositions of one kind and preparation method thereof - Google Patents

13 kinds of Compsoite vitamin injection pharmaceutical compositions of one kind and preparation method thereof Download PDF

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CN104415041B
CN104415041B CN201310376256.8A CN201310376256A CN104415041B CN 104415041 B CN104415041 B CN 104415041B CN 201310376256 A CN201310376256 A CN 201310376256A CN 104415041 B CN104415041 B CN 104415041B
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vitamin
injection
adjusting agent
preparation
ampoule
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CN104415041A (en
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余悦东
冯卫
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Liaoning Haisco Pharmaceutical Co Ltd
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Liaoning Haisco Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

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Abstract

The present invention provides a kind of 13 kinds of Compsoite vitamin injection pharmaceutical compositions and preparation method thereof.The composition includes 4 kinds of liposoluble vitamins altogether, and 9 kinds of water soluble vitamins are sub-packed in two ampoules, wherein the first ampoule contains Retinol Palmitate, vitamin K1, vitamin D3, vitamin E, vitamin C, vitamin B1, Riboflavine sodium phosphate, Dexpanthenol, vitamin B6, niacinamide and cosolvent, antioxidant and pH adjusting agent, the second ampoule contain vitamin B12, folic acid, biotin, stabilizer and pH adjusting agent.Preparation method includes: that first bottle of preparation includes with liquefaction phase medical fluid, water phase medical fluid, mixing, adjusts pH value, filtering, filling, sterilizing, and second bottle of preparation includes preparating liquid, adjusts pH value, activated carbon adsorption, de- charcoal, filtering, filling, sealing, sterilizing.The present invention has carried out new improvement with regard to the solubilizer, antioxidant and preparation process of 13 kinds of Compsoite vitamin injection pharmaceutical compositions, make it have supplementary product kind using less, stability is good, clarity is high, highly-safe, preparation method easy the advantages that being easily industrialized.

Description

13 kinds of Compsoite vitamin injection pharmaceutical compositions of one kind and preparation method thereof
Technical field
The present invention is to belong to field of pharmaceutical preparations, and in particular to a kind of 13 kinds of Compsoite vitamin injection pharmaceutical compositions and Preparation method.
Background technique
Parenteral alimentation plays important supporting function in the treatment of disease, is widely used in as congenital alimentary canal is abnormal Shape, middle severe malnutrition, disease of digestive tract (severe diarrhea, necrotizing enterocolitis, short bowel syndrome early stage, intestinal obstruction, Intestinal fistula, necrotizing pancreatitis), the newborn of danger again that cannot normally ingest, the reaction of caused by radiotherapy and chemotherapy serious gastrointestinal, serious sense The treatment of dye, biggish operation, wound, burn etc..Vitamin is one kind micro-content organism necessary to maintain human life activity Matter cannot generally synthesize in human body through the assimilation of itself, and normal human can be obtained the dimension of needed by human body by food Raw element, burn, operation, severe trauma, infection etc. may cause superelevation and be metabolized etc. that will lead to human nutrition bad, including vitamin Shortage, patient increases vitamin requirement, supplements parenteral vitamin conducive to Rehabilitation.
By dissolution properties point, vitamin can be divided into liposoluble vitamin and water soluble vitamin, and liposoluble vitamin is main For VitAVitE, vitamin K, vitamin D and its their analog, water soluble vitamin is mainly vitamin B1、 Vitamin B2, vitamin B6, vitamin B12, folic acid, Dexpanthenol, biotin, niacinamide, vitamin C and its their analog.
Prior art shows that vitamins ingredient physicochemical property is complicated, and dissolution properties are different, how unstable, multipair light, The sensitivities such as heat, oxygen, metal ion, acidity, storage requirement mostly requirement is stringenter, and if folic acid is unstable to soda acid, vitamin D is wanted Ask be protected from light, seal, nitrogen charging, cold place save；It is also unstable between each ingredient of vitamin, such as vitamin B1, vitamin B12Phase interaction With content being made to reduce, vitamin B12Vitamin C content can be made to reduce.
Clinically single composition vitamin injection such as vitamin E injection, vitamin D2Injection using its it is fat-soluble and Use oil for solvent preparation, and water soluble vitamin such as vitamin B1Injection, vitamin B2Injection, vitamin C injection etc. Different pH ranges and addition antioxidant etc. are adjusted according to its different physicochemical property etc. and are prepared；Domestic listing is more at present Kind of vitamin ejection preparation have fat-soluble vitamin for injection, Liposoluble Vitamin Injection, Vitamin H and 12 kinds of multi-vitamins of injection (also known as: injection multivitamin (12), trade name: Shi Niweita)；Foreign countries listing as 13 kinds of vitamin injections (Infuvite Adult) of U.S. Sabex Inc., 13 kinds of the injection of Nippon Kayaku K. K Vitamin (ネ オ ラ ミ Application マ Le チ V injection).
For reliable and stable multivitamin injection is prepared, solves its dissolubility and stability is main means, The Liposoluble Vitamin Injection of listing uses soybean oil, lecithin to be prepared into stable emulsion for excipient；Baxter company 12 kinds of multi-vitamins (Shi Niweita) of injection of import use soybean lecithin, glycocholic acid for cosolvent and stabilizer； " Infuvite Adult " uses the form of A, B bottles of packing；CN101433547 disclose one kind using glycine as filler, with Soybean lecithin, 12 kinds of vitamin freeze-dried powder injection preparations that glycocholic acid is cosolvent.In addition, CN1989975A, CN101491499A、CN1843362A、CN1679582A、JP2006143599、JP4235925、EP0247616、 CN1843327A, CN103006683A also disclose a series of multivitamin ejection preparations, are substantially using addition phosphatide The mode of class, Cholic acids cosolvent and stabilizer is come the problems such as solving dissolubility, stability.
13 kinds of Compsoite vitamin injections increase vitamin K on the basis of 12 kinds of Compsoite vitamin injections1, equally need Overcome the problems, such as dissolubility and stability.CN101073580A uses 2 bottled forms, and Tween-80, propylene glycol, hydroxyl is added Propyl beta-cyclodextrin cyclodextrin makees cosolvent and stabilizer, makees antioxidant with BHT, BHA, sodium hydrogensulfite, sodium pyrosulfite； CN101181289A uses 2 bottled forms, makees solubilizer with phospholipid, tween, polyethylene glycol, with butylated hydroxy anisole, two Tertiary fourth paracresol makees antioxidant, is additionally added disodium EDTA, calcium disodium chelate salt or gentisic acid ethanolamine Make complexing agent；CN102652744A also uses 2 bottled forms, makees cosolvent and stabilizer, fourth with Tween 80, propylene glycol, ethyl alcohol Hydroxyl fennel ether, Butylated Hydroxytoluene, rough gentian acyl ethanol amine make antioxidant.
Vitamin K1Belong to phytondione substance, meets light and easily decompose, be also easily oxidized.The report such as Zhou Xiaojie, dimension life Plain K1With vitamin B6, potassium chloride, vitamin C difference compatibility after, the pH value and vitamin K of solution1Content changes, i.e., The stability of solution is poor after compatibility, probably due to vitamin K1(Zhou Xiaojie etc., vitamin K caused by being oxidized1Compatibility stablize Property investigate, medical Leader (2005) Vol.24 (5): 448).Therefore, how to make vitamin K in multi-vitamins1It can not be by compatibility It influences, keeps preferable stability, to improve the activity of multi-vitamins, just become the critical issue for having to solve.It is right This, there are no practical, effective methods both at home and abroad at present.
Summary of the invention
In view of the foregoing, the present inventor can improve vitamin K to provide113 kinds of stability in compatibility are compound Vitamin injection pharmaceutical composition has carried out system research, repetition test, has finally found, uses the different mountain of cosolvent dimethyl The pure and mild antioxidant propyl benzoate of pears and the ratio and their contents in the first ampoule injection both rationally adjusted, not only may be used So that all kinds of vitamin ingredients is reached preferable dissolved state, and vitamin K can also be made1It is not influenced by compatibility and keeps fine Stability.In first ampoule injection, when Isosorbide dimethyl ether content is lower than 3.2mg/mL, multi-vitamins dissolve not very It is ideal；Multi-vitamins dissolution is good when more than 4.1mg/mL, and injection clarity is stablized, but vitamin K1Due to by compatibility It is poor to influence stability；Therefore it is added through screening the obtained antioxidant propyl benzoate for being suitble to this solution system, finds its use Amount rises to 1.5mg/mL from 0.05mg/mL, fails to make vitamin K1Have preferable stability, and rises with its dosage and infuse Liquid clarity is penetrated to decline instead；Therefore it is further added by the dosage of cosolvent Isosorbide dimethyl ether, is at this moment surprisingly found that, with clear The improvement spent clearly, vitamin K1Stability also available raising, when Isosorbide dimethyl ether dosage rise to 8mg/mL, training acid When propyl ester dosage is only 0.1mg/mL, injection can preferably clarify and vitamin K1It also can be preferably stable；Finally by anti- Review card and optimization, determine Isosorbide dimethyl ether amount ranges be 8~20mg/mL, propyl benzoate amount ranges be 0.1~ 0.2mg/mL, the two in the range, not only make the first ampoule injection have preferable clarity, and make vitamin K1 It can not interfered completely by compatibility and have good stability, various other vitamin ingredients can similarly have under this condition Good stability.
Technical scheme is as follows:
The present invention provides a kind of 13 kinds of Compsoite vitamin injection pharmaceutical compositions, it by two ampoules injection group At the first ampoule contains Retinol Palmitate, vitamin K1, vitamin D3, vitamin E, vitamin C, vitamin B1, core yellow Plain sodium phosphate, Dexpanthenol, vitamin B6, niacinamide and pH adjusting agent, the second ampoule contain vitamin B12, folic acid, biotin and PH adjusting agent.
In above-mentioned composition, the first ampoule injection also contains cosolvent Isosorbide dimethyl ether, antioxidant propyl benzoate, the Two ampoule injections also contain stabilizer propylene glycol.
PH adjusting agent in above-mentioned first ampoule injection is sodium hydroxide, the pH adjusting agent choosing in the second ampoule injection From citric acid, sodium citrate or their mixture.
Amount containing following ingredient in the above-mentioned every 5 milliliters of volumes of first ampoule injection are as follows: Retinol Palmitate 2500 ~4000IU, vitamin K10.05~0.25mg, vitamin D350~300IU, 5~25IU of vitamin E, vitamin C 50~ 300mg, vitamin B12.5~10mg, 2.5~10mg of Riboflavine sodium phosphate (1.8~7.2mg in terms of riboflavin), Dexpanthenol 5 ~25mg, vitamin B62.5~10mg, 25~75mg of niacinamide, Isosorbide dimethyl ether dosage are 40~100mg, training acid third The dosage of ester is 0.5~1.0mg, and pH adjusting agent adjusts pH value to 3~7；Containing following in the every 5 milliliters of volumes of second ampoule injection The amount of each ingredient are as follows: vitamin B122~10 μ g, 0.3~1.0mg of folic acid, 30~80 μ g of biotin, propylene glycol 0.005~ 2.0g, pH adjusting agent adjust pH value to 3~7.
Further, the amount containing following ingredient in the every 5 milliliters of volumes of above-mentioned first ampoule injection are as follows: vitamin A palm fibre Glycerin monostearate 3300IU, vitamin K10.15mg, vitamin D3200IU, vitamin E 10IU, vitamin C 200mg, vitamin B16mg, Riboflavine sodium phosphate 5mg (3.6mg in terms of riboflavin), Dexpanthenol 15mg, vitamin B66mg, niacinamide 40mg, two Methyl isobide 60mg, propyl benzoate 0.8mg, pH adjusting agent adjust pH value to 4~7；Every 5 milli of second ampoule injection Rise the amount containing following ingredient in volume are as follows: vitamin B125 μ g, folic acid 0.6mg, 60 μ g of biotin, propylene glycol 1.5g, pH tune It saves agent and adjusts pH value to 4.5~7.
The present invention also provides the preparation methods of 13 kinds of Compsoite vitamin injection pharmaceutical compositions, specifically include following step It is rapid:
The preparation of (1) first ampoule injection: Retinol Palmitate, vitamin K are weighed by recipe quantity1, vitamin D3、 Vitamin E, Isosorbide dimethyl ether, are placed in container, are uniformly mixed, obtain oil-phase solution；Vitamin C, dimension are weighed by recipe quantity Raw element B1, Riboflavine sodium phosphate, Dexpanthenol, niacinamide, vitamin B6It is placed in container, the water for injection being cooled to room temperature is added to stir Mix to dissolution, adjust pH to 3~5 with pH adjusting agent, with 0.22 μm of filtering with microporous membrane, in filtrate by 0.03% (W/V) plus Enter needle-use activated carbon, decarbonization filtering after 10~20min of stirring and adsorbing obtains aqueous phase solution；Oil-phase solution is slowly added into quickly In the aqueous phase solution of stirring, pH adjusting agent adjusts pH to 4~7, and benefit adds to the full amount of water for injection, and filters, is filling, sterilizing to obtain the final product；
The preparation of (2) second ampoule injections: weighing recipe quantity folic acid, biotin, and the injection being cooled to room temperature is added Water, stirred under nitrogen atmosphere dissolution；Recipe quantity stabilizer is added and stirs miscible, pH adjusting agent tune pH to 4.5~7, concentrated compounding is added The needle-use activated carbon of volume 0.05% (W/V) stirring at normal temperature 15 minutes, takes off charcoal filtration；Take the vitamin B of recipe quantity12Add a small amount of The water for injection dissolution being cooled to room temperature, is added in previous solu, adds water for injection to full dose, stir evenly, and 0.22 μm Miillpore filter refined filtration, it is filling, seal, sterilize to obtain the final product.
Compound vitamin composition main ingredient component content measuring method of the invention can carry out by the following method:
(1) Retinol Palmitate, vitamin D3, vitamin E and vitamin K1According to high performance liquid chromatography (Chinese Pharmacopoeia Two V D of annex of version in 2010) measurement (being protected from light operation).
Chromatographic condition and system suitability are filler (4.6 × 150mm), column with octadecylsilane chemically bonded silica 25 DEG C of temperature, with acetonitrile-water (60: 5) for Mobile phase B, carries out ladder by following procedure with methanol/ethanol (15: 25) for mobile phase A Degree elution:
Overall flow rate is 1.0ml/min, Detection wavelength 265nm, and theoretical cam curve is calculated by Retinol Palmitate peak, 4000 should be not less than, vitamin D3Between peak and vitamin E peak, vitamin E peak and vitamin K1Between peak and vitamin K1 Separating degree between peak and vitamin E peak should all meet the requirements.Vitamin D3Peak, vitamin E peak, Retinol Palmitate peak It respectively may be about 0.8,1.2,1.6 with the relative retention time of vitamin E.
The preparation of reference substance solution takes vitamin D3Reference substance about 5.5mg, it is accurately weighed, set in 100ml measuring bottle, add just oneself Appropriate alkane, shaking make to dissolve and be diluted to scale, shake up, and precision measures 2ml, set in 10ml measuring bottle, n-hexane is added to be diluted to quarter Degree, shakes up, as vitamin D3Reference substance stock solution；Retinol Palmitate reference substance about 21.0mg is taken, it is accurately weighed, it sets In 25ml measuring bottle, add n-hexane appropriate, shaking makes to dissolve and be diluted to scale, shakes up, as Retinol Palmitate reference substance Stock solution；Precision measures vitamin D3Reference substance stock solution 1ml and Retinol Palmitate reference substance stock solution 5ml, sets 50ml In measuring bottle, vitamin E, vitamin K are separately taken respectively1Reference substance about 20.4mg, 40.0mg, it is accurately weighed, set above-mentioned same measuring bottle In, adding n-hexane to shake in right amount makes to dissolve and be diluted to scale, shakes up, as reference substance solution.
The preparation of sample solution takes the content under this product content uniformity item, finely ground, takes about one bottle of fine powder of amount, and precision claims It is fixed, it is transferred in 250ml separatory funnel by several times with 65% ethyl alcohol 50ml, precision plus n-hexane 25ml shake, and extract, and place It is clarified to upper layer, takes supernatant liquid as sample solution.
Measuring method precision measures reference substance solution and each 20 μ l of sample solution is injected separately into liquid chromatograph, records chromatography Figure；By external standard method with calculated by peak area to get.
(2) vitamin B1, Riboflavine sodium phosphate, vitamin B6, vitamin C, niacinamide, Dexpanthenol shine high performance liquid chromatography Method (two V D of annex of Chinese Pharmacopoeia version in 2010) measures (being protected from light operation).
Chromatographic condition and system suitability 5 μm of ODS2 4.6 × 150mm chromatographic columns of Inertsil, column temperature 40 DEG C, using 0.1% phosphoric acid solution of 0.005mol/L sodium pentanesulfonate as mobile phase A, with 0.005mol/L sodium pentanesulfonate 0.1% phosphoric acid solution-acetonitrile (20: 80) is Mobile phase B, carries out gradient elution by following procedure:
Overall flow rate is 1.0ml/min, and Detection wavelength 210nm, theoretical cam curve should not by the calculating of Riboflavine sodium phosphate peak Lower than 15000.Vitamin B1Peak, vitamin C peak, niacinamide peak, vitamin B6Peak, Dexpanthenol peak and Riboflavine sodium phosphate peak Relative retention time respectively may be about 0.11,0.13,0.18,0.36,0.42.
The preparation of reference substance solution takes cocarboxylase tetrahydrate reference substance about 11.6mg, Riboflavine sodium phosphate reference substance about 11.34mg, vitamin B6Reference substance about 11.0mg, it is accurately weighed, it sets in 10ml measuring bottle, adds appropriate amount of water, shaking makes dissolution and dilute It releases to scale, shakes up, as reference substance stock solution A；Dexpanthenol reference substance about 16.16mg is taken, it is accurately weighed, set 10ml measuring bottle In, add appropriate amount of water, shaking makes to dissolve and be diluted to scale, shake up, as reference substance stock solution C；Precision measures reference substance deposit Liquid A 1ml and reference substance stock solution C 2ml, sets in 50ml measuring bottle, vitamin C reference substance about 25.0mg is separately taken to compare with niacinamide Product about 9.2mg, it is accurately weighed, it sets in above-mentioned same measuring bottle, adds appropriate amount of water shaking to make to dissolve and be diluted to scale, shake up, as Reference substance solution.
The preparation of sample solution takes the content under this product content uniformity item, finely ground, takes about one bottle of fine powder of amount, and precision claims Fixed, until adding appropriate amount of water to make to dissolve and be diluted to scale in 50ml volumetric flask, shaking up, precision measures solution 5ml, sets 25ml capacity In bottle, it is diluted with water to scale, is shaken up, as sample solution.
Measuring method precision measures reference substance solution and each 20 μ l of sample solution is injected separately into liquid chromatograph, records chromatography Figure；By external standard method with calculated by peak area to get.
(3) vitamin B12, folic acid and biotin shine high performance liquid chromatography (two V D of annex of Chinese Pharmacopoeia version in 2010) Measurement.
Chromatographic condition and system suitability 5 μm of ODS2 4.6 × 150mm chromatographic columns of Inertsil, column temperature 40 DEG C, it is with 0.0015mol/L sodium hexanesulfonate-methanol (83: 17) (adjusting pH to 2.65 ± 0.05 with phosphoric acid solution (1 → 10)) Mobile phase (can appropriate adjustment ratio according to chromatographic column situation), Detection wavelength 210nm.Theoretical cam curve presses vitamin B12Peak meter 1800 should be not less than by calculating, biotin peak, folic acid peak, vitamin B12Separating degree between peak should meet the requirements.
The preparation of reference substance solution takes vitamin B12Reference substance about 18mg, it is accurately weighed, it sets in 500ml measuring bottle, adds water suitable Amount, shaking make to dissolve and be diluted to scale, shake up, as vitamin B12Reference substance stock solution；Folic acid reference substance about 8.28mg is taken, It is accurately weighed, it sets in 100ml measuring bottle, adds appropriate amount of water and sodium hydroxide test solution a little, shaking makes to dissolve and be diluted with water to scale, It shakes up, as folic acid reference substance stock solution；Biotin reference substance about 20.7mg is taken, it is accurately weighed, it sets in 50ml measuring bottle, adds water suitable Amount and sodium hydroxide test solution are a little, and shaking makes to dissolve and be diluted with water to scale, shake up, as biotin reference substance stock solution； Precision measures above two each 1ml of stock solution in 100ml measuring bottle, adds appropriate amount of water to be diluted to scale, shakes up, molten as reference substance Liquid.
The preparation of sample solution takes the content under this product content uniformity item, finely ground, takes about one bottle of fine powder of amount, and precision claims Fixed, precision plus water 5ml, shaking are dissolved, and precision measures 3ml, are set in l0ml volumetric flask, are diluted with water to scale, shake up, as sample Product solution.
Measuring method precision measures reference substance solution and each 20 μ l of sample solution is injected separately into liquid chromatograph, records chromatography Figure；By external standard method with calculated by peak area to get.
13 kinds of Compsoite vitamin injection pharmaceutical compositions provided by the invention and preparation method thereof have the advantage that
1) vitamin K in Compsoite vitamin injection is solved1Because being influenced by compatibility, unstable problem, is improved The safety of product quality and clinical application.
2) a kind of antioxidant of propyl benzoate is used only, reducing the use of antioxidant supplementary product kind, (13 kinds of the prior art multiple A variety of antioxidant such as Butylated Hydroxyanisole, Butylated Hydroxytoluene, rough gentian acyl ethanol amine need to be added simultaneously by closing vitamin injection), this is not But it reduces preparation cost, improve quality controllability, and it is possible clinical secondary to also overcome a variety of antioxidant auxiliary materials Effect, to further increase the safety of product clinical application.
3) 13 kinds of Compsoite vitamin injection pharmaceutical compositions preparation method provided by the invention is easy, it is easy to accomplish industry Change.
Specific embodiment
Below will by embodiment, the invention will be further described, these description be not the content of present invention is made into The restriction of one step.It should be understood by those skilled in the art that equivalent replacement made by the content of present invention, or be correspondingly improved, still Within belonging to the scope of protection of the present invention.
Embodiment 1
Prescription:
The every 5 milliliters of injections of first ampoule contain: Retinol Palmitate 3300IU, vitamin K10.15mg, vitamin D3 200IU, vitamin E 10IU, vitamin C 200mg, vitamin B16mg, Riboflavine sodium phosphate 5mg are (in terms of riboflavin 3.6mg), Dexpanthenol 15mg, vitamin B66mg, niacinamide 40mg, Isosorbide dimethyl ether 60mg, propyl benzoate 0.8mg, pH Regulator adjusts pH value to about 6；
The every 5 milliliters of injections of second ampoule contain: vitamin B125 μ g, folic acid 0.6mg, biotin 60 μ g, propylene glycol 1.5g, PH adjusting agent adjusts pH value to about 6.
Preparation method:
First ampoule injection: Retinol Palmitate, vitamin K are weighed by recipe quantity1, vitamin D3, vitamin E, Isosorbide dimethyl ether is placed in container, is uniformly mixed, is obtained oil-phase solution；Vitamin C, vitamin B are weighed by recipe quantity1, core Flavine sodium phosphate, Dexpanthenol, niacinamide, vitamin B6It is placed in container, the water for injection being cooled to room temperature is added to stir to dissolution, PH to 3~5 is adjusted with pH adjusting agent, it is active by 0.03% (W/V) needle to be added with 0.22 μm of filtering with microporous membrane, in filtrate Charcoal, decarbonization filtering after 10~20min of stirring and adsorbing, obtains aqueous phase solution；Oil-phase solution is slowly added into the water phase quickly stirred In solution, pH adjusting agent adjusts pH to 4~7, and benefit adds to the full amount of water for injection, and filters, is filling, sterilizing to obtain the final product；
Second ampoule injection: weighing recipe quantity folic acid, biotin, and the water for injection being cooled to room temperature is added, and nitrogen is protected Protect lower stirring and dissolving；Recipe quantity stabilizer is added and stirs miscible, pH adjusting agent tune pH to 4.5~7, concentrated compounding volume 0.05% is added (W/V) needle-use activated carbon stirring at normal temperature 15 minutes, takes off charcoal filtration；Take the vitamin B of recipe quantity12Add and is cooled to room temperature on a small quantity Water for injection dissolution, be added in previous solu, add water for injection to full dose, stir evenly, 0.22 μm of miillpore filter essence Filter, it is filling, seal, sterilize to obtain the final product.
Embodiment 2
Prescription:
The every 5 milliliters of injections of first ampoule contain: Retinol Palmitate 2800IU, vitamin K10.10mg, vitamin D3 150IU, vitamin E 8IU, vitamin C 150mg, vitamin B14mg, Riboflavine sodium phosphate 4mg are (in terms of riboflavin 2.88mg), Dexpanthenol 10mg, vitamin B64mg, niacinamide 30mg, Isosorbide dimethyl ether 50mg, propyl benzoate 0.65mg, PH adjusting agent adjusts pH value to about 5.5；
The every 5 milliliters of injections of second ampoule contain: vitamin B123 μ g, folic acid 0.45mg, 45 μ g of biotin, propylene glycol 0.5g, pH adjusting agent adjust pH value to about 5.5.
Preparation method: with embodiment 1.
Embodiment 3
Prescription:
The every 5 milliliters of injections of first ampoule contain: Retinol Palmitate 3800IU, vitamin K10.20mg, vitamin D3 250IU, vitamin E 20IU, vitamin C 250mg, vitamin B18mg, Riboflavine sodium phosphate 8mg are (in terms of riboflavin 5.76mg), Dexpanthenol 20mg, vitamin B68mg, niacinamide 60mg, Isosorbide dimethyl ether 80mg, propyl benzoate 0.9mg, PH adjusting agent adjusts pH value to about 6.5；
The every 5 milliliters of injections of second ampoule contain: vitamin B128 μ g, folic acid 0.8mg, biotin 70 μ g, propylene glycol 1.8g, PH adjusting agent adjusts pH value to about 6.5.
Preparation method: with embodiment 1.
Embodiment 4
Prescription:
The every 5 milliliters of injections of first ampoule contain: Retinol Palmitate 2500IU, vitamin K10.05mg, vitamin D3 50IU, vitamin E 5IU, vitamin C 50mg, vitamin B12.5mg, Riboflavine sodium phosphate 2.5mg are (in terms of riboflavin 1.8mg), Dexpanthenol 5mg, vitamin B62.5mg, niacinamide 25mg, Isosorbide dimethyl ether dosage are 40mg, propyl benzoate Dosage be 0.5mg, pH adjusting agent adjusts pH value to about 3；
The every 5 milliliters of injections of second ampoule contain: vitamin B122 μ g, folic acid 0.3mg, 30 μ g of biotin, propylene glycol 0.005g, pH adjusting agent adjust pH value to about 3.
Preparation method: with embodiment 1.
Embodiment 5
Prescription:
The every 5 milliliters of injections of first ampoule contain: Retinol Palmitate 4000IU, vitamin K10.25mg, vitamin D3 300IU, vitamin E 25IU, vitamin C 300mg, vitamin B110mg, Riboflavine sodium phosphate 10mg are (in terms of riboflavin 7.2mg), Dexpanthenol 25mg, vitamin B610mg, niacinamide 75mg, Isosorbide dimethyl ether dosage are 100mg, propyl benzoate Dosage be 1.0mg, pH adjusting agent adjusts pH value to about 7；
The every 5 milliliters of injections of second ampoule contain: vitamin B1210 μ g, folic acid 1.0mg, 80 μ g of biotin, propylene glycol 2.0g, pH adjusting agent adjust pH value to about 7.
Preparation method: with embodiment 1.
Test example (study on the stability)-accelerated test
Test method: taking sample, places under the conditions of being placed in 30 DEG C ± 2 DEG C of temperature, takes when placing 1,2,3,6 month full Sample analysis, measures the content of all kinds of vitamin ingredients in each sample, is 100% as reference using initial 0 day testing result, counts Calculate the content of sample after placing.
The following table 1 is the assay result of each vitamin ingredients when each sample accelerated test is 6 months full:
The above results show: sample of the present invention indices in accelerated test 6 months meet regulation, especially dimension life Plain K1, vitamin K with 1 sample of CN102652744A embodiment1Compare, hence it is evident that show better stability.Sample of the present invention The stability of each vitamin ingredients is integrally better than 1 sample of CN102652744A embodiment.

Claims (3)

1. a kind of 13 kinds of Compsoite vitamin injection pharmaceutical compositions, it is characterised in that: it is made of the injection of two ampoules, Amount containing following ingredient in the every 5 milliliters of volumes of first ampoule injection are as follows: 2500~4000IU of Retinol Palmitate, dimension Raw element K10.05~0.25mg, vitamin D350~300IU, 5~25IU of vitamin E, 50~300mg of vitamin C, dimension life Plain B12.5~10mg, 2.5~10mg of Riboflavine sodium phosphate (1.8~7.2mg in terms of riboflavin), 5~25mg of Dexpanthenol, dimension life Plain B62.5~10mg, 25~75mg of niacinamide, 40~100mg of cosolvent Isosorbide dimethyl ether, antioxidant propyl benzoate 0.5 ~1.0mg, pH adjusting agent adjust pH value to 3~7；Amount containing following ingredient in the every 5 milliliters of volumes of second ampoule injection are as follows: Vitamin B122~10 μ g, 0.3~1.0mg of folic acid, 30~80 μ g of biotin, stabilizer propylene glycol 0.005~2.0g, pH adjusting Agent adjusts pH value to 3~7；PH adjusting agent in the first ampoule injection is sodium hydroxide, the second ampoule injection In pH adjusting agent be selected from citric acid, sodium citrate or their mixture.
2. pharmaceutical composition as described in claim 1, it is characterised in that: in the every 5 milliliters of volumes of the first ampoule injection Amount containing following ingredient are as follows: Retinol Palmitate 3300IU, vitamin K10.15mg, vitamin D3200IU, vitamin E 10IU, vitamin C 200mg, vitamin B16mg, Riboflavine sodium phosphate 5mg (3.6mg in terms of riboflavin), Dexpanthenol 15mg, vitamin B66mg, niacinamide 40mg, Isosorbide dimethyl ether 60mg, propyl benzoate 0.8mg, pH adjusting agent adjust pH It is worth to 4~7；Amount containing following ingredient in the every 5 milliliters of volumes of second ampoule injection are as follows: vitamin B125 μ g, folic acid 0.6mg, biotin 60 μ g, propylene glycol 1.5g, pH adjusting agent adjust pH value to 4.5~7.
3. the preparation method of the described in any item 13 kinds of Compsoite vitamin injection pharmaceutical compositions of claims 1 or 2, feature Be the following steps are included:
The preparation of (1) first ampoule injection: Retinol Palmitate, vitamin K are weighed by recipe quantity1, vitamin D3, dimension life Plain E, Isosorbide dimethyl ether, are placed in container, are uniformly mixed, obtain oil-phase solution；Vitamin C, vitamin are weighed by recipe quantity B1, Riboflavine sodium phosphate, Dexpanthenol, niacinamide, vitamin B6, be placed in container, add the water for injection being cooled to room temperature stir to Dissolution adjusts pH to 3~5 with pH adjusting agent, and with 0.22 μm of filtering with microporous membrane, needle is added by 0.03% (W/V) in filtrate With active carbon, decarbonization filtering after 10~20min of stirring and adsorbing obtains aqueous phase solution；Oil-phase solution is slowly added into quick stirring Aqueous phase solution in, pH adjusting agent adjust pH to 4~7, benefit adds to the full amount of water for injection, filtering, it is filling, sterilize to obtain the final product；
The preparation of (2) second ampoule injections: weighing recipe quantity folic acid, biotin, and the water for injection being cooled to room temperature, nitrogen is added Stirring and dissolving under gas shielded；Recipe quantity stabilizer propylene glycol is added and stirs miscible, pH adjusting agent tune pH to 4.5~7, concentrated compounding is added The needle-use activated carbon of volume 0.05% (W/V) stirring at normal temperature 15 minutes, takes off charcoal filtration；Take the vitamin B of recipe quantity12Add a small amount of The water for injection dissolution being cooled to room temperature, is added in previous solu, adds water for injection to full dose, stir evenly, and 0.22 μm Miillpore filter refined filtration, it is filling, seal, sterilize to obtain the final product.
CN201310376256.8A 2013-08-23 2013-08-23 13 kinds of Compsoite vitamin injection pharmaceutical compositions of one kind and preparation method thereof Active CN104415041B (en)

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CN104224820A (en) * 2014-09-19 2014-12-24 辽宁海思科制药有限公司 Pharmaceutical composition containing 13 kinds of multivitamins and preparation method thereof
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CN114601846A (en) * 2020-12-03 2022-06-10 河北科星药业有限公司 Complex vitamin amino acid injection for livestock and preparation method and application thereof

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CN101073580A (en) * 2007-06-22 2007-11-21 北京润德康医药技术有限公司 Compsoite vitamin injection and its production
CN101181289A (en) * 2007-11-28 2008-05-21 南京海陵中药制药工艺技术研究有限公司 Injection of 13 kinds complex vitamin and preparing technique thereof
CN102652744A (en) * 2011-03-03 2012-09-05 西藏海思科药业集团股份有限公司 Modified injection containing 13 compound vitamins and preparation method thereof
CN102657663A (en) * 2012-04-18 2012-09-12 宁辉 Fat-soluble composite vitamin I composition freeze-dried powder injection and preparation method thereof

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CN101073580A (en) * 2007-06-22 2007-11-21 北京润德康医药技术有限公司 Compsoite vitamin injection and its production
CN101181289A (en) * 2007-11-28 2008-05-21 南京海陵中药制药工艺技术研究有限公司 Injection of 13 kinds complex vitamin and preparing technique thereof
CN102652744A (en) * 2011-03-03 2012-09-05 西藏海思科药业集团股份有限公司 Modified injection containing 13 compound vitamins and preparation method thereof
CN102657663A (en) * 2012-04-18 2012-09-12 宁辉 Fat-soluble composite vitamin I composition freeze-dried powder injection and preparation method thereof

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