CN107898805A - A kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof - Google Patents

A kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof Download PDF

Info

Publication number
CN107898805A
CN107898805A CN201710933326.3A CN201710933326A CN107898805A CN 107898805 A CN107898805 A CN 107898805A CN 201710933326 A CN201710933326 A CN 201710933326A CN 107898805 A CN107898805 A CN 107898805A
Authority
CN
China
Prior art keywords
vitamin
kinds
freeze
preparation
injection
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201710933326.3A
Other languages
Chinese (zh)
Inventor
张颖
杨江勇
李鹏
张作平
杨春芬
朱文霞
何花
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
JINAN KANGHE MEDICAL TECHNOLOGY Co Ltd
Original Assignee
JINAN KANGHE MEDICAL TECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by JINAN KANGHE MEDICAL TECHNOLOGY Co Ltd filed Critical JINAN KANGHE MEDICAL TECHNOLOGY Co Ltd
Priority to CN201710933326.3A priority Critical patent/CN107898805A/en
Publication of CN107898805A publication Critical patent/CN107898805A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/721—Dextrans
    • 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
    • A61K31/16—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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/519—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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Abstract

The invention belongs to field of pharmaceutical preparations, and in particular to a kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof.The lyophilized formulations with water-soluble and liposoluble vitamin totally 12 kinds for active ingredient, it is characterized in that, after active ingredient is dissolved using suitable hydrotropy method, add complexing of metal ion agent, adjust pH value 7.1 7.6, and freezed with pharmaceutically acceptable excipient, obtain aseptic injection lyophilized formulations.Present invention also offers the preparation method of the lyophilized formulations, and using the multivitamin parenteral solution sterile freeze-drying preparation of this method preparation gained, liquid is clarified after solubility, and no drug particles separate out；Not oxidizable, long-time stability are good；Avoid using toxic organic solvent, drug safety is high.

Description

A kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of injection 12 kinds of vitamin freeze-dried preparations and its preparation sides Method.
Background technology
Vitamin is a kind of trace organic substance that human body must obtain for the normal physiological function of maintenance from food. Its species is very much, and chemical constitution is different, and the constituent of most of coenzyme (or prothetic group) for being some enzymes, is maintenance machine Body normal growth (growth, health, breeding and production function) indispensable compound, plays catalytic action, promotes master in vivo The synthesis and degraded of nutrient (protein, fat, carbohydrate etc.) are wanted, so as to control metabolism.Vitamin is in the nature low point Sub- organic compound, they cannot be synthesized in vivo, or synthesized amount is difficult to the needs that meet body, so must be by outer Boundary supplies.Important confactor of the vitamin as metabolism, is the main component of parenteral alimentation.Sent out in disease treatment Important supporting function is waved, even more plays the key effect to sustain life.Clinically, for that can not feed or have malabsorption Patient, vitamin insufficiency of intake can cause metabolic disorder, immunity lower, extend the course of disease, long-term insufficiency of intake, will lead Cause other more diseases.
Parenteral alimentation is widely used in the treatment of a variety of diseases and the nutritional support of average of operation periods patient, and vitamin is as new old The important confactor of metabolism, is the main component of parenteral alimentation.Clinic is mainly used for due to operation, large-area burns, bone The reason such as folding and other wounds, seriousness infectious disease and comatose state cannot be fed, the patient that need to parenterally absorb nourishment. The composite vitamin of injection for intravenous solves problem above, clinically for that can not feed or have the patient of malabsorption can Vein gives a certain amount of vitamin, and long-term parenteral adds in supporting, supplements the exogenous insufficiency of intake of patient.
Domestic clinically available composite vitamin is of less types at present, and mostly import.In view of vitamin species is more, Water soluble vitamin and liposoluble vitamin nature difference are larger, and current existing vitamin kind is mostly single component dimension life Element, composite vitamin kind are mostly simple compound water soluble vitamin or compound liposoluble vitamin.But through clinical for many years Application it was verified that in most cases, the absorption of vitamin is that have certain synergistic effect, that is supplement it is single A kind of or a biostearin effect is good not as the effect for supplementing a variety of or more biostearins at the same time, so clinically using more Or Cernevit-12.
12 kinds of vitamin freeze-dried preparations of injection contain water-soluble and fat-soluble two big biostearin, are a kind of full nutrition classes Parenteral vitamin replenisher, is clinically widely used in not feeding or having the patient of malabsorption, is conducive to improve cure rate, It is the good adjuvant of drug therapy.
Liposoluble vitamin since its solubility in water is extremely low, therefore need to use certain solubilized means by its with it is water-soluble Property vitamin is codissolved in water-based system；Simultaneously as various vitamin ingredients are sensitive to light, heat, pH, particularly to metal from Muonic catalysis susceptible, therefore to overcome in preparation process the effect of light, heat, pH value and metal ion；In addition, vitamin category In component needed for bacterial growth, therefore vitamin medicaments kind easily grows bacterium.At present, the compound referred in existing patent Vitamin injection has the feature of following aspect：1. the means using solubilising are mostly to be had using toxicity such as ethanol, chloroform, propane diols Solvent uses foreign surfaces' activating agents such as a large amount of Tween 80s, and there are larger security risk；2. add dibutyl hydroxyl The antioxidant such as base toluene, propylgallate, sodium hydrogensulfite, sodium pyrosulfite, preservative or bacteriostatic agent suppress vitamin Oxidation and bacterial growth, patient are likely to occur the adverse reactions such as allergy；3. improve liposoluble vitamin using high temperature means Dissolution velocity and solubility, are highly vulnerable to breakage the stability of vitamin, cause vitamin oxidation and decompose, and related material increase is living Property component reduce, not only curative effect reduce, security is also without guarantee；4. pH value controls below 7.0 more, cause folic acid, biotin Separated out Deng easy, the problem of blocking blood vessel, the life and health of serious threat patient occur in infusion process in the drug particles of precipitation.
The content of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of injection 12 kinds of vitamin freeze-dried preparations and its preparation sides Method, the technical scheme is that：
A kind of 12 kinds of vitamin freeze-dried preparations of injection be with water-soluble and liposoluble vitamin totally 12 kinds for active ingredient, It is characterized in that, after active ingredient is dissolved using suitable hydrotropy method, complexing of metal ion agent is added, pH value is adjusted and exists 7.1-7.6, and being freezed with pharmaceutically acceptable excipient, obtains aseptic injection lyophilized formulations, its specifically include as Lower component：
The present invention provides a kind of preparation method of 12 kinds of vitamin freeze-dried preparations of injection, its specific preparation method is：
(1) preparation of water soluble ingredient：
By Water-solubility Material (vitamin C, cocarboxylase tetrahydrate, Riboflavine sodium phosphate, puridoxine hydrochloride, the right side of recipe quantity Panthenol, niacinamide, dextran, complexing of metal ion agent) it is dissolved in one by one in appropriate water for injection, stir and evenly mix, obtain water-soluble Property liquid A.
(2) preparation of liposoluble constituent
The phosphatide of recipe quantity is weighed, is heated to dissolving, glycocholic acid and the stirring of appropriate water for injection for adding recipe quantity are molten Solution, after being cooled to room temperature, adds liposoluble vitamin, stirring and dissolving, up to fat-soluble medical liquid B one by one.
(3) mix：
1. gained water solubility liquid A and fat-soluble medical liquid B are mixed to clarification, constant volume, adjusts pH value to 7.1-7.6 In the range of, up to admixing medical solutions C；
2. adding activated carbon to gained admixing medical solutions C, stirring and adsorbing, takes off charcoal, up to de- charcoal liquid D；
3. by the vitamin D of recipe quantity3, biotin, folic acid and vitamin B12Add in de- charcoal liquid D, stir and evenly mix, essence Filter, up to lyophilized preceding liquid E.
(4) it is filling, partly jump a queue, freeze
Liquid E before obtained freeze-drying is filling in brown cillin bottle, 5ml/ bottles, partly jump a queue, freezed.
(5) total head plug, roll lid, packaging
Vacuum tamponade or nitrogen charging pressure dam, roll lid, pack up to 12 kinds of vitamin freeze-dried preparation finished products of injection.
(6) above procedure, whole nitrogen charging, lucifuge.
The present invention has the advantages that：
1. preparation process whole process inflated with nitrogen, lucifuge, in liquid dissolved oxygen content control effectively avoided in the range of 1mg/L The decomposition of illumination and oxygen to vitamin in preparation process, ensures that the content of active ingredient is constant, curative effect is preferable；2. freeze Preparation water content is low, and moisture is controlled in 1.0-1.5%, effectively prevent the hydrolysis of vitamin；At the same time avoid antioxidant, The use of bacteriostatic agent and preservative, effectively prevent anaphylactoid generation, adds drug safety.3. efficiently solve water The problem of dissolubility and liposoluble vitamin are molten altogether, using needed by human body phosphatide with glycocholic acid as cosolvent, avoid and spit The use of warm 80 grade foreign surfaces' activating agents, reduces the toxicity of medicine.4. with high-temperature digestion phosphatide and glycocholic acid, avoid Using the toxic organic solvent of the ethanol for having stimulation to blood vessel or the chloroform for having genotoxicity etc., complying with for medication is added Property and security.5. using complexing of metal ion agent, the catalytic action of metal ion in preparation process is effectively avoided.6. folic acid, Biotin dissolubility in alkaline environment is good, considers the stability of other kind of vitamin, the pH of present invention control product Value effectively prevent the precipitation of folic acid and biotin after redissolving, clarity is good after redissolution, is less prone in the range of 7.1-7.6 Turbid phenomenon, avoids the problem that occurring blocking blood vessel during venoclysis, drug safety improves.7. life is tieed up in prescription Plain D3, biotin, folic acid and vitamin B12Dosage is less, and after activated carbon adsorption, its content substantially reduces.The present invention passes through control Vitamin D processed3, biotin, folic acid and vitamin B12Bacterial endotoxin in four kinds of raw materials is horizontal, is added directly into pH value In the de- charcoal liquid of 7.1-7.6, to add outside biotin and folic acid dissolution velocity, meanwhile, activated carbon is effectively prevent to this The suction-operated of four kinds of raw materials, the effect of product has been effectively ensured.
Embodiment
The present invention is described in detail with reference to embodiment and comparative example, following embodiments are to the present invention One kind describes in detail rather than is limitation of the present invention.
1. embodiment
1.1 prescription：
1.2 preparation process
(1) preparation of water soluble ingredient：
By Water-solubility Material (vitamin C, cocarboxylase tetrahydrate, Riboflavine sodium phosphate, puridoxine hydrochloride, the right side of recipe quantity Panthenol, niacinamide, dextran, complexing of metal ion agent) it is dissolved in one by one in appropriate water for injection, stir and evenly mix, obtain water-soluble Property liquid A.
(2) preparation of liposoluble constituent
The phosphatide of recipe quantity is weighed, is heated to dissolving, glycocholic acid and the stirring of appropriate water for injection for adding recipe quantity are molten Solution, after being cooled to room temperature, adds liposoluble vitamin (vitamin A or its pharmaceutically acceptable active ester, tocopherol) one by one, Stirring and dissolving, up to fat-soluble medical liquid B.
(3) mix：
1. gained water solubility liquid A and fat-soluble medical liquid B are mixed to clarification, constant volume, adjusts pH value to 7.1-7.6 In the range of, up to admixing medical solutions C；
2. adding activated carbon to gained admixing medical solutions C, stirring and adsorbing, takes off charcoal, up to de- charcoal liquid D；
3. by the vitamin D of recipe quantity3, biotin, folic acid and vitamin B12Add in de- charcoal liquid D, stir and evenly mix, essence Filter, up to lyophilized preceding liquid E.
(4) it is filling, partly jump a queue, freeze
Liquid E before obtained freeze-drying is filling in brown cillin bottle, 5ml/ bottles, partly jump a queue, freezed.
(5) total head plug, roll lid, packaging
Vacuum tamponade or nitrogen charging pressure dam, roll lid, pack up to 12 kinds of vitamin freeze-dried preparation finished products of injection.
(6) above procedure, whole nitrogen charging, lucifuge.
2. comparative example
2.1 prescription
Supplementary material Comparative example 1 Comparative example 2 Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Comparative example 7 Comparative example 8
Retinol Palmitate 0.5g 0.5g 0.5g 0.5g 0.5g 0.5g 0.5g 0.5g
Vitamin D3 1.5mg 1.5mg 1.5mg 1.5mg 1.5mg 1.5mg 1.5mg 1.5mg
Tocopherol 2.3g 2.3g 2.3g 2.3g 2.3g 2.3g 2.3g 2.3g
Vitamin C 27g 27g 27g 27g 27g 27g 27g 27g
Cocarboxylase tetrahydrate 1.5g 1.5g 1.5g 1.5g 1.5g 1.5g 1.5g 1.5g
Riboflavine sodium phosphate 1.35g 1.35g 1.35g 1.35g 1.35g 1.35g 1.35g 1.35g
Puridoxine hydrochloride 1.5g 1.5g 1.5g 1.5g 1.5g 1.5g 1.5g 1.5g
Vitamin B12 1.3mg 1.3mg 1.3mg 1.3mg 1.3mg 1.3mg 1.3mg 1.3mg
Folic acid 90mg 90mg 90mg 90mg 90mg 90mg 90mg 90mg
Dexpanthenol 3.5g 3.5g 3.5g 3.5g 3.5g 3.5g 3.5g 3.5g
Biotin 15mg 15mg 15mg 15mg 15mg 15mg 15mg 15mg
Niacinamide 6g 6g 6g 6g 6g 6g 6g 6g
Glycocholic acid 27g 27g 27g 27g 27g 27g 27g 27g
Soybean lecithin 23g 23g 23g 23g 23g 23g 23g 23g
Dextran 28.5g 28.5g 28.5g 28.5g 28.5g 28.5g 28.5g 28.5g
Natrium adetate 100mg 100mg 100mg / 100mg 100mg 100mg 100mg
PH adjusting agent 7.3 7.3 6.0 7.3 7.3 7.3 7.3 7.3
Tween 80 / / / / / 10g / /
Ethanol / / / / 10ml / / /
Sodium hydrogensulfite / / / / / / 50mg /
Water for injection adds to 1000ml 1000ml 1000ml 1000ml 1000ml 1000ml 1000ml 1000ml
2.2 preparation process
2.2.1 1 preparation process of comparative example
Nitrogen charging and lucifuge measure are not taken in preparation process, the preparation of remaining component is the same as 2 preparation process of embodiment.
2.2.2 2 preparation process of comparative example
(1) preparation of water soluble ingredient：
By Water-solubility Material (vitamin C, cocarboxylase tetrahydrate, Riboflavine sodium phosphate, puridoxine hydrochloride, the right side of recipe quantity Panthenol, niacinamide, dextran, complexing of metal ion agent, folic acid, biotin, vitamin B12) appropriate injection is dissolved in one by one In water, stir and evenly mix, obtain water-soluble liquid A.
(2) preparation of liposoluble constituent
The phosphatide of recipe quantity is weighed, is heated to dissolving, glycocholic acid and the stirring of appropriate water for injection for adding recipe quantity are molten Solution, after being cooled to room temperature, adds liposoluble vitamin (Retinol Palmitate, tocopherol, vitamin D one by one3), stirring is molten Solution, up to fat-soluble medical liquid B.
(3) mix：
1. gained water solubility liquid A and fat-soluble medical liquid B are mixed to clarification, constant volume, adjusts pH value to 7.1-7.6 In the range of, up to admixing medical solutions C；
2. adding activated carbon to gained admixing medical solutions C, stirring and adsorbing, takes off charcoal, refined filtration, up to lyophilized preceding liquid D；
(4) it is filling, partly jump a queue, freeze
Liquid D before obtained freeze-drying is filling in brown cillin bottle, 5ml/ bottles, partly jump a queue, freezed.
(5) total head plug, roll lid, packaging
Vacuum tamponade or nitrogen charging pressure dam, roll lid, pack up to 12 kinds of vitamin freeze-dried preparation finished products of injection.
(6) above procedure, whole nitrogen charging, lucifuge.
2.2.3 3 preparation process of comparative example
The pH value of product is adjusted 6.0 or so, the preparation of remaining component is the same as 2 preparation process of embodiment.
2.2.4 4 preparation process of comparative example
Complexing of metal ion agent natrium adetate is not added with product, the preparation of remaining component is the same as 2 preparation process of embodiment.
2.2.5 comparative example 5,6 preparation process of comparative example
The preparation of liposoluble constituent：Phosphatide, glycocholic acid and the ethanol or Tween 80 stirring and dissolving of recipe quantity are weighed, one by one Add liposoluble vitamin (Retinol Palmitate, tocopherol), stirring and dissolving, up to fat-soluble liquid.
The preparation of remaining component is the same as 2 preparation process of embodiment.
2.2.6 7 preparation process of comparative example
The preparation of water soluble ingredient：By Water-solubility Material (vitamin C, cocarboxylase tetrahydrate, the riboflavin phosphate of recipe quantity Sodium, puridoxine hydrochloride, Dexpanthenol, niacinamide, dextran, complexing of metal ion agent, sodium hydrogensulfite) it is dissolved in one by one in right amount In water for injection, stir and evenly mix, obtain water-soluble liquid.
The preparation of remaining component is the same as the preparation process in embodiment 1.
2.2.7 8 preparation process of comparative example
The preparation of liposoluble constituent：Add appropriate water for injection to dissolve recipe quantity glycocholic acid, after adding ethanol in proper amount, add Enter soybean lecithin and liposoluble vitamin (Retinol Palmitate, tocopherol), the stirring and dissolving at 55 DEG C, up to fat-soluble Liquid.
The preparation of remaining component is the same as the preparation process in embodiment 1.
2.3 result of the tests and conclusion
1. prescription used in the present invention and the embodiment 1-3 products obtained by preparation process it can be seen from result in upper table Each index meets regulation, and the clarity of liquid is good after redissolution, no erythrocyte hemolysis, detects content and the place of vitamin Measure almost indifference in side.2. compared with embodiment, the safeguard measures such as nitrogen charging, lucifuge are not taken in 1 whole preparation process of comparative example, Vitamin is caused to produce decomposition, content reduces, corresponding related material increases, and excessive toxic impurities cause red blood cell slightly Generation hemolytic reaction.3. compared with embodiment, the product obtained by comparative example 2, due to biotin, folic acid, vitamin D3And dimension Raw element B12It is subject to the suction-operated of activated carbon in preparation process, causes its content substantially to reduce, drug effect reduces, and therapeutic effect is not Substantially.4. compared with embodiment, product obtained by comparative example 3 causes folic acid and biology during redissolving since pH value is relatively low Element separates out, and the clarity of liquid is bad, easily leads to the phenomenon for occurring blocking blood vessel in infusion process, the life of serious threat patient Health.5. compared with embodiment, complexing of metal ion agent is not used in 4 preparation process of comparative example, causes vitamin C to be subject to metal The catalytic action of ion produces decomposition reaction, causes ascorbic content substantially to lower, drug effect cannot get strong guarantee.⑥ Compared with embodiment, comparative example 5, due to using the toxic co-solvents such as ethanol or Tween 80 in preparation process, causes with comparative example 6 Final products have certain hemolytic toxicity and potential blood vessel irritation, and medication compliance and the security of patient reduce.⑦ Embodiment does not add antioxidant to prevent the oxidation of vitamin in preparation process, and prepared product is with comparative example 7 without bright Significant difference is different, shows to reduce clinically because using without the necessity using oxidant with prescription provided by the present invention and technique Oxidant causes anaphylactoid risk.8. liposoluble constituent is in preparation process it can be seen from 8 result of the test of comparative example, To increase the means that solubility and the dissolution velocity of liposoluble vitamin use high temperature, cause containing for liposoluble vitamin in product Amount is obvious to be reduced, and curative effect reduces, meanwhile, corresponding related material increase, excessive toxic impurities cause the hair of red blood cell slightly Raw hemolytic reaction.
In conclusion prescription and preparation process products obtained therefrom according to the present invention, clarity is good after redissolution, no drug particles analysis Go out；Not oxidizable, long-time stability are good；Avoid using toxic organic solvent, drug safety is high.Meanwhile to needed by human body The vitamin wanted has carried out supplement in all directions, avoids the defects of being caused using single vitamin, substantially increases treatment effect Fruit.

Claims (8)

  1. A kind of 1. 12 kinds of vitamin freeze-dried preparations of injection, it is characterised in that each material including following components by weight percent：
  2. A kind of 2. 12 kinds of vitamin freeze-dried preparations of injection according to claim 1, it is characterised in that the vitamin A or its pharmaceutically acceptable active ester are vitamin A, Retinol Palmitate, one kind in vitamine A acetate or several Kind.
  3. A kind of 3. 12 kinds of vitamin freeze-dried preparations of injection according to claim 1, it is characterised in that the metal from Sub- complexing agent is one or both of natrium adetate, mosatil.
  4. 4. 12 kinds of vitamin freeze-dried preparations of a kind of injection according to claim 1, it is characterised in that the phosphatide is One or both of soybean lecithin or egg yolk lecithin.
  5. A kind of 5. 12 kinds of vitamin freeze-dried preparations of injection according to claim 1, it is characterised in that the pH of the product Value is preferably 7.3.
  6. 6. 12 kinds of vitamin freeze-dried preparations of a kind of injection according to claim 1, it is characterised in that preparation method includes Following steps：
    (1) preparation of water soluble ingredient：
    By the Water-solubility Material of recipe quantity：Vitamin C, cocarboxylase tetrahydrate, Riboflavine sodium phosphate, puridoxine hydrochloride, Dexpanthenol, Niacinamide, dextran, complexing of metal ion agent are dissolved in appropriate water for injection one by one, are stirred and evenly mixed, and obtain water-soluble liquid A；
    (2) preparation of liposoluble constituent
    The phosphatide of recipe quantity is weighed, is heated to dissolving, adds the glycocholic acid of recipe quantity and appropriate water for injection stirring and dissolving, it is cold But to after room temperature, liposoluble vitamin stirring and dissolving is added one by one, up to fat-soluble medical liquid B；
    (3) mix：
    1. gained water solubility liquid A and fat-soluble medical liquid B are mixed to clarification, constant volume, adjusts pH value, up to admixing medical solutions C；
    2. adding activated carbon to gained admixing medical solutions C, stirring and adsorbing, takes off charcoal, up to de- charcoal liquid D；
    3. by the vitamin D of recipe quantity3, biotin, folic acid and vitamin B12Add in de- charcoal liquid D, stir and evenly mix, refined filtration, Up to lyophilized preceding liquid E；
    (4) it is filling, partly jump a queue, freeze
    Liquid E before obtained freeze-drying is filling in brown cillin bottle, 5ml/ bottles, partly jump a queue, freezed；
    (5) total head plug, roll lid, packaging
    Vacuum tamponade or nitrogen charging pressure dam, roll lid, pack up to 12 kinds of vitamin freeze-dried preparation finished products of injection；
    (6) above procedure, whole nitrogen charging, lucifuge.
  7. A kind of 7. 12 kinds of vitamin freeze-dried preparations of injection according to claim 6, it is characterised in that institute in step (2) State liposoluble vitamin and refer to vitamin A or its pharmaceutically acceptable active ester and tocopherol；The liposoluble vitamin After charging time is reduced to 20-25 DEG C for phosphatide with glycocholic acid temperature.
  8. 8. 12 kinds of vitamin freeze-dried preparations of a kind of injection according to claim 6, it is characterised in that step (3) is described Vitamin D3, biotin, folic acid and vitamin B12Feed intake after bacterial endotoxin controls, and charging time is step 2. after de- charcoal.
CN201710933326.3A 2017-10-10 2017-10-10 A kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof Pending CN107898805A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710933326.3A CN107898805A (en) 2017-10-10 2017-10-10 A kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710933326.3A CN107898805A (en) 2017-10-10 2017-10-10 A kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof

Publications (1)

Publication Number Publication Date
CN107898805A true CN107898805A (en) 2018-04-13

Family

ID=61841131

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710933326.3A Pending CN107898805A (en) 2017-10-10 2017-10-10 A kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof

Country Status (1)

Country Link
CN (1) CN107898805A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110251461A (en) * 2019-07-16 2019-09-20 河南益华动物药业有限公司 Vitamin B complex injection and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1843327A (en) * 2006-04-17 2006-10-11 重庆医药工业研究院有限责任公司 Stable freeze-dried formulation containing multiple kinds of vitamin and its preparation method
CN101433547A (en) * 2008-12-19 2009-05-20 江苏万邦生化医药股份有限公司 Method for preparing twelve kinds of composite vitamins for injection
CN104688762A (en) * 2013-12-05 2015-06-10 天津汉瑞药业有限公司 Medicinal composition containing 12 vitamins and used for intravenous injection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1843327A (en) * 2006-04-17 2006-10-11 重庆医药工业研究院有限责任公司 Stable freeze-dried formulation containing multiple kinds of vitamin and its preparation method
CN101433547A (en) * 2008-12-19 2009-05-20 江苏万邦生化医药股份有限公司 Method for preparing twelve kinds of composite vitamins for injection
CN104688762A (en) * 2013-12-05 2015-06-10 天津汉瑞药业有限公司 Medicinal composition containing 12 vitamins and used for intravenous injection

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110251461A (en) * 2019-07-16 2019-09-20 河南益华动物药业有限公司 Vitamin B complex injection and preparation method thereof
CN110251461B (en) * 2019-07-16 2021-07-13 河南益华动物药业有限公司 Vitamin B complex injection and preparation method thereof

Similar Documents

Publication Publication Date Title
CN101711769A (en) Stable injection composite of 12 complex vitamins and preparation method thereof
CN1278682C (en) Nanometer preparation of natural vitamin E and its preparation
CN102512437B (en) Medicinal composition of liposoluble vitamin injection (I) and water-soluble vitamin for injection and preparation method thereof
CN104337829B (en) The one bottled compound 13 kinds of vitamin freeze-dried preparations of fat micro emulsion
CN102429864B (en) Medicinal compound of fat-soluble vitamin injection (II) and water-soluble vitamin for injection and preparation method thereof
CN102552293A (en) Compound vitamin submicron emulsion lyophilized powder for injection and preparation method of compound vitamin submicron emulsion lyophilized powder
CN107898805A (en) A kind of 12 kinds of vitamin freeze-dried preparations of injection and preparation method thereof
CN105726473A (en) Oral solution of tomoxetine or medicinal salt thereof and preparation method thereof
CN102499939B (en) Pharmaceutical compositions of fat-soluble vitamins for injection and water-soluble vitamins for injection and preparation method thereof
CN103169756B (en) Pharmaceutical composition of water-soluble vitamins for injection, fat-soluble vitamin injection and fat emulsion injection
CN102552134A (en) Fat emulsion containing vitamin K1
CN103169755B (en) Pharmaceutical composition of water-soluble vitamins for injection, fat-soluble vitamins for injection and fat emulsion injection
CN105147609A (en) Diethylstilbestrol fat emulsion injection
CN106214635B (en) A kind of Fluorouracil Injection pharmaceutical composition
CN103768088B (en) Pharmaceutical composition containing water-soluble vitamins for injection, fat-soluble vitamins for injection and medium/long-chain fat emulsion injection
CN104688762A (en) Medicinal composition containing 12 vitamins and used for intravenous injection
CN102670501B (en) Orally taken vitamin K1 lipid emulsion
CN102757471B (en) Novel active cytidine disodium triphosphate compound and pharmaceutical composition thereof
CN105232465A (en) Fenbendazole liposome preparation and preparing method thereof
CN102488664B (en) Pharmaceutical composition containing 12 vitamins
CN103768132B (en) Pharmaceutical composition containing water-soluble vitamins for injection, fat-soluble vitamin injection and medium/long-chain fat emulsion injection
CN103877013A (en) Asarin injection and preparation method thereof
CN105919951B (en) The pharmaceutical composition of Vitamin H and liposoluble vitamin II
CN115212200B (en) Puerarin-containing compound preparation for treating diabetic complications and preparation method thereof
CN111329839B (en) Composite vitamin freeze-dried preparation and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20180413

RJ01 Rejection of invention patent application after publication