CN104337829A - Bottled grease micro emulsion freeze-dried preparation with 13 composite vitamins - Google Patents

Bottled grease micro emulsion freeze-dried preparation with 13 composite vitamins Download PDF

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CN104337829A
CN104337829A CN201410430836.5A CN201410430836A CN104337829A CN 104337829 A CN104337829 A CN 104337829A CN 201410430836 A CN201410430836 A CN 201410430836A CN 104337829 A CN104337829 A CN 104337829A
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vitamin
freeze
kinds
bottled
fat
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CN104337829B (en
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马玉樊
陈涛
惠民权
张婉直
王汝涛
余惟平
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XI'AN LIBANGZHAO NEW BIOLOGICAL TECHNOLOGY Co Ltd
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XI'AN LIBANGZHAO NEW BIOLOGICAL TECHNOLOGY 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
    • A61K31/70—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
    • 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
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    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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

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Abstract

The invention discloses a bottled grease micro emulsion freeze-dried preparation with 13 composite vitamins. The preparation is prepared by wrapping lipid-soluble vitamins A, D, E and K in grease micro emulsion of which the particle size is smaller than 120nm, mixing with water-soluble vitamins B and C, folic acid, nicotinamide and the like, adding a freeze-drying forming agent and a redissolution additive, and freeze-drying. The novel freeze-dried preparation, which contains 13 vitamins and is developed according to the above formula and the preparation method, is simple in process, the stability of the vitamins can be improved, and the side effect caused by medicine decomposition and decomposition products is alleviated; the problem of codissolution of lipid-soluble vitamins and water-soluble vitamins is effectively solved, sufficient dissolution of medicine compounds is ensured, and the side effect of undissolved substances on human bodies is avoided.

Description

One bottled fat microemulsion compound, 13 kinds of vitamin freeze-dried preparations
Technical field
The invention belongs to medical drugs technical field, relate to avitaminotic pharmaceutical preparation of a kind of prevention and therapy and preparation method thereof.Exactly an a kind of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations.This novel formulation adopts special prescription and technique water solublity and fatsoluble vitamin to be combined cleverly, forms single lyophilizing compound recipe molten altogether.The stability of vitamin can be improved, decrease the decomposition of medicine, and the side effect that catabolite causes; The problem that effective solution is fat-soluble and water soluble vitamins is molten altogether, eliminates the pollution risk that the extraction-mixing repeatedly in use of tradition 2 bottled preparations may cause; The abundant dissolving of pharmaceutical compounds can be ensured simultaneously, avoid the side effect injury that insoluble matter causes health.Be suitable for multivitamin to lack and parenteral nutrition clinical practice.
Background technology
Total parenteral nutrition (Total Parenteral Nutrition, TPN) support to be applicable to patient when can not or not absorbed nourishment by gastrointestinal tract cmpletely, by intravenous nutrition liquids such as venous access input glucose, aminoacid, fat milk, electrolyte, trace element, vitamin, make supplementary a kind of method that can reach the degree be comparatively satisfied with of these nutrient substance.Be mainly used in the treatment of following disease clinically: gastrointestinal fistula, short intestinal are comprehensively demonstrate,proved, renal failure, large-area burns, serious wound, infection, acute pancreatitis etc.; Also for the auxiliary treatment of following disease: major operation peri-operation period, respiratory failure, long-time assisted mechanical ventilator, patients with severe brain injury are early stage, bone marrow transplantation, malignant tumor patient, the heavily danger neonate etc. that can not normally ingest.
Vitamin is that maintenance body normal function is necessary, often by the small molecule organic compound of food supply.Vitamin neither forms body tissue composition, and also oxidation Decomposition does not release energy, but plays a significant role in vivo by participating in multiple different physiological and biochemical procedure.The every day requirement of body to vitamin is few, often calculate with microgram, normal human can obtain required vitamin by food, but may cause vitamin Deficiency of Intake in some special situations or the pathogenetic situation of disease, therefore the nutritional support of vitamin is a requisite part in Parenteral nutrition.The kind of vitamin is a lot, configurations, is usually divided into fatsoluble vitamin and the large class of water soluble vitamins two according to the difference of its dissolution properties.Fatsoluble vitamin comprises vitamin A. D. E, K etc.; Water soluble vitamins mainly comprises vitamin C and vitamin B group, and vitamin B group comprises vitamin B 1, B 2, PP, B 6, B 12, folic acid, pantothenic acid, biotin etc.
The chemical constitution of vitamin A is the unsaturated monohydric alcohol containing alicyclic ring, has A 1and A 2two kinds, A 1for retinol, A 2for 3-dehydroretinol, in plant, beta-carotene is provitamin A.Vitamin A has growth promoting effects, maintains epithelial tissue as the normal function of skin, conjunctiva, cornea etc., and participates in the synthesis of rhodopsin, strengthens retinal photoreceptor power, can cause xerophthalmia during shortage; Vitamin A is by participating in the synthesis of steroid, and promote body growth, growth, breeding, vitamin A deficiency will cause body growth to be stagnated, dysplasia.Vitamin A 250 ~ 800 μ g of adult's daily requirement, vitamin A is mainly used in preventing hypovitaminosis A and some treating for skin disease clinically.
Vitamin D is steroid derivatives, mainly contains vitamin D 2and D 3two kinds, D 2for ergocalciferol, D 3for cholecalciferol.Vitamin D mainly participates in the adjustment of Ca,P metabolism, increases body to the utilization of calcium, phosphorus, promotes skeleton normal growth.Be deficient in vitamin D or its active substance time, can there is rickets due to ossification obstacle in child, adult then occurs osteomalacia.Adult's daily requirement vitamin D 5 μ g, child, anemia of pregnant woman and nursing women's daily requirement 10 μ g.Vitamin D is mainly used in control rickets, osteomalacia, senile osteoporosis etc. clinically.
Vitamin E, also known as tocopherol, chemical constitution is the derivant of benzene a pair of horses going side by side dihydropyran.Vitamin E is very responsive to oxygen, easily oxidized, therefore can exempt from Oxidative demage by the interior important compounds of protective, play antioxidation, can maintain integrity and the stability of the organelle of cell membrane; Vitamin E also can resist the harm of radical pair human body, for defying age; Vitamin E has antisterility effect.Adult's daily requirement vitamin E 5 ~ 150mg.Vitamin E is used for the treatment of the ancillary drug of infertility, habitual abortion, muscular dystrophy and arteriosclerosis etc. clinically.
Vitamin K is the derivant of 2-MNQ, and naturally occurring have K 1and K 2two kinds, be fat-soluble, synthetic K 3and K 4for water-soluble substances.Vitamin K is main relevant with blood coagulation, and can promote prothrombin, the synthesis of IV, IX and X, this several thrombin during shortage in blood all reduces, cruor time extending, and subcutaneous, muscle and gastrointestinal hemorrhage occur; Vitamin K can also increase enterokinesia, has relieving spasm to stop pain effect.Adult's daily requirement vitamin K 20 ~ 100mg.Vitamin K is mainly used in sweet-clover disease and hemorrhage caused by vitamin K deficiency clinically, as the patient, premature infant etc. of obstructive jaundice, liver cirrhosis, long-term taking broad ectrum antibiotic.
Vitamin C is also called ascorbic acid, easily oxidized, and in neutrality or alkaline solution, heat is easily destroyed.Vitamin C participates in the hydroxylation reaction of substance in vivo metabolism by the form of cofactor, can promote the metabolism of the conversion of collagen protein synthesis, cholesterol and aromatic series fatty acid, if lacked, cause vitamin C deficiency; Vitamin C, also by participating in redox reaction, playing antioxidant radical damage, enhancing antibody generates and promote the effect of hemopoietic; In addition, vitamin C can stop nitrosamine to be synthesized and promote that it decomposes, and therefore has certain protective effect on cancer risk.Adult's daily requirement vitamin C 30 ~ 500mg.Vitamin C is used for the treatment of scurvy, methemoglobinemia clinically, and the auxiliary treatment of various acute and chronic infectious diseases, wound, anaphylactic disease etc.
Vitamin B 1also known as thiamine, in neutrality and alkaline solution, heat is very easily destroyed, and oxidant or reducing agent can make its inactivation.Vitamin B 1play an important role in carbohydrate metabolism, energy can be caused under-supply if lacked, impact cardiac muscle, skeletal muscle and neural function, form vitamin B1 deficiency; In addition, vitamin B 1also can affect the synthesis of acetylcholine, during shortage, acetylcholine synthesis reduces, and decomposition increases, and cholinergic nerve is affected, and causes nerve impulse conduction obstacle, affects gastrointestinal, myocardial function.Adult's daily requirement vitamin B 10.5 ~ 20mg.Clinical being mainly used in prevents and treats vitamin B 1deficiency disease, and the auxiliary treatment of polyneuritis, peripheral neuritis, facial palsy, dyspepsia etc.
Vitamin B 2also known as riboflavin, heat-resisting, stable in neutrality or acid solution, but easily by alkali and ultraviolet damage.Vitamin B 2the prothetic group of to be FMN and FAD, FMN and FAD the be various flavo-enzyme of activity form in vivo, can play and pass hydrogen effect, vitamin B in biological oxidation process 2during shortage, cheilitis, glossitis, angular cheilitis, scrotitis, seborrheic dermatitis and eye conjunctivitis etc. can be there are.Adult's daily requirement vitamin B 20.5 ~ 20mg.
Vitamin B 6comprise pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. and pyridoxamine, be the derivant of pyridine, all responsive to light, alkali, heat, at high temperature destroy rapidly.Adult's daily requirement vitamin B 60.5 ~ 10mg.B clinically 6be mainly used in vomiting, anemia, leukopenia etc. that treatment central nervous excitation symptom and peripheral neuritis, medicine and gestation etc. cause.
Vitamin B 12also known as cobalamine, to photaesthesia, oxidant or reducing agent all easily make it destroy.Vitamin B 12it is the coenzyme of transmethylase, in participation endochylema, homocysteine methylates, the metabolism of methionine and the synthesis of the important substance such as choline, creatine is affected during shortage, tetrahydrofolic acid free in body can also be caused to lack, produce megaloblastic anemia, cause the degeneration of neural myelin sheath degeneration, intellectual deterioration etc.Adult's daily requirement vitamin B 121 ~ 10 μ g.Vitamin B clinically 12be mainly used in treating pernicious anemia and megaloblastic anemia, neuritis, neuratrophia etc.
Vitamin PP has nicotinic acid and nicotiamide two kinds at occurring in nature, belongs to the derivant of pyridine.Vitamin PP is the ingredient of coenzyme, and play in biological oxidation process and pass hydrogen effect, can cause pellagra during shortage, clinical manifestation is that the exposed position of body is blown by symmetry dermatitis.Adult's daily requirement vitamin PP 12 ~ 17mg.Clinical in preventing and treating pellagra, also can be used for peripheral vessel spasm, thromboangiitis obliterans, retinitis, hypertension, angina pectoris, hyperlipemia and atherosclerosis etc.
Pantothenic acid, also known as pantothenic acid, plays an important role in sugar, fat and protein metabolism process, adult's daily requirement pantothenic acid 2 ~ 20mg.The hydrogenation products of pantothenic acid is pantothenylol, and pantothenylol can strengthen normal skin hydration function, can improve drying, coarse, desquamation, antipruritic and treatment multiple dermatosis (as atopic dermatitis, psoriasis, psoriasis and contact dermatitis).
Folic acid, also known as pteroylglutamic acid, easily decomposes destruction in an acidic solution.Folic acid plays an important role in the synthesis of purine, pyrimidine, and during shortage, DNA synthesis is suppressed, and cell cycle can be caused to stop at the S phase, and erythrocytic reaching maturity is affected, and occurs megaloblastic anemia.Adult's daily requirement folic acid 100 ~ 400 μ g.Folic acid is used for the treatment of the auxiliary treatment of megaloblastic anemia, aplastic anemia and leukopenia clinically.
Biology have α-biotin and β-biotin, destructible in alkaline solution, and oxidant and high temperature can make its inactivation.Biotin is the coenzyme of carboxylase, and its carboxylation reaction participated in is significant to sugared, fatty etc. metabolism.During shortage, geroderma pathological changes easily occurs, lose weight, asthenia is drowsy, myalgia, feels sick.Adult's daily requirement biotin 10 ~ 100 μ g.
Large quantity research confirms to need vitamin 13 kinds in intravenous nutrition liquid, wherein water soluble vitamins 9 kinds, fatsoluble vitamin 4 kinds, but due to fatsoluble vitamin water insoluble, therefore need during preparation to adopt special adjuvant or technology to make two biostearins be present in same system.Further, because the most of physicochemical property of vitamins composition is unstable, the sensitivities such as multipair light, heat, oxygen, metal ion, soda acid, therefore also need to adopt special dosage form to keep the stability of product.At present, the two class Cernevit-12s that comprise gone on the market both at home and abroad all adopt the mode adding solubilizing agent (tween, phospholipid) to increase the dissolubility of fatsoluble vitamin, and dosage form has lyophilized injectable powder and concentrated solution for injection, all needs to dilute rear use.
Shi Niweita is the lyophilized injectable powder uniquely comprising two biostearins of current domestic listing, containing 12 kinds of vitamin (not containing vitamin K), forms mixed micelle solubilising with 2.25% soybean phospholipid and 2.8% glycocholic acid.The principle of its solubilising is: soybean phospholipid and glycocholic acid are all have hydrophilic and compound that is hydrophobic group, after being greater than critical micelle concentration, soybean phospholipid and glycocholic acid can be alternately arranged and form the micelle that flocks together towards water, hydrophobic C-H bond of hydrophilic group, and vitamin molecules inserts micelle hydrocarbon core with its non-polar group and by solubilising.As can be seen here, vitamin is not encapsulated by micelle completely, Micellar Solubilization defines solubilizing agent-medicine dynamic aggregating body, this aggregation has unstability, micelle all may be caused to disintegrate when injection dilutes or mixes with other nutritional solutions, and then occur that injection is muddy, generate the situation such as suspended matter or precipitation, be unfavorable for the stability of product.
" adult's multivitamin injection (INFUVITE ADULT) " is 13 kinds of vitamin injections in U.S.'s listing, is the form avoiding the interaction of vitamin under water environment to adopt two bottles of subpackages.Wherein, bottle 1 is containing vitamin A. D. E, K, vitamin B 1, B 2, B 6, nicotiamide and Dexpanthenol, adopt 1.4% Tween 80 solubilising, its solubilising principle is also Micellar Solubilization.Bottle 2 is containing vitamin B 12, biotin and folic acid, adopt 30% propylene glycol to be solvent.Find in prolonged application, Tween 80 has certain pharmacological action and toxicity, the most outstanding is haemolysis, inhibitory action is had in addition to heart, blood pressure can be caused slightly to decline, can also bring out human lymphocyte Sister Chromatid Exchange Frequency to increase, and damage dna copies template, have mutagenic probability.Therefore, the improper solubilizing agent as intravenous administration formulation of Tweens.Further, this kind adopts two bottles of subpackages, needs when in use repeatedly to extract-mix, brings inconvenience to clinical practice, add the possibility of pollution.
CN101491499 provides a kind of composite liposome for injection containing 12 vitamins and preparation method thereof, in this patent, first forms liposome, then is encapsulated by the hot mixt of two biostearins simultaneously, and the particle diameter of liposome is between 150nm ~ 200nm.But the preparation process of liposome is more complicated, and introduce the organic reagents such as chloroform in the preparation of liposome, be unfavorable for the safety of product.In addition, liposome quality is not easy to control, and vitamin easily leaks.
CN1989975 provides a kind of preparation method of 12 kinds of composite vitamin injections, the object of this patent is to provide that a kind of cost is low, the simple 12 kinds of composite vitamin injections of technique, the main innovate point of said preparation dissolves fat-soluble and water solublity two kinds of vitamin respectively by suitable solubilizing agent and cosolvent, then by activated carbon adsorption, two biostearins are combined.Although this method can make the vitamin that two classes can not be dissolved each other combine, but add due to active carbon the content that membership obviously reduces principal agent, and activated carbon is to the sensitive of temperature and pH value, so can not ensure that this preparation can dissolve completely when Clinical practice, stable in properties.
Patent about Compsoite vitamin injection also has CN101297680, CN101433547 etc., its main component, preparation characteristic and as follows with the contrast of this patent:
Patent No. CN101297680, its main component is 9 kinds of vitamin, and the form in aqueous solution is emulsion droplet, formulation characteristic: containing the emulsion of 1% edible oil, 2% Tween 80,0.7% sorbester p37, drink for poultry; Advantage: can with water arbitrarily than mixing, not stratified, do not precipitate, simple to operate; Shortcoming: the toxicity such as the tween added, span are comparatively large, easily cause haemolysis.
Patent No. CN101491499, its main component is 12 kinds of vitamin, and the form in aqueous solution is liposome, formulation characteristic: containing the lipidosome freeze-dried preparation of soybean lecithin and glycocholic acid; Advantage: the encapsulating completely realizing vitamin, avoids decomposing, improves stability; Shortcoming: introduce the organic reagents such as chloroform in the preparation of liposome, is unfavorable for the safety of product.
Patent No. CN101433547, its main component is 12 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: with glycocholic acid and lecithin for solubilizing agent, by the injectable powder of activated carbon adsorption; Advantage: technique is simple, easily operates; Shortcoming: the active carbon that adds obviously can reduce the content of principal agent, and activated carbon is to the sensitive of temperature and pH value, can not ensure that this preparation can dissolve completely when Clinical practice, stable in properties.
Patent No. CN1843362, its main component is 9 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: the lyophilized formulations taking Tween 80 as cosolvent; Advantage: water content is low, not oxidizable, good stability, list is bottled avoids repeatedly dosing to operate the pollution caused; Shortcoming: Tween 80 has certain toxicity, as: haemolysis, has inhibitory action to heart.
Patent No. CN1843327, its main component is 9 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: the lyophilized formulations being solubilizing agent with Cholic acids material and phospholipid; Advantage: technique is simple, easily operates; Shortcoming: vitamin contamination is few.
Patent No. CN1989975, its main component is 12 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: with 2.25% phospholipid for solubilizing agent, and 2.4% sodium cholate is cosolvent, active carbon is the lyophilized formulations of adsorbent; Advantage: cost is low, technique is simple; Shortcoming: active carbon add the content that membership obviously reduces principal agent, and activated carbon is to the sensitive of temperature and pH value, can not ensure that this preparation can dissolve completely when Clinical practice, stable in properties.
Patent No. CN1879648, its main component is 13 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: the lyophilized formulations taking Tween 80 as solubilizing agent; Advantage: good stability, easy to use; Shortcoming: the tween toxicity added is comparatively large, easily causes haemolysis.
Patent No. CN101711769, its main component is 12 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: be the lyophilized formulations of cosolvent with 3.8% ~ 5.0% poly yamanashi esters; Advantage: good stability; Shortcoming: poly yamanashi esters has certain toxicity, is unfavorable for the safety of preparation.
Patent No. CN103006683, its main component is 12 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: be the lyophilized formulations of cosolvent with 1.0% ~ 6.0% polyoxyethylene sorbitan monoleate; Advantage: not containing glycocholic acid, clinically can be used for the too high crowd of glycocholic acid; Shortcoming: poly yamanashi esters has certain toxicity, does not utilize the safety of preparation.
Patent No. CN102652744, its main component is 13 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: the injection comprising two bottles, and bottle 1 is containing Tween 80, propylene glycol or ethanol; Advantage: improve stability; Shortcoming: Tween 80 etc. have certain toxicity, the safety of impact injection.
Patent No. CN101073580, its main component is 13 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: the injection comprising two bottles, bottle 1 with 1.4% Tween 80 for cosolvent; Advantage: product is Aqueous injection agent, good stability; Shortcoming the: 1. extraction-mixing repeatedly in use of two bottled preparations may pollute; 2. Tween 80 has certain toxicity, as: haemolysis, has inhibitory action to heart.
Patent No. CN101181289, its main component is 13 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: two dosage forms, fatsoluble vitamin Tweens solubilizing agent (Tween 80,20 coordinates in the ratio of 100:1 ~ 20:1); Advantage: direct injection, without the need to redissolving, good stability; Shortcoming: 1. two dress preparations may pollute in use; 2. Tween 80 has certain toxicity, as: haemolysis, has inhibitory action to heart.
Patent No. CN102526089, its main component is 13 kinds of vitamin, and the form in aqueous solution is micelle, formulation characteristic: with glycocholic acid and soybean phospholipid for solubilizing agent, by injection or the lyophilized injectable powder of activated carbon adsorption; Advantage: not containing harmful antioxidant and antiseptic; Shortcoming: 1. containing glycocholic acid, is clinically not useable for the too high crowd of glycocholic acid; 2. activated carbon adsorption is unfavorable for preparation stabilization and preserves for a long time.
The present invention, its main component is 13 kinds of compound vitamines, and the form in aqueous solution is fat microemulsion, formulation characteristic: single dosage form, the lyophilized formulations be made up of vegetable oil, phospholipid emulsifier, co-emulsifier; Advantage: 1. efficiently solve fat-soluble and that water soluble vitamins is molten altogether problem, eliminate the pollution risk that tradition 2 bottled preparations may cause in use; 2. compare traditional Micellar Solubilization, use fat microemulsion parcel that the dissolubility of vitamin in water is improved greatly, and improve stability, the safety of drug loading and preparation; 3. do not add the safety of preparation containing the solubilizing agent such as tween, not containing glycocholic acid, clinically can be used for the too high crowd of glycocholic acid; 4. after lyophilizing, water content is low, not easily oxidized, is beneficial to storage.Shortcoming: nothing.
The contrast situation of this patent and the composite vitamin injection that gone on the market both at home and abroad is in table 1, and a kind of injection provided by the invention 13 kinds of compound vitamin lyophilized formulations have much for other preparations as can be seen from Table 1 innovative point:
(1) fatsoluble vitamin is wrapped in particle diameter to be less than in the fat microemulsion of 120nm, compares traditional Micellar Solubilization, use fat microemulsion parcel that the dissolubility of vitamin in water is improved greatly, and improve the stability of drug loading and preparation.
(2) the key component vegetable oil of fat microemulsion and lecithin are natural product, not only nontoxic, have no side effect, or nutrition that patient commonly uses, that easily absorb and energy supplement material, and well can dissolve fatsoluble vitamin, avoid using the solubilizing agents such as heavy dose of tween, propylene glycol to cause untoward reaction, improve drug effect and safety;
(3) containing 13 kinds of vitamin, 9 kinds is water soluble vitamins, and 4 kinds is fatsoluble vitamin, vitamin A wide selection of colours and designs, and consumption is suitable for; And current domestic unique injection Shi Niweita containing two biostearins only comprises 12 kinds of vitamin;
(4) easy to use, avoid and use tradition 2 bottled preparations to complete in multi-pass operation the liquid medicine contamination that dosing causes, improve the stability of preparation;
(5) after this product lyophilizing, water content is low, not easily oxidized, is beneficial to the long-distance transport of formulation products and long-term keeps, giving full play to the advantage of fat micro emulsion drug carrying system, prolong drug action time in vivo, reduces its toxic and side effects, improves bioavailability.
Wherein the important pointthat injection provided by the invention 13 kinds of compound vitamin lyophilized formulations are not containing tween, the solubilizing agents such as propylene glycol, fatsoluble vitamin in the present invention is directly dissolved in vegetable oil, without the need to adding solubilizing agent, avoid patent family CN1879648, CN101073580, CN102652744, CN101181289, CN102526089 and home products: Shi Niweita, external product: adult's multivitamin injection (INFUVITE ADULT), the potential safety hazard existed in adult's multivitamin injection (M.I.V. ADULT) etc., simultaneously not containing glycocholic acid, clinically can be used for the too high crowd of glycocholic acid, expand Clinical practice scope.
Along with in recent years, the untoward reaction caused by adjuvant clinically gets more and more, the anaphylaxis event caused as Tween 80 in neat two medicine events, Chinese medicine and plasticiser phthalate pollute the problems such as medicine event, and adjuvant also causes the attention of Drug Administration department day by day on the impact of drug safety.Point out in paper " Safety Situation of injections in common use solubilizing auxiliary materials " on Zhang Haiyan etc. are published in " the Shaanxi traditional Chinese medical science ": when Tween 80 local and intramuscular injection, there will be anaphylaxis, separately have serious adverse reaction, it is lethal that the vitamin E intravenous injection as tween 80 is used for neonate.Tween 80 is commonly used for solubilizing agent or the emulsifying agent of insoluble drug, such as: intravenous anesthetic etomidate (Fu Erli), antineoplastic agent etoposide (etoposide) and docetaxel, vitamin K1 injection, its anaphylaxis happens occasionally, and main manifestations is hypotension, bronchospasm, flush, erythra, dyspnea, increased heart rate, fever, shiver with cold.Above-mentioned untoward reaction is common in rapid intravenous infusion, and by taking antihistaminic, steroid hormone class medicine is eased.Point out in paper on Wang Xiaoxuan etc. are published in " Chinese J Pharmacol Toxicol (Chinese Journal of Pharmacology and Toxicology) " " tween 80 brings out human lymphocyte sister chromosomes monomer and exchanges and damage to DNA ": can serious antiproliferative effect and division when tween 80 concentration is 1mg/mL, also can damage DNA replication dna template, have obvious haemolysis simultaneously.Also find that tween 80 may also have mutagenesis or carcinogenesis herein.Point out in paper " injection and medicinal polyoxyethylene sorbitan monooleate dehydration (tween 80) anaphylactoid reaction comparative study " on Wang Yunting etc. are published in " CHINA JOURNAL OF CHINESE MATERIA MEDICA ": when tween 80 consumption increases, larger micelle will be formed, drug release, absorption, distribution etc. are had an impact.Tween 80 certain causes except anaphylactoid except itself having in addition, and factor also can cause allergy with quality after injection compatibility is unstable etc., and after as long in the storage time, in injection, tween oxidation deterioration can cause sensitization to improve.The domestic anaphylactoid reaction caused tween 80 has had certain research, but the molecular biology mechanism caused allergic reaction is not clear at present, need by study further tween in vivo and in vitro mechanism of action prevent and treat the untoward reaction occurred clinically.Yang Rui etc. are published in when analyzing polyoxyethylene sorbitan monoleate for injecting in the paper " pharmaceutic adjuvant is on the impact of drug safety " on " pharmaceutical analysis magazine " for 2012 can one of the reason producing toxic and side effects: polyoxyethylene sorbitan monoleate is common emulsifying agent, because its excellent emulsifiability is particularly widely used in injection in pharmaceutical preparation, due to the raw materials for production that part producer adopts-the purity of oleic acid is lower, so the polyoxyethylene sorbitan monoleate colourity produced by it is poor, do not reach the colour of solution item requirement of Chinese Pharmacopoeia to polyoxyethylene sorbitan monoleate, so producer with the addition of this operation of decolouring in the final step of production technology, namely a certain amount of hydrogen peroxide bleaching is added in polyoxyethylene sorbitan monoleate finished product in post synthesis, product colour is made to meet the requirement of Chinese Pharmacopoeia.Hydrogen peroxide, is commonly called as hydrogen peroxide, stir and illumination condition under can be decomposed into water and oxygen, there is extremely strong oxidisability and corrosivity, be thus widely used as bleach and disinfectant.The hydrogen peroxide of 3% is used as the disinfectant of wound, abscess in medical treatment, has the effects such as purification wound surface, anticorrosion, deodorization, sterilization, sterilization.If be used in medicine, particularly in injection, harm will be difficult to estimate.Point out in the paper " injecting hydrogen peroxide causing death 1 example " that Yu Yu is published in " Forensic Science ": hydrogen peroxide injects treatment as cavity disinfectant, and the possibility of result can cause patient allergy that patient even can be made to die instantly.Hydrogen peroxide serious threat residual in Tween 80, to its safety as pharmaceutic adjuvant, particularly contains the injection of Tween 80.Further, the existing pharmacopeia of China is as pharmaceutic adjuvant, and solubilizing agent and emulsifying agent etc. record, and than 2005 editions pharmacopeia, its quality standard improves, reduces the gap of the existing pharmacopeia with Europe, the United States, day etc., but does not record injection stage Tween 80 yet.Therefore need find harmless and can solve the fat-soluble problem common molten with water soluble vitamins, to improve the quality and safety that contain 13 kinds of compound vitamin ejection preparations, the difficult problem that this 13 kinds of compound vitamin ejection preparation being the current quality of production is stable must solve, but be not resolved up to now.
For the above-mentioned defect of prior art, the invention provides a kind of Novel injection 13 kinds of compound vitamin lyophilized formulations, be specially: fat-soluble A, D, E, K are wrapped in particle diameter and are less than in the fat microemulsion of 120nm, and then with water soluble vitamins, lyophilizing excipient with redissolve that auxiliary agent is freeze-dried mixed to be formed, can injection for intravenous through dilution after redissolution.Fat microemulsion is prepared from the vegetable oil of science dosage (main component is for fatty acid triglycercide), phospholipid emulsifier, co-emulsifier and fatsoluble vitamin.Wherein, vegetable oil, as the solvent of fatsoluble vitamin, has good Drug loading capacity, and phospholipid emulsifier and co-emulsifier are then arranged in drop surface regularly and form emulsifying film, stop droplet coalescence.Primary emulsion phospholipid is a kind of amphoteric compound of the natural phospholipid extracted from egg yolk or Semen sojae atricolor, formal name used at school is glycerolphosphocholine di fatty acid ester, its phosphatidylcholine part is hydrophilic, fatty acid glycerine ester moiety oleophylic, under surface tension effects, lipophilic end points to oil droplet, and water-wet side outwards forms small spheroid, medicine carrying oil droplet is wrapped in core, forms stable oil droplet.The stability of fat microemulsion and phospholipid concentration in the solution has much relations, the formation of fat microemulsion must reach more than minimum one-tenth micellar concentration at phospholipid, if the fat microemulsion particle diameter that consumption less (consumption of such as common fats Emulsion is 1% ~ 3%) is formed is larger, and the consumption increasing emulsifying agent can make particle diameter reduce, the stability of increase system, as lecithin concentration is adjusted to 5 ~ 30%, and combine with the polyethyleneglycol derivative as co-emulsifier, then can form the fat microemulsion that particle diameter is less than 120nm, can ensure that vitamin is effectively wrapped in fat microemulsion simultaneously, improve the stability of fat microemulsion.The injection 13 kinds of compound vitamin lyophilized formulations prepared due to this patent need fat microemulsion filtration sterilization before lyophilizing, so require that the mean diameter of fat microemulsion need be less than 120nm, and its particle size distribution 99% should be less than 220nm or near 220nm, and the average particle size distribution of the injection compound vitamin submicron emulsion of preparation is 160 ~ 210nm in patent family CN 102552293, most of particle diameter is 180 ~ 210nm, refer to table 1 in this patent, 4, 7, 10 and 13, larger according to submicron emulsion particle diameter prepared by the method for this patent, corresponding distribution is also wider, when the submicron emulsion having more than 10% when the membrane filtration of 0.22um is degerming is filtered, the content of vitamin in submicron emulsion can be affected like this, strict quality control cannot be carried out to vitamin simultaneously.
so, be more of paramount importancelythis patent additionally provides a kind of fat microemulsion that can be applicable to filtration sterilization of preparing and prepares formula and method.This patent has carried out strict size and distributed controll when preparation 13 kinds of vitamin liposoluble lyophilized formulations, find: when mean diameter is 191.7nm, its particle size distribution can only reach 75% and be less than 228.8nm, 99% and be less than 413.3nm, the visible Emulsion being only less than 75% by filter membrane, can be shown in accompanying drawing 1; When mean diameter is 184.7nm, its particle size distribution can only reach 75% and be less than 219.7nm, 99% and be less than 391.1nm, only has the Emulsion of 75% by filter membrane, can see accompanying drawing 2 as seen; When mean diameter is 165.9nm, its particle size distribution can only reach 90% and be less than 253.3nm, 99% and be less than 380.7nm, and the Emulsion being only less than 90% as seen by filter membrane, can be shown in accompanying drawing 3; As can be seen here, have in the injection compound vitamin submicron emulsion prepared in patent CN 102552293 the Emulsion of at least 20% is not by the filter membrane of 220nm, this can not meet the requirement of filtration sterilization.
Therefore, this patent is innovated on pharmaceutical formulation and preparation method for this problem, prepare the fat microemulsion of a series of different-grain diameter size and distribution, as: mean diameter is the Emulsion of 154.7nm, its particle size distribution can only reach 90% and be less than 229.7nm, 99% and be less than 334.2nm, the visible Emulsion being only less than 90% by filter membrane, can be shown in accompanying drawing 4; Mean diameter is the Emulsion of 146.0nm, and its particle size distribution can only reach 90% and be less than 209.5nm, 99% and be less than 293.6nm, only has the Emulsion of 90% by filter membrane, can see accompanying drawing 5 as seen; Mean diameter is the Emulsion of 139.5nm, and its particle size distribution can only reach 90% and be less than 204.4nm, 99% and be less than 293.1nm, only has the Emulsion of 90% by filter membrane, can see accompanying drawing 6 as seen; Mean diameter is the Emulsion of 121.1nm, and its particle size distribution can reach 90% and be less than 178.2nm, 99% and be less than 256.9nm, has the Emulsion being greater than 90% by filter membrane, can see accompanying drawing 7 as seen.Mean diameter is the Emulsion of 91.1nm, and its particle size distribution can reach 90% and be less than 145.1nm, 99% and be less than 229.5nm, has at least 90% even Emulsion of 99% by filter membrane, can see accompanying drawing 9 as seen; Mean diameter is the Emulsion of 87.8nm, and its particle size distribution can reach 90% and be less than 142.9nm, 99% and be less than 232.0nm, has the Emulsion of nearly 99% by filter membrane, can see accompanying drawing 11 as seen; Mean diameter is the Emulsion of 75.5nm, and its particle size distribution can reach 90% and be less than 119.2nm, 99% and be less than 186.5nm, has the Emulsion more than 99% by filter membrane, can see accompanying drawing 13 as seen; Mean diameter is the Emulsion of 68.7nm, and its particle size distribution can reach 90% and be less than 110.4nm, 99% and be less than 176.7nm, has at least 99% even Emulsion of 100% by filter membrane, can see accompanying drawing 15 as seen; Mean diameter is the Emulsion of 48.7nm, and its particle size distribution can reach 90% and be less than 73.5nm, 99% and be less than 108.8nm, has the Emulsion of 100% by filter membrane, can see accompanying drawing 17 as seen.This patent is finally prepared according to these screenings can 100% by the Emulsion of filtration sterilization, and this is this patent just also one of innovation.In addition, this patent adopts fat microemulsion parcel fatsoluble vitamin, preferably resolves the common molten problem of water soluble vitamins and fatsoluble vitamin in same system, does not contain simultaneously tweendeng cosolvent, provide the safety of preparation, and fat microemulsion particle diameter is little, is evenly distributed, good stability, non-stimulated to vein, clinical practice is safer, and this is this patent just also two of innovation.
The domestic and international composite vitamin injection situation (the representative kind of part) of having gone on the market of table 1
Summary of the invention
The invention provides an a kind of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations and preparation method thereof, novel formulation adopts special prescription and technique water solublity and fatsoluble vitamin to be combined cleverly, forms single lyophilizing compound recipe molten altogether.This novel multivitamin lyophilized formulations efficiently solves fat-soluble and that water soluble vitamins is molten altogether problem, improves the stability of vitamin, decreases the decomposition of medicine, and the side effect that catabolite causes; Eliminate the pollution risk that tradition 2 bottled preparations may cause in use; The abundant dissolving of pharmaceutical compounds can be ensured simultaneously, avoid the side effect injury that insoluble matter causes health.The vitamin intestinal being particularly suitable for the patient that multivitamin lacks and normally can not take food through digestive tract supplements outward.
An object of the present invention is to provide an a kind of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations, it can avoid using the cosolvents such as tween to reduce its pharmacology toxicity, again can with the water for injection of arbitrary proportion, water, NaCL solution, glucose solution, blank fat milk or other aqueous solution, and there is not precipitation or crystallization, also can be used for the crowd that glycocholic acid is too high.
Second object of the present invention is to provide a kind of compound 13 kinds of vitamin fat microemulsion being directly used in filtration sterilization, and its preparation technology is easy, reliable, is convenient to industrialization, the fat microemulsion particle diameter prepared is little, distribute, make medicament contg more controlled simultaneously, improve the stability of medicine and adjuvant.For extensive patients provides safer, stable, effective freeze-dried emulsion.
The present invention is achieved through the following technical solutions:
An a kind of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations, it is characterized in that, this lyophilized formulations adopts emulsifying technology that fatsoluble vitamin is wrapped in fat microemulsion, then fat microemulsion is mixed with into lyophilized formulations with water soluble vitamins, lyophilizing excipient, the adjuvant that redissolves, wherein the mean diameter of fat microemulsion answers <120nm, best <100nm, particle size distribution 99%<220nm, more be conducive to filtration sterilization, after the lyophilized formulations prepared redissolves, particle diameter is substantially constant.
An a kind of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations, it is characterized in that, described fatsoluble vitamin is vitamin A. D. E, K.
An a kind of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations, it is characterized in that, described water soluble vitamins is vitamin C and vitamin B 1, B 2, B 6, B 12, nicotiamide, pantothenylol, folic acid, biotin.
An a kind of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations, is characterized in that, the weight proportion theoretical amount of obtained each component needed for 1000 bottles of unit formulations can be:
The weight proportion theoretical amount of each component is preferably:
The weight proportion theoretical amount of each component is preferably:
An a kind of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations, is characterized in that,
Described phospholipid emulsifier, Ke Yishi: any one in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, synthetic lecithin or mixture.
Described polyethyleneglycol derivative, Ke Yishi: any one in Polyethylene Glycol-cephalin derivant, PEG-CHOL derivant, Polyethylene Glycol-two-fatty acid glycerine ester derivant, Polyethylene Glycol-aliphatic ester derivatives, Polyethylene Glycol-aliphatic amine derivative, Polyethylene Glycol-fatty alcohol derivative or mixture.
Described lyophilizing excipient is: one or more in mannitol, sorbic acid, lactose, sucrose, dextran, gelatin, monosaccharide (as: glucose, fructose etc.) or polysaccharide (as: starch, cellulose etc.), amino acids (as glycine, alanine, histidine, arginine etc.) or oligopeptide.
Described redissolution auxiliary agent is: one or more of PEG-4000, Polyethylene Glycol-600, PEG-6000, PEG-4000 or PEG-4000.
A bottled fat microemulsion compound according to claim 1 13 kinds of vitamin freeze-dried preparations, is characterized in that:
The preparation method of any one bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations described in a kind of claim 1 ~ 8, is characterized in that step is as follows:
Step 1: by the vitamin A of recipe quantity, vitamin D 3, vitamin E, vitamin K 1mix with the injection soybean oil of recipe quantity, add the lecithin of recipe quantity and the polyethyleneglycol derivative of recipe quantity under nitrogen protection, be heated to 30 ~ 70 DEG C and form oil mixture;
Step 2: the enuatrol of recipe quantity, PLURONICS F87 and water for injection are mixed at 30 ~ 80 DEG C, forms aqueous mixture;
Step 3: the oil mixture that aqueous mixture step 2 obtained under nitrogen protection and step 1 obtain mixes, then at 30 ~ 80 DEG C, under 5000 ~ 50000r/min condition after high speed dispersion 5 ~ 30min, pH to 6.0 ~ 9.0 are regulated with 0.1mol/L NaOH or HCL, under pressure is 90 ~ 210MPa condition, carry out homogenizing 5 ~ 15 times, obtain uniform fat microemulsion;
Step 4: the water soluble vitamins by recipe quantity: vitamin C, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid, freeze drying protectant and the auxiliary agent that redissolves, be dissolved in water for injection, adjust pH about 4 ~ 7,0.22um filtering with microporous membrane, obtained water soluble vitamins solution;
Step 5: step 3 gained fat microemulsion solution mixed homogeneously with step 4 gained water soluble vitamins solution, 0.22um filtering with microporous membrane is degerming, logical nitrogen-sealed;
Step 6: every bottle of 2mL or 5mL is divided in cillin bottle, pre-freeze 2 ~ 18h at-20 ~-60 DEG C ,-20 ~-45 DEG C of 4 ~ 60h that next time distil, 0 ~ 40 DEG C of secondary distillation 1 ~ 30h, takes out, logical nitrogen envelope bottle.
(vitamin injection that meets provided is mainly used in non-bowel nutritional administration, also for needing other situations of intravenously administrable.These situations comprise: surgical operation, extensively burn, fracture and other wounds, treating severe infectious diseases and stupor situation.These situations make internal metabolism demand very large change occur and and then make histotrophic nutrition loss.The lyophilized formulations provided needs to redissolve rear use, and double solvents used can be glucose sugar transfusion, normal saline etc.）
four, accompanying drawing explanation
The grain size distribution of Fig. 1 to be mean diameter be 191.7nm fat microemulsion;
The grain size distribution of Fig. 2 to be mean diameter be 184.7nm fat microemulsion;
The grain size distribution of Fig. 3 to be mean diameter be 165.9nm fat microemulsion;
The grain size distribution of Fig. 4 to be mean diameter be 154.7nm fat microemulsion;
The grain size distribution of Fig. 5 to be mean diameter be 146.0nm fat microemulsion;
The grain size distribution of Fig. 6 to be mean diameter be 139.5nm fat microemulsion;
The grain size distribution of Fig. 7 to be mean diameter be 121.1nm fat microemulsion;
The grain size distribution of Fig. 8 to be mean diameter be 100.0nm fat microemulsion;
The grain size distribution of Fig. 9 to be mean diameter be 91.1nm fat microemulsion;
The grain size distribution of Figure 10 to be mean diameter be 92.8nm fat microemulsion;
The grain size distribution of Figure 11 to be mean diameter be 87.8nm fat microemulsion;
The grain size distribution of Figure 12 to be mean diameter be 80.1nm fat microemulsion;
The grain size distribution of Figure 13 to be mean diameter be 75.5nm fat microemulsion;
The grain size distribution of Figure 14 to be mean diameter be 71.8nm fat microemulsion;
The grain size distribution of Figure 15 to be mean diameter be 68.7nm fat microemulsion;
The grain size distribution of Figure 16 to be mean diameter be 55.7nm fat microemulsion;
The grain size distribution of Figure 17 to be mean diameter be 48.7nm fat microemulsion
five, the preparation embodiment of a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations
The present invention verifies the amount ranges of various adjuvant in the pharmaceutical formulation of a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations and preparation technology.Below in conjunction with embodiment, the present invention is elaborated, but be not limited only to following Examples.
One, the preparation embodiment of a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations
example 1a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations prepared by different ratio phospholipid emulsifier content
Example 1.1 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the Ovum Gallus domesticus Flavus lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 10 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity mannitol, glycine and Polyethylene Glycol-600, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 5mL is divided in cillin bottle, and condition is: pre-freeze 14 hours at-50 DEG C, drains 22 hours at-35 DEG C, and 10 DEG C of sublimation dryings obtain finished product in 2 hours, then fill nitrogen, roll lid, pack.
Example 1.2 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the soybean lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 12 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity mannitol, glycine and Polyethylene Glycol-600, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 5mL is divided in cillin bottle, and condition is: pre-freeze 15 hours at-50 DEG C, drains 20 hours at-30 DEG C, and 20 DEG C of sublimation dryings obtain finished product in 1 hour, then fill nitrogen, roll lid, pack.
Example 1.3 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the hydrogenated yolk lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 11 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity mannitol, glycine and Polyethylene Glycol-600, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 5mL is divided in cillin bottle, and condition is: pre-freeze 15 hours at-55 DEG C, drains 22 hours at-25 DEG C, and 25 DEG C of sublimation dryings obtain finished product in 2 hours, then fill nitrogen, roll lid, pack.
example 2a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations prepared by different ratio frozen-dried protective agent content
Example 2.1 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the hydrogenated yolk lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 11 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity mannitol, serine and PEG-6000, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 2mL is divided in cillin bottle, and condition is: pre-freeze 14 hours at-60 DEG C, drains 26 hours at-40 DEG C, and 10 DEG C of sublimation dryings obtain finished product in 2 hours, then fill nitrogen, roll lid, pack.
Example 2.2 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the soybean lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 11 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity lactose, glycine and PEG-6000, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 5mL is divided in cillin bottle, and condition is: pre-freeze 14 hours at-55 DEG C, drains 25 hours at-25 DEG C, and 20 DEG C of sublimation dryings obtain finished product in 2 hours, then fill nitrogen, roll lid, pack.
Example 2.3 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the Ovum Gallus domesticus Flavus lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 12 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity lactose, serine and PEG-6000, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 2mL is divided in cillin bottle, and condition is: pre-freeze 15 hours at-50 DEG C, drains 24 hours at-25 DEG C, and 20 DEG C of sublimation dryings obtain finished product in 2 hours, then fill nitrogen, roll lid, pack.
example 3a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations prepared by different ratio redissolution auxiliary agent content
Example 3.1 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the Ovum Gallus domesticus Flavus lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 12 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity mannitol, serine and Polyethylene Glycol-200, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 5mL is divided in cillin bottle, and condition is: pre-freeze 16 hours at-50 DEG C, drains 25 hours at-25 DEG C, and 20 DEG C of sublimation dryings obtain finished product in 3 hours, then fill nitrogen, roll lid, pack.
Example 3.2 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the Ovum Gallus domesticus Flavus lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 12 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity mannitol, serine and PEG-4000, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 5mL is divided in cillin bottle, and condition is: pre-freeze 15 hours at-50 DEG C, drains 22 hours at-25 DEG C, and 20 DEG C of sublimation dryings obtain finished product in 2 hours, then fill nitrogen, roll lid, pack.
Example 3.3 prescription:
Preparation method:
(1) vitamin A of above-mentioned recipe quantity, vitamin D, vitamin E, vitamin K are dissolved in soybean oil under 60 DEG C of water-baths, nitrogen protection; to be dissolved completely after add the soybean lecithin of recipe quantity; add poloxamer and the Polyethylene Glycol-cephalin derivant of recipe quantity after continuing stirring and dissolving to dissolving, continue stirring and dissolving and form oil mixture to solution clarification.Simultaneously, the enuatrol of recipe quantity and water for injection are dissolved in 60 DEG C of water-baths and is fully formed aqueous mixture, again aqueous mixture is slowly joined in oil mixture and form colostrum, then colostrum is placed in high-speed shearing machine 14000rpm down cut 10min, finally be placed in high pressure homogenizer and carry out homogenizing 10 times under pressure is 1250 bar conditions, obtain the fat microemulsion that particle diameter is less than 120 nm;
(2) by the vitamin C of recipe quantity, vitamin B 1, vitamin B 2, vitamin B 6, vitamin B 12, nicotiamide, pantothenylol, biotin, folic acid is fully dissolved in water for injection the aqueous solution forming clarification, again this aqueous solution is joined in the fat microemulsion solution of step one gained, add recipe quantity lactose, glycine and Polyethylene Glycol-600, by 10% sodium hydroxide solution adjust ph to 5 ~ 7, the filtering with microporous membrane then through 0.22 μm is degerming;
(3) semi-finished product after filtration sterilization are carried out lyophilizing, every bottle of 5mL is divided in cillin bottle, and condition is: pre-freeze 13 hours at-55 DEG C, drains 22 hours at-30 DEG C, and 25 DEG C of sublimation dryings obtain finished product in 2 hours, then fill nitrogen, roll lid, pack.
Two, the quality research of a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations
example 1particle size distribution detects
Adopt shine particle diameter/potentiometer of dynamic optical to detect the situation of change of bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations particle diameter before and after lyophilizing that above 9 embodiments are prepared, the results are shown in Table 2.
The change of size of table 2 one bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations before and after lyophilizing
* PdI: Polydispersion index polydispersity index (for weighing particle size distribution range)
As shown in Table 2: the particle diameter that above 9 prescriptions and preparation technology obtain all meets the requirements, and lyophilizing forward backward averaging size and particle size distribution range all do not have significant change, in addition dried frozen aquatic products appearance character, redissolve situation all more satisfactory, illustrates before and after a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparation lyophilizing prepared by the present invention stablize.
example 2the situation of change of one bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations and normal injection and the mixed solution physical character of diluent
Above sample and water for injection, water, NaCL solution, glucose solution, blank fat milk mix by 1 ︰ 1 and 1 ︰ 5 respectively.Emulsion is recovered to after hydration concussion, place 6 hours all without crystallize, precipitation, layering or demulsifying phenomenon, illustrate a bottled fat microemulsion compound vitamin lyophilized formulations prepared by the present invention can with the water for injection of arbitrary proportion, water, NaCL solution, glucose solution, blank fat milk or other aqueous solution, occupation mode is extensive.
example 3the Detection of Stability of one bottled fat microemulsion compound, 13 kinds of vitamin freeze-dried preparations
The three routine products extracted in above-mentioned 9 embodiments are placed and are carried out influence factor's experiment investigation in 10 days under high temperature 60 DEG C, illumination 4500Lx condition, the results are shown in Table 3; Under high temperature 40 DEG C, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate and the results are shown in Table 4; Under temperature 25 DEG C, relative humidity 60% ± 10% condition 18 months, carry out long term test investigation, detect the change of every quality index, the results are shown in Table 5.
Table 3 one bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations affect experiment investigation (high temperature 60 DEG C, illumination 4500Lx)
The accelerated test (high temperature 40 DEG C, relative humidity 75% ± 5%) of table 4 one bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations
Table 5 one bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparation long-time stability (temperature 25 DEG C, relative humidity 60% ± 10%)
Conclusion:
Through influence factor 10 days, acceleration after 6 months and long-term 18 months, the product quality conformance with standard requirement that the present invention obtains, and also every quality index is without significant change, all meets quality standard, describes constant product quality of the present invention fine.

Claims (9)

1. a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations, it is characterized in that, this lyophilized formulations adopts emulsifying technology that fatsoluble vitamin is wrapped in fat microemulsion, then fat microemulsion is mixed with into lyophilized formulations with water soluble vitamins, lyophilizing excipient, the adjuvant that redissolves, wherein the mean diameter of fat microemulsion answers <120nm, best <100nm, particle size distribution 99%<220nm, more be conducive to filtration sterilization, after the lyophilized formulations prepared redissolves, particle diameter is substantially constant.
2. lyophilized formulations according to claim 1, is characterized in that, described fatsoluble vitamin is vitamin A. D. E, K.
3. lyophilized formulations according to claim 1, is characterized in that, described water soluble vitamins is vitamin C and vitamin B 1, B 2, B 6, B 12, nicotiamide, pantothenylol, folic acid, biotin.
4. a bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations, is characterized in that, preparation according to claim 1, and the weight proportion theoretical amount of obtained each component needed for 1000 bottles of unit formulations can be:
The weight proportion theoretical amount of each component is preferably:
The weight proportion theoretical amount of each component is preferably:
。
5. a bottled fat microemulsion compound according to claim 1 13 kinds of vitamin freeze-dried preparations, it is characterized in that, described lecithin, Ke Yishi: any one in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, synthetic lecithin or mixture.
6. a bottled fat microemulsion compound according to claim 1 13 kinds of vitamin freeze-dried preparations, it is characterized in that, described polyethyleneglycol derivative, Ke Yishi: any one in Polyethylene Glycol-cephalin derivant, PEG-CHOL derivant, Polyethylene Glycol-two-fatty acid glycerine ester derivant, Polyethylene Glycol-aliphatic ester derivatives, Polyethylene Glycol-aliphatic amine derivative, Polyethylene Glycol-fatty alcohol derivative or mixture.
7. a bottled fat microemulsion compound according to claim 1 13 kinds of vitamin freeze-dried preparations, it is characterized in that, described lyophilizing excipient is: one or more in mannitol, sorbic acid, lactose, sucrose, dextran, gelatin, monosaccharide (as: glucose, fructose etc.) or polysaccharide (as: starch, cellulose etc.), amino acids (as glycine, alanine, histidine, arginine etc.) or oligopeptide.
8. a bottled fat microemulsion compound according to claim 1 13 kinds of vitamin freeze-dried preparations, it is characterized in that, described redissolution auxiliary agent is: one or more of PEG-4000, Polyethylene Glycol-600, PEG-6000, PEG-4000 or PEG-4000.
9. a bottled fat microemulsion compound according to claim 1 13 kinds of vitamin freeze-dried preparations, is characterized in that:
The preparation method of any one bottled fat microemulsion compound 13 kinds of vitamin freeze-dried preparations described in a kind of claim 1 ~ 8, is characterized in that step is as follows:
Step 1: the vitamin A of recipe quantity, vitamin D3, vitamin E, vitamin K1 are mixed with the injection soybean oil of recipe quantity, add the lecithin of recipe quantity and the polyethyleneglycol derivative of recipe quantity under nitrogen protection, be heated to 30 ~ 70 DEG C and form oil mixture;
Step 2: the enuatrol of recipe quantity, PLURONICS F87 and water for injection are mixed at 30 ~ 80 DEG C, forms aqueous mixture;
Step 3: the oil mixture that aqueous mixture step 2 obtained under nitrogen protection and step 1 obtain mixes, then at 30 ~ 80 DEG C, under 5000 ~ 50000r/min condition after high speed dispersion 5 ~ 30min, pH to 6.0 ~ 9.0 are regulated with 0.1mol/L NaOH or HCL, under pressure is 90 ~ 210MPa condition, carry out homogenizing 5 ~ 15 times, obtain uniform fat microemulsion;
Step 4: the water soluble vitamins by recipe quantity: vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin B12, nicotiamide, pantothenylol, biotin, folic acid, freeze drying protectant and the auxiliary agent that redissolves, be dissolved in water for injection, adjust pH about 4 ~ 7,0.22um filtering with microporous membrane, obtained water soluble vitamins solution;
Step 5: step 3 gained fat microemulsion solution mixed homogeneously with step 4 gained water soluble vitamins solution, 0.22um filtering with microporous membrane is degerming, logical nitrogen-sealed;
Step 6: every bottle of 2mL or 5mL is divided in cillin bottle, pre-freeze 2 ~ 18h at-20 ~-60 DEG C ,-20 ~-45 DEG C of 4 ~ 60h that next time distil, 0 ~ 40 DEG C of secondary distillation 1 ~ 30h, takes out, logical nitrogen envelope bottle.
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CN106821998A (en) * 2017-03-28 2017-06-13 深圳万和制药有限公司 Prepare the method and its compound amino acid capsule composition of vitaminAD micropill
CN107115349A (en) * 2017-05-05 2017-09-01 宁夏智弘生物科技有限公司 A kind of vitaminAD E microemulsion injections for animals and preparation method thereof
CN109010292A (en) * 2018-09-19 2018-12-18 广州汉光药业股份有限公司 One kind of multiple vitamin parenteral nutrition agent nanoparticles freeze dried injections and preparation method thereof
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CN110339169A (en) * 2018-09-06 2019-10-18 澳汀斯（广州）生物医药科技有限公司 Coat nano vesicle preparations and its application of vitamin D and vitamin K

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CN1843362A (en) * 2006-04-30 2006-10-11 贵阳云岩西创药物科技开发有限公司 Composite vitamin injection and its preparation method
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CN106821998A (en) * 2017-03-28 2017-06-13 深圳万和制药有限公司 Prepare the method and its compound amino acid capsule composition of vitaminAD micropill
CN107115349A (en) * 2017-05-05 2017-09-01 宁夏智弘生物科技有限公司 A kind of vitaminAD E microemulsion injections for animals and preparation method thereof
WO2019081435A1 (en) * 2017-10-25 2019-05-02 Fresenius Kabi Deutschland Gmbh All-in-one lyophilized multivitamin emulsion for parenteral application
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CN110339169A (en) * 2018-09-06 2019-10-18 澳汀斯（广州）生物医药科技有限公司 Coat nano vesicle preparations and its application of vitamin D and vitamin K
CN109010292A (en) * 2018-09-19 2018-12-18 广州汉光药业股份有限公司 One kind of multiple vitamin parenteral nutrition agent nanoparticles freeze dried injections and preparation method thereof

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