CN102688191B - Medicine composition containing vitamin K1 and oil - Google Patents
Medicine composition containing vitamin K1 and oil Download PDFInfo
- Publication number
- CN102688191B CN102688191B CN 201210203095 CN201210203095A CN102688191B CN 102688191 B CN102688191 B CN 102688191B CN 201210203095 CN201210203095 CN 201210203095 CN 201210203095 A CN201210203095 A CN 201210203095A CN 102688191 B CN102688191 B CN 102688191B
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- vitamin
- pharmaceutical composition
- oil
- preparation
- composition
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a medicine composition containing vitamin K1 and oil. Concretely, the medicine composition comprises 1 part of vitamin K1 by weight and 10-2,000 parts of oil by weight; and the iodine value of the composition is less than 1.0, and the saponification value is 310-360. The medicine composition containing vitamin K1, provided by the invention, can be orally taken, has good pharmaceutical characteristics and can be applied to wider population including infants.
Description
Technical field
The invention belongs to medical technical field, relating to a kind of is the pharmaceutical composition of substrate with oil, particularly relates to a kind of for the pharmaceutical composition that comprises vitamin K1 and oil that orally uses.The invention further relates to preparation oil-containing preparation of drug combination method of the present invention.
Background technology
Vitamin K1 is the clarifying thick liquid of a kind of Yellow-to-orange, and odorless or odorless are almost met light and easily decomposed.Vitamin K1 is easily molten in chloroform, ether or vegetable oil, and is molten in the ethanol part omitted, insoluble in water.The chemical name of vitamin K1 is: 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecene base)-1, and the mixture of the trans and cis-isomer of 4-naphthalenedione, its molecular formula: C31H46O2, molecular weight: 450.71, structural formula is:
Vitamin K1 is a kind of fatsoluble vitamin, extensively is present in the green plants, exist with the form of phylloquinone (phylloquinone), but also synthetic.Vitamin K1 is the yellow oily liquid of coming out of purifying from alfalfa the earliest, and the called after vitamin K1, and people just utilize vitamin K1 to do hemorrhage very early.Its hemostatic medical value was found in the thirties in 20th century.The conspicuous Garrick of the biochemist of Denmark reaches the disease of nurse research chicken internal hemorrhage, he finds chicken haemophilia when injured, can't condense, and adds certain feedstuff in food, found to be rich in this feedstuff a kind of material of hemostatic immediately afterwards, this hemostatic material is exactly a vitamin K1.After this vitamin K1 is applied to various hemorrhages gradually.Through basic research and clinical use for many years, the pharmacologically active beyond the vitamin K1 hemostasis is found gradually: treat respiratory tract disease, relieving spasm to stop pain, prevent and treat osteoporosis, treat hepatitis, beauty treatment, antitumor etc.Its pharmacologically active is definite, and toxic and side effects is light, so be widely used in clinically, existing vitamin K1 is a clinical commonly used drug.
Vitamin K1 is a vitamin K class medicine, and vitamin K is liver composition-factor II, VII, IX, the necessary material of X, and vitamin K deficiency can cause these thrombin dyssynthesises or unusual, clinical visible bleeding tendency and prolonged prothrombin.What vitamin K1 can be used for that vitamin K deficiency causes clinically is hemorrhage, as hemorrhage due to obstructive jaundice, leak, the chronic diarrhea etc., vitamin K deficiency in the body due to the Hypoprothrombinemia due to Coumarins, the sodium salicylate etc., prevention hemorrhage of newborn and prolonged application broad ectrum antibiotic.Through basic research and clinical use for many years, find that also vitamin K1 can prevent and treat respiratory tract disease, relieving spasm to stop pain and treatment hepatitis.In addition also with osteoporosis and improve looks relevant.The vitamin K1 pharmacologically active is definite, and poison is secondary light, so be widely used in clinically, now is clinical commonly used drug.
Human body can not synthesize or secrete vitamin K1, and needed vitamin K1 is mainly derived from food, but the escherichia coli in the intestinal also synthetic vitamin K1 be the human body utilization.Vitamin K1 is a main component of forming prothrombing in the blood of human body, can promote liver to make thrombinogen, organize when hemorrhage, platelet is destroyed, discharge thrombokinase and calcium ion, thrombinogen can combine with thrombokinase and calcium ion, changes thrombin into, change insoluble fibrin into but soluble fibrin is former in the thrombin catalysis blood plasma, reach haemostatic effect.
Vitamin K1 can be removed the smooth muscle spasm contraction, removes oxygen-derived free radicals, and has parahormone sample antiinflammatory action, hinders the release of chemical mediators such as histamine, alleviate the respiratory mucosa inflammation, minimizing is oozed out, blood vessel dilating, improve blood fortune, alleviate heart front and back load, correct heart failure; Excited respiratory center suppresses cerebral cortex, improves brain microcirculation and prevents cerebral edema, helps respiratory failure and corrects, and therefore can alleviate and improve the clinical symptoms of infantile pneumonia.Vitamin K1 can strengthen the effect of some antibiotics in addition, thereby suppresses the pathogen growth, and pertussis is also had curative effect preferably.
Vitamin K1 can directly act on multiple visceral smooth muscle, smooth muscle by lax spasm stops the internal organs pain due to the multiple illness, as biliary colic, renal colic, and ureter and cystolith angor etc., effective percentage can reach 80～90%, and analgesic effect is fast, effect is lasting, safety, curative effect height.
The shortage of vitamin K1 can cause blood not solidify, and mostly is neonate because of vitamin K1 lacks hemorrhage patient in clinical.1～2 day diet of neonate birth is limited, the intake of vitamin K is few, vitamin content is low in the breast milk, and is aseptic in the intestinal in addition, influences the synthetic of vitamin K, cause vitamin K deficiency, liver is not mature enough, and liver synthesizes the process of prothrombin, VII, IX, X and is obstructed cruor time extending, cause hemorrhagely, this disease is a hemorrhagic disease of the newborn.The generation and the avitaminous relation of hemorrhagic disease of the newborn (HDN) have just been described as far back as nineteen fifty-two Dam etc.Can be divided into three kinds according to disease time: early hair style hemorrhage, typical hemorrhage, delayed.K1 is deficient in vitamin in the body when neonate just has been born, the pure breast feeding time, long neonate can fast-developingly lack to serious vitamin K1: children's can taken place typical or the delayed hemorrhage occurring in 2 months in first week after the birth, and the both of these case morbidity causes that suddenly, easily intracranial hemorrhage damage, disability rate height, mortality rate are also high.The sickness rate of China is up to 0.5～2%, and the geographic sickness rate in Yantai is up to 9.03%, and China is the hotspot of vitamin K deficiency hemorrhagic disease.Medical research shows that the neonate birth gives vitamin K1 can prevent vitamin K1 shortage property hemorrhage.The route of administration of vitamin K1 also influences drug effect.Oral vitamin K1 only can prevent typical hemorrhage, and is invalid to the delayed hemorrhage, and Longhan finds that vitamin K1 is sustainable more than 2 months with 2mg intramuscular injection drug effect, oral relatively poor relatively.2000, the intramuscular injection of the interior conventional application vitamin K1 of neonate birth 24h was promoted once in Heng County, China Guangxi, and result of study shows: baby's vitamin K deficiency number of hospitalized obviously reduces, and vitamin K deficiency patient descends.In addition, because of the human liver can synthesize thrombinogen, hepatic disfunction person or surgery large operation person all need give a certain amount of vitamin K1 and can prevent hemorrhage.
Infantile respiratory disease is occupied pediatric disease sickness rate 70%, and the winter-spring season sickness rate is higher, mainly shows as pneumonia, asthma, bronchitis, pertussis.
Infantile pneumonia is meant by various different pathogens and other caused by factors pneumonias, causes the lung microcirculation disturbance, and reasons such as anoxia, infection, heating make blood present highly enriched, high gathering, high thickness state, can cause and increase the weight of microcirculation disturbance.Vitamin K1 can change (cAMP/cGMP) ratio in the cell, removes the smooth muscle spasm contraction, removes oxygen-derived free radicals, and have parahormone sample antiinflammatory action, and hinder the release of chemical mediators such as histamine, alleviate the respiratory mucosa inflammation, minimizing is oozed out, and reaches the effect that cough-relieving is coughed and relievingd asthma; The also expansible blood vessel of vitamin K1 improves blood fortune, alleviates heart front and back load, corrects heart failure; Excited respiratory center; suppress cerebral cortex; improve brain microcirculation and prevent cerebral edema; can reduce airway resistance; increase alveolar ventilation; the ventilation ventilation of alleviating crisis life is depleted; help exhaling the correction that declines; therefore the clinical symptoms of infantile pneumonia can be alleviated and improve to vitamin K1, also can reduce the case fatality rate of severe pneumonia simultaneously greatly, shortens the hospital stays; measure nonresponders such as aminophylline, promethazine, dexamethasone, oxygen uptake are used again; still can receive promising result, have the people that severe pneumonia of infants 100 examples are assisted a ruler in governing a country with vitamin K1 and treat 50 examples, obtain effect preferably.
Vitamin K1 treatment bronchiolitis and bronchial asthma report are also many, the domestic 41 routine children asthmatic brouchitis case intravenous applications vitamin K1 treatment asthmatic bronchitiss that research is arranged from institute in October in October, 1998 to calendar year 2001, satisfactory effect.Behind the child vein instillation vitamin K1, infant is quiet rapidly, and very fast sleeping, cough with asthma obviously reduces, and breathes smooth-going.
Vitamin K1 also has curative effect preferably to pertussis.Pertussis is the acute respiratory infectious disease that is caused by bordetella pertussis.Infectiousness is strong, is more common in infant, with liver source property blood coagulation disorders, causes the petechial hemorrhage of respiratory mucosa during the pertussis outbreak, and this produces paroxysmal spasmodic cough the cause of disease, and the respiratory tract petechial hemorrhage is relevant with venous stasis or blood vessel toxic lesion.Though vitamin K1 can not directly act on pathogen, it can strengthen the effect of some antibiotics, thereby suppresses the pathogen growth.
Animal experiment study proved in 1974, the vitamin K1 intestinal that myenteron shrinks automatically and acetylcholine causes to exsomatizing shrinks the obvious suppression effect is arranged, in recent years clinical trial shows: vitamin K1 can directly act on multiple visceral smooth muscle, smooth muscle by lax spasm, and stop internal organs pain due to the multiple illness, as biliary colic, renal colic, ureter and cystolith angor etc., effective percentage can reach 80～90%, and clinical also have good effect with vitamin K1 treatment children's gastrointestinal convulsion stomachache.
Vitamin K1 can be used for treatment or prevention and osteoporosis diseases associated or disease.Nineteen sixty, people such as Bouckaert report that vitamin K can promote the union of fracture of rat and rabbit.Discovery pregnant woman oral anticoagulant such as Pettifor produced baby's nasal bone hypoplasia in 1975, reported first the influence of vitamin K deficiency to the human body bone development, the hypothesis of vitamin K participant bone metabolism; Pettifor thinks that vitimin supplement K can promote bone formation, reduce bone catabolism, osteoporosis there are positive prevention and therapeutical effect, its mechanism of action is to be converted into γ-Qiang Jiguansuan residue (Gla) as the glutaminic acid residue in some protein of cofactor catalysis of enzyme, this albuminoid is called vitamin K dependent protein matter again, and the γ-Qiang Jiguansuan residue after its activation has in conjunction with Ca
++Characteristic, thereby make vitamin k-dependent protein bring into play its biological activity, work as vitamin K deficiency, therefore this proteinoid hydroxylation obstacle, its biological activity also reduce.More bases and clinical trial have illustrated vitamin K and osteoporotic relation.Other has the recycling clear proof that causes vitamin K deficiency of vitamin K in the anticoagulant body capable of blocking.The side effect of clinical report anticoagulant to bone metabolism arranged in 1975, and after this crowd and animal experiment constantly are confirmed, behind the long diaphysis bone, and the too early calcification of end growth hone lamella.More than test all points out vitamin K deficiency can disturb the osseous tissue homergy.
Vitamin K1 helps the treatment or the prevention of liver inflammatory diseases.Studies confirm that vitamin K1 can strengthen the effect of pathological changes hepatocyte vigor and absorbability.Also have report to adopt megavitamin K " to swash and raise therapy " the treatment hepatopathy, vitamin K can promote the hepatocyte vigor of impending death, strengthens the absorbing power to nutrient substance, quickens histiocytic recovery.
Version Chinese Pharmacopoeia in 2010 has recorded vitamin K 1 injection (referring to two ones the 910th page of version Chinese Pharmacopoeia in 2010), this is that a kind of principal agent concentration is the aquesterilisa dispersion liquid that is yellow liquid of 10mg/m1, it allows little apparent muddiness, need antifreeze preservation, if oil droplet is arranged separates out or layering, can under the shading condition, be heated to 70-80 ℃, jolting makes its natural cooling, if clarity normally still can continue to use, these information show that the injection of this pharmacopeia record is a kind of injection that uses solubilizing agent that medicine directly is dissolved in the water, rather than the Emulsion of pharmaceutics field common sense because Emulsion generation oil droplet is separated out or layering after can't after being heated to 70-80 ℃ and jolting, can reach clinical acceptable clarity.
WO2011/153513A2 discloses the micro emulsion composition of fatsoluble vitamin K, it is said vitamin K1 injectable emulsion (the Phytonadione Injectable Emulsion of the alternative American Pharmacopeia of this micro emulsion composition, USP, can abbreviate PIE-USP as, its former name is a vitamin K 1 injection) be used for clinical treatment.PIE-USP is a kind of aqueous dispersions, wherein contains polyoxyethylene fatty acid (also being called Cremophor), and this is a kind of potent surfactant.Although nomenclature of drug is recited as the injection breast, the former product that grinds of vitamin K1 injectable emulsion (USP) is a Merck ﹠ Co., Inc.
It does not in fact contain any oil, therefore is different from the vitamin K1 lipomul of indication of the present invention.Other manufacturer also uses the surfactant that is similar to Cremophor to come the solubilising vitamin K1, for example uses the HCO-60 of high HLB value.The shortcoming of using this type of surfactant has been described among the WO2011/153513A2, and by not using this type of reagent, but prepare a microemulsion to substitute existing P IE-USP, this microemulsion for example contains 0.2～1% vitamin K1,0.5～2% soybean oil, 0.5～2% MCT, 4～25% phospholipid and 10% sucrose, and phospholipid is 13-25 times of vitamin K1 amount.Yet this microemulsion that constitutes with relatively large phospholipid and more a spot of oil is a kind of metastable state that is in the critical state between solution and the Emulsion, its easily because of outside cause for example pressure sterilizing break away from this metastable state, for example in the preparation embodiment of WO2011/153513A2, need with 0.22 μ m membrane filtration degerming.In addition, contain a certain amount of oil for example soybean oil be favourable, the soybean oil of 10% amount for example, its can for human body provide can't or the energy of inconvenience picked-up.Than the safety of oil for injection (for example safflower oil, the Fructus Canarii albi wet goods) soybean oil of other kind and effectiveness is what fully to have proved, and the heavy dose of soybean oil that provides with the fat emulsion injection form has used many decades clinically.
Yet the route of administration of existing vitamin K1 mainly biases toward injection system, and this mode is difficult with respect to oral administration for patient's compliance, but oral administration makes people face the challenge aspect drug bioavailability again.In addition, although existing VK1 tablet applications in clinical, this kind tablet is suitable for for the part adult, for infant, swallow inconvenient patient and inapplicable.
People expect that still new Vitamin K1 preparation is arranged, and for example it can be taken orally and has good pharmaceutics character again, and going for widely, the crowd for example comprises infant.
Summary of the invention
The objective of the invention is provides a kind of new Vitamin K1 preparation for clinical, and it can be taken orally and has good pharmaceutics character again, and going for widely, the crowd for example comprises infant.The inventor finds, unexpectedly has advantage as described in the present invention by the oil with specific composition as the oil agent composition of the substrate preparation of the present composition, for example comprises infant applicable to crowd widely.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention provides a kind of pharmaceutical composition, and it comprises the vitamin K1 of 1 weight portion and the oil of 10～2000 weight portions; The said composition iodine number is less than 1.0, and saponification number is 310-360.
According to the pharmaceutical composition of first aspect present invention, wherein the said composition iodine number is less than 1.0, and saponification number is 320-355.
According to the pharmaceutical composition of first aspect present invention, wherein the said composition iodine number is less than 1.0, and saponification number is 330-350.
According to the pharmaceutical composition of first aspect present invention, wherein comprise the vitamin K1 of 1 weight portion and the oil of 25～1500 weight portions.In one embodiment, this pharmaceutical composition comprises the vitamin K1 of 1 weight portion and the oil of 200～2000 weight portions.In one embodiment, this pharmaceutical composition comprises the vitamin K1 of 1 weight portion and the oil of 50～1500 weight portions.In one embodiment, this pharmaceutical composition comprises the vitamin K1 of 1 weight portion and the oil of 100～1500 weight portions.In one embodiment, this pharmaceutical composition comprises the vitamin K1 of 1 weight portion and the oil of 250～1500 weight portions.In one embodiment, this pharmaceutical composition comprises the vitamin K1 of 1 weight portion and the oil of 500～1200 weight portions.
According to the pharmaceutical composition of first aspect present invention, wherein said oil is the satisfied fatty acid triglyceride, and comprises the fatty acid of the C6～C12 chain length more than 95% in the described satisfied fatty acid.
According to the pharmaceutical composition of first aspect present invention, comprise the fatty acid of the C8～C10 chain length more than 95% in the wherein said satisfied fatty acid.
According to the pharmaceutical composition of first aspect present invention, comprise the sad and capric acid more than 95% in the wherein said satisfied fatty acid.
According to the pharmaceutical composition of first aspect present invention, wherein in whole sad and capric acid, sad ratio with capric acid is (0.5～5): 1.
According to the pharmaceutical composition of first aspect present invention, wherein in whole sad and capric acid, sad ratio with capric acid is (1～4): 1.
According to the pharmaceutical composition of first aspect present invention, wherein in whole sad and capric acid, sad ratio with capric acid is (1.25～3.75): 1.
According to the pharmaceutical composition of first aspect present invention, wherein in whole sad and capric acid, sad ratio with capric acid is (1.5～3.5): 1.
According to the pharmaceutical composition of first aspect present invention, in all fatty acids of wherein said oil, sad amount is 45～85%, preferred 50～80%, preferred 55～80%.
According to the pharmaceutical composition of first aspect present invention, in all fatty acids of wherein said oil, the amount of capric acid is 15～55%, preferred 20～50%, preferred 20～40%.
According to the pharmaceutical composition of first aspect present invention, comprise the sad and capric acid more than 95% in the wherein said satisfied fatty acid; Sad amount is 45～85% (preferred 50～80%, preferred 55～80%), and the amount of capric acid is 15～55% (preferred 20～50%, preferred 20～40%).
According to the pharmaceutical composition of first aspect present invention, comprise the sad and capric acid more than 95% in the wherein said satisfied fatty acid; Sad amount is 45～85% (preferred 50～80%, preferred 55～80%), and the amount of capric acid is 15～55% (preferred 20～50%, preferred 20～40%); And wherein in whole sad and capric acid, sad ratio with capric acid is (0.5～5): 1[for example (1～4): 1, for example (1.25～3.75): 1, for example (1.5～3.5): 1].
According to the pharmaceutical composition of first aspect present invention, wherein can also contain one or more medicinal additive, be selected from correctives class, antioxidant class, surfactant-based, viscosifier class.The amount of these medicinal additives is no more than 1% of composition total weight, and perhaps preferably, the amount of medicinal additive is no more than 5 times of vitamin K1 weight.
Pharmaceutical composition according to first aspect present invention, wherein said correctives class, can improve the product taste, as menthol, Oleum menthae, milk chocolate essence (as the BFL1227 type, International Flavors﹠Fragrances company product), sorbitol etc.
According to the pharmaceutical composition of first aspect present invention, wherein said antioxidant class can improve the product chemical stability, as to hydroxyl tert-butyl group methoxybenzene (BHA), toluene di-tert-butyl phenol (BHT) etc.
According to the pharmaceutical composition of first aspect present invention, the wherein said surfactant-based dissolubility that increases medicine (for example in digestive tract with Digestive system mixed dissolution) is as tween 80, Arlacel-80 etc.
According to the pharmaceutical composition of first aspect present invention, it is formed according to gas chromatography determination fatty acid, and wherein the amount of caproic acid, lauric acid and tetradecylic acid is lower than 3% separately, and sad and capric acid amount sum is higher than 95%.
According to the pharmaceutical composition of first aspect present invention, it is formed according to gas chromatography determination fatty acid, and wherein caproic acid is lower than 2.0%, and lauric acid is lower than 3.0%, and tetradecylic acid is lower than 1.0%, and sad and capric acid amount sum is higher than 95%.
According to the pharmaceutical composition of first aspect present invention, it is formed according to the gas chromatography determination fatty acid, and wherein sad amount is 45～85%, and preferred 50～80%, preferred 55～80%.
According to the pharmaceutical composition of first aspect present invention, it is formed according to the gas chromatography determination fatty acid, and wherein the amount of capric acid is 15～55%, and preferred 20～50%, preferred 20～40%.
According to the pharmaceutical composition of first aspect present invention, it is formed according to the gas chromatography determination fatty acid, and wherein sad amount is 45～85% (preferred 50～80%, preferred 55～80%), and the amount of capric acid is 15～5% (preferred 20～50%, preferred 20～40%).
According to the pharmaceutical composition of first aspect present invention, it is formed according to the gas chromatography determination fatty acid, and wherein sad amount is 45～85% (preferred 50～80%, preferred 55～80%), and the amount of capric acid is 15～55% (preferred 20～50%, preferred 20～40%); And in whole sad and capric acid, sad ratio with capric acid is (0.5～5): 1[for example (1～4): 1, for example (1.25～3.75): 1, for example (1.5～3.5): 1].
According to the pharmaceutical composition of first aspect present invention, wherein be substantially devoid of lower alcohol, this lower alcohol is such as but not limited to ethanol, glycerol, propylene glycol.
According to the pharmaceutical composition of first aspect present invention, the method that wherein is used to measure iodine number is any method that can be used for iodine number known in the art.The iodine number deter mination of enumerating in for example relevant drug standard, for example iodine number deter mination for example enumerated in the pharmacopeia of various countries or international organization's drug standard.For example Chinese Pharmacopoeia, American Pharmacopeia, European Pharmacopoeia, Pharmacopeia of Japan etc. and the various version in their any age.For example can be with reference to the method for record among two appendix VIIH of version Chinese Pharmacopoeia in 2010 " fat and fatty oil algoscopy ".
According to the pharmaceutical composition of first aspect present invention, the method that wherein is used to measure saponification number is any method that can be used for saponification number known in the art.The soap value test method of enumerating in for example relevant drug standard, for example the soap value test method for example enumerated in the pharmacopeia of various countries or international organization's drug standard.For example Chinese Pharmacopoeia, American Pharmacopeia, European Pharmacopoeia, Pharmacopeia of Japan etc. and the various version in their any age.For example can be with reference to the method for record among two appendix VII of version Chinese Pharmacopoeia in 2010 H " fat and fatty oil algoscopy ".
According to the pharmaceutical composition of first aspect present invention, wherein being used to measure the gas chromatography that fatty acid forms is any gas chromatography that fatty acid is formed that can be used to measure known in the art.The gas chromatography of enumerating in for example relevant drug standard, for example gas chromatography for example enumerated in the pharmacopeia of various countries or international organization's drug standard.For example Chinese Pharmacopoeia, American Pharmacopeia, European Pharmacopoeia, Pharmacopeia of Japan etc. and the various version in their any age.For example can be with reference to the method under " fatty acid composition " item of two " soybean oil " kinds of version Chinese Pharmacopoeia in 2010.
According to the pharmaceutical composition of first aspect present invention, it is as follows wherein to be used to measure the gas chromatography that fatty acid forms:
Test solution: (present composition or prepare their oil) 0.1g materialses, put in the 50ml conical flask, add 0.5mol/L potassium hydroxide methanol solution 2ml, reflux is 30 minutes in 65 ℃ of water-baths, puts cold, add 15% boron trifluoride methanol solution 2ml, reflux 30 minutes in 65 ℃ of water-baths is again put coldly, adds heptane 4ml, continuation reflux in 65 ℃ of water-baths was put cold after 5 minutes.Add saturated nacl aqueous solution 10ml washing, shake up, leave standstill and make layering, get upper strata liquid, wash with water 3 times, each 2ml, upper strata liquid is through anhydrous sodium sulfate drying, as need testing solution.In addition get methyl caproate, methyl caprylate, methyl caprate, methyl laurate, methyl myristate reference substance respectively, add n-hexane dissolution and the solution that contains above-mentioned each 0.1mg of reference substance among every 1ml, product solution are in contrast made in dilution.Reference solution (a) is methyl caproate, methyl caprylate, methyl caprate, methyl laurate, methyl myristate with weight ratio 2: 60: 30: the solution of usefulness normal hexane preparation in 4: 2.Reference solution (b): (a) is diluted to 10.0ml with heptane with the 1.0ml reference solution;
Chromatographic column: material is fused silica (fused silica), long 30m,
Immobile phase is a Macrogol 2000 0, the thick 0.5 μ m of thin film;
Carrier gas: chromatographic grade helium;
Flow velocity: 1.3ml/min;
Temperature:
Detect: flame ion;
Split ratio: 1: 100;
Sample size: 1 μ l;
Sensitivity: the main peak peak height is 50% to 70% of a monitor full scale in the chromatogram of reference solution (a);
The system suitability test: methyl caprylate and the peak-to-peak separating degree of methyl caprate are not less than 4.0 in the chromatogram of reference solution (a), the signal to noise ratio at methyl caproate peak is not less than 5 in the chromatogram of reference solution (b), and the number of theoretical plate at methyl caprate peak is not less than 15000 in the chromatogram of reference solution (a);
Get each test fluid 1 μ l inject gas chromatograph, the record chromatogram; Press area normalization method with calculated by peak area.
Because iodine number, saponification number or gas chromatography are to well known to a person skilled in the art method, though they are highly suitable for measuring the parameters of the present composition, yet these methods are to do suitably to revise according to those skilled in the art's experience, perhaps can adopt to well known to a person skilled in the art that other method measures these parameters.Therefore, for realizing the object of the invention, need when advocating claim, not limit the assay method of these parameters.
According to the pharmaceutical composition of first aspect present invention, the concentration of wherein said vitamin K1 in this pharmaceutical composition is 1mg: 0.2～2ml, for example 1mg: 0.5～1.5ml, for example 1mg: 0.8～1.2ml.According to pharmaceutical composition of the present invention, its relative density is 0.92-1.2, for example 0.92-1.1; The present invention hereinafter described the relative density of the pharmaceutical composition of embodiment A 1-A12 all in the 0.92-1.2 scope.
Second aspect present invention also relates to a kind of pharmaceutical preparation, and it comprises first aspect present invention or the described pharmaceutical composition of second aspect, and the acceptable lapping of pharmacy of parcel said composition.
According to the pharmaceutical preparation of second aspect present invention, wherein said lapping includes but not limited to: plastics, glass, capsule shell.
According to the pharmaceutical preparation of second aspect present invention, it is the soft capsule or the drop of capsule shell parcel, or the oral solutions or the drop of plastic bottle or vial parcel.
The documents and materials of the present invention's citation, its full content is incorporated this paper by reference into.In either side of the present invention, any one of its arbitrary embodiment or a plurality of technical characterictic can be combined in arbitrary other embodiment of this aspect, also can be combined in arbitrary embodiment on the other hand, as long as this combination contradiction can not occur.
The various terms that the present invention uses have the conventional general sense of understanding of those skilled in the art,, are being as the criterion with the present invention when inconsistent with this general sense.
In the present invention, for writing conveniently, vitamin K1 can simply be written as VK1.
In the present invention, as the oil of satisfied fatty acid triglyceride, it can be product or the natural origin and the product through handling such as but not limited to extraction, purification, purification, make with extra care etc. of natural origin, and for example described natural origin can be a vegetable oil.In the present invention, as the oil of satisfied fatty acid triglyceride, it can also be artificial manufactured goods, and for example it can be that satisfied fatty acid and glycerol carry out esterification and the glyceride that forms triglyceride particularly.
In the present invention, when relating to percent, percentage ratio, %, ratio, ratio etc., as do not have other explanation, be meant the ratio of weight.
In the present invention, mention " comprising the sad and capric acid more than 95% in the satisfied fatty acid " or similar statement, be meant according to gas chromatography (being called for short GC or GC method) GC method for example of the present invention and measure, in the used oil of the present composition, in whole saturated satisfied fatty acid, sad and capric acid summation accounts for more than 95%.Other similar statement also has similar meaning.
In the present invention, mention " in whole sad and capric acid; sad ratio with capric acid is (0.5～5): 1 " or similar statement, be meant according to gas chromatography (being called for short GC or GC method) GC method for example of the present invention and measure, in the used oil of the present composition, in whole sad and capric acid, sad ratio with capric acid is (0.5～5): 1.Other similar statement also has similar meaning.
In the present invention, mention " in all fatty acids of described oil; sad amount is 45～85% " or similar statement, be meant according to gas chromatography (being called for short GC or GC method) GC method for example of the present invention and measure, in the used oil of the present composition, in whole satisfied fatty acid, sad amount is 45～85%.Other similar statement also has similar meaning.
In the present invention, described oil is the main part of the present composition; And vitamin K1 is the active component of the present composition.Therefore, the oil in the pharmaceutical composition of the present invention can be used as the drug matrices or the medicinal liquid carrier of pharmaceutical composition of the present invention basically, in the pharmaceutics field, its definition is clear and definite, promptly form the main material of medicament, or main adjuvant, can play an important role the physicochemical property of medicament.In addition, the invention provides a kind of pharmaceutical composition, when mentioning " the said composition iodine number is less than 1.0, and saponification number is 310-360 ", be meant that said composition directly measures iodine number and the saponification number that obtains according to iodine number deter mination and soap value test method.It will be appreciated by those skilled in the art that since in the present composition relative amount of vitamin K1 very low, the therefore iodine number and the saponification number of directly testing with said composition, it will be identical with saponification number or close with the iodine number of the oil of formation said composition.
In the present invention, described oil is a kind of fatty acid triglycercide with medium chain as a kind of oil medicinal liquid carrier, and is often referred to and has C6～fatty acid triglycercide of C14 chain length.More preferably, above-mentioned fatty acid triglycercide refers to the fatty glyceride of C8～C12; As to have the fatty acid triglycercide of C8～C12 satisfied fatty acid preparation, particularly has the fatty acid triglycercide of C8 and C10 satisfied fatty acid preparation.These fatty acid triglycercides can be the products of German CONDEA chemical company (CONDEA Chemie GmbH)
812 or
810; Or the product LABRAFAC CC of French GATTEFOSSE company; Or available from the product of U.S. LONZA company
MCT.The product of these different brands is having difference aspect the ratio of sad (C8) and capric acid (C10) slightly, as
812 contain sad 50～65%, capric acid 30～45%;
810 contain sad 65～80%, capric acid 20～35%; LABRAFAC CC contains sad 50～80%, capric acid 20～50%;
MCT contains sad 65～80%, capric acid 20～35%.Certainly, be to allow to exist with a spot of other fatty acids of the conceptual understanding of " impurity " in the pharmaceutical field, this is conceptive and without prejudice to spirit of the present invention.
In the present invention, described oil can also be artificial preparation, and for example it can be to prepare with reference to the method for being put down in writing among CN1594274A, the CN1594274A.
Used in the present invention oil can be above-mentioned a kind of natural or artificial source's oil, or the mixture of multiple natural or artificial source's oil.
In addition, for the present invention, can also use that the present invention mentions or NM two or more the fatty acid triglycercide mixing arbitrarily of the present invention, be met the performance requirement of oil of the present invention, and and then realization the object of the invention.For example can use two or more, iodine number less than 1.0 for example less than 0.5, saponification number as 310-360 for example 320-355 for example 330-350, sad amount be lower than 45% or be higher than 85% and the capric acid amount be lower than 15% or be higher than 55% fatty acid triglycercide, they are mixed in certain proportion, be met the performance requirement of oil of the present invention.In this sense, oil of the present invention can be the artificial preparation of two or more oil.
The specific embodiment
Following examples further specify the present invention, rather than restriction the present invention.Preparation process purpose for example hereinafter, and done some based on the comparability of respectively giving an example and specifically describe, those skilled in the art can therefrom summarize the method that obtains pharmaceutical compositions of the present invention fully according to existing knowledge.
In the present invention's some examples hereinafter, preparation is during the present composition, as explanation in addition, used adjuvant all be pharmaceutical grade other, thus composition prepared both can for mammal for example the people for example infant orally use.
Below among the embodiment, when using homemade caprylic/capric triglyceride, it is homemade in different batches with reference to the method among the CN1594274A, in this method for making, use a certain proportion of high-purity octanoic acid and capric acid and highly purified glycerol to carry out esterification, obtain caprylic/capric triglyceride, wherein iodine number, saponification number and suffering summation in the last of the ten Heavenly stems are more as mentioned below than each parameter suffering/last of the ten Heavenly stems.
Below among the embodiment, as not specifying, used oil is the satisfied fatty acid triglyceride, hereinafter described testing example 1 described GC method through this measures, comprise sad and capric acid more than 95% (can abbreviate " the hot last of the ten Heavenly stems is total " in this article as) in the satisfied fatty acid wherein, and sad ratio with capric acid be (1～4): 1 (can abbreviate " compare suffering/last of the ten Heavenly stems " in this article as).Below the compositions of each embodiment preparation, as show other explanation, the hot last of the ten Heavenly stems of final composition, always between 95.5%～99.8%, suffering/last of the ten Heavenly stems was than between 1.07～4.02.In addition, as not specifying, used caprylic/capric triglyceride is formed according to the gas chromatography determination fatty acid, and wherein sad amount is 45～85%, and the amount of capric acid is 15～55%.
The method of vitamin K1 content can be carried out with reference to the method under two " vitamin K1 " middle assay items of Chinese Pharmacopoeia version in 2010 in the various compositionss in various compositionss that the present invention mentions and the claim scope of the present invention.
Below among the embodiment, as specifying, the method that is used for measuring iodine number is the method for putting down in writing with reference to two appendix VII of version Chinese Pharmacopoeia in 2010 H " fat and fatty oil algoscopy ".
Below among the embodiment, as specifying, the method that is used for measuring saponification number is the method for putting down in writing with reference to two appendix VII of version Chinese Pharmacopoeia in 2010 H " fat and fatty oil algoscopy ".
Below the compositions of each embodiment preparation, as show other explanation, all be that sealing by fusing is in the vial of inflated with nitrogen, so that the test of being correlated with.
Embodiment A 1: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method: get vitamin K1, add the oil of about 90% formula ratio, stirring and dissolving is added oil to full dose, stirs, and promptly gets the present composition.
The compositions of present embodiment is packaged in vial or the plastic bottle (for example high-density polyethylene bottle), perhaps is prepared into soft capsule preparation by the following method:
Capsule shell prescription: gelatin 40%, glycerol 18%, sorbitol 7%, water 35%.
Use following step method, the invention described above compositions is wrapped in the capsule shell of preparation, the capsule skin of the inclusions of 0.3g/ grain and 0.2g/ grain.
Get gelatin, add suitable quantity of water and make the gelatin water absorption and swelling.Other gets other compositions except that gelatin, places glue pot, and is heated to 70 ℃.Behind the dissolving mixing, to glue pot add swollen gelatin, stir evenly, fusion and keep jar in about 70 ℃ of temperature, being evacuated to glue does not again have bubble.Put glue then, 100 orders filter, and leave standstill more than 2 hours the filtrate insulation standby.Fused gelatin frozen glue liquid by the capsule machine (RGY6-20 type encapsulating machine) of rotation pressure automatically, is cast on the cold drum, make the wide frozen glue bar of the about 5～6in of each twice.The frozen glue bar passes across roller, provides suitable bar to arrange, and the rotation automatically of then capsule heart vitamin K1 medicinal liquid being packed into is pressed in the capsule machine.Capsule psychological treatment liquid temp is controlled at about 25 ℃, carries out pelleting.Extrude soft gelatin capsule and, use 95% washing with alcohol by after the typing.Dry, treat the ethanol volatilization after, enter dry 3-5 hour of the exsiccator that automatic rotation presses the capsule machine.Dried soft gelatin capsule is selected ball.After selecting qualified ball, pack promptly.
Embodiment A 2: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method:, obtain the present composition according to the preparation of embodiment A1 method.Can further said composition be packaged in vial or the plastic bottle, or be prepared into soft capsule preparation.
Embodiment A 3: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method:, obtain the present composition according to the preparation of embodiment A1 method.Can further said composition be packaged in vial or the plastic bottle, or be prepared into soft capsule preparation.
Embodiment A 4: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| Caprylic/capric triglyceride (self-control) | Add to 200mg |
| Final composition: iodine number 0.52, saponification number 322 |
Preparation method:, obtain the present composition according to the preparation of embodiment A1 method.Can further said composition be packaged in vial or the plastic bottle, or be prepared into soft capsule preparation.
Embodiment A 5: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| Caprylic/capric triglyceride (self-control) | Add to 1000mg |
| Final composition: iodine number 0.31, saponification number 341 |
Preparation method:, obtain the present composition according to the preparation of embodiment A1 method.Can further said composition be packaged in vial or the plastic bottle, or be prepared into soft capsule preparation.
Embodiment A 6: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| Tween 80 | 1mg |
| Caprylic/capric triglyceride (self-control) | Add to 2000mg |
| Final composition: iodine number 0.68, saponification number 355 |
Preparation method:, obtain the present composition according to the preparation of embodiment A1 method.Can further said composition be packaged in vial or the plastic bottle, or be prepared into soft capsule preparation.
Embodiment A 7: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method:, obtain the present composition according to the preparation of embodiment A1 method.Can further said composition be packaged in vial or the plastic bottle, or be prepared into soft capsule preparation.
Embodiment A 8: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method:, obtain the present composition according to the preparation of embodiment A1 method.Can further said composition be packaged in vial or the plastic bottle, or be prepared into soft capsule preparation.
Embodiment A 9: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method:, obtain the present composition according to the preparation of embodiment A1 method.Can further said composition be packaged in vial or the plastic bottle, or be prepared into soft capsule preparation.
Embodiment A 10: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| VK1 | 1mg |
| M-812/M-810 (mixing at 1: 1) | To 500mg |
| Iodine number 0.38, saponification number 336 |
Reference example A1 preparation, hereinafter every test result and embodiment A 1 be basically identical as a result.
Embodiment A 11: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| VK1 | 1mg |
| M-810/L-CC (mixing at 2: 3) | To 1000mg |
| Iodine number 0.23, saponification number 341 |
Reference example A2 preparation, hereinafter every test result and embodiment A 2 be basically identical as a result.
Embodiment A 12: the preparation present composition
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| VK1 | 1mg |
| M-810/ALDO (mixing at 3: 2) | To 1500mg |
| Iodine number 0.53, saponification number 336 |
Reference example A3 preparation, hereinafter every test result and embodiment A 3 be basically identical as a result.
Embodiment B 1: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method: according to the preparation of embodiment A1 method.
Embodiment B 2: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method: according to the preparation of embodiment A1 method.
Embodiment B 3: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
Preparation method: according to the preparation of embodiment A1 method.
Embodiment B 4: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| Caprylic/capric triglyceride (self-control adds 1% soybean oil) | To 200mg |
| Iodine number 1.44, saponification number 296 |
Preparation method: according to the preparation of embodiment A1 method.
Embodiment B 5: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| Caprylic/capric triglyceride (self-control): soybean oil=85: 15 mixture | To 1000mg |
| Iodine number 23.7, saponification number 271 |
Preparation method: according to the preparation of embodiment A1 method.Always be lower than 90% the hot last of the ten Heavenly stems of the compositions of present embodiment, and whether the suffering/last of the ten Heavenly stems than in the scope 1～4 or not.
Embodiment B 6: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| Tween 80 | 1mg |
| Caprylic/capric triglyceride (self-control): soybean oil=80: 20 mixture | To 2000mg |
| Iodine number 42.1, saponification number 253 |
Preparation method: according to the preparation of embodiment A1 method.Always be lower than 90% the hot last of the ten Heavenly stems of the compositions of present embodiment, and whether the suffering/last of the ten Heavenly stems than in the scope 1～4 or not.
Embodiment B 7: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| BHA | 0.1mg |
| Caprylic/capric triglyceride (self-control): Oleum Brassicae campestris=50: 50 mixture | To 1000mg |
| Iodine number 77.8, saponification number 237 |
Preparation method: according to the preparation of embodiment A1 method.Always be lower than 90% the hot last of the ten Heavenly stems of the compositions of present embodiment, and whether the suffering/last of the ten Heavenly stems than in the scope 1～4 or not.
Embodiment B 8: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| BFL1227 | 5mg |
| Soybean oil | To 1000mg |
| Iodine number 133.1, saponification number 195 |
Preparation method: according to the preparation of embodiment A1 method.
Embodiment B 9: preparation contains the compositions of vitamin K1
Prescription:
| Vitamin K1 | 10g |
| Dehydrated alcohol | 30g |
| 1, the 2-propylene glycol | 9.5g |
| Menthol | 0.5g |
| Toluene di-tert-butyl phenol | 0.02g |
| MIGLYOL810 | Add to 100ml |
Preparation method: get vitamin K1, add ethanol, propylene glycol, menthol, toluene di-tert-butyl phenol, stirring and dissolving adds MIGLYOL810 to 100ml, and said composition is packaged in vial or the plastic bottle.
Embodiment B 10: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| Caprylic/capric triglyceride (self-control) | To 1000mg |
| Iodine number 1.07, saponification number 301 |
Preparation method: according to the preparation of embodiment A1 method.
Embodiment B 11: preparation contains the compositions of vitamin K1
Prescription (with 1000 parts of preparations, the prescription of every deal is as follows):
| Vitamin K1 | 1mg |
| Caprylic/capric triglyceride (self-control) | To 1000mg |
| Iodine number 1.14, saponification number 288 |
Preparation method: according to the preparation of embodiment A1 method.
Test example 1: the method that the fatty acid in gas chromatogram test composition or the oil is formed
Test solution: (present composition or prepare their oil) 0.1g materialses, put in the 50ml conical flask, add 0.5mol/L potassium hydroxide methanol solution 2ml, reflux is 30 minutes in 65 ℃ of water-baths, puts cold, add 15% boron trifluoride methanol solution 2ml, reflux 30 minutes in 65 ℃ of water-baths is again put coldly, adds heptane 4ml, continuation reflux after 5 minutes in 65 ℃ of water-baths, put coldly, add saturated nacl aqueous solution 10ml washing, shake up, leave standstill and make layering, get upper strata liquid, wash with water 3 times, each 2ml, upper strata liquid is through anhydrous sodium sulfate drying, as need testing solution.In addition get methyl caproate, methyl caprylate, methyl caprate, methyl laurate, methyl myristate reference substance respectively, add n-hexane dissolution and the solution that contains above-mentioned each 0.1mg of reference substance among every 1ml, product solution are in contrast made in dilution.Reference solution (a) is methyl caproate, methyl caprylate, methyl caprate, methyl laurate, methyl myristate with weight ratio 2: 60: 30: the solution of usefulness normal hexane preparation in 4: 2.Reference solution (b): (a) is diluted to 10.0ml with heptane with the 1.0ml reference solution;
Chromatographic column: material is fused silica (fused silica), long 30m,
Immobile phase is a Macrogol 2000 0, the thick 0.5 μ m of thin film;
Carrier gas: chromatographic grade helium;
Flow velocity: 1.3ml/min;
Temperature:
Detect: flame ion;
Split ratio: 1: 100;
Sample size: 1 μ l;
Sensitivity: the main peak peak height is 50% to 70% of a monitor full scale in the chromatogram of reference solution (a);
The system suitability test: methyl caprylate and the peak-to-peak separating degree of methyl caprate are not less than 4.0 in the chromatogram of reference solution (a), the signal to noise ratio at methyl caproate peak is not less than 5 in the chromatogram of reference solution (b), and the number of theoretical plate at methyl caprate peak is not less than 15000 in the chromatogram of reference solution (a);
Get each test fluid 1 μ l inject gas chromatograph, the record chromatogram.Press area normalization method with calculated by peak area.
Test example 2: temperature is disposed test
The compositions sealing by fusing of each embodiment preparation is in the vial of inflated with nitrogen, place 43 ℃ of calorstats to place May, test vitamin K1 content in each compositions, and with the 0 month reagent of 43 ℃ of disposal (promptly without) sample in vitamin K1 content relatively, calculate the remaining rate (%) of vitamin K1 after 5 months temperature are disposed in each compositions.The result shows, tests routine A1 to testing routine A9 remaining rates of each sample (%) all between 95.4%～99.3%, all is lower than 92% and test routine B1 to testing routine B11 remaining rates of each sample (%), between 79.6%～91.2%; And along with the rising of the iodine number and/or the saponification number of compositions, the remaining rate of vitamin K1 is low more in the said composition; For example test routine A4, the routine A5 of test and test the remaining rate of routine A6 and be respectively 96.8%, 97.9% and 97.2%, be respectively 90.6%, 88.5% and 84.7% and test routine B4, the routine B5 of test and test the remaining rate of routine B6, test routine B10 and test routine B11 being respectively 91.7% and 90.3%.
Claims (10)
1. pharmaceutical composition, it comprises the vitamin K1 of 1 weight portion and the oil of 10～2000 weight portions; The said composition iodine number is less than 1.0, and saponification number is 330-350; Described oil is the satisfied fatty acid triglyceride, comprises the sad and capric acid more than 95% in the described satisfied fatty acid, and in whole sad and capric acid, sad ratio with capric acid is (1～4): 1.
2. according to the pharmaceutical composition of claim 1, wherein the concentration of vitamin K1 in this pharmaceutical composition is 1mg: 0.2～2ml.
3. according to the pharmaceutical composition of claim 1, wherein this pharmaceutical composition comprises the vitamin K1 of 1 weight portion and the oil of 100～1500 weight portions.
4. according to the pharmaceutical composition of claim 1, in all fatty acids of wherein said oil: sad amount is 45～85%, and/or the amount of capric acid is 15～55%.
5. according to the pharmaceutical composition of claim 1, wherein also contain one or more medicinal additive, select white correctives class, antioxidant class, surfactant-based, viscosifier class.
6. according to the pharmaceutical composition of claim 1, wherein do not contain lower alcohol.
7. according to the pharmaceutical composition of claim 6, wherein said lower alcohol is selected from ethanol, glycerol, propylene glycol.
8. pharmaceutical preparation, it comprises each pharmaceutical composition of claim 1 to 7, and the acceptable lapping of pharmacy of parcel said composition.
9. pharmaceutical preparation according to Claim 8, wherein said lapping selects white plastics, glass, capsule shell.
10. pharmaceutical preparation according to Claim 8, it is the soft capsule or the drop of capsule shell parcel, or the oral solutions or the drop of plastic bottle or vial parcel.
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| CN 201210203095 CN102688191B (en) | 2012-06-20 | 2012-06-20 | Medicine composition containing vitamin K1 and oil |
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| CN108309951A (en) * | 2018-03-23 | 2018-07-24 | 广西铭磊维生药业有限公司 | A kind of vitamin K1 drops and preparation method thereof |
| CN108272751A (en) * | 2018-03-23 | 2018-07-13 | 广西铭磊维生药业有限公司 | A kind of vitamin K drops and preparation method thereof |
| CN108272752A (en) * | 2018-03-23 | 2018-07-13 | 广西铭磊维生药业有限公司 | A kind of farnoquinone drops and preparation method thereof |
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| CN1861061A (en) * | 2005-06-22 | 2006-11-15 | 王杰华 | Medicine for treating or preventing newborn hemorrhagic disease |
| CN100536849C (en) * | 2006-05-10 | 2009-09-09 | 鲁南制药集团股份有限公司 | Medicine composition containing theocin-like medicines and vitamin K |
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