CN103230402B - Drug composition containing various lipid-soluble vitamins and preparation thereof - Google Patents
Drug composition containing various lipid-soluble vitamins and preparation thereof Download PDFInfo
- Publication number
- CN103230402B CN103230402B CN201310149980.7A CN201310149980A CN103230402B CN 103230402 B CN103230402 B CN 103230402B CN 201310149980 A CN201310149980 A CN 201310149980A CN 103230402 B CN103230402 B CN 103230402B
- Authority
- CN
- China
- Prior art keywords
- vitamin
- preparation
- palmitate
- tween
- composition containing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a drug composition containing various lipid-soluble vitamins. The composition contains 600-750mg of vitamin A palmitate, 1.5-12mg of vitamin D2, 3000-8000mg of vitamin E, 50-1200mg of vitamin K1 and 10-100g of Tween-80. The composition can be prepared into freeze-dried powder injection or injection. The composition containing various lipid-soluble vitamins is small in auxiliary dosage and is safe and effective in clinical use. The preparation prepared from the composition has good drug stability. Stability tests prove that the preparation is stable in contents of active ingredients of the drug and is more suitable for clinical application.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, specifically, relate to a kind of pharmaceutical composition and preparation thereof containing multiple fatsoluble vitamin.
Background technology
Vitamin (vitamin) is that humans and animals is to maintain normal physiological function and the class trace organic substance that must obtain from food, in people's bulk-growth, metabolism, growth course, plays an important role.Vitamin is a huge family, and vitamin known today just has tens kinds, is broadly divided into the fat-soluble and large class of water solublity two.Water soluble vitamins does not need digestion, and directly, from intestinal absorption, by being recycled in the tissue of body requirement, unnecessary part is discharged by urine mostly, stores in vivo very few.Fatsoluble vitamin is dissolved in oils and fats, through bile emulsifying, at intestinal absorption, enters into each organ in body by lymph circulation system.In body, can store a large amount of fatsoluble vitamiies.Vitamin A and D major storage are in liver, and vitamin E is mainly stored in body fat tissue, and vitamin K stores less.Water soluble vitamins is soluble in water and be not soluble in non-polar organic solvent, after absorbing in body storage seldom, excessive manyly discharge from urine; Fatsoluble vitamin is soluble in non-polar organic solvent, and not soluble in water, can be absorption of human body and accumulate in vivo with fat, and excretion rate is not high.
Vitamin A is found 1912 to 1914 by Elmer McCollum and M.Davis, and undersaturated unary alcohol belongs to fatsoluble vitamin.When be deficient in vitamin A due to human body or mammal, be prone to xerophthalmia, therefore be called again axerophthol.Known vitamin A has A
1and A
2two kinds, A
1be present in the retina of animal livers, blood and eyeball, be called again retinol, natural vitamin A mainly exists with this form.A
2mainly be present in the liver of fresh-water fishes.Retinol1 is a kind of fat-soluble faint yellow flaky crystal, 64 DEG C of fusing points, vitamin A
217～19 DEG C of fusing points, are generally golden yellow grease.Because retinol is unstable, commodity vitamin A all provides market with the form of ester.In the esters series of products of vitamin A, with the market share amount maximum of vitamin A acetate, be secondly vitamin A palmitate.Due to the carbon chain length of vitamin A palmitate, fusing point is low, and oil-soluble is good, is widely used in food, medicine, cosmetics.Vitamin A palmitate is with respect to vitamin A acetate, and low-temperature stability is good, is not easy to occur crystal and separates out.There is the vision of maintaining, enhancing development, maintain the physiological functions such as the complete of epithelial structure and sound, booster immunization ability.
Vitamin D is steroid derivatives, belongs to fatsoluble vitamin.First from cod-liver oil, being extracted by chemist Ka Er in nineteen twenty-six, is light yellow crystal, water insoluble, can be dissolved in the organic solvents such as ether.In human body skin, there is a kind of 7-DHC, under the ultraviolet radiation of the sun, be transformed into vitamin D.The essential element that forms skeleton is calcium and phosphorus, and human body must be by means of vitamin D to the absorption of calcium and phosphorus.If lack vitamin D in body, even if having enough calcium and phosphorus in diet, normally calcification of skeleton, thus making skeleton weakness, flexible distortion causes bung flange lower limb, pigeon chest, rickets under the pressure of body.
Vitamin K belongs to fatsoluble vitamin, has the function that promotes blood coagulation, therefore claim again coagulation vitamin.Common are vitamin K
1and K
2.Vitamin K is the derivant of 2-MNQ.Vitamin K
1yellow oil, K
2be faint yellow crystallization, all have thermostability, but be subject to ultraviolet radiation and destroy, therefore will keep in Dark Place.
Vitamin E is all the have tocopherol of alpha-tocopherol activity and general names of tocotrienol and derivant thereof, has another name called tocopherol, is a kind of fatsoluble vitamin, is mainly present among vegetable, beans, and in wheat germ oil, content is the abundantest.Naturally occurring vitamin E has 8 kinds, is the derivant of benzene a pair of horses going side by side dihydropyran, can be divided into tocopherol and tocotrienol two classes according to its chemical constitution, and every class again can be different with position according to the number of methyl, be divided into α-, β-, γ-and δ-tetra-kind.Vitamin E is micro-adhesive faint yellow grease, comparatively stable under oxygen free condition, is even heated to 200 DEG C and is not also destroyed above.
Fatsoluble vitamin injection is applicable to through the patient of the normal feed of digestive tract, to have launched a series of research at present for fatsoluble vitamin:
Patent ZL201110387733.1 discloses pharmaceutical composition and the method for making thereof of a kind of fatsoluble vitamin injection (II) and Vitamin H, is added with soybean oil, lecithin and glycerol in this injection, and the adjuvant of interpolation is wide in variety, and consumption is large.A large amount of oily adjuvants enters human body by injecting or infusing simultaneously, can produce certain side reaction, and be not suitable for clinical practice.
Patent application 201010575712.8 discloses a kind of fat-soluble vitamin freeze-dried injection and preparation method thereof, and this lyophilized injection is containing vitamin A palmitate, vitamin D
2, vitamin E, vitamin K
1, ethanol, polyoxyethylene sorbitan monoleate, tween 20, mannitol, sodium hydroxide.Supplementary product consumption in this lyophilized formulations is large, and solubility has much room for improvement, and the particulate matter that dissolves rear lyophilized powder is not considered, and has certain potential safety hazard.
For the defect of disclosed fatsoluble vitamin preparation in currently available technology, special proposition the present invention.
Summary of the invention
Primary goal of the invention of the present invention has been to propose a kind of pharmaceutical composition containing multiple fatsoluble vitamin.
The second goal of the invention of the present invention has been to propose this preparation containing multiple fatsoluble vitamin.
The 3rd goal of the invention of the present invention has been to propose this preparation method containing the preparation of multiple fatsoluble vitamin.
In order to realize object of the present invention, the technical scheme of employing is:
Containing a pharmaceutical composition for multiple fatsoluble vitamin, contain vitamin A palmitate 600～750mg, vitamin D
21.5～12mg, vitamin E 3000～8000mg, vitamin K
150～1200mg, tween 80 10～100g; Preferably contain vitamin A palmitate 650～700mg, vitamin D
21.5～6mg, vitamin E 5000～8000mg, vitamin K
1500～1000mg, tween 80 10～80g; More preferably contain vitamin A palmitate 687.5mg, vitamin D
22.5mg, vitamin E 7500mg, vitamin K
11000mg, tween 80 10～80g.
The first optimal technical scheme of the present invention is: the X-ray powder diffraction pattern that described vitamin A palmitate compound use Cu-K alpha ray measures as shown in Figure 1.
The second optimal technical scheme of the present invention is: the preparation method of described vitamin A palmitate compound comprises the following steps: vitamin A palmitate is dissolved in the mixed solvent of acetone, ethyl acetate and petroleum ether of 20～25 DEG C, filling nitrogen condition borehole cooling to-10～-5 DEG C, leave standstill growing the grain 1～5 hour, filtration, washing, vacuum drying obtain the light yellow crystalline powder of vitamin A palmitate.
The 3rd optimal technical scheme of the present invention is: in described mixed solvent, the volume ratio of acetone, ethyl acetate and petroleum ether is 2～4:1～2:3～6, preferably 2～4:1～2:4～6.
The 4th optimal technical scheme of the present invention is: described vitamin D
2for crystalline compounds, the X-ray powder diffraction pattern that use Cu-K alpha ray measures as shown in Figure 2.
The 5th optimal technical scheme of the present invention is: described vitamin D
2the preparation method of compound is: by vitamin D
2be dissolved in the mixed solution of 0～5 DEG C of dehydrated alcohol and chloroform, add while stirring the distilled water of 0 DEG C filling, and be cooled to 0 DEG C under nitrogen condition, leave standstill growing the grain 1～5 hour, filtration, washing, vacuum drying obtain vitamin D
2white crystalline powder.
The 6th optimal technical scheme of the present invention is: in described mixed solution, the volume ratio of dehydrated alcohol and chloroform is 1～5:1～2, preferably 1～5:1; The volume of described distilled water is 1:1～3 with the ratio of dehydrated alcohol and chloroform mixed liquor volume.
The 7th optimal technical scheme of the present invention is: in described pharmaceutical composition, also contain at least one in excipient, stabilizing agent, antioxidant, antiseptic, pH adjusting agent.
The preparation that the invention still further relates to a kind of pharmaceutical composition containing multiple fatsoluble vitamin, described preparation is aqueous injection or lyophilized injectable powder; In described preparation, in every dosage unit, contain vitamin A palmitate 1.2～1.5mg, vitamin D
23～24 μ g, vitamin E 6～16mg, vitamin K
10.1～2.4mg, tween 80 20～200mg; Preferably contain vitamin A palmitate 1.3～1.4mg, vitamin D
23～12 μ g, vitamin e1 0～16mg, vitamin K
11～2mg, tween 80 20～160mg; More preferably contain vitamin A palmitate 1.375mg, vitamin D
25 μ g, vitamin e1 5mg, vitamin K
12mg, tween 80 20～160mg.
The preparation method of liquid drugs injection is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection of 80% recipe quantity of room temperature, rapid stirring, under the condition of filling nitrogen, inject water and complement to full dose, regulating pH value is 6.5～7.5, add the medical activated carbon absorption of 0.01% mass volume ratio, filtration, fine straining, embedding, sterilizing.
The preparation method of freeze-dried powder is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection of 80% recipe quantity of room temperature, and rapid stirring, then add the sorbitol of recipe quantity to stir; Under the condition of filling nitrogen, inject water and complement to full dose, regulating pH value is 6.5～7.5, adds the medical activated carbon absorption of 0.01% mass volume ratio, filters; Fine straining, subpackage, partly jump a queue, lyophilization, tamponade;
Lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: shelf temperature is down to-25～-20 DEG C with the speed of 3.0 DEG C/min, stops cooling, be incubated 1～2 hour, then be cooled to-50～-55 DEG C with the speed of 6.0 DEG C/min, evacuation;
The primary drying stage: shelf temperature is slowly risen to-10～-5 DEG C with the speed of 0.5 DEG C/min, be incubated 1～2 hour;
The redrying stage: shelf temperature is risen to 15～20 DEG C with the speed of 0.8 DEG C/min, be incubated 1～2 hour, shelf continues to rise to 40 DEG C with the speed of 0.5 DEG C/min.
The mixing speed of the rapid stirring in the present invention is 240～480 revs/min, preferably 240～360 revs/min; Fine straining is excellent further first adopts 0.22 μ m aperture filter membrane to filter, and adopts 0.22 μ m aperture filter membrane to filter once after filtrate is cooled to 0～5 DEG C, with the macromole in filtering solution to greatest extent, the quality of raising preparation.
Below technical scheme of the present invention is made further explanation.
The compositions that contains multiple fatsoluble vitamin of the present invention, its supplementary product consumption is few, and clinical use is safe and effective.And preparation prepared by compositions according to the present invention, its medicine stability is good, confirms through stability test, and it is effective ingredient stable content not only, and particulate matter is little, lower than national standard, is more applicable for the needs of clinical practice.
The present invention proposes a kind of crystalline compounds of vitamin A palmitate, the X-ray powder diffraction pattern that use Cu-K alpha ray measures as shown in Figure 1, confirm through proton nmr spectra by its structure.Fusing point is 32～34 DEG C.Preparation method is: vitamin A palmitate is dissolved in the mixed solvent of acetone, ethyl acetate and petroleum ether of 20～25 DEG C, filling nitrogen condition borehole cooling to-10～-5 DEG C, growing the grain 1～5 hour, filtration, washing, vacuum drying obtain the light yellow crystalline powder of vitamin A palmitate; In mixed solvent, the volume ratio of acetone, ethyl acetate and petroleum ether is 2～4:1～2:4～6.This compound detects through high performance liquid chromatography, purity 99.8～99.9%, and far above prior art, product quality is higher than national standard.
The invention allows for a kind of vitamin D
2crystalline compounds, the X-ray powder diffraction pattern that use Cu-K alpha ray measures as shown in Figure 2, confirm through proton nmr spectra by its structure.Fusing point is 121～123 DEG C.Preparation method is: by vitamin D
2be dissolved in the mixed solution of dehydrated alcohol and chloroform, the volume ratio of dehydrated alcohol and chloroform is 1～5:1; Filling under nitrogen condition the distilled water that adds while stirring-10～0 DEG C, the volume of distilled water is 1:1～3 with the ratio of dehydrated alcohol and chloroform volume; And be cooled to 0 DEG C, and leaving standstill growing the grain 1～5 hour, filtration, washing, vacuum drying obtain vitamin D
2white crystalline powder.This compound detects through high performance liquid chromatography, and purity 99.6～99.9%, far above prior art.
The preparation of the pharmaceutical composition containing multiple fatsoluble vitamin of the present invention can be aqueous injection or lyophilized injectable powder.In every dosage unit, contain vitamin A palmitate 1.375mg, vitamin D
25 μ g, vitamin e1 5mg, vitamin K
12mg, tween 80 0.02～0.16g.
The present invention passes through vitamin A palmitate and vitamin D
2further purification and refining, reduced the impurity in medicine, the stability containing multivitamin pharmaceutical composition of the present invention is strengthened greatly.In pharmaceutical composition of the present invention, also contain at least one in stabilizing agent, antioxidant, antiseptic, pH adjusting agent, thereby further improve the character of compositions of the present invention.
The present invention is by the improvement to injection preparation, further improve the standard of injection, filtered a filter at low temperature through a room temperature, remove by filter to greatest extent impurity, the polymer etc. that in solution, may cause untoward reaction etc., the security performance of medicine is further strengthened.And the present invention is simple to the operation improving of technique, be suitable for large-scale promotion and application.
Brief description of the drawings:
Fig. 1 is the X-ray powder diffraction pattern that the Cu-K alpha ray of the vitamin A palmitate crystal prepared of embodiment 1 measures;
Fig. 2 is vitamin D prepared by embodiment 3
2the X-ray powder diffraction pattern that the Cu-K alpha ray of crystal measures.
The specific embodiment of the present invention only limits to further explain and explanation the present invention, not to Composition of contents restriction of the present invention.
Detailed description of the invention
Embodiment 1
By vitamin A palmitate material dissolution in the mixed solvent of acetone, ethyl acetate and the petroleum ether of 20 DEG C, the volume ratio of acetone, ethyl acetate and petroleum ether is 1:1:2;
2. filling nitrogen condition borehole cooling to-10 DEG C, leaving standstill growing the grain 5 hours, filtration, washing, vacuum drying obtain cryopreservation after the light yellow crystalline powder of vitamin A palmitate.
This compound crystal detects through high performance liquid chromatography, and purity is 99.92%, yield 97.5%, and the X-ray powder diffraction pattern that use Cu-K alpha ray measures is as shown in Figure 1.
Embodiment 2
By vitamin A palmitate material dissolution in the mixed solvent of acetone, ethyl acetate and the petroleum ether of 20 DEG C, the volume ratio of acetone, ethyl acetate and petroleum ether is 2:1:4;
2. filling nitrogen condition borehole cooling to-8 DEG C, leaving standstill growing the grain 4 hours, filtration, washing, vacuum drying obtain cryopreservation after the light yellow crystalline powder of vitamin A palmitate.
This compound crystal detects through high performance liquid chromatography, and purity is 99.93%, yield 98.2%; The X-ray powder diffraction pattern that use Cu-K alpha ray measures as shown in Figure 1.
Embodiment 3
1. by vitamin D
2solid material is dissolved in the dehydrated alcohol and chloroform mixed solution of 2 DEG C, and the volume ratio of dehydrated alcohol and chloroform is 1:1;
2. filling the distilled water that adds while stirring 0 DEG C under nitrogen condition, the volume of distilled water is 1:1 with the ratio of dehydrated alcohol and chloroform mixed liquor volume, and is cooled to 0 DEG C, leaves standstill growing the grain 5 hours, and filtration, washing, vacuum drying obtain vitamin D
2white crystalline powder.
This compound crystal detects through high performance liquid chromatography, and purity is 99.83%, yield 98.25%; The X-ray powder diffraction pattern that use Cu-K alpha ray measures as shown in Figure 2.
Embodiment 4
1. by vitamin D
2solid material is dissolved in the mixed solution of 5 DEG C of dehydrated alcohol and chloroform, and the volume ratio of dehydrated alcohol and chloroform is 5:1;
2. filling the distilled water that adds while stirring 0 DEG C under nitrogen condition, the volume of distilled water is 1:3 with the ratio of dehydrated alcohol and chloroform volume; And be cooled to 0 DEG C, and leaving standstill growing the grain 5 hours, filtration, washing, vacuum drying obtain vitamin D
2white crystalline powder.
This compound crystal detects through high performance liquid chromatography, and purity is 99.78%, yield 98.55%; The X-ray powder diffraction pattern that use Cu-K alpha ray measures as shown in Figure 2.
Embodiment 5: the preparation of injection
Formula: the vitamin A palmitate compound 600mg that embodiment 1 prepares, the vitamin D that embodiment 3 prepares
2compound 1.5mg, vitamin E 7g, vitamin K1 0.5g, tween 80 50g;
Preparation method is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection 800ml of room temperature, rapid stirring, under the condition of filling nitrogen, inject water and complement to 1000ml, regulating pH value is 6.5～7.0, add 0.01%(w/v) medical activated carbon absorption, filter; Fine straining, embedding, sterilizing.
Be distributed into 2ml dosage: in every dosage unit, contain vitamin A palmitate 1.2mg, vitamin D
23 μ g, vitamin e1 4mg, vitamin K
11mg, tween 80 0.1g.
Embodiment 6: the preparation of injection
Formula: the vitamin A palmitate compound 750mg that embodiment 2 prepares, the vitamin D that embodiment 4 prepares
2crystalline compounds 3.5mg, vitamin E 9g, vitamin K1 1.5g, tween 80 100g;
Preparation method is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection 800ml of room temperature, rapid stirring, under the condition of filling nitrogen, inject water and complement to 1000ml, regulating pH value is 6.5～7.0, add 0.01%(w/v) medical activated carbon absorption, filter; Fine straining, embedding, sterilizing.
Be distributed into 2ml dosage: in every dosage unit, contain vitamin A palmitate 1.5mg, vitamin D
27 μ g, vitamin e1 8mg, vitamin K
13mg, tween 80 0.2g; .
Embodiment 7: the preparation of injection
Formula: the vitamin A palmitate compound 700mg that embodiment 2 prepares, the vitamin D that embodiment 4 prepares
2compound 2.5mg, vitamin E 8g, vitamin K
11.25g, tween 80 80g;
Preparation method is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection 800ml of room temperature, rapid stirring, under the condition of filling nitrogen, inject water and complement to 1000ml, regulating pH value is 6.5～7.0, add 0.01%(w/v) medical activated carbon absorption, filter; Fine straining, embedding, sterilizing.
Be distributed into 2ml dosage: in every dosage unit, contain vitamin A palmitate 1.4mg, vitamin D
25 μ g, vitamin e1 6mg, vitamin K
12.5mg, tween 80 0.16g.
Embodiment 8: the preparation of injection
Formula: vitamin A palmitate crystalline compounds 687.5mg prepared by embodiment 1, vitamin D prepared by embodiment 3
2crystalline compounds 2.5mg, vitamin E 7.5g, vitamin K
11g, tween 80 80g.
Preparation method is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection 800ml of room temperature, rapid stirring, under the condition of filling nitrogen, inject water and complement to 1000ml, regulating pH value is 6.5～7.0, add 0.01%(w/v) medical activated carbon absorption, filter; Fine straining, embedding, sterilizing;
Wherein, the mixing speed of rapid stirring is 360 revs/min; Fine straining is for first adopting 0.22 μ m aperture filter membrane to filter, and adopts 0.22 μ m aperture filter membrane to filter once after filtrate is cooled to 5 DEG C
Be distributed into 2ml dosage: in every dosage unit, contain vitamin A palmitate 1.375mg, vitamin D
25 μ g, vitamin e1 5mg, vitamin K
12mg, tween 80 0.16g.
Embodiment 9: the preparation of lyophilized powder
Formula: vitamin A palmitate crystalline compounds 600mg prepared by embodiment 2, vitamin D prepared by embodiment 4
2crystalline compounds 1.5mg, vitamin E 7g, vitamin K
10.5g, tween 80 100g, sorbitol 50g;
Preparation method is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection 800ml of room temperature, rapid stirring, add again the sorbitol of recipe quantity to stir to inject water under the condition of filling nitrogen and complement to 1000ml, regulating pH value is 6.5～7.0, add 0.01%(w/v) medical activated carbon absorption, filter; Fine straining, subpackage, partly jump a queue, lyophilization, tamponade;
Lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: shelf temperature is down to-25 DEG C with the speed of 3.0 DEG C/min, stops cooling, be incubated 2 hours, then be cooled to-50～-55 DEG C with the speed of 6.0 DEG C/min, evacuation;
The primary drying stage: shelf temperature is slowly risen to-10 DEG C with the speed of 0.5 DEG C/min, be incubated 1 hour;
The redrying stage: shelf temperature is risen to 20 DEG C with the speed of 0.8 DEG C/min, be incubated 2 hours, shelf continues to rise to 40 DEG C with the speed of 0.5 DEG C/min.
Be distributed into 2ml dosage: in every dosage unit, contain vitamin A palmitate 1.2mg, vitamin D
23 μ g, vitamin e1 4mg, vitamin K
11mg, tween 80 0.2g, sorbitol 0.1g.
Embodiment 10
Formula: vitamin A palmitate crystalline compounds 687.5mg prepared by embodiment 1, the vitamin D obtaining prepared by embodiment 3
2crystalline compounds 2.5mg, vitamin E 7.5g, vitamin K
11g, tween 80 80g, sorbitol 50g;
Preparation method is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection 800ml of room temperature, and rapid stirring, then add the sorbitol of recipe quantity to stir; Under the condition of filling nitrogen, inject water and complement to 1000ml, regulating pH value is 6.5～7.0, adds 0.01%(w/v) medical activated carbon absorption, filter; Fine straining, subpackage, partly jump a queue, lyophilization, tamponade;
Lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: shelf temperature is down to-25 DEG C with the speed of 3.0 DEG C/min, stops cooling, be incubated 2 hours, then be cooled to-50～-55 DEG C with the speed of 6.0 DEG C/min, evacuation;
The primary drying stage: shelf temperature is slowly risen to-10 DEG C with the speed of 0.5 DEG C/min, be incubated 1 hour;
The redrying stage: shelf temperature is risen to 20 DEG C with the speed of 0.8 DEG C/min, be incubated 2 hours, shelf continues to rise to 40 DEG C with the speed of 0.5 DEG C/min.
Be distributed into 2ml dosage: in every dosage unit, contain vitamin A palmitate 1.375mg, vitamin D
25 μ g, vitamin e1 5mg, vitamin K
12mg, tween 80 0.16g, sorbitol 0.1g.
Wherein, the mixing speed of rapid stirring is 360 revs/min; Fine straining is for first adopting 0.22 μ m aperture filter membrane to filter, and adopts 0.22 μ m aperture filter membrane to filter once after filtrate is cooled to 1 DEG C
Experimental example 1: stability test
1. hot test
Get that embodiment 8 prepares containing three batches 101 of the liquid drugs injections of multiple fatsoluble vitamin, 102,103, simulation listing packaging, put in sealing clean container, at 40 ± 2 DEG C of temperature, place 10 days, in the 5th day and sampling in the 10th day, detect result of the test and comparison in 0 day by stability high spot reviews project.
2. high humility test
Get that embodiment 8 prepares containing three batches 101 of the liquid drugs injections of multiple fatsoluble vitamin, 102,103, simulation listing packaging, put in sealing clean container, under the condition of 25 ± 2 DEG C of relative humiditys 90% ± 5%, place 10 days, in the 5th day and sampling in the 10th day, detect result of the test and comparison in 0 day by stability high spot reviews project.
3. strong illumination test
Get that embodiment 8 prepares containing three batches 101 of the liquid drugs injections of multiple fatsoluble vitamin, 102,103, simulation listing packaging, put in sealing clean container, be placed under the condition that illumination is 4500lx and place 10 days, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stability high spot reviews project.
Influence factor's result of the test is as shown in table 1.
Table 1:
Result shows: the multiple fatsoluble vitamin aqueous injection that the present invention prepares, and its stability is good, and under high temperature, high humidity, intense light irradiation condition, all retention is stable.
Prepared by other embodiment of the present invention carries out influence factor's experiment containing multiple fatsoluble vitamin aqueous injection, has obtained identical experimental result.In order to save the length of application documents, only provide the experimental result in embodiment 8 at this.But can not think at this point and only have this embodiment can reach this technique effect.
Experimental example 2: accelerate experiment
Get embodiment 8 gained containing three batches 201,202,203 of multiple fatsoluble vitamin aqueous injection, simulation listing packaging, put in sealing clean container, under 42 DEG C, 80%RH condition, place 6 months,, respectively at sampling once 1,2,3,6 the end of month each stability high spot reviews project is tested at duration of test.
Particulate matter adopts light blockage method to detect.Result of the test is as shown in table 2.
Table 2:
Result shows: the multiple fatsoluble vitamin aqueous injection that the present invention prepares, known through accelerated test result, its stability is good.
Prepared by other embodiment of the present invention accelerates experiment containing multiple fatsoluble vitamin aqueous injection, has obtained identical experimental result.In order to save the length of application documents, only provide the experimental result of embodiment 8 at this.But can not think at this point and only have this embodiment can reach this technique effect.
Experimental example 3: long term test
Get three batches 301,302,303 of multiple fatsoluble vitamin aqueous injection of embodiment 8 gained, simulation listing packaging, put in sealing clean container, under 20 DEG C ± 2 DEG C conditions of temperature, place 18 months,, respectively at sampling once the 3rd, 6,9,12,18 the end of month each inspection item are tested at duration of test.Result of the test is as shown in table 3:
Table 3:
Result shows: what the present invention prepared contains multiple fatsoluble vitamin aqueous injection, and known through long-term test results, its stability is good, and all retention is stable.
Prepared by other embodiment of the present invention carries out long-term experiment containing multiple fatsoluble vitamin aqueous injection, has obtained identical experimental result.In order to save the length of application documents, only provide the experimental result of embodiment 8 at this.But can not think at this point and only have this embodiment can reach this technique effect.
Experimental example 4: lyophilized injectable powder stability test
1. hot test
Get three batches 101 of the multiple fat-soluble vitamin freeze-dried powder needles, 102,103 that embodiment 10 prepares, simulation listing packaging, put in sealing clean container, at 40 ± 2 DEG C of temperature, place 10 days, in the 5th day and sampling in the 10th day, detect result of the test and comparison in 0 day by stability high spot reviews project.
2. high humility test
Get three batches 101 of the multiple fat-soluble vitamin freeze-dried powder needles, 102,103 that embodiment 10 prepares, simulation listing packaging, put in sealing clean container, under the condition of 25 ± 2 DEG C of relative humiditys 90% ± 5%, place 10 days, in the 5th day and sampling in the 10th day, detect result of the test and comparison in 0 day by stability high spot reviews project.
3. strong illumination test
Get three batches 101 of the multiple fat-soluble vitamin freeze-dried powder needles, 102,103 that embodiment 10 prepares, simulation listing packaging, put in sealing clean container, be placed under the condition that illumination is 4500lx and place 10 days, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stability high spot reviews project.
Influence factor's result of the test is as shown in table 4.
Table 4:
Result shows: what the present invention prepared contains multiple fat-soluble vitamin freeze-dried powder needle, and its stability is good, and under high temperature, high humidity, intense light irradiation condition, all retention is stable.
Prepared by other embodiment of the present invention carries out influence factor's experiment containing multiple fat-soluble vitamin freeze-dried powder needle, has obtained identical experimental result.In order to save the length of application documents, only provide the experimental result in embodiment 10 at this.But can not think at this point and only have this embodiment can reach this technique effect.
Experimental example 5: lyophilized powder accelerates experiment
Get three batches 201,202,203 of multiple fat-soluble vitamin freeze-dried powder needle agent of embodiment 10 gained, simulation listing packaging, put in sealing clean container, under 42 DEG C, 80%RH condition, place 6 months,, respectively at sampling once 1,2,3,6 the end of month each stability high spot reviews project is tested at duration of test.
Particulate matter adopts light blockage method to detect.Result of the test is as shown in table 5.
Table 5:
Result shows: the freeze-dried powder containing multiple fatsoluble vitamin that the present invention prepares, known through accelerated test result, its stability is good.
Prepared by other embodiment of the present invention accelerates experiment containing multiple fat-soluble vitamin freeze-dried powder needle, has obtained identical experimental result.In order to save the length of application documents, only provide the experimental result of embodiment 10 at this.But can not think at this point and only have this embodiment can reach this technique effect.
Experimental example 6: lyophilized powder long term test
Get three batches 301,302,303 of multiple fat-soluble vitamin freeze-dried powder needle agent of embodiment 10 gained, simulation listing packaging, put in sealing clean container, under 20 DEG C ± 2 DEG C conditions of temperature, place 18 months,, respectively at sampling once the 3rd, 6,9,12,18 the end of month each inspection item are tested at duration of test.
Particulate matter adopts light blockage method to detect.Result of the test is as shown in table 6:
Table 6:
Result shows: what the present invention prepared contains multiple fat-soluble vitamin freeze-dried powder needle, and known through long-term test results, its stability is good, and all retention is stable.
Multiple fat-soluble vitamin freeze-dried powder needle prepared by other embodiment of the present invention carries out long-term experiment, has obtained identical experimental result.In order to save the length of application documents, only provide the experimental result of embodiment 10 at this.But can not think at this point and only have this embodiment can reach this technique effect.
Experimental example 7: contrast test
Comparative example 1, commercially available vitamin A palmitate (Wuhan prosper together bio tech ltd, lot number 20120601), commercially available vitamin D
2(Zhengzhou Tian Yao Science and Technology Ltd., lot number 20120505) prepares aqueous injection according to the preparation method of embodiment 8;
Comparative example 2: prepare fatsoluble vitamin injection (II) according to the method for embodiment 1 in patent 201110387733.1;
Get the multiple fatsoluble vitamin aqueous injection of embodiment 8 gained, simulation listing packaging;
Above-mentioned preparation is put in sealing clean container, under 42 DEG C, 80%RH condition, places 6 months,, respectively at sampling once 1,2,3,6 the end of month each stability high spot reviews project is tested at duration of test.Result of the test is as shown in table 7.
Table 7:
Result shows: the multiple fatsoluble vitamin aqueous injection that the present invention prepares, known through accelerated test result, its stability is good, is better than comparative example preparation.The aqueous injection that marketable material adopts preparation method of the present invention to prepare, its insoluble granule is less than comparative example 2, illustrates that the preparation method of preparing aqueous injection of the present invention can effectively reduce the insoluble granule in injection, thereby makes clinical use more safe and reliable.
Experimental example 8: lyophilized powder accelerates experiment
Comparative example 1, commercially available vitamin A palmitate (Wuhan prosper together bio tech ltd, lot number 20120601), commercially available vitamin D
2(Zhengzhou Tian Yao Science and Technology Ltd., lot number 20120505) prepares lyophilized injectable powder according to the preparation method of embodiment 10;
Comparative example 2: the method according to embodiment 1 in patent 201010575712.8 is prepared fat-soluble vitamin freeze-dried powder needle agent;
Comparative example 3: the method according to embodiment 2 in patent 200910089635.2 is prepared fat-soluble vitamin freeze-dried powder needle agent;
Get the multiple fat-soluble vitamin freeze-dried powder needle agent of embodiment 10 gained, simulation listing packaging;
Above-mentioned preparation is put in sealing clean container, under 42 DEG C, 80%RH condition, placed 6 months,, respectively at sampling once 1,2,3,6 the end of month each stability high spot reviews project is tested at duration of test.Result of the test is as shown in table 8.
Table 8:
Result shows: the multiple fat-soluble vitamin freeze-dried powder needle that the present invention prepares, known through accelerated test result, its stability is good.The lyophilized injection that marketable material adopts preparation method of the present invention to prepare, its insoluble granule is less than comparative example 2,3, illustrate that the preparation method of preparing lyophilized injection of the present invention can effectively reduce the insoluble granule in injection, thereby make clinical use more safe and reliable.
Experimental example 9: dissolubility contrast experiment
Adopt the multiple fat-soluble vitamin freeze-dried powder needle of embodiment 9,10 preparations, prepare comparative example 1～3 according to the method for experimental example 8, under identical condition, test.
Get freeze-dried powder 2g prepared by each preparation, add the water for injection of 10ml, according to the jolting of obtain solution conventional method, under identical experiment condition, its dissolving situation is measured, experimental result is in table 9;
Table 9:
| 25 DEG C of dissolution times (s) | |
| Embodiment 9 | Within 5 seconds, dissolve solution clarification completely |
| Embodiment 10 | Within 5 seconds, dissolve solution clarification completely |
| Comparative example 1 | Within 21 seconds, dissolve solution clarification completely |
| Comparative example 2 | Within 15 seconds, dissolve solution clarification completely |
| Comparative example 3 | Within 12 seconds, dissolve solution clarification completely |
Known according to dissolution experiment, prepared by the present invention lyophilized injectable powder, solubility is good, is better than prior art.
Experimental example 10: the screening experiment of activated carbon concentration
Other technological parameter, all with embodiment 8, selects respectively the injection active carbon of variable concentrations to adsorb, with vitamin D
2productive rate, purity for investigating index, the consumption of screening active carbon.The results are shown in Table 10:
Table 10: activated carbon dosage screening test
| Concentration of activated carbon (w/v) % | Productive rate (%) | Purity (%) |
| 0.1 | 90.2 | 99.72 |
| 0.05 | 92.6 | 99.80 |
| 0.03 | 94.2 | 99.92 |
| 0.02 | 95.5 | 99.95 |
| 0.01 | 98.5 | 99.99 |
By drawing in table, 0.01% the passable vitamin D of active carbon
2it is best that purity and yield reach, to vitamin D
2adsorbing littlely, and pollute minimumly, is 0.01%(g/ml so select concentration) active carbon adsorb the while under this concentration of activated carbon, to vitamin A palmitate, vitamin E and vitamin K
1adsorbance all less.
Claims (13)
1. containing a pharmaceutical composition for multiple fatsoluble vitamin, it is characterized in that, described compositions is by vitamin A palmitate 650～700mg, vitamin D
21.5～6mg, vitamin E 5000～8000mg, vitamin K
1500～1000mg, tween 80 10～80g composition; The X-ray powder diffraction pattern that described vitamin A palmitate compound use Cu-K alpha ray measures as shown in Figure 1; Described vitamin D
2the X-ray powder diffraction pattern that compound use Cu-K alpha ray measures as shown in Figure 2.
2. the pharmaceutical composition containing multiple fatsoluble vitamin according to claim 1, described compositions is by vitamin A palmitate 687.5mg, vitamin D
22.5mg, vitamin E 7500mg, vitamin K
11000mg and tween 80 10～80g composition.
3. the pharmaceutical composition containing multiple fatsoluble vitamin according to claim 1, it is characterized in that, the preparation method of described vitamin A palmitate compound comprises the following steps: vitamin A palmitate is dissolved in the mixed solvent of acetone, ethyl acetate and petroleum ether of 20～25 DEG C, filling nitrogen condition borehole cooling to-10～-5 DEG C, leave standstill growing the grain 1～5 hour, filtration, washing, vacuum drying obtain the light yellow crystalline powder of vitamin A palmitate.
4. the pharmaceutical composition containing multiple fatsoluble vitamin according to claim 3, is characterized in that, in described mixed solvent, the volume ratio of acetone, ethyl acetate and petroleum ether is 2～4:1～2:3～6.
5. the pharmaceutical composition containing multiple fatsoluble vitamin according to claim 4, is characterized in that, in described mixed solvent, the volume ratio of acetone, ethyl acetate and petroleum ether is 2～4:1～2:4～6.
6. the pharmaceutical composition containing multiple fatsoluble vitamin according to claim 1, is characterized in that described vitamin D
2the preparation method of compound is: by vitamin D
2be dissolved in the mixed solution of 0～5 DEG C of dehydrated alcohol and chloroform, add while stirring the distilled water of 0 DEG C filling, and be cooled to 0 DEG C under nitrogen condition, leave standstill growing the grain 1～5 hour, filtration, washing, vacuum drying obtain vitamin D
2white crystalline powder.
7. the pharmaceutical composition containing multiple fatsoluble vitamin according to claim 6, is characterized in that, in described mixed solution, the volume ratio of dehydrated alcohol and chloroform is 1～5:1～2; The volume of described distilled water is 1:1～3 with the ratio of dehydrated alcohol and chloroform mixed liquor volume.
8. the pharmaceutical composition containing multiple fatsoluble vitamin according to claim 7, is characterized in that, in described mixed solution, the volume ratio of dehydrated alcohol and chloroform is 1～5:1.
9. a preparation for the pharmaceutical composition containing multiple fatsoluble vitamin as claimed in claim 1, is characterized in that, described preparation is aqueous injection or lyophilized injectable powder; In described preparation, in every dosage unit, contain vitamin A palmitate 1.2～1.5mg, vitamin D
23～24 μ g, vitamin E 6～16mg, vitamin K
10.1～2.4mg, tween 80 20～200mg.
10. preparation according to claim 9, is characterized in that, contains vitamin A palmitate 1.3～1.4mg, vitamin D in described preparation in every dosage unit
23～12 μ g, vitamin e1 0～16mg, vitamin K
11～2mg, tween 80 20～160mg.
11. preparations according to claim 9, is characterized in that, contain vitamin A palmitate 1.375mg, vitamin D in described preparation in every dosage unit
25 μ g, vitamin e1 5mg, vitamin K
12mg, tween 80 20～160mg.
12. according to the preparation described in the arbitrary claim of claim 9～11, it is characterized in that, also contains excipient in described preparation.
13. 1 kinds of preparation methoies of preparation as claimed in claim 12, is characterized in that:
The preparation method of liquid drugs injection is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection of 80% recipe quantity of room temperature, rapid stirring, under the condition of filling nitrogen, inject water and complement to full dose, regulating pH value is 6.5～7.5, add the medical activated carbon absorption of 0.01% mass volume ratio, filter; Fine straining, embedding, sterilizing;
The preparation method of freeze-dried powder is: after taking and adding tween 80 to stir the vitamin of recipe quantity, under the condition of filling nitrogen, add the water for injection of 80% recipe quantity of room temperature, and rapid stirring, then add the sorbitol of recipe quantity to stir; Under the condition of filling nitrogen, inject water and complement to full dose, regulating pH value is 6.5～7.5, adds the medical activated carbon absorption of 0.01% mass volume ratio, filters; Fine straining, subpackage, partly jump a queue, lyophilization, tamponade;
Lyophilization is divided into pre-freeze, primary drying and redrying three phases;
The pre-freeze stage: shelf temperature is down to-25～-20 DEG C with the speed of 3.0 DEG C/min, stops cooling, be incubated 1～2 hour, then be cooled to-50～-55 DEG C with the speed of 6.0 DEG C/min, evacuation;
The primary drying stage: shelf temperature is slowly risen to-10～-5 DEG C with the speed of 0.5 DEG C/min, be incubated 1～2 hour;
The redrying stage: shelf temperature is risen to 15～20 DEG C with the speed of 0.8 DEG C/min, be incubated 1～2 hour, shelf continues to rise to 40 DEG C with the speed of 0.5 DEG C/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310149980.7A CN103230402B (en) | 2013-04-26 | 2013-04-26 | Drug composition containing various lipid-soluble vitamins and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310149980.7A CN103230402B (en) | 2013-04-26 | 2013-04-26 | Drug composition containing various lipid-soluble vitamins and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103230402A CN103230402A (en) | 2013-08-07 |
| CN103230402B true CN103230402B (en) | 2014-10-08 |
Family
ID=48878520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310149980.7A Expired - Fee Related CN103230402B (en) | 2013-04-26 | 2013-04-26 | Drug composition containing various lipid-soluble vitamins and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103230402B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940557A (en) * | 2009-07-10 | 2011-01-12 | 华北制药集团制剂有限公司 | Method for preparing fat-soluble vitamin freeze-dried powder injection |
| CN102657663A (en) * | 2012-04-18 | 2012-09-12 | 宁辉 | Fat-soluble composite vitamin I composition freeze-dried powder injection and preparation method thereof |
-
2013
- 2013-04-26 CN CN201310149980.7A patent/CN103230402B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940557A (en) * | 2009-07-10 | 2011-01-12 | 华北制药集团制剂有限公司 | Method for preparing fat-soluble vitamin freeze-dried powder injection |
| CN102657663A (en) * | 2012-04-18 | 2012-09-12 | 宁辉 | Fat-soluble composite vitamin I composition freeze-dried powder injection and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| Crystalline Aliphatic Esters of Vitamin A;James G. Baxter等;《Journal of the American Chemical Society》;19421031;第64卷(第10期);2407-2410 * |
| James G. Baxter等.Crystalline Aliphatic Esters of Vitamin A.《Journal of the American Chemical Society》.1942,第64卷(第10期),2407-2410. |
| S. E. Hull等.The Crystal and Molecular Structure of Ergocalciferol (Vitamin D2).《Acta Cryst.》.1976,(第B32期),2374-2381. |
| The Crystal and Molecular Structure of Ergocalciferol (Vitamin D2);S. E. Hull等;《Acta Cryst.》;19761231(第B32期);2374-2381 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103230402A (en) | 2013-08-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105287666B (en) | A kind of preparation method of Seabuckthorm Seed Oil | |
| JPH0249091A (en) | Astaxanthin-containing composition | |
| US10314915B2 (en) | Catechin bioavailability enhancer comprising cyclodextrin | |
| CN101883575A (en) | Guava extract | |
| KR20220082812A (en) | Xanthophyll composition with enhanced bioavailability comprising lutein and zeaxanthin | |
| CN101982176B (en) | Compound sodium selenite-vitamin E oral nano-emulsion preparation for livestock and preparation method thereof | |
| US20190223486A1 (en) | Catechin absorption enhancer for enhancing catechin absorption in small intestinal epithelial cells | |
| CN103191134B (en) | Pharmaceutical composition of lipid-soluble vitamin and preparation method thereof | |
| CN103230402B (en) | Drug composition containing various lipid-soluble vitamins and preparation thereof | |
| US20160297971A1 (en) | Anti-angiogenesis agent, cosmetic, medicine, crystallized red pigment, composition, and food comprising extract or red pigment from saw palmetto fruit and method of producing thereof | |
| KR20120086438A (en) | Cosmetic composition for slimming comprising Salicornia herbacea L. and Rosa rugosa THUNB extract | |
| KR20150139025A (en) | Moringa extracts having anti-oxidant and anti-diabetic activity | |
| CN104274826B (en) | A kind of oil-in-water type compound colistin nano-emulsion | |
| KR101820944B1 (en) | Companion animal ophthalmology disease management assistance nutrient and the manufacture Method | |
| TWI576118B (en) | Neovascularization inhibitor including ethanol extract or red pigment of serenoa repens fruit, cosmetic, medicine, crystallized red pigment, composition and food and method of fabricating the same | |
| JP5893438B2 (en) | Retinopathy preventive or ameliorating agent | |
| JP6224899B2 (en) | Hypoglycemic agent | |
| EP1864658A1 (en) | Agent for alleviating vascular insufficiency | |
| CN107648307B (en) | Composition, preparation method and application thereof | |
| JP2006290807A (en) | Composition having lipase inhibiting activity and antioxidation activity | |
| JP2010043036A (en) | Saccharometabolism promoter | |
| CN101129374B (en) | Vinflunine pharmaceutical composition and method of producing the same and application of the same | |
| JP2010105984A (en) | Oral administration composition | |
| EL Bazzar et al. | Pharmacodynamics evaluation of Eggplant wastes formulated as lyophilized tablets in an attempt for preparation of a bioactive natural antidiabetic dosage form | |
| CN110101681B (en) | Method for preparing microparticles for improving bioavailability of pitaya gamma-tocopherol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20141008 Termination date: 20200426 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |