CN1923207A - Compound recipe vitamin freeze-dried powder for injection and its preparing process - Google Patents
Compound recipe vitamin freeze-dried powder for injection and its preparing process Download PDFInfo
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- CN1923207A CN1923207A CN 200510029352 CN200510029352A CN1923207A CN 1923207 A CN1923207 A CN 1923207A CN 200510029352 CN200510029352 CN 200510029352 CN 200510029352 A CN200510029352 A CN 200510029352A CN 1923207 A CN1923207 A CN 1923207A
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Abstract
The invention relates to a composite vitamin freeze dried and relative production. Wherein, said method comprises (1), adding alcohol dissolved with antihypertensive, with vitamin A palmitate, vitamin D2, vitamin E acetic ester and vitamin K1, and adding 10% injection water, adding stabilizer and dissolving; (2), dissolving support agent into 70% injection water, adding 0.01-0.1% active carbon, mixing for 5-30mins, filtering, and collecting acetic ester; (3), mixing the products of steps (1, 2), adding injection water to full, using pH adjuster to adjust the pH valve to 7.4-7.6, using 0.2-0.4 mum porous membrane to filter, and freezing. The invention has fine frozen crystal, quick dissolution, and highs stability.
Description
Technical field
The present invention relates to a kind of vitamin freeze-dried powder for injection and preparation method thereof, relate to compound vitamin lyophilized formulations and preparation method thereof particularly.
Background technology
Every compound vitamin contains vitamin A palmitate 2500IU, vitamin D
2200IU, Vitamin E acetate 15mg, vitamin K
12mg, clinical being used for can not replenish outside the intestinal of the normal patient's vitamin A of taking food of digestive tract, D, E, K.The compound vitamin injection goes on the market, but because vitamin ties up in the aqueous solution easily oxidation, and therefore stability is to need the problem that solves always.In addition, redissolution speed is the problem that freeze-dried powder runs into often.Therefore develop and a kind ofly not only stablized redissolution speed but also fast compound vitamin preparation has far-reaching clinical meaning.(annotate: 1 iu (IU) vitamin A is equivalent to 0.55 μ g vitamin cetylate; The biological value of the pure product 0.025 μ g of vitamin D2 is 1 iu (IU)).
Summary of the invention
The invention provides a kind of compound vitamin freeze-dried powder to overcome the existing defective of existing compound vitamin injection.
Another technical problem that the present invention need solve provides the preparation method of compound vitamin freeze-dried powder.
The component and the parts by weight of compound vitamin freeze-dried powder of the present invention comprise:
Vitamin A palmitate 0.61875g (1125000IU)～0.75625g (1375000IU)
Vitamin D
20.00225g (90000IU)～0.00275g (110000IU)
Vitamin E acetate 6.75g～8.25g
Vitamin K
10.9g～1.1g
Cosolvent 35.5g～58.5g
The pH regulator agent;
The consumption of pH regulator agent is that to make the pH that contains the aqueous solution of above-mentioned raw materials before the lyophilizing be 7.4～7.6;
Said cosolvent is soybean phospholipid or lecithin;
Said pH regulator agent is selected from a kind of or its mixture in sodium hydroxide or the potassium hydroxide;
Compound vitamin freeze-dried powder provided by the invention can also contain stabilizing agent and/or proppant.
Stabilizing agent is selected from one or more in cholic acid, ascorbic acid, butylhydroxy anisole (BHA), the dibenzylatiooluene (BHT), and it is 2～5: 1 with the drug weight ratio, is preferably 3～4: 1;
Proppant is selected from one or more in mannitol or the glucose, and it is 10～30: 1 with the drug weight ratio, is preferably 15～25: 1;
Said drug weight refers to vitamin A palmitate, vitamin D
2, Vitamin E acetate and vitamin K
1Weight.
The preparation method of the said lyophilized preparation of the present invention comprises the steps:
(1) ethanol of cosolvent be will be dissolved with, vitamin A palmitate, vitamin D added
2, Vitamin E acetate and vitamin K
1, add 10% water for injection of full dose again, add stabilizing agent, dissolving;
(2) proppant is dissolved in 70% the water for injection of full dose, the pin that adds gross weight 0.01～0.1% stirred 5～30 minutes with activated carbon, filtered, and collected filtrate;
(3) product with step (1) and step (2) mixes, and adds to the full amount of water for injection, and the pH that regulates mixture with the pH regulator agent is 7.4～7.6, and with 0.2～0.4 μ m filtering with microporous membrane, lyophilizing promptly;
Before the lyophilizing, in the water for injection, vitamin A palmitate, vitamin D
2, Vitamin E acetate and vitamin K
1Bulking value concentration be 40～80g/1000ml;
Freeze drying process:
At first start cools the temperature to-35 ℃, pre-freeze 3～5h, preferred 4h.Pre-freeze is to the stipulated time, and the observation sample outward appearance is found to freeze reality, freezes good forming ability.Begin evacuation then, make drying sublimation.
Sublimation temperature is respectively:
-35℃～-25℃、-20℃～15℃、-10℃、-5℃、0℃、10℃、20℃～28℃、25℃～30℃。
Each temperature duration is respectively:
2～3h、1～2h、2～3h、2～3h、1～2h、3～6h、2～3h、3～5h。
Adopt freeze drying process provided by the invention, the obtained freeze-drying product freezes brilliant tiny, dissolves during recovery soon, and the uniform and stable property of composition in the goods is good.
The specific embodiment
Embodiment 1
Prescription:
Vitamin A palmitate 0.61875g (1125000IU)
Vitamin D
20.00225g (90000IU)
Vitamin E acetate 6.75g
Vitamin K
10.9g
Mannitol 150g
Soybean phospholipid 25g
Cholic acid 18.85g
Technology:
The immersion of 25g soybean phospholipid is dissolved in 5ml ethanol; Add vitamin A palmitate 0.61875g (1125000IU), vitamin D
20.00225g (90000IU), Vitamin E acetate 6.75g, vitamin K
10.9g four kinds of vitamin add 100ml water for injection again, add 18.85g cholic acid, stirring and dissolving.Add 150g mannitol in 700ml water for injection, add 0.1% pin and stirred 10 minutes, filter decarburization with activated carbon; With the two mixing, regulate pH 7.5 with the 1.0mol/L sodium hydroxide solution, add the injection water to 1000ml, with 0.22 μ m filtering with microporous membrane, middle product are checked, fine straining, fill, lyophilizing are promptly.Sublimation temperature in the freeze-drying process is respectively:
-35℃～-25℃、-20℃～15℃、-10℃、-5℃、0℃、10℃、20℃～28℃、25℃～30℃；
Each temperature duration is respectively;
2.5h、1.5h、1.5h、1.5h、1.5h、4.5h、2.5h、3h。
Embodiment 2
The preparation freeze-dried powder
Vitamin A palmitate 0.6875g (1250,000IU)
Vitamin D
20.0025g (100,000IU)
Vitamin E acetate 7.5g
Vitamin K
11g
Mannitol 125g
Soybean phospholipid 30g
Cholic acid 18.9g
Technology:
The immersion of 30g soybean phospholipid is dissolved in 5ml ethanol; Add vitamin A palmitate, vitamin D
20.0025g (100,000IU), Vitamin E acetate 7.5g, vitamin K
1Four kinds of vitamin of 1g add 100ml water for injection again, add 18.9g cholic acid, stirring and dissolving.Add 125g mannitol in 700ml water for injection, add 0.1% pin and stirred 10 minutes, filter decarburization with activated carbon; With the two mixing, regulate pH 7.5 with the 1.0mol/L sodium hydroxide solution, add the injection water to 1000ml, with 0.22 μ m filtering with microporous membrane, middle product are checked, fine straining, fill, lyophilizing are promptly.Sublimation temperature in the freeze-drying process is respectively:
-35℃～-25℃、-20℃～15℃、-10℃、-5℃、0℃、10℃、20℃～28℃、25℃～30℃；
Each temperature duration is respectively:
2.5h、1.5h、1.5h、1.5h、1.5h、4.5h、2.5h、3h。
Preparation method is with embodiment 1.
Embodiment 3
Vitamin A palmitate 0.75625g (1375000IU)
Vitamin D
20.00275g (110000IU)
Vitamin E acetate 8.25g
Vitamin K
11.1g
Mannitol 130g
Soybean phospholipid 36g
Cholic acid 19g
Technology:
The immersion of 36g soybean phospholipid is dissolved in 5ml ethanol; Add vitamin A palmitate 0.75625g (1375000IU), vitamin D
20.00275g (110000IU), Vitamin E acetate 8.25g, vitamin K
11.1g four kinds of vitamin add 100ml water for injection again, add 19g cholic acid, stirring and dissolving.Add 130g mannitol in 700ml water for injection, add 0.1% pin and stirred 10 minutes, filter decarburization with activated carbon; With the two mixing, regulate pH 7.5 with the 1.0mol/L potassium hydroxide solution, add the injection water to 1000ml, with 0.22 μ m filtering with microporous membrane, middle product are checked, fine straining, fill, lyophilizing are promptly.Sublimation temperature in the freeze-drying process is respectively:
-35℃～-25℃、-20℃～15℃、-10℃、-5℃、0℃、10℃、20℃～28℃、25℃～30℃；
Each temperature duration is respectively:
2.5h、1.5h、1.5h、1.5h、1.5h、4.5h、2.5h、3h。
Embodiment 4
Chemical stability test (test items such as high temperature, illumination quality standard result relatively)
Press the prescription of embodiment 1, measure 0.5ml ethanol, add and soak dissolving in the 3g soybean phospholipid; Adding vitamin A palmitate 0.06875g (125,000IU), vitamin D
20.00025g (10,000IU), Vitamin E acetate 0.75g, vitamin K
10.1g four kinds of vitamin add 10ml water for injection again, add 1.89g cholic acid, stirring and dissolving.Add 15g mannitol in 70ml water for injection, add 0.1% pin and stirred 10 minutes, filter decarburization with activated carbon; With the two mixing, regulate pH 7.5 with the 1.0mol/L sodium hydroxide solution, add the injection water to 100ml, with every fill of 2ml.Make 50 compound vitamin injections, placing 60 ℃ of calorstats and light intensity respectively is that the 4500LX growth cabinet carries out stability test;
Get the product of embodiment 1, with every fill of 2ml, lyophilizing.Make 50 compound recipe vitamin freeze-dried powder for injection, placing 60 ℃ of calorstats and light intensity respectively is that the 4500LX growth cabinet carries out stability test, measure 5 days and 10 days sample sizes with the HPLC method, with compared in 0 day, investigate compound vitamin injection and compound recipe vitamin freeze-dried powder for injection stability.
Experimental result is as follows: (n=50)
| The influence factor | 60℃ | Illumination (4500LX) | ||||
| Time | 0 day | 5 days | 10 days | 0 day | 5 days | 10 days |
| The injection meansigma methods | 100％ | 95％ | 85％ | 100％ | 96％ | 89％ |
| The freeze-dried powder meansigma methods | 100％ | 98％ | 98％ | 100％ | 100％ | 99％ |
Experimental result shows that compound vitamin freeze-dried powder provided by the invention is more stable than its compound vitamin injection.
Meansigma methods refers to each content will measure 3 data, asks its meansigma methods again.
Embodiment 5
Different temperature fall times of lyophilizing stage are to the influence experiment of lyophilizing sample rehydration speed
Press the method for embodiment 1, measure 0.5ml ethanol, add and soak dissolving in the 2.5g soybean phospholipid; Adding vitamin A palmitate 0.06875g (125,000IU), vitamin D
20.00025g (10,000IU), Vitamin E acetate 0.75g, vitamin K
10.1g four kinds of vitamin add 10ml water for injection again, add 1.885g cholic acid, stirring and dissolving.Add 15g mannitol in 70ml water for injection, add 0.1% pin and stirred 10 minutes, filter decarburization with activated carbon; With the two mixing, regulate pH7.6 with the 1.0mol/L sodium hydroxide solution, add the injection water to 100ml, with 0.22 μ m filtering with microporous membrane, make 50 in sample, divide 3 groups, wherein 1,2 group is relatively more conventional freeze drying process.
(1) start cools the temperature to-35 ℃, pre-freeze 4h (comprising temperature fall time).
Pre-freeze is to the stipulated time, and the observation sample outward appearance is found to freeze reality, freezes good forming ability.Begin evacuation then, make drying sublimation.
Sublimation temperature is respectively :-10 ℃ 0 ℃ 10 ℃ 28 ℃ 30 ℃
Each temperature duration is respectively: 7h 3h 5h 3h 3h
The result: the lyophilizing formability is better, but serious " overlap " phenomenon is arranged, and inside is damp, and outside one deck is little hard, rehydration time 25 seconds.
(2) start cools the temperature to-35 ℃, pre-freeze 4h (comprising temperature fall time).
Pre-freeze is to the stipulated time, and the observation sample outward appearance is found to freeze reality, freezes good forming ability.Begin evacuation then, make drying sublimation.
Sublimation temperature is respectively :-20 ℃ 10 ℃ 30 ℃
Each temperature duration is respectively: 8h 7h 7h
The result: the lyophilizing formability is better, does not have " overlap " phenomenon, but the still little tide in inside, rehydration time is 26 seconds.
(3) start cools the temperature to-35 ℃, pre-freeze 4h (comprising temperature fall time).
Pre-freeze is to the stipulated time, and the observation sample outward appearance is found to freeze reality, freezes good forming ability.Begin evacuation then, make drying sublimation.
Sublimation temperature is respectively :-25 ℃-20 ℃-10 ℃-5 ℃ 0 ℃ 10 ℃ 28 ℃ 30 ℃
Each temperature duration is respectively: 2h 1h 3h 3h 2h 5h 2h 5h
The result: the lyophilizing formability is better, does not have " overlap " phenomenon, and inside is not moist, the no duricrust in surface.Sample is orange-yellow loose block, surfacing, and jolting is non-friable.Add water, can disperse rapidly.The solution clarification does not wherein have insoluble matter and granule, and rehydration time is 11 seconds.
As seen, implement the temperature-rising method that the multistage temperature keeps, the effect that product appearance, rehydration time are all produced.
Claims (8)
1. a compound recipe vitamin freeze-dried powder for injection is characterized in that, component and parts by weight comprise:
Vitamin A palmitate 0.61875g (1125000IU)～0.75625g (1375000IU)
Vitamin D
20.00225g (90000IU)～0.00275g (110000IU)
Vitamin E acetate 6.75g～8.25g
Vitamin K
10.9g～1.1g
Cosolvent 16.5g～40.5g
The pH regulator agent;
The consumption of pH regulator agent is that to make the pH that contains the aqueous solution of above-mentioned raw materials before the lyophilizing be 7.4～7.6;
Said cosolvent is soybean phospholipid or lecithin or its mixture.
2. compound recipe vitamin freeze-dried powder for injection according to claim 1 is characterized in that, said pH regulator agent is selected from a kind of or its mixture in sodium hydroxide or the potassium hydroxide.
3. compound recipe vitamin freeze-dried powder for injection according to claim 2 is characterized in that, compound vitamin freeze-dried powder provided by the invention contains stabilizing agent and/or proppant;
Stabilizing agent is selected from one or more in cholic acid, ascorbic acid, butylhydroxy anisole or the dibenzylatiooluene, and it is 2～5: 1 with the drug weight ratio;
Proppant is selected from one or more in mannitol, lecithin or the glucose, and it is 10～30: 1 with the drug weight ratio;
Said drug weight refers to vitamin A palmitate, vitamin D
2, Vitamin E acetate and vitamin K
1Weight.
4. compound recipe vitamin freeze-dried powder for injection according to claim 3 is characterized in that, stabilizing agent is 3～4: 1 with the drug weight ratio.
5. compound recipe vitamin freeze-dried powder for injection according to claim 3 is characterized in that, proppant is 15～25: 1 with the drug weight ratio.
6. according to the preparation method of each described compound recipe vitamin freeze-dried powder for injection of claim 1～5, it is characterized in that, comprise the steps:
(1) ethanol of cosolvent be will be dissolved with, vitamin A palmitate, vitamin D added
2, Vitamin E acetate and vitamin K
1, add 10% water for injection of full dose again, add stabilizing agent, dissolving;
(2) proppant is dissolved in 70% the water for injection of full dose, the pin that adds gross weight 0.01～0.1% stirred 5～30 minutes with activated carbon, filtered, and collected filtrate;
(3) product with step (1) and step (2) mixes, and adds to the full amount of water for injection, and the pH that regulates mixture with the pH regulator agent is 7.4～7.6, and with 0.2～0.4 μ m filtering with microporous membrane, lyophilizing promptly.
7. method according to claim 6 is characterized in that, before the lyophilizing, and in the water for injection, vitamin A palmitate, vitamin D
2, Vitamin E acetate and vitamin K
1Bulking value concentration be 40～80g/1000ml.
8. method according to claim 6 is characterized in that freeze drying process comprises the steps:
At first start cools the temperature to-35 ℃, and pre-freeze 3～5h begins evacuation then, makes drying sublimation;
Sublimation temperature is respectively:
-35℃～-25℃、-20℃～15℃、-10℃、-5℃、0℃、10℃、20℃～28℃、25℃～30℃；
Each temperature duration is respectively:
2～3h、1～2h、2～3h、2～3h、1～2h、3～6h、2～3h、3～5h。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510029352 CN1923207A (en) | 2005-09-02 | 2005-09-02 | Compound recipe vitamin freeze-dried powder for injection and its preparing process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510029352 CN1923207A (en) | 2005-09-02 | 2005-09-02 | Compound recipe vitamin freeze-dried powder for injection and its preparing process |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101366712B (en) * | 2008-09-26 | 2011-07-27 | 北京博时安泰科技发展有限公司 | Method for preparing fat-soluble vitamin for injection |
| CN102525959A (en) * | 2012-01-13 | 2012-07-04 | 海南良方医药有限公司 | Fat-soluble vitamin composition for injection and preparation method thereof |
-
2005
- 2005-09-02 CN CN 200510029352 patent/CN1923207A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101366712B (en) * | 2008-09-26 | 2011-07-27 | 北京博时安泰科技发展有限公司 | Method for preparing fat-soluble vitamin for injection |
| CN102525959A (en) * | 2012-01-13 | 2012-07-04 | 海南良方医药有限公司 | Fat-soluble vitamin composition for injection and preparation method thereof |
| CN102525959B (en) * | 2012-01-13 | 2013-12-18 | 海南良方医药有限公司 | Fat-soluble vitamin composition for injection and preparation method thereof |
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Open date: 20070307 |