CN1524530A - Method for preparing ganciclovir intravenous fluid - Google Patents
Method for preparing ganciclovir intravenous fluid Download PDFInfo
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- CN1524530A CN1524530A CNA031254225A CN03125422A CN1524530A CN 1524530 A CN1524530 A CN 1524530A CN A031254225 A CNA031254225 A CN A031254225A CN 03125422 A CN03125422 A CN 03125422A CN 1524530 A CN1524530 A CN 1524530A
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- injection
- ganciclovir
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Abstract
The invention relates to a process for preparing Ganciclovir injection which comprises the steps of, preparing water for injection, dissolving the medicinal carrier by 70-100 deg. C water for injection to prepare medicinal carrier solution, adding 0.01wt%-10wt% of adsorbent according to preparation amount, stirring, heating to 90-100 deg. C, adsorbing for 5-60 minutes, filtering, charging active raw material Ganciclovir and alkali according to the proportion of gram molecule ratio of 1:0.1-1 into the filtered medicinal carrier solution, adding water for injection into active Ganciclovir to concentration of 0.01wt%-1wt%, stirring to dissolve, preparing medicinal solution, adding 0.01wt%-1wt% of activated charcoal for injection, stirring, filtering, filtering and degerming through microporous filtering film, split charging, high pressure sterilizing.
Description
Technical field
The present invention relates to a kind of preparation method of ganciclovir intravenous fluid.
Background technology
Ganciclovir " chemical name: 9-(1,3-dihydroxy-2-third oxygen methyl)-guanine " is a kind of wide spectrum anti-herpesvirus medicament, and especially the activity to human cytomegalic inclusion disease virus is strong especially, has become the choice drug that the control giant cell infects at present.Main uses is control: accept secondary cytomegalovirus infection after the organ transplantation; Leukemia is accepted secondary cytomegalovirus infection after the bone marrow transplantation; Tumor patient is the secondary cytomegalovirus infection after accepting radiotherapy, chemotherapy; The HIV sufferers cytomegalovirus infection that occurs together; Test is used for infant cytomegalovirus infection, intractable genital herpes and intractable hepatitis B etc.The ganciclovir water fast, its oral formulations bioavailability is lower, and individual variation is bigger; Ophthalmic is planted and is buried agent and gel for eye only plays local action, and therefore preparing the ganciclovir intravenous fluid has important clinical significance.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of ganciclovir intravenous fluid, be subjected to ectocine little in this method drug production process, condition is easy to control, and product stability is good, the drug effect height, and it is little that poison is paid effect, and technology is simple, and cost is low.
Technical scheme provided by the invention is: preparation water for injection; Pharmaceutical carrier is added 70～100 ℃ water for injection dissolving, be mixed with pharmaceutical carrier solution; Add 0.01wt%～10wt% adsorbent needle-use activated carbon by amount of preparation, stir evenly, be heated to 90～100 ℃, adsorbed 5～60 minutes, filter; Is that 1: 0.1～1 ratio adds in the pharmaceutical carrier solution after filtering with activated feedstock ganciclovir and alkali in mole ratio, adds the concentration 0.01wt%～1wt% of injection water to the activated feedstock ganciclovir, and stirring and dissolving is prepared into drug solution; Add 0.01wt%～1wt% needle-use activated carbon, stir evenly, filter; The filtering with microporous membrane degerming; Packing, autoclaving promptly get required ganciclovir injection.
The preferred concentration that above-mentioned pharmaceutical carrier solution filters used active carbon is 0.05wt%～1wt%, adsorption time 10～30 minutes; The preferred concentration that drug solution filters used active carbon is 0.01wt%～0.5wt%.
The used alkali of the present invention is sodium hydroxide, potassium hydroxide, sodium acetate, sodium lactate, arginine or glycine, or the mixture of above-mentioned two or more alkali.Used pharmaceutical carrier is that sodium chloride, glucose, potassium chloride, calcium chloride, xylitol, fructose, mannitol are or/and sorbitol.
There is hydroxyl to exist in the ganciclovir molecule, can forms salt with alkali, so soluble in water, and the present invention utilizes this specific character to prepare the ganciclovir intravenous fluid.The preparation method of ganciclovir intravenous fluid provided by the invention is with ganciclovir and alkali reaction salify, is dissolved in the water, thereby makes the ganciclovir intravenous fluid.
The ganciclovir injection that the present invention makes can be the pharmaceutical preparation that contains ganciclovir, derivant or its pharmaceutical salts.
Characteristics of the present invention: catalogue is designated as safe, effective, quality controllable
1, raw material and the adjuvant that uses in the production all meets the quality standard that pharmacopeia regulation or national Bureau of Drugs Supervision ratify, and the kind of adjuvant, consumption do not influence safe and effective for medication, the check generation do not disturbed.
2, transfusion is directly to enter intravital large bolus injection agent by vein, and therefore the control to its clarity and pyrogen requires extremely strictness, otherwise after the injection, side effect takes place easily, even cause life danger.Among the present invention, the fresh water for injection of preparation can directly add pharmaceutical carrier without cooling, is mixed with pharmaceutical carrier solution after the dissolving; The water for injection temperature of preparing is greatly about 70～100 ℃, and not only dissolving is rapid in this temperature range for pharmaceutical carrier and activated feedstock, and filters soon, does not need control appliance pressure and fluid temperature, has reduced production cost.
3, adopt active carbon as adsorbent, not only technology is simple, cost is low, and can efficiently adsorb impurity, pigment, the pyrogen of removing wherein and improve clarity, also plays filtrating aid function simultaneously, guarantees end product quality.
1. this preparation technology gropes middle discovery, uses active carbon gradation absorption more effective than primary sorption.
When 2. activated carbon of sorbent contacted with adsorbate, owing to the adsorption bond that forms needs certain hour, through practice, adsorption time can be 5～60 minutes, and Best Times is 10～30 minutes.
4, in process for preparation of the present invention, in the pharmaceutical carrier solution after activated feedstock ganciclovir and the alkali adding filtration, utilize ganciclovir and alkali reaction salify and improve the dissolubility of ganciclovir in water for injection, can solve ganciclovir insoluble problem in water, both guaranteed the stability of injection of the present invention, improved drug effect, reduced the stimulation of injection again, guaranteed the safety of medication tissue.
The specific embodiment
Embodiment 1
Ganciclovir 0.5g
Sodium chloride 9g
Sodium hydroxide 0.015g
Water for injection an amount of (1000ml adds to the full amount of water for injection)
Full dose 1000ml
Preparation process: (1) preparation water for injection; (2) sodium chloride is added the injection water in 80 ℃ of dissolvings, be mixed with sodium chloride solution (I); (3) add needle-use activated carbon 0.2%, be heated to 100 ℃, adsorb 30 minutes depyrogenations; (4) activated feedstock ganciclovir and sodium hydroxide are added in the above-mentioned solution I, add the injection water to capacity, stirring and dissolving is prepared into drug solution II; (5) cross charcoal layer (0.02%) depyrogenation; (6) filtering with microporous membrane degerming; (7) after the packing, autoclaving; (8) test package.
Ganciclovir injection by this prescription and preparation method system has carried out study on the stability, and this product is steady quality in 3 years, sees table 1 for details:
Table 1 ganciclovir injection long-term stable experiment result
Time is investigated project
Lot number
(moon) solution appearance clarity pH value indicates % sterilization of content % related substance and pyrogen
0 achromatism and clarity solution qualified 8.88 96.5 0.56 is qualified
1
36 no changes qualified 8.60 100.2 0.60 are qualified
0 achromatism and clarity solution qualified 8.89 95.7 0.55 is qualified
2
36 no changes qualified 8.60 100.2 0.60 are qualified
0 achromatism and clarity solution qualified 8.89 96.4 0.55 is qualified
3
36 no changes qualified 8.709 99.4 0.60 are qualified
This injection is carried out safety testing, comprised haemolysis, anaphylaxis and blood vessel irritation test.
(1) hemolytic test: get Sanguis Leporis seu oryctolagi and prepare defibrinated blood and prepare 2% red blood cell suspension, respectively with 0.5,0.4,0.3,0.2,0.1ml ganciclovir injection mixing, observation in 37 ℃ of calorstats 0.5,1.0,2.0,3.0, the reaction condition of 6.0h, erythrocyte all sinks then negative.The result: the reaction of ganciclovir injection and 2% cell suspension is subjected to respectively that solution all is water white transparency in the test tube, and erythrocyte all sinks, no flocculent deposit.
(2) hypersensitive test: 6 ip ganciclovir injections of healthy male albino guinea-pig 0.5ml, the next day once, inject 3 times, as sensitization.At the first time injection 14 days and iv 1ml medicinal liquid on the 21st, annotate and finish back 15min respectively, observe symptoms of allergic in 4h, the 8h.The result: after sensitized guinea pig the 14th day and difference vein on the 21st injected ganciclovir injection, allergic symptoms such as perpendicular hair, dyspnea, sneeze, retch cough all occurred in the point each observing time, also do not have death.
(3) blood vessel irritation test: 3 of the big ear rabbit of healthy Japan, to exempt from left ear vein and instil and be subjected to reagent liquid, auris dextra is with fast instillation sodium chloride injection, once a day, after continuous 3 times, gets the rabbit ear and dissects the injection blood vessel and make the pathology sections observation.The result: the intravascular injection position does not see that animal is restless, ear's flushing during seeing swelling, ulceration, necrosis, instillation; The pathology light microscopic does not see that this product is to blood vessel wall and surrounding tissue damage.
Conclusion: (1) ganciclovir injection hemolytic test feminine gender, (2) ganciclovir injection does not produce anaphylaxis, (3) ganciclovir injection vacuum response.
Embodiment 2:
Ganciclovir 1g
Sodium chloride 9g
Sodium hydroxide 0.03g
Water for injection an amount of (1000ml adds to the full amount of water for injection)
Full dose 1000ml
Preparation process: (1) preparation water for injection; (2) sodium chloride is added the injection water in 75 ℃ of dissolvings, be mixed with sodium chloride solution (I); (3) add needle-use activated carbon 0.5%, adsorb 20 minutes depyrogenations; (4) activated feedstock ganciclovir and sodium hydroxide are added in the above-mentioned solution I, add the injection water to capacity (1000ml), stirring and dissolving is prepared into drug solution II; (5) cross charcoal layer (0.05%) depyrogenation; (6) filtering with microporous membrane degerming; (7) after the packing, autoclaving; (8) test package.
Ganciclovir injection by this prescription and preparation method system has carried out study on the stability, and this product is steady quality in 3 years, sees table 2 for details:
Table 2 ganciclovir injection long-term stable experiment result
Time is investigated project
Lot number
(moon) solution appearance clarity pH value indicates % sterilization of content % related substance and pyrogen
0 achromatism and clarity solution qualified 8.84 99.9 0.56 is qualified
1
36 no changes qualified 8.60 98.4 0.60 are qualified
0 achromatism and clarity solution qualified 8.85 99.6 0.56 is qualified
2
36 no changes qualified 8.70 99.9 0.60 are qualified
0 achromatism and clarity solution qualified 8.84 99.9 0.55 is qualified
3
36 no changes qualified 8.70 98.6 0.60 are qualified
This injection is carried out safety testing, comprised haemolysis, anaphylaxis and blood vessel irritation test.
(1) hemolytic test: get Sanguis Leporis seu oryctolagi and prepare defibrinated blood and prepare 2% red blood cell suspension, respectively with 0.5,0.4,0.3,0.2,0.1ml ganciclovir injection mixing, observation in 37 ℃ of calorstats 0.5,1.0,2.0,3.0, the reaction condition of 6.0h, erythrocyte all sinks then negative.The result: the reaction of ganciclovir injection and 2% cell suspension is subjected to respectively that solution all is water white transparency in the test tube, and erythrocyte all sinks, no flocculent deposit.
(2) hypersensitive test: 6 ip ganciclovir injections of healthy male albino guinea-pig 0.5ml, the next day once, inject 3 times, as sensitization.At the first time injection 14 days and iv 1ml medicinal liquid on the 21st, annotate and finish back 15min respectively, observe symptoms of allergic in 4h, the 8h.The result: after sensitized guinea pig the 14th day and difference vein on the 21st injected ganciclovir injection, allergic symptoms such as perpendicular hair, dyspnea, sneeze, retch cough all occurred in the point each observing time, also do not have death.
(3) blood vessel irritation test: 3 of the big ear rabbit of healthy Japan, to exempt from left ear vein and instil and be subjected to reagent liquid, auris dextra is with fast instillation sodium chloride injection, once a day, after continuous 3 times, gets the rabbit ear and dissects the injection blood vessel and make the pathology sections observation.The result: the intravascular injection position does not see that animal is restless, ear's flushing during seeing swelling, ulceration, necrosis, instillation; The pathology light microscopic does not see that this product is to blood vessel wall and surrounding tissue damage.
Conclusion: (1) ganciclovir injection hemolytic test feminine gender, (2) ganciclovir injection does not produce anaphylaxis, (3) ganciclovir injection vacuum response.
Embodiment 3
Ganciclovir 1g
Sodium chloride 6g
Sodium lactate 3.10g
Potassium chloride 0.30g
Calcium chloride 0.20g
Water for injection an amount of (1000ml adds to the full amount of water for injection)
Full dose 1000ml
Claims (4)
1. the preparation method of ganciclovir intravenous fluid may further comprise the steps: preparation water for injection; Pharmaceutical carrier is added 70～100 ℃ water for injection dissolving, be mixed with pharmaceutical carrier solution; Add 0.01wt%～10wt% adsorbent by amount of preparation, stir evenly, be heated to 90～100 ℃, adsorbed 5～60 minutes, filter; Is that 1: 0.1～1 ratio adds in the pharmaceutical carrier solution after filtering with activated feedstock ganciclovir and alkali in mole ratio, adds the concentration 0.01wt%～1wt% of injection water to the activated feedstock ganciclovir, and stirring and dissolving is prepared into drug solution; Add 0.01wt%～1wt% needle-use activated carbon, stir evenly, filter; The filtering with microporous membrane degerming; Packing, autoclaving promptly get required ganciclovir injection.
2. preparation method according to claim 1 is characterized in that: the concentration that above-mentioned pharmaceutical carrier solution filters used active carbon is 0.05wt%～1wt%, adsorption time 10～30 minutes; The concentration that drug solution filters used active carbon is 0.01wt%～0.5wt%.
3. preparation method according to claim 1 and 2 is characterized in that: used alkali is sodium hydroxide, potassium hydroxide, sodium acetate, sodium lactate, arginine or glycine, or the mixture of above-mentioned two or more alkali.
4. preparation method according to claim 1 and 2 is characterized in that: used pharmaceutical carrier is that sodium chloride, glucose, potassium chloride, calcium chloride, xylitol, fructose, mannitol are or/and sorbitol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031254225A CN1524530A (en) | 2003-09-16 | 2003-09-16 | Method for preparing ganciclovir intravenous fluid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031254225A CN1524530A (en) | 2003-09-16 | 2003-09-16 | Method for preparing ganciclovir intravenous fluid |
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| CN1524530A true CN1524530A (en) | 2004-09-01 |
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| CNA031254225A Pending CN1524530A (en) | 2003-09-16 | 2003-09-16 | Method for preparing ganciclovir intravenous fluid |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102018666A (en) * | 2010-09-17 | 2011-04-20 | 张登科 | Preparation method and new clinic application of penciclovir injection solution |
| CN102274197A (en) * | 2011-07-19 | 2011-12-14 | 江苏奥赛康药业股份有限公司 | Ganciclovir composition for injection and preparation method thereof |
| CN103340831A (en) * | 2013-07-16 | 2013-10-09 | 成都天台山制药有限公司 | Ganciclovir powder-injection for injection |
| CN104414967A (en) * | 2013-09-06 | 2015-03-18 | 康普药业股份有限公司 | Ganciclovir injection solution and preparation method thereof |
-
2003
- 2003-09-16 CN CNA031254225A patent/CN1524530A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102018666A (en) * | 2010-09-17 | 2011-04-20 | 张登科 | Preparation method and new clinic application of penciclovir injection solution |
| CN102018666B (en) * | 2010-09-17 | 2011-12-21 | 西安新通药物研究有限公司 | Preparation method and new clinic application of penciclovir injection |
| CN102274197A (en) * | 2011-07-19 | 2011-12-14 | 江苏奥赛康药业股份有限公司 | Ganciclovir composition for injection and preparation method thereof |
| CN102274197B (en) * | 2011-07-19 | 2013-01-16 | 江苏奥赛康药业股份有限公司 | Ganciclovir composition for injection and preparation method thereof |
| CN103340831A (en) * | 2013-07-16 | 2013-10-09 | 成都天台山制药有限公司 | Ganciclovir powder-injection for injection |
| CN104414967A (en) * | 2013-09-06 | 2015-03-18 | 康普药业股份有限公司 | Ganciclovir injection solution and preparation method thereof |
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