CN1383827A - Prepn of antiviral N-9 substituted guanine medicine powder for injection - Google Patents
Prepn of antiviral N-9 substituted guanine medicine powder for injection Download PDFInfo
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- CN1383827A CN1383827A CN 02115836 CN02115836A CN1383827A CN 1383827 A CN1383827 A CN 1383827A CN 02115836 CN02115836 CN 02115836 CN 02115836 A CN02115836 A CN 02115836A CN 1383827 A CN1383827 A CN 1383827A
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Abstract
The present invention features that antiviral N-9 substituted guanine medicine is first dissolved in isomolar sodium hydroxide solution and the solution is then produced into powder through pH value regulation, decoloring with active cccc, filtering to eliminate carbon, fine filtering in bacteria-free condition and spraying to dry; or it is first dissolved in low-toxicity organic solvent and then produced to powder through crystallization, filtering and drying in 40-80 deg.c. It has short production period, low power consumption, high yield, low cost and stable product quality.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, more specifically relate to a kind of preparation method of N-9 9 substituted guanine antiviral drugs injectable powder.
Background technology
N-9 9 substituted guanine class antiviral drugs commonly used has following structure:
Wherein R is:
Represent ganciclovir (Ganciclovir);
R is:
Represent acyclovir (Acyclovir);
R is:
Represent penciclovir (Penciclovir).
The class that said medicine is is used wider antiviral drugs.Chemical property is all also more stable, bioavailability lower (being lower than 10%) during because of its oral medication, and clinically modes of intravenously administrable that adopt to improve bioavailability more.In real work, because this class medicine dissolubility in water all less (less than 0.5%), often need add the dissolving earlier of a certain amount of cosolvent at the preparation injection, adopt cryodesiccated method to make injectable powder then, this method not only energy consumption is big, production cycle is long, and every batch takes 2-3 days, yields poorly and (invest 1,000,000 yuan of 10m
2About 1.5 ten thousand bottles of every batch of output of freeze dryer, average every day, output was 0.5 ten thousand bottles), and quality instability, the moisture absorption easily, but also can add untoward reaction such as too much producing vein irritating because of cosolvent.
Summary of the invention
The shortcoming and defect that in preparation process, exists in view of existing N-9 9 substituted guanine class antiviral drugs injectable powder, the object of the present invention is to provide a kind of preparation method of N-9 9 substituted guanine class antiviral drugs injectable powder, this method technology is easy, easy to implement the method, production cost is low, with short production cycle, the untoward reaction when having reduced clinical use simultaneously.
In order to achieve the above object, the present invention is by the following technical solutions:
N-9 9 substituted guanine class antiviral drugs is dissolved in the equimolar sodium hydroxide solution, the pH value of regulator solution is to 10-12 in case of necessity, add activated carbon decolorizing 20-30min, the coarse filtration carbon removal, fine straining filters under aseptic condition, with the filtrate spray drying, be 3-5 hour drying time, make dry powder or adopt organic solvent (as containing five carbon following unit alcohol or the ketone) crystallization and filtration that adds low toxicity, make dry powder 40-80 ℃ of drying then, specification by every bottle of 0.05-1g is sub-packed in the cillin bottle, promptly at last.
According to technical scheme of the present invention, described N-9 9 substituted guanine class antiviral drugs is acyclovir (Acyclovir), ganciclovir (Ganciclovir) and penciclovir (Penciclovir); Prepared injectable powder is Acycloguanosine sodium or its dihydrate, ganciclovir sodium or its dihydrate and penciclovir sodium or its monohydrate; Used drying means is spray drying method and crystallization oven drying method, and final products (injectable powder) then directly carry out packing under aseptic condition.
The present invention compared with prior art, have the following advantages and effect: (every batch take be no more than 1 day) not only with short production cycle, energy consumption is low, output is high (investing 1,000,000 yuan drying equipment and every batch of output of dispensing apparatus greater than 100,000 bottles), low production cost, steady quality can also be avoided adding the untoward reaction such as vein irritating that too much produce because of cosolvent simultaneously.
Specific embodiment embodiment 1: one of preparation method of ganciclovir injectable powder
Get ganciclovir 1kg, add equimolar sodium hydroxide solution dissolving, and the pH of regulator solution is 10.5, add activated carbon decolorizing 30min, the coarse filtration carbon removal, fine straining is to clear and bright under aseptic condition, the alcoholic solution that under agitation adds 5 times of amounts, continue to stir after 30 minutes, sucking filtration reclaims ethanol, gained was deposited in 60 ℃ of drying under reduced pressure 4 hours, promptly get the 1.12kg white crystalline powder, the specification by every bottle of 0.05-1g is sub-packed in the cillin bottle of 10ml, promptly then.After tested, its content is the ganciclovir sodium dihydrate, and dissolubility is greater than 20%, and pH is about 10.5.Ooze the concentration that transfusion is diluted to 0.2-2mg/ml with suitable grade during use, for intravenous drip, each 0.05-1g.Embodiment 2: two of the preparation method of ganciclovir injectable powder
Get ganciclovir 1kg, add equimolar sodium hydroxide solution dissolving, and the pH of regulator solution is 10.5, add activated carbon decolorizing 30min, the coarse filtration carbon removal, fine straining is to clear and bright under aseptic condition, spray drying, promptly get 1.05kg white superfine powder, the specification by every bottle of 0.05-1g is sub-packed in the cillin bottle of 10ml, promptly then.After tested, its content is the ganciclovir sodium anhydride, and dissolubility is greater than 25%, and pH is about 11.Ooze the concentration that transfusion is diluted to 0.2-2mg/ml with suitable grade during use, for intravenous drip, each 0.05-1g.Embodiment 3: one of preparation method of acyclovir injectable powder
Get acyclovir 1kg, add equimolar sodium hydroxide solution dissolving, and the pH of regulator solution is 11, add activated carbon decolorizing 30min, the coarse filtration carbon removal, fine straining is to clear and bright under aseptic condition, the alcoholic solution that under agitation adds 5 times of amounts, continue to stir after 30 minutes, sucking filtration reclaims ethanol, gained was deposited in 70 ℃ of drying under reduced pressure 3 hours, promptly get the 1.08kg white crystalline powder, the specification by every bottle of 0.05-1g is sub-packed in the cillin bottle, promptly then.After tested, its content is the Acycloguanosine sodium dihydrate, and dissolubility is greater than 25%, and pH is about 11.Ooze the concentration that transfusion is diluted to 0.2-2mg/ml with suitable grade during use, for intravenous drip, each 0.05-1g.Embodiment 4: two of the preparation method of acyclovir injectable powder
Get acyclovir 1kg, add equimolar sodium hydroxide solution dissolving, and the pH of regulator solution is 11, add activated carbon decolorizing 30min, the coarse filtration carbon removal, fine straining is to clear and bright under aseptic condition, spray drying, promptly get 1kg white superfine powder, the specification by every bottle of 0.05-1g is sub-packed in the cillin bottle, promptly then.After tested, its content is the ganciclovir sodium anhydride, and dissolubility is greater than 25%, and pH is about 11.Ooze the concentration that transfusion is diluted to 0.2-2mg/ml with suitable grade during use, for intravenous drip, each 0.05-1g.Embodiment 5: one of preparation method of penciclovir injectable powder
Get penciclovir 1kg, add equimolar sodium hydroxide solution dissolving, and the pH of regulator solution is 11, add activated carbon decolorizing 30min, the coarse filtration carbon removal, fine straining is to clear and bright under aseptic condition, the alcoholic solution that under agitation adds 5 times of amounts, continue to stir after 30 minutes, sucking filtration reclaims ethanol, gained was deposited in 50 ℃ of drying under reduced pressure 5 hours, promptly get the 1kg white crystalline powder, the specification by every bottle of 0.05-1g is sub-packed in the cillin bottle, promptly then.After tested, its content is a Penciclovir sodium hydrate, and dissolubility is greater than 25%, and pH is about 11.Ooze the concentration that transfusion is diluted to 0.2-2mg/ml with suitable grade during use, for intravenous drip, each 0.05-1g.Embodiment 6: two of the preparation method of penciclovir injectable powder
Get penciclovir 1kg, add equimolar sodium hydroxide solution dissolving, and the pH of regulator solution is 11, add activated carbon decolorizing 30min, the coarse filtration carbon removal, fine straining is to clear and bright under aseptic condition, spray drying, promptly get 1kg white superfine powder, the specification by every bottle of 0.05-1g is sub-packed in the cillin bottle, promptly then.After tested, its content is the penciclovir sodium anhydride, and dissolubility is greater than 25%, and pH is about 11.Ooze the concentration that transfusion is diluted to 0.2-2mg/ml with suitable grade during use, for intravenous drip, each 0.05-1g.The performance test of prepared injectable powder
1, antiviral activity test
Adopt the described method of document [Acta Pharmaceutica Sinica 24 (5): 331,1989], extracorporeal antivirus effect activity by the sample of embodiment two methods preparations is tested, compare simultaneously with commercial ganciclovir injectable powder (dried frozen aquatic products), the result shows that strain suppresses the concentration (IC that 50% plaque forms to herpes simplex I type (HSV-1) KOS in tissue culture for this product and commercial ganciclovir injectable powder
50) be 0.125 μ g/ml.That is: the injectable powder by the inventive method preparation does not influence its antiviral activity.
2,50 of Kunming kind white mice are got in acute toxicity test, and body weight 20 ± 1g is divided into 5 groups (every group of male and female half and half) at random; The sample solution 0.4ml of the 1st group of every tail vein injection 7.5%, dosage are 1.5g/kg; The sample solution 0.4ml of the 2nd group of every tail vein injection 6.5%, dosage are 1.3g/kg; The sample solution 0.4ml of the 3rd group of every tail vein injection 5.5%, dosage are 1.1g/kg; The sample solution 0.4ml of the 4th group of every tail vein injection 4.5%, dosage are 0.9g/kg; The sample solution 0.4ml of the 5th group of every tail vein injection 4%, dosage are 0.8g/kg.At once observe the death condition of animal behind the drug administration by injection.The result shows: the LD of the sample (embodiment one) of the present invention's preparation
50Be 1.25g/kg, with the LD of method to commercial ganciclovir injectable powder sample (freeze-drying preparation)
50Test, the result is 1.10g/kg, i.e. the toxicity that the present invention prepares sample is low slightly.
3, dissolubility and pH value test
Get each 2.5g of sample by the embodiment of the invention one to embodiment six preparation, add jolting behind the water 7.5ml respectively, all dissolvings fully in 1 minute of result illustrate that thus its dissolubility is greater than 25%; Its pH value is measured, the result is respectively 9.6,10.7,10.4,11.1,10.5 and 10.9 in accordance with the law, all less than 12.
4, humidity stability is tested
Get sample and commercial acyclovir and each about 1g of ganciclovir injectable powder sample (freeze-drying preparation) by the embodiment of the invention one and embodiment three preparations, after accurate title is fixed, put simultaneously in 75% the exsiccator, take out after 8 hours and claim to decide weight, and calculating moisture absorption ratio (moisture absorption ratio=[(example weight before test back example weight-test)/preceding example weight of test] * 100%), the result shows, the moisture absorption ratio of sample in 8 hours of the embodiment of the invention one and embodiment three preparations is respectively 1.3% and 1.5%, be respectively 9.3% and 10.1% and commercial sample legal system is equipped with the moisture absorption ratio of sample in 8 hours, that is: the wet stability by the prepared sample of the inventive method is higher than commercial sample (freeze-drying preparation).
5, loss on drying, moisture determination and differential thermal analysis test
Sample and commercial sample with the embodiment of the invention one to six preparation, be dried to constant weight and measure wherein moisture at 110 ℃ respectively with Ka Shi aquametry (two appendix VIII of Chinese Pharmacopoeia version in 2000 M), result's (shown in seeing attached list) shows: 2 kinds of method measurement result unanimities, be only to contain moisture in all samples, do not contain other solvent.Sample is carried out differential thermal analysis, the result: embodiment one, three and five endothermic peak occurs about 110 ℃, and this shows in these 3 kinds of samples and contain water of crystallization, in conjunction with loss on drying and moisture determination result as can be known its crystallization water number be respectively 2,2 and 1.
Subordinate list: the loss on drying of different samples, moisture determination and differential thermal analysis result of the test
| Specimen | Loss on drying (%) | Moisture determination (%) | Difference analysis thermal result (50-150 ℃) | The crystallization water number |
| Embodiment one | ????11.7 | ????11.6 | 110 ℃ have endothermic peak | 2 molecules |
| Embodiment two | ????1.0 | ????0.9 | No endothermic peak | Do not have |
| Embodiment two | ????12.7 | ????12.5 | 110 ℃ have endothermic peak | 2 molecules |
| Embodiment four | ????0.7 | ????0.8 | No endothermic peak | Do not have |
| Embodiment five | ????6.1 | ????5.9 | 110 ℃ have endothermic peak | 1 molecule |
| Embodiment six | ????0.6 | ????0.5 | No endothermic peak | Do not have |
| Commercial acyclovir powder pin (freeze-dry process) | ????3.5 | ????3.6 | No endothermic peak | Do not have |
| Commercial ganciclovir powder pin (freeze-dry process) | ????4.1 | ????4.3 | No endothermic peak | Do not have |
| Self-control penciclovir powder pin (freeze-dry process) | ????2.5 | ????2.7 | No endothermic peak | Do not have |
Claims (2)
1, a kind of preparation method of N-9 9 substituted guanine class antiviral drugs injectable powder, this method comprises the following steps: at first N-9 9 substituted guanine class antiviral drugs to be dissolved in the equimolar sodium hydroxide solution, regulates pH value to 10-12; Next is to add activated carbon decolorizing 20-30min; The 3rd is the coarse filtration carbon removal, and fine straining filters under aseptic condition; The 4th is that filtrate is used spray drying, and be to make dry powder in 3-5 hour or add the organic solvent crystallization and filtration drying time, makes dry powder 40-80 ℃ of drying.
2, the preparation method of a kind of N-9 9 substituted guanine class antiviral drugs injectable powder according to claim 1 is characterized in that injectable powder is Acycloguanosine sodium or its dihydrate, ganciclovir sodium or its dihydrate and penciclovir sodium or its monohydrate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02115836 CN1383827A (en) | 2002-05-14 | 2002-05-14 | Prepn of antiviral N-9 substituted guanine medicine powder for injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02115836 CN1383827A (en) | 2002-05-14 | 2002-05-14 | Prepn of antiviral N-9 substituted guanine medicine powder for injection |
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| CN1383827A true CN1383827A (en) | 2002-12-11 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004111049A1 (en) * | 2003-06-13 | 2004-12-23 | Lyogen Limited | Ganciclovir sodium salt in crystalline form |
| 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 |
| CN101851239B (en) * | 2009-04-03 | 2012-11-28 | 上海益威实业有限公司 | Ganciclovir recovery method |
| CN101987851B (en) * | 2009-08-04 | 2014-06-18 | 北京利乐生制药科技有限公司 | Crystal forms of Acyclovir sodium dihydrate and preparation method thereof |
| CN110627793A (en) * | 2019-09-10 | 2019-12-31 | 天津理工大学 | Penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal and preparation method thereof |
-
2002
- 2002-05-14 CN CN 02115836 patent/CN1383827A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004111049A1 (en) * | 2003-06-13 | 2004-12-23 | Lyogen Limited | Ganciclovir sodium salt in crystalline form |
| CN101851239B (en) * | 2009-04-03 | 2012-11-28 | 上海益威实业有限公司 | Ganciclovir recovery method |
| CN101987851B (en) * | 2009-08-04 | 2014-06-18 | 北京利乐生制药科技有限公司 | Crystal forms of Acyclovir sodium dihydrate and preparation method thereof |
| 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 |
| CN110627793A (en) * | 2019-09-10 | 2019-12-31 | 天津理工大学 | Penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal and preparation method thereof |
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