CN101632643A - Azacitidine freeze-drying powder injection and preparation method thereof - Google Patents
Azacitidine freeze-drying powder injection and preparation method thereof Download PDFInfo
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- CN101632643A CN101632643A CN200910101901A CN200910101901A CN101632643A CN 101632643 A CN101632643 A CN 101632643A CN 200910101901 A CN200910101901 A CN 200910101901A CN 200910101901 A CN200910101901 A CN 200910101901A CN 101632643 A CN101632643 A CN 101632643A
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Abstract
The invention discloses a medicinal azacitidine freeze-drying powder injection for treating myelodysplastic syndrome and a preparation method thereof. The prescription of the azacitidine freeze-drying powder injection comprises azacitidine, mannitol and vitamin C. The invention solves the problem of rapid impurity increase caused by different crystal forms formed in the processes of rapidly freezing and drying the prior powder injection by optimizing the prescription and improving the preparation method.
Description
Technical field
The present invention relates to the medicine azacitidine (Azacitidine) of a kind of treatment myelodysplastic syndrome (MDS), specifically is azacitidine freeze-dried powder and preparation method thereof.
Background technology
Azacitidine (Azacitidine) is a kind of cytosine nucleoside analogs, is mainly used in treatment myelodysplastic syndrome (MDS).U.S. FDA is ratified this medicine Vidaza listing in May, 2004, because the active component azacitidine less stable of this medicine (hydrolysis rapidly in water), the preparation on the market is a powder injection formulation.But by discovering, this powder injection formulation can form different crystal forms in the quick freezing dry run, cause stability to change, and storage life impurity increases, thereby has caused potential influence for clinical drug safety and effectiveness.
Summary of the invention
The purpose of this invention is to provide a kind of stable azacitidine freeze-dried powder that is used for the treatment of myelodysplastic syndrome.
Another object of the present invention provides a kind of preparation method that is used for the treatment of the stable azacitidine freeze-dried powder of myelodysplastic syndrome.
Purpose of the present invention can reach by following measure:
Azacitidine freeze-dried powder of the present invention is made up of principal agent azacitidine, mannitol and vitamin C.
The invention of described azacitidine freeze-dried powder, every consist of:
Principal agent azacitidine 100mg,
Mannitol 100mg,
Vitamin C 5 ~ 30mg.
Described azacitidine freeze-dried powder invention, every composition is preferably: principal agent azacitidine 100mg, mannitol 100mg, vitamin C 10～15mg.
More preferably: principal agent azacitidine 100mg, mannitol 100mg, vitamin C 10mg.
The preparation method of azacitidine freeze-dried powder, mainly take following steps:
1) by above-mentioned preparation prescription batching, get azacitidine raw material, mannitol, the vitamin C of recipe quantity, add an amount of solvent dissolving;
2) above-mentioned solution adds activated carbon decolorizing, filters carbon removal;
3) be diluted to amount of preparation with above-mentioned solvent, measure liquor strength, medicinal liquid pH value scope is 3.5～6.0;
4) pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
The main pointed injection water of solvent.
In the above-mentioned steps, the consumption of described active carbon is more preferably pressed 1% of medicine liquid volume amount adding after each components dissolved in the prescription.
The present invention is in preparation lyophilized injectable powder process, and lay special stress on divides the multistage lyophilizing at the freeze-drying process herb liquid.In freeze-drying process, medicinal liquid kept 2～10 hours down freeze-drying curve temperature descending section temperature low spot-30～-70 ℃, and the high point of section temperature kept 1～25 hour down for 0～70 ℃ heating up.
Adopt noble gas to fill when encapsulation, guarantee to be difficult for oxidation takes place storage period, period of storage is long.
The present invention has the following advantages with respect to existing azacitidine powder injection formulation:
(1) overall process is carried out the sterile working, adopts the micropore filtering film degerming, cold drying, and product is not destroyed; Noble gas during packing is filled, and guarantees that further drug component is difficult for oxidation takes place, and period of storage is long.
(2) in drug prescription, increased vitamin C, make drug component itself increase stabilizing factor, the situation of crystal formation can not appear forming, solved the problem of poor stability storage period from root, guarantee to reconfigure with water for injection in use the stability of back medicinal liquid, help storing, transport and use, finally guarantee the drug quality in effect duration, guarantee drug safety.
Description of drawings
Fig. 1 is embodiment 1 a medicinal liquid freeze temperature curve chart
Fig. 2 is embodiment 2 medicinal liquid freeze temperature curve charts
Fig. 3 is embodiment 3 medicinal liquid freeze temperature curve charts
The specific embodiment
Embodiment 1
The preparation of azacitidine freeze-dried powder
1.1 prescription:
Azacitidine 100g
Mannitol 100g
Vitamin C 10g
Water for injection adds to 3000ml
Make 1000 altogether.
1.2 take the following steps preparation:
A. by above-mentioned preparation prescription, get azacitidine raw material, the mannitol of 100g, the 10g vitamin C of 100g, with the water for injection dissolving of 2400ml;
B. add the active carbon of dissolving back medicine liquid volume amount 1%, carbon removal is filtered in decolouring;
C. be diluted to amount of preparation with above-mentioned water for injection, measure liquor strength, medicinal liquid pH value scope is 3.5～6.0;
D. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
Degerming measure: medicinal liquid disposable filtering membrane filtration degerming; Plugs etc. adopt the sterilization of vacuum and steam sterilization cabinet, drying; Material-compound tank, equipment such as receiver, injection water pot, freeze dryer and pipeline adopt online sterilization.
This example adopts general freeze dryer lyophilizing.
Temperature descending section temperature low spot :-55 ℃ keep in 7 hours lyophilizing this moment casings not evacuation
The section that heats up heating rate: 20 ℃ of/hour vacuums are 40～50umHg
The high point of the section temperature that heats up: 20 ℃ of vacuums are 40～50umHg
The high some retention time of temperature: 10 hours vacuum is 40～50umHg
The medicinal liquid freeze-drying curve as shown in Figure 1.
Be packed into noble gas N during the medicine encapsulation
2
Embodiment 2
The preparation of azacitidine freeze-dried powder
2.1 prescription:
Azacitidine 100g
Mannitol 100g
Vitamin C 15g
Water for injection adds to 2500ml
Make 1000 altogether.
2.2 take the following steps preparation:
A. by above-mentioned preparation prescription, get azacitidine raw material, the mannitol of 100g, the 15g vitamin C of 100g, with the water for injection dissolving of 2000ml;
B. add the activated carbon decolorizing of dissolving back medicine liquid volume amount 0.8%, filter carbon removal;
C. be diluted to amount of preparation with above-mentioned water for injection, measure liquor strength, medicinal liquid pH value scope is 3.5～6.0;
D. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
This example adopts general freeze dryer lyophilizing.
Temperature descending section temperature low spot :-55 ℃ keep in 7 hours lyophilizing this moment casings not evacuation
A first intensification section heating rate: 20 ℃ of/hour vacuums are 40～50umHg
The high point of the first intensification section temperature: 20 ℃ keep 7 hours vacuum is 40～50umHg
A second intensification section heating rate: 20 ℃ of/hour vacuums are 40～50umHg
The high point of the second intensification section temperature: 60 ℃ keep 7 hours vacuum is 40～50umHg
The medicinal liquid freeze-drying curve as shown in Figure 2.
Be packed into noble gas N during the medicine encapsulation
2
Embodiment 3
The preparation of azacitidine freeze-dried powder
3.1 prescription:
Azacitidine 100g
Mannitol 100g
Vitamin C 28g
Water for injection adds to 4000ml
Make 1000 altogether.
3.2 take the following steps preparation:
A. by above-mentioned preparation prescription, get the azacitidine raw material of 100g and the mannitol of 100g, the 28g vitamin C is with the water for injection dissolving of 3200ml;
B. 1.5% the activated carbon decolorizing that adds the injection water yield filters carbon removal;
C. be diluted to amount of preparation with above-mentioned water for injection, measure liquor strength, medicinal liquid pH value scope is 3.5～6.0;
D. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
This example adopts general freeze dryer lyophilizing.
Temperature descending section temperature low spot :-55 ℃ keep in 7 hours lyophilizing this moment casings not evacuation
A first intensification section heating rate: 15 ℃ of/hour vacuums are 40～50umHg
The high point of the first intensification section temperature: 5 ℃ keep 7 hours vacuum is 40～50umHg
A second intensification section heating rate: 20 ℃ of/hour vacuums are 40～50umHg
The high point of the second intensification section temperature: 30 ℃ keep 7 hours vacuum is 40～50umHg
The 3rd an intensification section heating rate: 10 ℃ of/hour vacuums are 40～50umHg
The high point of the 3rd intensification section temperature: 50 ℃ keep 7 hours vacuum is 40～50umHg
The medicinal liquid freeze-drying curve as shown in Figure 3.
Be packed into noble gas N during the medicine encapsulation
2
Embodiment 4:
The preparation of azacitidine freeze-dried powder
4.1 prescription:
Azacitidine 100g
Mannitol 100g
Vitamin C 5g
Water for injection adds to 4500ml
Make 1000 altogether.
4.2 take the following steps preparation:
A. by above-mentioned preparation prescription, get azacitidine raw material, the mannitol of 100g, the 5g vitamin C of 100g, with the water for injection dissolving of 3500ml;
B. add the activated carbon decolorizing of dissolving back medicine liquid volume amount 1.2%, filter carbon removal;
C. be diluted to amount of preparation with above-mentioned water for injection, measure liquor strength, medicinal liquid pH value scope is 3.5～6.0;
D. pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.
This example adopts general freeze dryer lyophilizing.
Temperature descending section temperature low spot :-55 ℃ keep in 7 hours lyophilizing this moment casings not evacuation
A first intensification section heating rate: 20 ℃ of/hour vacuums are 40～50umHg
The high point of the first intensification section temperature: 20 ℃ keep 7 hours vacuum is 40～50umHg
A second intensification section heating rate: 20 ℃ of/hour vacuums are 40～50umHg
The high point of the second intensification section temperature: 60 ℃ keep 7 hours vacuum is 40～50umHg
Be packed into noble gas N during the medicine encapsulation
2
Embodiment 5:
Azacitidine lyophilized injectable powder of the present invention and the quality stability comparison of criticizing the made preparation of azacitidine injection prescription of freeze-drying powder (not vitaminize C) storage period according to U.S. FDA.
Get the azacitidine lyophilized injectable powder for preparing by embodiment 1 and criticize azacitidine injection prescription of freeze-drying powder (VIDAZA according to U.S. FDA, azacitidine 100mg, mannitol 100mg) made preparation is observed respectively relatively their (40 ℃ of stability by accelerated test, RH75%), azacitidine lyophilized injectable powder accelerated test of the present invention the results are shown in Table 1, criticizes the made preparation accelerated test of azacitidine injection prescription of freeze-drying powder according to U.S. FDA and the results are shown in Table 2.
Table 1 azacitidine lyophilized injectable powder of the present invention accelerated test result
Table 2 is criticized the made preparation accelerated test of azacitidine injection prescription of freeze-drying powder result according to U.S. FDA
Can see from above result: criticize the made preparation of azacitidine injection prescription of freeze-drying powder (40 ℃ of accelerated tests according to U.S. FDA, RH75%) it is just against regulation that condition will indicate content during following February, and the embodiment of the invention 1 made azacitidine freeze-dried powder was then still stablized in the time of 2 years.The stability difference highly significant can find out that thus the present invention improves greatly in the stability of lay up period.
Claims (6)
1. azacitidine freeze-dried powder is characterized in that described azacitidine freeze-dried powder is made up of principal agent azacitidine, mannitol and vitamin C.
2. azacitidine freeze-dried powder as claimed in claim 1 is characterized in that containing principal agent azacitidine 100mg in every component of described azacitidine freeze-dried powder, mannitol 100mg, vitamin C 5 ~ 30mg.
3. azacitidine freeze-dried powder as claimed in claim 1 or 2 is characterized in that containing principal agent azacitidine 100mg in every component of described azacitidine freeze-dried powder, mannitol 100mg, vitamin C 10 ~ 15mg.
4. as the described azacitidine freeze-dried powder of claim 1-3, it is characterized in that containing principal agent azacitidine 100mg in every component of described azacitidine freeze-dried powder, mannitol 100mg, vitamin C 10mg.
5. the preparation method of an azacitidine freeze-dried powder is characterized in that taking following method preparation:
1) presses the preparation prescription batching, get azacitidine raw material, mannitol, the vitamin C of recipe quantity, add an amount of solvent dissolving;
2) above-mentioned solution adds activated carbon decolorizing, filters carbon removal;
3) be diluted to amount of preparation with above-mentioned solvent, measure liquor strength, medicinal liquid pH value scope is 3.5～6.0;
4) pass through the filter membrane filtration sterilization to receiver, packing according to the preset temperature lyophilizing, is rolled lid, packing.Solvent pointed injection water.
6. the preparation method of azacitidine freeze-dried powder as claimed in claim 5, the consumption that it is characterized in that described active carbon is for adding by 1% of medicine liquid volume amount after each components dissolved in the prescription.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102397548A (en) * | 2010-09-19 | 2012-04-04 | 山东新时代药业有限公司 | Medicinal composition containing arctigenin and medical application thereof |
| CN104321649A (en) * | 2012-02-28 | 2015-01-28 | 尼斯-索菲亚·安蒂波利斯大学 | Test for diagnosing resistance to azacitidine |
| CN104739778A (en) * | 2013-12-26 | 2015-07-01 | 山东新时代药业有限公司 | Azacitidine for injection, and preparation method thereof |
| WO2017162103A1 (en) * | 2016-03-24 | 2017-09-28 | 浙江华海药业股份有限公司 | Preparation method for azacitidine injection |
| CN108451901A (en) * | 2018-01-22 | 2018-08-28 | 宁波蒙曼生物科技有限公司 | A kind of preparation of azacitidine and preparation method thereof |
| CN109646410A (en) * | 2019-02-27 | 2019-04-19 | 江苏豪森药业集团有限公司 | Stable azacitidine lyophilized preparation and preparation method thereof |
| CN114224852A (en) * | 2017-04-14 | 2022-03-25 | 鲁南制药集团股份有限公司 | Azacitidine freeze-dried preparation for injection |
-
2009
- 2009-08-18 CN CN200910101901A patent/CN101632643A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102397548A (en) * | 2010-09-19 | 2012-04-04 | 山东新时代药业有限公司 | Medicinal composition containing arctigenin and medical application thereof |
| CN102397548B (en) * | 2010-09-19 | 2014-10-08 | 山东新时代药业有限公司 | Medicinal composition containing arctigenin and medical application thereof |
| CN104321649A (en) * | 2012-02-28 | 2015-01-28 | 尼斯-索菲亚·安蒂波利斯大学 | Test for diagnosing resistance to azacitidine |
| CN104739778A (en) * | 2013-12-26 | 2015-07-01 | 山东新时代药业有限公司 | Azacitidine for injection, and preparation method thereof |
| WO2017162103A1 (en) * | 2016-03-24 | 2017-09-28 | 浙江华海药业股份有限公司 | Preparation method for azacitidine injection |
| CN114224852A (en) * | 2017-04-14 | 2022-03-25 | 鲁南制药集团股份有限公司 | Azacitidine freeze-dried preparation for injection |
| CN108451901A (en) * | 2018-01-22 | 2018-08-28 | 宁波蒙曼生物科技有限公司 | A kind of preparation of azacitidine and preparation method thereof |
| CN108451901B (en) * | 2018-01-22 | 2020-07-17 | 青岛市中心医院 | Azacitidine preparation and preparation method thereof |
| CN109646410A (en) * | 2019-02-27 | 2019-04-19 | 江苏豪森药业集团有限公司 | Stable azacitidine lyophilized preparation and preparation method thereof |
| CN109646410B (en) * | 2019-02-27 | 2021-07-16 | 江苏豪森药业集团有限公司 | Stable azacitidine freeze-dried preparation and preparation method thereof |
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Application publication date: 20100127 |