CN101984968A - Preparation method of pharmaceutical preparation of antitumor agent temozolomide - Google Patents
Preparation method of pharmaceutical preparation of antitumor agent temozolomide Download PDFInfo
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- CN101984968A CN101984968A CN2010105266126A CN201010526612A CN101984968A CN 101984968 A CN101984968 A CN 101984968A CN 2010105266126 A CN2010105266126 A CN 2010105266126A CN 201010526612 A CN201010526612 A CN 201010526612A CN 101984968 A CN101984968 A CN 101984968A
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Abstract
The invention relates to a preparation method of the pharmaceutical preparation of antitumor agent temozolomide. The aim of the invention is to make up for the defects of the prior art and provide a safe, effective and stable new preparation for a large number of patients and medical workers, wherein the new preparation is convenient to take and can increase the bioavailability and blood concentration of the medicine, shorten the peak time and increase the antitumor fuction. The preparation method of the freeze-dried powder injection of the antitumor agent temozolomide is that temozolomide is used as the raw material, certain kinds of accessories in a defined ratio are added in the raw material, and the freeze drying technology of the pharmaceutics is utilized to prepare the freeze-dried powder injection.
Description
Technical field
The present invention relates to pharmaceutical preparation, it comprises antineoplastic agent temozolomide and solubilizing agent.The temozolomide freeze-dried powder preparation of the present invention is compared with existing medicine better therapeutic and lower toxic and side effects, and steady quality, controlled, safe and effective belongs to medical technical field.
Background technology
Adopt the technology of the present invention that the temozolomide is prepared into freeze-dried powder preparation, not only expanded temozolomide's dosage form range of application, particularly through selection to the present invention's prescription, obtain stable, clinical easy to use, storage period of limit for length, bioavailability height, can improve antineoplastic curative effect, the little pharmaceutical preparation of side effect, and preparation method is simple, is fit to large-scale production.
Summary of the invention
The temozolomide is a kind of water-fast chemical compound.The patient takes the temozolomide with the form of micronized suspension, yet suspension preparation is unfavorable, because they can cause blood vessel blockage.Medicine and biological preparation, especially antineoplastic agent is stored as frozen soln, can cause active component rapid damage wherein.The purpose of this invention is to provide a kind of stable, clinical easy to use, storage period of limit for length, bioavailability height, can improve antineoplastic curative effect, the little pharmaceutical preparation of side effect.
Temozolomide freeze-dried powder preparation provided by the invention contains temozolomide's active ingredient and the excipient substance that is fit to make freeze-dried powder preparation, and wherein temozolomide's percentage by weight is 1-50%, and the percentage by weight of adjuvant is 50-99%.Described temozolomide freeze-dried powder preparation preferably contains temozolomide 100-400mg for every bottle.
Described adjuvant is selected from excipient, filler, buffer agent, pH regulator agent, aqueous diluent, wherein the percentage by weight of excipient is 2-60%, the percentage by weight of filler is 20-80%, the percentage by weight of buffer agent is 5-60%, the percentage by weight of pH regulator agent is 1-20%, and the volume of aqueous diluent is 80% of a cumulative volume.
Excipient wherein is selected from polysorbate-20, Polyoxyethylene Sorbitan Monooleate and their mixture; Filler is selected from mannitol, trehalose, dextrose, lactose, glycine, sucrose, carboxyethyl starch, cellulose, cyclodextrin, sodium chloride, starch and their mixture; Buffer agent is selected from citrate hydrate and their mixture; The pH regulator agent is selected from hydrochloric acid, phosphoric acid, lactic acid, sodium hydroxide, succinic acid, citric acid, tartaric acid and their mixture; Aqueous diluent is selected from water, normal saline, 5% dextrose solution and their mixture.
The most preferred prescription composition of the present invention is listed among the embodiment.
The specific embodiment
Following case study on implementation is used to explain the present invention, but is not limited thereto.
Embodiment 1:
Make 1000ml solution before the lyophilization with the supplementary material of following weight proportion.
Preparation method:
1. 6.33g thiourea, 3.0g Polyoxyethylene Sorbitan Monooleate, 15.0g mannitol, 5.88g sodium citrate are stirred in order and dissolve in the water, the water yield is about 80% of a cumulative volume.
2. stir and add concentrated hydrochloric acid adjusting pH value between the 3.8-4.2.
With temozolomide's stirring and dissolving in above-mentioned steps 2 solution.
4. add entry and make batch of material reach final volume, it mixes solution 15 minutes under 25 ℃ at least.
With solution by 0.22 a μ m filter membrane that the test of rinsing well is intact.Filtrate is carried out packing, lyophilizing.
Embodiment 2
Make 1000ml solution before the lyophilization with the supplementary material of following weight proportion.
Preparation method:
1. 2.0g L-arginine, 3.0g Polyoxyethylene Sorbitan Monooleate, 15.0g mannitol, 5.88g sodium citrate are stirred in order and dissolve in the water, the water yield is about 80% of a cumulative volume.
2. stir and add concentrated hydrochloric acid adjusting pH value between the 3.8-4.2.
With temozolomide's stirring and dissolving in above-mentioned steps 2 solution.
4. add entry and make batch of material reach final volume, solution was mixed 15 minutes at least.
With solution by 0.22 a μ m filter membrane that the test of rinsing well is intact, filtrate packing and lyophilizing.
Embodiment 3
Make 1000ml solution before the lyophilization with the supplementary material of following weight proportion.
Preparation method:
1. 2.0g L-glycine, 3.0g Polyoxyethylene Sorbitan Monooleate, 15.0g mannitol, 5.88g sodium citrate are stirred in order and dissolve in the water, the water yield is about 80% of a cumulative volume.
2. stir and add concentrated hydrochloric acid adjusting pH value between the 3.8-4.2.
With temozolomide's stirring and dissolving in above-mentioned steps 2 solution.
4. add entry and make batch of material reach final volume, solution was mixed 15 minutes at least.
With solution by 0.22 a μ m filter membrane that the test of rinsing well is intact, liquid subpackage also carries out lyophilizing.
Embodiment 4
Make 1000ml solution before the lyophilization with the supplementary material of following weight proportion.
Preparation method:
1. 2.0g L-aspartic acid, 3.0g Polyoxyethylene Sorbitan Monooleate, 15.0g mannitol, 5.88g sodium citrate are stirred in order and dissolve in the water, the water yield is about 80% of a cumulative volume.
2. stir and add concentrated hydrochloric acid adjusting pH value between the 3.8-4.2.
With temozolomide's stirring and dissolving in above-mentioned steps 2 solution.
4. add entry and make batch of material reach final volume, solution was mixed 15 minutes at least.
With solution by 0.22 μ m filter membrane, liquid subpackage and a lyophilizing that the test of rinsing well is intact.
Embodiment 5
Make 1000ml solution before the lyophilization with the supplementary material of following weight proportion.
Preparation method:
1. 2.0g L-leucine, 3.0g Polyoxyethylene Sorbitan Monooleate, 15.0g mannitol, 5.88g sodium citrate are stirred in order and dissolve in the water, the water yield is about 80% of a cumulative volume.
2. stir and add concentrated hydrochloric acid adjusting pH value between the 3.8-4.2.
With temozolomide's stirring and dissolving in above-mentioned steps 2 solution.
4. add entry and make batch of material reach final volume, solution was mixed 15 minutes at least.
With solution by 0.22 μ m filter membrane, liquid subpackage and a lyophilizing that the test of rinsing well is intact.
Embodiment 6
Make 1000ml solution before the lyophilization with the supplementary material of following weight proportion.
Preparation method:
1. 2.0g L-proline, 3.0g Polyoxyethylene Sorbitan Monooleate, 15.0g mannitol, 5.88g sodium citrate are stirred in order and dissolve in the water, the water yield is about 80% of a cumulative volume.
2. stir and add 1.48g hydrochloric acid adjusting pH value between the 3.8-4.2.
With temozolomide's stirring and dissolving in above-mentioned steps 2 solution.
4. add entry and make batch of material reach final volume, solution was mixed 15 minutes at least.
With solution by 0.22 μ m filter membrane, liquid subpackage and a lyophilizing that the test of rinsing well is intact.
Claims (6)
1. anti-tumor medicinal preparation, comprise temozolomide or its pharmaceutically acceptable salt, at least a aqueous diluent and at least a solubilizing agent that is enough to dissolve in fact described temozolomide, wherein said solubilizing agent is thiourea, L-lysine, L-methionine, L-tryptophan, L-valine, L-leucine, L-isoleucine, L-aspartic acid, L-cystine, L-cysteine, L-glycine, L-alanine, L-proline, L-arginine, L-tyrosine, L-phenylalanine.
2. pharmaceutical preparation as claimed in claim 1 is characterized in that, said preparation is a freeze dried powder, and temozolomide's content is 1%-50%.
3. freeze dried powder as claimed in claim 2, it is characterized in that, also comprise a kind of filler in the prescription, be selected from mannitol, trehalose, dextrose, lactose, glycine, sucrose, carboxyethyl starch, cellulose, cyclodextrin, sodium chloride, starch and their mixture, content is 20%-80%.
4. as freeze dried powder as described in the claim 2, it is characterized in that, also comprise a kind of pH regulator agent in the prescription, be selected from hydrochloric acid, phosphoric acid, lactic acid, sodium hydroxide, succinic acid, citric acid, tartaric acid and their mixture, content is 1%-20%.
5. freeze dried powder as claimed in claim 4 is characterized in that the pH scope is in the 3.8-4.2 scope.
6. freeze dried powder as claimed in claim 1 is characterized in that, wherein said aqueous diluent is selected from water, normal saline, 5% dextrose solution and their mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105266126A CN101984968A (en) | 2010-10-29 | 2010-10-29 | Preparation method of pharmaceutical preparation of antitumor agent temozolomide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105266126A CN101984968A (en) | 2010-10-29 | 2010-10-29 | Preparation method of pharmaceutical preparation of antitumor agent temozolomide |
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| CN101984968A true CN101984968A (en) | 2011-03-16 |
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| CN2010105266126A Pending CN101984968A (en) | 2010-10-29 | 2010-10-29 | Preparation method of pharmaceutical preparation of antitumor agent temozolomide |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012013116A1 (en) * | 2010-07-29 | 2012-02-02 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| CN102688202A (en) * | 2012-06-07 | 2012-09-26 | 北京莱瑞森医药科技有限公司 | Temozolomide freeze-dried preparation |
| CN102949351A (en) * | 2011-08-16 | 2013-03-06 | 上海汇伦生命科技有限公司 | Preparation method of temozolomide lyophilized preparation |
| CN102949350A (en) * | 2011-08-16 | 2013-03-06 | 上海汇伦生命科技有限公司 | Lyophilized preparation of temozolomide and its preparation method |
| CN103432576A (en) * | 2013-09-09 | 2013-12-11 | 华中农业大学 | Ovomucin liquid preparation and preparation method thereof |
| CN103432085A (en) * | 2013-08-19 | 2013-12-11 | 南京海纳医药科技有限公司 | Temozolomide freeze-drying preparation containing amino acid solubilizer, and preparation method thereof |
| CN103845294A (en) * | 2012-12-03 | 2014-06-11 | 杭州容立医药科技有限公司 | Injectable temozolomide powder injection preparation and preparation method thereof |
| CN104258403A (en) * | 2014-09-28 | 2015-01-07 | 苏州普罗达生物科技有限公司 | Cilostazol composition and preparation method thereof |
| CN104274412A (en) * | 2013-07-01 | 2015-01-14 | 北京恒瑞康达医药科技发展有限公司 | Pharmaceutical preparation containing temozolomide, pharmaceutically acceptable salts or other derivatives thereof |
| CN104721155A (en) * | 2015-04-07 | 2015-06-24 | 齐鲁制药(海南)有限公司 | Temozolomide lyophilized powder preparation and preparation method thereof |
| TWI561526B (en) * | 2011-07-13 | 2016-12-11 | Jiangsu Hengrui Medicine Co | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| CN107875396A (en) * | 2017-12-11 | 2018-04-06 | 上海创诺制药有限公司 | Temozolomide injectable composition and preparation method thereof |
| CN109745292A (en) * | 2017-11-08 | 2019-05-14 | 上海汇伦生命科技有限公司 | A kind of preparation method of temozolomide freeze-dried preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1635871A (en) * | 2002-02-22 | 2005-07-06 | 先灵公司 | Pharmaceutical formulations of antineoplastic agents,in particular temozolomide, processes of making and using the same |
-
2010
- 2010-10-29 CN CN2010105266126A patent/CN101984968A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1635871A (en) * | 2002-02-22 | 2005-07-06 | 先灵公司 | Pharmaceutical formulations of antineoplastic agents,in particular temozolomide, processes of making and using the same |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012013116A1 (en) * | 2010-07-29 | 2012-02-02 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| CN102481288A (en) * | 2010-07-29 | 2012-05-30 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| CN102481288B (en) * | 2010-07-29 | 2014-02-19 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| TWI561526B (en) * | 2011-07-13 | 2016-12-11 | Jiangsu Hengrui Medicine Co | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| CN102949351A (en) * | 2011-08-16 | 2013-03-06 | 上海汇伦生命科技有限公司 | Preparation method of temozolomide lyophilized preparation |
| CN102949350A (en) * | 2011-08-16 | 2013-03-06 | 上海汇伦生命科技有限公司 | Lyophilized preparation of temozolomide and its preparation method |
| CN102949351B (en) * | 2011-08-16 | 2015-05-13 | 上海汇伦生命科技有限公司 | Preparation method of temozolomide lyophilized preparation |
| CN102688202A (en) * | 2012-06-07 | 2012-09-26 | 北京莱瑞森医药科技有限公司 | Temozolomide freeze-dried preparation |
| CN103845294A (en) * | 2012-12-03 | 2014-06-11 | 杭州容立医药科技有限公司 | Injectable temozolomide powder injection preparation and preparation method thereof |
| CN104274412A (en) * | 2013-07-01 | 2015-01-14 | 北京恒瑞康达医药科技发展有限公司 | Pharmaceutical preparation containing temozolomide, pharmaceutically acceptable salts or other derivatives thereof |
| CN103432085A (en) * | 2013-08-19 | 2013-12-11 | 南京海纳医药科技有限公司 | Temozolomide freeze-drying preparation containing amino acid solubilizer, and preparation method thereof |
| CN103432576A (en) * | 2013-09-09 | 2013-12-11 | 华中农业大学 | Ovomucin liquid preparation and preparation method thereof |
| CN104258403A (en) * | 2014-09-28 | 2015-01-07 | 苏州普罗达生物科技有限公司 | Cilostazol composition and preparation method thereof |
| CN104258403B (en) * | 2014-09-28 | 2017-03-01 | 刘宗侠 | A kind of Cilostazol compositionss and preparation method thereof |
| CN104721155A (en) * | 2015-04-07 | 2015-06-24 | 齐鲁制药(海南)有限公司 | Temozolomide lyophilized powder preparation and preparation method thereof |
| CN109745292A (en) * | 2017-11-08 | 2019-05-14 | 上海汇伦生命科技有限公司 | A kind of preparation method of temozolomide freeze-dried preparation |
| CN107875396A (en) * | 2017-12-11 | 2018-04-06 | 上海创诺制药有限公司 | Temozolomide injectable composition and preparation method thereof |
| CN107875396B (en) * | 2017-12-11 | 2020-11-27 | 上海创诺制药有限公司 | Injectable composition of temozolomide and preparation method thereof |
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Application publication date: 20110316 |