CN1923197A - Freeze-dried temzolomide powder for injection and its preparing process - Google Patents
Freeze-dried temzolomide powder for injection and its preparing process Download PDFInfo
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- CN1923197A CN1923197A CN 200510014962 CN200510014962A CN1923197A CN 1923197 A CN1923197 A CN 1923197A CN 200510014962 CN200510014962 CN 200510014962 CN 200510014962 A CN200510014962 A CN 200510014962A CN 1923197 A CN1923197 A CN 1923197A
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Abstract
The invention relates to an injection motiol freeze dried, and relative preparation. Wherein, it comprises 1, using injection water to solve motiol; 2, dissolving freeze dried into injection solvent, adding motiol, to reduce the contact time between motiol and supporter in water and reduce the heated time of motiol; 3, heating, mixing and processing with ultrasonic wave, to dissolve, and using freeze drying technique to prepare needed freeze dried. The invention can reduce side effect, improve stability and support batch production.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of freeze-dried temzolomide powder for injection and preparation method.
Background technology
Temozolomide (temozolomide, trade name Temodar) is the treatment cerebral glioma of Schering-Plough company production and the PTS of malignant melanoma, goes on the market in the U.S. by the FDA approval on August 11st, 1999, its chemistry by name 3,4-dihydro-3-methyl-4-oxo-imidazole is [5,1-d]-1,2 also, 3,5-tetrazine-8-amide, crude drug are white or light brown/pale pink powder, and relative molecular mass is 194.15, pH＜5 time are stable, and o'clock easily decompose pH＞7.It is first chemical compound that a class is referred to as imidazoles tetrazine novel substance, its toxicity is little, better tolerance and step an important step in glioma treatment, can be absorbed fully after it is oral, and bioavailability is up to 98%, tissue distribution is good, can see through blood brain barrier.Because its toxic and side effects is low, also just can the long period medication, improved long-term efficacy, patient's body ﹠ mind state equal be improved significantly, improved quality of life of patient.Still effective after conventional chemotherapy (BCNU, the CCNU) drug resistance with the temozolomide, and this two classes medicine does not only have cross resistance and synergistic function is arranged.Therefore, the temozolomide is the present best relatively treatment cerebral glioma and the medicine of malignant melanoma.In addition, the temozolomide also has curative effect preferably to leukemia, melanoma, lymphoma and solid tumor.At present, be used for the clinical oral temozolomide's capsule that has only, though absorption fully after it is oral, bioavailability height, tissue distribution be good, can see through blood brain barrier, but its main side effect for feel sick, vomiting, weak, constipation and slight bone marrow depression etc., the sickness rate of severe nausea and vomiting is respectively 10% and 6%.Because nauseating, vomiting causes drug absorption incomplete, takes Bendectin usually before taking medicine earlier, brings great misery and financial burden to the patient.The normal inapplicable solid drugs of patients after surgery is added traditional clinical application custom in addition, and temozolomide's intravenous injection will be more suitable for patients clinical and use, and improve the compliance of patient's medication, also can satisfy clinician's medication custom.Consider temozolomide's unsettled characteristic in water, we are made into freeze-dried powder, thereby improve stability of formulation.
Summary of the invention
Main purpose of the present invention is to provide a kind of stable freeze-dried temzolomide powder for injection, it has good stable and water solublity, can directly be dissolved in 5%, 10% glucose or 0.9% sodium chloride injection posterior vein instils, its content is the 98%-102% of labelled amount after 72 hours in injection, and is up to specification.The toxic and side effects that the present invention has avoided oral temozolomide to cause has been complied with the clinical application custom, has alleviated patient's misery.
Another object of the present invention is to provide the preparation method of this freeze-dried powder.
Freeze-dried temzolomide powder for injection of the present invention adopts following scheme to be prepared from:
A. by following percentage by weight (W/V) thing of getting it filled: temozolomide 0.01-2%, lyophilizing proppant 1-20%, pH regulator agent and water for injection;
B. temozolomide and lyophilizing proppant are dissolved in water, regulate pH to certain limit with the pH regulator agent, lyophilizing obtains freeze-dried temzolomide powder.
Wherein, comprise among the step b, add water for injection, heated and stirred or ultrasonicly make dissolving above-mentioned lyophilizing proppant, add the temozolomide, heated and stirred or ultrasonicly dissolve fully to the temozolomide is regulated pH with the pH regulator agent, filters, lyophilizing, nitrogen is filled in sterilization, obtains freeze-dried temzolomide powder; Filter and adopt microporous filter membrane, sand filtration rod, vertical molten funnel or filter press device; Heating-up temperature is 25 ℃-60 ℃; Methods such as 0.22um microporous filter membrane, flowing steam, high steam, temperature 100-121 ℃, time 5-120 minute were adopted in sterilization.
This lyophilized injectable powder is diluted in 5%, 10% glucose or 0.9% sodium chloride injection rear stability is good, side effect is little, has guaranteed the safety of medication, has further guaranteed effective utilization of temozolomide; And need not to take Bendectin before the administration, make patient acceptant, made things convenient for clinical application, alleviated patient's burden simultaneously.This lyophilized injectable powder preparation technology method is simple, applicable to a large amount of preparations and suitability for industrialized production.
Lyophilizing liquid of the present invention is write out a prescription substantially:
| Form | Percentage composition (w/v) |
| Temozolomide freeze-dried proppant pH regulator agent water for injection | 0.01-2 an amount of surplus of 1-20 |
Wherein the lyophilizing proppant includes but not limited to sodium chloride, glucose sugar, lactose, mannitol, sodium alginate, xylitol, sorbitol, dextran, albumin etc., is used alone or as a mixture, and total consumption is the 1-20% of injection.
The pH regulator agent includes but not limited to hydrochloric acid, sodium hydroxide, glacial acetic acid, sodium acetate, phosphoric acid, citric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate etc., is used alone or as a mixture.
A kind of temozolomide freeze-dried powder needle set preparation of the present invention is as follows:
Take by weighing the lyophilizing proppant of recipe quantity, the water for injection that adds recipe quantity, heated and stirred or ultrasonicly make dissolving adds the temozolomide of recipe quantity, heated and stirred or ultrasonicly dissolve fully to the temozolomide, regulate pH to 1.2～7 with the pH regulator agent, filter packing, lyophilizing, fill nitrogen, get freeze-dried temzolomide powder for injection.
Wherein, the temperature of all heating is 25 ℃-60 ℃ in the said method.
Filter method in this preparation method includes but not limited to microporous filter membrane, sand filtration rod, vertical molten funnel, filter press device etc.
Sterilization method in this preparation method is meant including, but not limited to methods such as 0.22um microporous filter membrane, flowing steam, high steam, temperature 100-121 ℃, time 5-120 minute.
Earlier the lyophilizing proppant is dissolved in the solvent for injection in this preparation method, adds the temozolomide again, purpose is to reduce temozolomide and the time of contact of proppant in aqueous solution, reduces temozolomide's heated time simultaneously.
The freeze-dried temzolomide powder for injection of this method preparation is white or yellowish solid freeze-dried powder.Lyophilizing liquid drug loading is 0.1-20mg/ml.
The specific embodiment
Below by embodiment, the invention will be further described.
Embodiment 1 preparation freeze-dried temzolomide powder for injection
Take by weighing sodium chloride 5 grams, add 80 milliliters of waters for injection, be stirred to dissolving under the room temperature, add 400 milligrams of temozolomides, water-bath is ultrasonic dissolves fully to the temozolomide, adds water to 100 milliliters, regulates pH to 3.0 with dilute hydrochloric acid, with 0.22 μ m filtering with microporous membrane degerming, packing, nitrogen is filled in lyophilizing, packing promptly gets freeze-dried temzolomide powder for injection.
Embodiment 2 preparation freeze-dried temzolomide powder for injection
Take by weighing sodium chloride 50 grams, mannitol 50 grams, add 850 milliliters of waters for injection, be stirred to dissolving under the room temperature, add 500 milligrams of temozolomides, the temozolomide is dissolved fully, add water to 1000 milliliters in 50 ℃ of heated and stirred, regulate pH to 3.0 with glacial acetic acid, filter 115 ℃ of sterilizations of flowing steam 30 minutes, packing with the sand filtration rod, lyophilizing, fill nitrogen, packing promptly gets freeze-dried temzolomide powder for injection.
Embodiment 3 preparation freeze-dried temzolomide powder for injection
Take by weighing dextran 5 grams, lactose 8 grams, albumin 2 grams, add 90 milliliters of waters for injection, make dissolving in 60 ℃ of heated and stirred, add 1500 milligrams of temozolomides, 60 ℃ of heated and stirred are dissolved the dissolving temozolomide fully, add water to 100 milliliters, regulate pH to 4.5 with phosphate buffer, filter 115 ℃ of sterilizations of high steam 30 minutes, packing with the molten funnel that hangs down, lyophilizing, fill nitrogen, packing promptly gets freeze-dried temzolomide powder for injection.
Embodiment 4 preparation freeze-dried temzolomide powder for injection
Take by weighing mannitol 40 grams, xylitol 10 grams, sorbitol 25 grams, add 425 milliliters of waters for injection, make dissolving in 40 ℃ of heated and stirred, add 5000 milligrams of temozolomides, 40 ℃ of heated and stirred are dissolved the dissolving temozolomide fully, add water to 500 milliliters, regulate pH to 5.0 with phosphate buffer, filter 115 ℃ of sterilizations of high steam 30 minutes, packing with the filter press device, lyophilizing, fill nitrogen, packing promptly gets freeze-dried temzolomide powder for injection.
Embodiment 5 preparation freeze-dried temzolomide powder for injection
Take by weighing sodium chloride 100 grams, glucose sugar 200 grams, sodium alginate 60 grams, add 1.6 liters of waters for injection, be stirred to dissolving under the room temperature, add temozolomide's 36 grams, water-bath is ultrasonic dissolves fully to the temozolomide, adds water to 2 liters, and phosphate buffer is regulated pH to 7.0, with 0.22 μ m filtering with microporous membrane degerming, packing, nitrogen is filled in lyophilizing, packing promptly gets freeze-dried temzolomide powder for injection.
Embodiment 6 preparation freeze-dried temzolomide powder for injection
Take by weighing sodium chloride 2 grams, add 80 milliliters of waters for injection, be stirred to dissolving under the room temperature, add 200 milligrams of temozolomides, water-bath is ultrasonic dissolves fully to the temozolomide, adds water to 100 milliliters, regulates pH to 1.5 with dilute hydrochloric acid, with 0.22 μ m filtering with microporous membrane degerming, packing, nitrogen is filled in lyophilizing, packing promptly gets freeze-dried temzolomide powder for injection.
Changes of contents (pressing three batches of embodiment 1 preparations) before and after the embodiment 7 examination freeze-dried temzolomide powder for injection lyophilizing
Temozolomide's content adopts rp-hplc determination, and chromatographic condition is Agilent 1100 serial HPLC; Agilent G1314A VWD detector; Agilent 1100 chromatographic work stations, Kromasil C
18Analytical column (5 μ, 4.6mm * 25mm); Mobile phase is acetonitrile-water (10: 90), flow velocity 1.0ml/min, and sample size 20 μ l detect wavelength 329nm, ambient operation.By the changes of contents before and after the variation investigation freeze-dried temzolomide powder lyophilizing of peak area, the result is as shown in table 1:
Changes of contents before and after the lyophilizing of the temozolomide freeze-dried powder pin of table 1 injection
| Lot number | 05081801 | 05081802 | 05081803 |
| Peak area before the lyophilizing | 23070.6 | 22902.5 | 22894.0 |
| Peak area after the lyophilizing | 23185.9 | 22833.8 | 23214.5 |
| Indicate percentage composition | 100.5％ | 99.7％ | 101.4％ |
The result shows that content does not almost change before and after the lyophilizing, and this description of test lyophilizing does not destroy principal agent.
The stability of embodiment 8 examination freeze-dried temzolomide powder for injection in 5% glucose liquid glucose
Temozolomide freeze-dried powder pin is according to the preparation of embodiment 1 method, and content assaying method and chromatographic condition are with embodiment 7.
Embodiment 1 temozolomide freeze-dried powder pin is dissolved in 5% glucose injection, is made into 0.02% solution, place at normal temperatures, adopt rp-hplc determination different time content of medicines to change, the result is as shown in table 2:
The stability of table 2 injection lyophilizing temozolomide powder pin in 5% Glucose Liquid
| Time (h) | 0 | 2 | 4 | 8 | 12 | 18 | 24 | 36 | 48 | 60 | 72 |
| Peak area | 3620.3 | 3627.1 | 3618.4 | 3622.1 | 3618.0 | 3619.2 | 3616.0 | 3612.0 | 3590.2 | 3556.5 | 3544.9 |
| Indicate (%) | 100.00 | 100.20 | 99.95 | 100.05 | 99.94 | 99.97 | 99.88 | 99.77 | 99.17 | 98.24 | 97.92 |
The result shows that freeze-dried temzolomide powder for injection 72 hours content in 5% glucose liquid glucose is 97.92%～100.2% of labelled amount, and stability meets the requirements.
Embodiment 9 examinations are freeze-dried temzolomide powder for injection and the stability comparison therein of temozolomide's aqueous solution under 60 ℃ of environment
Temozolomide freeze-dried powder pin prepares according to embodiment 1 method, measure the content of different time points with high-efficient liquid phase technique, recently compare freeze-dried temzolomide powder for injection and the stability of temozolomide's aqueous solution in 60 ℃ with peak area and labelled amount percentage, its chromatographic condition is with embodiment 7.
Sample treatment: take from system freeze-dried temzolomide powder for injection to the 60 ℃ baking oven and observe, take out one bottle during detection, add the 5ml water dissolution, precision is measured the volumetric flask of this lysate 1ml to 10ml, adds water to scale, sample introduction; Dispose the temozolomide's aqueous solution for injection of 4mg/ml and the hydrochloric acid solution of 0.1mol/L respectively, to 60 ℃ of baking ovens, observe equally.Investigation the results are shown in Table 3.
Table 3 freeze-dried temzolomide powder for injection and temozolomide's aqueous solution stability therein relatively
| Time | 0 | 2 | 4 | 8 | 12 | 16 | 20 | 24 |
| The injectable powder peak area | 35682.1 | 36395.7 | 35789.1 | 35111.2 | 35361.0 | 36324.4 | 35575.053 | 36253.0 |
| The injectable powder labelled amount | 100％ | 102％ | 100.3％ | 98.4％ | 99.1％ | 101.8％ | 99.7％ | 101.6％ |
| The aqueous solution peak area | 16397.1 | 11827.2 | 8859.6 | 4851.6 | 2293.2 | 837.9 | 126.9 | 101.0 |
| The aqueous solution labelled amount | 100％ | 72.1％ | 54.0％ | 29.6％ | 14％ | 5.1％ | 0.77％ | 0.62％ |
| The acid solution peak area | 31589.65 | 30762.3 | 29500.2 | 27740.6 | 25820.3 | 24050.9 | 21782.2 | 20417.7 |
| The acid solution labelled amount | 100％ | 97.4％ | 93.4％ | 87.8％ | 81.7％ | 76％ | 69％ | 64.6％ |
Interpretation of result: drawn by this experiment, under 60 ℃ of conditions, freeze-dried temzolomide powder for injection content is no change almost, and stability better; And the temozolomide only is 0.62% of labelled amount after 24 hours in aqueous solution, almost completely degraded; The temozolomide is stable in aqueous solution relatively in the hydrochloric acid solution of 0.1mol/L, but only is 64.6% of labelled amount after 24 hours, and its stability is far away not as good as lyophilized injectable powder; So freeze-dried temzolomide powder for injection can satisfy galenic pharmacy and clinical needs.
Claims (10)
1. freeze-dried temzolomide powder for injection is characterized in that adopting following method to be prepared from:
A. by following percentage by weight (W/V) thing of getting it filled: temozolomide 0.01-2%, lyophilizing proppant 1-20%, pH regulator agent and water for injection;
B. temozolomide and lyophilizing proppant are dissolved in water, regulate pH to certain limit with the pH regulator agent, lyophilizing obtains freeze-dried temzolomide powder.
2. the described powder pin of claim 1, it is characterized in that comprising among the described step b with above-mentioned lyophilizing proppant, add water for injection, heated and stirred or ultrasonicly make dissolving, add the temozolomide, heated and stirred or ultrasonicly dissolve fully to the temozolomide is regulated pH with the pH regulator agent, filters, lyophilizing, nitrogen is filled in sterilization, obtains freeze-dried temzolomide powder.
3. claim 1 or 2 described powder pins is characterized in that described proppant is selected from following a kind of or its mixing: sodium chloride, glucose, lactose, mannitol, sodium alginate, xylitol, sorbitol, dextran, albumin.
4. claim 1 or 2 described powder pins is characterized in that described proppant is selected from following a kind of or its mixing: sodium chloride, mannitol, dextran, xylitol, glucose.
5. claim 1 or 2 described powder pins is characterized in that described pH regulator agent is selected from following a kind of or its mixing: hydrochloric acid, sodium hydroxide, glacial acetic acid, sodium acetate, phosphoric acid, citric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate.
6. claim 1 or 2 described powder pins is characterized in that pH to 1.2～7.0 are regulated in the pH regulator agent among the step b; Filter and adopt microporous filter membrane, sand filtration rod, vertical molten funnel or filter press device; Hot temperature is 25 ℃-60 ℃; Methods such as 0.22um microporous filter membrane, flowing steam, high steam, temperature 100-121 ℃, time 5-120 minute were adopted in sterilization.
7. claim 1 or 2 described powder pins is characterized in that the freeze-dried powder drug loading is 0.1-20mg/ml.
8. the preparation method of the described freeze-dried temzolomide powder for injection of claim 1 comprises the steps:
A. by following percentage by weight (W/V) thing of getting it filled: temozolomide 0.01-2%, lyophilizing proppant 1-20%, pH regulator agent and water for injection;
B. temozolomide and lyophilizing proppant are dissolved in water, regulate pH to certain limit with the pH regulator agent, lyophilizing obtains freeze-dried temzolomide powder.
9. the described method of claim 8, it is characterized in that comprising among the described step b with above-mentioned lyophilizing proppant, add water for injection, heated and stirred or ultrasonicly make dissolving, add the temozolomide, heated and stirred or ultrasonicly dissolve fully to the temozolomide is regulated pH with the pH regulator agent, filters, lyophilizing, nitrogen is filled in sterilization, obtains freeze-dried temzolomide powder.
10. the described method of claim 8 is characterized in that the proppant among the step a is selected from: sodium chloride, glucose, lactose, mannitol, sodium alginate, xylitol, sorbitol, dextran, albumin; PH to 1.2～7.0 are regulated in the pH regulator agent among the step b; Filter and adopt microporous filter membrane, sand filtration rod, vertical molten funnel or filter press device; Heating-up temperature is 25 ℃-60 ℃; Methods such as 0.22um microporous filter membrane, flowing steam, high steam, temperature 100-121 ℃, time 5-120 minute were adopted in sterilization.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101869551A (en) * | 2010-06-28 | 2010-10-27 | 江苏奥赛康药业有限公司 | Temozolomide freeze-dried preparation |
| CN101467967B (en) * | 2007-12-29 | 2012-05-23 | 北京京卫燕康药物研究所有限公司 | Double-element solution type preparation for intravenous injection and intracerebral injection |
| CN101559037B (en) * | 2008-04-16 | 2013-01-30 | 北京京卫燕康药物研究所有限公司 | Binary solution type preparation for intravenous injection and intracerebral injection |
| 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 |
| 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 |
| CN110327361A (en) * | 2019-08-11 | 2019-10-15 | 天津乾丰瑞科技有限公司 | A kind of pharmaceutical composition of clindamycin phosphate and preparation method thereof |
| US10806732B2 (en) | 2016-05-02 | 2020-10-20 | Double Bond Pharmaceutical AB | Stable anti-neoplastic pharmaceutical composition comprising temozolomide and method of preparing the composition |
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2005
- 2005-09-01 CN CN200510014962A patent/CN100588399C/en active Active
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101467967B (en) * | 2007-12-29 | 2012-05-23 | 北京京卫燕康药物研究所有限公司 | Double-element solution type preparation for intravenous injection and intracerebral injection |
| CN101559037B (en) * | 2008-04-16 | 2013-01-30 | 北京京卫燕康药物研究所有限公司 | Binary solution type preparation for intravenous injection and intracerebral injection |
| CN101869551A (en) * | 2010-06-28 | 2010-10-27 | 江苏奥赛康药业有限公司 | Temozolomide freeze-dried preparation |
| CN101869551B (en) * | 2010-06-28 | 2012-04-18 | 江苏奥赛康药业股份有限公司 | 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 |
| 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 |
| 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 |
| US10806732B2 (en) | 2016-05-02 | 2020-10-20 | Double Bond Pharmaceutical AB | Stable anti-neoplastic pharmaceutical composition comprising temozolomide and method of preparing the composition |
| 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 |
| CN113616605A (en) * | 2017-11-08 | 2021-11-09 | 上海汇伦生物科技有限公司 | Preparation method of temozolomide freeze-dried preparation |
| CN110327361A (en) * | 2019-08-11 | 2019-10-15 | 天津乾丰瑞科技有限公司 | A kind of pharmaceutical composition of clindamycin phosphate and preparation method thereof |
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|---|---|
| CN100588399C (en) | 2010-02-10 |
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Application publication date: 20070307 Assignee: Tianshili Diyi Pharmaceutical Ind Co., Ltd., Jiangsu Assignor: Dishili Investment Holding Group Co., Ltd., Tianjin Contract record no.: 2015320000053 Denomination of invention: Freeze-dried temzolomide powder for injection and its preparing process Granted publication date: 20100210 License type: Exclusive License Record date: 20150312 |
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Effective date of registration: 20160728 Address after: 223003 Huaian City, Jiangsu province Qingpu Industrial Park, Chaoyang Road No. 168 Patentee after: Tianshili Diyi Pharmaceutical Ind Co., Ltd., Jiangsu Address before: 300402, No. 1, Liaohe East Road, Beichen Science Park, Beichen District, Tianjin Patentee before: Dishili Investment Holding Group Co., Ltd., Tianjin |