CN103432085A - Temozolomide freeze-drying preparation containing amino acid solubilizer, and preparation method thereof - Google Patents
Temozolomide freeze-drying preparation containing amino acid solubilizer, and preparation method thereof Download PDFInfo
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- CN103432085A CN103432085A CN201310360550XA CN201310360550A CN103432085A CN 103432085 A CN103432085 A CN 103432085A CN 201310360550X A CN201310360550X A CN 201310360550XA CN 201310360550 A CN201310360550 A CN 201310360550A CN 103432085 A CN103432085 A CN 103432085A
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- temozolomide
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Abstract
The invention provides a temozolomide freeze-drying preparation containing an amino acid solubilizer. The temozolomide freeze-drying preparation is prepared from 40 ml of a solution, wherein the solution comprises 50-150 mg of an antitumor activity component temozolomide, and 150-350 mg of at least one amino acid solubilizer, and the amino acid solubilizer is selected from one or a mixture of L-arginine, arginine hydrochloride, lysine hydrochloride, L-phenylalanine and asparaginate. The temperature of the preparation in the stirring and dissolving process is 10-15 DEG C, and the pH value is adjusted to be 3.0 to 3.5 by using hydrochloric acid for two times. The temozolomide freeze-drying preparation prepared by using the technique of the invention is rapid in redissolving time, related substances are free of remarkable variation in the standing process, the quality is more stable, the use is convenient, and moreover as the preparation process is simple, the temozolomide freeze-drying preparation is applicable to large-scale production.
Description
Technical field
What the present invention relates to is a kind of temozolomide freeze-dried preparation containing the aminoacid solubilizing agent, belongs to the pharmaceutical chemistry technical field.
Background technology
Temozolomide (Temozolomide, trade name Temodar) is the treatment cerebral glioma of first Ling-Bao Ya (Schering-Plough) company production and the PTS of malignant melanoma.
Temozolomide's chemistry 3,4-dihydro-3-methyl-4-oxomidazo by name is [5,1-d]-1,2,3 also, and 5-tetrazine-8-Methanamide, be for No. CAS 85622-93-1, molecular formula: C
6h
6n
60
2, molecular weight 194.15.Chemical structural formula is:
The temozolomide ratified to go on the market in the U.S. by FDA on August 11st, 1999.Injection temozolomide ratified to go on the market in the U.S. by FDA on February 27th, 2009.It is first compound that a class is referred to as imidazoles tetrazine novel substance, because its toxicity is little, better tolerance and step an important step in the glioma treatment.Still effective with the temozolomide after conventional chemotherapy (BCNU, CCNU) drug resistance, and this two classes medicine is not only without cross resistance and synergistic function is arranged.
The temozolomide is with strong points, specificity is high, can see through blood brain barrier, is the specific drug for the treatment of glioblastoma multiforme or human anaplastic astrocytoma.Because its toxic and side effects is low, can the long period medication, improved patient's quality of life and therapeutic effect.
In addition, the temozolomide also has curative effect preferably to leukemia, melanoma, lymphoma and solid tumor.At present, domestic for the clinical oral temozolomide's capsule that only has, although its orally absorb fully afterwards, bioavailability is high, tissue distribution good, can see through blood brain barrier, its main side effect is nauseating, vomiting, weak and slight bone marrow depression etc.Owing to feeling sick, vomitting, cause drug absorption incomplete, usually before taking medicine, first take Bendectin, to the patient, bring great misery and financial burden.In addition, the normal inapplicable solid drugs of patients after surgery, add traditional clinical application custom, and temozolomide's intravenous injection will be more suitable for patients clinical and use, and improve the compliance of patient's medication, also can meet the medication custom of clinical doctor's dirt.
The temozolomide is slightly soluble in water, soluble,very slightly in methanol, almost insoluble in ethanol, acetone or chloroform, it is poor that the temozolomide has aqueous stability, pH value is greater than under 5 condition the shortcomings such as degraded rapidly, to the preparation of temozolomide freeze-dried preparation, brings very large difficulty.
Current disclosed bibliographical information mainly contains the following aspects to the research of temozolomide freeze-dried preparation:
Disclose a kind of injection of the temozolomide with micronized form of suspension administration in US6251886, but can cause blood vessel blockage, said preparation is also unsuccessful.
A kind of freeze-dried temzolomide powder is disclosed in Chinese patent CN200510014962.3, said preparation dissolves by regulating pH value and heating the ultrasonic temozolomide of making, but the whole layoutprocedure time is long, temozolomide's solution is unstable, produce a large amount of hydrolyzate of dirt in layoutprocedure, there is security-hidden trouble in the use of this ejection preparation.
A kind of freeze-dried temzolomide powder is disclosed in Chinese patent CN03804363.7, said preparation contains the temozolomide, and at least one is enough to dissolve temozolomide's solubilizing agent, described solubilizing agent is urea, L-Histidine, L-threonine, altheine acid, Serine, L-glutaminate or their mixture.Although this lyophilized formulations method has increased the stability of temozolomide's solution to a certain extent, but the solution that this preparation method forms after existing and dissolving is easy to separate out solid, patent adopts the method for secondary filter to solve this problem, but there are the shortcomings such as dirt product time length, complex operation, principal agent waste in the method, industrialization is difficult to realize repeating in batches.
Summary of the invention
The purpose of this invention is to provide one or more better solubilizing agents, improve temozolomide's dissolubility and the stability of solution, shorten temozolomide freeze-dried preparation and redissolve the time, overcome the deficiencies in the prior art part, a kind of stay-in-grade temozolomide freeze-dried preparation is provided.
The present invention selects one or more aminoacid as solubilizing agent, has increased temozolomide's dissolubility and the stability of solution.A kind of in the preferred L-arginine of aminoacid, arginine hydrochloride, lysine hydrochloride, L-Phe, agedoite or their mixture.Experiment showed, in order to upper amino acid and do solubilizing agent, the stability of solution formed after dissolving is good, has reduced the step of secondary filter in producing, and is more conducive to the suitability for industrialized production of preparation.
Temozolomide freeze-dried preparation containing the aminoacid solubilizing agent provided by the invention, it is made by 40ml solution, described solution comprises the active component temozolomide, with at least one aminoacid solubilizing agent, wherein said solubilizing agent is selected from a kind of in L-arginine, arginine hydrochloride, lysine hydrochloride, L-Phe, agedoite or their mixture.Active component temozolomide 50-150mg wherein, aminoacid solubilizing agent 150-350mg.
Temozolomide freeze-dried preparation provided by the invention also comprises a kind of excipient: Tween-80 120mg, a kind of filler: mannitol 600mg, a kind of buffer agent: sodium citrate 235mg, a kind of pH value regulator: hydrochloric acid 160mg.
The preparation method of temozolomide freeze-dried preparation of the present invention comprises the following steps:
(1) take Tween-80, mannitol, solubilizing agent, sodium citrate, 10-15 ℃ of lower stirring and dissolving is in appropriate water for injection, regulate pH value to 3.0-3.5 with hydrochloric acid, add active carbon to stir 30 minutes, decarburization, add the temozolomide, is stirred to the temozolomide and dissolves fully, again with hydrochloric acid, regulate pH value to 3.0-3.5, benefit adds to the full amount of water for injection;
(2) aseptic filtration, fill, lyophilization.
The present invention, after preferably, uses L-arginine, arginine hydrochloride, lysine hydrochloride, L-Phe, agedoite as solubilizing agent, and the temozolomide freeze-dried preparation redissolution time made is very fast, and stability is better in put procedure.
The specific embodiment
Further illustrate the present invention below by embodiment, but content of the present invention is not limited to this fully.
Embodiment 1:
The single dose prescription forms
Preparation method:
(1) compound method:
Take mannitol, L-arginine, Tween-80, the sodium citrate of recipe quantity, add about 80% the water for injection of preparation total amount, stir under 10-15 ℃ and make to dissolve fully and mix homogeneously, with hydrochloric acid solution, regulate pH value to 3.0-3.5.Add active carbon to stir 30 minutes, decarburization, add the temozolomide of recipe quantity, stirring makes the temozolomide dissolve fully and be mixed evenly, and again with hydrochloric acid, regulates pH value to 3.0-3.5, adds water for injection to preparing total amount, aseptic filtration, fill 40ml/ bottle in 100ml lyophilizing bottle, lyophilization.
(2) freeze-drying process:
Sample temperature is reduced to-45 ℃ and keep 5 hours, open vacuum system, current box vacuum reaches 20Pa when following, start lyophilization, and make shelf temperature be increased to-20 ℃ and maintain 12 hours in 1 hour, then in 1 hour, make shelf temperature be increased to-10 ℃ and maintain 18 hours, then in 1 hour, make shelf temperature be increased to-1 ℃ and maintain 12 hours, then in 1 hour, make shelf temperature be increased to 20 ℃ and maintain 10 hours, finally by tamponade, put into and filter the filtrated air outlet.
Embodiment 2:
The single dose prescription forms
Preparation method: with embodiment 1.
Embodiment 3:
The single dose prescription forms
Preparation method: with embodiment 1.
Embodiment 4:
The single dose prescription forms
Preparation method: with embodiment 1.
Embodiment 5:
The single dose prescription forms
Preparation method: with embodiment 1.
Reference examples 1: with reference to Chinese patent CN200510014962.3
The single dose prescription forms
Preparation method:
(1) compound method:
Take recipe quantity sodium chloride, add water for injection, stir and make to dissolve fully under room temperature, the temozolomide who adds recipe quantity, 40 ℃ of stirring in water bath make the temozolomide dissolve fully and be mixed evenly, and add to the full amount of water for injection, regulate pH value to 3.0 with hydrochloric acid, with 0.22 μ m microporous filter membrane aseptic filtration, fill 40ml/ bottle in 100ml lyophilizing bottle, lyophilization.
(2) freeze-drying process: with embodiment 1.
Reference examples 2:
The single dose prescription forms
Preparation method: with embodiment 1.
Reference examples 3: with reference to Chinese patent CN03804363.7
The single dose prescription forms
Preparation method:
(1) compound method:
Take mannitol, L-threonine, Tween-80, sodium citrate, the hydrochloric acid of recipe quantity, add water for injection, stir and within 5 minutes, make to dissolve fully and mix homogeneously, add the temozolomide of recipe quantity, stir and make the temozolomide dissolve fully and be mixed evenly, add to the full amount of water for injection, with 0.22 μ .m microporous filter membrane aseptic filtration, solution is placed 8 hours, again uses 0.22 μ m microporous filter membrane aseptic filtration, fill 40ml/ bottle in 100ml lyophilizing bottle, lyophilization.
(2) freeze-drying process: with embodiment 1.
Reference examples 4:
The single dose prescription forms
Preparation method: with embodiment 1.
Embodiment 6:
Get temozolomide's solution of embodiment 1-5 preparation and temozolomide's solution of reference examples 1-4 preparation, measured respectively the related substance of temozolomide's solution at 0.5 hour, 2 hours, 4 hours, 6 hours, 8 hours, the results are shown in Table 1.
Table 1
As can be seen from the above results, temozolomide's stability of solution of embodiment of the present invention preparation is better than the solution of Comparative Examples preparation.
Embodiment 7:
Prepare temozolomide freeze-dried preparation according to the method in embodiment 1-5 and reference examples 1-4, check respectively its outward appearance, redissolution time, visible foreign matters, particulate matter, moisture, content and related substance, the results are shown in Table 2.
Table 2
As can be seen from the above results, the temozolomide freeze-dried preparation related substance of the embodiment of the present invention is starkly lower than Comparative Examples.
Claims (6)
1. the temozolomide freeze-dried preparation containing the aminoacid solubilizing agent, it is made by 40ml solution, described solution comprises the active component temozolomide, with at least one aminoacid solubilizing agent, it is characterized in that, described solubilizing agent is selected from a kind of in L-arginine, arginine hydrochloride, lysine hydrochloride, L-Phe, agedoite or their mixture.
2. lyophilized formulations as claimed in claim 1, is characterized in that, active component temozolomide 50-150mg.
3. lyophilized formulations as claimed in claim 1, is characterized in that, aminoacid solubilizing agent 150-350mg.
4. lyophilized formulations as claimed in claim 1 adopts following method to be prepared from:
Take Tween-80, mannitol, solubilizing agent, sodium citrate, 10-15 ℃ of lower stirring and dissolving, in appropriate water for injection, regulated pH value to 3.0-3.5 with hydrochloric acid, adds active carbon to stir 30 minutes, decarburization, add the temozolomide, be stirred to the temozolomide and dissolve fully, again with hydrochloric acid, regulate pH value to 3.0-3.5, benefit adds to the full amount of water for injection, aseptic filtration, fill, lyophilization.
5. lyophilized formulations preparation method as claimed in claim 4, is characterized in that, the stirring and dissolving process temperature is 10-15 ℃.
6. lyophilized formulations preparation method as claimed in claim 4, is characterized in that, twice use hydrochloric acid is regulated pH value to 3.0-3.5.
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| CN201310360550XA CN103432085A (en) | 2013-08-19 | 2013-08-19 | Temozolomide freeze-drying preparation containing amino acid solubilizer, and preparation method thereof |
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| CN201310360550XA CN103432085A (en) | 2013-08-19 | 2013-08-19 | Temozolomide freeze-drying preparation containing amino acid solubilizer, and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003072082A1 (en) * | 2002-02-22 | 2003-09-04 | Schering Corporation | Pharmaceutical formulations of antineoplastic agents, in particular temozolomide, processes of making and using the same |
| CN101869551A (en) * | 2010-06-28 | 2010-10-27 | 江苏奥赛康药业有限公司 | Temozolomide freeze-dried preparation |
| CN101984968A (en) * | 2010-10-29 | 2011-03-16 | 北京润德康医药技术有限公司 | Preparation method of pharmaceutical preparation of antitumor agent temozolomide |
-
2013
- 2013-08-19 CN CN201310360550XA patent/CN103432085A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003072082A1 (en) * | 2002-02-22 | 2003-09-04 | Schering Corporation | Pharmaceutical formulations of antineoplastic agents, in particular temozolomide, processes of making and using the same |
| CN101869551A (en) * | 2010-06-28 | 2010-10-27 | 江苏奥赛康药业有限公司 | Temozolomide freeze-dried preparation |
| CN101984968A (en) * | 2010-10-29 | 2011-03-16 | 北京润德康医药技术有限公司 | Preparation method of pharmaceutical preparation of antitumor agent temozolomide |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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Application publication date: 20131211 |