CN104721155A - Temozolomide lyophilized powder preparation and preparation method thereof - Google Patents
Temozolomide lyophilized powder preparation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical preparations and specifically relates to a temozolomide lyophilized powder preparation. The temozolomide lyophilized powder preparation comprises an active ingredient of temozolomide or a pharmaceutically acceptable salt thereof, and a solution before lyophilization further contains an excipient, a wetting agent, a buffer agent, an osmotic pressure regulating agent, a pH regulating agent, water for injection and an organic solvent, wherein the organic solvent is selected from one or any combination of ethanol, acetone, isopropanol, n-propanol, butanone, sec-butyl alcohol and methanol, and is preferably ethanol. The temozolomide lyophilized powder preparation provided by the invention has the advantages of stable quality, high re-dissolution speed and a small residual amount of the organic solvent. The invention further provides a method for preparing the preparation. The process provided by the invention is simple and convenient in preparation process and easy to control production links, the organic solvent accounts for a relatively small part of total volume of material liquid, the pollution to production equipment and environment caused by the organic solvent is reduced, and thus the method is suitable for large-scale production.
Description
Technical field
The invention belongs to technical field of medicine.Be specifically related to a kind of steady quality, redissolve fireballing temozolomide's lyophilization powder injection formulation and preparation method thereof.
Background technology
Temozolomide (temozolomide) chemical name: 3,4-dihydro-3-methyl-4-oxomidazo is [5, l-d]-l also, 2,3,5-tetrazine-8-amide, for imidazo tetrazine class has the protective embankment agent of anti-tumor activity, chemical structural formula is as follows:
This product is the treatment cerebral glioma of first Ling-Bao Ya (Schering-Plough) company production and the medicine of malignant melanoma.The domestic temozolomide preparation that goes on the market is hard capsule, oral formulations is easy to use, and can be completely absorbed after oral, bioavailability is up to 98%, main side effect is Nausea and vomiting, weak, constipation and slight bone marrow depression, and wherein the side reaction such as severe nausea, vomiting is common.This usually causes the fluctuation of drug absorption, thus affects bioavailability.The reaction of some patient's Nausea and vomiting is too serious and be difficult to by oral administration, and has a lot of patient's dysphagia clinically, and not by oral administration, urgent clinical needs can temozolomide's preparation of intravenously administrable.But temozolomide is stable under pH<7, easily decompose during pH>7, temozolomide is as prodrug, easily be degraded to activated product in aqueous, preparation becomes conventional intravenous fluid can not ensure long-time stability, therefore considers it to be solidified by lyophilization and prepares and become aseptic freeze-dried powder, using the aqueous diluent of front injection to rebuild, obtaining temozolomide's injection, is a breakthrough of temozolomide's preparation.
For realizing the parenteral administration of temozolomide, disclose a kind of with temozolomide's preparation of micronized suspension administration in US Patent No. 6251886, but suspension formulation is unsatisfactory, it can cause blood vessel blockage.Consider the characteristic that temozolomide is unstable in aqueous, therefore it is solidified by lyophilization and prepare and become aseptic freeze-dried powder, being used the aqueous diluent of injection to rebuild before use to obtain can temozolomide's injection of parenteral administration, is a well strategy.
Because temozolomide's dissolubility in water is poor, about 3.1mg/ml, and dissolution velocity is comparatively slow, and cause batching overlong time, product related substance is higher.Adopt ordinary recipe and technique batching speed slowly, be unfavorable for ensureing product quality, the lyophilized powder solubility of final preparation is poor, makes troubles and risk, make doctor and patient throw doubt upon to product quality simultaneously, be unfavorable for clinical practice to Clinical practice.
Disclose a kind of freeze-dried temzolomide powder in Chinese patent CN100588399, said preparation dissolves by regulating pH and the ultrasonic temozolomide of making of heating, and the batching time is longer, and heating produces a large amount of hydrolyzate, is unfavorable for solution-stabilized.In addition, its preparation solubility is poor, needs the long period could redissolve completely before Clinical practice.The longer redissolution time brings tripartite face risk: on the one hand as fruit product will produce serious clinical application risk at the basic upper vein infusion all do not dissolved, on the other hand, long period does not redissolve and doctor and patient may be made to throw doubt upon to product quality, is unfavorable for clinical practice; The third aspect, longer redissolution disadvantage in time is stablized in feed liquid, affects product quality.
Disclose a kind of freeze-dried temzolomide powder in Chinese patent CN 102949350, it adopts nicotiamide, biuret or mixture as solubilizing agent in order to improve redissolution speed.But these two kinds of solubilizing agents have certain pharmacological action after injecting human body with preparation, can not ensure preparation clinical safety when dosage is larger.
Disclose a kind of freeze-dried temzolomide powder in Chinese patent CN 101172104, which use solubilizing agent, comprise urea, L-threonine, L-Histidine, L-Aspartic acid, Serine, L-glutaminate or its mixture.Its batching speed is slow, and stirring at least 2 hours raw materials can dissolve, and longer batching disadvantage in time is in production assurance.
A kind of preparation method of temozolomide freeze-dried preparation is disclosed in Chinese patent CN 102949351; wherein have employed the mixed solvent system of butanol/water; its technique batching speed is slow; be unfavorable for amplifying and produce; the organic solvent adopted is the lower toxicity organic solvent that the tert-butyl alcohol does not belong to " Chinese Pharmacopoeia " version in 2010 and specifies; its consumption in prescription is general comparatively large, is unfavorable for safety and environmental conservation.Tert-butyl alcohol freezing point is higher, not easily removes in freezing dry process, and residual concentration is higher in the formulation to cause it, is unfavorable for drug safety.
Current temozolomide's injectable powder ubiquitous problem in preparation process is: the time of 1, preparing burden is long, produces hydrolysis impurity, is unfavorable for the guarantee of product quality; 2, product solubility is poor, is unfavorable for clinical preparation and use, has Clinical practice risk.3, in order to improve product solubility, with the addition of extra material as solubilizing agent, and these solubilizing agents has Pharmacological, are unfavorable for the safety of clinical application.4, the consumption of organic solvent adopted is large, is unfavorable for safety and environmental conservation, and organic solvent is residual higher in the formulation, is unfavorable for drug safety.
Summary of the invention
Technical problem to be solved by this invention overcomes the deficiencies in the prior art, provides a kind of and can prepare burden fast, steady quality, redissolution speed are fast, facilitates Clinical practice, temozolomide freeze-dried powder injection formulation reducing clinical application risk and preparation method thereof.
The temozolomide freeze-dried powder preparation of one of the present invention, active component is temozolomide or its pharmaceutically acceptable salt, also contain excipient, wetting agent, buffer agent, osmotic pressure regulator, pH adjusting agent, water for injection and organic solvent in solution before lyophilizing, wherein said organic solvent is selected from one of ethanol, acetone, isopropyl alcohol, normal propyl alcohol, butanone, sec-butyl alcohol, methanol or combination in any.
In a preferred embodiment of the invention, described organic solvent is ethanol.
In a preferred embodiment of the invention, described organic solvent accounts for 0.01% ~ 10% of overall solution volume before lyophilizing, and preferably 0.05% ~ 5%, most preferably 0.1% ~ 4.5%.
In a preferred embodiment of the invention, the mass percent of temozolomide before lyophilizing in solution is 0.1 ~ 2%.
In a preferred embodiment of the invention, in described temozolomide freeze-dried powder preparation, the mass percentage content of temozolomide is 1% ~ 50%.
In temozolomide freeze-dried powder preparation of the present invention, the mass percent of excipient in temozolomide freeze-dried powder preparation is 30% ~ 90%, and described excipient is selected from one of glucose, albumin, sodium chloride, lactose, mannitol, sorbitol, xylitol, dextran, sodium alginate or combination in any;
The mass percent of wetting agent in temozolomide freeze-dried powder preparation is 0% ~ 50%, and described wetting agent is selected from one of Tween-20, Tween-80, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, bile salts, lecithin, Polyethylene Glycol or combination in any;
The mass percent of buffer agent in temozolomide freeze-dried powder preparation is 1% ~ 50%, and described buffer agent is selected from one of citrate, lactate, acetate, tartrate, succinate, phosphate or combination in any, preferably citric acid salt;
Described pH adjusting agent is selected from one of hydrochloric acid, citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid or combination in any;
The mass percent of osmotic pressure regulator in temozolomide freeze-dried powder preparation is 1% ~ 50%, and described osmotic pressure regulator is selected from one of glycerol, sodium chloride, potassium chloride, mannitol, glucose, sorbitol or combination in any
In a preferred embodiment of the invention, excipient is mannitol, and wetting agent is polyoxyethylene sorbitan monoleate, and buffer agent is sodium citrate, and pH adjusting agent is hydrochloric acid, and osmotic pressure regulator is sodium chloride.
In a preferred embodiment of the invention, before lyophilizing, the pH scope of solution is 2 ~ 7.
Temozolomide freeze-dried powder preparation of the present invention, steady quality, speed of redissolving is fast, and Clinical practice is convenient, safety.
The present invention also provides a kind of preparation method of above-mentioned temozolomide freeze-dried powder preparation, comprises the following steps:
1) excipient of recipe quantity, wetting agent, buffer agent, osmotic pressure regulator stirring and dissolving is taken in water for injection;
2) adopt pH adjusting agent by step 1) in the pH value of gained feed liquid be adjusted to 2-7;
3) take temozolomide or its officinal salt of recipe quantity, disperseed in organic solvent, dispersion liquid to be added step 2) in gained feed liquid, stirring and dissolving;
4) feed liquid is settled to cumulative volume, after filtration sterilization, is dispensed into vial;
5) carry out lyophilization, obtain the temozolomide freeze-dried powder preparation of final products.
Preferably, in above-mentioned preparation method, step 3) described dispersion method is in organic solvent the mode adopting high-shearing dispersion emulsifying machine dispersion.The mode rate of dispersion adopting high-shearing dispersion emulsifying machine to carry out disperseing is fast, save time, and dispersion effect is good than common dispersed with stirring mode.
Find in the present inventor's process of the test, raw material is unstable in aqueous, batch temperature is higher, raw material and water longer for time of contact, impurity increase more remarkable.And temozolomide's raw material belongs to insoluble drug, when temperature is lower, dissolution velocity is slow in aqueous, thus cause the batching time longer, a large amount of impurity is produced in blending process, raised temperature can shorten the material dissolution time to a certain extent, but raw material is same in the short time in high-temperature water solution produces a large amount of impurity, be unfavorable for production assurance.Therefore, under the prerequisite not raising batch temperature, the shortening batching time fundamentally could ensure product quality.
The present inventor finds, do not raising under batch temperature prerequisite, introduce organic solvent in proportioning process and can reach the object shortening the batching time, innovation of the present invention is, selected organic solvent is the poor solvent of temozolomide, and temozolomide is almost insoluble in these organic solvents.Introduce the dissolution velocity that this poor solvent can reduce raw material in solution, but inventor find, if first raw material is disperseed in organic solvent, and then add in aqueous solution stir significantly can accelerate drug dissolution rates.It is this that in preparation technology, to introduce adverse drug solvent and reach the effect speeding drug dissolution rates be beyond thought.
The present inventor find, the organic solvent freezing point selected by the present invention is lower, but due in prescription consumption less, therefore do not affect product lyophilization.Under the prerequisite not having solubilizing agent, organic solvent is introduced in preparation prescription, organic solvent is removed eventually through lyophilization, the preparation speed of redissolving of final preparation is significantly accelerated, the organic solvent introduced can change the crystallization behavior of freezing dry process Chinese medicine, generate the fireballing drug crystal forms of redissolution, thus fundamentally accelerate preparation redissolution speed, this by introducing lower boiling raw material poor solvent, change the crystallization behavior in pharmaceutical freeze dry run, thus quickening preparation speed of redissolving is beyond thought.
Organic solvent selected by the present invention is the Equations of The Second Kind or the 3rd class organic solvent that " Chinese Pharmacopoeia " specify in version for 2010, this two classes organic solvent toxicity is lower, organic solvent proportion in prescription is less simultaneously, therefore to the pollution of environment and the infringement of equipment less, and final residue in the formulation all meets " Chinese Pharmacopoeia " version requirement in 2010, therefore, it is possible to ensure Product Safety.
To sum up, the discovery that inventor is pleasantly surprised, introduce organic solvent in this product preparation technology, preparation is had to the benefit of two aspects, the subject matter that temozolomide freeze-dried preparation exists at present can be solved:
First: do not raising under batch temperature prerequisite, can significantly shorten the material dissolution time, fundamentally ensure product quality.
Second: 1. additionally do not add solubilizing agent in prescription, but the preparation obtained to redissolve speed satisfactory equally, to reduce in Clinical practice process owing to redissolving the drug risk not exclusively caused, decrease the untoward reaction that solubilizing agent brings; 2. adopted organic solvent is low-toxic organic solvent, and in preparation, organic residue is lower, and meet " Chinese Pharmacopoeia " version requirement in 2010, consumption of organic solvent is less, and toxicity is lower, and environmental pollution is little, constant product quality, is applicable to large-scale production.
Preparation technology of the present invention is simple, facilitates feasible, reproducible, is easy to industry and amplifies, and ensure that product can the industry requirement of amplifying; Shorten the batching time, saved cost, reduce product impurity, ensure that Product Safety and effectiveness; The preparation solubility of preparation is good, reduces clinical application risk, facilitates Clinical practice, ensure that the safety of clinical application.
Detailed description of the invention
Following specific embodiment further illustrates the present invention.In embodiments of the invention, method is just for illustration of the present invention, and limits the scope of protection of present invention never in any form.
Embodiment 1
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 4g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 4g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml ethanol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, after stirring and dissolving is complete, standardize solution is to 4000ml, feed liquid is through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 2
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Ethanol | 180ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.0.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 180ml ethanol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 3
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 15g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Ethanol | 10ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 15g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 4.5.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 10ml ethanol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 4
| Temozolomide | 10g |
| Mannitol | 80g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Acetone | 15ml |
| Water for injection | Add to 4000ml |
Preparation method: 80g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g citric acid, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 2.0.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 15ml acetone and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 5
| Temozolomide | 10g |
| Mannitol | 50g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 25g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Isopropyl alcohol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 50g mannitol, 12g polyoxyethylene sorbitan monoleate, 25g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 6.0.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml isopropyl alcohol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 6
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Normal propyl alcohol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 7.0.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml normal propyl alcohol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 7
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 10g |
| Sodium citrate | 23.5g |
| Hydrochloric acid | In right amount |
| Sodium chloride | 5g |
| Butanone | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 10g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml butanone and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 8
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Sec-butyl alcohol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml sec-butyl alcohol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 9
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Methanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml methanol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 10
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Ethanol | 20ml |
| Acetone | 20ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in the mixed solution of 20ml ethanol and 20ml acetone composition and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 11
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 5g |
| Hydrochloric acid | In right amount |
| Methanol | 10ml |
| Ethanol | 10ml |
| Acetone | 10ml |
| Isopropyl alcohol | 10ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 5g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in the mixed solvent of methanol, ethanol, acetone, each 10ml composition of isopropyl alcohol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, stirring and dissolving is complete, standardize solution is to 4000ml, through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 12
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Glycerol | 16g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 16g glycerol are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml ethanol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, after stirring and dissolving is complete, standardize solution is to 4000ml, feed liquid is through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 13
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Glucose | 26g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 26g glucose are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml ethanol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, after stirring and dissolving is complete, standardize solution is to 4000ml, feed liquid is through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 14
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sorbitol | 26g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 26g sorbitol are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml ethanol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, after stirring and dissolving is complete, standardize solution is to 4000ml, feed liquid is through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Embodiment 15
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Potassium chloride | 4g |
| Hydrochloric acid | In right amount |
| Ethanol | 40ml |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 4g potassium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Adopt high-shearing dispersion emulsifying machine temozolomide to be distributed in 40ml ethanol and obtain dispersion liquid, dispersion liquid is added in above-mentioned aqueous solution, after stirring and dissolving is complete, standardize solution is to 4000ml, feed liquid is through 0.22 μm of microporous filter membrane aseptic filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Reference examples 1 (not adding the lyophilization prescription of organic solvent)
| Temozolomide | 10g |
| Mannitol | 60g |
| Polyoxyethylene sorbitan monoleate | 12g |
| Sodium citrate | 23.5g |
| Sodium chloride | 4g |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 4000ml |
Preparation method: 60g mannitol, 12g polyoxyethylene sorbitan monoleate, 23.5g sodium citrate, 4g sodium chloride are added successively in water for injection, stirring and dissolving is complete, adopts salt acid for adjusting pH to 3.7.Temozolomide added in above-mentioned aqueous solution, after stirring and dissolving is complete, standardize solution is to 4000ml, and feed liquid is through 0.22 μm of microporous filter membrane aseptic filtration, and be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Reference examples 2 (with reference to Chinese patent CN100588399)
Take 20g sodium chloride, add in water for injection, stirred at ambient temperature makes to dissolve completely, add 1g temozolomide, stir and temozolomide is dissolved completely and mix homogeneously, add water for injection to 400ml, with salt acid for adjusting pH value to 3.0, with 0.22 μm of microporous filter membrane aseptic filtration, fill 40ml/ bottle in 100ml lyophilizing bottle, lyophilization.
Reference examples 3 (Chinese patent CN 101172104 embodiment 2)
Take 15.00g mannitol, 3.00g Tween-80,4.00gL-threonine, 5.88g sodium citrate dihydrate, 1.48g hydrochloric acid adds the water for injection that 800mL has been chilled to room temperature, and stirring and dissolving adds 2.5g temozolomide, after stirring and dissolving is complete, add water to 1000mL, with 0.22 micrometer Millipore membrane filtration, be dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Reference examples 4 (Chinese patent CN 102949351 embodiment 5)
Take the 1000ml tert-butyl alcohol and be placed in container, add water for injection 3200ml, add 60g mannitol, 12g Tween-80,24g sodium citrate, 16g hydrochloric acid, stir and mix homogeneously, add 10g temozolomide, stirring and dissolving is complete, add water for injection and supply 4000ml, solution, through 0.22 μm of microporous filter membrane aseptic filtration, is dispensed in 100ml cillin bottle, every bottle of 40ml, lyophilization obtains temozolomide freeze-dried powder injection formulation.
Measure the material dissolution time of embodiment 1-15 and comparative example 1-4 in blending process, final preparation organic residue, result is as follows:
The material dissolution time of table 1 embodiment and reference examples contrasts, dissolvent residual testing result
| Classification | The material dissolution time (min) | Dissolvent residual (%) |
| Embodiment 1 | 20 | 0.08 |
| Embodiment 2 | 14 | 0.06 |
| Embodiment 3 | 18 | 0.08 |
| Embodiment 4 | 20 | 0.09 |
| Embodiment 5 | 24 | 0.05 |
| Embodiment 6 | 26 | 0.06 |
| Embodiment 7 | 18 | 0.07 |
| Embodiment 8 | 20 | 0.06 |
| Embodiment 9 | 22 | 0.07 |
| Embodiment 10 | 25 | 0.04 |
| Embodiment 11 | 22 | 0.05 |
| Embodiment 12 | 20 | 0.06 |
| Embodiment 13 | 20 | 0.05 |
| Embodiment 14 | 21 | 0.05 |
| Embodiment 15 | 20 | 0.04 |
| Contrast 1 | 180 | \ |
| Contrast 2 | 180 | \ |
| Contrast 3 | 120 | \ |
| Contrast 4 | 200 | 0.26 |
Result shows, the distribution of dissolving again after adopting organic solvent dispersion raw material can significantly reduce the material dissolution time, and the organic solvent adopted can be removed in lyophilization, the organic residue of final preparation is lower, all meets " Chinese Pharmacopoeia " version in 2010 to the residual bound requirements of solvent.And the reference examples 4 material dissolution time is longer, and organic residue is obviously higher.
To dried frozen aquatic products prepared by embodiment and comparative example, carry out 25 DEG C of conditions lower 1 month study on the stability, inspection target comprises redissolution speed and (adds 40ml sterilized water for injection in every bottle, slight wobble, observe redissolution situation under lamp inspection instrument), related substance, result is as follows:
Table 2 embodiment and reference examples are redissolved time, stability and are contrasted
Result shows, in the present invention, in embodiment 1-15, lyophilized powder is obviously better than matched group 1 and 2 in redissolution speed, illustrate that the sample prepared according to this patent can significantly improve product redissolution speed, reduce owing to redissolving the not exclusively clinical application risk caused, facilitate Clinical practice, simultaneously because batching speed is fast, lyophilized powder related substance prepared by this patent is lower than matched group 1,2,3 and 4, and have good stability, the safety of product, stability and effectiveness can be ensured.
Claims (10)
1. a temozolomide freeze-dried powder preparation, active component is temozolomide or its pharmaceutically acceptable salt, it is characterized in that, also contain excipient, wetting agent, buffer agent, osmotic pressure regulator, pH adjusting agent, water for injection and organic solvent in solution before lyophilizing, wherein said organic solvent is selected from one of ethanol, acetone, isopropyl alcohol, normal propyl alcohol, butanone, sec-butyl alcohol, methanol or combination in any.
2. temozolomide freeze-dried powder preparation according to claim 1, is characterized in that, described organic solvent is ethanol.
3. temozolomide freeze-dried powder preparation according to claim 1, is characterized in that, described organic solvent accounts for 0.01% ~ 10% of overall solution volume before lyophilizing, preferably 0.05% ~ 5%, most preferably 0.1% ~ 4.5%.
4. temozolomide freeze-dried powder preparation according to claim 1, is characterized in that, the mass percent of temozolomide before lyophilizing in solution is 0.1 ~ 2%.
5. temozolomide freeze-dried powder preparation according to claim 1, is characterized in that, in described temozolomide freeze-dried powder preparation, the mass percent of temozolomide is 1% ~ 50%.
6. temozolomide freeze-dried powder preparation according to claim 1, it is characterized in that, the mass percent of excipient in temozolomide freeze-dried powder preparation is 30% ~ 90%, and described excipient is selected from one of glucose, albumin, sodium chloride, lactose, mannitol, sorbitol, xylitol, dextran, sodium alginate or combination in any;
The mass percent of wetting agent in temozolomide freeze-dried powder preparation is 0% ~ 50%, and described wetting agent is selected from one of Tween-20, Tween-80, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, bile salts, lecithin, Polyethylene Glycol or combination in any;
The mass percent of buffer agent in temozolomide freeze-dried powder preparation is 1% ~ 50%, and described buffer agent is selected from one of citrate, lactate, acetate, tartrate, succinate, phosphate or combination in any, preferably citric acid salt;
Described pH adjusting agent is selected from one of hydrochloric acid, citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid or combination in any;
The mass percent of osmotic pressure regulator in temozolomide freeze-dried powder preparation is 1% ~ 50%, and described osmotic pressure regulator is selected from one of glycerol, sodium chloride, potassium chloride, mannitol, glucose, sorbitol or combination in any.
7. temozolomide freeze-dried powder preparation according to claim 1, is characterized in that, excipient is mannitol, and wetting agent is polyoxyethylene sorbitan monoleate, and buffer agent is sodium citrate, and pH adjusting agent is hydrochloric acid, and osmotic pressure regulator is sodium chloride.
8. temozolomide freeze-dried powder preparation according to claim 1, is characterized in that, before described lyophilizing, the pH scope of solution is 2 ~ 7.
9. the preparation method of temozolomide freeze-dried powder preparation according to any one of claim 1-8, comprises the following steps:
1) excipient of recipe quantity, wetting agent, buffer agent, osmotic pressure regulator stirring and dissolving is taken in water for injection;
2) pH adjusting agent is adopted by step 1) pH value of gained feed liquid is adjusted to 2-7;
3) take temozolomide or its officinal salt of recipe quantity, disperseed in organic solvent, dispersion liquid to be added step 2) in gained feed liquid, stirring and dissolving;
4) feed liquid is settled to cumulative volume, after filtration sterilization, is dispensed into vial;
5) carry out lyophilization, obtain the temozolomide freeze-dried powder preparation of final products.
10. preparation method according to claim 9, is characterized in that, step 3) described stock dispersion method is in organic solvent adopt the mode of high-shearing dispersion emulsifying machine.
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