CN102342931B - Injectable parenteral medicinal preparation of temozolomide and preparation method thereof - Google Patents

Injectable parenteral medicinal preparation of temozolomide and preparation method thereof Download PDF

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CN102342931B
CN102342931B CN201010244080.7A CN201010244080A CN102342931B CN 102342931 B CN102342931 B CN 102342931B CN 201010244080 A CN201010244080 A CN 201010244080A CN 102342931 B CN102342931 B CN 102342931B
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temozolomide
injectable parenteral
agent
preparation
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CN102342931A (en
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孙飘扬
张辉
吴玉霞
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Jiangsu Hengrui Medicine Co Ltd
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Priority to CN201010244080.7A priority Critical patent/CN102342931B/en
Priority to PCT/CN2011/077095 priority patent/WO2012013117A1/en
Priority to CN2011800037655A priority patent/CN102481287B/en
Priority to CN201180003766.XA priority patent/CN102481288B/en
Priority to PCT/CN2011/077093 priority patent/WO2012013116A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

The invention relates to an injectable parenteral medicinal preparation of temozolomide and a preparation method thereof. The medicinal preparation comprises (1) temozolomide or pharmaceutically acceptable salt thereof, (2) at least one stabilizer, and (3) at least one aqueous diluent, wherein the stabilizer is selected from L-alanine, L-glycine, L-cysteine, L-cysteine hydrochloride anhydride, L-cysteine hydrochloride monohydrate, acetyl cysteine, S-carboxymethyl-L-cysteine, L-ethyl cysteine hydrochloride, L-methyl cysteine hydrochloride, vitamin C or a mixture thereof. The invention further relates to lyophilized power containing the medicinal preparation and products thereof.

Description

Injectable parenteral medicinal of temozolomide and preparation method thereof
Technical field
The present invention relates to a kind of injectable parenteral medicinal, it comprises at least one stabilizing agent of antineoplastic agent temozolomide and at least one aqueous diluent.
Background technology
Temozolomide (temozolomide) chemical name: 3,4-dihydro-3-methyl-4-oxomidazo is [5,1-d]-1,2,3 also, 5-tetrazine-8-amide, for imidazo tetrazine class has the alkylating agent of anti-tumor activity, by Schering Plough, company develops.Temozolomide is applicable to the glioblastoma multiforme of new diagnosis, starts first and chemotherapy combined radiotherapy treatment, subsequently as auxiliary treatment; Temozolomide is also applicable to the glioblastoma multiforme or the human anaplastic astrocytoma that after conventional therapy, recur or make progress.Within 1998, first temozolomide's capsule goes on the market in European Union, within 1999 subsequently, through U.S. FDA approval, in the U.S., goes on the market.Temozolomide is the first-line drug for the treatment of at present malignant brain tumor, by the U.S. and European medical circle, is assessed as " goldstandard " for the treatment of malignant brain tumor.
The current domestic temozolomide preparation that goes on the market is hard capsule, oral formulations is easy to use, can be completely absorbed after oral, and bioavailability is up to 98%, main side effect be feel sick, vomiting, weak, constipation and slight bone marrow depression, wherein severe is felt sick, the side reaction such as vomiting is common.This usually causes the fluctuation of drug absorption, thereby affects bioavailability.Some patients feel sick, vomiting reaction is too serious and be difficult to by oral administration, and have clinically a lot of patient's dysphagias, can not pass through oral administration, temozolomide's preparation that urgent clinical needs can intravenously administrable.But temozolomide stablizes for 7 times at pH <, during pH > 7, easily decompose, temozolomide, as prodrug, is easily degraded to activated product in aqueous solution, and preparation becomes conventional intravenous fluid and can not guarantee long-time stability.
For realizing temozolomide's parenteral administration, a kind of temozolomide's preparation with micronized suspension administration is disclosed in U.S. Pat 6251886, still, suspension formulation is unsatisfactory, and it can cause blood vessel blockage.Consider temozolomide's unsettled characteristic in aqueous solution, therefore by its by lyophilization solidify prepare become aqueous diluent that aseptic freeze-dried powder used injection before use rebuild obtain can parenteral administration temozolomide's injection, will be a well strategy.
In addition, U.S. Pat 6987108 (Chinese patent families CN03804363.7) discloses a kind of temozolomide's lyophilized injectable powder, for temozolomide's intravenous administration.Above-mentioned temozolomide's lyophilized powder color under long-term and acceleration environment can become pale pink from white, and this is indicating that its quality or stability may exist some problems.And the change of lyophilized powder color easily makes patient suspect the quality of medicine, and reduce patient's compliance and degree of recognition.Therefore need to research and develop one and can guarantee temozolomide's parenteral administration, stable and applicable long-term technology and the preparation thereof of preserving.
Summary of the invention
Main purpose of the present invention is to realize temozolomide's parenteral administration, provide a kind of water miscible, stable temozolomide's pharmaceutical preparation, its preparation method, the freeze-drying method of pharmaceutical preparation, lyophilized powder and their goods, comprise the pharmaceutical preparation that is reconstructed into the lyophilized powder at least one aqueous diluent.
The invention provides a kind of injectable pharmaceutical preparation, comprise:
1) temozolomide or its pharmaceutically acceptable salt;
2) at least one stabilizing agent;
3) at least one aqueous diluent;
Wherein said stabilizing agent is selected from ALANINE, L-glycine, Cys, Cys hydrochlorate anhydride, Cys hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-Cys, Cys carbethoxy hydrochloride, Cys methyl ester hydrochloride, vitamin c or their mixture, is preferably selected from vitamin c, Cys hydrochlorate anhydride, Cys hydrochloride monohydrate or their mixture.
In pharmaceutical preparation of the present invention, described aqueous diluent is selected from water for injection, normal saline, 5% dextrose solution or their mixture.
In a specific embodiments of the present invention, described pharmaceutical preparation also comprises at least one excipient.Described excipient is selected from sodium chloride, glucose, lactose, mannitol, trehalose, xylitol, sucrose, sorbitol, dextrose, albumin, hetastarch, cyclodextrin, glycine or their mixture, is preferably mannitol.
In another specific embodiments of the present invention, described pharmaceutical preparation also comprises at least one wetting agent.Described wetting agent is selected from polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, bile salts, lecithin, Polyethylene Glycol or their mixture, be preferably selected from polysorbate-20, polysorbate-40, polysorbate-60, Polyoxyethylene Sorbitan Monooleate or their mixture, most preferably be Polyoxyethylene Sorbitan Monooleate.
In another specific embodiments of the present invention, described pharmaceutical preparation also comprises at least one buffer agent.Described buffer agent is selected from citrate, lactate, and acetate, tartrate, succinate, phosphate or their mixture, be preferably selected from citrate, acetate, phosphate or their mixture, most preferably is acetate or citrate.
In another specific embodiments of the present invention, it also comprises at least one pH adjusting agent described pharmaceutical preparation.Described pH adjusting agent is selected from hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid or their mixture, is preferably hydrochloric acid or acetic acid.
In another specific embodiments of the present invention, the pH of described pharmaceutical preparation is in 2.0 to 6.0 scope, preferably in 2.5 to 4.5 scope, most preferably in 3.5 to 4.0 scope.
In another specific embodiments of the present invention, described stabilizing agent is selected from L-glycine, ALANINE, Cys, Cys hydrochlorate anhydride, Cys hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-Cys, Cys carbethoxy hydrochloride, Cys methyl ester hydrochloride, vitamin c or their mixture, and described pharmaceutical preparation also comprises at least one and is selected from the pH adjusting agent of hydrochloric acid or acetic acid, and at least one is selected from buffer agent and the mannitol of citrate, acetate.Further, described temozolomide's content is 1wt% to 50wt%, and the content of described pH adjusting agent is 0.1wt% to 20wt%, and the content of described buffer agent is 5wt% to 60wt%, the content of described stabilizing agent is 4wt% to 60wt%, and the content of described mannitol is 20wt% to 80wt%.
In another specific embodiments of the present invention, described stabilizing agent is selected from L-glycine, ALANINE, Cys, Cys hydrochlorate anhydride, Cys hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-Cys, Cys carbethoxy hydrochloride, Cys methyl ester hydrochloride, vitamin c or their mixture, and described pharmaceutical preparation also comprises at least one and is selected from hydrochloric acid, acetic acid pH adjusting agent, at least one is selected from citrate or acetate buffer, polysorbate and mannitol.Further described temozolomide's content is 1wt% to 50wt%, the content of described pH adjusting agent is 0.1wt% to 20wt%, the content of described buffer agent is 5wt% to 60wt%, the content of described stabilizing agent is 2wt% to 60wt%, the content of described polysorbate is 1wt% to 50wt%, and the content of described mannitol is 20wt% to 80wt%.
For term of the present invention " percentage by weight ", be (wt%) to calculate on the basis of the gross weight of pharmaceutical preparation.
The present invention relates to a kind of method of preparing described injectable pharmaceutical preparation on the other hand, comprises the following steps:
1) at least one stabilizing agent is dissolved at least one aqueous diluent, solution temperature 0-60 ℃, wherein said stabilizing agent is selected from L-glycine, ALANINE, Cys, Cys hydrochlorate anhydride, Cys hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-Cys, Cys ethyl ester, Cys methyl ester hydrochloride, vitamin c or their mixture; With
2) add temozolomide or its pharmaceutically acceptable salt.
In another specific embodiments of the present invention, described preparation method also comprises:
1) add at least one wetting agent;
2) add at least one excipient;
3) add at least one buffer agent;
4) add at least one pH adjusting agent to form a kind of solution; With
5) filter above-mentioned solution.
In another specific embodiments of the present invention, described preparation method also comprises step 5) solution that obtains carries out lyophilization, to obtain a kind of lyophilized powder.
The present invention relates to the lyophilized powder being made by method as above on the other hand.
The present invention relates to a kind of pharmaceutical preparation on the other hand, comprises a kind of container that contains lyophilized powder as above.Described container is syringe or bottle.
The present invention relates to a kind of being suitable for to the pharmaceutical preparation of patient's administration on the other hand, and described preparation is by above-mentioned lyophilized powder is rebuild and made at least one aqueous diluent.
Further, preparation method provided by the invention, preferably includes these steps:
1. stabilizing agent, wetting agent, excipient, buffer agent are dissolved in aqueous diluent.
2. temozolomide or its pharmaceutically acceptable salt are dissolved in above-mentioned solution.
3. measure pH value, as needs, use pH adjusting agent to be adjusted to suitable pH scope.
4. by above-mentioned solution filter and degerming.
5. the sterile solution after filtering is divided and is filled in suitable container.
6. above-mentioned solution lyophilization is made to temozolomide's lyophilized injectable powder.
The concrete preparation method of a kind of freeze-dried temzolomide powder provided by the invention is as follows:
1. take stabilizing agent, wetting agent, the excipient of recipe quantity, buffer agent, stirring and dissolving in water, 90% left and right that water is recipe quantity, water temperature is controlled at 15-60 ℃.
2. take the temozolomide of recipe quantity, stirring and dissolving, in above-mentioned solution, is measured pH value, as required, pH value is adjusted by pH adjusting agent.
3. add water to final volume, solution stirring is mixed at least 15 minutes.
4. solution is passed through to the filtering with microporous membrane degerming of 0.22 μ m, be distributed into through the lyophilizing of sterilization and use in cillin bottle, half tamponade, lyophilization obtains lyophilized powder.
The present invention adds by wetting agent, has improved temozolomide because of slightly water-soluble, the feature that is difficult to be dissolved by water-wet, increased temozolomide's rate of dissolution, reduce the preparation time of whole solution, reduced the time of temozolomide's degradation, thereby reduced temozolomide's degraded.
In pharmaceutical preparation, temozolomide's percentage by weight (wt%) can be at 1wt% to 50wt%.
The present invention adds by excipient, has guaranteed the formability that freeze-dried temzolomide powder is last, and has the protection supporting role of excipient, makes freeze-dried temzolomide powder be redeveloped into the time of the preparation of suitable patient's administration, greatly reduces.When excipient is used in pharmaceutical preparation, its wt% in pharmaceutical preparation can be at 20wt% to 80wt%.
The present invention adds by buffer agent and pH adjusting agent, guaranteed temozolomide when solution state in lower pH environment and certain buffer system, reduced its degradation rate.When buffer agent is used in pharmaceutical preparation, its wt% in pharmaceutical preparation can be at 5wt% to 60wt%.When pH adjusting agent is used in pharmaceutical preparation, its wt% in pharmaceutical preparation can be at 0.1wt% to 20wt%.
The present invention is by reducing the degradation speed of temozolomide at dissolving and solution state, and guaranteed that temozolomide can keep stable the long period under solution state, thereby be conducive to its preparation, fill, the whole process such as lyophilization, and be easy to realize industrialized production.
The present invention adds by stabilizing agent, has amazingly obtained not only stablely but also the freeze-dried temzolomide powder of change color does not occur under long-term and acceleration environment, and the freeze-dried temzolomide powder obtaining keeps the white lyophilized powder outward appearance to off-white color.In pharmaceutical preparation, the wt% of stabilizing agent can be at 4wt% to 60wt%.
Control temperature that can be suitable in this preparation method, can increase temozolomide's dissolution velocity, and reduces its degraded.
The freeze-dried temzolomide powder that this legal system is standby is the solid freeze-dried powder of white or off-white color.The standby freeze-dried temzolomide powder of this legal system is in long-term and accelerated test process, not only guaranteed temozolomide stablizing under solid state, there is not lyophilized powder color and become the phenomenon of pale pink in amazing discovery also, still keeps the lyophilized powder outward appearance of white to off-white color.
Adopt Freeze Drying Technique, prepared freeze-dried temzolomide powder, increased temozolomide's stability, and using before use aqueous diluent to rebuild, and good stability, side effect is little, can realize parenteral administration, met before those needs that have been difficult to oral administration patient and administration without taking Bendectin, made patient acceptant, facilitated clinical application.
The specific embodiment
Following examples are in order to set forth invention, and limit the scope of the invention never in any form.
Embodiment 1
Pharmaceutical preparation of the present invention makes by step below conventionally:
1. take stabilizing agent, wetting agent, the excipient of recipe quantity, buffer agent, stirring and dissolving at least one aqueous diluent, 90% left and right that aqueous diluent is recipe quantity, water temperature is controlled at 0-60 ℃.
2. take the temozolomide of recipe quantity, stirring and dissolving, in above-mentioned solution, is measured the pH value of solution after dissolving completely, as required, use pH adjusting agent to adjust pH.
3. add aqueous diluent to final volume, solution is continued to be stirred to mix homogeneously.
4. by above-mentioned solution filter sterilizing.
Embodiment 2
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g Cys hydrochloride monohydrate, 25.00g mannitol, 9.90g acetic acid, 2.04g sodium acetate, adds 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, adds 2.50g temozolomide (Hengrui Medicine Co., Ltd., Jiangsu Prov. originates in following examples identical), stirring and dissolving, add water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 3
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g Cys hydrochloride monohydrate, 15.00g mannitol, 2.35g Sodium Citrate, usp, Dihydrate Powder, 0.63g hydrochloric acid, adds 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, add 2.50g temozolomide, stirring and dissolving, injects water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 4
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 5.00g vitamin c, 6.00g mannitol, 5.67g acetic acid, 5.03g sodium acetate, adds 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, add 2.50g temozolomide, stirring and dissolving, adds water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 5
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 5.00g vitamin c, 6.00g mannitol, 2.35g Sodium Citrate, usp, Dihydrate Powder, 2.00g hydrochloric acid, adds 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, add 2.50g temozolomide, stirring and dissolving, adds water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 6
Take 4.00g Cys hydrochloride monohydrate, 10.00g mannitol, 5.67g acetic acid, 5.03g sodium acetate, add 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, adds 2.50g temozolomide, stirring and dissolving, add water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 7
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g L-glycine, 10.00g mannitol, 5.67g acetic acid, 5.03g sodium acetate, adds 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, add 2.50g temozolomide, stirring and dissolving, adds water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 8
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g ALANINE, 10.00g mannitol, 5.67g acetic acid, 5.03g sodium acetate, adds 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, add 2.50g temozolomide, stirring and dissolving, adds water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 9
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 2.00g Cys hydrochloride monohydrate, 2.00g vitamin c, 6.00g mannitol, 6.615g acetic acid, 3.604g sodium acetate, add 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, adds 2.50g temozolomide, stirring and dissolving, add water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 10
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g Cys hydrochloride monohydrate, 12.00g mannitol, 4.00g acetic acid, add 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, adds 2.50g temozolomide, stirring and dissolving, add water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 11
Take 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g Cys hydrochloride monohydrate, 25.00g mannitol, adds 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, add 2.50g temozolomide, stirring and dissolving, adds water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 12
Take 2.50g vitamin c, 2.50g mannitol, 2.35g Sodium Citrate, usp, Dihydrate Powder, 0.80g hydrochloric acid, add 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths, adds 2.50g temozolomide, stirring and dissolving, add water to 1000mL, with 0.22 μ m filtering with microporous membrane, subpackage, lyophilization, obtains temozolomide freeze-dried powder.
Embodiment 13
According to solution before embodiment 2,3 preparation temozolomides' lyophilizing, lyophilization, prepares freeze-dried temzolomide powder.Use reverse high performance liquid chromatography (HPLC) to measure respectively the stability of solution after the solution reconstruction after stability of solution and the lyophilizing of the front solution of lyophilizing, and the freeze-dried temzolomide powder preparing is kept sample, after different time, rebuild and measure related substance, investigate its stability.
With reference to disclosed embodiment 2 in U.S. Pat 6987108 (Chinese patent families CN03804363.7): solution before preparation temozolomide's lyophilizing, and according to the freeze-drying method lyophilization in patent, prepared a collection of freeze-dried temzolomide powder.Use reverse high performance liquid chromatography (HPLC) to measure the stability of solution after the solution reconstruction after stability of solution and the lyophilizing of the front solution of lyophilizing, and the freeze-dried temzolomide powder preparing is kept sample, after different time, rebuild and measure related substance, data in the data that obtain and embodiment 2,3 are contrasted.Result is as shown in the table:
Stability of solution before the lyophilizing of table 1 U.S. Pat 6987108 embodiment 2 and the embodiment of the present invention 3 prescription preparations
Figure BSA00000215802700091
The stability of solution of rebuilding after the lyophilizing of table 2 U.S. Pat 6987108 embodiment 2 and the embodiment of the present invention 3 prescription preparations
Figure BSA00000215802700092
Table 1,2 result shows, in the degradation rate of the temozolomide freeze-dried front solution state in the prescription in the present invention and U.S. Pat 6987108, the degradation rate of prescription is close, and after lyophilizing rebuild after degradation rate a little less than the degradation rate of writing out a prescription in U.S. Pat 6987108, thereby illustrate that preparation of the present invention has good stability.
The stability of the freeze-dried temzolomide powder that table 3 U.S. Pat 6987108 embodiment 2 obtain
Figure BSA00000215802700101
The stability of the freeze-dried temzolomide powder that table 4 embodiment of the present invention 2 obtains
Figure BSA00000215802700102
The stability of the freeze-dried temzolomide powder that table 5 embodiment of the present invention 3 obtains
Figure BSA00000215802700103
Table 3,4,5 results show that the temozolomide in the present invention still kept stable after 2 months, the stability of preparation prepared by the stability of the preparation of preparing by U.S. Pat 6987108 and the present invention is suitable, all keeps stable.But 40 ℃, preparation prepared by U.S. Pat 6987108, stores color after January and becomes pale pink from white or off-white color, color burn after February, 25 ℃, store February after color from white or off-white color, become pale pink; And the lyophilized powder color obtaining in the present invention does not change, keep white constant to off-white color.This amazing result, freeze-dried temzolomide powder prepared by indication the present invention has better stability.

Claims (25)

1. an injectable parenteral medicinal, comprises:
1) temozolomide or its pharmaceutically acceptable salt;
2) at least one stabilizing agent
3) at least one aqueous diluent;
Wherein said stabilizing agent is selected from Cys, Cys hydrochlorate anhydride, Cys hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-Cys, Cys carbethoxy hydrochloride, Cys methyl ester hydrochloride or their mixture.
2. injectable parenteral medicinal according to claim 1, wherein said aqueous diluent is selected from water for injection, normal saline, physiology sugar-salt-water, 5% dextrose solution or their mixture.
3. injectable parenteral medicinal according to claim 1, also comprises at least one excipient.
4. injectable parenteral medicinal according to claim 3, wherein said excipient is selected from sodium chloride, glucose, lactose, mannitol, trehalose, xylitol, sucrose, sorbitol, dextrose, albumin, hetastarch, cyclodextrin, glycine or their mixture.
5. injectable parenteral medicinal according to claim 1, also comprises at least one wetting agent.
6. injectable parenteral medicinal according to claim 5, wherein said wetting agent is selected from polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, bile salts, lecithin, Polyethylene Glycol or their mixture.
7. injectable parenteral medicinal according to claim 5, wherein said wetting agent is selected from polysorbate-20, polysorbate-40, polysorbate-60, Polyoxyethylene Sorbitan Monooleate or their mixture.
8. injectable parenteral medicinal according to claim 1, also comprises at least one buffer agent.
9. injectable parenteral medicinal according to claim 8, wherein said buffer agent is selected from citrate, lactate, acetate, tartrate, succinate, phosphate or their mixture.
10. injectable parenteral medicinal according to claim 1, it also comprises at least one pH adjusting agent.
11. injectable parenteral medicinals according to claim 10, wherein said pH adjusting agent is selected from hydrochloric acid, sodium hydroxide, citric acid, phosphoric acid, lactic acid, tartaric acid, succinic acid or their mixture.
12. injectable parenteral medicinals according to claim 1, the pH of wherein said preparation is in 2.0 to 6.0 scope.
13. injectable parenteral medicinals according to claim 12, the pH of wherein said preparation is in 2.5 to 4.5 scope.
14. injectable parenteral medicinals according to claim 13, the pH of wherein said preparation is in 3.5 to 4.0 scope.
15. injectable parenteral medicinals according to claim 1, wherein said pharmaceutical preparation also comprises at least one and is selected from the pH adjusting agent of hydrochloric acid or acetic acid, and at least one is selected from buffer agent and the mannitol of citrate, acetate.
16. according to the injectable parenteral medicinal of claim 15, wherein in the gross weight of pharmaceutical preparation, described temozolomide's content is 1wt% to 50wt%, the content of described pH adjusting agent is 0.1wt% to 20wt%, the content of described buffer agent is 5wt% to 60wt%, the content of described stabilizing agent is 4wt% to 60wt%, and the content of described mannitol is 20wt% to 80wt%.
17. injectable parenteral medicinals according to claim 1, wherein said pharmaceutical preparation also comprises at least one and is selected from hydrochloric acid, acetic acid pH adjusting agent, and at least one is selected from citrate or acetate buffer, polysorbate and mannitol.
18. injectable parenteral medicinals according to claim 17, wherein in the gross weight of pharmaceutical preparation, described temozolomide's content is 1wt% to 50wt%, the content of described pH adjusting agent is 0.1wt% to 20wt%, the content of described buffer agent is 5wt% to 60wt%, the content of described stabilizing agent is 2wt% to 60wt%, and the content of described polysorbate is 1wt% to 50wt%, and the content of described mannitol is 20wt% to 80wt%.
Prepare the method for injectable parenteral medicinal as claimed in claim 1, comprise the following steps: for 19. 1 kinds
1) at least one stabilizing agent is dissolved at least one aqueous diluent to solution temperature 0-60 ℃; With
2) add temozolomide or its pharmaceutically acceptable salt.
20. methods according to claim 19, it also comprises:
1) add at least one wetting agent;
2) add at least one excipient;
3) add at least one buffer agent;
4) add at least one pH adjusting agent to form a kind of solution; With
5) filter above-mentioned solution.
21. methods according to claim 20, it also comprises step 5) solution that obtains carries out lyophilization, to obtain a kind of lyophilized powder.
22. lyophilized powders that made by method as claimed in claim 21.
23. 1 kinds of pharmaceutical preparations, comprise a kind of container that contains lyophilized powder as claimed in claim 22.
24. pharmaceutical preparations according to claim 23, wherein said container is syringe or bottle.
25. 1 kinds are suitable for to the pharmaceutical preparation of patient's administration, and described preparation is by the lyophilized powder of claim 22 is rebuild and made at least one aqueous diluent.
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CN2011800037655A CN102481287B (en) 2010-07-29 2011-07-13 Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof
CN201180003766.XA CN102481288B (en) 2010-07-29 2011-07-13 Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof
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CN103705446A (en) * 2012-10-08 2014-04-09 正大天晴药业集团股份有限公司 Polyene phosphatidyl choline injection, and preparation method thereof
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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
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100346784C (en) * 2002-02-22 2007-11-07 先灵公司 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

Family Cites Families (3)

* Cited by examiner, † Cited by third party
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
US20090270397A1 (en) * 2008-04-08 2009-10-29 Orlow Seth J Methods and compositions for the treatment of cancers, such as melanomas and gliomas
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100346784C (en) * 2002-02-22 2007-11-07 先灵公司 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

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