CN102342931A - Injectable parenteral medicinal preparation of temozolomide and preparation method thereof - Google Patents
Injectable parenteral medicinal preparation of temozolomide and preparation method thereof Download PDFInfo
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- CN102342931A CN102342931A CN2010102440807A CN201010244080A CN102342931A CN 102342931 A CN102342931 A CN 102342931A CN 2010102440807 A CN2010102440807 A CN 2010102440807A CN 201010244080 A CN201010244080 A CN 201010244080A CN 102342931 A CN102342931 A CN 102342931A
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- injectable
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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
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- 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
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- 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
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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
- A61K9/0012—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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
Technical field
The present invention relates to a kind of injectable gastrointestinal external medicine preparation, it comprises at least a stabilizing agent of antineoplastic agent temozolomide and at least a aqueous diluent.
Background technology
Temozolomide (temozolomide) chemical name: 3,4-dihydro-3-methyl-4-oxo-imidazole is [5,1-d]-1,2,3 also, and 5-tetrazine-8-amide for imidazo tetrazine class has the alkylating agent of anti-tumor activity, is developed by Schering Plough company.The temozolomide is applicable to the glioblastoma multiforme of new diagnosis, and beginning elder generation and radiotherapy therapeutic alliance are subsequently as auxiliary treatment; The temozolomide also is applicable to glioblastoma multiforme or the anaplastic astrocytoma that recurs or make progress behind the conventional therapy.Temozolomide's capsule at first went on the market in European Union in 1998, went on the market in the U.S. through drugs approved by FDA in 1999 subsequently.The temozolomide is a line medicine of treating malignant brain tumor at present, is assessed as " goldstandard " of treating malignant brain tumor by the U.S. and European medical circle.
The present domestic temozolomide preparation that goes on the market is a hard capsule; Oral formulations is easy to use, can be absorbed fully after oral, and bioavailability is up to 98%; Main side effect for feel sick, vomiting, weak, constipation and slight bone marrow depression, wherein severe is felt sick, side reaction such as vomiting is common.This usually causes the fluctuation of drug absorption, thereby influences bioavailability.Some patients feel sick, vomiting reaction is too serious and be difficult to the administered through oral administration, and a lot of patient's dysphagias are arranged clinically, can not the administered through oral administration, and temozolomide's preparation that urgent clinical needs can intravenously administrable.But the temozolomide is stable in pH＜7 time, and pH＞7 o'clock are prone to decompose, and the temozolomide is prone to be degraded to activated product as prodrug in aqueous solution, and preparation becomes conventional intravenous fluid 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 the US Patent No. 6251886, still, suspension formulation is unsatisfactory, and it can cause blood vessel blockage.Consider temozolomide's unsettled characteristic in aqueous solution; Therefore with its through lyophilization solidify prepare become aseptic freeze-dried powder face with preceding with its use the aqueous diluent of injection to rebuild to obtain can parenteral administration temozolomide's injection, will be one good tactful.
In addition, US Patent No. 6987108 (Chinese patent families CN03804363.7) discloses a kind of temozolomide's lyophilized injectable powder, is used for temozolomide's intravenous administration.Above-mentioned temozolomide's lyophilized powder color under long-term and acceleration environment can become pale pink by white, and this is indicating that possibly there are certain problem in its quality or stability.And the change of lyophilized powder color is prone to make the patient to suspect the quality of medicine, and reduces patient's compliance and degree of recognition.Therefore the needs research and development are a kind of can guarantee temozolomide's parenteral administration, stable and technology suitable long preservation and preparation thereof.
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 a aqueous diluent.
The present invention provides a kind of injectable pharmaceutical preparation, comprises:
1) temozolomide or its pharmaceutically acceptable salt;
2) at least a stabilizing agent;
3) at least a aqueous diluent;
Wherein said stabilizing agent is selected from L-alanine, L-glycine, L-cysteine, L-cysteine hydrochloride anhydride, L-cysteine hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-L-cysteine, L-ethylcysteine hydrochloride, L-acthiol-J hydrochlorate, vitamin c or their mixture, is preferably selected from vitamin c, L-cysteine hydrochloride anhydride, L-cysteine 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 a 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 a 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 a buffer agent.Described buffer agent is selected from citrate, lactate, and acetate, tartrate, succinate, phosphate or their mixture are preferably selected from citrate, acetate, phosphate or their mixture, most preferably are acetate or citrate.
In another specific embodiments of the present invention, it also comprises at least a pH regulator agent described pharmaceutical preparation.Described pH regulator 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, L-alanine, L-cysteine, L-cysteine hydrochloride anhydride, L-cysteine hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-L-cysteine, L-ethylcysteine hydrochloride, L-acthiol-J hydrochlorate, vitamin c or their mixture; And described pharmaceutical preparation also comprises at least a pH regulator agent that is selected from hydrochloric acid or acetic acid, at least a buffer agent and the mannitol that is selected from citrate, acetate.Further; Described temozolomide's content is 1wt% to 50wt%, and the content of said pH regulator agent is 0.1wt% to 20wt%, and the content of said buffer agent is 5wt% to 60wt%; The content of said stabilizing agent is 4wt% to 60wt%, and the content of said mannitol is 20wt% to 80wt%.
In another specific embodiments of the present invention; Described stabilizing agent is selected from L-glycine, L-alanine, L-cysteine, L-cysteine hydrochloride anhydride, L-cysteine hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-L-cysteine, L-ethylcysteine hydrochloride, L-acthiol-J hydrochlorate, vitamin c or their mixture; And described pharmaceutical preparation also comprises at least a be selected from hydrochloric acid, the agent of acetic acid pH regulator; At least a citrate or acetate buffer, polysorbate and the mannitol of being selected from.Further said temozolomide's content is 1wt% to 50wt%; The content of said pH regulator agent is 0.1wt% to 20wt%; The content of said buffer agent is 5wt% to 60wt%; The content of said 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%.
Being used for term of the present invention " percentage by weight " is on the basis of the gross weight of pharmaceutical preparation, to calculate (wt%).
The present invention relates to a kind of method for preparing described injectable pharmaceutical preparation on the other hand, comprises the following steps:
1) at least a stabilizing agent is dissolved at least a aqueous diluent; Solution temperature 0-60 ℃, wherein said stabilizing agent is selected from L-glycine, L-alanine, L-cysteine, L-cysteine hydrochloride anhydride, L-cysteine hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-L-cysteine, L-ethycysteine hydrochloric acid, L-acthiol-J hydrochlorate, vitamin c or their mixture; With
2) add temozolomide or its pharmaceutically acceptable salt.
In another specific embodiments of the present invention, said method for preparing also comprises:
1) adds at least a wetting agent;
2) add at least a excipient;
3) add at least a buffer agent;
4) add at least a pH regulator agent to form a kind of solution; With
5) filter above-mentioned solution.
In another specific embodiments of the present invention, said method for preparing comprises that also the solution that step 5) is obtained carries out lyophilization, to obtain a kind of lyophilized powder.
The present invention relates to the lyophilized powder that is made by aforesaid method 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 aforesaid lyophilized powder.Said container is syringe or bottle.
The present invention relates to a kind of pharmaceutical preparation that is suitable for to patient's administration on the other hand, and said preparation is to make through above-mentioned lyophilized powder is rebuild at least a aqueous diluent.
Further, method for preparing provided by the invention preferably includes these steps:
1. stabilizing agent, wetting agent, excipient, buffer agent are dissolved in the aqueous diluent.
2. temozolomide or its pharmaceutically acceptable salt are dissolved in the above-mentioned solution.
3. the mensuration pH value like needs, uses the pH regulator agent to be adjusted to suitable pH scope.
4. above-mentioned solution is filtered and degerming.
5. the sterile solution branch after will filtering is filled in the proper container.
6. above-mentioned solution lyophilization is made temozolomide's lyophilized injectable powder.
The concrete method for preparing of a kind of freeze-dried temzolomide powder provided by the invention is following:
1. take by weighing stabilizing agent, wetting agent, the excipient of recipe quantity, buffer agent, stirring and dissolving is in water, and water is about 90% of recipe quantity, and water temperature is controlled at 15-60 ℃.
2. take by weighing the temozolomide of recipe quantity, stirring and dissolving is measured pH value in above-mentioned solution, as required, with the pH regulator agent pH value is adjusted.
3. add entry to final volume, solution stirring was mixed 15 minutes at least.
4. with the filtering with microporous membrane degerming of solution through 0.22 μ m, divide the lyophilizing of packing into through sterilization with cillin bottle in, half tamponade, lyophilization obtains lyophilized powder.
The present invention has improved the temozolomide because slightly water-soluble is difficult to by the dissolved characteristics of water-wet through the adding of wetting agent; 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.
Temozolomide's percentage by weight (wt%) can be at 1wt% to 50wt% in pharmaceutical preparation.
The present invention has guaranteed the formability that freeze-dried temzolomide powder is last through the adding of excipient, and the protection supporting role of excipient is arranged, and makes freeze-dried temzolomide powder be redeveloped into the time of the preparation of suitable patient's administration, significantly reduces.When excipient used in pharmaceutical preparation, its wt% in pharmaceutical preparation can be at 20wt% to 80wt%.
The present invention is through the adding of buffer agent and pH regulator agent, guaranteed the temozolomide when solution state in a lower pH environment and certain buffer system, reduced its degradation rate.When buffer agent used in pharmaceutical preparation, its wt% in pharmaceutical preparation can be at 5wt% to 60wt%.When the pH regulator agent was used in pharmaceutical preparation, its wt% in pharmaceutical preparation can be at 0.1wt% to 20wt%.
The present invention is through reducing the degradation speed of temozolomide at dissolving and solution state; And guaranteed that the temozolomide can keep stable the long period under solution state, thereby help its preparation, fill; Whole process such as lyophilization, and be easy to realize industrialized production.
The present invention is through the adding of stabilizing agent, amazingly obtained not only stable but also the freeze-dried temzolomide powder of change color does not take place under long-term and acceleration environment, and the freeze-dried temzolomide powder that obtains keeps white lyophilized powder outward appearance to off-white color.The wt% of stabilizing agent can be at 4wt% to 60wt% in pharmaceutical preparation.
Control temperature that can be suitable in this method for preparing can increase temozolomide's dissolution velocity, and reduces its degraded.
The freeze-dried temzolomide powder of this method preparation is the solid freeze-dried powder of white or off-white color.The freeze-dried temzolomide powder of this method preparation is in long-term and accelerated test process; Not only guaranteed temozolomide stablizing under solid state; The phenomenon that the lyophilized powder color becomes pale pink does not take place in also amazing discovery, 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 facing with preceding use aqueous diluent reconstruction, good stability, side effect is little; Can realize parenteral administration; Need not to take Bendectin before having satisfied those needs that have been difficult to the oral administration patient and administration, make patient acceptant, made things convenient for clinical application.
The specific embodiment
Following examples are in order to set forth invention, and limit scope of the present invention never in any form.
Embodiment 1
Pharmaceutical preparation of the present invention makes through following step usually:
1. take by weighing stabilizing agent, wetting agent, the excipient of recipe quantity, buffer agent, stirring and dissolving is at least a aqueous diluent, and aqueous diluent is about 90% of a recipe quantity, and water temperature is controlled at 0-60 ℃.
2. take by weighing the temozolomide of recipe quantity, stirring and dissolving is in above-mentioned solution, and the pH value of solution is measured in the dissolving back fully, as required, uses the pH regulator agent that the solution pH value is adjusted.
3. add aqueous diluent to final volume, solution is continued to be stirred to mix homogeneously.
4. with above-mentioned solution filtration sterilization.
Embodiment 2
Take by weighing the 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g L-cysteine hydrochloride monohydrate, 25.00g mannitol; 9.90g acetic acid, the 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., the source is identical in following examples); Stirring and dissolving; Add water to 1000mL, with 0.22 μ m filtering with microporous membrane, packing; Lyophilization obtains temozolomide freeze-dried powder.
Embodiment 3
Take by weighing the 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g L-cysteine 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 the 2.50g temozolomide, stirring and dissolving adds the injection water to 1000mL; With 0.22 μ m filtering with microporous membrane; Packing, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 4
Take by weighing the 3.00g Polyoxyethylene Sorbitan Monooleate, 5.00g vitamin c, 6.00g mannitol; 5.67g acetic acid, the 5.03g sodium acetate adds 900mL water for injection; Stirring and dissolving under 40 ℃ of water-baths; Add the 2.50g temozolomide, stirring and dissolving adds water to 1000mL; With 0.22 μ m filtering with microporous membrane; Packing, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 5
Take by weighing the 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 the 2.50g temozolomide, stirring and dissolving adds water to 1000mL; With 0.22 μ m filtering with microporous membrane; Packing, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 6
Take by weighing 4.00g L-cysteine 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 the 2.50g temozolomide; Stirring and dissolving; Add water to 1000mL, with 0.22 μ m filtering with microporous membrane, packing; Lyophilization obtains temozolomide freeze-dried powder.
Embodiment 7
Take by weighing the 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g L-glycine, 10.00g mannitol; 5.67g acetic acid, the 5.03g sodium acetate adds 900mL water for injection; Stirring and dissolving under 40 ℃ of water-baths; Add the 2.50g temozolomide, stirring and dissolving adds water to 1000mL; With 0.22 μ m filtering with microporous membrane; Packing, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 8
Take by weighing the 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g L-alanine, 10.00g mannitol; 5.67g acetic acid, the 5.03g sodium acetate adds 900mL water for injection; Stirring and dissolving under 40 ℃ of water-baths; Add the 2.50g temozolomide, stirring and dissolving adds water to 1000mL; With 0.22 μ m filtering with microporous membrane; Packing, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 9
Take by weighing the 3.00g Polyoxyethylene Sorbitan Monooleate, 2.00g L-cysteine 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 the 2.50g temozolomide; Stirring and dissolving; Add water to 1000mL, with 0.22 μ m filtering with microporous membrane, packing; Lyophilization obtains temozolomide freeze-dried powder.
Embodiment 10
Take by weighing the 3.00g Polyoxyethylene Sorbitan Monooleate, 4.00g L-cysteine hydrochloride monohydrate, 12.00g mannitol; 4.00g acetic acid; Add 900mL water for injection, stirring and dissolving under 40 ℃ of water-baths adds the 2.50g temozolomide; Stirring and dissolving; Add water to 1000mL, with 0.22 μ m filtering with microporous membrane, packing; Lyophilization obtains temozolomide freeze-dried powder.
Embodiment 11
Take by weighing the 3.00g Polyoxyethylene Sorbitan Monooleate; 4.00g L-cysteine hydrochloride monohydrate, 25.00g mannitol adds 900mL water for injection; Stirring and dissolving under 40 ℃ of water-baths; Add the 2.50g temozolomide, stirring and dissolving adds water to 1000mL; With 0.22 μ m filtering with microporous membrane; Packing, lyophilization obtains temozolomide freeze-dried powder.
Embodiment 12
Take by weighing the 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 the 2.50g temozolomide; Stirring and dissolving; Add water to 1000mL, with 0.22 μ m filtering with microporous membrane, packing; Lyophilization obtains temozolomide freeze-dried powder.
Embodiment 13
According to solution before embodiment 2,3 preparation temozolomides' the lyophilizing, lyophilization prepares freeze-dried temzolomide powder.Use reverse high performance liquid chromatography (HPLC) to measure the stability of solution of the preceding solution of lyophilizing and the stability of solution after the reconstruction of the solution after the lyophilizing respectively; And the freeze-dried temzolomide powder for preparing kept sample; Measure related substance through rebuilding behind the different time, investigate its stability.
With reference to disclosed embodiment 2 in the US Patent No. 6987108 (Chinese patent families CN03804363.7): solution before preparation temozolomide's the lyophilizing, and, prepared a collection of freeze-dried temzolomide powder according to the freeze-drying method lyophilization in the patent.Use reverse high performance liquid chromatography (HPLC) to measure the stability of solution of the preceding solution of lyophilizing and the stability of solution after the reconstruction of the solution after the lyophilizing; And the freeze-dried temzolomide powder for preparing kept sample; Measure related substance through rebuilding behind the different time; The data that obtain and the data among the embodiment 2,3 are compared.The result is as shown in the table:
Stability of solution before the lyophilizing of table 1 US Patent No. 6987108 embodiment 2 and the embodiment of the invention 3 prescription preparations
The stability of solution of rebuilding after the lyophilizing of table 2 US Patent No. 6987108 embodiment 2 and the embodiment of the invention 3 prescription preparations
Table 1; 2 result shows; The degradation rate of prescription is close in the degradation rate of the temozolomide freeze-dried preceding solution state in the prescription among the present invention and the US Patent No. 6987108; And the degradation rate after rebuilding after the lyophilizing is a little less than the degradation rate of writing out a prescription in the US Patent No. 6987108, thereby illustrates that preparation of the present invention has good stable property.
The stability of the freeze-dried temzolomide powder that table 3 US Patent No. 6987108 embodiment 2 obtain
The stability of the freeze-dried temzolomide powder that table 4 embodiment of the invention 2 obtains
The stability of the freeze-dried temzolomide powder that table 5 embodiment of the invention 3 obtains
Table 3,4,5 results show temozolomide among the present invention through still keeping stable after 2 months, and are suitable with the stability of formulation of the present invention's preparation through the stability of formulation of US Patent No. 6987108 preparations, all keep stablizing.But 40 ℃ in the preparation of US Patent No. 6987108 preparation, store January after color become pale pink by white or off-white color, color burn after February, 25 ℃, store February after color become pale pink by white or off-white color; And the lyophilized powder color that obtains among the present invention does not change, and keeps white constant to off-white color.This amazing result, the freeze-dried temzolomide powder of indication the present invention preparation has better stability.
Claims (22)
1. injectable gastrointestinal external medicine preparation comprises:
1) temozolomide or its pharmaceutically acceptable salt;
2) at least a stabilizing agent
3) at least a aqueous diluent;
Wherein said stabilizing agent is selected from L-alanine, L-glycine, L-cysteine, L-cysteine hydrochloride anhydride, L-cysteine hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-L-cysteine, L-ethylcysteine hydrochloride, L-acthiol-J hydrochlorate, vitamin c or their mixture, is preferably selected from vitamin c, L-cysteine hydrochloride anhydride, L-cysteine hydrochloride monohydrate or their mixture.
2. injectable gastrointestinal external medicine preparation according to claim 1, wherein said aqueous diluent are selected from water for injection, normal saline, physiology sugar-salt-water, 5% dextrose solution or their mixture.
3. injectable gastrointestinal external medicine preparation according to claim 1 also comprises at least a excipient.
4. injectable gastrointestinal external medicine preparation 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, is preferably mannitol.
5. injectable gastrointestinal external medicine preparation according to claim 1 also comprises at least a wetting agent.
6. injectable gastrointestinal external medicine preparation 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; Be preferably selected from polysorbate-20, polysorbate-40, polysorbate-60, Polyoxyethylene Sorbitan Monooleate or their mixture, most preferably be Polyoxyethylene Sorbitan Monooleate.
7. injectable gastrointestinal external medicine preparation according to claim 1 also comprises at least a buffer agent.
8. injectable gastrointestinal external medicine preparation according to claim 7; Wherein said buffer agent is selected from citrate; Lactate; Acetate, tartrate, succinate, phosphate or their mixture; Be preferably selected from citrate, acetate, phosphate or their mixture, most preferably be acetate or citrate.
9. injectable gastrointestinal external medicine preparation according to claim 1, it also comprises at least a pH regulator agent.
10. injectable gastrointestinal external medicine preparation according to claim 9, wherein said pH regulator 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.
11. injectable gastrointestinal external medicine preparation according to claim 1, the pH of wherein said preparation are in 2.0 to 6.0 scope, preferably in 2.5 to 4.5 scope, most preferably in 3.5 to 4.0 scope.
12. injectable gastrointestinal external medicine preparation according to claim 1; Wherein said stabilizing agent is selected from the L-glycine; The L-alanine; The L-cysteine; L-cysteine hydrochloride anhydride; L-cysteine hydrochloride monohydrate; Acetylcysteine; S-carboxymethyl-L-cysteine; The L-ethylcysteine hydrochloride; L-acthiol-J hydrochlorate; Vitamin c or their mixture; And described pharmaceutical preparation also comprises at least a pH regulator agent that is selected from hydrochloric acid or acetic acid, at least a citrate that is selected from; The buffer agent of acetate and mannitol.
13. injectable gastrointestinal external medicine preparation according to claim 12; Wherein in the gross weight of pharmaceutical preparation; Described temozolomide's content is 1wt% to 50wt%; The content of said pH regulator agent is 0.1wt% to 20wt%; The content of said buffer agent is 5wt% to 60wt%; The content of said stabilizing agent is 4wt% to 60wt%, and the content of said mannitol is the full 80wt% of 20wt%.
14. injectable gastrointestinal external medicine preparation according to claim 1; Wherein said stabilizing agent is selected from the L-glycine; The L-alanine; The L-cysteine; L-cysteine hydrochloride anhydride; L-cysteine hydrochloride monohydrate; Acetylcysteine; S-carboxymethyl-L-cysteine; The L-ethylcysteine hydrochloride; L-acthiol-J hydrochlorate; Vitamin c or their mixture; And described pharmaceutical preparation also comprises at least a hydrochloric acid that is selected from; The agent of acetic acid pH regulator; At least a citrate or acetate buffer, polysorbate and the mannitol of being selected from.
15. injectable gastrointestinal external medicine preparation according to claim 14; Wherein in the gross weight of pharmaceutical preparation; Said temozolomide's content is 1wt% to 50wt%; The content of said pH regulator agent is 0.1wt% to 20wt%; The content of said buffer agent is 5wt% to 60wt%; The content of said 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%.
16. a method for preparing injectable gastrointestinal external medicine preparation as claimed in claim 1 comprises the following steps:
1) at least a stabilizing agent is dissolved at least a aqueous diluent; Solution temperature 0-60 ℃, wherein said stabilizing agent is selected from L-glycine, L-alanine, L-cysteine, L-cysteine hydrochloride anhydride, L-cysteine hydrochloride monohydrate, acetylcysteine, S-carboxymethyl-L-cysteine, L-ethycysteine hydrochloric acid, L-acthiol-J hydrochlorate, vitamin c or their mixture; With
2) add temozolomide or its pharmaceutically acceptable salt.
17. method according to claim 16, it also comprises:
1) adds at least a wetting agent;
2) add at least a excipient;
3) add at least a buffer agent;
4) add at least a pH regulator agent to form a kind of solution; With
5) filter above-mentioned solution.
18. method according to claim 17, it comprises that also the solution that step 5) is obtained carries out lyophilization, to obtain a kind of lyophilized powder.
19. the lyophilized powder that makes by method as claimed in claim 18.
20. a pharmaceutical preparation comprises a kind of container that contains lyophilized powder as claimed in claim 19.
21. pharmaceutical preparation according to claim 20, wherein said container are syringe or bottle.
22. a pharmaceutical preparation that is suitable for to patient's administration, said preparation are to make through the lyophilized powder of claim 19 is rebuild at least a aqueous diluent.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010244080.7A CN102342931B (en) | 2010-07-29 | 2010-07-29 | Injectable parenteral medicinal preparation of temozolomide 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 |
| PCT/CN2011/077093 WO2012013116A1 (en) | 2010-07-29 | 2011-07-13 | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| PCT/CN2011/077095 WO2012013117A1 (en) | 2010-07-29 | 2011-07-13 | Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof |
| CN2011800037655A CN102481287B (en) | 2010-07-29 | 2011-07-13 | Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010244080.7A CN102342931B (en) | 2010-07-29 | 2010-07-29 | Injectable parenteral medicinal preparation of temozolomide and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102342931A true CN102342931A (en) | 2012-02-08 |
| CN102342931B CN102342931B (en) | 2014-04-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010244080.7A Active CN102342931B (en) | 2010-07-29 | 2010-07-29 | Injectable parenteral medicinal preparation of temozolomide and preparation method thereof |
| CN201180003766.XA Active CN102481288B (en) | 2010-07-29 | 2011-07-13 | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| CN2011800037655A Active CN102481287B (en) | 2010-07-29 | 2011-07-13 | Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
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| CN201180003766.XA Active CN102481288B (en) | 2010-07-29 | 2011-07-13 | Pharmaceutical composition of temozolomide comprising amino acid stabilizer and preparation method thereof |
| CN2011800037655A Active CN102481287B (en) | 2010-07-29 | 2011-07-13 | Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof |
Country Status (2)
| Country | Link |
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| CN (3) | CN102342931B (en) |
| WO (2) | WO2012013117A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN111107837A (en) * | 2017-09-27 | 2020-05-05 | 诺华股份有限公司 | Parenteral formulation comprising siponimod |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9033949B2 (en) * | 2012-11-27 | 2015-05-19 | Bang & Olufsen Medicom A/S | Needle protection device |
| ES2545553B1 (en) | 2014-11-26 | 2016-06-24 | Saitec, S.A. | Floating platform for wind energy use |
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| 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 |
| US20090270397A1 (en) * | 2008-04-08 | 2009-10-29 | Orlow Seth J | Methods and compositions for the treatment of cancers, such as melanomas and gliomas |
| 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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| 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 |
| 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 |
-
2010
- 2010-07-29 CN CN201010244080.7A patent/CN102342931B/en active Active
-
2011
- 2011-07-13 WO PCT/CN2011/077095 patent/WO2012013117A1/en active Application Filing
- 2011-07-13 CN CN201180003766.XA patent/CN102481288B/en active Active
- 2011-07-13 CN CN2011800037655A patent/CN102481287B/en active Active
- 2011-07-13 WO PCT/CN2011/077093 patent/WO2012013116A1/en active Application Filing
Patent Citations (3)
| 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 |
| US20090270397A1 (en) * | 2008-04-08 | 2009-10-29 | Orlow Seth J | Methods and compositions for the treatment of cancers, such as melanomas and gliomas |
| CN101869551A (en) * | 2010-06-28 | 2010-10-27 | 江苏奥赛康药业有限公司 | Temozolomide freeze-dried preparation |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN111107837A (en) * | 2017-09-27 | 2020-05-05 | 诺华股份有限公司 | Parenteral formulation comprising siponimod |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012013117A1 (en) | 2012-02-02 |
| WO2012013116A1 (en) | 2012-02-02 |
| CN102481287A (en) | 2012-05-30 |
| CN102342931B (en) | 2014-04-23 |
| CN102481288A (en) | 2012-05-30 |
| CN102481287B (en) | 2013-09-18 |
| CN102481288B (en) | 2014-02-19 |
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