CN116440087A - Preparation method of temozolomide freeze-dried preparation - Google Patents

Preparation method of temozolomide freeze-dried preparation Download PDF

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Publication number
CN116440087A
CN116440087A CN202310190495.8A CN202310190495A CN116440087A CN 116440087 A CN116440087 A CN 116440087A CN 202310190495 A CN202310190495 A CN 202310190495A CN 116440087 A CN116440087 A CN 116440087A
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temozolomide
freeze
preparation
injection
dried
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秦继红
李文华
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Shanghai Huilun Jiangsu Pharmaceutical Co ltd
Shanghai Huilun Pharmaceutical Co ltd
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Shanghai Huilun Jiangsu Pharmaceutical Co ltd
Shanghai Huilun Pharmaceutical Co ltd
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
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  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation method of temozolomide freeze-dried preparation, which comprises the following steps: dissolving a pH regulator, a buffering agent and a propping agent in water for injection; mixing temozolomide with water for injection or not more than 30% of the solution of step 1); mixing the mixed solution obtained in the step 2) with the solution obtained in the step 1); filtering the solution obtained in the step 3), and freeze-drying. Compared with the prior art, the preparation method provided by the invention has the advantages that the contact time of temozolomide and water for injection is obviously shortened, and the dissolution rate is improved, so that the impurity content generated by unstable aqueous solution of temozolomide is reduced.

Description

Preparation method of temozolomide freeze-dried preparation
Technical Field
The application belongs to the field of medicine invention, and in particular relates to a preparation method of temozolomide freeze-dried preparation.
Background
Temozolomide (chemical name 3, 4-dihydro-3-methyl-4-oxoimidazo [5,1-d ] -tetrazine-8-carboxamide. For the treatment of brain gliomas and malignant melanoma, FDA approval was obtained at 11, 8, 1999 in the united states. Temozolomide has poor solubility in water, has a solubility of about 3.1mg/ml, is stable at pH <5, and rapidly degrades to active metabolites at neutral or pH > 7. Because temozolomide is unstable in water and is easy to decompose, the long-term stability of the injection cannot be ensured.
Chinese invention CN1635871a discloses a freeze-dried powder injection of temozolomide, wherein in order to increase the solubility of temozolomide, a solubilizing agent such as urea, L-histidine, L-threonine and other amino acids is added into the freeze-dried preparation. The freeze-dried powder injection prepared in CN102342931A is added with a stabilizer such as L-alanine, L-glycine and the like. The freeze-dried powder injection prepared by the method needs to be added with a solvent or a stabilizer to improve the solubility or stability of temozolomide. However, the addition of a solvent or stabilizer may cause safety problems and increase toxic side effects.
Chinese patent No. 1923197A discloses a temozolomide freeze-dried powder injection for injection, which does not need to add a solubilizer or a stabilizer, but firstly dissolves a freeze-dried propping agent in a solvent for injection, then adds temozolomide, and improves the dissolution rate of the temozolomide by a heating or ultrasonic method so as to reduce the contact time of the temozolomide and the propping agent in an aqueous solution.
Because temozolomide is easily decomposed in an aqueous solution, when the method disclosed in the invention patent CN1923197a is adopted, although heating or ultrasonic treatment is beneficial to improving the dissolution rate of temozolomide, the content of decomposed impurities of temozolomide is obviously increased. Therefore, there is an urgent need to find a method for reducing the impurity content of temozolomide freeze-dried powder injection without adding a solubilizer or a stabilizer.
Disclosure of Invention
In order to solve the problems of the conventional temozolomide freeze-dried powder injection, the invention provides an effective method for reducing the decomposition of temozolomide and improving the quality of the temozolomide freeze-dried powder injection under the condition of not adding a solubilizer or a stabilizer.
A method for preparing a temozolomide freeze-dried preparation, which comprises the following steps:
1) Dissolving a pH regulator, a buffering agent and a propping agent in water for injection;
2) Mixing temozolomide with water for injection or not more than 30% of the solution of step 1);
3) Mixing the mixed solution obtained in the step 2) with the solution obtained in the step 1);
4) Filtering the solution obtained in the step 3), and freeze-drying.
Preferably, step 2) is carried out using high shear dispersive mixing; the temperature of the high shear dispersion is no higher than 35 ℃, preferably no more than 30 ℃. The high shear dispersion is for a period of no more than 10 minutes, preferably no more than 8 minutes, more preferably no more than 5 minutes. The high-shear dispersed suspension can obviously shorten the dissolution time of temozolomide in the solution in the step (1) and reduce temozolomide degradation impurities.
Wherein the propping agent is optionally selected from mannitol, sucrose, trehalose, lactose, glucose, preferably mannitol; the buffer is selected from sodium citrate, sodium acetate, sodium phosphate or any combination thereof; the pH adjustor is optionally selected from hydrochloric acid, citric acid, acetic acid, tartaric acid, oxalic acid, malic acid, maleic acid, fumaric acid, ascorbic acid, or any combination thereof.
Preferably, the temozolomide in the step (2) is mixed with water for injection, and the mass volume ratio of the temozolomide to the water for injection is 0.02-2:100, and preferably the volume ratio is 0.1-1:100. In addition, after the pH regulator, the buffer and the propping agent are dissolved in the water for injection, a part of the solution is taken and mixed with temozolomide, namely, the temozolomide is mixed with not more than 25 percent of the solution in the step (1); more preferably not more than 20% of the solution of step (1).
The pH regulator and buffer are added in step 1). Alternatively, a pH adjustor and a buffer are added in step 2). The amount of modifier and buffer added is sufficient to provide a pH of the solution of from 2.0 to 6.0, preferably from 3.0 to 5.0, and more preferably from 3.0 to 4.0.
In the preparation method of the invention, the step (1) and the step (2) have no strict sequence requirements, and in certain embodiments, according to the actual situation, a person skilled in the art can firstly mix temozolomide with water for injection, disperse the temozolomide in high shear, and then prepare a solution of an auxiliary material component, so that the purpose of the invention can be realized.
Specifically, the invention relates to a preparation method of a temozolomide freeze-dried preparation, wherein the freeze-dried preparation comprises temozolomide, at least one buffering agent, at least one pH regulator and at least one propping agent, and the preparation method comprises the following steps of:
(1) Dissolving a pH regulator, a buffering agent and a propping agent in water for injection;
(2) Mixing temozolomide with water for injection or not more than 30% of the solution in the step 1), and performing high-shear dispersion;
(3) Mixing and dissolving the suspension in the step (2) and the solution in the step (1);
(4) Filtering and freeze-drying the solution obtained in the step (3) to obtain a freeze-dried preparation.
In addition, the preparation method of the temozolomide freeze-dried preparation, which is related by the invention, comprises the following steps of:
(1) Dissolving hydrochloric acid, sodium citrate and mannitol in water for injection;
(2) Mixing the mixed temozolomide with water for injection or not more than 20% of the solution in the step (1), and performing high-shear operation for not more than 10 minutes;
(3) Mixing and dissolving the temozolomide suspension in the step (2) and the solution in the step (1);
(4) Filtering and freeze-drying the solution obtained in the step (3) to obtain a freeze-dried preparation.
Compared with the prior art, the preparation method provided by the invention has the advantages that the contact time of temozolomide and water for injection is obviously shortened, and the dissolution rate is improved, so that the impurity content generated by unstable aqueous solution of temozolomide is reduced.
Detailed Description
Example 1
Prescription of prescription
Preparation
The preparation is carried out in batches of 50L, and the specific preparation method is as follows: mannitol, hydrochloric acid and sodium citrate with the prescribed amounts are weighed and added into 50L of water for injection to prepare the auxiliary material composition with the pH value of 3.0-4.0. Taking part of the auxiliary material composition (5-20%) with the temperature of 20-25 ℃, adding temozolomide raw material medicine, and carrying out shearing dispersion for 1-3 min by using a high shearing dispersion emulsion machine to obtain the suspension of the raw material medicine-auxiliary material composition. The suspension is added into the rest auxiliary material composition (80-95%), and is stirred and dissolved at 20-25 ℃. Filtering and sterilizing the dissolved liquid medicine by a microporous filter membrane with the diameter of 0.22 mu m, sub-packaging, freeze-drying and nitrogen charging to obtain temozolomide freeze-dried powder injection for injection.
Example 2
Prescription of prescription
Preparation
The preparation is carried out in batches of 50L, and the specific preparation method is as follows: mannitol, hydrochloric acid and sodium citrate with the prescribed amounts are weighed and added into 50L of water for injection to prepare the auxiliary material composition with the pH value of 3.0-4.0. Taking part of the auxiliary material composition (5-20%) with the temperature of 25-30 ℃, adding temozolomide raw material medicine, and shearing and dispersing for 3-5 min by using a high shearing and dispersing emulsion machine to prepare a suspension of the raw material medicine-auxiliary material composition. The suspension is added into the rest auxiliary material composition (80-95%), and is stirred and dissolved at 25-30 ℃. Filtering and sterilizing the dissolved liquid medicine by a microporous filter membrane with the diameter of 0.22 mu m, sub-packaging, freeze-drying and nitrogen charging to obtain temozolomide freeze-dried powder injection for injection.
Example 3
Prescription of prescription
Preparation
The preparation was carried out in batches of 50L, the preparation method comprises the following steps: mannitol, hydrochloric acid and sodium citrate with the prescribed amounts are weighed and added into 70% of water for injection to prepare the auxiliary material composition with the pH value of 3.0-4.0. Taking about 10% of water for injection (the temperature is 20-30 ℃), adding temozolomide bulk drug, and shearing and dispersing for 1-5 min by using a high-shearing and dispersing emulsion machine to obtain bulk drug-water for injection suspension. Adding the suspension into an auxiliary material solution, adding water for injection (the temperature is 20-30 ℃) to the prescription amount, and stirring and dissolving at the temperature of 20-30 ℃. Filtering and sterilizing the dissolved liquid medicine by a microporous filter membrane with the diameter of 0.22 mu m, sub-packaging, freeze-drying and nitrogen charging to obtain temozolomide freeze-dried powder injection for injection.
Comparative example 4
The same prescription as in example 3 was used to examine the effect of the order of addition of pH adjuster on temozolomide lyophilized formulation by using different preparation techniques, and the specific steps are as follows:
the preparation is carried out in batches of 50L, and the specific preparation method is as follows: weighing mannitol, hydrochloric acid and sodium citrate with the prescribed amounts, adding the mannitol, the hydrochloric acid and the sodium citrate into all water for injection, and dissolving to obtain an auxiliary material solution with the pH range of 3.0-4.0. Adding temozolomide raw material medicine, stirring and dissolving. Filtering and sterilizing the dissolved liquid medicine by a microporous filter membrane with the diameter of 0.22 mu m, sub-packaging, freeze-drying and nitrogen charging to obtain temozolomide freeze-dried powder injection for injection.
Comparative example 5
The same recipe as in patent example 3 was prepared by the following process:
the preparation is carried out in batches of 50L, and the specific preparation method is as follows: weighing mannitol with a prescription amount, adding temozolomide raw material medicine after dissolving in all water for injection, stirring and dissolving, then adding hydrochloric acid and sodium citrate for regulating the pH value of the liquid medicine, and finally regulating the pH value of the liquid medicine to be 3.0-4.0. Filtering and sterilizing the dissolved liquid medicine by a microporous filter membrane with the diameter of 0.22 mu m, sub-packaging, freeze-drying and nitrogen charging to obtain temozolomide freeze-dried powder injection for injection.
Comparative example 6
The same recipe as in patent example 3 was prepared by the following process:
the preparation is carried out in batches of 50L, and the specific preparation method is as follows: weighing mannitol with a prescription amount, adding the mannitol into all water for injection for dissolution, adding temozolomide bulk drug suspension which is subjected to shearing dispersion for 1-5 min by a high-shearing dispersion emulsion machine, stirring for dissolution, then adding hydrochloric acid and sodium citrate for regulating the pH of the liquid medicine, and finally, regulating the pH range of the liquid medicine to 3.0-4.0. Filtering and sterilizing the dissolved liquid medicine by a microporous filter membrane with the diameter of 0.22 mu m, sub-packaging, freeze-drying and nitrogen charging to obtain temozolomide freeze-dried powder injection for injection.
Comparative example 7
The same formulation as in example 3 was prepared using different temperature conditions and the effect of temperature on the lyophilized formulation was measured and the results were as follows:
the above data show that when the temperature is higher than 35 ℃, the impurity content of temozolomide lyophilized preparation will increase significantly, resulting in failure to meet the drug preparation standard.
According to the formulations of examples 1 to comparative example 6, the content of the relevant substances was determined as follows:
examples Maximum mono-hetero (%) Total impurity (%)
Examples 1 to 3 0.1 0.15
Example 4 0.3 0.4
Example 5 0.6 0.8
Example 6 0.2 0.3
The impurity levels of examples 1-3 and 4 demonstrate that the high shear process can significantly reduce the impurity levels. Examples 5-6 show that the dissolution of temozolomide after the pre-addition of the pH adjustor is significantly lower than the dissolution of temozolomide before the pH adjustment.
According to the formulations of the examples of the present invention, the dissolution times of the formulations of examples 3,4, 5, 6 were determined
Examples Stirring time Dissolved state
Example 3 10min Completely dissolved and clarified solution
Example 4 2h Small amount of undissolved particles
Example 5 2h Small amount of undissolved particles
Example 6 10min Completely dissolved and clarified solution
The above results demonstrate that the use of high shear significantly shortens the dissolution time of the lyophilized formulation and reduces the presence of sparingly soluble particles.
According to the preparation of the embodiment of the invention, the total impurity content generated by decomposing the temozolomide freeze-dried preparation in an aqueous solution is measured:
therefore, the temozolomide freeze-dried preparation has obvious stability.
Although the present invention has been described in terms of the preferred embodiments, it is not intended to be limited to the embodiments, and any person skilled in the art can make any possible variations and modifications to the technical solution of the present invention by using the methods and technical matters disclosed above without departing from the spirit and scope of the present invention, so any simple modifications, equivalent variations and modifications to the embodiments described above according to the technical matters of the present invention are within the scope of the technical matters of the present invention.

Claims (10)

1. A method for preparing a temozolomide freeze-dried preparation, which is characterized by comprising the following steps:
1) Dissolving a pH regulator, a buffering agent and a propping agent in water for injection;
2) Mixing temozolomide with water for injection or not more than 30% of the solution of step 1);
3) Mixing the mixed solution obtained in the step 2) with the solution obtained in the step 1);
4) Filtering the solution obtained in the step 3), and freeze-drying.
2. The process for preparing a lyophilized temozolomide formulation as defined in claim 1, wherein in step 2) high shear dispersive mixing is employed.
3. A process for the preparation of a freeze-dried temozolomide formulation according to claim 2, wherein the high shear dispersion temperature is not higher than 35 ℃, preferably not higher than 30 ℃.
4. A process for the preparation of a freeze-dried temozolomide formulation according to any one of claims 2 or 3, wherein the high shear dispersion is carried out for a period of not more than 10 minutes, preferably not more than 8 minutes, more preferably not more than 5 minutes.
5. Process for the preparation of a freeze-dried formulation of temozolomide as claimed in claims 1 to 4, in step 2), characterized in that temozolomide is mixed with not more than 25% of the solution of step (1); more preferably not more than 20% of the solution of step (1).
6. The process for the preparation of a freeze-dried temozolomide formulation according to any one of claims 1 to 5, wherein the propping agent is optionally selected from mannitol, sucrose, trehalose, lactose, glucose, preferably mannitol; the buffer is selected from sodium citrate, sodium acetate, sodium phosphate or any combination thereof; the pH adjustor is optionally selected from hydrochloric acid, citric acid, acetic acid, tartaric acid, oxalic acid, malic acid, maleic acid, fumaric acid, ascorbic acid, or any combination thereof.
7. The process for preparing a freeze-dried temozolomide formulation according to claim 1, wherein when temozolomide is mixed with water for injection in step (2), the mass-to-volume ratio of temozolomide to water for injection is 0.02-2:100, preferably the volume ratio is 0.1-1:100.
8. Process for the preparation of a freeze-dried temozolomide formulation according to claim 1, characterized in that in step 1) a pH regulator and buffer is added at a pH of 3.0-5.0, preferably at a pH of 3.0-4.0.
9. A process for the preparation of a lyophilized formulation of temozolomide as defined in claim 1, wherein the lyophilized formulation comprises temozolomide, at least one buffer, at least one pH adjuster and at least one proppant, which process comprises the steps of:
(1) Dissolving a pH regulator, a buffering agent and a propping agent in water for injection;
(2) Mixing temozolomide with water for injection or not more than 30% of the solution in the step 1), and performing high-shear dispersion;
(3) Mixing and dissolving the suspension in the step (2) and the solution in the step (1);
(4) Filtering and freeze-drying the solution obtained in the step (3) to obtain a freeze-dried preparation.
10. The method for preparing the temozolomide freeze-dried preparation according to claim 1 or 9, wherein the freeze-dried preparation contains temozolomide, hydrochloric acid, sodium citrate and mannitol, and the preparation method comprises the following steps:
(1) Dissolving hydrochloric acid, sodium citrate and mannitol in water for injection;
(2) Mixing temozolomide, water for injection or not more than 20% of the solution in the step (1), and performing high-shear operation for not more than 10 minutes;
(3) Mixing and dissolving the temozolomide suspension in the step (2) and the solution in the step (1);
(4) Filtering and freeze-drying the solution obtained in the step (3) to obtain a freeze-dried preparation.
CN202310190495.8A 2017-11-08 2017-11-08 Preparation method of temozolomide freeze-dried preparation Pending CN116440087A (en)

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CN100588399C (en) * 2005-09-01 2010-02-10 天津帝士力投资控股集团有限公司 Freeze-dried temzolomide powder for injection and its preparing process
US20120283304A1 (en) * 2009-12-23 2012-11-08 Sahaj Life Sciences Pvt. Ltd. Formulations of Temozolomide for Parenteral Administration
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
US8974811B2 (en) * 2013-03-14 2015-03-10 Hikma Pharmaceuticals Stabilized pharmaceutical formulations comprising antineoplastic compounds
CN103405385B (en) * 2013-08-06 2015-10-21 山东大学 A kind of temozolomide's intravenous injection fatty breast and preparation method thereof
CN104721155B (en) * 2015-04-07 2017-09-29 齐鲁制药(海南)有限公司 A kind of temozolomide freeze-dried powder preparation and preparation method thereof

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