CN109745292A - A kind of preparation method of temozolomide freeze-dried preparation - Google Patents
A kind of preparation method of temozolomide freeze-dried preparation Download PDFInfo
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- CN109745292A CN109745292A CN201711089257.9A CN201711089257A CN109745292A CN 109745292 A CN109745292 A CN 109745292A CN 201711089257 A CN201711089257 A CN 201711089257A CN 109745292 A CN109745292 A CN 109745292A
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- preparation
- temozolomide
- freeze
- solution
- injection
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- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 74
- 229960004964 temozolomide Drugs 0.000 title claims abstract description 74
- 239000000243 solution Substances 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000008215 water for injection Substances 0.000 claims abstract description 28
- 238000004108 freeze drying Methods 0.000 claims abstract description 17
- 238000004090 dissolution Methods 0.000 claims abstract description 15
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 239000006185 dispersion Substances 0.000 claims description 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 14
- 229930195725 Mannitol Natural products 0.000 claims description 14
- 239000000594 mannitol Substances 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 14
- 239000001509 sodium citrate Substances 0.000 claims description 12
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- RLWRMIYXDPXIEX-UHFFFAOYSA-N muzolimine Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C)N1N=C(N)CC1=O RLWRMIYXDPXIEX-UHFFFAOYSA-N 0.000 claims description 3
- 229960001788 muzolimine Drugs 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- -1 Azoles amine Chemical class 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 10
- 239000007864 aqueous solution Substances 0.000 abstract description 5
- 238000004904 shortening Methods 0.000 abstract description 2
- 239000007924 injection Substances 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000000843 powder Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000012530 fluid Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- 239000012982 microporous membrane Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000004945 emulsification Methods 0.000 description 4
- 238000010008 shearing Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 240000004307 Citrus medica Species 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Natural products C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 229960002885 histidine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960002898 threonine Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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)
- Epidemiology (AREA)
- 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)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation method of temozolomide freeze-dried preparation, the method includes the following steps: for pH adjusting agent, buffer, proppant to be dissolved in water for injection；The solution of step 1) by Temozolomide with water for injection or no more than 30% mixes；Mixed liquor obtained in step 2) is mixed with the solution in step 1)；By the resulting solution filtering of step 3), freeze-drying.Preparation method of the invention compared with prior art, the significant time of contact for shortening Temozolomide and water for injection, improves rate of dissolution, to reduce the impurity content because of the unstable generation of the aqueous solution of Temozolomide.
Description
Technical field
The application belongs to field of medicine invention, and in particular to a kind of preparation method of temozolomide freeze-dried preparation.
Background technique
Temozolomide (temozolomide), chemical name 3,4- dihydro-3-methyl-4-oxomidazo simultaneously [5,1-d]-four
Piperazine -8- formamide.For treating glioma and malignant mela noma, in the acquisition FDA approval on the 11st of August in 1999 in the U.S.
City.Solvability is poor in water for Temozolomide, and solubility is about 3.1mg/ml, and stablizes under pH<5, in neutral or pH>7
Under the conditions of Temozolomide degrade rapidly to active metabolite.Since Temozolomide is unstable in water, easily decomposes, cause to be prepared into
Injection cannot be guaranteed long-term stability.
Chinese invention CN1635871A discloses a kind of freeze drying powder injection of Temozolomide, in order to increase the molten of Temozolomide
Performance is solved, solubilizer, such as urea, L-Histidine, L-threonine amino acid are added in lyophilized preparation.It is made in CN102342931A
In standby freeze drying powder injection, stabilizer, such as l-Alanine, L- glycine is added.Freeze drying powder injection made above requires
The dissolubility or stability of solubilizer or stabilizer to improve Temozolomide is added.However addition solubilizer or stabilizer may
Lead to safety issue and increases toxic side effect.
Chinese invention patent CN1923197A discloses a kind of freeze-dried temzolomide powder for injection, it is not necessary that solubilizer is added
Or stabilizer, but first freeze-drying proppant is dissolved in solvent for injection, Temozolomide is added, and by adding thermally or ultrasonically
Method improve Temozolomide rate of dissolution, to reduce Temozolomide and proppant in the time of contact of aqueous solution.
Since Temozolomide easily decomposes in aqueous solution, when using method disclosed in patent of invention CN1923197A, add
Although thermally or ultrasonically to improving, Temozolomide rate of dissolution is beneficial, and the decomposition impurity content that will lead to Temozolomide obviously increases
Add.Therefore there is an urgent need to find one kind both not needed that solubilizer or stabilizer is added, and it can reduce temozolomide freeze-dried powder
The method of injection impurity content.
Summary of the invention
To solve the problems, such as that existing freeze-dried temzolomide powder exists, the present invention provide it is a kind of be added without solubilizer or
Under conditions of stabilizer, Temozolomide decomposition can be reduced, the effective ways of freeze-dried temzolomide powder quality are improved.
A kind of preparation method of temozolomide freeze-dried preparation, the method include the following steps:
1) pH adjusting agent, buffer, proppant are dissolved in water for injection；
2) solution of the step 1) by Temozolomide with water for injection or no more than 30% mixes；
3) mixed liquor obtained in step 2) is mixed with the solution in step 1)；
4) the resulting solution of step 3) is filtered, freeze-drying.
Preferably, it is mixed in step 2) using high shear dispersion；The temperature of the high shear dispersion is excellent not higher than 35 DEG C
Selection of land is no more than 30 DEG C.The time of the high shear dispersion is no more than 10 minutes, it is preferable that no more than 8 minutes, more preferably
Ground is no more than 5 minutes.Dissolution of the Temozolomide in step (1) solution can significantly be shortened by the suspension of high shear dispersion
Time, and reduce Temozolomide degradation impurity.
Wherein, the proppant is optionally from mannitol, sucrose, trehalose, lactose, glucose, it is therefore preferable to mannitol；Institute
Buffer is stated optionally from sodium citrate, sodium acetate, sodium phosphate or any combination thereof；The pH adjusting agent is optionally from hydrochloric acid, citron
Acid, acetic acid, tartaric acid, oxalic acid, malic acid, maleic acid, fumaric acid, ascorbic acid or any combination thereof.
Preferably, step (2) Temozolomide is mixed with water for injection, and the mass volume ratio of Temozolomide and water for injection is
0.02-2:100, preferred volume ratio 0.1-1:100.In addition, water for injection can be dissolved in for pH adjusting agent, buffer, proppant
Afterwards, it takes the part solution to mix with Temozolomide, i.e., mixes Temozolomide with the solution of (1) the step of being no more than 25%；More
The solution of preferably more than 20% the step of (1) mixes.
PH adjusting agent and buffer are added in step 1).Alternatively, pH adjusting agent and buffer are added in step 2).Regulator
It is enough to make the pH value of the solution in 2.0-6.0 with the additional amount of buffer, preferable ph exists in 3.0-5.0, more preferable pH value
3.0-4.0。
In preparation method of the present invention, step (1) and step (2) have no stringent sequence requirement, in some embodiments,
Those skilled in the art first will can be reconfigured auxiliary material after Temozolomide and water for injection mixing high shear dispersion according to the actual situation
The purpose of the present invention equally may be implemented in the solution of component.
In particular it relates to temozolomide freeze-dried preparation preparation method, lyophilized preparation includes Temozolomide, extremely
A kind of few buffer, at least one pH adjusting agent and at least one proppant, preparation method includes the following steps:
(1) pH adjusting agent, buffer, proppant are dissolved in water for injection；
(2) solution of the step 1) by Temozolomide with water for injection or no more than 30% mixes, and carries out high shear point
It dissipates；
(3) the solution mixed dissolution of the suspension of step (2) and step 1)；
(4) by solution filtering, the freeze-drying of step (3), lyophilized preparation is obtained.
Moreover, it relates to temozolomide freeze-dried preparation preparation method, lyophilized preparation contains Temozolomide, salt
Acid, sodium citrate, mannitol, the preparation method the following steps are included:
(1) hydrochloric acid, sodium citrate, mannitol are dissolved in water for injection；
(2) solution for mixing the step of Temozolomide is with water for injection or no more than 20% (1) is mixed, and carries out height and cuts
Operation is cut to be no more than 10 minutes；
(3) the solution mixed dissolution of the Temozolomide suspension of step (2) and step (1)；
(4) by solution filtering, the freeze-drying of step (3), lyophilized preparation is obtained.
Preparation method of the invention compared with prior art, significantly shortens the time of contact of Temozolomide and water for injection,
Rate of dissolution is improved, to reduce the impurity content because of the unstable generation of the aqueous solution of Temozolomide.
Specific embodiment
Embodiment 1
Prescription
Preparation
It is prepared by the batch of 50L, specifically the preparation method is as follows: weighing the mannitol of recipe quantity, hydrochloric acid, sodium citrate
It is added in 50L water for injection, the adjuvant composition that pH value is 3.0~4.0 is made.Take the above-mentioned temperature in part in 20~25 DEG C of auxiliary materials
Temozolomide bulk pharmaceutical chemicals are added in composition (5~20%), carry out shearing 1~3min of dispersion, value using high shear dispersion dispersing emulsification machine
Obtain bulk pharmaceutical chemicals-adjuvant composition suspension.Above-mentioned suspension is added in remaining adjuvant composition (80~95%), 20
Stirring and dissolving at~25 DEG C.Medical fluid is dissolved through 0.22 μm of filtering with microporous membrane degerming, is dispensed, freeze-drying, nitrogen charging is replaced to get injection
Muzolimine freeze-dried powder.
Embodiment 2
Prescription
Preparation
It is prepared by the batch of 50L, specifically the preparation method is as follows: weighing the mannitol of recipe quantity, hydrochloric acid, sodium citrate
It is added in 50L water for injection, the adjuvant composition that pH value is 3.0~4.0 is made.Take the above-mentioned temperature in part in 25~30 DEG C of auxiliary materials
Temozolomide bulk pharmaceutical chemicals are added in composition (5~20%), carry out shearing 3~5min of dispersion, system using high shear dispersion dispersing emulsification machine
Obtain bulk pharmaceutical chemicals-adjuvant composition suspension.Above-mentioned suspension is added in remaining adjuvant composition (80~95%), 25
Stirring and dissolving at~30 DEG C.Medical fluid is dissolved through 0.22 μm of filtering with microporous membrane degerming, is dispensed, freeze-drying, nitrogen charging is replaced to get injection
Muzolimine freeze-dried powder.
Embodiment 3
Prescription
Preparation
It is prepared by the batch of 50L, specifically the preparation method is as follows: weighing the mannitol of recipe quantity, hydrochloric acid, sodium citrate
It is added in 70% water for injection, the adjuvant composition that pH value is 3.0~4.0 is made.Take about 10% water for injection (temperature: 20~
30 DEG C), Temozolomide bulk pharmaceutical chemicals are added, carry out 1~5min of shearing dispersion using high shear dispersion dispersing emulsification machine to get bulk pharmaceutical chemicals-
The suspension of water for injection.Above-mentioned suspension is added in auxiliary material solution, adds water for injection (temperature: 20~30 DEG C) to prescription
Amount, the stirring and dissolving at 20~30 DEG C.Dissolve medical fluid through 0.22 μm of filtering with microporous membrane degerming, dispense, freeze-drying, nitrogen charging to get
The temozolomide freeze-dried powder needle of injection.
Comparative example 4
Prescription same as Example 3 investigates pH adjusting agent addition sequence to Temozolomide using different preparation processes
The influence of lyophilized preparation, the specific steps are as follows:
It is prepared by the batch of 50L, specifically the preparation method is as follows: weighing the mannitol of recipe quantity, hydrochloric acid, sodium citrate
It is added in whole waters for injection, auxiliary material pH value of solution range 3.0~4.0 is obtained after dissolution.Temozolomide bulk pharmaceutical chemicals are added, stir molten
Solution.Medical fluid is dissolved through 0.22 μm of filtering with microporous membrane degerming, is dispensed, freeze-drying, nitrogen charging is to get the temozolomide freeze-dried powder of injection
Needle.
Comparative example 5
Prescription identical with patent Example 3, different preparation processes are as follows:
It is prepared by the batch of 50L, it is specific the preparation method is as follows: whole injections are added in the mannitol for weighing recipe quantity
After dissolving in water, Temozolomide bulk pharmaceutical chemicals are added, stirring and dissolving, is then added hydrochloric acid and sodium citrate carries out medical fluid pH adjusting,
Final medical fluid pH range 3.0~4.0.Medical fluid is dissolved through 0.22 μm of filtering with microporous membrane degerming, is dispensed, freeze-drying, nitrogen charging is to get note
It penetrates with temozolomide freeze-dried powder needle.
Comparative example 6
Prescription identical with patent Example 3, different preparation processes are as follows:
It is prepared by the batch of 50L, it is specific the preparation method is as follows: whole injections are added in the mannitol for weighing recipe quantity
After dissolving in water, addition carries out the Temozolomide bulk pharmaceutical chemicals suspension of 1~5min of shearing dispersion with high shear dispersion dispersing emulsification machine, stirs
Dissolution is mixed, hydrochloric acid is then added and sodium citrate carries out medical fluid pH adjusting, final medical fluid pH range 3.0~4.0.Dissolve medical fluid warp
0.22 μm of filtering with microporous membrane degerming dispenses, and freeze-drying, nitrogen charging is to get the temozolomide freeze-dried powder needle of injection.
Comparative example 7
Prescription same as Example 3, preparation process use different temperature conditions, shadow of the measuring temperature to lyophilized preparation
It rings, as a result as follows:
Above data shows that, when temperature is higher than 35 DEG C, the impurity content of temozolomide freeze-dried preparation will dramatically increase, and lead
Cause is unable to satisfy medicine preparation standard.
According to embodiment 1 to the preparation of comparative example 6, related content of material is measured, specific as follows:
| Embodiment | Largest single impurity (%) | Total miscellaneous (%) |
| Embodiment 1-3 | 0.1 | 0.15 |
| Embodiment 4 | 0.3 | 0.4 |
| Embodiment 5 | 0.6 | 0.8 |
| Embodiment 6 | 0.2 | 0.3 |
The impurity content of embodiment 1 to embodiment 3 and embodiment 4 illustrates that the technique of high shear can significantly reduce containing for impurity
Amount.And embodiment 5-6 shows to be previously added the mode that Temozolomide dissolution is added after pH adjusting agent is prepared, in relation to substance
Significantly lower than the mode for carrying out pH adjusting after first dissolution Temozolomide.
Preparation according to an embodiment of the present invention measures the dissolution time of preparation in embodiment 3,4,5,6
| Embodiment | Mixing time | Dissolved state |
| Embodiment 3 | 10min | It has been be completely dissolved that, clear solution |
| Embodiment 4 | 2h | A small amount of undissolved particles |
| Embodiment 5 | 2h | A small amount of undissolved particles |
| Embodiment 6 | 10min | It has been be completely dissolved that, clear solution |
These results suggest that significantly shortening the dissolution time of lyophilized preparation using the method for high shear, and reduce slightly soluble
The presence of grain.
Preparation according to an embodiment of the present invention, measurement temozolomide freeze-dried preparation decompose the total impurities of generation in aqueous solution
Content:
Therefore temozolomide freeze-dried preparation of the invention has apparent stability.
Although the invention has been described by way of example and in terms of the preferred embodiments, but it is not for limiting the present invention, any this field
Technical staff without departing from the spirit and scope of the present invention, may be by the methods and technical content of the disclosure above to this hair
Bright technical solution makes possible variation and modification, therefore, anything that does not depart from the technical scheme of the invention, and according to the present invention
Technical spirit any simple modifications, equivalents, and modifications to the above embodiments, belong to technical solution of the present invention
Protection scope.
Claims (10)
1. a kind of preparation method of temozolomide freeze-dried preparation, which is characterized in that the method includes the following steps:
1) pH adjusting agent, buffer, proppant are dissolved in water for injection；
2) solution of the step 1) by Temozolomide with water for injection or no more than 30% mixes；
3) mixed liquor obtained in step 2) is mixed with the solution in step 1)；
4) the resulting solution of step 3) is filtered, freeze-drying.
2. the preparation method of temozolomide freeze-dried preparation as described in claim 1, which is characterized in that cut in step 2) using height
Cut dispersion mixing.
3. the preparation method of temozolomide freeze-dried preparation as claimed in claim 2, which is characterized in that the high shear dispersion
Temperature be not higher than 35 DEG C, it is preferable that be no more than 30 DEG C.
4. the preparation method of the temozolomide freeze-dried preparation as described in Claims 2 or 3 is described in any item, which is characterized in that
The time of the high shear dispersion is no more than 10 minutes, it is preferable that is no more than 8 minutes, it is highly preferred that being no more than 5 minutes.
5. the preparation method of the temozolomide freeze-dried preparation as described in Claims 1-4, in step 2), which is characterized in that will replace
Muzolimine is mixed with the solution of (1) the step of being no more than 25%；The solution of more preferably no more than 20% the step of (1) mixes.
6. such as the preparation method of temozolomide freeze-dried preparation described in any one of claim 1 to 5, wherein the proppant is appointed
Selected from mannitol, sucrose, trehalose, lactose, glucose, it is therefore preferable to mannitol；The buffer is optionally from sodium citrate, second
Sour sodium, sodium phosphate or any combination thereof；The pH adjusting agent is optionally from hydrochloric acid, citric acid, acetic acid, tartaric acid, oxalic acid, apple
Acid, maleic acid, fumaric acid, ascorbic acid or any combination thereof.
7. the preparation method of temozolomide freeze-dried preparation as described in claim 1, which is characterized in that step (2) Temozolomide
When mixing with water for injection, the mass volume ratio of Temozolomide and water for injection is 0.02-2:100, preferred volume ratio 0.1-
1:100。
8. the preparation method of temozolomide freeze-dried preparation as described in claim 1, which is characterized in that in step 1), pH is added
The pH value of regulator and buffer is 3.0-5.0, and preferably pH value is 3.0-4.0.
9. the preparation method of temozolomide freeze-dried preparation as described in claim 1, which is characterized in that lyophilized preparation includes for not
Azoles amine, at least one buffer, at least one pH adjusting agent and at least one proppant, preparation method includes the following steps:
(1) pH adjusting agent, buffer, proppant are dissolved in water for injection；
(2) solution of the step 1) by Temozolomide with water for injection or no more than 30% mixes, and carries out high shear dispersion；
(3) the solution mixed dissolution of the suspension of step (2) and step 1)；
(4) by solution filtering, the freeze-drying of step (3), lyophilized preparation is obtained.
10. preparation side's method of the temozolomide freeze-dried preparation as described in claim 1 or 9, which is characterized in that lyophilized preparation contains
Have Temozolomide, hydrochloric acid, sodium citrate, mannitol, the preparation method the following steps are included:
(1) hydrochloric acid, sodium citrate, mannitol are dissolved in water for injection；
(2) solution of the step of mixing Temozolomide, water for injection or being no more than 20% (1) mixes, and carries out high shear behaviour
Make to be no more than 10 minutes；
(3) the solution mixed dissolution of the Temozolomide suspension of step (2) and step (1)；
(4) by solution filtering, the freeze-drying of step (3), lyophilized preparation is obtained.
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| CN201711089257.9A CN109745292A (en) | 2017-11-08 | 2017-11-08 | A kind of preparation method of temozolomide freeze-dried preparation |
| CN202110867281.0A CN113616605A (en) | 2017-11-08 | 2017-11-08 | Preparation method of temozolomide freeze-dried preparation |
| CN202310190495.8A CN116440087A (en) | 2017-11-08 | 2017-11-08 | Preparation method of temozolomide freeze-dried preparation |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923197A (en) * | 2005-09-01 | 2007-03-07 | 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 |
| 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 |
| WO2011077458A1 (en) * | 2009-12-23 | 2011-06-30 | Sahaj Life Sciences Pvt. Ltd. | Formulations of temozolomide for parenteral administration |
| CN103405385A (en) * | 2013-08-06 | 2013-11-27 | 山东大学 | Temozolomide intravenous injection fat emulsion and preparation method thereof |
| EP2777702A1 (en) * | 2013-03-14 | 2014-09-17 | Hikma Pharmaceuticals | Stabilized pharmaceutical formulations comprising antineoplastic compounds |
| CN104721155A (en) * | 2015-04-07 | 2015-06-24 | 齐鲁制药(海南)有限公司 | Temozolomide lyophilized powder preparation and preparation method thereof |
-
2017
- 2017-11-08 CN CN202310190495.8A patent/CN116440087A/en active Pending
- 2017-11-08 CN CN202110867281.0A patent/CN113616605A/en active Pending
- 2017-11-08 CN CN201711089257.9A patent/CN109745292A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923197A (en) * | 2005-09-01 | 2007-03-07 | 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 |
| WO2011077458A1 (en) * | 2009-12-23 | 2011-06-30 | 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 |
| EP2777702A1 (en) * | 2013-03-14 | 2014-09-17 | Hikma Pharmaceuticals | Stabilized pharmaceutical formulations comprising antineoplastic compounds |
| CN103405385A (en) * | 2013-08-06 | 2013-11-27 | 山东大学 | Temozolomide intravenous injection fat emulsion and preparation method thereof |
| CN104721155A (en) * | 2015-04-07 | 2015-06-24 | 齐鲁制药(海南)有限公司 | Temozolomide lyophilized powder preparation and preparation method thereof |
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| CN113616605A (en) | 2021-11-09 |
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Address after: Room 650-10, building 2, 351 GuoShouJing Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201203 Applicant after: Shanghai Hui Bio Technology Co.,Ltd. Applicant after: SHANGHAI HUILUN JIANGSU PHARMACEUTICAL Co.,Ltd. Address before: 201203 Shanghai Guo Shou Jing Road, Zhangjiang High Tech Park of Pudong New Area No. 351 Building No. 2 room 650-10 Applicant before: SHANGHAI HUILUN LIFE SCIENCE & TECHNOLOGY Co.,Ltd. Applicant before: SHANGHAI HUILUN JIANGSU PHARMACEUTICAL Co.,Ltd. |
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Address after: 200241 floor 10, building 5, No. 525, Yuanjiang Road, Minhang District, Shanghai Applicant after: Shanghai Huilun Pharmaceutical Co.,Ltd. Applicant after: SHANGHAI HUILUN JIANGSU PHARMACEUTICAL Co.,Ltd. Address before: Room 650-10, building 2, No. 351, GuoShouJing Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201203 Applicant before: Shanghai Hui Bio Technology Co.,Ltd. Applicant before: SHANGHAI HUILUN JIANGSU PHARMACEUTICAL Co.,Ltd. |
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