WO2017207719A1 - Composition de cyclophosphamide et son procédé de préparation - Google Patents
Composition de cyclophosphamide et son procédé de préparation Download PDFInfo
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- WO2017207719A1 WO2017207719A1 PCT/EP2017/063369 EP2017063369W WO2017207719A1 WO 2017207719 A1 WO2017207719 A1 WO 2017207719A1 EP 2017063369 W EP2017063369 W EP 2017063369W WO 2017207719 A1 WO2017207719 A1 WO 2017207719A1
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- WO
- WIPO (PCT)
- Prior art keywords
- cyclophosphamide
- process according
- solvent
- suitable solvent
- gas
- Prior art date
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- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 229960004397 cyclophosphamide Drugs 0.000 title claims abstract description 83
- 238000000034 method Methods 0.000 title claims abstract description 56
- 239000000203 mixture Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 40
- 239000000843 powder Substances 0.000 claims abstract description 23
- 238000010926 purge Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 239000007789 gas Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000011049 filling Methods 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 abstract description 15
- 238000004108 freeze drying Methods 0.000 abstract description 10
- 239000008174 sterile solution Substances 0.000 abstract 1
- 150000004682 monohydrates Chemical class 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- PWOQRKCAHTVFLB-UHFFFAOYSA-N cyclophosphamide hydrate Chemical compound O.ClCCN(CCCl)P1(=O)NCCCO1 PWOQRKCAHTVFLB-UHFFFAOYSA-N 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 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 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- -1 cyclic phosphoric acid ester amides Chemical class 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 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 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- 0 *=*CNP1(O)OCCCN1 Chemical compound *=*CNP1(O)OCCCN1 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 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
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960003815 cyclophosphamide lyophilized Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
Definitions
- the present invention provides a stable formulation of cyclophosphamide and process for the preparation of the same.
- Cyclophosphamide is a widely used synthetic antineoplastic drug chemically related to the nitrogen mustards.
- the chemical name for cyclophosphamide is 2-[bis(2- chloroethyl)amino]tetrahydro-2H-l,3,2-oxazaphosphorine 2-oxide, and has the followin structural formula:
- Cyclophosphamide was one example of a group of cyclic phosphoric acid ester amides which were disclosed in US 3,018,302.
- Cyclophosphamide comprises of monohydrate and anhydrous forms. Further interconversion between the anhydrous and monohydrate forms is well known in the art, however monohydrate form is more stable.
- US 4,537,883 (Mead Johnson & Co.) describes various lyophilizates of cyclophosphamide. Preparation involves lyophilizing a solution of cyclophosphamide and one or more excipients (mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid.) and then re-hydrating the product such that it contains about 4% moisture. It was found that use of mannitol as the primary excipient provides superior lyophilizate with thermal stability compared to lyophilizates obtained using other excipients.
- excipients mannitol, sodium bicarbonate, lactose, polyvinyl pyrrolidone (PVP), arginine, and tartaric acid.
- US 5,066,647 discloses a stable rapidly dissolving lyophilized composition of cyclophosphamide and alanine.
- US 5,130,305 discloses lyophilized composition containing cyclophosphamide and sodium bicarbonate as an excipient.
- Lyophilization has several advantages over the previous dry powder premix formulation such as drying without elevated temperatures, and hence avoids adverse thermal effects. Further it is stored in dry state in which there are relatively few stability problems.
- cyclophosphamide monohydrate is relatively stable compared to anhydrous cyclophosphamide.
- the bound water or water of crystallization is removed from the cyclophosphamide in the lyophilizer and so there are stability issues associated with this process.
- the present invention provides a pharmaceutical composition comprising cyclophosphamide and process for the preparation of the same without lyophilisation. Further, process for the powder formulation of cyclophosphamide according to the present invention doesn't require any terminal sterilization or heat to evaporate solvent used during crystallisation. According to present invention process for preparation of pharmaceutical formulation comprising cyclophosphamide comprises preparation of solution of cyclophosphamide, aseptic filtration and solvent evaporation by means of stirring and gas purging.
- Figure 1 X PD of the cyclophosphamide prepared according to the present invention.
- Figure 2 Microscopic images of cyclophosphamide prepared according to the present invention.
- Present invention provides a stable pharmaceutical composition comprising cyclophosphamide compared to cyclophosphamide formulation prepared using terminal sterilisation or lyophilisation.
- Present invention further provides process for preparation of a stable pharmaceutical composition comprising cyclophosphamide.
- composition refers to the composition of a cyclophosphamide compound in a form suitable for administration to a mammalian subject, preferably a human.
- composition of the cyclophosphamide compound comprises addition of pharmaceutically acceptable excipients, diluents, or carriers.
- the formulation is preferably a powder formulation for parenteral administration after reconstitution.
- the term “stable composition” refers to any composition having sufficient stability to have utility as a pharmaceutical agent.
- the formulation has sufficient stability to allow storage at a convenient temperature, preferably between 0° C. and 30° C, for a reasonable period of time, preferably longer than one month, more preferably longer than three months, even more preferably longer than six months, and most preferably longer than one year.
- composition and “formulation” are interchangeable and have same meaning.
- Cyclophosphamide refers to 2-[bis(2-chloroethyl)amino]tetrahydro-2H-l,3,2- oxazaphosphorine 2-oxide, pharmaceutically acceptable salts thereof or hydrates thereof. Following is structure of cyclophosphamide monohydrate.
- Process for the preparation of stable composition comprising cyclophosphamide comprises following steps.
- Suitable solvent according to present invention refer to solvent having boiling point less than 100°C. Suitable solvent according to present invention further refer to aprotic solvent having water content less than 10%, more preferably solvent having water content less than 5%, most preferably solvent having water content less than 3%.
- Aprotic solvent according to present invention is selected from but not limited to acetone, Dichloromethane, Tetrahydrofuran, Ethyl acetate, Cyclohexane, or Acetonitrile.
- Suitable solvent according to present invention further selected from but not limited to Pentane, Cyclopentane, Hexane, Cyclohexane, Benzene, Chloroform, Diethyl ether, Isopropanol (IPA), n-Propanol, Ethanol, Methanol, tertiary butyl alcohol (TBA), methyl tert-butyl ether (MTBE). More preferably suitable solvents according to present invention is Acetone, Dichloromethane, Acetonitrile, Ethyl acetate, Isopropanol, Ethanol, tertiary butyl alcohol, methyl tert-butyl ether or mixture thereof.
- solution prepared as mentioned above is filtered aseptically through less than 0.22 ⁇ filter, more preferably 0.2 ⁇ filter, most preferably less than 0.2 ⁇ filter.
- solution comprising cyclophosphamide is collected in the specialized vessel wherein the solvent is removed during the processing.
- the solvent is removed during the process by stirring and/or purging/blanketing with gas throughout the process at temperature less than 30°C and solvent vapour is removed.
- the gas used in the present invention is, but not limited to, inert gas such as nitrogen, argon or the like or mixtures thereof.
- the gas preferably used in the present invention is nitrogen.
- the gas Preferred temperature for the process is 5-30°C, more preferably 10-20°C and most preferably at less than 15°C.
- Specialized vessel according to present invention refers to a pre-sterilized closed vessel comprising a stirrer, inlet for gas and outlet for gas and solvent vapour.
- Specialised vessel further comprises inlet for filtered solution. Furthermore, specialised vessel optionally comprises one outlet to collect cyclophosphamide after solvent removal. Cyclophosphamide obtained using process described herein does not require terminal sterilisation as the obtained cyclophosphamide according to process described in present invention provides sterile cyclophosphamide.
- specialised vessel is, but not limited to, figure 3.
- E is closed vessel
- C is inlet for filtered solution
- B is inlet for gas
- D is outlet for gas and solvent vapour
- A stirrer
- F is outlet to collect cyclophosphamide after solvent removal from E.
- cyclophosphamide powder is aseptically collected in suitable container.
- suitable container according to present invention is pre-sterilized bag or pre-sterilized container.
- cyclophosphamide powder is filled in pharmaceutical container in which pharmaceutical formulation is supplied by maintaining aseptic condition. More preferably pharmaceutical container of the present invention is vial. Most preferably pharmaceutical container of the present invention is pre-sterilized / depyrogenated vial.
- to collect cyclophosphamide in suitable container after solvent removal is optional. After solvent removal cyclophosphamide is filled in pharmaceutical container.
- Specifically present invention provides a process for the preparation of a stable composition comprising cyclophosphamide, the steps comprising:
- process step b to f is carried out in aseptic condition.
- step b to f Due to the continuous process and maintenance of aseptic condition throughout step b to f provides stable composition.
- Impurity B 0.012 0.009 0.0090 0.007 0.01
- Cyclophosphamide product obtained as per example 1 have a powder X-ray diffraction pattern substantially as depicted in FIG. 1.
- Powder X-ray Diffraction was performed using Bruker AXS D8 Advance, the powder X-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (45kV, 40 mA) as the X- ray source with a wide-angle goniometer, a 1° scattering slit DS, in the range of 2.5° to 50°.
- FIG. 2 Microscopic images of cyclophosphamide product obtained as per example 1 is depicted in FIG. 2. Microscope Analysis was performed on Carl Zeiss microscope. Sample was prepared by dispersing cyclophosphamide in Glycerol. Observation was done at 40X optical zoom.
- process of the present invention provide more stable formulation as process of the present invention avoids high processing temperature by use of hot air and degradation due to the same.
- Process of the present invention is more friendly compared to spray drying or lyophilisation.
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une formulation stable de cyclophosphamide, n'impliquant pas d'étape de lyophilisation. La présente invention concerne en outre un procédé de préparation d'une composition comprenant du cyclophosphamide. Le procédé comprend les étapes de dissolution du cyclophosphamide, de filtration aseptique de solutions stériles, d'élimination du solvant dans des conditions aseptiques par purge ou isolement du gaz inerte pour obtenir de la poudre de cyclophosphamide, cela étant suivi de l'introduction directe du cyclophosphamide dans le contenant pharmaceutique.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201621019138 | 2016-06-02 | ||
| IN201621019138 | 2016-06-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2017207719A1 true WO2017207719A1 (fr) | 2017-12-07 |
Family
ID=59055195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2017/063369 WO2017207719A1 (fr) | 2016-06-02 | 2017-06-01 | Composition de cyclophosphamide et son procédé de préparation |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2017207719A1 (fr) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3018302A (en) | 1956-12-20 | 1962-01-23 | Asta Werke Ag Chem Fab | Novel cyclic phosphoric acid ester amides, and the production thereof |
| US4537883A (en) | 1982-11-12 | 1985-08-27 | Mead Johnson & Company | Lyophilized cyclophosphamide |
| US5036060A (en) | 1988-07-25 | 1991-07-30 | Fujisawa Usa, Inc. | Cyclophosphamide |
| US5066647A (en) | 1989-04-20 | 1991-11-19 | Erbamont, Inc. | Cyclophosphamide - alanine lyophilizates |
| US5130305A (en) | 1988-11-14 | 1992-07-14 | Erbamont, Inc. | Cyclophosphamide - sodium bicarbonate lyophilizates |
| US5418223A (en) | 1993-05-20 | 1995-05-23 | Erbamont, Inc. | Method for lyophilization of cyclophosphamide and product |
| US20130172271A1 (en) * | 2012-01-04 | 2013-07-04 | Cynthia Fragale | Pharmaceutical Spray Drying |
| US20150290226A1 (en) * | 2012-10-29 | 2015-10-15 | Leiutis Pharmaceuticals Pvt. Ltd. | Novel lyophilized compositions of cyclophosphamide |
| WO2016046797A1 (fr) * | 2014-09-26 | 2016-03-31 | Intas Pharmaceuticals Ltd. | Composition pharmaceutique présentant une uniformité de teneur améliorée |
-
2017
- 2017-06-01 WO PCT/EP2017/063369 patent/WO2017207719A1/fr active Application Filing
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3018302A (en) | 1956-12-20 | 1962-01-23 | Asta Werke Ag Chem Fab | Novel cyclic phosphoric acid ester amides, and the production thereof |
| US4537883A (en) | 1982-11-12 | 1985-08-27 | Mead Johnson & Company | Lyophilized cyclophosphamide |
| US5036060A (en) | 1988-07-25 | 1991-07-30 | Fujisawa Usa, Inc. | Cyclophosphamide |
| US5130305A (en) | 1988-11-14 | 1992-07-14 | Erbamont, Inc. | Cyclophosphamide - sodium bicarbonate lyophilizates |
| US5066647A (en) | 1989-04-20 | 1991-11-19 | Erbamont, Inc. | Cyclophosphamide - alanine lyophilizates |
| US5418223A (en) | 1993-05-20 | 1995-05-23 | Erbamont, Inc. | Method for lyophilization of cyclophosphamide and product |
| US20130172271A1 (en) * | 2012-01-04 | 2013-07-04 | Cynthia Fragale | Pharmaceutical Spray Drying |
| US20150290226A1 (en) * | 2012-10-29 | 2015-10-15 | Leiutis Pharmaceuticals Pvt. Ltd. | Novel lyophilized compositions of cyclophosphamide |
| WO2016046797A1 (fr) * | 2014-09-26 | 2016-03-31 | Intas Pharmaceuticals Ltd. | Composition pharmaceutique présentant une uniformité de teneur améliorée |
Non-Patent Citations (1)
| Title |
|---|
| M E CBG: "Cyclofosfamide Sandoz 500 mg, 1000 mg and 2000 mg, powder for solution for injection/infusion, (cyclophosphamide) )Public assessment report", 29 December 2014 (2014-12-29), XP055394536, Retrieved from the Internet <URL:https://mri.cts-mrp.eu/Human/Downloads/NL_H_2977_002_PAR.pdf> [retrieved on 20170728] * |
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