DK2732811T3 - Fremgangsmåde til fremstilling af en frysetørret sammensætning - Google Patents
Fremgangsmåde til fremstilling af en frysetørret sammensætning Download PDFInfo
- Publication number
- DK2732811T3 DK2732811T3 DK12193209.9T DK12193209T DK2732811T3 DK 2732811 T3 DK2732811 T3 DK 2732811T3 DK 12193209 T DK12193209 T DK 12193209T DK 2732811 T3 DK2732811 T3 DK 2732811T3
- Authority
- DK
- Denmark
- Prior art keywords
- freeze
- temperature
- hours
- solution
- process according
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 38
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 claims description 52
- 238000001035 drying Methods 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 23
- 229960002707 bendamustine Drugs 0.000 claims description 19
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 19
- 238000001816 cooling Methods 0.000 claims description 18
- 238000007710 freezing Methods 0.000 claims description 15
- 230000008014 freezing Effects 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 12
- 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 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 238000005496 tempering Methods 0.000 claims description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-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
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 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
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-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
- 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
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 150000002772 monosaccharides Chemical class 0.000 claims description 2
- 229920001542 oligosaccharide Polymers 0.000 claims description 2
- 150000002482 oligosaccharides Chemical class 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 150000005846 sugar alcohols Chemical class 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 2
- 239000004471 Glycine Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 description 41
- 239000007924 injection Substances 0.000 description 16
- 238000002347 injection Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000004108 freeze drying Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 6
- 239000008215 water for injection Substances 0.000 description 5
- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-UHFFFAOYSA-N 0.000 description 4
- 229960001215 bendamustine hydrochloride Drugs 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003978 infusion fluid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005303 weighing Methods 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
- A61K9/0012—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
- 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
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Claims (16)
1. Fremgangsmåde til fremstilling af en frysetørret sammensætning indeholdende bendamustin eller et salt deraf, ved hvilken (a) en opløsning, som indeholder bendamustin eller et salt deraf, fryses ved en første frysetemperatur, (b) eventuelt (b1) den frosne opløsning tempereres ved en temperatur på -25 til -10°C og (b2) fryses ved en anden frysetemperatur, som er lavere end temperaturen under (b1), og (c) den frosne opløsning, som er tilvejebragt i overensstemmelse med trin (a) eller (b) tørres ved en første tørretemperatur på -5 til +5°C over en periode på i det mindste 10 timer med henblik på at fremstille en frysetørret sammensætning.
2. Fremgangsmåde ifølge krav 1, hvor afkøling til den første frysetemperatur i trin (a) finder sted med en kølehastighed på 0,6 til 1,2°C/min.
3. Fremgangsmåde ifølge krav 1 eller 2, ved hvilken den første frysetemperatur i trin (a) er -40°C eller lavere, fortrinsvis -40 til -55°C og især fortrinsvis -40 til -50°C.
4. Fremgangsmåde ifølge ethvert af kravene 1 til 3, ved hvilken trin (b) udføres.
5. Fremgangsmåde ifølge krav 4, ved hvilken den frosne opløsning i trin (b1) tempereres over en periode på i det mindste 3 timer, fortrinsvis i det mindste 4 timer og særligt foretrukkent i det mindste 5 timer.
6. Fremgangsmåde ifølge krav 4 eller 5, ved hvilken opvarmning til temperaturen til temperering i trin (b1) finder sted med en opvarmningshastighed på 0,9 til 1,0°C/min.
7. Fremgangsmåde ifølge ethvert af kravene 4 til 6, ved hvilken afkøling til den anden frysetemperatur i trin (b2) finder sted med en kølehastighed på 0,9 til 1,5°C/min
8. Fremgangsmåde ifølge ethvert af kravene 1 til 7, ved hvilken den første tørretemperatur i trin (c) er -2°C til +2°C og fortrinsvis omkring 0°C.
9. Fremgangsmåde ifølge ethvert af kravene 1 til 8, ved hvilken tørring i trin (c) udføres over en periode på i det mindste 12, især i det mindste 14, fortrinsvis i det mindste 16 og særligt foretrukkent i det mindste 18 timer.
10. Fremgangsmåde ifølge ethvert af kravene 1 til 9, ved hvilken opvarmning til den første tørretemperatur i trin (c) finder sted med en opvarmningshastighed på 0,38 til 0,46°C/min.
11. Fremgangsmåde ifølge ethvert af kravene 1 til 10, ved hvilken (d) den frysetørrede sammensætning tilvejebragt i overensstemmelse med trin (c) tørres yderligere ved en anden tørretemperatur på +20°C til +40°C, fortrinsvis +30°C til +40°C og særligt foretrukkent ved omkring +40°C.
12. Fremgangsmåde ifølge krav 11, ved hvilken yderligere tørring i trin (d) udføres over i det mindste 6, fortrinsvis i det mindste 8 og særligt foretrukkent i det mindste 12 timer.
13. Fremgangsmåde ifølge krav 11 eller 12, ved hvilken opvarmning til den anden tørretemperatur i trin (d) finder sted med en opvarmningshastighed på 0,10 til 0,25°C/min.
14. Fremgangsmåde ifølge ethvert af kravene 1 til 13, hvor opløsningen, som anvendes i trin (a), indeholder i det mindste én alkohol, fortrinsvis ethanol, propanol eller tert.butanol, og især foretrukkent ethanol.
15. Fremgangsmåde ifølge ethvert af kravene 1 til 14, hvor opløsningen, som anvendes i trin (a), indeholder i det mindste én monosaccharid, oligosaccharid eller sukkeralkohol, fortrinsvis sukrose, dextrose, maltose, lactose, sorbitol, glycin, mannitol eller dextran, og særligt foretrukkent mannitol.
16. Frysetørret sammensætning indeholdende bendamustin eller et salt deraf, hvor sammensætningen kan tilvejebringes ved fremgangsmåden i overensstemmelse med ethvert af kravene 1 til 15.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12193209.9A EP2732811B1 (de) | 2012-11-19 | 2012-11-19 | Verfahren zur Herstellung einer gefriergetrockneten Zusammensetzung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2732811T3 true DK2732811T3 (da) | 2016-03-21 |
Family
ID=47191627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK12193209.9T DK2732811T3 (da) | 2012-11-19 | 2012-11-19 | Fremgangsmåde til fremstilling af en frysetørret sammensætning |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2732811B1 (da) |
| DK (1) | DK2732811T3 (da) |
| ES (1) | ES2564274T3 (da) |
| HU (1) | HUE027287T2 (da) |
| PL (1) | PL2732811T3 (da) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4537883A (en) * | 1982-11-12 | 1985-08-27 | Mead Johnson & Company | Lyophilized cyclophosphamide |
| US8436190B2 (en) | 2005-01-14 | 2013-05-07 | Cephalon, Inc. | Bendamustine pharmaceutical compositions |
| JP5670335B2 (ja) * | 2008-09-25 | 2015-02-18 | セファロン、インク． | ベンダムスチン液体製剤 |
| WO2011103150A2 (en) | 2010-02-18 | 2011-08-25 | Cephalon, Inc. | Lyophilized preparations of bendamustine |
-
2012
- 2012-11-19 HU HUE12193209A patent/HUE027287T2/en unknown
- 2012-11-19 DK DK12193209.9T patent/DK2732811T3/da active
- 2012-11-19 PL PL12193209T patent/PL2732811T3/pl unknown
- 2012-11-19 ES ES12193209.9T patent/ES2564274T3/es active Active
- 2012-11-19 EP EP12193209.9A patent/EP2732811B1/de not_active Not-in-force
Also Published As
| Publication number | Publication date |
|---|---|
| EP2732811A1 (de) | 2014-05-21 |
| ES2564274T3 (es) | 2016-03-21 |
| PL2732811T3 (pl) | 2016-05-31 |
| EP2732811B1 (de) | 2016-01-13 |
| HUE027287T2 (en) | 2016-09-28 |
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