CA2290412C - Crystalline macrolides and process for their preparation - Google Patents

Crystalline macrolides and process for their preparation Download PDF

Info

Publication number: CA2290412C
Authority: CA; Canada
Prior art keywords: compound; solution; formula; crystalline; crystallization
Prior art date: 1997-06-30
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

CA002290412A

Other languages

English (en)

French (fr)

Other versions

CA2290412A1 (en

Inventor

Cornelia Dosenbach

Maximilian Grassberger

Otto Hartmann

Amarylla Horvath

Jean-Paul Mutz

Gerhard Penn

Sabine Pfeffer

Dierk Wieckhusen

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Meda Pharma SARL

Original Assignee

Novartis AG

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1997-06-30

Filing date

1998-06-26

Publication date

2009-11-10

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10815103&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2290412(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1998-06-26 Application filed by Novartis AG filed Critical Novartis AG

1999-01-14 Publication of CA2290412A1 publication Critical patent/CA2290412A1/en

2009-11-10 Application granted granted Critical

2009-11-10 Publication of CA2290412C publication Critical patent/CA2290412C/en

2018-06-26 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

238000002360 preparation method Methods 0.000 title claims abstract description 20
238000000034 method Methods 0.000 title claims description 19
239000003120 macrolide antibiotic agent Substances 0.000 title description 6
229940041033 macrolides Drugs 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 79
239000013078 crystal Substances 0.000 claims abstract description 39
238000002425 crystallisation Methods 0.000 claims abstract description 28
230000008025 crystallization Effects 0.000 claims abstract description 28
230000001939 inductive effect Effects 0.000 claims abstract description 10
239000002904 solvent Substances 0.000 claims description 34
239000012453 solvate Substances 0.000 claims description 11
238000001157 Fourier transform infrared spectrum Methods 0.000 claims description 8
238000010899 nucleation Methods 0.000 claims description 8
238000001816 cooling Methods 0.000 claims description 7
230000003110 anti-inflammatory effect Effects 0.000 claims description 6
230000001028 anti-proliverative effect Effects 0.000 claims description 6
239000003795 chemical substances by application Substances 0.000 claims description 5
229960003444 immunosuppressant agent Drugs 0.000 claims description 5
230000001861 immunosuppressant effect Effects 0.000 claims description 5
239000003018 immunosuppressive agent Substances 0.000 claims description 5
239000007788 liquid Substances 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 4
239000003814 drug Substances 0.000 claims description 2
201000010099 disease Diseases 0.000 claims 4
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 4
238000001914 filtration Methods 0.000 claims 3
239000003085 diluting agent Substances 0.000 claims 2
239000003937 drug carrier Substances 0.000 claims 2
239000006071 cream Substances 0.000 abstract description 14
KASDHRXLYQOAKZ-OLHLVPFQSA-N pimecrolimus Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C\C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@H](Cl)[C@H](OC)C1 KASDHRXLYQOAKZ-OLHLVPFQSA-N 0.000 abstract description 7
239000000839 emulsion Substances 0.000 abstract description 3
239000002674 ointment Substances 0.000 abstract description 3
230000000699 topical effect Effects 0.000 abstract description 2
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
239000000203 mixture Substances 0.000 description 11
239000000047 product Substances 0.000 description 9
239000008186 active pharmaceutical agent Substances 0.000 description 8
229940088679 drug related substance Drugs 0.000 description 8
238000002844 melting Methods 0.000 description 8
230000008018 melting Effects 0.000 description 8
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
239000007858 starting material Substances 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
230000015572 biosynthetic process Effects 0.000 description 5
238000004090 dissolution Methods 0.000 description 5
238000004519 manufacturing process Methods 0.000 description 5
239000007787 solid Substances 0.000 description 5
238000003860 storage Methods 0.000 description 5
238000002411 thermogravimetry Methods 0.000 description 5
230000005540 biological transmission Effects 0.000 description 4
229960004132 diethyl ether Drugs 0.000 description 4
238000001938 differential scanning calorimetry curve Methods 0.000 description 4
238000001035 drying Methods 0.000 description 4
230000000694 effects Effects 0.000 description 4
239000006260 foam Substances 0.000 description 4
238000010438 heat treatment Methods 0.000 description 4
239000000463 material Substances 0.000 description 4
239000000843 powder Substances 0.000 description 4
238000003756 stirring Methods 0.000 description 4
239000000126 substance Substances 0.000 description 4
239000000725 suspension Substances 0.000 description 4
101150041968 CDC13 gene Proteins 0.000 description 3
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
238000009835 boiling Methods 0.000 description 3
239000007795 chemical reaction product Substances 0.000 description 3
239000002178 crystalline material Substances 0.000 description 3
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
239000012535 impurity Substances 0.000 description 3
238000000634 powder X-ray diffraction Methods 0.000 description 3
238000011084 recovery Methods 0.000 description 3
239000011347 resin Substances 0.000 description 3
229920005989 resin Polymers 0.000 description 3
238000004809 thin layer chromatography Methods 0.000 description 3
238000005160 1H NMR spectroscopy Methods 0.000 description 2
238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
230000009286 beneficial effect Effects 0.000 description 2
229910052799 carbon Inorganic materials 0.000 description 2
125000004432 carbon atom Chemical group C* 0.000 description 2
238000011083 clear filtration Methods 0.000 description 2
238000011835 investigation Methods 0.000 description 2
230000007774 longterm Effects 0.000 description 2
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
229910002027 silica gel Inorganic materials 0.000 description 2
239000000741 silica gel Substances 0.000 description 2
229960001866 silicon dioxide Drugs 0.000 description 2
125000001424 substituent group Chemical group 0.000 description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 1
CKOZVEHVVHCMGD-UHFFFAOYSA-N 5-[(4-fluorophenyl)methyl]-n,n-dimethyltetrazole-1-carboxamide Chemical compound CN(C)C(=O)N1N=NN=C1CC1=CC=C(F)C=C1 CKOZVEHVVHCMGD-UHFFFAOYSA-N 0.000 description 1
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
238000013019 agitation Methods 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
244000052616 bacterial pathogen Species 0.000 description 1
239000013590 bulk material Substances 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
238000012512 characterization method Methods 0.000 description 1
238000006243 chemical reaction Methods 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
239000000460 chlorine Substances 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
239000012043 crude product Substances 0.000 description 1
230000001351 cycling effect Effects 0.000 description 1
238000006731 degradation reaction Methods 0.000 description 1
238000000113 differential scanning calorimetry Methods 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
238000009472 formulation Methods 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
238000002329 infrared spectrum Methods 0.000 description 1
238000001819 mass spectrum Methods 0.000 description 1
238000005259 measurement Methods 0.000 description 1
239000000155 melt Substances 0.000 description 1
NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
239000012046 mixed solvent Substances 0.000 description 1
229940055577 oleyl alcohol Drugs 0.000 description 1
XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
239000002245 particle Substances 0.000 description 1
238000013379 physicochemical characterization Methods 0.000 description 1
239000003495 polar organic solvent Substances 0.000 description 1
238000012545 processing Methods 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 1
238000000746 purification Methods 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
150000003839 salts Chemical class 0.000 description 1
238000004626 scanning electron microscopy Methods 0.000 description 1
230000007928 solubilization Effects 0.000 description 1
238000005063 solubilization Methods 0.000 description 1
238000012430 stability testing Methods 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
150000003892 tartrate salts Chemical class 0.000 description 1
238000012360 testing method Methods 0.000 description 1
238000004448 titration Methods 0.000 description 1
230000009466 transformation Effects 0.000 description 1
230000001052 transient effect Effects 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Veterinary Medicine (AREA)
Engineering & Computer Science (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Chemical Kinetics & Catalysis (AREA)
Immunology (AREA)
Bioinformatics & Cheminformatics (AREA)
Crystallography & Structural Chemistry (AREA)
Metallurgy (AREA)
Materials Engineering (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
Communicable Diseases (AREA)
Transplantation (AREA)
Oncology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Saccharide Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Medicinal Preparation (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

CA002290412A 1997-06-30 1998-06-26 Crystalline macrolides and process for their preparation Expired - Lifetime CA2290412C (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
GB9713730.1		1997-06-30
GBGB9713730.1A GB9713730D0 (en)	1997-06-30	1997-06-30	Organic compounds
PCT/EP1998/003929 WO1999001458A1 (en)	1997-06-30	1998-06-26	Crystalline macrolides and process for their preparation

Publications (2)

Publication Number	Publication Date
CA2290412A1 CA2290412A1 (en)	1999-01-14
CA2290412C true CA2290412C (en)	2009-11-10

Family

ID=10815103

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002290412A Expired - Lifetime CA2290412C (en)	1997-06-30	1998-06-26	Crystalline macrolides and process for their preparation

Country Status (31)

Country	Link
US (1)	US6423722B1 (2)
EP (1)	EP0994880B1 (2)
JP (2)	JP3880634B2 (2)
KR (1)	KR100399765B1 (2)
CN (1)	CN1139595C (2)
AR (1)	AR017754A1 (2)
AT (1)	ATE287410T1 (2)
AU (1)	AU739211B2 (2)
BR (1)	BR9810956A (2)
CA (1)	CA2290412C (2)
CO (1)	CO4940463A1 (2)
CZ (1)	CZ297244B6 (2)
DE (1)	DE69828692T2 (2)
DK (1)	DK0994880T3 (2)
ES (1)	ES2236922T3 (2)
GB (1)	GB9713730D0 (2)
HU (1)	HU227755B1 (2)
ID (1)	ID24897A (2)
IL (1)	IL132761A0 (2)
MY (1)	MY118718A (2)
NO (1)	NO312765B1 (2)
NZ (1)	NZ500994A (2)
PE (1)	PE97699A1 (2)
PL (1)	PL192761B1 (2)
PT (1)	PT994880E (2)
RU (1)	RU2219181C2 (2)
SK (1)	SK285665B6 (2)
TR (1)	TR199903189T2 (2)
TW (1)	TW552264B (2)
WO (1)	WO1999001458A1 (2)
ZA (1)	ZA985655B (2)

Families Citing this family (19)

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Publication number	Priority date	Publication date	Assignee	Title
GB9713730D0 (en) *	1997-06-30	1997-09-03	Ciba Geigy Ag	Organic compounds
GB9826656D0 (en)	1998-12-03	1999-01-27	Novartis Ag	Organic compounds
GB0125443D0 (en) *	2001-10-23	2001-12-12	Novartis Ag	Organic Compounds
EP1663220B1 (en) *	2003-09-03	2009-12-02	Glaxo Group Limited	Novel process for the preparation of pleuromutilin derivatives
PT1734927E (pt) *	2004-04-08	2012-09-05	Meda Pharma S A R L	Composição em espuma de pimecrolimus contendo hexilenoglicol, opcionalmente álcool oleílico, dimetilisossorbida e/ou triglicéridos de cadeia média
CA2584430A1 (en) *	2004-12-01	2006-06-08	Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag	Methods for preparing pimecrolimus
TW200837067A (en) *	2006-11-06	2008-09-16	Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag	Ascomycin and pimecrolimus having reduced levels of desmethylascomycin and 32-deoxy-32-epichloro-desmethylascomycin respectively, and methods for preparation thereof
JP2010512333A (ja) *	2006-12-07	2010-04-22	ヘルシンヘルスケアソシエテアノニム	塩酸パロノセトロンの結晶及び非晶質形
US9192697B2 (en)	2007-07-03	2015-11-24	Hemoteq Ag	Balloon catheter for treating stenosis of body passages and for preventing threatening restenosis
EP2944332B1 (en)	2009-07-10	2016-08-17	Boston Scientific Scimed, Inc.	Use of nanocrystals for a drug delivery balloon
EP2453938B1 (en)	2009-07-17	2015-08-19	Boston Scientific Scimed, Inc.	Nucleation of drug delivery balloons to provide improved crystal size and density
EP2611476B1 (en)	2010-09-02	2016-08-10	Boston Scientific Scimed, Inc.	Coating process for drug delivery balloons using heat-induced rewrap memory
US8669360B2 (en) *	2011-08-05	2014-03-11	Boston Scientific Scimed, Inc.	Methods of converting amorphous drug substance into crystalline form
WO2013028208A1 (en)	2011-08-25	2013-02-28	Boston Scientific Scimed, Inc.	Medical device with crystalline drug coating
WO2014145780A1 (en)	2013-03-15	2014-09-18	Biosensors International Group, Ltd.	Purification of rapamycin derivatives
EP3178824A1 (en)	2015-12-08	2017-06-14	Medichem, S.A.	Process for preparing pimecrolimus
ES2906158T3 (es) *	2017-05-01	2022-04-13	Meda Pharma Gmbh & Co Kg	Proceso para convertir ascomicina bruta en pimecrolimus purificado
EP3741367A1 (en)	2019-05-21	2020-11-25	Premark Pharma GmbH	Treatment of ocular disease
WO2024209038A1 (en)	2023-04-06	2024-10-10	Premark Pharma Gmbh	Use of pimecrolimus for the treatment of dry eye in patients characterized by a corneal staining score of 4 or 5 on the oxford grading scale

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JPS51118816A (en) *	1975-04-08	1976-10-19	Meiji Seika Kaisha Ltd	A process for stabilizing non-crystalloidal solid
US4127647A (en) *	1975-04-08	1978-11-28	Meiji Seika Kaisha, Ltd.	Process for preparation of stable amorphous macrolide antibiotic solids
CY1306A (en)	1980-10-01	1985-12-06	Glaxo Group Ltd	Aminoalkyl furan derivative
JP2728482B2 (ja) *	1989-01-26	1998-03-18	協和醗酵工業株式会社	マクロライド系抗生物質の精製法
JPH089630B2 (ja)	1989-07-10	1996-01-31	ヘマ・ソシエダード・アノニマ	有機化合物の、または関連する改善
DK0427680T3 (da) *	1989-11-09	1995-12-18	Sandoz Ltd	Heteroatom-holdige cykliske forbindelser
EP0594600A1 (en) *	1990-03-13	1994-05-04	FISONS plc	Immunosuppressive macrocyclic compounds
EP0480623A1 (en) *	1990-10-11	1992-04-15	Merck & Co. Inc.	New halomacrolides and derivatives having immunosuppressive activity
US5143918A (en) *	1990-10-11	1992-09-01	Merck & Co., Inc.	Halomacrolides and derivatives having immunosuppressive activity
ES2100291T3 (es)	1991-07-30	1997-06-16	Ajinomoto Kk	Cristales de n-(trans-4-isopropilciclohexilcarbonil)-d-fenilalanina y metodos para prepararlos.
US5247076A (en)	1991-09-09	1993-09-21	Merck & Co., Inc.	Imidazolidyl macrolides having immunosuppressive activity
US5221740A (en)	1992-01-16	1993-06-22	American Home Products Corporation	Oxepane isomers of rapamycin useful as immunosuppressive agents
UA41884C2 (uk) *	1993-11-05	2001-10-15	Амерікан Хоум Продактс Корпорейшн	Спосіб відокремлення рапаміцину від кислотних, основних та неполярних нейтральних домішок, присутніх в концентраті екстрактів ферментаційного бульйону або маточних розчинів
JP3808500B2 (ja) *	1994-02-22	2006-08-09	キューレータズオブディユニバーシティオブミズーリ	分離剤としての大環状抗生物質
CA2229718A1 (en) *	1995-08-24	1997-03-06	David J. Mathre	Process for the preparation of imidazolyl macrolide immunosuppressants
GB9713730D0 (en) *	1997-06-30	1997-09-03	Ciba Geigy Ag	Organic compounds

1997
- 1997-06-30 GB GBGB9713730.1A patent/GB9713730D0/en active Pending
1998
- 1998-06-25 CO CO98036359A patent/CO4940463A1/es unknown
- 1998-06-26 PL PL336719A patent/PL192761B1/pl unknown
- 1998-06-26 PE PE1998000568A patent/PE97699A1/es not_active IP Right Cessation
- 1998-06-26 JP JP50628799A patent/JP3880634B2/ja not_active Expired - Lifetime
- 1998-06-26 DK DK98936392T patent/DK0994880T3/da active
- 1998-06-26 SK SK1866-99A patent/SK285665B6/sk not_active IP Right Cessation
- 1998-06-26 WO PCT/EP1998/003929 patent/WO1999001458A1/en not_active Ceased
- 1998-06-26 CA CA002290412A patent/CA2290412C/en not_active Expired - Lifetime
- 1998-06-26 PT PT98936392T patent/PT994880E/pt unknown
- 1998-06-26 ES ES98936392T patent/ES2236922T3/es not_active Expired - Lifetime
- 1998-06-26 TR TR1999/03189T patent/TR199903189T2/xx unknown
- 1998-06-26 BR BR9810956-1A patent/BR9810956A/pt not_active Application Discontinuation
- 1998-06-26 NZ NZ500994A patent/NZ500994A/en not_active IP Right Cessation
- 1998-06-26 AT AT98936392T patent/ATE287410T1/de active
- 1998-06-26 AU AU85409/98A patent/AU739211B2/en not_active Expired
- 1998-06-26 RU RU2000101826/04A patent/RU2219181C2/ru active
- 1998-06-26 ID IDW991682A patent/ID24897A/id unknown
- 1998-06-26 DE DE69828692T patent/DE69828692T2/de not_active Expired - Lifetime
- 1998-06-26 IL IL13276198A patent/IL132761A0/xx not_active IP Right Cessation
- 1998-06-26 KR KR10-1999-7010048A patent/KR100399765B1/ko not_active Expired - Lifetime
- 1998-06-26 HU HU0003053A patent/HU227755B1/hu unknown
- 1998-06-26 EP EP98936392A patent/EP0994880B1/en not_active Expired - Lifetime
- 1998-06-26 CN CNB988064677A patent/CN1139595C/zh not_active Expired - Lifetime
- 1998-06-26 CZ CZ0474099A patent/CZ297244B6/cs not_active IP Right Cessation
- 1998-06-26 AR ARP980103094A patent/AR017754A1/es active IP Right Grant
- 1998-06-29 ZA ZA985655A patent/ZA985655B/xx unknown
- 1998-06-29 MY MYPI98002955A patent/MY118718A/en unknown
- 1998-07-21 TW TW087111867A patent/TW552264B/zh not_active IP Right Cessation
1999
- 1999-12-02 NO NO19995909A patent/NO312765B1/no not_active IP Right Cessation
2000
- 2000-10-17 US US09/690,404 patent/US6423722B1/en not_active Expired - Lifetime
2006
- 2006-03-01 JP JP2006055107A patent/JP4504323B2/ja not_active Expired - Lifetime

Also Published As

Publication number	Publication date
SK186699A3 (en)	2000-05-16
CA2290412A1 (en)	1999-01-14
HU227755B1 (en)	2012-02-28
AR017754A1 (es)	2001-10-24
EP0994880B1 (en)	2005-01-19
US6423722B1 (en)	2002-07-23
IL132761A0 (en)	2001-03-19
PT994880E (pt)	2005-06-30
HK1028597A1 (en)	2001-02-23
CN1261365A (zh)	2000-07-26
TW552264B (en)	2003-09-11
CO4940463A1 (es)	2000-07-24
CZ297244B6 (cs)	2006-10-11
HUP0003053A2 (hu)	2001-02-28
JP3880634B2 (ja)	2007-02-14
CN1139595C (zh)	2004-02-25
JP2001506279A (ja)	2001-05-15
ID24897A (id)	2000-08-31
WO1999001458A1 (en)	1999-01-14
MY118718A (en)	2005-01-31
KR20010020423A (ko)	2001-03-15
NO995909L (no)	1999-12-02
PE97699A1 (es)	1999-10-29
ZA985655B (en)	1998-12-30
ATE287410T1 (de)	2005-02-15
AU739211B2 (en)	2001-10-04
TR199903189T2 (xx)	2000-06-21
PL192761B1 (pl)	2006-12-29
JP2006151999A (ja)	2006-06-15
SK285665B6 (sk)	2007-05-03
NO995909D0 (no)	1999-12-02
KR100399765B1 (ko)	2003-09-29
NZ500994A (en)	2001-08-31
DE69828692T2 (de)	2006-01-12
GB9713730D0 (en)	1997-09-03
DK0994880T3 (da)	2005-05-30
JP4504323B2 (ja)	2010-07-14
PL336719A1 (en)	2000-07-03
NO312765B1 (no)	2002-07-01
DE69828692D1 (de)	2005-02-24
EP0994880A1 (en)	2000-04-26
HUP0003053A3 (en)	2003-03-28
ES2236922T3 (es)	2005-07-16
CZ474099A3 (cs)	2000-04-12
AU8540998A (en)	1999-01-25
RU2219181C2 (ru)	2003-12-20
BR9810956A (pt)	2000-09-26

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2003-06-23	EEER	Examination request
2018-08-28	MKEX	Expiry	Effective date: 20180626

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