WO1999027932A1 - Injectable antifungal formulations - Google Patents
Injectable antifungal formulations Download PDFInfo
- Publication number
- WO1999027932A1 WO1999027932A1 PCT/US1998/024938 US9824938W WO9927932A1 WO 1999027932 A1 WO1999027932 A1 WO 1999027932A1 US 9824938 W US9824938 W US 9824938W WO 9927932 A1 WO9927932 A1 WO 9927932A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cyclodextrin
- pharmaceutical composition
- glucosyl
- effective amount
- formula
- Prior art date
Links
- 230000000843 anti-fungal effect Effects 0.000 title description 11
- 229940121375 antifungal agent Drugs 0.000 title description 10
- 238000009472 formulation Methods 0.000 title description 3
- 239000000203 mixture Substances 0.000 title description 3
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 40
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 37
- 229960004853 betadex Drugs 0.000 claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 238000007911 parenteral administration Methods 0.000 claims abstract description 5
- 206010017533 Fungal infection Diseases 0.000 claims description 13
- 208000031888 Mycoses Diseases 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 9
- 201000003984 candidiasis Diseases 0.000 description 6
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 201000002909 Aspergillosis Diseases 0.000 description 4
- 208000036641 Aspergillus infections Diseases 0.000 description 4
- 241000222122 Candida albicans Species 0.000 description 4
- 201000007336 Cryptococcosis Diseases 0.000 description 4
- 241000221204 Cryptococcus neoformans Species 0.000 description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 4
- 0 *c1cc(*)c([C@]2(C[n]3ncnc3)OC[C@@](COc(cc3)ccc3N(CC3)CCN3c(cc3)ccc3N(C=NN3*)C3=O)C2)cc1 Chemical compound *c1cc(*)c([C@]2(C[n]3ncnc3)OC[C@@](COc(cc3)ccc3N(CC3)CCN3c(cc3)ccc3N(C=NN3*)C3=O)C2)cc1 0.000 description 3
- 206010007134 Candida infections Diseases 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 3
- 229960004884 fluconazole Drugs 0.000 description 3
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 3
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
- 241000335423 Blastomyces Species 0.000 description 2
- 241000223203 Coccidioides Species 0.000 description 2
- 241001527609 Cryptococcus Species 0.000 description 2
- 241001480035 Epidermophyton Species 0.000 description 2
- 241000122862 Fonsecaea Species 0.000 description 2
- 241000223218 Fusarium Species 0.000 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 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 241000235395 Mucor Species 0.000 description 2
- 241000235070 Saccharomyces Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241001149962 Sporothrix Species 0.000 description 2
- 241000223238 Trichophyton Species 0.000 description 2
- 241000223230 Trichosporon Species 0.000 description 2
- 244000037640 animal pathogen Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 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 description 2
- 239000000872 buffer Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 244000052637 human pathogen Species 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- QFSFPJHBIGWPMD-PBVGKYIBSA-N 104723-60-6 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](OC[C@@H]2[C@H]3O[C@@H]4[C@H](O)[C@@H](O)[C@@H]([C@H](O4)CO)O[C@@H]4[C@H](O)[C@@H](O)[C@@H]([C@H](O4)CO)O[C@@H]4[C@H](O)[C@@H](O)[C@@H]([C@H](O4)CO)OC4[C@H](O)[C@@H](O)[C@@H]([C@H](O4)CO)O[C@@H]4[C@H](O)[C@@H](O)[C@@H]([C@H](O4)CO)O[C@@H]4[C@H](O)[C@@H](O)[C@@H]([C@H](O4)CO)O[C@H]([C@@H]([C@H]3O)O)O2)[C@H](O)[C@H]1O QFSFPJHBIGWPMD-PBVGKYIBSA-N 0.000 description 1
- ICRBJWBMXZYUGP-UHFFFAOYSA-N 2-(2,4-difluorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-3-[6-(1,2,4-triazol-1-yl)pyridazin-3-yl]sulfanylbutan-2-ol Chemical compound C1=NC=NN1CC(O)(C=1C(=CC(F)=CC=1)F)C(C)(C)SC(N=N1)=CC=C1N1C=NC=N1 ICRBJWBMXZYUGP-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- XXFANTYPKDIONG-UHFFFAOYSA-N 6-O-alpha-D-glucosyl-beta-cyclodextrin Natural products OC1C(O)C(O)C(CO)OC1OCC1C(C(O)C2O)OC(OC3CO)C(O)C(O)C3OC(OC3CO)C(O)C(O)C3OC(OC3CO)C(O)C(O)C3OC(OC3CO)C(O)C(O)C3OC(OC3CO)C(O)C(O)C3OC(OC3CO)C(O)C(O)C3OC2O1 XXFANTYPKDIONG-UHFFFAOYSA-N 0.000 description 1
- XXFANTYPKDIONG-WJMYNTJYSA-N 6-o-α-d-glucosyl-β-cyclodextrin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@H]([C@H](O)[C@H]2O)O[C@@H](O[C@@H]3CO)[C@H](O)[C@@H](O)[C@@H]3O[C@@H](O[C@@H]3CO)[C@H](O)[C@@H](O)[C@@H]3O[C@@H](O[C@@H]3CO)[C@H](O)[C@@H](O)[C@@H]3O[C@@H](O[C@@H]3CO)[C@H](O)[C@@H](O)[C@@H]3O[C@@H](O[C@@H]3CO)[C@H](O)[C@@H](O)[C@@H]3O[C@@H](O[C@@H]3CO)[C@H](O)[C@@H](O)[C@@H]3O[C@H]2O1 XXFANTYPKDIONG-WJMYNTJYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 241000228257 Aspergillus sp. Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FKOIMSQYVZHCCH-UHFFFAOYSA-N CCC1(CC1)[IH]C(F)(F)F Chemical compound CCC1(CC1)[IH]C(F)(F)F FKOIMSQYVZHCCH-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001716 anti-fugal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011393 cytotoxic chemotherapy Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- -1 e.g. Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
Definitions
- Ri is a straight or branched chain (C4-C5) alkyl group substituted by a hydroxy moiety; and an effective amount of maltosyi- ⁇ -cyclodextrin or glucosyl- ⁇ -cyclodextrin.
- Compounds represented by formula I exhibit broad spectrum antifungal activity in conventional antifungal screening tests, against human and animal pathogens, such as the following: Aspergillus, Blastomyces, Candida, Cryptococcus, Coccidioides, Epidermophyton, Fonsecaea, Fusarium, Mucor, Saccharomyces, Torulopsis, Trichophyton, Trichosporon, Sporothrix and Pneumocysitis.
- the antifungal compounds of formula I are orally active but development of commercially viable injectable formulations for the compounds of formula I has been stalled due to the poor solubility of these compounds in aqueous and pharmaceutically acceptable non-aqueous solvents.
- U.S. Patent No. 5,312,815 discloses inclusion complexes of the single antifugal agent, (+)-2-(2,4-difluorophenyl)-3-methyl-1-(1 H-1 ,2,4-triazol-1-yl)-3-(6- (1 H-1 ,2,4-triazol-1-yl)pyridazin-3-ylthio)butan-2-ol, and alpha-, beta- or gamma- cyclodextrins such as glucosyl- or maltosyl-cyclodextrin.
- aqueous solutions of glucosyl- ⁇ -cyclodextrin and maltosyl- ⁇ -cyclodextrin are able to solubilize the compounds of formula II to provide chemically stable pharmaceutical compositions suitable for parenteral administration, preferably intravenous administration.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising (a) an antifungally effective amount of a compound represented by the formula I
- X is independently both F or both Cl or one X is independently F and the other is independently Cl;
- Ri is a straight or branched chain (C4-C5) alkyl group substituted by a hydroxy moiety; or a pharmaceutically acceptable salt thereof;
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising (a) an antifungally effective amount of the compound represented by the formula II
- compositions of the present invention are chemically stable and are suitable for parenteral administration.
- the present invention also provides a method of treating a susceptible fungal infection in mammals which comprises administering to a mammal afflicted with such a fungal infection an antifungally effective amount of the pharmaceutical compositions of the present invention.
- glucosyl- ⁇ -cyclodextrin as used herein means a ⁇ - cyclodextrin in which one of the free hydroxy moieties in each of the 7 glucose units in ⁇ -cyclodextrin has been substituted by glucosyl groups. See K. Koizumi, et al. Chem Pharm Bull. 35 (8)3413-3418 (1987).
- the preferred glucosyl- ⁇ - cyclodextrin is 6-O- ⁇ -D-glucosyl- ⁇ -cyclodextrin (G1 - ⁇ -CD) which is available from Ensuiko Sugar Refining Co. Ltd., Yokohama, 230 Japan as mono G1- ⁇ -CD.
- maltosyl- ⁇ -cyclodextrin as used herein means a ⁇ -cyclodextrin wherein one of the free hydroxy moieties in each of the seven (7) glucosyl units of ⁇ -cyclodextrin has been substituted by a maltosyl group by procedures such as disclosed in U.S. Patent 4,668,626 or the paper by Y. Okada et al. in Chem. Pharm. Bull. 36 (6) 2176-2185 (1998).
- the preferred maltosyl- ⁇ -cyclodextrin is 6-O- ⁇ - maltosyl- ⁇ -cyclodextrin ("G2- ⁇ -CD") available from Ensuiko Sugar Refining Co. Ltd. under the trade name mono-G2- ⁇ -CD.
- the term "susceptible fungal infections” includes the major opportunistic fungal infections such as candidiasis, aspergillosis and cryptococcosis.
- the compounds represented by formula I e.g., the compound of formula II, exhibit broad spectrum antifungal activity in conventional antifungal screening tests, against human and animal pathogens, such as the following: Aspergillus, Blastomyces, Candida, Cryptococcus, Coccidioides, Epidermophyton, Fonsecaea, Fusarium, Mucor, Saccharomyces, Torulopsis, Trichophyton, Trichosporon, Sporothrix and Pneumocysitis.
- the pharmaceutical compositions of the present invention are expected to exhibit similar antifungal activity.
- compositions comprise an antifungally effective amount of a compound represented by formula I
- X is independently both F or both Cl or one X is independently F and the other is independently Cl; preferably each X is F , and Ri is
- the compounds of formulas I and II may be prepared in accordance with the procedures, schemes and examples of U.S. Patent No. 5,661 ,151.
- the pharmaceutically acceptable salts of the compounds of the present invention include pharmaceutically acceptable acid and base addition salts.
- the preferred pharmaceutically acceptable acid addition salts are nontoxic acid addition salts formed by adding to the compounds of the present invention about a calculated amount of a mineral acid, such as HCI, HBr, H2SO4, HNO3 or H3PO4, or of an alkyl or arylsulfonic acid such as methanesulfonic, isithionic, paratoluenesulfonic, naphthylsulfonic and the like.
- a mineral acid such as HCI, HBr, H2SO4, HNO3 or H3PO4
- an alkyl or arylsulfonic acid such as methanesulfonic, isithionic, paratoluenesulfonic, naphthylsulfonic and the like.
- compositions of the present invention may be prepared by admixing the appropriate amount of glucosyl- ⁇ -cyclodextrin or maltosyl- ⁇ - cyclodextrin in water and adding thereto an antifungally effective amount of a compound of formulas I or II.
- Other excipients such as buffer or tonicity agents may be added and dissolved and additional water added to final volume.
- the resultant solution is sterile filtered and filled in to appropriate containers and sealed.
- the water may be removed by well known methods, e.g. rotary evaporation or lyophilization.
- the dry powder may be reconstituted with water at a temperature of 15° to 35°C.
- the water is normally sterile water for injection and may contain pharmaceutically acceptable buffers, e.g., phosphate, citrate, as well as tonicity adjusting agents and preservatives.
- suitable tonicity adjusting agents include dextrose, mannitol, glycine and sodium chloride.
- the desired pH is in the range of 3 to 8, especially 6-8.
- the antifungally effective amount of a compound of formulas I or II is about 2mg/ml to 15 mg/ml and preferably is about 4 to about 12 mg/ml, more preferably about 10 mg/ml of solution.
- the effective amount of glucosyl- ⁇ -cyclodextrin is about 50 to 250 mg/ml and preferably about 100 mg/ml to about 220 mg/ml, and more preferably about 200 mg/ml of water.
- the effective amount of maltosyl- ⁇ -cyclodextrin is about 80 mg/ml to 400 mg/ml preferably about 100 mg/ml to 300 mg/ml and more preferably about 200 mg/ml.
- Parenteral forms to be injected intravenously, intramuscularly, or subcutaneously are usually in the form of a sterile solution, and may contain salts or glucose to make the solution isotonic.
- parenteral dosage for humans for antifungal use ranges from about 0.25 mg per kilogram of body weight per day to about 20 mg per kilogram of body weight per day, in single or divided doses, with about 0.5 to about 10 mg per kilogram of body weight per day being preferred.
- the stability of the compound of formula II in a solution containing about 2 mg of the compound of formula II per mL of a solution of 60 mg of 6-O-glucosyl- ⁇ - cyclodextrin per mL of distilled water for injection is at various pH was measured at 65°C.
- a phosphate buffer (20mM) was used to adjust the pH range from 6.0 to 7.4. The results are summarized in Table 2.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nanotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Biotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A pharmaceutical composition suitable for parenteral administration comprising an antifungally effective amount of a compound represented by formula (I), wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl; R1 is a straight or branched chain (C4-C5) alkyl group substituted by a hydroxy moiety; and an effective amount of maltosyl-β-cyclodextrin or glucosyl-β-cyclodextrin, is disclosed.
Description
Injectable Antifungal Formulations
This invention relates to pharmaceutical compositions suitable for parenteral administration comprising an antifungally effective amount of a compound represented by formula I
wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl; Ri is a straight or branched chain (C4-C5) alkyl group substituted by a hydroxy moiety; and an effective amount of maltosyi-β-cyclodextrin or glucosyl-β-cyclodextrin.
Compounds of formula I are disclosed in U.S. Patent 5,661 ,151 as exhibiting broad spectrum antifungal activity against the major fungal infections including candidosis, cryptococcosis, and asperillosis as well as candidosis resistant to currently available antifungal agents such as fluconazole. Compounds represented by formula I exhibit broad spectrum antifungal activity in conventional antifungal screening tests, against human and animal pathogens, such as the following: Aspergillus, Blastomyces, Candida, Cryptococcus, Coccidioides, Epidermophyton, Fonsecaea, Fusarium, Mucor, Saccharomyces, Torulopsis, Trichophyton, Trichosporon, Sporothrix and Pneumocysitis. The antifungal compounds of formula I are orally active but development of commercially viable injectable formulations for the compounds of formula I has been stalled due to the poor solubility of these compounds in aqueous and pharmaceutically acceptable non-aqueous solvents.
Over the past 30 years, fungal infections, especially the above listed major fungal infections, have become prevalent due to an increased number of immunocompromised patients (neutropenic cancer, bone marrow transplantation, solid organ transplant, HIV/AIDS), patients in intensive care units and patients with debilitating underlying diseases. The factors that place these patients at risk include: advanced life support interventions, cytotoxic chemotherapy or other types of immunosuppression surgical procedures, prolonged hospitalization and use of
broad-spectrum antibiotics. The major opportunistic fungal infections are candidiasis, aspergillosis and cryptococcosis. The incidence of nosocomial candidiasis and aspergillosis has dramatically increased in the last ten to fifteen years, and Candida albicans has emerged as a new pathogen causing life- threatening nosocomial infections. The market success of fluconazole in the 1990's has contributed to emergence of Aspergillus sp. and fluconazole-resistant Candida sp.
Morbidity and mortality from these major opportunistic fungal infections remain high despite the availability of antifungal agents. The less than optimal efficacy provided by current agents is further limited by: dose-limiting toxicity, development of fungal resistance, unreliable and unpredictable blood levels, and a limited spectrum of activity or limited dosage forms (i.e., orally only, IV only).
U.S. Patent No. 5,312,815 discloses inclusion complexes of the single antifugal agent, (+)-2-(2,4-difluorophenyl)-3-methyl-1-(1 H-1 ,2,4-triazol-1-yl)-3-(6- (1 H-1 ,2,4-triazol-1-yl)pyridazin-3-ylthio)butan-2-ol, and alpha-, beta- or gamma- cyclodextrins such as glucosyl- or maltosyl-cyclodextrin.
Thus, there is a need for an injectable dosage formulation of an antifungal agent that exhibits low toxicity and which is capable of maintaining improved efficacy against candidosis, cryptococcosis and aspergillosis.
Summary of the Invention
Surprisingly, we have discovered that aqueous solutions of glucosyl- β-cyclodextrin and maltosyl-β-cyclodextrin are able to solubilize the compounds of formula II to provide chemically stable pharmaceutical compositions suitable for parenteral administration, preferably intravenous administration.
Thus, the present invention provides a pharmaceutical composition comprising (a) an antifungally effective amount of a compound represented by the formula I
wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl;
Ri is a straight or branched chain (C4-C5) alkyl group substituted by a hydroxy moiety; or a pharmaceutically acceptable salt thereof; and
(b) an effective amount of one of maltosyl-β-cyclodextrin or glucosyl-β-cyclodextrin, and
(c) a pharmaceutically acceptable carrier
The present invention also provides a pharmaceutical composition comprising (a) an antifungally effective amount of the compound represented by the formula II
or an ester of the OH group convertible in vivo into OH; or a pharmaceutically acceptable salt thereof; and
(b) an effective amount of one of maltosyl-β-cyclodextrin or glucosyl-β-cyclodextrin and
(c) a pharmaceutically acceptable carrier
The pharmaceutical compositions of the present invention are chemically stable and are suitable for parenteral administration.
The present invention also provides a method of treating a susceptible fungal infection in mammals which comprises administering to a mammal afflicted with such a fungal infection an antifungally effective amount of the pharmaceutical compositions of the present invention.
Detailed Description of the Invention
The term "glucosyl-β-cyclodextrin" as used herein means a β- cyclodextrin in which one of the free hydroxy moieties in each of the 7 glucose units in β-cyclodextrin has been substituted by glucosyl groups. See K. Koizumi, et al. Chem Pharm Bull. 35 (8)3413-3418 (1987). The preferred glucosyl-β- cyclodextrin is 6-O-α-D-glucosyl-β-cyclodextrin (G1 -β-CD) which is available from Ensuiko Sugar Refining Co. Ltd., Yokohama, 230 Japan as mono G1-β-CD.
The term "maltosyl-β-cyclodextrin" as used herein means a β-cyclodextrin wherein one of the free hydroxy moieties in each of the seven (7) glucosyl units of β-cyclodextrin has been substituted by a maltosyl group by procedures such as disclosed in U.S. Patent 4,668,626 or the paper by Y. Okada et al. in Chem. Pharm. Bull. 36 (6) 2176-2185 (1998). The preferred maltosyl-β-cyclodextrin is 6-O-α- maltosyl-β-cyclodextrin ("G2-β-CD") available from Ensuiko Sugar Refining Co. Ltd. under the trade name mono-G2-β-CD.
The term "susceptible fungal infections" includes the major opportunistic fungal infections such as candidiasis, aspergillosis and cryptococcosis. As noted herein above, the compounds represented by formula I, e.g., the compound of formula II, exhibit broad spectrum antifungal activity in conventional antifungal screening tests, against human and animal pathogens, such as the following: Aspergillus, Blastomyces, Candida, Cryptococcus, Coccidioides, Epidermophyton, Fonsecaea, Fusarium, Mucor, Saccharomyces, Torulopsis, Trichophyton,
Trichosporon, Sporothrix and Pneumocysitis. The pharmaceutical compositions of the present invention are expected to exhibit similar antifungal activity.
In a preferred aspect of the present invention, the pharmaceutical compositions comprise an antifungally effective amount of a compound represented by formula I
wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl; preferably each X is F , and Ri is
The compounds of formulas I and II may be prepared in accordance with the procedures, schemes and examples of U.S. Patent No. 5,661 ,151.
The pharmaceutically acceptable salts of the compounds of the present invention include pharmaceutically acceptable acid and base addition salts.
The preferred pharmaceutically acceptable acid addition salts are nontoxic acid addition salts formed by adding to the compounds of the present invention about a calculated amount of a mineral acid, such as HCI, HBr, H2SO4, HNO3 or H3PO4, or of an alkyl or arylsulfonic acid such as methanesulfonic, isithionic, paratoluenesulfonic, naphthylsulfonic and the like.
The pharmaceutical compositions of the present invention may be prepared by admixing the appropriate amount of glucosyl-β-cyclodextrin or maltosyl-β- cyclodextrin in water and adding thereto an antifungally effective amount of a compound of formulas I or II. Other excipients such as buffer or tonicity agents may be added and dissolved and additional water added to final volume. The resultant solution is sterile filtered and filled in to appropriate containers and sealed. Optionally, the water may be removed by well known methods, e.g. rotary evaporation or lyophilization. The dry powder may be reconstituted with water at a temperature of 15° to 35°C. The water is normally sterile water for injection and may contain pharmaceutically acceptable buffers, e.g., phosphate, citrate, as well as tonicity adjusting agents and preservatives.
Typically suitable tonicity adjusting agents include dextrose, mannitol, glycine and sodium chloride.
The desired pH is in the range of 3 to 8, especially 6-8.
The antifungally effective amount of a compound of formulas I or II is about 2mg/ml to 15 mg/ml and preferably is about 4 to about 12 mg/ml, more preferably about 10 mg/ml of solution.
The effective amount of glucosyl-β-cyclodextrin is about 50 to 250 mg/ml and preferably about 100 mg/ml to about 220 mg/ml, and more preferably about 200 mg/ml of water.
The effective amount of maltosyl-β-cyclodextrin is about 80 mg/ml to 400 mg/ml preferably about 100 mg/ml to 300 mg/ml and more preferably about 200 mg/ml.
Parenteral forms to be injected intravenously, intramuscularly, or subcutaneously are usually in the form of a sterile solution, and may contain salts or glucose to make the solution isotonic.
In general, the parenteral dosage for humans for antifungal use ranges from about 0.25 mg per kilogram of body weight per day to about 20 mg per kilogram of body weight per day, in single or divided doses, with about 0.5 to about 10 mg per kilogram of body weight per day being preferred.
The exact amount, frequency and period of administration of the compounds of the present invention for antifungal use will very, of course, depending upon the sex, age and medical condition of the patent as well as the severity of the infection as determined by the attending clinician.
General Experimental
Example 1
Dissolve one g of 6-O-glucosyl-β-cyclodextrin (obtained from ENSUIKO Sugar Refining Co. Ltd., Yokohama 230 Japan) as mono-G1-β-CD) in 5 ml of distilled water to obtain a final concentration of 200 mg of 6-O-glucosyl-β- cyclodextrin per ml of water. Add and dissolve at room termperature 25 mg of the compound of formula II (which may be prepared in accordance with Example 30 of USP 5,661 ,151) in 2 ml of the above 6-O-glucosyl-β-cyclodextrin solution. Filter the resulting solution to obtain a clear solution containing 12.5 mg of compound of formula II per ml and 200 mg of 6-O-glucosyl-β-cyclodextrin per ml .
Examples 2-10
Table 1
Follow the procedure of Example 1 to determine the equilibrium solubility of the compound of formula II in solutions of various concentrates of 6-O-glucosyl-β- cyclodextrin at 5° and room temperature. The results are reported in Table 1.
TABLE 1 Equilibrium solubility of the compound of formula II in 6-O-glucosyl-β- cyclodext n (G1-β-CD)
Example 11
The stability of the compound of formula II in a solution containing about 2 mg of the compound of formula II per mL of a solution of 60 mg of 6-O-glucosyl-β- cyclodextrin per mL of distilled water for injection is at various pH was measured at 65°C. A phosphate buffer (20mM) was used to adjust the pH range from 6.0 to 7.4. The results are summarized in Table 2.
Table 2
STABILITY OF THE COMPOUND OF FORMULA II IN AQUEOUS SOLUTION OF G1-β-CD AT 65° C
Practically no increase in degradation products was observed with time.
Claims
(1 ) A pharmaceutical composition comprising
(a) an antifungally effective amount of a compound represented by the formula I
wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl;
Ri is a straight or branched chain (C4- C5) alkyl group substituted by a hydroxy moiety;
or a pharmaceutically acceptable salt thereof; and
(b) an effective amount of one of maltosyl-β-cyclodextrin or glucosyl-β-cyclodextrin and
(c) a pharmaceutically acceptable carrier
(2) The pharmaceutical composition of claim 1 wherein Ri is
(3) The pharmaceutical composition of claim 1 wherein glucosyl-β- cyclodextrin is used.
(4) The pharmaceutical composition of claim 1 wherein maltosyl-β- cyclodextrin is used.
(5) The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable carrier is water.
(6) A pharmaceutical composition comprising
(a) an antifungally effective amount of the compounds represented by the formula II
or an ester of the OH group convertible in vivo into OH; or a pharmaceutically acceptable salt thereof; and
(b) an effective amount of one of maltosyl-β-cyclodextrin or glucosyl-β-cyclodextrin and
(c) a pharmaceutically acceptable carrier.
(7) The pharmaceutical composition of claim 6 wherein the compound of formula II is used
(8) The pharmaceutical composition of claim 6 wherein maltosyl-β- cyclodextrin is used.
(9) The pharmaceutical composition of claim 6 wherein glucosyl-β- cyclodextrin is used.
(10) The pharmaceutical composition of claim 6 wherein the pharmaceutically acceptable carrier is water.
(11 ) The pharmaceutical composition of claim 6 which comprises 12.5 mg of compound of formula II per ml and 200 mg of 6-0-glucosyl-β- cyclodextrin per ml
(12) The pharmaceutical composition of claim 6 which adapted for parenteral administration.
(13) A method of treating a susceptible fungal infection in mammals which comprises administering to a mammal afflicted with such a fungal infection an antifungally effective amount of the pharmaceutical composition of claim 1.
(14) A method of treating a susceptible fungal infection in mammals which comprises administering to a mammal afflicted with such a fungal infection an antifungally effective amount of the pharmaceutical composition of claim 6.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU15983/99A AU1598399A (en) | 1997-12-01 | 1998-11-30 | Injectable antifungal formulations |
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US98095097A | 1997-12-01 | 1997-12-01 | |
US08/980,950 | 1997-12-01 |
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WO1999027932A1 true WO1999027932A1 (en) | 1999-06-10 |
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PCT/US1998/024938 WO1999027932A1 (en) | 1997-12-01 | 1998-11-30 | Injectable antifungal formulations |
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AU (1) | AU1598399A (en) |
WO (1) | WO1999027932A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6989381B2 (en) | 2000-08-22 | 2006-01-24 | Pharmacia Corporation | Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading |
US10040872B2 (en) | 2012-10-22 | 2018-08-07 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
US10117951B2 (en) | 2008-04-28 | 2018-11-06 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
US10323103B2 (en) | 2012-02-28 | 2019-06-18 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
US10633462B2 (en) | 2012-02-15 | 2020-04-28 | Cydex Pharmaceuticals, Inc. | Manufacturing process for cyclodextrin derivatives |
US10851184B2 (en) | 2014-08-22 | 2020-12-01 | Cydex Pharmaceuticals, Inc. | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
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US5661151A (en) * | 1993-12-21 | 1997-08-26 | Schering Corporation | Tetrahydrofuran antifungals |
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1998
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- 1998-11-30 AU AU15983/99A patent/AU1598399A/en not_active Abandoned
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US5661151A (en) * | 1993-12-21 | 1997-08-26 | Schering Corporation | Tetrahydrofuran antifungals |
Non-Patent Citations (1)
Title |
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DUCHENE D ET AL: "PHYSICOCHEMICAL CHARACTERISTICS AND PHARMACEUTICAL USES OF CYCLODEXTRIN DERIVATIVES, PART II", PHARMACEUTICAL TECHNOLOGY, vol. 14, no. 8, August 1990 (1990-08-01), pages 22 - 22 - 26 - 28 - 30, XP002053301 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6989381B2 (en) | 2000-08-22 | 2006-01-24 | Pharmacia Corporation | Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading |
US10117951B2 (en) | 2008-04-28 | 2018-11-06 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
US10780177B2 (en) | 2008-04-28 | 2020-09-22 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
US11806402B2 (en) | 2008-04-28 | 2023-11-07 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions |
US10633462B2 (en) | 2012-02-15 | 2020-04-28 | Cydex Pharmaceuticals, Inc. | Manufacturing process for cyclodextrin derivatives |
US11208500B2 (en) | 2012-02-15 | 2021-12-28 | Cydex Pharmaceuticals, Inc. | Manufacturing process for cyclodextrin derivatives |
US10323103B2 (en) | 2012-02-28 | 2019-06-18 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
US10040872B2 (en) | 2012-10-22 | 2018-08-07 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
US10800861B2 (en) | 2012-10-22 | 2020-10-13 | Cydex Pharmaceuticals, Inc. | Alkylated cyclodextrin compositions and processes for preparing and using the same |
US10851184B2 (en) | 2014-08-22 | 2020-12-01 | Cydex Pharmaceuticals, Inc. | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
US11795241B2 (en) | 2014-08-22 | 2023-10-24 | Cydex Pharmaceuticals, Inc. | Fractionated alkylated cyclodextrin compositions and processes for preparing and using the same |
Also Published As
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AU1598399A (en) | 1999-06-16 |
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