WO1999027932A1 - Injectable antifungal formulations - Google Patents

Injectable antifungal formulations Download PDF

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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
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Prior art keywords
cyclodextrin
pharmaceutical composition
glucosyl
effective amount
formula
Prior art date
Application number
PCT/US1998/024938
Other languages
French (fr)
Inventor
Vijay H. Naringrekar
Original Assignee
Schering Corporation
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.)
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Priority to AU15983/99A priority Critical patent/AU1598399A/en
Publication of WO1999027932A1 publication Critical patent/WO1999027932A1/en

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    • 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
    • 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.

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
Figure imgf000003_0001
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
Figure imgf000005_0001
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
Figure imgf000005_0002
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
Figure imgf000007_0001
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
Figure imgf000007_0002
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)
Figure imgf000010_0001
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
Figure imgf000010_0002
Practically no increase in degradation products was observed with time.

Claims

What is claimed is
(1 ) A pharmaceutical composition comprising
(a) an antifungally effective amount of a compound represented by the formula I
Figure imgf000011_0001
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
Figure imgf000011_0002
Figure imgf000012_0001
(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
Figure imgf000012_0002
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.
PCT/US1998/024938 1997-12-01 1998-11-30 Injectable antifungal formulations WO1999027932A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
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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Non-Patent Citations (1)

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Title
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)

* Cited by examiner, † Cited by third party
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

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