Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-02-22
1998-01-13
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514252, A61K 9127
Patent
active
057079757
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT application Ser. No. PCT/EP 94/03169, filed Sep. 22, 1994, which claims priority from U.S. patent application Ser. No. 08/129,504, filed on Sep. 30, 1993 now abandoned.
The present invention is concerned with novel compositions of antifungal agents which have low solubility in aqueous media, a process for preparing said compositions and pharmaceutical dosage forms for oral administration comprising said novel compositions.
The development of efficacious pharmaceutical compositions of azole antifungals such as for example, itraconazole and saperconazole, is hampered considerably by the fact that said antifungals are only very sparingly soluble in water. The solubility and bioavailability of said compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO 85/02767 and U.S. Pat. No. 4,764,604. Alternatively, strongly acidic formulations (pH.ltoreq.1.5) of itraconazole and saperconazole can be formed in which the active ingredients are partially dissolved. Obviously such strongly acidic formulations are useless for oral administration. Aqueous formulations comprising a co-solvent such as PEG 400 completely dissolve itraconazole at pH 2.3-2.5. However, these acidic formulations have problems with regard to ease-of-preparation, acceptability, palatability and especially bioavailability: upon administration said formulations can precipitate irreversibly, e.g. in the stomach. Acidic formulations comprising cyclodextrin or a derivative thereof might appear an obvious alternative, but the mere combinations prove to suffer from a number of similar problems, in particular difficulty-of-preparation, lack of stability (shelf life) and palatability, and unreliable absorption. In short, there still exists an important demand for easily prepared formulations of antifungal agents with good bioavailability and acceptable organoleptic properties for oral administration.
The present invention relates to formulations for oral administration which comprise an antifungal, e.g. itraconazole or saperconazole, as active ingredient, a sufficient mount of a cyclodextrin or a derivative thereof as a solubilizer, an aqueous acidic medium as bulk liquid carrier and an alcoholic co-solvent that greatly simplifies the preparation of the composition. Preferred formulations are rendered more palatable by adding one or more pharmaceutically acceptable sweeteners, and one or more pharmaceutically acceptable flavours.
A low-dosage formulation according to the present invention is suitable for treating patients suffering from fungal infections, particularly for treating AIDS patients with oral candidiasis infections. The need for reliable formulations of itraconazole (and saperconazole) in this indication is especially high because of resistance to fluconazole developing in Candida strains. Generally, 400 mg/day represents the minimum dose required to obtain meaningful plasm levels. Suitable oral formulations typically comprise from about 0.5% to about 1.5% (w/v), preferably about 1% (w/v) of the active ingredient.
A high-dosage formulation according to the present invention is suitable for treating patients suffering from systemic fungal infections. Suitable oral formulations for combatting systemic fungal infections typically comprise from about 3% to about 5%, preferably about 4% (w/v) of the active ingredient.
The formulations of the present invention are also suitable for the treatment of fungal infections in non-human animals, in particular for the treatment of dermatophytoses.
Itraconazole or hyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!phenyl!-2,4-dihydro-2- (1-methylpropyl)-3H-1,2,4-triazol-3-one, is a broadspectrum antifungal compound developed for oral, parenteral and topical use and is disclosed in U.S. Pat. No. 4,267,179. Its difluoro analog, saperconazole or hyl)-1,3-dioxolan-4-yl!methoxy!phenyl!-1-piperazinyl!-phenyl!-2,4-dihydro-2 -(1-methoxypropyl)-3H-1,2,4-triazol-3-one, has improved activity against A
REFERENCES:
patent: 3459731 (1969-08-01), Gramera et al.
patent: 4267179 (1981-05-01), Heeres et al.
patent: 4383992 (1983-05-01), Lipari
patent: 4659696 (1987-04-01), Hirai et al.
patent: 4764604 (1988-08-01), Muller
patent: 4863737 (1989-09-01), Stanley et al.
patent: 4870060 (1989-09-01), Muller
patent: 4883785 (1989-11-01), Chow et al.
patent: 4916134 (1990-04-01), Heeres et al.
patent: 4983586 (1991-01-01), Bodor
patent: 4990337 (1991-02-01), Kurihara et al.
Hostetler et al., "Effect of Cyclodextrin on the Pharmacology of Antifungal Oral Azoles", Antimicrobial Agents And Chemotherapy, Feb. 1992, pp. 477-480.
Pitha et al., "Preparation of drug:hydroxypropylcyclodextrin complexes by a method using ethanol or aqueous ammonium hydroxide as co-solubilizers", International Journal of Pharmaceutics, 80 (1992) 253-258.
Dries Willy Maria Albert Carlo
Fran.cedilla.ois Marc Karel Jozef
Janssen Pharmaceutica N.V.
Metz Charles J.
Reamer James H.
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