Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-03-10
2002-07-02
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C514S772200, C514S937000, C514S975000
Reexamination Certificate
active
06413537
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable.
BACKGROUND OF THE INVENTION
The present invention relates to the antifungal drug nystatin, and, in particular, a novel parenteral formulation of nystatin which avoids the side adverse effects associated with parenteral administration of known nystatin formulations.
Nystatin is an intracellular product first isolated from
Streptomyces noursei.
Nystatin is a polyene antibiotic, having a large, conjugated double bond ring system linked to a mycosamine (a 3-amino-3,6-dideoxy-D-manno-pyranose) moiety, an epoxy group, and an all-trans tetraene system. Its structure is similar to erythromycin and amphotericin B, other macrocyclic lactones. Its empirical formula is C
47
H
75
NO
17
and molecular weight is 926.13. Nystatin is only slightly soluble in water.
Nystatin has been found to inhibit the growth of a variety of pathogenic and non-pathogenic yeast and fungi, and to be effective in treating histoplasmosis and cryptococcosis (E. Hazen and R. Brown,
Proc. Soc. Exp. Biol. Med.
1951, 76, 93-97). Nystatin is both fungistatic and fungicidal in vitro against a wide variety of yeasts and fungi. It has dependable efficacy for treatment of cutaneous, oral and intestinal infections caused by
Candida albicans
and other Candida species. Nystatin exhibits no appreciable activity toward bacteria, protozoa or viruses.
Nystatin and other polyene macrolides are known to act at the cell membrane level by binding to sterols and forming pores in the membrane that lead to cell death. The selectivity of nystatin for fungal cells over mammalian cells appears to be due to preferred binding to ergosterol, the primary fungal sterol, over mammalian cholesterol.
Nystatin is well tolerated in both oral and topical forms, and is generally administered as an ointment, an oral suspension, an oral tablet, and a vaginal tablet. Nystatin USP contains not less than 5000 units of nystatin activity per mg. Nystatin is available as oral tablets of 500,000 units per tablet, and as an ointment of 100,000 units/g ointment.
Recently, nystatin has been used to treat systemic fungal infections in immunocompromised patients, although it is too toxic for parenteral use. Systemic administration of polyene macrolides such as nystatin can cause serious side effects such as hemolytic toxicity and nephrotoxicity. Because of its high toxicity and insolubility in water, nystatin is thus not commercially available in parenteral formulations. These properties have generally precluded its use for systemic infection.
The toxicity of nystatin for parenteral administration appears to be related to its low solubility. Nystatin forms aggregates in water, and aggregated species are correlated with increased toxicity toward mammalian cells in vitro and in vivo. Detergents have been suggested as deaggregating agents. However, the high levels of detergent typically required to reduce formation of aggregates also result in high toxicity.
Some prior art has suggested that these problems could be overcome by formulating nystatin in phopholipid vesicles or liposomes (See, e.g., U.S. Pat. No. 4,812,312 issued to Lopez-Bernstein, et al.; U.S. Pat. No. 5,874,104 issued to Alder-Moore, et al.). An improved liposomal formulation is disclosed in U.S. Pat. No. 5,830,498 issued to Lenk, et al. Liposomes, however, are difficult to prepare reproducibly in bulk and can be unstable. Others have suggested that liquid dispersion forms can be administered parenterally (See, e.g., U.S. Pat. No. 5,776,904 issued to Seki et al.). Such dispersion forms also suffer from stability problems.
Notwithstanding the known problems with parenteral use of nystatin, the art has not adequately responded to date with a formulation of nystatin suitable for the treatment of systemic fungal infections that is relatively easy to prepare and has a lower toxicity for parenteral administration than nystatin alone while still maintaining adequate efficacy.
SUMMARY OF THE INVENTION
The present invention provides a formulation of nystatin in lyophilized, solid dispersion form which is readily reconstituted with water to be suitable for parenteral administration. The novel formulation is less toxic and more soluble in water than conventional nystatin formulations while maintaining adequate antifungal properties.
The foregoing and other advantages of the present invention are realized in one aspect thereof in a formulation comprising a solid dispersion which is a lyophilized homogeneous mixture that includes, by weight, 1% to 10% nystatin, 10 to 98% dispersing agent, 0 to 1% co-solvent and water. The dispersing agents are surface active agents that are suitably nonionic block copolymers of ethylene oxide and propylene oxide, generically referred to as poloxamers, e.g., poloxamer 407, poloxamer 188, or suitably sorbitan esters, generally polysorbates, e.g., polysorbate 80. The dispersing agent is present in an amount effective to reduce aggregate formation of nystatin in an aqueous solution. The co-solvent is suitably a polar organic solvent that is present in the formulation in an amount effective to increase solubility of nystatin in water. Preferably, the co-solvent is selected from the group consisting of dimethylsulfoxide, dimethylacetamide, dimethylformamide and methanol. Optionally, other inert excipients are suitably present in the formulation.
In another aspect, the present invention provides a method for preparing the nystatin formulation. The method includes the steps of (a) dissolving nystatin in an aqueous solution of a dispersing agent and a co-solvent, (b) sonicating the solution of step (a) to promote a substantially homogeneous dispersion, and (c) freeze-drying the dispersion of step (b) to form a solid dispersion. Preferably, the solid dispersion thus formed remains stable for long periods of time, suitably several months. The solid dispersion in lyophilized form or powder is suitably reconstituted with an aqueous solvent, preferably water or saline, to form a nystatin solution suitable for parenteral administration to a subject, e.g., a human or animal, in need thereof.
In yet another aspect, the present invention provides a composition comprising a solid dispersion formulation of nystatin and a sterile aqueous vehicle. Preferably, the composition includes nystatin at a concentration from about 100 &mgr;M to about 1000 &mgr;M.
In a further aspect, the present invention provides a method of treating a fungal infection in a human or animal subject which includes the step of administering to the human or animal in need thereof an antifungally effective amount of the nystatin composition in accordance with the present invention.
Other advantages and a fuller appreciation of the specific attributes of the invention will be gained upon an examination of the following drawings, detailed description of preferred embodiments, and appended claims.
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Physicians Desk Reference “Mytrex” 54th Editing 2000.*
Martindale The Extra Pharmacopoeia “Nystatin”, 1993.*
Alliance Pharmaceutical Corp., “About FloGel”, http://www.allp.com/FloGel/fg_about.htm.
Alliance Pharmaceutical Corp., “FloGel Technology Overview” http://www.allp.com/FloGel/fg_ovr.htm, p. 1-2.
Barwicz, J., et al., “Effects
Kwon Glen S.
Yoo Bong K.
Fahrlander Jill A.
Fubara Blessing
Michael & Best & Friedrich LLP
Spear James M.
Welch Teresa J.
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