Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-10-10
2002-12-03
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C424S455000
Reexamination Certificate
active
06489363
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to pharmaceutical compositions comprising a modafinil compound in solution, and in particular, to non-aqueous solutions comprising at least one organic solvent. The invention is further directed to methods of using of the compositions in the treatment of diseases.
BACKGROUND OF THE INVENTION
Modafinil (C
15
H
15
NO
2
S), is 2-(benzhydryl-sulfinyl)acetamide, and is also known as 2-[(diphenylmethyl) sulfinyl] acetamide.
Modafinil has been described as presenting a “neuropsychopharmacological spectrum characterized by the presence of excitation with hyperactivity and of hypermotility; and by the absence of stereotypy (except in high doses) and of potentialization of the effects of apomorphine and amphetamine” (U.S. Pat. No. 4,177,290; hereinafter the “'290 patent,” which is incorporated in its entirety herein by reference). A single administration of modafinil results in increased locomotor activity in mice and increased nocturnal activity in monkeys (Duteil et al., Eur. J. Pharmacol. 180:49 (1990)). Modafinil has been successfully tested in humans for treatment of idiopathic hypersomnia and narcolepsy (Bastuji et al., Prog. Neuro-Psych. Biol. Psych. 12:695 (1988)).
Other uses of modafinil have been presented. U.S. Pat. No. 5,180,745, incorporated in its entirety herein by reference, discloses the use of modafinil for providing a neuroprotective effect in humans, and in particular for the treatment of Parkinson's disease. The levorotatory form of modafinil, i.e.,(-)benzhydrylsulfinyl-acetamide, may have potential benefit for treatment of depression, hypersomnia and Alzheimer's disease (U.S. Pat. No. 4,927,855, incorporated in its entirety herein by reference). European Published Application 547952 (published Jun. 23, 1993) discloses the use of modafinil as an anti-ischemic agent. European Published Application 594507 (published Apr. 27, 1994) discloses the use of modafinil to treat urinary incontinence.
Preparations of modafinil having a defined solid particle size have been described in U.S. Pat. No. 5,618,845, incorporated in its entirety herein by reference, and preparations of a levorotatory isomer of modafinil was described in U.S. Pat. No. 4,927,855. Heterocyclic derivatives of modafinil are disclosed in U.S. patent application No. 60/204,789, incorporated in its entirety herein by reference.
Modafinil has been approved for use in humans in 100 mg and 200 mg solid unit dose forms in the U.S. It is also desirable to formulate modafinil in liquid compositions. It has been observed that modafinil has very poor water and lipid solubility and it is therefore difficult to solubilize modafinil in pharmaceutically-acceptable compositions. Conventional solid and liquid formulations that include modafinil are described in the '290 patent. Liquid suspensions or emulsions of modafinil were mentioned in U.S. Pat. No. 5,618,845. A suspension of modafinil was reported in U.S. Pat. No. 5,180,745.
It has been discovered that the solubility of a modafinil compound in pharmaceutically acceptable solvents is difficult and unpredictable. The inventors have discovered that many of the solubilizing agents were either not USP/NF listed, or they had toxicity profiles which did not allow their use at levels higher than a few tenths of a percent. The purpose of this invention is to overcome these problems and formulate a pharmaceutically acceptable composition of a modafinil compound and to provide for effective bioavailable delivery of a modafinil compound to a subject in need thereof.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide pharmaceutical compositions comprising a modafinil compound in solution. Particularly, the compositions of the present invention are non-aqueous and optionally comprise other excipients. Preferably, the compositions comprise at least one organic solvent.
It is another object of the invention to provide a method of treating a disease or disorder in a subject which comprises administering to the subject a therapeutically effective amount of the compositions of the present invention.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that despite its poor solubility, a modafinil compound can be formulated as a pharmaceutical composition, wherein the modafinil compound is bioavailable upon administration to a subject in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
Thus, in a first embodiment, the present invention provides a pharmaceutical composition comprising a modafinil compound in solution. Preferably the pharmaceutical composition is non-aqueous. Preferably the pharmaceutical composition comprises modafinil.
As used herein, a “pharmaceutical composition” refers to a composition that is pharmaceutically acceptable.
As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
As used herein, “a modafinil compound” or “modafinil compound” and the like, refers to modafinil, its racemic mixtures, individual isomers, acid addition salts, such as a metabolic acid of modafinil, benzhydrylsulfinylacetic acids, and its sulfone forms, hydroxylated forms, polymorphic forms, analogs, derivatives, cogeners and prodrugs thereof. Prodrugs are known in the art as compounds that are converted to the active agent (a modafinil compound) in the body of a subject. These and other modafinil compounds, and their preparation, have been disclosed in U.S. Pat. Nos. 4,177,290, 4,927,855, 5,719,168 and in U.S. patent application No. 60/204,789. In preferred embodiments, the modafinil compound is modafinil.
As used herein, a “solution” refers to a chemically and physically homogeneous mixture of two or more substances. The solution may comprise a solid dispersed in a liquid, solid or semi-solid medium. Preferably the solution comprises a solid in a liquid medium. In more preferred embodiments, the solid that is solubilized is a particle of molecular dimensions. In context of the present application, a solution does not include inclusion complexes, such as those complexations of a drug with cyclodextrins.
As used herein, a “non-aqueous” composition refers to a composition that contains from 0-10% water by weight.
As used herein, a “polyol” refers to an alcohol with more than one hydroxy group. Examples include, but are not limited to glycols, such as ethylene glycol and propylene glycol, and other diols; glycerol, and other triol derivatives; and sugar alcohols.
As used herein, a “lower alkyl alcohol” refers to a branched or straight-chained C
1
-C
6
alkyl group containing one hydroxy group, such as ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol, sec-butyl alcohol, t-butyl alcohol, pentanol, hexanol, etc; with preferred lower alkyl alcohols including ethanol, propanol and isopropanol.
As used herein, the term “arylalkyl alcohol” refers to an aryl-substituted C
1
-C
6
alkyl group containing one hydroxy group, such as benzyl alcohol, phenethyl alcohol, diphenylmethyl alcohol (benzhydrol), etc.; with preferred arylalkyl alcohols including benzyl alcohol, &agr;-phenethyl alcohol and &bgr;-phenethyl alcohol.
As used herein, “therapeutically effective amount” refers to an amount which is effective in reducing, eliminating, treating, preventing or controlling the symptoms of the herein-described diseases and conditions. The term “controlling” is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatmen
Jacobs Martin J.
McIntyre Bradley T.
Patel Piyush R.
Cephalon Inc.
Hrubiec Robert T.
Reamer James H.
Voelk Eric K.
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