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Modafinil compositions

Modafinil compositions description/claims

The present invention relates to modafinil-containing compositions, pharmaceutical compositions comprising modafinil, and methods for preparing the same.

Active pharmaceutical ingredients (API or APIs (plural)) in pharmaceutical compositions can be prepared in a variety of different forms. Such APIs can be prepared so as to have a variety of different chemical forms including chemical derivatives, solvates, hydrates, co-crystals, or salts. Such APIs can also be prepared to have different physical forms. For example, the APIs may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states. By varying the form of an API, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapour pressure, density, colour, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical properties thereof.

It would be advantageous to have new forms of these APIs that have improved properties, in particular, as oral formulations. Specifically, it is desirable to identify improved forms of APIs that exhibit significantly improved properties including increased aqueous solubility and stability. Further, it is desirable to improve the processability, or preparation of pharmaceutical formulations. For example, needle-like crystal forms or habits of APIs can cause aggregation, even in compositions where the API is mixed with other substances, such that a non-uniform mixture is obtained. Needle-like morphologies can also give rise to filtration problems (See e.g., Mirmehrabi et al. J. Pharm. Sci. Vol. 93, No. 7, pp. 1692-1700, 2004). It is also desirable to increase the dissolution rate of API-containing pharmaceutical compositions in water, increase the bioavailability of orally-administered compositions, and provide a more rapid onset to therapeutic effect. It is also desirable to have a form of the API which, when administered to a subject, reaches a peak plasma level faster, has a longer lasting therapeutic plasma concentration, and higher overall exposure when compared to equivalent amounts of the API in its presently-known form.

Modafinil, an API used to treat subjects with narcolepsy, is practically insoluble in water. Modafinil (CAS Registry Number: 68693-11-8) is represented by the structure (I):

Modafinil is a chiral molecule due to the chiral S═O group. Therefore, modafinil exists as two isomers, R-(−)-modafinil and S-(+)-modafinil. It would be advantageous to have new forms of modafinil that have improved properties, in particular, as oral formulations. Specifically, it is desirable to identify improved forms of modafinil that exhibit significantly increased aqueous solubilities and both chemical and form stability. It is also desirable to increase the dissolution rate of API-containing pharmaceutical compositions in water, increase the bioavailability of orally-administered compositions, and provide a more rapid onset to therapeutic effect. It is also desirable to have a form of the API which, when administered to a subject, reaches a peak plasma level faster and/or has a longer lasting plasma concentration and higher overall exposure at high doses when compared to equivalent amounts of the API in its presently-known form.

It has now been found that polymorphs and solvates of modafinil can be obtained. Some of which can have different properties as compared to the free form of the API.

Embodiments of the present invention including, but not limited to, polymorphs and solvates can comprise racemic modafinil, enantiomerically pure modafinil (i.e., R-(−)-modafinil or S-(+)-modafinil), or enriched modafinil (e.g., between about 55 and about 90 percent ee). Similarly, solvent molecules (e.g., in a solvate) can also exist as racemic, enantiomerically pure, or an enriched form in embodiments of the present invention.

In another embodiment, the present invention provides the following modafinil solvates: chloroform, chlorobenzene, ethyl acetate, and acetic acid.

The processes according to the present invention may each comprise a further step or steps in which a modafinil polymorph or solvate produced thereby is incorporated into a pharmaceutical composition.

In a further embodiment, the present invention provides a novel polymorph of R-(−)-modafinil. In a specific embodiment, the present invention provides Forms III, IV, and V of R-(−)-modafinil. The present invention also provides a method of making a polymorph of R-(−)-modafinil.

In a further embodiment, the present invention provides a method of making a polymorph of R-(−)-modafinil, comprising:

(a) providing R-(−)-modafinil;

(b) crystallizing the polymorph of R-(−)-modafinil from an appropriate solvent.

In a further embodiment, a polymorph of R-(−)-modafinil is crystallized from an organic solvent. In particular embodiments, the organic solvent can be acetonitrile, dimethyl formamide (DMF), methanol, methyl ethyl ketone, N-methyl pyrollidone, ethanol, isopropanol, isobutanol, formamide, isobutyl acetate, 1,4-dioxane, tetrahydrofuran (THF), ethyl acetate, o-xylene, isopropyl acetate, dichloromethane, propylene glycol, acetic acid, water, acetone, nitromethane, toluene, and benzyl alcohol. Both pure solvents and mixed solvents are considered organic solvent, according to the present invention. In a particular embodiment, the organic solvent is ethanol. In another embodiment, a mixed solvent system is used to crystallize a polymorph of R-(−)-modafinil. Mixed solvent systems can be, for example, ethanol and isopropyl alcohol, or ethyl acetate and ethanol. In a further embodiment, the crystallization in step (b) is completed via thermal crystallization. In a further embodiment, the crystallization in step (b) is completed via evaporation of the solvent.

In another embodiment, a pharmaceutical composition comprises a modified release profile of one or more of racemic modafinil, R-(−)-modafinil, and S-(+)-modafinil. The modified release profile can comprise, for example, two or more maxima of plasma concentration, such as a dual-release profile.

The invention further provides a medicament comprising a polymorph or a solvate of modafinil and methods of making the same. Typically, the medicament further comprises one or more pharmaceutically-acceptable carriers, diluents or excipients. Medicaments according to the invention are described in further detail below.

• Provisional Patent
• Utility Patent

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