Field of the Invention:

The present invention relates to an oral pharmaceutical composition of (-) modafinil and the process for its preparation thereof.

Background of the invention:

(-)Modafinil has C15H15NO2S molecular formula, and also known as (-)-2-[(R)-
(diphenylmethyl)sulfinyl]acetamide, it is an acetamide derivative and (R)-enantiomer of modafinil. The said compound is used in the treatment of narcolepsy.

Modafinil is currently marketed by Cephalon, Inc. under the trade name PROVIGIL as a racemic mixture of its R and S enantiomers. It is indicated for the treatment of excessive sleepiness associated with narcolepsy, shift work sleep disorder and obstructive sleep apnea/hypopnea syndrome. Modafinil is thought to modulate the central postsynaptic alpha 1-adrenergic receptor, without participation of the dopaminirgic system. 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)). Modafinil is a vigilance-inducing agent used in the treatment of paroxysmal narcolepsy and idiopathic hypersomnia.

U.S. 4,177,290 describes modafinil in racemic form, also known as (±) 2-(benzhydryl sulphinyl) acetamide or (±) 2-[{diphenylmethyl) sulphinyl] acetamide, as a compound having properties of stimulating the central nervous system. It also describes solid and liquid formulations for modafinil.
U.S. 5,180,745 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. The levorotatory form of modafinil is known as (-) modafinil and has the chemical name 2-[(R)-(diphenylmethyl) sulfinyl] acetamide. (-) Modafinil is approved by USFDA under the brand name NUVIGIL. (-) Modafinil is well tolerated and its safety profile is comparable with modafinil.

(-) Modafinil was first disclosed in the U.S. 4,927,855 which was originally assigned to Lafon Laboratories. It has been known that modafinil has very poor water and lipid solubility and it is therefore difficult to make a composition of modafinil possessing a high dissolution profile.

Similarly, (-) modafinil is also practically insoluble in water as well as in buffers ranging from pH 1.0 to 6.8. The insoluble nature of (-) modafinil creates absorption problems, and preparation of bioavailable dosage forms of modafinil a challenging task.

The most common approach used to address the problem of drug insolubility is by either reducing the drug's particle size or micronizing the drug to the size of a few microns, which increases the effective exposed surface areas.

Dosage forms that contain micronized drug particles exhibit enhanced solubility and consequently an increase in the bioavailability of the drugs. However, technical and economical problems can arise. For example, highly micronized drug particles possess poor flow properties and an increased chance of re-agglomeration during processing. In some cases, re-agglomeration of micronized drug particles may be so problematic that the basic objective of enhancing the solubility by increasing the effective surface area may be unmet.

U.S. RE 37,516 discloses improving solubility by a method of size reduction and a pharmaceutical composition that has at least about 95% of the modafinil particles having a diameter of less than about 200 μm and having a median size smaller than about 60 μm.

U.S. 7,115,281 relates to processes for preparing pharmaceutical compositions of modafmil dosage forms for oral administration. The dosage forms include a mixture of coarse and fine particles of modafinil. The process for preparing modafinil oral dosage forms includes forming a dosage form that includes about 7%-25% by weight of modafinil particles having diameters greater than 220 um and about 75-93% by weight of modafinil particles having diameters less than 220 um. It further describes a composition containing complexes of a modafinil compound and a cyclodextrin, preferably a β-cyclodextrin for enhancing the solubility of modafinil. But cyclodextrin complexes have either limited applicability to therapeutic agents or the bioavailability of a drug; cyclodextrin mixture is often unpredictable.

WO 2004/010979 describes a combination of modafinil with one or more surface active agents and/ or one or more pharmaceutical carriers in the preparation of pharmaceutical compositions of modafinil which provide dosage forms with improved bioavailability.

It is desirable to optimize the formulation of (-)modafinil and method of their preparation on a commercial scale. In a particular, new formulations of (-)modafinil have been discovered which exhibit comparable stability, dissolution rate, hardness, friability, thickness, disintegration, size and shape, and the weight variation characteristics to that of Nuvigil. Further, it has been discovered that solid dose forms of (-)modafmil can be prepared, with properties similar to that of Nuvigil.

The present invention provides novel composition for (-) modafinil with high solubility in the form of oral pharmaceutical composition. In the present invention the usage of two disintegrants (i.e., intra and extra granular) improves the solubility of the product and produce a stable pharmaceutical composition.

In addition, the newly discovered formulations preferably use a minimal number of excepients, and use of pharmaceutical grade excipients that are inexpensive. Readily available and that facilitate cost-effective manufacture on a commercial scale.

Furthermore, there is a need to improve upon the manufacturing process of the tablet form of (-)modafinil. Improvement in the commercial preparation include minimizing the number of excipients, eliminating the use of organic solvents, reducing the number of steps, and reducing the time and cost. The present invention is directed to these, as well as other, important ends.

Summary of the Invention:

The first aspect of the present invention is to provide a novel pharmaceutical composition of solid oral dosage form comprises (-) modafinil with one or more diluents, the disintegrant and at least one lubricant selected from stearic acid and optionally other excipients. In a certain embodiments, the solid dose is in tablet form.

The second aspect of the present invention is to provide an improved process for the preparation of oral solid dosage form of (-) modafinil composition. Advantages of the present invention:

• The usage of dibasic calcium phosphate improves the flow properties and com-paction.

• The usage of sodiumstarch glycolate as disintegrant to produce a stable pharma-ceutical composition.

Detailed Description of the Invention:

The present invention relates to an oral pharmaceutical composition of (-) modafinil compound of formula-I and also relates to the process for its preparation thereof.

The oral pharmaceutical composition of the present invention comprises of (-) modafinil with one or more diluents, disintegrants, binders and lubricants. Preferably, the excipients meet the standards of United States of Pharmacopoeia ("USP") and National Formulary ("NF"). In a preferred manner the composition comprises of (-) modafinil with one or more diluents, disintegrants, binders and lubricants.

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 tissue of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.

According to the first aspect of the present invention, the oral pharmaceutical composition comprises of:

a) (-) modafinil or its pharmaceutically acceptable salts,
b) one or more diluents,
c) the disintegrant,
d) at least one binder,
e) at least one lubricant selected from stearic acid and/or
f) optionally coating agents,

wherein at least part of disintegrant is intragranular and at least part of the disin-terant is extragranular.

The excipients are selected to ensure the delivery of consistent amount of (-) modafinil in a convenient unit dosage form and developed dosage form is cost effective and can be affordable by common needy people. All the excipients must be inert, organoleptically acceptable, and compatible with the (-)modafinil. Generally the excipients used in the solid dosage form include diluents or fillers, disintegrants, binders, lubricants, antiadherents, glidants, wetting agents coloring agents, pigments, coating agent, sweeteners, flavouring agents, and taste masking agents.

Diluents or fillers are added to increase the bulk or size of the tablet. The diluents are selected from dibasic calcium phosphate and mannitol, but are not limited to calcium monohydrogen phosphate, tricalcium phosphate, dibasic calcium phosphate, calcium sulfate, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, mannitol, sorbitol, lactose, sucrose, sugar compressible, sugar confectioners, starch or mixtures thereof or well-known diluents known by the person skilled in the art. Preferred diluents are dibasic calcium phosphate and mannitol.

Diluents may include lactose, starch derivatives, cellulose derivatives such as microcrystalline cellulose, powdered cellulose. Starches include native starch obtained from wheat, corn, rice. The starch derivatives also function as disintegrants. Many diluents generally have a dual function, which acts both as diluents and disintegrants. This properties should also be taken into consideration while developing a formulation.

Disintegrants are agents included in the tablet formulations to promote the breakup of the tablet into smaller fragments thereby increasing the available surface area and promoting a more rapid dissolution of the active ingredient. That will enhance the bioavailability of the active pharmaceutical ingredients. The disintegrants are selected from but are not limited to starch derivatives like pregelatinized starch (starch 1500), cross linked sodium salt of a carboxymethyl ether of starch such as sodium starch glycolate, croscramellose sodium (Ac-di-sol), cellulose derivatives such as microcrystalline cellulose, and the like. Preferred disintegrants are sodium starch glycolate, croscarmellose sodium, pregelatinized starch and mixtures thereof.

Binders are used as a wet granulation excipient to agglomerate the powder mixture of active pharmaceutical ingredient and the other excipients. The binder is selected to improve the flow properties of powder and to improve compatibility. The binders are selected from but are not limited to cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl cellulose, carboxymethylcellulose sodium, microcrystalline cellulose, polyvinyl pyrrolidone (povidone), gelatin, starch paste, gum arabic, sodium alginate, agar, tragacanth, polyene glycol, pregelatinized starch, sucrose and natural gums, and the like. A preferred binder is hydroxypropylcellulose.

Lubricants are used in the tablet formulation is to reduce the friction during the compression stages and to prevent the sticking of the tablet to the punch faces. Lubricant is selected from stearic acid and its salts such as magnesium stearate, calcium stearate, vegetable oils (corn oil), hydrogenated castor oil, sodium stearyl fumarate, mineral oils, polyethylene glycol, inorganic salts (such as sodium chloride), organic salts (sodium benzoate, sodium acetate), and polyvinyl alcohols. A preferred lubricant is stearic acid.

(-)Modafinil comprises from about 40-60% of the composition by weight. The composition comprises diluent(s) from about 20-60% in weight based on the total weight of the composition; disintegrant(s) from about 2 to 15% in weight based on the total weight of the composition; a binder from about 0.5 to 6% in weight based on the total weight of the composition and lubricant from about 0.2 to 2% in weight based on the total weight of the composition.

The preferred embodiment of the present invention provides an improved solid oral pharmaceutical composition comprises of:

a) (-) modafinil,
b) dibasic calcium phosphate and mannitol,
c) pregelatinized starch,
d) hydroxypropyl methyl cellulose dissolved in purified water,
e) sodium starch glycolate,
f) stearic acid.

According to the second aspect of the present invention, an improved process for the oral pharmaceutical composition comprises the steps of:

a) Sifting all the ingredients,
b) mixing (-) modafinil with disintegrant(s) and diluent(s),
c) granulating the dry mixture with binder solution,
d) drying the granulate and sizing,
e) mixing the blend with other disintegrant,
f) lubricanting the blend,

g) compressing the final blended into a solid dosage form suitable for oral administration. Wherein, in step-c) the binder solution defined as the binder dissolved in water. The oral pharmaceutical composition of dosage form may be in tablet or capsule form or pellets. However, the tablet form is particularly suitable for the present composition.

The composition of the present invention is indicated to improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea, narcolepsy and shift work disorder.

The functions and advantages of the present invention will be explicable from the examples mentioned in the below table. The following examples are intended to illustrate the benefits of the present invention, but do not exemplify the full scope of the invention.

EXAMPLES: Example-1:
Table-1
Procedure:

Shifted all the ingredients through an appropriate seive. (-) Modafinil, dibasic calcium phosphate, mannitol and pregelatinized starch were homogeneously mixed and granulated with hydroxypropylcellulose in water. Granulate was dried and sieved. The sieved granulate was homogeneously mixed with sodium starch glycolate and stearic acid. The homogeneous granulate was compressed into tablets on a conventional tablet press.

Example-2 to 5:
Table-2

Manufacturing process:
The tablets were manufactured using wet granulation process:
(-)Modafinil was dry blended with Dibasic Calcium phosphate, mannitol and pregelati-nized starch. A water solution of hydroxypropyl cellulose was prepared and used for granulating the above blend to form granules. Additional water can be added to reach de¬sired end point. The obtained granules were dried and sized to eliminate large agglomer¬ates. Finally, blend the granules with sodium starch glycolate and then lubricated with stearic acid and compressed into tablets.

Example-6:
Table-3

Manufacturing Process:
The tablets were manufactured using wet granulation process:
The blend is prepared by mixing (-)modafinil, microcrystalline cellulose, lactose mono-hydrate, starchl500, Ac-di-sol .A water solution of povidone was prepared and used for granulating the above blend to form granules. Additional water can be added to reach de¬sired end point. The wet granules are dried and sized to eliminate large agglomerates..

The resulting sized granulation is blended with extra granular disintegrant (i.e., Ac-di-sol) and then lubricated with magnesium stearate and compressed into tablet.

Example-7:
Table-4

Manufacturing Process:
The tablets were manufactured using wet granulation process:

The blend is prepared by mixing (-)modafinil, microcrystalline cellulose, tribasic calcium phosphate and Ac-di-sol .A water solution of hydroxy propyl cellulose was prepared and used for granulating the above blend to form granules. Additional water can be added to reach desired end point. The wet granules are dried and screened. The resulting screened granulation is blended with extra granular disintegrant (microcrystalline cellulose) and then lubricated the obtained granules with magnesium stearate and compressed into tablet.

Example-8:

Table 5

Manufacturing Process:

The tablets were manufactured using wet granulation process:
(-)Modafinil, mannitol, lactose monohydrate, Starch.1500 and Ac-di-sol (I) were mixed to form a blend. A water solution of hydroxypropyl cellulose was prepared and used for granulating the above blend to form granules. The obtained granules were dried and sized to eliminate large agglomerates. Finally, blend the granules with Ac-di-sol (II) and then lubricated with magnesium stearate and compressed into tablet.

Example-9
Table-6

Manufacturing Process:
The tablets were manufactured using wet granulation process:
(-)Modafinil, microcrystalline cellulose, tribasic calcium phosphate, starch 1500 and sodium starch glycolate were mixed to form a blend. A water solution of hydroxypropyl cellulose was prepared and used for granulating the above blend to form granules. The obtained granules were dried and sized to eliminate large agglomerates. Finally, blend the granules with sodium starch glycolate and then lubricated with magnesium stearate and compressed into tablet. Example-10:

Table-7
Manufacturing Process:
The tablets were manufactured using wet granulation process:
(-)Modafinil, microcrystalline cellulose, lactose monohydrate, starchl500 and Ac-di-sol (I) were mixed to form a blend. A water solution of povidone was prepared and used for granulating the above blend to form granules. The obtained granules were dried and sized to eliminate large agglomerates. Finally, blend the granules with Ac-di-sol (II) & then lubricated with magnesium stearate and compressed into tablet.

Test Example-1: Stability Test:
The tablets of (-)modafinil of example-5 were evaluated for stability. Results of the tab¬lets stored at 40°C and 75%RH for 1st, 2nd & 3rd months are given below.

Table-8
Test Example-2: Dissolution Profile Test:
Dissolution studies were carried out with tablets of Example-5 of the present invention and innovator formulation (Nuvigil).

Table-9 shows the comparative dissolution profile of Example-5 and Nuvigil. Based on the dissolution profile, pharmaceutical composition of the present invention is having uniform dissolution pattern as that of innovator and it is expected that pharmaceu¬tical composition of the present invention to show similar activity compare with Nuvigil.

Comparative dissolution profile of Example-5 (50mg) of the present invention and
Nuvigil (50mg).

Dissolution medium: 900ml of 0.1N HC1
Dissolution apparatus: Paddle, 50RPM

Table-9

We Claim:

1. A solid oral pharmaceutical composition comprising of:

a) (-) modafinil,
b) at least one binder,
c) at least one diluent,
d) the disintegrant,
e) at least one lubricant,
f) optionally coating agents,
wherein at least part of disintegrant is intragranular and at least part of the disintergrant is extragranular.

2. A solid oral pharmaceutical composition of claim 1, wherein the binder is selected from the group consisting of povidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or gelatine, and mixtures thereof, the disintegrant is selected from cross linked sodium salt of a carboxymethyl ether of starch such as sodium starch glycolate, croscarmellose sodium, crospovidone, prege-latinized starch, cellulose derivatives such as microcrystalline cellulose and mixtures thereof,
the diluent is selected from calcium monohydrogen phosphate, dibasic calcium phos¬phate, tricalcium phosphate, lactose, mannitol, starch derivatives and cellulose deriva¬tives such as microcrystalline cellulose and mixtures thereof, the lubricant is selected from stearic acid and its salts such as magnesium stearate, calcium stearate, vegetable oils, polyethylene glycol, polyvinyl alcohols and mixtures thereof.

3. A solid oral pharmaceutical composition of claim 2, wherein the disintegrant is sodium starch glycolate, croscarmellose sodium and mixtures thereof,

the binder is hydroxypropyl cellulose,

the diluent is lactose, mannitol, microcrystalline cellulose and mixtures thereof,

the lubricant is stearic acid.

4. A solid oral pharmaceutical composition of claim 1, wherein the (-)modafinil is present in an amount of 40-60% in weight based on the total weight of the composition.

5. A solid oral pharmaceutical composition of claim 3, wherein the disintegrant is present in amount of 2 to 15% in weight based on the total weight of the composition,

the diluent is present in amount of 20 to 60% in weight based on the total weight of the composition,

the binder is present in amount of 0.5 to 6% in weight based on the total weight of the composition,

the lubricant is present in amount of 0.2 to 2% in weight based on the total weight of the composition.

6. A solid oral pharmaceutical composition comprising of:

a) (-) modafinil is present in an amount of 40-60% in weight based on the total weight of the composition,

b) dibasic calcium phosphate and mannitol are present in an amount of 20-60% in weight based on the total weight of the composition,

c) intragranular disintegrant, preferably pregelatinized starch is present in an amount of 1 to 5% in weight based on the total weight of the composition,

d) hydroxypropyl methyl cellulose is present in an amount of 0.5 to 6% in weight based on the total weight of the composition,

e) extragranular disintegrant, preferably sodium starch glycolate is present in an amount of 1 to 5% in weight based on the total weight of the composition,

f) stearic acid is present in an amount of 0.2 to 2% in weight based on the total weight of the composition.

7. According to any preceding claims, the method of the preparing the solid oral
pharmaceutical composition is wet granulation method.

8. A method for preparing the solid oral dosage pharmaceutical composition of any
preceding claims, comprising of the following steps:

a) sifting all the excipients,
b) mixing (-) modafinil with at least one disintegrant and at least one diluent,
c) granulating the dry mixture with binder solution,
d) drying the granulate and sizing,
e) mixing the blend with at least one disintegrant,
f) lubricating the blend,
g) compressing the final blend into a solid dosage form suitable for oral administra-tion.
Wherein, in step-c) the binder solution defined as a binder dissolved in water.

9. A solid oral pharmaceutical composition of any of preceding claims is in the form of tablet.

10. The use of the solid oral pharmaceutical composition of any preceding claims as a medicament for the treatment of sleepiness, sleep apneas, for promoting of wakeful-ness, or for improvement of cognitive dysfunction.