FIELD OF INVENTION
The present invention relates to solid oral dosage forms containing armodafinil and colloidal silicon dioxide for enhancing the drug release and extent of dissolution of the composition.
BACKGROUND OF THE VENTION AND RELATED PRIOR ART
Modafinil is currently marketed by Cephalon, Inc. under the trade name PROVIGIL'11 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 dopamini1rgic system. Modafinil has been successfully tested in humans for treatment of iciiopathic 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-(benzhydrylsulphinyl) acetamide or (±) 2-[{diphenylmethyl) sulphinyl] acetamide, as a compound having properties of stimulating the central nervous system. It also describes solid and liquid forrdulations 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 R enantiomer of modafinil is known as Armodafinil and has the chemical name 2-[(R)-(diphenylmethyl) sulfinyl] acetamide. Armodafinil is approved by USFDA under the brand name NUVIGIL1"1. Armodafinil is well tolerated and its safety profile is comparable with modafinil.
Armodafinil 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 solubiHty and it is therefore difficult to make a composition of modafinil possessing a high dissolution profile.
Similarly, armodafin:.! is also practically insoluble in water as well as in buffers ranging from pH 1.0 to 6.8. The insoluble nature of armodafinil 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 pharmaceutit;al composition that has at least about 95% of the modafinil particles having a diameter of less than about 200 |im and having a median size smaller than about 60 jam.
U.S. 7,115,281 relates to processes for preparing and pharmaceutical compositions of modafinil 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 220pm and about 75S^i-93% by weight of modafinil particles having diameters less than 220pm. It further describes a composition containing complexes of a modafinil compound and a cyclodextrin, preferably a p-

cyclodextrin for enhancing the solubility of modafmil. 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 modafmil with one or more surface active agents and/ or one or more pharmaceutical carriers in the preparation of pharmaceutical compositions of modafmil which provide dosage forms with improved bioavailability.
In the present invention we have found that when armodafmil mixed with pharmaceutical inert carriers, these inert carriers improve the uptake of water by capillary action, thereby enhancing the drug's dissolution rate.
In view of the prior art, there lies a need to provide a stable and cost effective oral pharmaceutic-al formulations comprising armodafmil without utilizing expensive and or complicated technology.
SUMMARY AND OBJECTIVES OF THE INVENTION
The present invention relates to oral pharmaceutical compositions comprising armodafmil and the processes for their manufacture. In one general aspect there is provided an oral pharmaceutical composition comprising armodafinil that includes colloidal silicon dioxide.
Particularly, the present invention relates to oral pharmaceutical compositions comprising a) armodafinil or its pharmaceutically acceptable salt thereof; b) colloidal silicon dioxide and c) other pharmaceutically acceptable additives.
More particular, armodafmil are admixed with colloidal silicon dioxide and other pharmaceutically acceptable excipients to formulate a solid pharmaceutical composition comprising armodafmil. In one embodiment, the solid dose can be in tablet form or in capsule form. An objective of the invention is to provide a pharmaceutically acceptable solid composition of armodafmil,

where the drug release and extent of dissolution of the composition is enhanced by incorporating colloidal silicon dioxide in the composition.
Another objective of the invention is to provide a solid oral composition comprising armodafmil from about 35 to 70% by weight relative to total composition.
A further objective of the invention provides a solid oral composition comprising armodafmil wherein colloidal silicon dioxide is present in an amount from about 3% to 20% by weight relative to total composition.
Still another objective of the invention is to provide a process of preparing a pharmaceutically acceptable solid composition of armodafmil, comprising colloidal silicon dioxide and optionally other pharmaceutically acceptable excipients
These and other objectives, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that despite its poor solubility, armodafmil can be formulated as an oral pharmaceutical composition, wherein the drug release and extent of dissolution of the composition is enhanced vis-a-vis composition not comprising colloidal silicon dioxide.
DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF
THE INVENTION:
The present invention relates to oral pharmaceutical compositions comprising armodafmil and the processes for their manufacture. In one general aspect there is provided an oral pharmaceutical composition comprising armodafinil that includes colloidal silicon dioxide.

Particularly, the present invention relates to oral pharmaceutical compositions comprising a) armodafinil or its pharmaceutically acceptable salt thereof; b) colloidal silicon dioxide and c) other pharmaceutically acceptable additives, wherein the drug release and extent of dissolution of the composition is enhanced vis-a-vis composition without comprising colloidal silicon dioxide.
In the context of the present invention, "armodafmil" as used herein includes armodafinil, their pharmaceutically acceptable salts, esters, pro-drugs, and other pharmaceutically acceptable forms.
"An effective amount", as used herein, is an amount of the pharmaceutical composition that is effective for treating a somnolent or somnolescent state, i.e., an amount of armodafinil that is able to reduce, eliminate, treat, prevent or control the symptoms of a somnolescent state. An effective amount of a pharmaceutical composition of the invention is useful for enhancing alertness, or increasing regularity of sleep rhythms.
In the context of the present invention, "colloidal silicon dioxide" as used herein includes colloidal silicon dioxide is a submicroscopic filmed silica with a particle size of about 15 nm.
The product itself is usually a submicron, fluffy, light, loose, bluish-white, odourless and tasteless amori:)hous powder which is commercially available from a number of sources, including Cabot Corporation (under the trade name Cab-0-Sil); Degussa, Inc. (under th(; trade name Aerosil); Huber Engineered Materials (Huber GLIOO and GL200); Wacker (Wacker HDK ®); and E.I. Colloidal silicon dioxide is generally used as a glidant to improve the flow of powders while making dosage forms like tablets or granules.
The oral pharmaceutical composition according to the invention include solid dosage forms such as granules, pellets, beads, mini-tablets, tablets, capsules and the like, prepared by com'entional methods well kno\\'n to a person skilled in the art.

The pharmaceutical composition of the invention can contain at least about 25 mg, to about 300 mg of ^irmodafinil. Preferably the unit dose is in a solid dose form, and more preferably is a tablet. In particular, the tablet can include 50 mg of armodafinil in 100 mg tablet, 100 mg of drug in 200 mg tablet, 200 mg of armodafinil in a 400 mg tablet, 300 mg of armodafinil in a 600 mg tablet, and 400 mg armodafinil in 800 mg tablet.
The oral pharmaceutical composition of the invention may further comprise pharmaceutically acceptable additives known in the art. The term 'pharmaceutically acceptable additive' includes 'pharmaceutically acceptable excipient' within its ambit aiid the singular term includes plural as well. As used herein, "pharmaceutical excipients" refers to substances that are used in the formulation of pharmaceutical compositions, and, by themselves, generally have little or no therapeutic value. The excipients may be hygroscopic or non-hygroscopic. Typical excipients include fillers or diluents, granulating agent/ binders, disintegrant, lubricants, glidants, antioxidants, anti-bacterial agents and other preservatives; chelating agents; buffering agents; agents for adjusting toxicity; coloring, flavoring and other substances with pharmaceutical applications.
Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, dextrates, dextrin, dextrose, mannitol, micro-crystalline cellulose, powdered cellulose, spray-dried monohydrate or anhydrous lactose, sucrose, starch, , sorbitol, talc, xylitol, and the like can be used. The pharmaceutically inert diluent may be used in an amount of about 10% to about 50% by weight of the total weight of the dosage form.
Binders/granulating agent, which include, but are not limited to, alkyl celluloses such as methyl cellulose, ethyl cellulose; hydroxyalkylcelluloses such as hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose;, sodium carboxymethylcellulose; microcrystalline

cellulose; gelatin, acacia, jjolyvinyl alcohol, polyvinylpyrrolidone (Povidone), propylene glycol, sodium alginate, starches (e.g. potato starch, wheat starch, com starch, pregelatinised maize starch), tragacanth etc.
Examples of suitable granulating fluids employed in the preparation of dosage forms include methjiene chloride, isopropyl alcohol, acetone, methanol, ethanol, water, and the like.
Disintegrants, which include but are not limhed to, cross linked polyvinylpyrolidone (Crospovidone, polyplasdone XL, KoUidon CL); starches such as maize starch and dried starch sodium starch glycolate; gums such as alginic acid, sodium alginate, guar gum; croscarmellose sodium; croscarmellose calcium; cellulose products such as microcrystalline cellulose and its salts, microfme cellulose, low substituted hydroxypropylcellulose and mixtures thereof. Most preferably disintegrants are crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose and crosslinked sodium carboxymethylcellulose.
Glidants improve the; flowability of the powder making up the tablet during production. Glidants can be selected from selected from the group consisting of; silicon dioxidis, colloidal silicon dioxide, fumed silicon dioxide, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, com starch, sodium benzoate, calcium carbonate, magnesium carbonate, asbestos free talc, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stear-o-wet C, starch, starch 1500, magnesium lauryl sulfate, or magnesium oxide., where colloidal silicon dioxide is the preferred glidant.
Lubricants may be selected from the group of magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, hydrogenated cottonseed oil, sodium benzoate, sodium lauryl sulfate, polyethylene glycol, talc etc. Coloring agents include any FDA approved colors for oral use.
The compression can be carried out in a conventional tabletting machine, eccentric tabletting machine or a rotary compression machine. The tablets can

further be coated (functional or non-functional coating) by using any of the conventional coating techniciues, such as pan or perforated pan, well known to the persons skilled in the art.
These coating layers comprise of one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, coloring agents, anti-tacking agents and the like.
Coating agents which are useful in the coating process, include, but are not limited to, polysaccharides such as malto-dextrin, alkyl celluloses such as methyl or ethyl cellulose, hydroxyalkyl celluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcelluloses); polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinylpyrroUdone and vinyl acetate (e.g. marketed under the brand name of Plasdone) and polymers based on methacrylic acid such as those marketed under the brand name of Eudragit.
These may be applied from aqueous or non-aqueous systems or combinations of aqueous and non aqueous systems as appropriate. Additives can be included along with the film formers to obtain satisfactory films. These additives can include plast.cizers such as dibutyl phthalate, triethyl citrate, polyethylene glycol and the like, antitacking agents such as talc, stearic acid, magnesium stearate and colloidal silicon dioxide and the like, surfactants such as polysorbates and sodium lauj^l sulphate and opacifying agents such as titanium dioxide and the like. All these excipients can be used at levels well known to the persons skilled in the art.
In a preferred embodiment, there is also provided a process of making the solid oral dosage forms as heiein above described comprising the steps -i) Mixing armodafinil and colloidal silicon dioxide in a blender; ii) mixing this admixture with lactose in a blender; iii) granulate with povidone solution; iv) mix the dry granulate with other excipiems and colloidal silicon dioxide; v) compressing the lubricated granules into tablets; or fiUing it into capsules.

In another embodiment, the pharmaceutical composition of drug is prepared by a dry granulation process that includes the steps of blending armodafinil with colloidal silicon dioxide to form a blend; dry granulating the blend by roller compactor or slugging to form granules; sizing the granules; optionally blending the sized granules with one or more pharmaceutically inert extra-granular excipients to form a blend; and compressing that blend into tablets or filling that blend into capsules. The pharmaceutical composition may optionally be coated with or more functional and/or non-functional coatings.
The functions and advantages of these and other embodiments of the present invention will be more fully understood from the examples below. The following examples are intended to illustrate the benefits of the present invention, but do not exemplify the full scope of the invention.
EXAMPLE 1;
Unit Composition

Ingredients mg/tab %w/w
Armodafmil 250.00 50.00
Lactose 88.50 17.70
Croscarmellose Sodium 20.00 4.00
Povidone 10.00 2.00
Mg Stearate 2.50 0.50
Microcrystalline cellulose 19.00 3.80
Pregelatinizeti starch 110.00 22.00
Total 500.00 100.00
Brief manufacturing procedi^re:
1. Sift Lactose through 40 # / 24 R screen and mix it with armodafinil material in blender.
2. Mix step I materials in blender then sift through 40 # / 24 R screen and repeat the process for twice.
3. Dissolve Povidone in Purified Water with constant sfirring to get clear solution.
4. Load material of step 2 into Granulator and mix.

5. Granulate the material of Step 4 with the addition of binder solution of step 3 in Granulator.
6. Dry the wet mass of Step 5 in dryer at a temperature of 50°C to 70°C.
7. Mill the material of Step 6 through 40 G screen.
8. Sift Crosscarmellose Sodium through 40 # / 24 R screen.
9. Sift magnesium stearate through 40 # / 24 R screen.
10. Load the material of Step 7 and Step 8 into the blender and blend. Add the material of Step 9 into it and blend
11. Compress the tablet with appropriate tooling using Compression Machine.
EXAMPLE 2:
Unit Composition:

Ingredients mg/tab %w/w
Armodafinil 250.00 50.00
Lactose 208.50 41.70
Colloidal Silicon Dioxide 19.00 3.80
Croscarmelloss Sodium 10.00 2.00
Povidone 10.00 2.00
Mg Stearate 2.50 0.50
Total 500.00 100.00
Brief manufacturing procedure:
1. Mix Armodafinil and Colloidal Silicon Dioxide (part quantity) in blender.
2. Sift step 1 material thi-ough 40 # / 24 R screen.
3. Mix step 2 materials in blender then sift through 40 # / 24 R screen and repeat the process for twice.
4. Sift Lactose through 40 # / 24 R screen and mix it with step 3 material in blender.
5. Mix step 4 materials in blender then sift through 40 # / 24 R screen and repeat the process for twice.
6. Dissolve Povidone in Purified Water with constant stirring to get clear solution.
7. Load material of step 5 into Granulator and mix.
8. Granulate the material of Step 7 with the addition of binder solution of step 6 in Granulator.

9. Dry the wet mass of Step 7 in dryer at a temperature of 50°C to 70°C. 10.
10. Mill the material of Step 9 through 40 G screen.
11. Sift Crosscarmellose Sodium and Colloidal Silicon Dioxide (remaining qty) through 40 # / 24 R screen.
12. Sift magnesium stearate through 40 # / 24 R screen.
13. Load the material of Step 10 and Step 11 into the blender and blend. Add the material of Step 12 into it and blend.
14. Compress the tablet with appropriate tooling using Compression Machine.
EXAMPLE 3:
Unit Composition

Ingredients mg/tab %w/w
Armodafinil 250.00 50.00
Lactose 150.00 30.00
Colloidal Silicon Dioxide 29.00 5.80
Crosscarmellose Sodium 20.00 4.00
Povidone 10.00 2.00
Mg Stearate 2.50 0.50
Corn starch 38.50 7.70
Total 500.00 100.00
Brief manufacturing procedure:
1. Mix Armodafinil and Colloidal Silicon Dioxide (part quantity) in blender.
2. Sift step 1 material through 40 # / 24 R screen.
3. Mix step 2 materials in blender then sift through 40 # / 24 R screen and repeat the process for twice.
4. Sift Lactose through 40 # / 24 R screen and mix it with step 3 material in blender.
5. Mix step 4 materials in blender then sift through 40 # / 24 R screen and repeat the process for l:wice.
6. Dissolve Povidone in Purified Water with constant stirring to get clear solution.
7. Load material of step 5 into Granulator and mix.
8. Granulate the materia' of Step 7 with the addition of binder solution of step 6 in Granulator.

9. Dry the wet mass of Step 7 in dryer at a temperature of 50°C to 70°C.
10. Mill the material of Step 9 through 40 G screen.
11. Sift Crosscannellose Sodium and Colloidal Silicon Dioxide (remaining qty) through 40 # / 24 R screen.
12. Sift magnesium stearate through 40 # / 24 R screen.
13. Load the material of Step 10 and Step 11 into the blender and blend. Add the material of Step 12 into it and blend.
14. Compress the tablet with appropriate tooling using Compression Machine.
Dissolution Studies:
The above compositions were subjected to the following dissolution conditions, and the enhancement of the drug release and dissolution extent can be seen against the compositions which does not contain colloidal silicon dioxide, thus establishing the fact colloidal silicon dioxide contributes to drug release and dissolution extent.
Conditions:
Apparatus; USP II, 50 rpm Medium: 0.1 NHCl Volume: 900 ml
Results:

Time (Minute) % Drug Released

Example 1
(Without colloidal silicon dioxide) Example 2
(With 3.8% w/w colloidal silicon dioxide) Example 3
(With 5.8% w/w colloidal silicon dioxide)
5 46 79 65
10 62 93 80
15 69 96 86
20 73 96 90
30 77 97 92
Based on the above data dissolution rate it is seen that colloidal silicon dioxide enhances the drug release and extent of dissolution in the said media, probably due to the channeling effect caused by the same in the tablet matrix, which renders greater availability of armodafinil in the dissolution medium.

We Claim:
1. An oral pharmaceutical composition comprising armodafmil, colloidal silicon dioxide and optionally one or more pharmaceutically acceptable excipients.
2. The pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable excipients are selected from binders, diluents, disimegrants, lubricants, glidants, and coloring agents
3. The pharmaceutical composition of claim 2, wherein said binder is selected from a group consisting of hydroxypropyl cellulose and cellulose derivatives, polyvidone, polyvinyl pyrrolidone, gelatin, natural gums, starch paste, pre-gelatinized starch, sucrose, corn syrup, polyethylene glycols and sodium alginate, ammonium calcium alginate, magnesium aluminum silicate, polyethylene glycols, and mixtures thereof
4. The pharmaceutical composition of claim 3, wherein said binder is povidone.
5. The pharmaceutical composition of claim 2, wherein said disintegrants are selected from a group consisting of starch and starch derivatives, pre-gelatinized starch, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, crospovidone and cross-linked polyvinylpyrrolidone, microcrystalline cellulose and mixtures thereof.

6. The pharmaceutical composition of claim 5, wherein said disintegrant is croscarmellose sodium.
7. The pharmaceutical composition of claim 2, wherein said diluent is selected from a group consisting of lactose, sucrose, dextrose, starch, pre-gelatinized starch, polyols, cellulose, inorganic salts, and mixtures thereof

8. The pharmaceutical composition of claim 7, wherein said diluent is lactose.
9. A process for preparing a pharmaceutical composition comprising the steps of; (i) blending armodafmil and colloidal silicon dioxide to form a mixture;
(ii) blending said admixture with lactose;
(iii) granulating mixture of step (ii) with povidone solution and sizing resultant
granules;
(iv) blending above sized granules of step [iii] with one or more
pharmaceutically acceptable inert excipients;
(v) compressing blend of step (iv) into a final composition.
10. The pharmaceutical coraposition of claim 1, wherein said formulation
releases at least 60% of armodafmil within 5 minutes and more than 90% of
armodafmil within 30 minutes.