Patent Application
20080044468
As evident from the above description, there exists a need for simpler and cost effective approaches for preparing bioavailable dosage forms of modafinil. The inventors have now discovered that combinations of modafinil with one or more surface active agents and/or one or more pharmaceutical carriers in the preparation of pharmaceutical compositions of modafinil provide dosage forms with improved bioavailability.
In the present invention, the inventors have obtained desired dissolution profiles and bioavailability by adding either or both of one or more surface active agents and one or more pharmaceutical carriers to modafinil by one or more of co-mixing, co-sifting, and co-grinding. Modafinil used in the preparation of dosage forms is a mixture of coarse particles (diameters greater than 220 μm) and fine particles (diameters less than 220 μm) in the ratio of approximately 10:90 to 25:75 by weight. A preferred mean particle size of fines is less than 180 μm. A more preferred mean particle size of fines is approximately 15-60 μm. The ratio of coarse and fine particles may vary from a value of 10:90 to 25:75 by weight. Variations within this range do not generally affect the dissolution profile of modafinil dosage forms. The specific surface area of the fine modafinil particles should be at least 0.2 m2/gm. The combination of coarse and fine particles improves the flow properties of blend and thereby facilitates processing of dosage forms. The problems of re-agglomeration of fines and drug loss are addressed and better homogeneity is provided.
The term “surface active agent” as used herein refers to substances that improve the dissolution rate and bioavailability of modafinil by acting at the interface of the drug surface and dissolution media. For example, the term “surface active agent” can include wetting agents, solubilizers, emulsifiers, and some plasticizers. Specifically, surface active agents can include anionic, cationic, and non-ionic substances suitable as surface active agents. Suitable anionic surface active agents include those containing carboxylate, sulfonate and sulphate ions, such as sodium lauryl sulphate, sodium laurate, dialkyl sodium sulfosuccinates, particularly bis (2-ethylhexyl) sodium sulfosuccinate, sodium stearate, potassium stearate, sodium oleate and the like. Suitable cationic surfactants include those containing long chain cations, such as benzalkonium chloride, bis-2-hydroxyethyl oleyl amine and the like. Suitable non-ionic surface active agents include polyoxyethylene sorbitari fatty acid esters, fatty alcohols, such as lauryl, cetyl and stearyl alcohols, glyceryl esters, such as the naturally occurring mono-, di- and triglycerides; fatty acid esters of fatty alcohols and other alcohols, such as propylene glycol, polyethylene glycol, sorbitan, sucrose and cholesterol. Generally the surface active agent is selected from solid surface active agent so that it can be one or more of co-mixed, co-sifted, and co-grinded with modafinil. The surface-active agent may be used in amount of about 0.2% to about 10.0% by weight of the total weight of the dosage form.
The term “pharmaceutically inert carrier” refers to a substance that is physiologically acceptable and compatible with the drug and other excipients in the dosage form and has a capacity to adsorb the drug on its surface. By virtue of such adsorption, the effective surface area of the drug exposed to the dissolution media is increased manifold, which thereby increases the rate of dissolution. Such adsorption of drug on the carrier surface also prevents the re-agglomeration of drug particles due to neutralization of surface charges on the drug particles generated during milling by an inert carrier. Carriers also help in wetting the drug, which involves the uptake of water by capillary action and thereby enhances the drug dissolution further. The pharmaceutically inert carrier may be used in an amount of about 2% to about 25% by weight of the total weight of the dosage form.
Suitable pharmaceutically inert carriers include one or more of cellulose derivatives, such as microcrystalline cellulose and carboxymethylcellulose; silicate derivatives such as magnesium silicate, colloidal silicon dioxide, magnesium trisilicate, and magnesium aluminum silicate; and clays, such as veegum, bentonite; and the like.
The process of co-grinding and /or co-sifting of modafinil, and surface active agent and/or pharmaceutically inert carrier may be carried out in conventional milling instruments such as air jet mill, multi mill, ball mill, or any other method of particle attrition and/or sifting.
In one of the embodiments, the process of co-grinding modafinil and the one or more solid surface active agents and/or pharmaceutical carriers may advantageously be carried out in an accelerated air-jet mill or ball mill until the powder obtained is such that the mean particle diameter is less than or equal to 180 μm and in particular less than or equal to 60 μm.
In another embodiment, modafinil may be adsorbed onto the carrier by co-sifting the finer fraction of modafinil with the one or more pharmaceutically inert carriers and mixing repeatedly until a uniform mixture is formed.
The above co-grinded and/or co-sifted mixture of modafinil and surface active agent and/or pharmaceutical carrier may be further processed with pharmaceutically inert excipients into various dosage forms, such as tablet, capsule, pill and the like, using processes known in the art, for example, by comminuting, mixing, granulating, melting, sizing, filling, drying, molding, immersing, coating, compressing, etc.
In one of the embodiments, the bioavailable dosage form of modafinil may be prepared by a process that includes the steps of blending the above co-grinded and/or co-sifted mixture with one or more extragranular pharmaceutically inert excipients; wet granulating the blend with a granulating fluid or solution/dispersion of one or more pharmaceutically inert excipients in the granulating fluid; drying and sizing the granules; optionally blending with one or more pharmaceutically inert extragranular excipients; and compressing into tablets or filling into capsules.
In another embodiment, the bioavailable dosage form of modafinil may be prepared by a process that includes the steps of blending the above co-grinded and/or co-sifted mixture with one or more extragranular pharmaceutically inert excipients; dry granulating the blend by roller compactor or slugging; sizing the granules; optionally blending with one or more pharmaceutically inert extragranular excipients; and compressing into tablets or filling into capsules.
In yet another embodiment, the bioavailable dosage form of modafinil may be prepared by a process that includes the steps of blending the above co-grinded and/or co-sifted mixture with one or more pharmaceutically inert excipients; and compressing into tablets or filling into capsules.
Dosage forms prepared by any of the above methods may optionally be coated with one or more functional and/or non-functional coatings as desired.
The term “pharmaceutically inert excipients” as used herein includes excipients used in the art of manufacturing solid dosage forms. Examples of pharmaceutically inert excipients include binders, diluents, disintegrants, surface-active agents, lubricants/glidants, coloring agents, and the like.
Examples of suitable binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pollutant, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Examples of suitable diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Examples of suitable disintegrants include croscarmellose sodium, crospovidone and sodium starch glycolate and the like.
Examples of suitable lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, magnesium silicate, hydrogenated vegetable oils, sodium stearyl fumarate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Coloring agents include any FDA approved colors for oral use.
Examples of suitable granulating fluids employed in the preparation of dosage forms include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water, and the like.
The inventions will be understood more clearly from the following description of the Preparative Examples (Table 1), the dissolution profile (Table 2), and the bioavailability data (Table 3). These examples further exemplify the inventions and are not intended to limit the scope of the inventions.
Modafinil tablets according to the above compositions of Examples 1-6 were prepared according to the following method:
The in vitro release of modafinil from the tablets of Examples 1-6 was studied in USP dissolution apparatus II, in 900 ml water, and at a paddle speed of 25 rpm. The results are presented in Table 2.
An in vivo bioequivalence study of the modafinil tablets of Examples 2 and 3 was carried out on healthy male volunteers (n=12) with the marketed Provigil® tablets (200 mg) produced by Abbott Laboratories as the reference. The results of this study are presented in Table 3. The objective of this study was to show that formulations of Examples 2 and 3 provide an activity and safety profile that is similar to or better than that obtained with an equivalent product in the market.
The results show that modafinil tablets prepared according to Examples 2 and 3 described herein have bioavailability comparable to the reference product, Provigil®.
While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. For example, the bioavailable dosage forms of modafinil that include modafinil and one or more of a surface active agent and a pharmaceutically inert carrier can be used to treat narcolepsy and/or idiopathic hypersomnia. Moreover, the oral dosage forms of modafinil described herein can be provided with labeling for one or more of wakefulness promotion, to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy, and idiopathic hypersomnia. Further, although the examples above are directed to application of the inventive concepts described herein to one particular poorly soluble active pharmaceutical ingredient, these concepts can be applied to other active pharmaceutical ingredients, such antidiabetics, antineoplastic agents, antihypertensives, psychopharmacological agents, cardiovascular agents, platelet aggregation inhibitors, analgesics, antimicrobials, diuretics, spasmolytics, and the like. Specific examples of poorly soluble active pharmaceutical ingredients include glipizide, doxazosin, verapamil, prazosin, isradipine, cilostazol, nifedipine, nisoldipine, bendroflumethazide, chlorpropamide, hydrocortisone, ibuprofen, diclofenac, and the like. Finally, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed inventions and be so described as a negative limitation. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 771/DEL/2002 | Jul 2002 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB03/02962 | 7/24/2003 | WO | 00 | 6/7/2006 |
