PHARMACEUTICAL COMPOSITIONS COMPRISING METAXALONE

INTRODUCTION

In an aspect, the present invention relates to high dose pharmaceutical compositions comprising metaxalone, including pharmaceutically acceptable derivatives and mixtures thereof. In a further aspect, the invention relates to low dose controlled release pharmaceutical compositions comprising metaxalone, including its derivatives. The invention a so relates to processes for preparing high dose pharmaceutical compositions, low dose controlled release pharmaceutical compositions and their methods of use for the relief of discomforts associated with acute, painful musculoskeletal conditions.

Metaxalone has a chemical name 5-[(3,5-dimethyphenoxy)methyl]-2-oxazolidinone a id is represented by structural Formula I.

Formula I
Metaxalone is a white to almost white, odorless crystalline powder freely soluble in chloroform, soluble in methanol and in 96% ethanol, but practically insoluble in ether or water. Metaxalone is a skeletal muscle relaxant and is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions.

Metaxalone is present in a commercial product having the brand SKELAXIN®, as tablets containing 800 mg of the drug. The usual dosing for adults and children over 12 years of age is one 800 mg tablet, taken three to four times daily.

Metaxalone is disclosed in U.S. Patent No. 3,062,827. U.S. Patent No. 4,722,938 discloses a method of use of metaxalone. U.S. Patent Nos. 6,407,128 and 6,683,102 disclose methods of increasing the oral bioavailability of metaxalone by administration of an oral dosage form with food. The administration with food results in an increase in the maximum plasma drug concentration (Cmax) and extent of absorption (AUC0-t) of metaxalone as compared to administration without food. International Application Publication Nos. WO 2004/019937, WO 2004 /066981, WO 2005/048996, WO 2005/087204, and WO 2007/010508, and U.S. Patent Application Publication No. 2005/0063913, disclose various pharmaceutical compositions of metaxalone.

Drugs such as metaxalone that require frequent dosing result in fluctuations in the drug plasma levels.

Controlled release formulations can be effective in maintaining therapeutic blood levels over extended periods of time resulting in optimal therapy. They not only reduce the frequency of dosing for enhanced patient convenience and compliance, but they also reduce the severity and frequency of side effects, as they maintain substantially constant blood levels and avoid fluctuations associated with conventional immediate release formulations which are administered three to four times a day.

When poorly soluble, hydrophobic drugs such as metaxalone are orally administered, the rate of dissolution is slow resulting in poor absorption. However if such drugs are to be administered in oral dosage forms for clinical indications such as pain, rapid onset of therapeutic activity is desirable. In such case, the slow rate of dissolution and absorption may put limitations on their therapeutic utility. Painful, musculoskeletal conditions require prompt relief. Therefore, compositions that exhibit quick onset of action are desirable.

Metaxalone is an insoluble drug and further has relatively high dosing requirements. Thus, formulating high dose/low dose metaxalone into compositions/formulations presents difficulties due to the unacceptably large sizes of the dosage form.

Thus, there is a need for high dose compositions and relatively simple and economical low dose controlled release compositions and formulations of metaxalone for oral administration that are suitable for administration to have an effect over extended periods of time, e.g., about 12 to about 24 hours.

SUMMARY

An aspect of the present invention relates to high dose pharmaceutical compositions comprising metaxalone, including pharmaceutical^ acceptable derivatives or mixtures thereof.

A further aspect of the invention relates to low dose controlled release pharmaceutical compositions of metaxalone, including its derivatives.

In an embodiment the invention includes low dose controlled release compositions comprising metaxalone and at least one rate-controlling polymer.

In an embodiment, the present invention includes high dose pharmaceutical compositions of metaxalone wherein metaxalone is in a solubility-enhanced form.

In an embodiment the invention includes low dose controlled release pharmaceutical compositions comprising metaxalone, wherein metaxalone is in a solubility-enhanced foci.

In an embodiment the invention includes a solubility-enhanced form comprising metaxalone and at least one solubilizer.

In embodiments the invention includes modes of packing high dose pharmaceutical compositions and low dose controlled release compositions comprising metaxalone.

In embodiments, the invention relates to processes for preparing high dose pharmaceutical compositions and also low dose controlled release pharmaceutical compositions comprising metaxalone.

In embodiments, the invention relates to methods of using high dose pharmaceutical compositions and low dose controlled release compositions comprising metaxalone, in the treatment of discomforts associated with acute, painful musculoskeletal conditions.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows a pharmacokinetic profile from administration of a formulation prepared
according to Example 10.

Fig. 2 shows a pharmacokinetic profile from administration of a formulation prepared
according to Example 11.

Fig. 3 shows comparative pharmacokinetic profiles from administration of
formulations prepared according to Example 9 and Example 15, and the commercial

SKELAXIN tablets.

DETAILED DESCRIPTION
The present invention, in an aspect, relates to high dose pharmaceutical compositions comprising metaxalone, including pharmaceutically acceptable derivatives and mixtures thereof. A further aspect of the invention relates to low dose controlled release pharmaceutical compositions comprising metaxalone or its derivatives. Aspects of the invention also relates to processes for preparing compositions and their methods of use.

Metaxalone is a skeletal muscle relaxant used to relieve the pain of muscle injuries, spasms, sprains, and strains. The mechanism of action of metaxalone in humans has not been established, but may be due to general central nervous system depression. It has no direct action on the contractile mechanism of striated muscle, the motor end plate, or the nerve fiber. The drug does not directly relax tense skeletal muscles in man.

The pharmaceutically acceptable derivatives of metaxalone include but are not limited to salts, polymorphs, solvates, esters, hydrates, enantiomers, racemates, and mixtures thereof.

The term "high dose" for the purposes of the present invention includes total daily doses of metaxalone ranging from about 800 mg to about 4000 mg of metaxalone, per unit dose.

The term "low dose" for the purposes of the present invention includes total daily doses of metaxalone ranging from about 300 mg to about 3200 mg of metaxalone, per unit dose.

In an embodiment the daily dose of metaxalone is from 1600 mg to 3200 mg.

The term "unit dose" for purposes of the present invention refers to the amount of drug administered to a patient in a single dose, using dosage forms such as tablets, capsules, sachets, and liquids.

As used throughout this specification, the term 'controlled' indicates a formulation that releases drug in a manner different from that of an immediate release dosage form, such as providing a drug release that is delayed for a desired time period after administration, and/or a drug release that occurs during a desired time period after administration. The terms 'sustained,' 'extended,' 'delayed,' 'modified,' or 'prolonged' are included within the term 'controlled' and as applied include any drug delivery system which achieves the release of drug after and/or over a desired period of time, e.g., providing dosage forms that can be administered every 12 hours or 24 hours. The drug delivery systems include those such as modified-release matrix core, modified-release matrix core coated with release-modifying coating, enteric coated dosage form, dosage form surrounded by release-modifying coating, gastro-retentive dosage form, muco-adhesive dosage form, or osmotic release dosage form, etc.

It will be understood that embodiments within the scope of the invention are intended to display a monophasic, biphasic, or multiphasic release dissolution profile.

The term "dosage form" or "pharmaceutical formulation" as used herein relates to solid oral dosage forms such as tablets, mini-tablets, caplets, capsules, granules, pills, powders, microparticles, nanoparticles, etc.

The term "core" as used herein is defined to mean a pharmacologically inert particle or a solid vehicle in which, or onto which, metaxalone is uniformly or non-uniformly dispersed, The drug-containing core will desirably be formed by methods and materials well known in the art, such as for example by compressing, fusing, or extruding metaxalone alone or together with at least one pharmaceutically acceptable excipient, or coating metaxalone onto an inert substrate.

The term "multi-particulate" or "micro-particle" as used herein is defined to mean a plurality of drug-containing units, such as for example microspheres, spherical particles, microcapsules, particles, micro-particles, granules, spheroids, beads, pellets, or spherules.

The term "nanoparticle" or "nanosize" as used in the context of the present invention relates to particles of metaxalone where particle sizes are less than about 2000 nm.

Many drugs, when formulated as immediate release conventional dosage forms such as tablets, capsules or pellets, generally require administration two or more times each day
with concomitant peaks and troughs in the plasma levels of the drugs. However, for many disease states, it is advantageous to maintain the plasma levels of drug at or near a steady state. With controlled release dosage forms, the number of daily administrations may often be reduced from three or four, or more, to two, or from two administrations to one. Controlled release forms have the additional potential benefit that plasma levels of the drug are more constant than for immediate release forms, resulting in fewer side effects and a better therapeutic result.

When high doses of an insoluble drug have to be incorporated into compositions, formulation difficulties are presented. Difficulties in preparing suitable controlled release formulations of insoluble drugs are increased when the dose of the insoluble drug to be delivered to render a therapeutic effect over the desired period of time is relatively high.

In embodiments the invention includes high dose pharmaceutical compositions of metaxalone.

In other embodiments the invention includes low dose controlled release compositions of metaxalone.

In embodiments the invention includes low dose controlled release compositions comprising metaxalone and at least one rate-controlling polymer.

In embodiments the invention includes low dose controlled release compositions of metaxalone, wherein metaxalone is embedded in a matrix comprising one or more rate-controlling polymers.

In embodiments the invention includes low dose controlled release compositions of metaxalone, wherein metaxalone is present in reservoir form.

In embodiments the invention includes low dose controlled release compositions of metaxalone, wherein controlled release is provided by coating with rate-controlling polymers.

In embodiments the invention includes low dose controlled release compositions of metaxalone, wherein release is controlled by both a matrix as well as a coating.

A "rate-controlling polymer" for purposes of the present invention is any polymer that is able to control the release of metaxalone for a extended period of time, following immersion of a dosage form into an aqueous medium.

The rate-controlling polymers may be hydrophilic, hydrophobic, or lipophillic. Various rate controlling polymers that are useful in the present invention include but are not limited to hydroxypropyl methyl pthalates, methacrylic acid-based polymers (including methacrylic acid-acrylic acid copolymers), such as those sold by Evonik Industries, Germany as Eudragit™ RL, Eudragit RS, Eudragit NE, Eudragit S, and Eudragit L, polyvinylpyrrolidones, polyalkylene glycols such as polyethylene glycol, and cellulose derivatives such as cellulose acetate, hydroxypropyl celluloses, carboxymethyl celluloses, methylcelluloses, ethylcelluloses, propylcelluloses, hydroxyethyl celluloses, carboxyethyl celluloses, carboxymethyl hydroxyethyl celluloses, hydroxymethyl celluloses, cellulose acetate pthalates, hydroxypropyl methylcellulose acetate succinates (HPMCAS), cellulose acetate trimellitates, carboxymethylethylcelluloses, and hydroxypropyl methylcelluloses (including different grades such as Methocel K 4M, Type 2208, Methocel E 4M Type 2910 supplied by Colorcon Asia Private Limited), vinyl acetate copolymers, polysaccharides (such as alginic acid, sodium alginate, xanthan gum and the like), polyethylene oxides, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof, high molecular weight polyvinylalcohols; carbomers (e.g., Carbopol™), waxes like fatty acids and glycerides, and mixtures thereof.

In an embodiment the invention includes low dose controlled release compositions of metaxalone in monolithic or multiparticulate form.

Multiparticulate systems may be formed either by drug layering onto inert cores or by layering drug along with rate-controlling polymers.

Non-limiting examples of various substances that can be used as inert cores include insoluble inert materials such as glass particles/beads or silicon dioxide, non-pareil sugar seeds, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate, microcrystalline cellulose (e.g., spherical Celphere™ products sold by Asahi Kasei Corporation, Tokyo, Japan in various sizes), cellulose derivatives, calcium carbonate,dibasic calcium phosphate anhydrous, dibasic calcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, and magnesium oxide, soluble cores such as sugar spheres having sugars like dextrose, lactose, anhydrous lactose, spray-dried lactose, lactose monohydrate, mannitol, starches, sorbitol, and sucrose, insoluble inert plastic materials such as spherical or nearly spherical core beads of polyvinylchloride or polystyrene, and any other pharmaceutical^ acceptable insoluble synthetic materials and mixtures thereof.

In an embodiment the invention includes controlled release compositions comprising metaxalone, wherein compositions provide an early onset of action followed by controlled release of metaxalone.

In an embodiment the invention includes controlled release compositions of metaxalone comprising an immediate release fraction and a modified release fraction of metaxalone.
In another embodiment the pharmaceutical formulation comprising metaxalone, wherein a weight ratio of metaxalone in an immediate release fraction to metaxalone in an extended release fraction is in the range of about 1:1 to about 1:10.

In an embodiment the invention includes controlled release compositions comprising metaxalone wherein release of metaxalone is either by diffusion or by erosion.

Release of metaxalone is controlled for patient compliance and to reduce the numbers of daily peaks and troughs in the drug plasma concentration levels. At the same time it is also desired that metaxalone solubility will be improved so that it is effectively absorbed.

In an embodiment the invention includes controlled release compositions comprising metaxalone, wherein metaxalone is in a solubility-enhanced form.

In another embodiment the invention includes controlled release compositions comprising metaxalone, wherein metaxalone is in a solubility-enhanced form resulting in improved bioavailability.

In yet another embodiment the pharmaceutical formulation, containing metaxalone in the form of immediate release spheroids, wherein spheroids containing 800 mg of metaxalone have a metaxalone dissolution in 900 ml of 0.5% sodium lauryl sulphate in water, USP type II apparatus, and 100 rpm stirring in first 15 minutes is at least 2 times that of SKELAXIN 800 mg tablets.

In an embodiment the invention includes controlled release compositions comprising metaxalone, wherein metaxalone is dissolved or dispersed in a self-emulsifying system.
Being an insoluble drug, particle sizes of metaxalone would impact its solubility. The smaller the particle size, the greater the surface area, resulting in higher solubility and bioavailability.

In embodiments, the present invention includes a defined range of particle sizes of metaxalone.

In an embodiment, the invention includes pharmaceutical compositions comprising metaxalone having defined particle sizes.

The percentages of particles with different dimensions that exist in a total powder constitute the particle size distribution. It is represented in certain ways. Particle size is the maximum dimension of particles, normally given in micrometers or nanometers. Particle size distributions can be expressed in terms of, D10, D50, D90and D[4,3]. The D10, D50and D90 represent the 10th, median or 50th percentile, and the 90th percentile of the particle size distribution, respectively, as measured by volume. That is, the D™, D50, D90 are values of the distribution such that 10%, 50%, and 90% of the particles have a volume of the given sizes, or less, or are the percentages of particles smaller than those sizes. D50 also known as median diameter of particles. It is one of the important parameters representing characteristics of particles of a powder. For example, if D50=5 um, it means 50% of the particles are smaller than 5 pm. Similarly if D10=5 um, 10% of the particles are less than or equal to 5 pm, and if Dgo=5 pm, 90% of the particles are less than or equal to 5 pm. D[4,3] is the volume moment mean of the particles, or the volume weighted particle size.

The "Z" value is an arithmetic mean particle size. PDI is a poly-dispersion index and tower values signify that the sample has a narrow particle size distribution (PSD) range and the sample is closer to a mono-dispersed system having particles of the same size. Higher values signify that the PSD is of a broader range and the system can give a multi-modal PSD graph. So, the lower the PDI, the narrower is the PSD. The particle size and PDI may be determined using Malvern ZetaSizer supplied by Malvern Instruments Ltd.
In embodiments the invention includes pharmaceutical compositions of metaxalone wherein particle size distributions of metaxalone comprise D10 in the range of about 0.1 to about 25 urn, D50 in the range of about 1 to about 50 pm, and D90 in the range of about 10 to about 75 urn.

In an embodiment the invention includes low dose controlled release compositions of metaxalone, wherein particle sizes of metaxalone are less than about 2000 nm.

Nanoparticulate metaxalone compositions in the form of nanosuspensions can be made using process steps including, for example, milling, microfluidization, high pressure homogenization, or precipitation techniques. Following milling, homogenization, precipitation, etc., the resultant nanoparticulate metaxalone composition can be utilized in solid or liquid dosage formulations such as immediate release formulations and controlled release formulations.

In an embodiment, milling metaxalone to obtain a nanoparticulate dispersion comprises dispersing metaxalone particles in a liquid dispersion medium in which metaxalone is poorly soluble, followed by applying mechanical energy in the presence of grinding media to reduce the particle size of metaxalone to the desired effective average particle size. The dispersion media can be, for example, water, safflower oil, ethanol, t-butanol, glycerin, a polyethylene glycol (PEG), hexane, a glycol, or any combinations thereof.
Microfluidization is a technique by which samples (suspension based) are fluidized through a very small orifice, resulting in particle size reduction. An intensifier pump pushes a stream down a channel of fixed geometry and interacts with the interaction chamber to produce a very high shear. The particles consistently and uniformly collide with the walls and each other to enhance the process.

Another method of forming desired nanoparticulate metaxalone formulations is by micro precipitation. This is a method of preparing stable dispersions of poorly soluble active agents in the presence of one or more surface stabilizers and one or more colloid stability enhancing surfactants. Such a method comprises, for example: (1) dissolving metaxalone in a suitable solvent such as methanol, isopropyl alcohol, ethanol, n-butanol, etc; (2) adding the solution from (1) to a solution comprising at least one surface stabilizer; and (3) causing precipitation from (2) by adding an appropriate anti-solvent, such as water, tetrahydrofuran, etc.

Homogenization can be used to obtain metaxalone nanoparticulate formulations. High pressure homogenization processing involves passing a material through a small orifice under a very high pressure, driven by air or another gas. The temperature is controlled throughout the process. An example of a method comprises dispersing metaxalone particles in a liquid dispersion medium in which metaxalone is poorly soluble, followed by subjecting the dispersion to homogenization to reduce the particle size of the metaxalone to the desired effective average particle size. The dispersion medium can be, for example, water, safflower oil, sunflower oil, ethanol, t-butanol, glycerin, a polyethylene glycol (PEG), hexane, a glycol, or any combinations thereof.

In order to process nanosuspensions into pharmaceutical formulations, the nanosuspensions will be converted into solid powder form. Various processes to convert nanosuspensions into solid form include spray drying, bead layering, layering onto excipients, lyophilization, and freeze drying.

Spray drying is a commonly used method of drying a fluid feed with the assistance of heated air or other gases. The fluid feed (solution, colloid or suspension) varies depending on the material being dried and is transformed from a fluid state into a dried particulate form. These dried forms can then be used for further pharmaceutical processes like tableting, etc. They can also be used for drug layering by having a diluent in the spraying media.

Bead layering involves layering a drug solution or suspension onto various particles such as MCC, a sugar, etc. This process typically involves a fluidized bed processor for drug layering and the beads can be filled into a suitable capsule or compressed into tablets, etc.
Lyophilization is a process of converting a liquid form into solid form. Freeze drying works by freezing the material and then reducing the surrounding pressure and adding enough heat to allow the frozen water in the material to sublime directly from the solid phase to gas, thus leaving the solid material. This solid can then be suitably incorporated into a solid dosage form.

Improvement in solubility and thereby the bioavailability of metaxalone may also lead to reduction in the administered doses to achieve a desired therapeutic activity. Compositions with reduced doses are also within the scope of the invention.

In an embodiment the invention includes controlled release compositions including solubility-enhanced forms comprising metaxalone and at least one solubilizer.
The term "solubilizer" as used in the context of the present invention includes any solubilizing agent, surfactant, or wetting agent that is able to modify particle surface properties and improve the solubility of metaxalone.

The term "bioavailability enhancer" as used in the context of the present invention includes any enhancer which is able to enhance bioavailability of metaxalone.

Representative examples of solubilizers include but are not limited to various surfactants, hydroxypropyl methylcelluloses, hydroxypropylcelluloses, polyvinylpyrrolidones, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyethylene glycols (e.g., Carbowax™ 3550 and 934 (Union Carbide)), polyoxyethylene stearates, carboxymethylcellulose calciums, carboxymethyl cellulose sodiums, methylcelluloses, hydroxyethylcelluloses, hydroxypropyl methylcellulose phthalates, magnesium aluminium silicate, triethanolamine, polyvinyl alcohols (PVA), PEG-derivatized phospholipids, PEG-derivatized cholesterols, PEG-derivatized cholesterol derivatives, PEG-derivatized vitamin A, PEG-derivatized vitamin E, lysozyme, random copolymers of vinylpyrrolidone and vinyl acetate, and the like.

Surfactants may be Ionic or nonionic. Ionic surfactants may be anionic, cationic, or zwitterionic. Anionic surfactants include the alkoyl isethionates, alkyl and alkyl ether sulfates and salts thereof, alkyl and alkyl ether phosphates and salts thereof, alkyl methyl taurates, and soaps such as for example alkali metal salts including sodium or potassium salts of long chain fatty acids. Non-limiting examples include chenodeoxycholic acid, 1-octanesulfonic acid sodium salt, sodium deoxycholate, glycodeoxycholic acid sodium salt, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium cholate hydrate, sodium iauryt sulfate (SLS) and sodium dodecyl sulfate (SDS).

Examples of amphoteric and zwitterionic surfactants include but are not limited to carboxy, sulfonate, sulfate, phosphate, or phosphonate compounds. Examples are alkylimino acetates and iminodialkanoates and aminoalkanoates, imidazolinium and ammonium derivatives, betaines, sultaines, hydroxysultaines, alkyl sarcosinates and alkanoyl sarcosinates, and the like.

Nonionic surfactants include polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tween™ products, e.g., Tween 20 and Tween 800 (ICI Specialty Chemicals)); poloxamers (e.g., Pluronic™ products F68 and F108Q, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic™ 908, also known as poioxamine 908, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N. J.)), and Tetronic™ 15080 (T-1508) (BASF Wyandotte Corporation).

Examples of useful cationic surfactants include, but are not limited to, polymers, biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryl pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate, lysozyme, long-chain polymers such as alginic acid, carrageenan (FMC Corp.), and POLYOX™ (Dow, Midland, Ml); cationic lipids, sulfonium, phosphonium, and quaternary ammonium compounds, such as stearyltrimethylammonium chloride, and benzyl-di (2-chloroethyl) ethylammonium bromide.

In embodiments the invention includes the use of PEG 400 (Lutrol™ E 400), propylene glycol, caprylocaproyl macrogol-8 glycerides (Labrasol™). Capryol™ 90, diethylene glycol monoethyl ether (Transcutol™), polyethylene glycol 660 12-hydroxystearate (Solutol™), lauroglycol, polyoxylglycerides such as linoleoyl macrogolglycerides (such as Labrafil™), stearoyl macrogolglycerides (Gelucire™); sodium lauryl sulphate, poloxamers, and polysoarbates as solubilizers.

Metaxalone is indicated for painful musculoskeletal disorders, which require rapid onset of action, and it is desirable that a portion of metaxalone in a dosage form is made available to give a prompt therapeutic effect, after administration.

In embodiments the invention includes low dose controlled release compositions of metaxalone comprising combinations of an immediate release fraction and a modified release fraction.

The pharmaceutical formulations of the present invention includes various solid dosage forms such as tablets or minitablets, granules, pellets, spheroids, microparticles, microspheres, pills, capsules, etc.

In embodiments the invention includes granule compositions or pellet compositions, which are suitable for delivering high doses of the drug.

For solid oral dosage forms, there are various physical parameters of metaxalone, as well as that of blends with excipients, impacting the process of the preparation of formulations. These parameters include moisture content (determined by techniques such as Karl Fischer ("KF") apparatus or an infrared moisture balance), bulk density and tapped density, compressibility index, Hausner ratio such as determined by USP density apparatus), flow property (such as determined by a Flowdex apparatus), etc.

In an embodiment the invention includes stable high dose pharmaceutical compositions comprising metaxalone.

In an embodiment the invention includes high dose pharmaceutical compositions of metaxalone, wherein moisture content of the composition is not more than about 8% w/w.

The compositions of the present invention comprise comparatively high percentages of drug, i.e., up to about 95% by weight of the total composition.

In embodiments the invention includes pharmaceutical compositions wherein concentrations of metaxalone are more than about 30% w/w of the total composition.

In an embodiment the invention includes the low dose gastro-retentive controlled release compositions comprising metaxalone.

In an embodiment the invention includes low dose mucoadhesive controlled release compositions comprising metaxalone.

Approaches to prolong the gastro-residence time include but are not limited to low density systems such as floating drug delivery systems, gas generating systems, hydrodynamically balanced systems, raft systems, etc., mucoadhesive systems; expandable systems such as sweilable systems, unfolded systems, etc., high density systems, and also co-administration with drugs or excipients that alter gastric retention.

Floating systems that can be used for the purposes of this invention include expandable components which produce a gas such as, for example, carbon dioxide or nitrogen, on contact with gastric juice, in particular under the action of acid. Examples of these used according to the invention are carbonates and hydrogen carbonates of the alkali metals and alkaline earth metals, the ammonium cations or sodium azide, or mixtures thereof.

The pharmaceutical formulations comprising metaxalone of the present invention also comprise inactive ingredients or excipients such as but not limited to one or more of diluents, binders, disintegrants, glidants, lubricants, antioxidants, solvents, film-forming agents and other adjuvants. Desirably, the agents are chemically and physically compatible with the metaxalone.

Various useful fillers or diluents include but are not limited to starches and its different grades such as Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starch (commercially available as National 78-1551 from Essex Grain Products), lactose and its different grades (e.g., Flowlac™ from Meggle Products and Pharmatose™ available from DMV), cellulose and derivatives thereof, such as Avicel™ PH 101, PH102, PH301, PH302 and PH-F20, and PH-112 etc, confectioners sugar, carmellose, sugar alcohols such as mannitol (Pearlitol™ SD200), sorbitol, and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders include but are not limited to hydroxypropylcelluloses (Klucel™ LF and Klucel EXF) hydroxypropyl methylcelluloses or hypromelloses (Methocel™), polyvinylpyrrolidones or povidones (PVP-K25, PVP-K29, PVP-K30, PVP-K90), Plasdone™ S 630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (e.g. Carbopol™), methylcelluloses, polymethacrylates, and starches.

Various useful disintegrants include but are not limited to carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylstarch sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di-sol™, FMC-Asahi Chemical Industry Co., Ltd.), crospovidones (commercially available as Kollidon™ CL manufactured by BASF (Germany), Polyplasdone™ XL, XI-10, and INF-10 [manufactured by ISP Inc. (USA), and low-substituted hydroxypropylcelluloses and its different grades such as LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.), sodium starch glycolate, alginic acid, ammonium calcium alginate, ammonium alginate, calcium alginate, colloidal silicon dioxide, and starches.

Glidants that are useful include colloidal silicone dioxide, talc and combinations thereof.
Useful tablet lubricants include but are not limited to magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and combinations thereof.

Various solvents that can be used in processing include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, and mixtures thereof.

Some examples of useful antioxidants are butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid or a salt thereof (e.g., a sodium salt, a calcium salt, a magnesium salt, a potassium salt, a basic amino acid salt, or a meglumine salt), sodium nitrite, sodium hydrogen sulfite, sodium sulfite, a salt of edetic acid (e.g. a sodium salt, a potassium salt, or a calcium salt), erithorbic acid, cysteine hydrochloride, citric acid, cysteine, potassium dichloroisocyanurate, sodium thioglycolate, thioglycerol, sodium formaldehyde sulfoxylate, sodium pyrosuffite, and 1,3-butylene glycol, propyl gallate, and a tocopherol or its derivative.

Other adjuvants may be included, such as coloring agents, sweetening agents, flavoring agents, acidifying agents, basifying agents.

The formulations of the present invention may be further coated. The coating may be a functional coating or nonfunctional coating.

The term "functional coating" relates to any type of coating that modifies the release of metaxalone from a dosage form. The rate-controlling polymers as discussed above contribute to the functional coating.

The nonfunctional coating relates to a coating which does not contribute to controlling the release of metaxalone from the composition.

Various useful film-forming agents include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as methyl celluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethyethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc., acidic cellulose derivatives such as cellulose acetate phthalates, cellulose acetate trimellitates, and methylhydroxypropylcellulose phthalates, polyvinyl acetate phthalates, etc.; insoluble cellulose derivatives such as ethylcellu loses and the like, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acids, polyvinyl alcohols, polyvinyl acetates, polyvinylpyrrolidones, polymethacrylates and derivatives thereof (Eudragit™), chitosan and derivatives thereof, shellac and derivatives thereof, and waxes and fat substances.

If desired, the films may contain additional adjuvants for a coating process such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, and the like.

In addition to the above coating ingredients, sometimes pre-formulated coating products will be used, such as Opadry™ (supplied by Colorcon). These products sold in dry form require only dispersing in a liquid before use.

The formulations of the present invention may be prepared using any processing techniques, such as direct compression, wet granulation, dry granulation, fluid bed granulation such as top spray granulation, bottom spray granulation, extrusion and spheronization, drug layering, etc.

The present invention further relates to processes for preparing high dose controlled release pharmaceutical compositions of metaxalone, wherein an embodiment of a process comprises:

1) Sifting drug and intragranular and extragranular excipients through a suitable sieve.

2) Dry mixing the sifted drug with intragranular excipients;

3) Optionally step 2) materials are blended with glidants and lubricants and subjected to compression. Or, optionally, the drug and excipients, except glidants and lubricants, are subjected to roll compaction, then the compacted material is milled through a sieve followed by blending and compression.

4) Dissolving or dispersing a binder in a suitable solvent and using it to granulate the step 2) material.

5) Optionally, the wet mass is extruded and subjected to spheronization to form spheroids.

6) Drying the wet granules or spheroids.

7) Sizing the dried granules or spheroids through a sieve.

8) Blending the dried granules or spheroids with sifted extragranular excipients.

9) Blending the step 8 blend with lubricant.

10) Compressing the final blend of step 9) into tablets with a compression machine or, alternatively, filling the final blend of step 9) into empty hard gelatin capsules.

Optionally,coating tablets using a coating solution or dispersion.

Alternatively the drug along with at least one excipient may be loaded onto inert cores, different portions of which may be further coated with polymers to form an immediate release fraction and a controlled release fraction.

Equipment suitable for processing the composition and formulations of the present invention include rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, extruders, spheronizers, mechanical sifters, blenders, roller compactors, compression machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multimills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like.

The formulations are typically packed in sachets, bottles, unit dose dispensers, containers and lids of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, and blisters or strips composed of aluminium or high-density polypropylene, polyvinyl chloride, polyvinylidene dichloride, or aluminum/aluminum blisters with a laminated desiccant system. The packages may also comprise various desiccants such as silica gel bags, molecular sieves, etc.

A sachet is a small disposable bag, often used to contain single-use quantities of drug. Usually sachets are used to deliver powder, pellet, or granule formulations of high dose drugs. Sachets should not be opened until ready for use.

In embodiments the invention includes packaging a metaxalone-containing formulation into sachets.

In embodiments the invention includes granule compositions, pellet compositions, or minitablets filled into sachets.

The pharmacokinetic parameters can be determined by administering the products individually to a number of subjects, and determining blood levels of a contained drug substance at intervals thereafter. Frequently used pharmacokinetic parameters include:
AUCo-t = Area under a plasma drug concentration versus time curve, from time zero (administration) to the last measurable concentration.

AUCo-- = Area under a plasma drug concentration versus time curve, from time zero (administration) to infinity.

Cmax = Maximum plasma drug concentration.

Tmax = Elapsed time from administration until the maximum measured plasma drug concentration.

Absolute bioavailability (F) is a measure of the bioavailability (estimated as the area under the curve, or AUC) of the active drug in systemic circulation following non-intravenous administration. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug

Relative bioavailability is a measure for the bioavailability (estimated as area under the curve, or AUC) of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. Relative bioavailability is calculated as:

[AUC]A * doseB + [AUC]B * doseA .

In embodiments the invention includes methods of using the compositions of the present invention, wherein a method comprises directly administering the contents of a sachet into the mouth, or dissolving/dispersing the contents into approximately a liquid such as water prior to administration.

Pharmaceutical formulations can be subjected to in vitro dissolution evaluations according to Test 711 "Dissolution," in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc, Rockville, Maryland, 2005 ("USP"), to determine the rate at which the drug is released from the dosage forms, and the content of the drug can be determined in solutions using methods such as high performance liquid chromatography (HPLC).

Certain specific aspects and embodiments of the invention are described in further detail by the examples below, which examples are provided solely for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES EXAMPLE 1: Pharmaceutical formulation comprising immediate release and controlled release fractions of metaxalone.

Evaporates during processing. Manufacturing process:
solution. 4) 5) 6)

1) Metaxalone and SLS together were sifted through a BSS # 60 mesh sieve and dry mixed for about 10 minutes.

2) MCC was sifted through BSS # 22 mesh sieve and added to step 1) materials and drug mix for additional 10 minutes.

3) HPMC 6 cps (part 1) and SLS (part 2) was dissolved in water to form binder

Binder solution of step 3) was added to step 2) to form a wet mass.
The wet mass was extruded followed by spheronization.

The spheroids were dried in a fluid bed dryer and sieved to separate the desired size fraction passing through a BSS #18 mesh sieve, but retained on a BSS #30 mesh sieve.

7) The spheroids of step 6) were divided into an immediate release (IR) fraction (about 20% by weight) and a controlled release (CR) fraction (about 80% by weight).

8) HPMC 6 cps (part 2) was dissolved in water.

9) The IR fraction of metaxalone was coated with polymer solution of step 8).

10) Ethylcellulose and HPMC 6 cps (part 3) were dissolved in a mixture of dichloromethane and methanol.

11) The CR fraction of spheroids was coated using the polymer solution of step 10).

12) IR spheroids equivalent to 600 mg of metaxalone and CR spheroids equivalent to 2600 mg of metaxalone were mixed together and filled into sachets.

Alternatively, the process may include a wet granulation technique, where step 2) materials are granulated using step 3) binder solution, in place of the steps 4) and 5) mixing, extrusion and spheronization.

The uncoated spheroids of step 6 were subjected to a dissolution testing using the USP procedure and the following conditions: 900 mL of 2% sodium lauryl sulphate in water, USP type 2 apparatus, and 10Q rpm stirring. The data are tabulated below.

EXAMPLE 2: Preparation of metaxalone spheroids.

Evaporates during processing. Manufacturing process:

1) Metaxalone and Avicel were sifted through a BSS #60 mesh sieve and mixed in a granulatorfor 10 minutes.

2) HMPC 6 cps and SLS were dissolved in water to form a binder solution.

3) Step 1) materials were granulated using binder from step 2).

4) The wet mass was extruded through an extruder using a 0.8mm screen.

5) The extrudates were spheronized with a spheronizer having a 13 mm plate.

6) The spheroids were dried in a rapid bed dryer at 60 °C until loss on drying was below 2 % w/w at 105 °C.

7) The dry spheroids were sieved to obtain a fraction passing through a BSS #12 mesh sieve, but retained on a BSS # 30 mesh sieve.

EXAMPLES 3-6: Preparation of metaxalone spheroids with Cremophor, Lutrol and Avicel 102.

@ Lutrol E 400 chemically is polyethylene glycols and supplied by BASF. # Cremophor RH 40 chemically is polyoxyl 40 hydrogenated castor oil and supplied by BASF.
** Avicel 102 supplied by FMC. t Evaporates during processing. Manufacturing process:

1) Metaxalone was sifted through a BSS #25 mesh sieve.

2) Cremophor RH 40 was melted at 40°C and mixed with Lutrol E 400 thoroughly. This was then homogeneously blended with step 1) in a granulator for about 10 minutes.

3) Avicel (or mannitol) was sifted through a BSS #24 mesh sieve, added to step 2) and mixed for about 10 minutes. For example 5, HPMC 6 cps (first quantity) was added to the mixture and mixed for about 10 minutes.

4) HPMC 6 cps (for example 5, the second quantity) was dissolved in water to form a binder solution and combined with step 3) mixture to form wet mass.

5) The wet mass was extruded and spheronized to produce spheroids and dried at 37°C until loss on drying was not more than 2% w/w at 105 °C.
The spheroids of step 5 were subjected to dissolution testing, using 900 mL of 2% sodium lauryl sulphate in water, USP type 2 apparatus, and 100 rpm stirring. The data are tabulated below.

EXAMPLE 7: Pharmaceutical formulation comprising IR and CR fractions of metaxalone, with solubilizers.

Evaporates during processing. Manufacturing process:

1) Sift metaxalone through a BSS #22 mesh sieve and place into a granulator.

2) Dissolve Gelucire in isopropyl alcohol and combine with Lutrol or Cremophor to get a homogenous mixture, then add propyl gallate.

3) Add the step 2) mixture to step 1) and thoroughly mix.

4) 10 minutes. 5) 6) 7) 8)
Sift Avicel through a BSS #22 mesh sieve then add to step 3). Mix for about

Dissolve HPMC 6 cps (part 1) and SLS in water to form a binder solution. Granulate step

4) materials using binder solution of step 5). Extrude the wet mass of step 6) followed by spheronization. Dry the spheroids in a dryer and sieve to obtain the fraction passing through a BSS #18 mesh sieve, but retained on a BSS #30 mesh sieve.

9) Divide the spheroids and coat according to a process similar to that of steps 7) through 11) of Example 1.

10) Combine IR and CR spheroids, in a manner similar to that of step 12) of Example 1.

EXAMPLE 8: Pharmaceutical formulation comprising IR and CR fractions of metaxalone.

$ Evaporates during processing. Manufacturing process:

1) Dissolve Gelucire 50/13 in tPA. To this add either PEG 6000 or sodium lauryl sulphate, then add propyl gallate with continuous stirring.

2) Add HPC to step 1) with stirring.

3) Sift metaxalone through a BSS #60 mesh sieve and add to step 2) to form a uniform dispersion.

4) Coat the drug dispersion of step 3) onto Celphere or non-pareil seeds.

5) Divide the drug-loaded pellets of step 4) into an IR fraction and a CR fraction.

6) Dissolve HPMC 6 cps (part 1) in water to form a polymer solution.

7) Coat the IR pellets using polymer solution of step 6).

8) Dissolve ethylcellulose and HPMC 6 cps (part 2) in a mixture of dichloromethane and methanol.

9) Coat the CR pellets with polymer solution of step 8).

10) Combine IR pellets from step 7) equivalent to 600 mg of metaxalone with CR pellets from step 8) equivalent to 2600 mg of metaxalone, and fill into a sachet.

EXAMPLES 9-13: Pharmaceutical formulations comprising IR and CR fractions of metaxalone.

Evaporates during processing. Manufacturing process;

1. Metaxalone is sifted through a BSS #30 mesh sieve and transferred to a granulator.

2. Polyoxyl 40 hydrogenated castor oil and PEG 400 are mixed at 40°C, added to the step 1 mixture, and blended for about 5 minutes.

3. Mannitol, MCC, Prosolv SMCC 50, HPMC 6 cps (part 1) and Polyplasdone XL-
10 are sifted through a BSS #30 mesh sieve into a granulator and mixed for about 10 minutes.

4. HPMC 6 cps (part 2) is dissolved in water to form a binder solution and the mixture of step 3 is granulated using the binder solution.

5. The wet mass of step 4 is extruded, followed by spheronization, the spheroids are dried in a fluid bed dryer, and the desired size fraction passing through a BSS #14 mesh sieve, but retained on a BSS #24 mesh sieve, is separated.

6. The spheroids of step 5 (Examples 10 and 11) are divided into an IR portion equivalent to 400 mg of metaxalone and an ER portion equivalent to 2000 mg of metaxalone, respectively.

7. Ethyl cellulose and HPMC 6 cps (part 3) are dissolved in a mixture of dichloromethane and methanol to form a controlled release coating.

8. The ER portion of spheroids from step 6 is coated with coating solution from step

7.

9. The IR portion from step 6 and ER portion from step 8 are filled into sachets. For Example 9, IR spheroids are filed into sachets,
The spheroids and commercial SKELAXIN tablets are subjected to dissolution testing, using 900 mL of 2% sodium lauryl sulphate in water, USP type 2 apparatus, and 100 rpm stirring. The data are tabulated below.

Hours

Cumulative % of Drug Dissolved

Spheroids from Example 9 and SKELAXIN tablets are subjected to dissolution testing in 900 ml of 0.5% sodium lauryl sulphate in water, USP type 2 apparatus, and 100 rpm stirring. The data are tabulated below.

Hours Cumulative % of Drug Dissolved

SKELAXIN Example 9
15 17 72
30 41 82
45 59 92
60 73 94
90 86 100
120 95 -

Spheroids of Example 9 (T) and a commercial reference product (R) SKELAXIN were subjected to human bioequivalence study in 18 subjects in a 3-way crossover study, under fed conditions. The pharmacokinetic data are tabulated below.

Bioavailability is determined in female dogs, with a single dose oral pharmacokinetic study using capsules filled with spheroids prepared in Example 10 (3 dogs) and Example 11 (4 dogs), respectively. The spheroids from sachets are equally filled into four "Size 000" elongated capsules for ease of administration.
The following parameters are calculated:

AUCo-t = Area under plasma drug concentration versus time curve, from time zero to the last measurable concentration (16 hours).
Cmax = Maximum plasma drug concentration.

Tmax = Time after administration to the maximum measured plasma drug concentration.
F = Absolute bioavailability.
Relative bioavailability is calculated with respect to an oral metaxalone solution.

A pharmacokinetic profile for a formulation prepared according to Example 10, in female beagle dogs, is shown in Fig. 1, where the plasma concentration of metaxalone is plotted against time.

A pharmacokinetic profile for a formulation prepared according to Example 11, in female beagle dogs, is similarly shown in Fig. 2.

The formulation of Example 12 was filled into aluminum sachets (12A) and HDPE containers (12B), subjected to storage at 40°C and 75% RH for 3 months, and analyzed for drug assay (expressed as percentage of label content), impurities (expressed as percentage of label drug content), and drug dissolution. [USP II, 100 rpm, 900 mL, water + 2.0% SLS]. The data are tabulated below.

ND: Not detected.
*lmp A chemically is (3-(3,5-dimethyl phenoxy)-1,2-propane diot)
EXAMPLES 14-15: Metaxalone nanosuspensions.

Manufacturing process:

1) HPMC, 6 cps is dissolved in about half of the water.

2) In the remaining quantity of water metaxalone, Lutrol, Cremophor and sodium lauryl sulfate (for Example 13) are added and homogenized for about 1 hour in a homogenizer.

3) HPMC solution from step 1) is added to the step 2) mixture and further homogenized for about 30 minutes (for Example 12) or 1 hour (for Example 13).

4) The dispersion of step 3) is passed through a BSS # 100 mesh sieve and then circulated through a bead mill (manufactured and supplied by Netzch) for about 5 hours (for Example 14) or about 5 or 7 hours (for Example 15), with feed pump (Atex pump head) speed of 50 rpm and rotation rate of 2100 rpm, using 0.2 mm ceramic beads.
The particle size distribution is analyzed for the dispersion from step 4 using a Malvern Zetasizer, and the results are tabulated below.

Bioavailability is determined in a single dose oral pharmacokinetic study using metaxalone nanosuspension prepared in Example 15 (7 hours) administered to 3 female dogs, and compared with similarly administered commercial product SKELAXIN tablets and IR spheroids prepared according to Example 9. The nanosuspension is administered through oral gavages.

The following parameters are calculated:
AUCo-t = area under the plasma drug concentration vs. time curve, from time zero to the last measurable concentration (16 hours).

Cmax = maximum plasma drug concentration.
Tmax = time after administration to the maximum measured plasma drug concentration.

Fig. 3 shows the comparative pharmacokinetic profiles of IR spheroids prepared according to Example 9 (square data points), metaxalone nanosuspension prepared according to Example 15 (triangle data points), and SKELAXIN® 800 mg tablets (diamond data points). The metaxalone plasma concentration is plotted against time.
EXAMPLE 16: Pharmaceutical formulations comprising IR and CR fractions of metaxalone.

% Evaporates during processing.
Manufacturing process: similar to that of Example 10.

CLAIMS:

1. A pharmaceutical formulation comprising high dose of metaxalone and at least one pharmaceutical^ acceptable polymer.

2. The pharmaceutical formulation according to claim 1, wherein high dose of metaxalone is about 800 mg to about 4000 mg.

3. The pharmaceutical formulation according to claim 1, wherein a weight ratio of metaxalone in an immediate release fraction to metaxalone in an extended release fraction is in the range of about 1:1 to about 1:10.

4. The pharmaceutical formulation according to claim 1 wherein the formulation is having dissolution, using 900 mL of 2% sodium lauryl sulphate in water, USP type II apparatus, and 100 rpm stirring as

i) about 15 to 40% of contained metaxalone is released within about 1 hour; ii) about 30 to 60% of contained metaxalone is released within about 4 hours; iii) about 40 to 80% of contained metaxalone is released within about 8 hours; and

iv) more than about 70% of contained metaxalone is released within about 16 hours.

5. The pharmaceutical formulation according to claim 1, wherein particle size distributions of a metaxalone ingredient comprise D10 in the range of about 0.1 to about 25 um, D50 in the range of about 1 to about 50 um, and D90 in the range of about 10 to about 75 um.

6. The pharmaceutical formulation according to claim 1, comprising at least one metaxalone solubilizer which is a polyoxyl 40 hydrogenated castor oil, polyethylene glycols, povidone, cellulose derivative, macrogol glycerides, poloxamers and polysorbates.

7. The pharmaceutical formulation according to claim 1, comprising immediate release spheroids containing 800 mg of metaxalone having a metaxalone dissolution in 900 mL of 0.5% sodium lauryl sulphate in water, using USP type II apparatus and 100 rpm stirring in first 15 minutes is at least 2 times that of SKELAXIN 800 mg tablets.

8. The pharmaceutical formulation according to claim 1, in which metaxalone comprises more than about 30% and up to about 95 % by weight.

9. The pharmaceutical formulation according to any of claims 1-7, containing 800 mg of metaxalone and producing Cmax values about 5023 ng/mL to about 7850 ng/mL, AUC0-t values about 24232 nghour/mL to about 37865 nghour/mL, and AUC0-- values about 24725 nghour/mL to about 33635 nghour/mL in plasma after oral administration of a single dose to healthy humans underfed conditions.

10. A process for preparing a pharmaceutical formulation, comprising: a) combining metaxalone with at least one solubilizer; b) granulating the mixture with a binder solution; c) extruding the granulated mass followed by spheronization; d) optionally coating formed spheroids with a separating layer; and e) coating the spheroids of c) or d) with an extended release layer.