The present invention relates to liquid oral suspension dosage form for metaxalone; wherein the suspension provides a significantly enhanced bioavailability compared to marketed oral conventional tablets of metaxalone even when each is administered under fasting conditions. It also relates to a process for preparation of stable liquid suspension system, suitable for oral administration of metaxalone, which achieves a palatable dosage form for both geriatric and especially pediatric applications.
Background of the Invention
Metaxalone, 5-[(3,5-dimethylphenoxy) methyl]-2-oxazolidinone, is a muscle relaxant, indicated as adjunct to rest, physical therapy and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. It is marketed under the brand name "Skelaxin", in two strengths, 400mg and 800mg. The recommended dose of metaxalone for adults and children over 12 years of age is two 400 mg (or one 800mg) tablets, three to four times daily.
According to American Hospital Formulary Service (AHFS) Drug Information, following oral administration of a single 800 mg dosage of metaxalone, mean peak plasma concentrations are attained in 2 hours. The onset of action is within 1 hour and duration of action is about 4 to 6 hours. It has a plasma half-life of 2-3 hours, thus requiring multiple dosing. Repeated administration of a very high dosage drug effectuates patient inconvenience.
Painful, musculoskeletal conditions require prompt relief; therefore, compositions exhibiting a quick onset of action are desirable. When poorly soluble, hydrophobic drug substances, such as metaxalone, are administered in the form of solid dosage forms such as tablets or capsules, their rate of dissolution is rather slow. As a result, their absorption from the gastrointestinal tract into systemic circulation is also slow. However, if such drugs are to be administered in oral dosage forms and to be used for clinical indications where a rapid onset of therapeutic activity is desirable, the slow rate of dissolution and slow rate of absorption can put great limitations on their therapeutic utility.
-Furthermore, the marketed tablets of metaxalone are very large, making them difficult to swallow. Moreover, due to its size, children or adults who are not able to swallow tablets cannot use this drug. However, the present inventors realize that a liquid formulation would be useful for children and adults who cannot swallow large size tablets. Moreover, to date, no one has made a aqueous formulation of metaxalone.
Liquid dosage forms, generally have better bioavailability. Liquid pharmaceutical compositions offer many advantages over solid compositions. These are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Further, liquids provide a rapid onset of pharmacological action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract.
Liquid dosage forms may be administered in the form of solutions, suspensions, elixirs and syrups. For bitter tasting active agents, such as metaxalone, the liquid preparation should have a pleasant flavor in order to ensure patient compliance. In addition, the liquid preparation should preferably not contain any ethanol, since the possibility of ethanol having a harmful effect even in physiologically acceptable, non-toxic concentrations cannot be ruled out completely, particularly in children. Moreover, when ethanol is used, there is the risk of abuse or relapse in alcohol-dependent patients. The suitability of the formulation for diabetic patients should also be taken into account. Therefore, elixirs and syrups are generally not the preferred dosage forms.
One of the simplest liquid oral dosage forms is the oral solution. However, these are unsuitable in cases where the active agent possesses a bitter taste, since this taste is apparent in all the solvents, which can be used for the oral administration of solutions and cannot be adequately masked even by the addition of flavoring agents and sweeteners. It is difficult to prepare water insoluble pharmaceutical actives in storage stable ready-to-use solution dosage form. Water insoluble ingredients present in water-based solutions tend to separate or settle out and even shaking before administration does not insure a consistently accurate dosage regimen. Therefore, a suspension dosage form is particularly suitable for administering an insoluble, bitter-tasting active agent such as metaxalone.
Due to poor solubility, metaxalone exhibits poor bioavailability. Moreover, it also shows food effect.
US Patents No. 6,407,128 and 6,683,102 assigned to Elan Pharmaceuticals, disclose method 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 maximal drug concentration (Cmax) and extent of absorption (AUClast) of metaxalone as compared to administration without food.
International Application, published as WO 04019937, filed by Sun Pharmaceuticals, describes pharmaceutical composition comprising metaxalone and pharmaceutically acceptable excipients, characterized in that the pharmaceutical composition has enhanced oral bioavailability. The metaxalone that is used is a pharmaceutically acceptable solubility improved form, i.e. micronized metaxalone, salt form of metaxalone, high-energy crystalline form of metaxalone or amorphous metaxalone.
The inventors have presently developed a liquid oral suspension dosage form that achieves rapid onset of action and a pharmacokinetic profile that is not affected by fed or fasted state of a subject ingesting the dosage form.
In general, the properties of a liquid oral suspension are greatly influenced by the particle size of the suspended active substance. To achieve enhanced bioavailability, a small particle size ensures the fastest possible dissolution of the active substance in gastrointestinal tract. However, in the present invention, it is observed that the properties and the pharmacokinetic parameters of the liquid suspension dosage form are independent of even particle size limitations.
Summary of the Invention
The present invention is directed to a stable liquid suspension system, suitable for oral administration of metaxalone, which achieves a palatable dosage form for both geriatric and pediatric applications.
In another aspect, a liquid oral suspension dosage form for metaxalone is provided; wherein the suspension provides a significantly enhanced bioavailability compared to marketed oral conventional tablets of metaxalone even when each is administered under fasting conditions.
In another aspect, a liquid oral suspension dosage form for metaxalone is provided; wherein the suspension provides a quicker onset of action compared to marketed oral conventional tablets of metaxalone even when each is administered under fasting conditions.
In yet another aspect, a liquid oral suspension dosage form for metaxalone is provided; wherein the suspension exhibits comparable pharmacokinetics with micronized or milled as well as unmicronized or unmilled metaxalone.
It is one of the aspects to provide a liquid suspension dosage form for oral administration to a subject in need thereof which comprises a therapeutically effective amount of metaxalone in association with at least one thickening or suspending agent, at least one wetting agent, at least one sweetening agent and a pharmaceutically acceptable liquid carrier.
According to one of the embodiments, the liquid oral suspension dosage form of metaxalone additionally comprises conventional pharmaceutically acceptable excipients selected from amongst solubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.
According to another embodiment, the metaxalone used in the present suspension dosage form may be milled or unmilled. Micronization or milling is carried out for metaxalone alone or in the presence of suitable surface modifiers adsorbed onto the surface of metaxalone particles. When micronized, metaxalone particles have a D90 particle size of less than about 2000 nm and D50 particle size of less than about 600 nm.
According to another embodiment, the liquid suspension dosage form maintains acceptable physical, chemical, and microbial properties for at least 12 months, and
'particularly at least 24 months in ordinary pharmaceutical packaging under conditions encountered during normal distribution and storage of the aqueous product.
It is yet another aspect to provide a process for preparing micronized or milled metaxalone particles, the process comprising wet milling of metaxalone in presence of surface modifier.
It is yet another aspect to provide a process for preparing liquid oral suspension dosage form of metaxalone, the process comprising the steps of:
(a) dispersing milled or unmilled metaxalone particles in a portion of the carrier comprising at least one wetting agent,
(b) separately dispersing at least one thickening or suspending agent in another portion of the carrier,
(c) mixing the two dispersions and adding sweeteners and conventional pharmaceutically acceptable excipients;
(d) adjusting to the required volume with the carrier.
However, the sequence of mixing the components of the dosage form is not important.
It is yet another aspect to provide a method of treating discomforts associated with acute, painful musculoskeletal conditions, by administering to a person in need thereof, a liquid oral suspension dosage form of metaxalone.
The liquid oral suspension dosage form may further include a non steroidal antiinflammatory drug wherein said non-steroidal anti-inflammatory drug comprises a propionic acid derivative, acetic acid derivative, fenamic acid derivative, biphenylcarboxylic acid derivative or an oxicam or pharmaceutically acceptable salts thereof.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
It should be understood that herein "suspension" and "dispersion" are used interchangeably to mean a system in which solid particles are dispersed in a liquid.
As used herein the terms 'micronized' and 'milled' are interchangeable to mean a process of reducing the size of the particles.
As used herein, the term 'about' will be understood as upto plus or minus 10% of the particular value.
Metaxalone is described at Monograph no. 5838 of the Merck Index (Eleventh Addition, Merck & Co., 1989). It is also known by the drug code, AHR-438; and the drug product containing it is marketed as Skelaxin™ (a trademark of Elan Pharmaceuticals, Inc.).
Preparation of metaxalone is described in Lunsford et al., J. Am. Chem. Soc. 82, 1166 (1960) and U.S. Pat. No. 3,062,827 assigned to A. H. Robins, which is incorporated herein in its entirety by reference.
Suitable surface modifiers may be selected from amongst polymers, natural products and surfactants.
Representative examples of polymers as surface modifiers include polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyethylene glycols, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, hydroxypropyl cellulose, methylcellulose and polyvinyl alcohol.
Suitable natural products may be selected from amongst dextran, xanthan, chitosan, pectin, dextrin, maltodextrin, starch, alginates and pullulan.
The mechanical means applied to reduce the particle size of the drug substance may be carried out conveniently in a dispersion mill. Suitable dispersion mills include ball mills,
attrition mills, vibratory mills and media mills such as bead mill and high-pressure homogenizers. A media mill is preferred due to the relatively shorter milling time required to provide the intended result.
The relative amount of metaxalone and surface modifier will vary with respect to the type of surface modifier. Particularly, metaxalone and surface modifier are present in a ratio ranging from 1:2 to 1:50.
There are many considerations in the development and preparation of a liquid oral suspension. In addition to the therapeutic efficacy and chemical stability, the following features should exist in the suspensions:
1. The particles in the suspension should settle down slowly and should be readily redispersed upon gentle shaking.
2. The size of the particles in the suspension should remain constant throughout long periods of undisturbed standing.
3. The suspension should be easily and uniformly pourable.
The sedimentation of the solids suspended or dispersed cannot be prevented but it can be delayed by increasing the viscosity of the dispersing medium. The viscosity is increased by the addition of suitable thickening or suspending agents.
Suitable thickening agents function as suspending agents and are selected from amongst hydrocolloids known for such purpose, examples of which include xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth and starch. Alternatively, synthetic suspending agents may be used such as carbopols, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxy propylcellulose or mixtures thereof. The thickening agents of the present invention prevent rapid settling and caking of the suspension over time. Thickening agents are present in a concentration ranging from about 0.1 to 5% w/w of the dosage form.
Since metaxalone is insoluble in aqueous medium, suitable wetting agents are added to increase its dispersion throughout the medium. Wetting agents are surfactants which are capable of lowering the contact angle between a liquid and the solid surface over which is
spreads. This helps remove air at the solid surface and replaces it with the liquid. They hinder caking of the particles in suspensions during storage and facilitate rapid dispersion of the solid throughout the aqueous phase.
Suitable wetting agents may be selected from amongst nonionic, cationic, anionic, and zwitterionic surfactants. The wetting agents which can be employed are sodium lauryl sulphate, sorbiatn esters of fatty acids selected from sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate (available under the trade name polysorbate 20, 40, 60, 80, 65, 61, 85 and 21), ethylene oxide-propylene oxide block copolymers (available under the trade name poloxamers), lecithins, oleic acid and oleic acid salts, propylene glycol monostearate and monolaurate, glycerol monostearate and monooleate, fatty alcohol-polyethylene glycol ethers (for example PEG 10 cetyl ether, PEG 20 oleyl ether etc.), fatty acid-polyethylene glycol esters (for example PEG 40 monostearate; PEG 100 monostearate), sodium dodecylsulphate (SDS), dioctyl sodium sulphosuccinate (DOSS), ethoxylated mono- and diglycerides, sucrose fatty acid esters, fatty acid salts, ethoxylated triglycerides (polyoxyethylated castor oil (40), polyoxyethylated hydrogenated castor oil (40 and 60), polyoxyethylated vegetable oils), sterols (cholesterol and wool wax alcohols). Wetting agent(s) are included in a concentration of about 0.001% to about 2% w/w of the dosage form.
Suitable sweetening agents or sweeteners, which can be included, may be selected from the group consisting of especially sugars, cyclamates, aspartame, potassium acesulfame, sodium saccharine, neohesperidine, dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.
Pharmaceutically acceptable liquid carriers include those well known in the art, including purified water, liquid glucose, glycerol, aqueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol, and mixtures thereof.
In one of the embodiments, a mixture of sorbitol solution and purified water is used as the pharmaceutically acceptable liquid carrier. Sorbitol Solution is used to aid in forming and maintaining the particle size and shape of the solids in the suspension. It provides a smooth texture and sweet taste to the suspension. In addition, it acts as a cryoprotectant,
protecting the suspension from freezing. Sorbitol solution constitutes from about 10% to about 30% w/w of the dosage form.
The liquid oral suspension dosage form of metaxalone may additionally comprise conventional pharmaceutically acceptable excipients selected from amongst solubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.
Suitable solubilizers may be selected from amongst alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols; 2-pyrrolidone, 2-piperidone, caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone and polyvinylpyrrolidone. Solubilizers are included in the dosage form at a concentration of about 0.5% to about 1.5% w/w of the dosage form.
The suspension dosage form may also contain an antifoaming agent, such as any commercially available agent useful for such purpose including, simethicone emulsion. The antifoaming agent is present in sufficient concentration to allow control of the foam, which forms on dilution with water. In the present invention the antifoaming agent is present at concentration of from about 0.2% by weight to about 1% w/w.
The buffer systems suitable for the suspension dosage form of the present invention are those, which maintain the pH of the liquid suspension in the range of about 4 to about 6. Suitable buffers may be selected from citric acid or its corresponding salts and acetic acid or its salts. Suitable preservatives include sodium benzoate, methyl and propyl parabens, sodium citrate and benzalkonium chloride as well as other pharmaceutical acceptable preservatives. Particularly sodium benzoate is used. The opacifiers suitable for the present invention include pharmaceutically acceptable metal oxides, especially titanium dioxide. Suitable flavoring agents are those that are approved by FDA for use in sweetened pharmaceuticals, foods, candies, beverages and the like; these materials impart flavors such as grape, cherry, citrus, peach, strawberry, bubble gum, peppermint and wintergreen.
"The following examples describe compositions of the present invention containing metaxalone, but they are not to be interpreted as limiting the scope of the claims.
EXAMPLE 1: Preparation of an oral suspension of metaxalone (milled) Table 1(a): Preparation of milled metaxalone particles
(Table Removed)
Process:
1. Polyvinyl pyrrolidone and sodium lauryl sulphate were dissolved in purified water.
2. Metaxalone was added to the solution of Step 1 and dispersed.
3. The dispersion was Dyno milled.
Milling conditions:

(Table Removed)
‘An oral suspension was prepared utilizing the milled metaxalone. The formula of the suspension is given in Table 1 (b).
Table 1 (b): Preparation of an oral suspension of metaxalone (milled)

(Table Removed)
Procedure
1. Polyethylene glycol-35 castor oil was dissolved in warm purified water and the milled metaxalone (as per the details given in Table 1 (a)) was dispersed in it.
2. Xanthan gum was dispersed in sorbitol solution and added to the dispersion of step 1.
3. Sodium benzoate and aspartame were dissolved in a part of purified water and added to the dispersion of step 2.
4. Simethicone emulsion and the flavour were dispersed in the resulting dispersion.
5. The total weight was made up with purified water and the suspension obtained was stirred.
EXAMPLE 2
Table 2: Preparation of an oral suspension of metaxalone (unmilled)

(Table Removed)
Procedure
1. Polyethylene glycol-35 castor oil, polyvinylpyrrolidone and polysorbate 80 were dissolved in warm purified water and metaxalone was dispersed in it.
2. Xanthan gum was dispersed in sorbitol solution and added to the dispersion of step 1.
3. Sodium benzoate and aspartame were dissolved in a part of purified water and added to the dispersion of step 2.
4. Simethicone emulsion and the flavour were dispersed in the resulting dispersion.
5. The total weight was made up with purified water and the suspension obtained was stirred.
The metaxalone oral suspensions of the above Examples 1 and 2 were compared with the commercially available tablets (Skelaxin tablets; King Pharmaceuticals, 400 mg) in a bioavailability study under fasting conditions. The results of the study are presented in Table 3.
Test Drug (A): Metaxalone Oral Suspension prepared according to the Example 1 given
above (containing milled metaxalone).
Test Drug (B): Metaxalone Oral Suspension prepared according to the Example 2 given
above (containing unmilled metaxalone).
Reference Drug (R): Commercially available metaxalone tablets (Skelaxin 400 mg)
Table 3: Pharmacokinetic parameters

(Table Removed)
As is evident from the results, there is a substantial enhancement in the all the three parameters describing the rate and extent of bioavailability for suspensions containing milled as well as unmilled metaxalone when compared with the oral conventional marketed tablets even under fasting conditions.
Table 4 represents the time taken to achieve maximum concentration ((Table Removed)max).

(Table Removed)
Table 5 provides in vitro dissolution data for metaxalone suspensions prepared according to Examples 1 and 2 and for Skelaxin tablets carried out at 50 rpm in USP Apparatus II using 900 ml water containing 1 % sodium lauryl sulphate as the medium.
Table 5: Dissolution data using USP Apparatus II, 50rpm, Medium: 1% sodium lauryl sulphate in water, 900ml
(Table Removed)
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention.

WE CLAIM:
1. A liquid oral suspension dosage form comprising a therapeutically effective amount of metaxalone, at least one thickening agent, at least one wetting agent, at least one sweetening agent and a pharmaceutically acceptable liquid carrier.
2. The liquid oral suspension dosage form according to claim 1 wherein metaxalone is milled.
3. The liquid oral suspension dosage form according to claim 2 wherein the milled metaxalone particles have a D90 particle size of less than about 2000 nm and D50 particle size of less than about 600 nm.
4. The liquid oral suspension dosage form according to claim 2 wherein the metaxalone particles are milled in the presence of surface modifiers.
5. The liquid oral suspension dosage form according to claim 4 wherein surface modifier is selected from one or more of polymers, natural products and surface-active agents.
6. The liquid oral suspension dosage form according to claim 5 wherein polymers include one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, polyethylene glycols, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, hydroxy propyl cellulose and polyvinyl alcohol.
7. The liquid oral suspension dosage form according to claim 5 wherein natural products include one or more of dextran, xanthan, chitosan, pectin, dextrin, maltodextrin, starch, alginates and pullulan.
8. The liquid oral suspension dosage form according to claim 5 wherein the surface-active agents may be selected from amongst benzalkonium chloride, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, poloxamers, poloxamines, polyethylene glycol, vitamin E and polyethylene glycol-phospholipid.
9. The liquid oral suspension dosage form according to claim 4 wherein the ratio of metaxalone to surface modifier ranges from 1:2 to 1:50.
10. The liquid oral suspension dosage form according to claim 1 wherein thickening agents are selected from amongst xanthan gum, acacia, guar gum, locust bean
gum, gum tragacanth, starch, carbopols, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxy propylcellulose or mixtures thereof.
11. The liquid oral suspension dosage form according to claim 1 wherein the concentration of thickening agents ranges from about 0.1 to about 5% w/w of the dosage form.
12. The liquid oral suspension dosage form according to claim 1 wherein wetting agents are selected from amongst sodium lauryl sulphate, sorbiatn esters of fatty acids selected from sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, ethylene oxide-propylene oxide block copolymers, lecithins, oleic acid and oleic acid salts, propylene glycol monostearate and monolaurate, glycerol monostearate and monooleate, fatty alcohol-polyethylene glycol ethers, fatty acid-polyethylene glycol esters, sodium dodecylsulphate, dioctyl sodium sulphosuccinate, ethoxylated mono-and diglycerides, sucrose fatty acid esters, fatty acid salts, ethoxylated triglycerides , polyoxyethylated hydrogenated castor oil, sterols.
13. The liquid oral suspension dosage form according to claim 1 wherein the concentration of wetting agents ranges from about 0.001 to about 2% w/w of the dosage form.
14. The liquid oral suspension dosage form according to claim 1 wherein the sweetening agents are selected from the group consisting of especially sugars, cyclamates, aspartame, potassium acesulfame, sodium saccharine, neohesperidine, dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.
15.The liquid oral suspension dosage form according to claim 1 wherein the liquid carriers are selected from amongst purified water, liquid glucose, glycerol, aqueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol and mixtures thereof.
16. The liquid oral suspension dosage form according to claim 15 wherein the liquid carrier is a mixture of sorbitol solution and purified water.
17. The liquid oral suspension dosage form according to claim 16 wherein sorbitol solution constitutes from about 10% to about 30% w/w of the dosage form.
18. The liquid oral suspension dosage form according to claim 1 additionally comprising conventional pharmaceutically acceptable excipients selected from amongst
solubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.
19. The liquid oral suspension dosage form according to claim 18 wherein solubilizers are selected from amongst alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols; 2-pyrrolidone, 2-piperidone, caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone and polyvinylpyrrolidone.
20. The liquid oral suspension dosage form according to claim 18 wherein solubilizers are included in the dosage form at a concentration of about 0.5% to about 1.5% w/w of the dosage form.
21. The liquid oral suspension dosage form according to claim 18 wherein the antifoaming agent is simethicone emulsion.
22. The liquid oral suspension dosage form according to claim 18 wherein antifoaming agents constitute from about 0.2% to about 1.0% w/w of the dosage form.
23. The liquid oral suspension dosage form according to claim 18 wherein buffers are selected from citric acid or its corresponding salts and acetic acid or its salts.
24. The liquid oral suspension dosage form according to claim 18 wherein preservatives are selected from amongst sodium benzoate, methyl and propyl parabens, sodium citrate and benzalkonium chloride.
25. The liquid oral suspension dosage form according to claim 18 wherein the opacifier is titanium dioxide.
26. The liquid oral suspension dosage form according to claim 18 wherein flavoring agents are selected from amongst grape, cherry, citrus, peach, strawberry, bubble gum, peppermint and wintergreen flavours.
27. The liquid oral suspension dosage form according to claim 1; wherein the suspension provides a significantly enhanced bioavailability compared to marketed oral conventional tablets of metaxalone even when each is administered under fasting conditions.
28. The liquid oral suspension dosage form according to claim 1; wherein the suspension exhibits comparable pharmacokinetics with micronized or milled as well as unmicronized or unmilled metaxalone.
29. A process for preparing liquid oral suspension dosage form of metaxalone, the process comprising the steps of:

a) dispersing metaxalone particles in a portion of the carrier comprising at least one wetting agent,
b) separately dispersing at least one thickening or suspending agent in another portion of the carrier,
c) mixing the two dispersions and adding sweeteners and conventional pharmaceutically acceptable excipients;
d) adjusting to the required volume with the carrier.
30.The process according to claim 29 wherein metaxalone is milled.
31. The process according to claim 30 wherein the milled metaxalone particles have a D90 particle size of less than about 2000 nm and D50 particle size of less than about 600 nm.
32. The process according to claim 30 wherein the metaxalone particles are milled in the presence of surface modifiers.
33. The process according to claim 32 wherein surface modifier is selected from one or more of polymers, natural products and surface-active agents.
34. The process according to claim 33 wherein polymers include one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, polyethylene glycols, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, hydroxy propyl cellulose and polyvinyl alcohol.
35. The process according to claim 33 wherein natural products include one or more of dextran, xanthan, chitosan, pectin, dextrin, maltodextrin, starch, alginates and pullulan.
36. The process according to claim 33 wherein the surface-active agents may be selected from amongst benzalkonium chloride, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, poloxamers, poloxamines, polyethylene glycol, vitamin E and polyethylene glycol-phospholipid.
37. The process according to claim 32 wherein the ratio of metaxalone to surface modifier ranges from 1:2 to 1:50.
38. The process according to claim 29 wherein thickening agents are selected from amongst xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxy propylcellulose or mixtures thereof.
39. The process according to claim 29 wherein the concentration of thickening agents ranges from about 0.1 to about 5% w/w of the dosage form.
40. The process according to claim 29 wherein wetting agents are selected from amongst sodium lauryl sulphate, sorbiatn esters of fatty acids selected from sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, ethylene oxide-propylene oxide block copolymers, lecithins, oleic acid and oleic acid salts, propylene glycol monostearate and monolaurate, glycerol monostearate and monooleate, fatty alcohol-polyethylene glycol ethers, fatty acid-polyethylene glycol esters, sodium dodecylsulphate, dioctyl sodium sulphosuccinate, ethoxylated mono- and diglycerides, sucrose fatty acid esters, fatty acid salts, ethoxylated triglycerides , polyoxyethylated hydrogenated castor oil, sterols.
41. The process according to claim 29 wherein the concentration of wetting agents ranges from about 0.001 to about 2% w/w of the dosage form.
42. The process according to claim 29 wherein the sweetening agents are selected from the group consisting of especially sugars, cyclamates, aspartame, potassium acesulfame, sodium saccharine, neohesperidine, dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.
43. The process according to claim 29 wherein the liquid carriers are selected from amongst purified water, liquid glucose, glycerol, aqueous solutions of sugar alcohols such as sorbitol, mannitol and xylitol and mixtures thereof.
44. The process according to claim 43 wherein the liquid carrier is a mixture of sorbitol solution and purified water.
45. The process according to claim 44 wherein sorbitol solution constitutes from about 10% to about 30% w/w of the dosage form.
46. The process according to claim 29 wherein conventional pharmaceutically acceptable excipients are selected from amongst solubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.
47. The process according to claim 46 wherein solubilizers are selected from amongst alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols; 2-pyrrolidone, 2-piperidone, caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone and polyvinylpyrrolidone.
48. The process according to claim 46 wherein solubilizers are included in the dosage form at a concentration of about 0.5% to about 1.5% w/w of the dosage form.
49. The process according to claim 46 wherein the antifoaming agent is simethicone emulsion.
50. The process according to claim 46 wherein antifoaming agents constitute from about 0.2% to about 1.0% w/w of the dosage form.
51. The process according to claim 46 wherein buffers are selected from citric acid or its corresponding salts and acetic acid or its salts.
52. The process according to claim 46 wherein preservatives are selected from amongst sodium benzoate, methyl and propyl parabens, sodium citrate and benzalkonium chloride.
53. The process according to claim 46 wherein the opacifier is titanium dioxide.
54. The process according to claim 46 wherein flavoring agents are selected from amongst grape, cherry, citrus, peach, strawberry, bubble gum, peppermint and wintergreen flavours.
55. A method of treating discomforts associated with acute, painful musculoskeletal conditions, comprising administering to a person in need thereof, a liquid oral suspension dosage form of metaxalone.
56. The method according to claim 55 wherein the dosage form may further include a non steroidal anti-inflammatory drug wherein said non-steroidal anti-inflammatory drug comprises a propionic acid derivative, acetic acid derivative, fenamic acid
derivative, biphenylcarboxylic acid derivative or an oxicam or pharmaceutically acceptable salts thereof.
57. A liquid oral suspension dosage form comprising metaxalone; wherein the suspension provides a significantly enhanced bioavailability compared to marketed oral conventional tablets of metaxalone even when each is administered under fasting conditions.
58. A liquid oral suspension dosage form comprising metaxalone; wherein the suspension exhibits comparable pharmacokinetics with micronized or milled as well as unmicronized or unmilled metaxalone.