WO2006018814A2

WO2006018814A2 - Oral liquid suspensions of metaxalone

Info

Publication number: WO2006018814A2
Application number: PCT/IB2005/052705
Authority: WO
Inventors: Ajay Kumar Singla; Malluru Subba Rao; Tausif Monif
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-08-16
Filing date: 2005-08-16
Publication date: 2006-02-23
Also published as: WO2006018814A3

Abstract

The present invention relates to liquid oral suspension dosage forms of metaxalone and processes for their preparation.

Description

Description ORAL LIQUID SUSPENSIONS OF METAXALONE

[1] Technical Field of the Invention

[2] The present invention relates to liquid oral suspension dosage forms of metaxalone and processes for their preparation.

[3] Background of the Invention

[4] Metaxalone, 5-[(3,5-dimethylphenoxy) methyl] -2-oxazolidinone, is a muscle relaxant indicated as an 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®, and is available in two strengths, 400 mg and 800 mg. The recommended dose of metaxalone for adults and children over 12 years of age is two 400 mg (or one 800 mg) tablets, taken three to four times daily.

[5] 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 two hours. The onset of action is within one hour and duration of action is about four to six hours. It has a plasma half-life of two to three hours, thus requiring multiple dosing. Repeated administration of a very high dosage drug effectuates patient inconvenience.

[6] 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 solid dosage forms, such as tablets or capsules, their rate of dissolution is rather slow. As a result, absorption from the gastrointestinal tract into systemic circulation is also slow. However, if such drugs are to be administered in oral dosage forms and would be used for clinical indications, where a rapid onset of therapeutic activity is desirable, the slow rate of dissolution and absorption may put limitations on their therapeutic utility.

[7] Furthermore, the marketed tablets of metaxalone are very large, making them difficult to swallow. Due to this size, children and adults who are not able to swallow tablets cannot use this drug. Liquid pharmaceutical compositions offer many advantages over solid compositions. Liquid dosage forms generally have better bioavailability, are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Further, liquids provide a rapid onset of pharma¬ cological action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract.

[8] 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.

[9] One of the simplest liquid oral dosage forms is the oral solution. However, this form is unsuitable in cases where the active agent possesses a bitter taste, since this taste is apparent in all the solvents, and cannot be adequately masked even with the addition of one or more flavoring agents and sweeteners. It is difficult to prepare water insoluble pharmaceutical actives in storage stable ready-to-use solution dosage forms. Water insoluble ingredients present in water-based solutions tend to separate or settle out and even shaking before administration does not ensure a consistently accurate dosage regimen.

[10] U.S. Patents 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 maximal drug concentration (C max

) and extent of absorption (AUC ) of metaxalone as compared to administration last without food.

[11] WO 04/019937 discloses a pharmaceutical composition that includes metaxalone and pharmaceutically acceptable excipients, characterized in that the pharmaceutical composition has enhanced oral bioavailability. The metaxalone used may be a micronized, a salt form of metaxalone, a high-energy crystalline form of metaxalone or an amorphous metaxalone.

[12] In general, the properties of a liquid oral suspension are greatly influenced by the particle size of the suspended active substance. To achieve an 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 pharmacokinetic parameters of the liquid suspension dosage form are independent of even particle size limitations.

[13] 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 the fed or fasted state of a subject ingesting the dosage form.

[14] Summary of the Invention

[15] In one general aspect there is provided a liquid oral suspension dosage form which includes a therapeutically effective amount of metaxalone, at least one thickening agent, at least one wetting agent, at least one sweetening agent and one or more phar- maceutically acceptable liquid carriers.

[16] Embodiments of the liquid oral suspension dosage form include one or more of the following features. For example, the metaxalone may be milled to a D particle size of less than about 2000 nm and a D particle size of less than about 600 nm. The

50 ^r metaxalone particles may be milled in the presence of surface modifiers.

[17] The surface modifier may be one or more of polymers, natural products and surface-active agents. The polymers may be one or more of polyvinyl pyrrolidone, hy- droxypropyl methylcellulose, polyethylene glycols, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, hydroxy propyl cellulose and polyvinyl alcohol. The natural products may be one or more of dextran, xanthan, chitosan, pectin, dextrin, maltodextrin, starch, alginates and pullulan. The surface-active agents may be ben- zalkonium 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. The ratio of metaxalone to surface modifier ranges from about 1:2 to about 1:50.

[18] The thickening agents may be xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxy propylcellulose or mixtures thereof. The thickening agents are present at a concentration range of from about 0.1% to about 5% w/w of the dosage form.

[19] The wetting agents may be one or more of sodium lauryl sulphate, sorbitan esters of fatty acids, 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 dode- cylsulphate, dioctyl sodium sulphosuccinate, ethoxylated mono- and diglycerides, sucrose fatty acid esters, fatty acid salts, ethoxylated triglycerides , polyoxyethylated hydrogenated castor oil, and sterols. The wetting agent may be present at a con¬ centration range of from about 0.001% to about 2% w/w of the dosage form.

[20] The sweetening agents may be sugars, cyclamates, aspartame, potassium acesulfame, sodium saccharine, neohesperidine, dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.

[21] The liquid carriers may be purified water, liquid glucose, glycerol, and aqueous solutions of sugar alcohols. The aqueous solutions of sugar alcohols may be sorbitol, mannitol and xylitol and mixtures thereof. The liquid carrier may be present at a con¬ centration of from about 10% to about 30% w/w of the dosage form. [22] The dosage form may further include one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may be sol- ubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.

[23] In another general aspect there is provided a process for the preparation of a liquid oral suspension dosage form of metaxalone. The process includes dispersing metaxalone particles in a portion of the carrier comprising at least one wetting agent; dispersing at least one thickening or suspending agent in another portion of the carrier; mixing the two dispersions and adding sweeteners and one or more conventional phar¬ maceutically acceptable excipients; and adjusting to the required volume with the carrier.

[24] In another general aspect there is provided a method of treating discomforts associated with acute, painful musculoskeletal conditions in a patient in need thereof. The method includes administering 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 one or more pharmaceutically acceptable liquid carriers.

[25] Embodiments of the method may include one or more of the following features. For example, the dosage form may further include a non steroidal anti-inflammatory drug.

[26] Detailed Description of the Invention

[27] The present invention provides a liquid suspension dosage form for oral admin¬ istration that includes 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.

[28] It should be understood that herein "suspension" and "dispersion" are used inter¬ changeably to mean a system in which solid particles are dispersed in a liquid.

[29] As used herein the terms "micronized" and "milled" are interchangeable to mean a process of reducing the size of the particles.

[30] 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®.

[31] Suitable surface modifiers include one or more of polymers, natural products and surfactants. For example, the surface modifiers may be polyvinylpyrrolidone, hy- droxypropyl methylcellulose, polyethylene glycols, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, hydroxypropyl cellulose, methylcellulose, and polyvinyl alcohol.

[32] Suitable natural products may include dextran, xanthan, chitosan, pectin, dextrin, maltodextrin, starch, alginates, and pullulan. [33] The mechanical means applied to reduce the particle size of the drug substance may be carried out in a dispersion mill. Suitable dispersion mills include ball mills, attrition mills, vibratory mills and media mills, such as bead mill and high-pressure ho- mogenizers. A media mill is preferred due to the relatively shorter milling time required to provide the intended result.

[34] The relative amount of metaxalone and surface modifier will vary with respect to the type of surface modifier. For example, the metaxalone and surface modifier may be present in a ratio ranging from about 1:2 to about 1:50.

[35] There are many considerations in the development and preparation of liquid oral suspensions. 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; and 3) the suspension should be easily and uniformly pourable.

[36] 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 one or more suitable thickening or suspending agents.

[37] Suitable thickening agents function as suspending agents and include hydrocolloids known for such purpose, for example xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth and starch. Alternatively, synthetic suspending agents may be used. For example, carbopols, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxy propylcellulose or mixtures thereof may be used. The thickening agents of the present invention prevent rapid settling and caking of the suspension over time. The thickening agents may be present in a concentration ranging from about 0.1% to about 5% w/w of the dosage form.

[38] 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 it 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.

[39] Suitable wetting agents may include one or more of nonionic, cationic, anionic, and zwitterionic surfactants. The wetting agents which may be employed include sodium lauryl sulphate, sorbitan esters of fatty acids, such as sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate, and 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 hy- drogenated castor oil (40 and 60), polyoxyethylated vegetable oils), sterols (cholesterol and wool wax alcohols). The wetting agent(s) may be present at a concentration of about 0.001% to about 2% w/w of the dosage form.

[40] Suitable sweetening agents or sweeteners may include sugars, cyclamates, aspartame, potassium acesulfame, sodium saccharine, neohesperidine, dihy- drochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.

[41] Suitable pharmaceutically acceptable liquid carriers may include purified water, liquid glucose, glycerol, aqueous solutions of sugar alcohols, such as sorbitol, mannitol and xylitol, and mixtures thereof.

[42] In one embodiment, a mixture of sorbitol solution and purified water is used as the pharmaceutically acceptable liquid carrier. The 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. The sorbitol solution is present at a concentration from about 10% to about 30% w/w of the dosage form.

[43] The liquid oral suspension dosage form of metaxalone may additionally include one or more conventional pharmaceutically acceptable excipients. Suitable pharma¬ ceutically acceptable excipients include one or more solubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.

[44] Suitable solubilizers include 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 methyl- cellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols; 2-pyrrolidone, 2-piperidone, caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone and polyvinylpyrrolidone. Solubilizers may be present in the dosage form at a concentration of about 0.5% to about 1.5% w/w of the dosage form.

[45] 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.

[46] 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 include 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. For example, sodium benzoate may be used. Suitable opacifiers include pharmaceutically acceptable metal oxides, for example, titanium dioxide. Suitable flavoring agents include those that are approved by the 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.

[47] The following examples are intended to illustrate the invention and not be construed as limiting the scope of the invention in any way.

[48] EXAMPLE 1: Preparation of an oral suspension of metaxalone (milled) [49] Table l(a): Preparation of milled metaxalone particles [50]

[51] Process: [52] 1) Polyvinyl pyrrolidone and sodium lauryl sulphate were dissolved in purified water.

[53] 2) Metaxalone was added to the solution of Step 1 and dispersed. [54] 3) The dispersion was Dyno milled. [55] Milling conditions: [56]

[57] An oral suspension was prepared utilizing the milled metaxalone. The formula of the suspension is given in Table l(b).

[58] Table l(b): Preparation of an oral suspension of metaxalone (milled) [59]

[60] Procedure: [61] 1) Polyethylene glycol-35 castor oil was dissolved in warm purified water and the milled metaxalone (as per the details given in Table l(a)) was dispersed in it.

[62] 2) Xanthan gum was dispersed in sorbitol solution and added to the dispersion of step 1. [63] 3) Sodium benzoate and aspartame were dissolved in a part of purified water and added to the dispersion of step 2.

[64] 4) Simethicone emulsion and the flavour were dispersed in the resulting dispersion. [65] 5) The total weight was made up with purified water and the suspension obtained was stirred.

[66] EXAMPLE 2 [67] Table 2: Preparation of an oral suspension of metaxalone (unmilled)

[69] Procedure: [70] 1) Polyethylene glycol-35 castor oil, polyvinylpyrrolidone and polysorbate 80 were dissolved in warm purified water and metaxalone was dispersed in it.

[71] 2) Xanthan gum was dispersed in sorbitol solution and added to the dispersion of step 1. [72] 3) Sodium benzoate and aspartame were dissolved in a part of purified water and added to the dispersion of step 2.

[73] 4) Simethicone emulsion and the flavour were dispersed in the resulting dispersion. [74] 5) The total weight was made up with purified water and the suspension obtained was stirred.

[75] 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.

[76] Table 3: Pharmacokinetic parameters [77]

[78] Test Drug (A): Metaxalone Oral Suspension prepared according to Example 1 given above (containing milled metaxalone).

[79] Test Drug (B): Metaxalone Oral Suspension prepared according to Example 2 given above (containing unmilled metaxalone). [80] Reference Drug (R): Commercially available metaxalone tablets (SKELAXIN® 400 mg). [81] 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.

[82] Table 4: Represents the time taken to achieve maximum concentration (t ). [83]

[84] 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.

[85] Table 5: Dissolution data using USP Apparatus II, 50 rpm, Medium: 1% sodium lauryl sulphate in water, 900 mL [86]

[87] While the present invention has been described in terms of its specific em¬ bodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

[I] 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 one or more pharmaceutically acceptable liquid carriers.

[2] The dosage form according to claim 1, wherein the metaxalone is milled to a D 90 particle size of less than about 2000 nm and a D particle size of less than about

600 nm. [3] The dosage form according to claim 2, wherein the metaxalone particles are milled in the presence of surface modifiers. [4] The dosage form according to claim 3, wherein the surface modifier comprises one or more of polymers, natural products and surface-active agents. [5] The dosage form according to claim 4, wherein the polymers comprise one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, polyethylene glycols, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, hydroxy propyl cellulose and polyvinyl alcohol. [6] The dosage form according to claim 4, wherein the natural products comprise one or more of dextran, xanthan, chitosan, pectin, dextrin, maltodextrin, starch, alginates and pullulan. [7] The dosage form according to claim 4, wherein the surface-active agents comprise 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. [8] The dosage form according to claim 3, wherein the ratio of metaxalone to surface modifier ranges from about 1:2 to about 1:50. [9] The dosage form according to claim 1 , wherein the thickening agents comprise xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxy propylcellulose or mixtures thereof. [10] The dosage form according to claim 1, wherein the thickening agents are present at a concentration range of from about 0.1% to about 5% w/w of the dosage form.

[I I] The dosage form according to claim 1, wherein the wetting agents comprise one or more sodium lauryl sulphate, sorbitan esters of fatty acids, 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, and sterols.

[12] The dosage form according to claim 1, wherein the wetting agent is present at a concentration range of from about 0.001% to about 2% w/w of the dosage form.

[13] The dosage form according to claim 1, wherein the sweetening agents comprise sugars, cyclamates, aspartame, potassium acesulfame, sodium saccharine, neo- hesperidine, dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.

[14] The dosage form according to claim 1, wherein the liquid carriers comprise purified water, liquid glucose, glycerol, and aqueous solutions of sugar alcohols.

[15] The dosage form according to claim 14, wherein the aqueous solutions of sugar alcohols comprise sorbitol, mannitol and xylitol and mixtures thereof.

[16] The dosage form according to claim 14, wherein the liquid carrier is present at a concentration of from about 10% to about 30% w/w of the dosage form.

[17] The dosage form according to claim 1, further comprising one or more pharma¬ ceutically acceptable excipients.

[18] The dosage form according to claim 17, wherein the one or more pharma¬ ceutically acceptable excipients comprise solubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.

[19] A process for the preparation of a liquid oral suspension dosage form of metaxalone, the process comprising: dispersing metaxalone particles in a portion of the carrier comprising at least one wetting agent; dispersing at least one thickening or suspending agent in another portion of the carrier; mixing the two dispersions and adding sweeteners and one or more con¬ ventional pharmaceutically acceptable excipients; and adjusting to the required volume with the carrier.

[20] A method of treating discomforts associated with acute, painful musculoskeletal conditions in a patient in need thereof, the method comprising administering 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 one or more pharmaceutically acceptable liquid carriers. [21] The method according to claim 20, wherein the dosage form further comprises a non steroidal anti-inflammatory drug.