Low-dose metaxalone formulations

Abstract

Oral dosage forms of metaxalone with improved bioavailability in the fed and fasted states include dosage forms that utilize lower doses based on such improved bioavailability.

Description

[Technical Field]

[0001] The present invention relates to an oral dosage form of metaxalone that has improved bioavailability in the fed and fasted states, with a concomitant reduced food effect and reduced dosage associated with such improved bioavailability. [Background technology]

[0002] Metaxalone (Skelaxin®) is known chemically as 5-[(3,5-dimethylphenoxy)methyl]-2-oxazolidinone and has the following chemical structure:

[0003] [ka]

[0004] Skelaxin is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions. The mechanism of action of this drug has not been clearly identified but may be related to its sedative properties. Metaxalone does not directly relax tense skeletal muscles in humans. Commercially available tablets contain metaxalone 400 and 800 mg with inert compression tableting excipients.

[0005] The preparation of metaxalone is described in Lunsford et al., J. Am. Chem. Soc. 82, 1166 (1960), and U.S. Pat. No. 3,062,827 to Lunsford (November 6, 1962, assigned to AHRobins), the entire contents of which are incorporated herein by reference. The '827 patent discloses the compound and related species as anticonvulsant and anticonvulsive agents. However, these activities have not been supported by clinical experience.

[0006] The FDA-approved prescribing information for Skelaxin® suggests that the drug is significantly affected by food. Specifically, the prescribing information suggests that for the 800 mg dose, the presence of a high-fat meal at the time of drug administration, compared with the fasted state, significantly reduces C max increased by 193.6% and AUC(AUC 0-t , AUC ∞ ) by 146.4% and 142.2%, respectively. max ) was delayed (4.9 hours vs. 3.0 hours) and the terminal half-life was reduced (4.2 hours vs. 8.0 hours). This food effect generally limits drug administration to the fasting state (taking the drug on an empty stomach), greatly compromising the drug's usefulness. Summary of the Invention

[0007] The inventors unexpectedly discovered that the food effect associated with prior art metaxalone formulations can be avoided using 0.5% sodium lauryl sulfate ("SLS") and / or formulations that meet specified dissolution criteria in simulated fasted intestinal fluid ("FaSSIF") (pH 6.5). Thus, in a first principal embodiment, the present invention provides a solid oral pharmaceutical formulation comprising metaxalone and one or more pharmaceutically acceptable excipients, wherein (a) a 640 mg tablet or capsule of the formulation releases at least 50%, 55%, 60%, 65%, or 70% by weight of metaxalone within 60 minutes when tested in 900 mL of 0.5% SLS in water in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C, and / or (b) a 100 mg tablet or capsule of the formulation releases at least 65%, 70%, 75%, or 80% by weight of metaxalone within 300 minutes when tested in 900 mL of simulated fasted intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C.

[0008] This food effect associated with prior art formulations of metaxalone can also be overcome using formulations that meet the specified dissolution criteria in acetate buffer solution at pH 4.5 and phosphate buffer solution at pH 6.0. Thus, in a second principal embodiment, the present invention provides a solid oral pharmaceutical formulation comprising metaxalone and one or more pharmaceutically acceptable excipients, wherein (a) a 640 mg tablet or capsule of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C in 900 mL of pH 4.5 acetate buffer solution, and / or (b) a 640 mg tablet or capsule of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C in 900 mL of pH 6.0 phosphate buffer solution.

[0009] The present invention further provides formulations that achieve the dissolution criteria of the first and second principal embodiments, thereby overcoming the food effect of prior art metaxalone formulations. Accordingly, in a third principal embodiment, the present invention provides a solid oral pharmaceutical formulation selected from tablets and capsules comprising 40-80% by weight micronized particles of metaxalone and 20-60% by weight non-micronized particles of metaxalone, wherein (a) when tested according to the Malvern Method, 90% of the micronized particles of metaxalone are smaller than 500, 350, 200, 100, 75, or 50 microns, and (b) when tested by the Sieving Method, less than 10%, 5%, or 2% of the non-micronized particles are retained on a #30 sieve and at least 25%, 35%, or 45% of the non-micronized particles of metaxalone are retained on a #120 sieve.

[0010] In a fourth principal embodiment, the present invention provides a solid oral pharmaceutical formulation selected from a tablet and a capsule comprising: (a) 640 parts by weight of metaxalone, and (b) 10 to 30 parts by weight of propylene glycol alginate.

[0011] In a fifth main embodiment, the present invention provides a method for treating musculoskeletal pain, comprising administering 640 mg of metaxalone in a formulation of any of the main embodiments or subembodiments of this invention to a patient in a fasted or fed state, preferably a fasted state, in need thereof.

[0012] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

[0013] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and, together with the description, serve to explain the principles of the invention. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is a graphical depiction of the release rates of metaxalone from prior art Skelaxin® 800 mg tablets (diamonds) and 640 mg metaxalone tablets (squares) (prepared according to the present invention in sodium lauryl sulfate solution as described in Example 5). DETAILED DESCRIPTION OF THE INVENTION

[0015] Definitions and Use of Terms Where the singular forms "a," "an," and "the" or similar terms are used herein, these are considered to include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes mixtures of two or more such excipients, and the like. The word "or" or similar terms, when used herein, means any one member of a particular list and also includes any combination of members of that list.

[0016] The terms "about" or "approximately (ca.)," as used herein, account for differences in product strength and bioavailability due to variability accepted in the pharmaceutical industry and inherent in pharmaceuticals, such as manufacturing variations and time-induced product degradation. The terms allow for any variation that may be assessed in pharmaceutical practice such that the product is considered to be pharmaceutically equivalent or bioequivalent to the listed strength of the claimed product, or both as the context requires. It is understood that all numerical values ​​expressed in this document may be preceded by the term "about."

[0017] As used in this specification and the claims that follow, the word "comprise" and variations of that word, such as "comprising" and "comprises," mean "including, but not limited to," and are not intended to exclude, for example, other additives, components, integers, or steps. Where an element is described as comprising a plurality of components, steps, or conditions, it is understood that the element can also be described as including any combination of such a plurality, or as "consisting of" or "consisting essentially of" a plurality or combination of components, steps, or conditions.

[0018] When a range is given by specifying the lower end of the range separately from the upper end of the range, or by specifying a specific numerical value, it is understood that additional ranges may be defined by selectively combining any of the mathematically possible lower end variables, upper end variables, and specific numerical values. In a similar manner, when a range is defined as extending from one endpoint to another, it is understood that the range also encompasses the span in between and excludes the two endpoints.

[0019] As used herein, "therapeutically effective amount" refers to an amount sufficient to induce a desired biological response.The therapeutically effective amount or dose depends on the age, sex and weight of the patient and the patient's current medical condition.Those skilled in the art can determine the appropriate dose according to these and other factors in addition to the present disclosure.

[0020] "Pharmaceutically acceptable" means useful for preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise unsuitable, and includes those that are acceptable for pharmaceutical use in humans or animals. "Pharmaceutically acceptable salts" means salts that are pharmaceutically acceptable, as defined above, and that possess the desired pharmacological activity.

[0021] Where a dosage of a drug or a pharmaceutically acceptable salt thereof is described herein, it is understood that the dosage is based on the weight of the free base and excludes any hydrates or solvates thereof, unless the description states that the dosage is based on the weight of the salt, hydrate, or solvate.

[0022] Throughout this patent application, whenever an analysis is prescribed by a method prescribed in the United States Pharmacopeia ("USP"), it will be understood that the analysis will be performed in accordance with the USP Volume in effect on January 1, 2019. It will also be understood that a test need not be performed, but that if performed, the test will produce the claimed results. In a similar manner, any term not otherwise defined herein may be defined by reference to the USP Volume in effect on January 1, 2019.

[0023] The term fasted state simulated intestinal fluid or "FaSSIF" refers to the following solution at pH 6.5 as set forth in Table II by Klein S. The AAPS Journal, Vol. 12, No. 3, September 2010. Sodium taurocholate 3mM Lecithin 0.75mM NaH2P044.438g NaCl 6.186g Add NaOH to pH 6.5 Add deionized water to make up to 1L Osmolality (mOsmol / kg) approx. 270 Buffer capacity (mEq / pH / L) approx. 12 Surface tension (mN / m) 54

[0024] The sieve method refers to the method for particle size analysis described in the American Society for Testing and Materials (ASTM) Standard C136 (effective January 1, 2019). In this method, a representative, weighed sample is poured onto the top sieve with the largest mesh size. Each lower sieve in the column has smaller mesh sizes than the sieve above it. At the bottom is a round dish called a receiver. The column is typically placed in a mechanical shaker, such as a sonic sifter available from Endecotts (London, UK). See the Endecotts website at https: / / www.endecotts.com / products / sieve-shakers / sonic-sifter / product-specifications / . The shaker typically vibrates the column for a set period of time. After shaking is complete, the material on each sieve is weighed. The mass of the sample on each sieve is then divided by the total mass to obtain the percentage retained on each sieve. The average particle size on each sieve is then analyzed to obtain a cut-off point or specific size range that is then captured on the mesh.

[0025] Main embodiment The present invention is described herein in terms of a main embodiment and sub-embodiments. It is understood that each of the sub-embodiments can modify any of the main embodiments, provided that such modifications are not logically contradictory or expressly denied herein. It is further understood that the main embodiments can be combined in any manner, and that the sub-embodiments can be combined in any manner to further modify any of the main embodiments, provided that such combinations are not logically contradictory or expressly denied herein.

[0026] In a first principal embodiment, the present invention provides a solid oral pharmaceutical formulation comprising metaxalone and one or more pharmaceutically acceptable excipients, wherein (a) a 640 mg tablet or capsule of the formulation releases at least 50%, 55%, 60%, 65%, or 70% by weight of metaxalone within 60 minutes when tested in 900 mL of 0.5% SLS in water in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C, and / or (b) a 100 mg tablet or capsule of the formulation releases at least 65%, 70%, 75%, or 80% by weight of metaxalone within 300 minutes when tested in 900 mL of simulated fasted intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C.

[0027] In a second principal embodiment, the present invention provides a solid oral pharmaceutical formulation comprising metaxalone and one or more pharmaceutically acceptable excipients, wherein (a) a 640 mg tablet or capsule of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C in 900 mL of pH 4.5 acetate buffer solution, and / or (b) a 640 mg tablet or capsule of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C in 900 mL of pH 6.0 phosphate buffer solution.

[0028] In a third principal embodiment, the present invention provides a solid oral pharmaceutical formulation selected from tablets and capsules comprising 40-80% by weight micronized particles of metaxalone and 20-60% by weight non-micronized particles of metaxalone, wherein (a) 90% of the micronized particles of metaxalone are smaller than 500, 350, 200, 100, 75, or 50 microns when tested according to the Malvern Method, and (b) at least 20%, 25%, 30%, or 35% of the non-micronized particles of metaxalone are retained on a #120 sieve when tested by the Sieving Method.

[0029] In a fourth principal embodiment, the present invention provides a solid oral pharmaceutical formulation selected from a tablet and a capsule, comprising: (a) 640 parts by weight of metaxalone; and (b) 10 to 30 parts by weight of propylene glycol alginate.

[0030] In a fifth main embodiment, the present invention provides a method for treating musculoskeletal pain, comprising administering 640 mg of metaxalone in a formulation of any of the main embodiments or subembodiments of this invention to a patient in a fasted or fed state in need thereof.

[0031] Subembodiments The present invention can be further defined in terms of various subembodiments, each of which can modify the main embodiment alone or in any combination.

[0032] In various subembodiments of the invention, a 640 mg tablet or capsule of the formulation can release at least 50%, 55%, 60%, 65%, or 70% by weight of metaxalone within 60 minutes when tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C.

[0033] In a particularly preferred subembodiment, a 640 mg tablet or capsule of the formulation releases at least 60% by weight of metaxalone within 60 minutes when tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C.

[0034] In other subembodiments of the invention, when tested in 900 mL of simulated fasting intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C, a 100 mg tablet or capsule of the formulation releases at least 65%, 70%, 75%, or 80% by weight of metaxalone within 300 minutes.

[0035] In particularly preferred subembodiments, a 100 mg tablet or capsule of the formulation releases at least 75% by weight of metaxalone within 300 minutes when tested in 900 mL of simulated fasting intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C.

[0036] In another subembodiment, a 640 mg tablet or capsule of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C in 900 mL of pH 4.5 acetate buffer solution.

[0037] In a particularly preferred subembodiment, a 640 mg tablet or capsule of the formulation releases 65% or less of the metaxalone in 90 minutes when tested in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C in 900 mL of pH 4.5 acetate buffer solution.

[0038] In yet another subembodiment, a 640 mg tablet or capsule of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C in 900 mL of pH 6.0 phosphate buffer solution.

[0039] In a particularly preferred subembodiment, a 640 mg tablet or capsule of the formulation releases 65% or less of the metaxalone in 90 minutes when tested in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C in 900 mL of pH 6.0 phosphate buffer solution.

[0040] The formulations of the present invention can also be defined in terms of metaxalone particle size. In one subembodiment, the formulation comprises 40-80% by weight micronized particles of metaxalone and 20-60% by weight non-micronized particles of metaxalone. In one particular subembodiment, the formulation comprises 30-50% or 35-45% by weight micronized particles of metaxalone and 50-70% or 55-65% by weight non-micronized particles of metaxalone.

[0041] In one subembodiment, when the formulation is characterized based on metaxalone particle size, at least 50%, 70%, or 90% of the micronized particles of metaxalone are smaller than 200, 100, or 75 microns when tested according to the Malvern method (i.e., laser diffraction). Alternatively or additionally, at least 30%, 40%, or 50% of the micronized particles are less than 50, 30, or 20 microns when tested according to the Malvern method.

[0042] In another subembodiment, when tested by the Sieving Method, no more than 10%, 5%, or 2% of the non-micronized particles are retained on a #30 sieve, and at least 15%, 25%, 35%, or 45% of the non-micronized particles of metaxalone are retained on a #120 sieve. In a preferred subembodiment, additionally, when tested by the Sieving Method, at least 10% or 20% of the non-micronized particles are retained on a #325 sieve.

[0043] In yet further embodiments, the formulations of the invention are defined based on the ingredients used to make the formulation. Thus, in one subembodiment, the formulation of the invention comprises 640 parts by weight of metaxalone and 10-30 parts by weight or 15-25 parts by weight of propylene glycol alginate.

[0044] In a further subembodiment of the formulation containing propylene glycol alginate, the formulation comprises 20 to 35 parts by weight or 24 to 31 parts by weight of lactose monohydrate, 10 to 30 parts by weight or 15 to 25 parts by weight of alginic acid, 40 to 60 parts by weight or 45 to 55 parts by weight of povidone, and 2 to 8 parts by weight or 4 to 6 parts by weight of a lubricant, the preferred lubricant being magnesium stearate. [Example]

[0045] In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be expected. The following examples are presented so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed herein were made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.

[0046] [Example 1] Representative preparations Table 1 describes a representative batch formulation for a 640 mg tablet of the present invention:

[0047] [Table 1]

[0048] [Example 2] Representative metaxalone particle size Tables 2a and 2b list representative particle sizes for the micronized and non-micronized metaxalone particles used in the formulations of Table 1.

[0049] [Table 2a]

[0050] [Table 2b]

[0051] [Example 3] Typical manufacturing method This example contains detailed information describing the manner in which metaxalone tablets 640 mg were manufactured using the formulations and metaxalone described in Tables 1 and 2. Granulation Solution: Povidone was dissolved by slowly adding it to purified water while mixing using a mixer at the required speed. Premix: Micronized metaxalone, metaxalone, FD&C Yellow #6, propylene glycol alginate, and alginic acid were mixed at an appropriate head speed. Wet Granulation: To the above premix blend, the granulating solution was added while mixing at an appropriate head speed. Drying: The wet granules were dried in an oven to achieve the desired moisture content. Milling: Upon completion of the drying process, the dried granules were milled using a commuting mill. Final Blending: Magnesium stearate was added and the blend was milled and lubricated using a suitable blender. Compression: The final blend was compressed into tablets using a rotary tablet press.

[0052] [Example 4] Dissolution test results / intestinal fluid simulating fasting state Tables 4a and 4b set forth the dissolution test results for 640 mg and 800 mg Skelaxin® tablets produced by the method of Example 3 (unless otherwise indicated).

[0053] [Table 4a]

[0054] [Table 4b]

[0055] [Example 5] Dissolution test results / SLS and pH buffer Tables 5a and 5b and FIG. 1 set forth additional dissolution test results for 640 mg and 800 mg Skelaxin® tablets produced according to the method of Example 3.

[0056] [Table 5a]

[0057] [Table 5b]

[0058] [Example 6] Bioequivalence study results A randomized, single-dose, quadruple, open-label, crossover, fasted- and fed-state study comparing 640 mg metaxalone tablets produced by the method of Example 3 with the listed reference drug, Skelaxin® tablets 800 mg, was conducted in 47 healthy adult volunteers (29 men, 18 women). Data from the 47 subjects who completed the fasted- and fed-state study were used to calculate pharmacokinetic results using SAS. The 90% confidence intervals for the test-to-reference area and peak concentration ratios of the geometric means were within the bioequivalence interval of 0.80 to 1.25. The 640 mg tablets were demonstrated to be bioequivalent to Skelaxin® tablets 800 mg in the fasted and fed states.

[0059] The test results are presented in Tables 6a and 6b.

[0060] [Table 6a]

[0061] [Table 6b]

[0062] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims. The inventions described in the original claims of this application are set forth below. [1] A solid oral pharmaceutical formulation comprising metaxalone and one or more pharmaceutically acceptable excipients, a. When tested in 900 mL of 0.5% SLS in water in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C, a 640 mg tablet or capsule of said formulation releases at least 50%, 55%, 60%, 65%, or 70% by weight of metaxalone within 60 minutes; and / or b. When tested in 900 mL of simulated fasting intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C, a 100 mg tablet or capsule of the formulation releases at least 65%, 70%, 75%, or 80% by weight of metaxalone within 300 minutes. Solid oral pharmaceutical formulations. [2] The solid oral pharmaceutical formulation of [1], wherein a 640 mg tablet or capsule of the formulation releases at least 50%, 55%, 60%, 65%, or 70% by weight of metaxalone within 60 minutes when tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C. [3] The solid oral pharmaceutical formulation of [1], wherein a 100 mg tablet or capsule of the formulation releases at least 65%, 70%, 75%, or 80% by weight of metaxalone within 300 minutes when tested in 900 mL of intestinal fluid simulating fasted conditions in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C. [4] a. A 640 mg tablet or capsule of said formulation releases at least 60% by weight of metaxalone within 60 minutes when tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C; b. When tested in 900 mL of simulated fasting intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C, a 100 mg tablet or capsule of said formulation releases at least 75% by weight of metaxalone within 300 minutes. [1] A solid oral pharmaceutical formulation according to [1]. [5] The solid oral pharmaceutical formulation of [1], wherein a 640 mg tablet or capsule of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C in 900 mL of acetate buffer solution at pH 4.5. [6] The solid oral pharmaceutical formulation of [1], wherein a 640 mg tablet or capsule of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in 900 mL of pH 6.0 phosphate buffer solution in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C. [7] comprising 40-80% by weight micronized particles of metaxalone and 20-60% by weight non-micronized particles of metaxalone; a. 90% of the micronized particles of said metaxalone are smaller than 200 microns when tested according to the Malvern Method; b. when tested by sieving method, at least 35% of the non-micronized particles of said metaxalone are retained on a #120 sieve; [1] A solid oral pharmaceutical formulation according to [1]. [8] a. 640 parts by weight of metaxalone, and b. 10 to 30 parts by weight of propylene glycol alginate The solid oral pharmaceutical formulation according to [1], comprising: [9] A solid oral pharmaceutical formulation selected from tablets and capsules comprising 40-80% by weight micronized particles of metaxalone and 20-60% by weight non-micronized particles of metaxalone, a. 90% of the micronized particles of said metaxalone are smaller than 500, 350, 200, 100, 75, or 50 microns when tested according to the Malvern Method; b. when tested by sieving method, less than 10%, 5%, or 2% of the non-micronized particles are retained on a #30 sieve and at least 20%, 25%, 30%, or 35% of the non-micronized particles of the metaxalone are retained on a #120 sieve; Solid oral pharmaceutical formulations.

[10] a. 90% of the micronized particles of said metaxalone are smaller than 200 microns when tested according to the Malvern Method; b. when tested by sieving method, less than 5% of the non-micronized particles are retained on a #30 sieve and at least 35% of the non-micronized particles of metaxalone are retained on a #120 sieve; [9] A solid oral pharmaceutical formulation according to the present invention. a. A 640 mg tablet or capsule of the formulation releases at least 60% by weight of its metaxalone within 60 minutes when tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C; b. When tested in 900 mL of simulated fasting intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C, a 100 mg tablet or capsule of said formulation releases at least 75% by weight of metaxalone within 300 minutes. [9] A solid oral pharmaceutical formulation according to the present invention.

[12] a. When tested in a USP Type 2 (paddle) apparatus at 100 rpm and 37±0.5°C in 900 mL of acetate buffer solution at pH 4.5, a 640 mg tablet or capsule of the formulation releases 65% or less of its metaxalone in 90 minutes; b. A 640 mg tablet or capsule of said formulation releases 65% or less of metaxalone in 90 minutes when tested in 900 mL of pH 6.0 phosphate buffer solution in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C. [9] A solid oral pharmaceutical formulation according to the present invention.

[13] a. 640 parts by weight of metaxalone, and b. 10 to 30 parts by weight of propylene glycol alginate The solid oral pharmaceutical formulation according to [9], comprising:

[14] A method for treating musculoskeletal pain comprising administering 640 mg of metaxalone in the formulation described in [1] to a patient in a fasted or fed state in need thereof.

[15] The method according to

[14] , wherein the administration is performed in the fed state.

Claims

1. 1. A solid oral pharmaceutical formulation comprising metaxalone and one or more pharmaceutically acceptable excipients, a. When tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C, a 640 mg tablet of said formulation releases at least 50%, 55%, 60%, 65%, or 70% by weight of metaxalone within 60 minutes; and / or b. When tested in 900 mL of simulated fasted intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5° C., a 100 mg tablet of said formulation releases at least 65%, 70%, 75%, or 80% by weight of metaxalone within 300 minutes; comprising micronized particles of metaxalone and non-micronized particles of metaxalone in a weight ratio of 6:4; a. 90% (d ９０ ) is less than 50 microns, b. when tested by sieving method, less than 2% of the non-micronized particles of said metaxalone are retained on a #30 sieve and at least 45% of the non-micronized particles of said metaxalone are retained on a #120 sieve; The solid oral pharmaceutical formulation is a tablet. Solid oral pharmaceutical formulations.

2. 10. The solid oral pharmaceutical formulation of claim 1, wherein a 640 mg tablet of the formulation releases at least 50%, 55%, 60%, 65%, or 70% by weight of metaxalone within 60 minutes when tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C.

3. 10. The solid oral pharmaceutical formulation of claim 1, wherein a 100 mg tablet of the formulation releases at least 65%, 70%, 75%, or 80% by weight of metaxalone within 300 minutes when tested in 900 mL of intestinal fluid simulating fasted conditions in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5°C.

4. a. When tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5° C., a 640 mg tablet of said formulation releases at least 60% by weight of metaxalone within 60 minutes; b. When tested in 900 mL of simulated fasted intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5° C., a 100 mg tablet of said formulation releases at least 75% by weight of metaxalone within 300 minutes.

2. The solid oral pharmaceutical formulation of claim 1.

5. 10. The solid oral pharmaceutical formulation of claim 1, wherein a 640 mg tablet of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C in 900 mL of pH 4.5 acetate buffer solution.

6. 10. The solid oral pharmaceutical formulation of claim 1, wherein a 640 mg tablet of the formulation releases no more than 65%, 60%, 55%, 50%, or 45% by weight of metaxalone in 90 minutes when tested in 900 mL of pH 6.0 phosphate buffer solution in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5°C.

7. a. 640 parts by weight of metaxalone, and b. 10 to 30 parts by weight of propylene glycol alginate 2. The solid oral pharmaceutical formulation of claim 1, comprising:

8. A solid oral pharmaceutical formulation which is a tablet comprising micronized particles of metaxalone and non-micronized particles of metaxalone in a weight ratio of 6:4, a. 90% of the micronized particles of said metaxalone are smaller than 50 microns when tested according to the Malvern Method; b. When tested by sieving method, less than 2% of the non-micronized particles are retained on a #30 sieve and at least 45% of the non-micronized particles of metaxalone are retained on a #120 sieve. Solid oral pharmaceutical formulations.

9. a. When tested in 900 mL of 0.5% SLS in water in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5° C., a 640 mg tablet of said formulation releases at least 60% by weight of its metaxalone within 60 minutes; b. When tested in 900 mL of simulated fasted intestinal fluid in a USP Type 2 (paddle) apparatus at 50 rpm and 37±0.5° C., a 100 mg tablet of said formulation releases at least 75% by weight of metaxalone within 300 minutes.

9. The solid oral pharmaceutical formulation of claim 8.

10. a. When tested in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5° C. in 900 mL of pH 4.5 acetate buffer solution, a 640 mg tablet of the formulation releases within 65% of its metaxalone in 90 minutes; b. When tested in a USP Apparatus Type 2 (Paddle) at 100 rpm and 37±0.5° C. in 900 mL of pH 6.0 phosphate buffer solution, a 640 mg tablet of said formulation releases 65% or less of metaxalone in 90 minutes.

9. The solid oral pharmaceutical formulation of claim 8.

11. a. 640 parts by weight of metaxalone, and b. 10 to 30 parts by weight of propylene glycol alginate 9. The solid oral pharmaceutical formulation of claim 8, comprising:

12. 10. The solid oral pharmaceutical formulation of claim 1 for treating musculoskeletal pain, comprising 640 mg of metaxalone in the formulation, wherein the solid oral pharmaceutical formulation is administered to a patient in a fasted or fed state.

13. 13. The solid oral pharmaceutical formulation of claim 12, wherein the solid oral pharmaceutical formulation is administered to a patient in a fed state.

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