Reduced dose metaxalone formulations

Abstract

To provide oral dosage forms of metaxalone having improved bioavailability in the fed and fasted states.SOLUTION: Provided is a solid oral pharmaceutical formulation comprising metaxalone and one or more pharmaceutically acceptable excipients: a. a 640 mg tablet or capsule of the formulation releases at least 50 wt.%, 55 wt.%, 60 wt.%, 65 wt.%, or 70 wt.% of its metaxalone in 60 minutes when tested in 900 mL 0.5% SLS in water in a USP Apparatus Type 2 (paddle) at 100 rpm and 37±0.5°C; and / or b. a 100 mg tablet or capsule of the formulation releases at least 65 wt.%, 70 wt.%, 75 wt.%, or 80 wt.% of its metaxalone in 300 minutes when tested in 900 mL of fasted state simulated intestinal fluid in a USP Apparatus Type 2 (paddle) at 50 rpm and 37±0.5°C.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention provides improved bioavailability in both fed and fasted states, With improved bioavailability, food effect is reduced and doses can be reduced. This invention relates to an orally administered dosage form of metaxalone. [Background technology]

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

[0003] [ka]

[0004] Skelaxin is a prescription antihistamine used to treat acute, painful musculoskeletal conditions. It is indicated as an adjunct to physical therapy and other measures. The mechanism of action of this drug is unclear. Although not precisely identified, it may be related to its sedative properties. Metaxalone has been shown to reduce bone stiffness in humans. The commercially available tablets contain metabolites with inert compression tableting excipients. Contains 400 and 800 mg of xalone.

[0005] The preparation of metaxalone is described in Lunsford et al., which is incorporated herein by reference in its entirety. , J. Am. Chem. Soc. 82, 1166 (1960) and U.S. Pat. No. 3,066,000 to Lunsford. No. 2,827 (November 6, 1962, Assignee AHRobins) The '827 patent describes compounds and related species as anticonvulsants and antispasmodic agents. However, these activities have not been supported by clinical experience.

[0006] The FDA-approved prescribing information for Skelaxin® states that the drug may be ingested with food. In particular, the prescribing information suggests that the 800 mg dose In comparison with the fasting state, the presence of a high-fat meal at the time of drug administration significantly increased C max 1 AUC (AUC 0-t , AUC ∞ ) by 146.4% and reported that the highest concentration was increased by 142.2% in the fed state compared to the fasted state. degree arrival time (T max ) was also delayed (4.9 hours vs. 3.0 hours), and the terminal half-life was also reduced ( 4.2 hours vs. 8.0 hours). Due to this food effect, drug administration is generally limited to the fasting state. (taken on an empty stomach), which significantly reduces the usefulness of the drug. Summary of the Invention

[0007] The inventors unexpectedly found that the food effect associated with prior art metaxalone formulations was significantly greater than that observed with 0.5% laxatives. sodium lauryl sulfate (“SLS”) and / or intestinal fluid simulating fasting conditions ( Using a formulation that meets the specified dissolution criteria in FaSSIF (pH 6.5) Thus, in a first main embodiment, the present invention provides a method for producing a hologram comprising: A solid oral pharmaceutical formulation containing metaxalone and one or more pharmaceutically acceptable excipients. (a) 9 minutes in a USP Apparatus Type 2 (paddle) at 100 rpm and 37 ± 0.5°C When tested in 0.5% SLS in 0.00 mL of water, the formulation showed a 640 mg tablet or capsule The capsule comprises at least 50%, 55%, 60%, 65% by weight of metaxalone. %, or 70% by weight, of the active ingredient is released within 60 minutes, and / or (b) USP Type 2 Apparatus. (paddle) at 50 rpm and 37 ± 0.5°C, simulating a 900 mL fasting state. When tested in conditioned intestinal fluid, 100 mg tablets or capsules of the formulation At least 65%, 70%, 75%, or 80% by weight of taxalone The present invention provides a solid oral pharmaceutical formulation that releases the active ingredient in an active ingredient in an amount of 0.000 mg or less.

[0008] This food effect with prior art formulations of metaxalone was also observed in acetate buffered saline at pH 4.5. Using formulations that meet the specified solubility criteria in solution and phosphate buffer solution at pH 6.0 Thus, in a second main embodiment, the present invention provides a method for treating rheumatoid arthritis by administering metaxalone and and one or more pharmaceutically acceptable excipients, comprising: (a) a solid oral pharmaceutical formulation comprising: pH of 900 mL at 100 rpm and 37 ± 0.5°C in a P apparatus type 2 (paddle). 640 mg tablets or capsules of the formulation when tested in acetate buffer solution at 4.5 The agent is 65%, 60%, 55%, 50%, or 45% by weight of metaxalone. % by weight or less in 90 minutes, and / or (b) in a USP Apparatus Type 2 (paddle) in 900 mL of pH 6.0 phosphate buffer solution at 100 rpm and 37 ± 0.5 °C. When tested at 640 mg, the 640 mg tablet or capsule formulation provided 65 mg of metaxalone. Releases 60%, 55%, 50%, or 45% by weight or less in 90 minutes The present invention provides a solid oral pharmaceutical formulation.

[0009] The present invention achieves the dissolution criteria in the first and second main embodiments, thereby Further provided is a formulation capable of overcoming the food effect of prior art metaxalone formulations. Thus, in a third main embodiment, the present invention provides a micronized formulation of metaxalone containing 40-80% by weight. and tablets and capsules containing 20-60% by weight of micronized and non-micronized metaxalone particles. 1. A solid oral pharmaceutical formulation selected from the group consisting of: (a) when tested according to the Malvern method: 90% of the micronized particles of metaxalone are 500, 350, 200, 100, 75, or 5 0 microns, and (b) 10%, 5%, or less of the non-micronized particles when tested by sieving method. or less than 2% is retained on a #30 sieve and at least 25% of the non-micronized particles of metaxalone %, 35%, or 45% are retained on a #120 sieve.

[0010] In a fourth principal embodiment, the present invention provides a composition comprising: (a) 640 parts by weight of metaxalone; and b) tablets and capsules containing 10 to 30 parts by weight of propylene glycol alginate The present invention provides a solid oral pharmaceutical formulation selected from the following:

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

[0012] Additional advantages of the present invention are described in part in the description that follows and in part below. Advantages of the present invention will be apparent from or may be learned by practice of the invention. and Both the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to be limiting of the present invention. It should be understood that this is not a limitation 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 present invention. These examples serve to explain the principles of the invention together with the description. [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 The singular forms "a," "an," and "the" or similar terms As used herein, these are intended to be used in the plural unless the context clearly dictates otherwise. Therefore, for example, "an excipient" Reference to "or" includes mixtures of two or more such excipients. When used herein, the word "list" or similar terms refer to any one of a particular list. means any one member of that list and includes any combination of members of that list.

[0016] The terms "about" or "approximately (ca.)" as used herein mean a pharmaceutical Variability that is accepted in the pharmaceutical industry and is inherent in pharmaceuticals, e.g., manufacturing variations and Differences in product strength and bioavailability due to age- and time-induced product deterioration This term is used in pharmaceutical practice to indicate that a product is is pharmaceutically equivalent or bioequivalent to the listed strength of the product; or Any variation that can be assessed as being both when the context requires it. All numerical values ​​expressed in this document may be prefaced with the term "about." I want you to understand that it is possible.

[0017] As used in this specification and the claims that follow, the term "comprises" means Words and word variations, such as "comprising" and "comprise" "ses" means "including but not limited to," e.g., other additives It is not intended to exclude any component, integer or step. When described as including a component, step, or condition, this element also includes such any combination of a plurality of components, steps or conditions, or It is understood that the phrase "consisting of" or "consisting essentially of" may also be used interchangeably. sea ​​bream.

[0018] By specifying the lower end of a range separately from the upper end of a range, or by specifying a specific number If a range is given by and other ranges may be defined by selectively combining any of the specified values. In a similar manner, the range can be extended from one endpoint to another. If a range is defined to span two ends, this range also includes the span between them, This is understood to exclude end points.

[0019] As used herein, a "therapeutically effective amount" refers to an amount sufficient to elicit a desired biological response. A therapeutically effective amount or dose depends on the age, sex, and weight of the patient, as well as the patient's These and other factors, in addition to this disclosure, will be readily apparent to those skilled in the art. An appropriate dose can be determined depending on the patient's condition.

[0020] "Pharmaceutically acceptable" means generally safe, non-toxic, biologically or otherwise It means that it is useful for preparing pharmaceutical compositions that are not unsuitable for human or animal use. "Pharmaceutically acceptable salts" means salts of a compound, as defined above, which are acceptable for pharmaceutically use. By "salts" is meant pharmaceutically acceptable salts such as those mentioned above, which salts possess the desired pharmacological activity.

[0021] Where a dose of a drug or a pharmaceutically acceptable salt thereof is described herein, the description Unless stated that the dose is based on the weight of the salt, hydrate, or solvate, the dose is based on the weight of the salt, hydrate, or solvate. It is understood that the weight is based on the free base and excludes any hydrates or solvates thereof. sea ​​bream.

[0022] Throughout this patent application, the compounds are classified according to the methods prescribed in the United States Pharmacopeia ("USP"). Whenever an assay is prescribed, the assay must comply with the USP regulations effective January 1, 2019. It is understood that testing is not required, but if performed, It is also understood that the test will produce the claimed results. Any terms not defined elsewhere refer to the USP Volume effective January 1, 2019. can be defined as

[0023] The term fasted state simulated intestinal fluid or "FaSSIF" was coined by Klein S. The As listed in Table II of the AAPS Journal, Vol. 12, No. 3, September 2010, Refers to a solution with a pH of 6.5 or less. 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 is a method used by the American Society for Testing and Materials ) (ASTM) Standard C136 (effective January 1, 2019) for particle size analysis This method involves placing a representative weighed sample on the top sieve with the largest openings. Each lower sieve in the column has smaller openings than the one above. The column is usually shaken by a mechanical shaker, e.g., the End Place in a sonic shifter available from ecotts (London, UK). Endecotts website: https: / / www.endecotts.c om / products / sieve-shakers / sonic-sifter / p See product-specifications / . Shakers are usually The column is shaken 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 divided by the total mass to obtain the percentage retained on each sieve. The average particle size on each sieve is analyzed to obtain a cutoff point or a specific size range, and then Then capture it on your eye.

[0025] Main embodiment The present invention is described herein in terms of main and subembodiments. It is understood that each of the embodiments can be modified from any of the main embodiments. However, such modifications shall not be logically inconsistent or expressly denied in this document. The main embodiments can be combined in any way and sub-embodiments can be combined in any way. The aspects may be combined in any way to further modify any of the main embodiments. It is further understood, however, that such combinations are not logically contradictory or in any way inconsistent with the principles of this document. Any provision of this Agreement that is not expressly denied in the present Agreement shall be deemed to be a waiver of all rights granted in that Agreement.

[0026] In a first principal embodiment, the present invention provides a compound comprising metaxalone and one or more pharmaceutically acceptable salts of metaxalone. 1. A solid oral pharmaceutical formulation comprising an excipient that: (a) is sized in a USP Type 2 (paddle) apparatus; When tested in 900 mL of 0.5% SLS in water at 100 rpm and 37 ± 0.5°C In this case, the 640 mg tablet or capsule of said formulation contains at least 50 mg of metaxalone. 55%, 60%, 65%, or 70% by weight of the compound released within 60 minutes. and / or (b) in a USP Apparatus Type 2 (paddle) at 50 rpm and 37 ± 0 When tested in 900 mL of simulated fasting intestinal fluid at 0.5°C, the formulation A 100 mg tablet or capsule contains at least 65% by weight of metaxalone, 70% by weight of %, 75% by weight, or 80% by weight of the active ingredient is released within 300 minutes. do.

[0027] In a second principal embodiment, the present invention provides a compound comprising metaxalone and one or more pharmaceutically acceptable salts of metaxalone. 1. A solid oral pharmaceutical formulation comprising an excipient that: (a) is sized in a USP Type 2 (paddle) apparatus; Tests were conducted in 900 mL of acetate buffer solution at pH 4.5 at 100 rpm and 37 ± 0.5°C. In a study, a 640 mg tablet or capsule of the formulation contained 65 mg of metaxalone. %, 60%, 55%, 50%, or 45% or less by weight released in 90 minutes and / or (b) at 100 rpm and 37 ± 0°C in a USP Apparatus Type 2 (paddle). When tested in 900 mL of pH 6.0 phosphate buffer solution at 0.5°C, 64% of the formulation 0 mg tablets or capsules contain 65%, 60%, and 55% metaxalone by weight. and a solid oral pharmaceutical formulation that releases 50% by weight or less, or 45% by weight or less, of the active ingredient in the formulation in 90 minutes. do.

[0028] In a third main embodiment, the present invention provides micronized particles of metaxalone that are 40-80% by weight. and from tablets and capsules containing 20-60% by weight of non-micronized particles of metaxalone. Selected solid oral pharmaceutical dosage forms (a) exhibit metaxylamine when tested according to the Malvern method; 90% of salon micronized particles are 500, 350, 200, 100, 75, or 50 microns (b) the presence of non-micronized particles of metaxalone when tested by sieving 20%, 25%, 30%, or 35% of the solid oral pharmaceutical product is retained on a #120 sieve. A formulation is provided.

[0029] In a fourth principal embodiment, the present invention provides a composition comprising: (a) 640 parts by weight of metaxalone; and b) Tablets and capsules containing 10 to 30 parts by weight of propylene glycol alginate The present invention provides a solid oral pharmaceutical formulation selected from the group consisting of:

[0030] In a fifth main embodiment, the present invention provides a method for treating musculoskeletal pain, comprising administering to a subject a therapeutically effective amount of a compound of the present invention. 640 mg of metaxalone in the formulation of any of the main embodiments or subembodiments of 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, and Each can modify the main embodiment alone or in any combination.

[0032] In various subembodiments of the invention, the 640 mg tablet or capsule of the formulation is In a type 2 (paddle) apparatus, 100 rpm and 37 ± 0.5°C, 0 When tested in 0.5% SLS, at least 50%, 55%, and 6% by weight of metaxalone 0%, 65%, or 70% by weight can be released within 60 minutes.

[0033] In a particularly preferred subembodiment, the 640 mg tablet or capsule of the formulation is prepared using US in 900 mL of water at 100 rpm and 37 ± 0.5°C in a P apparatus type 2 (paddle). When tested in 0.5% SLS, at least 60% by weight of metaxalone was released within 60 minutes. Release.

[0034] In another subembodiment of the invention, the speed is adjusted to 50 rpm and 100 rpm in a USP Apparatus Type 2 (paddle). When tested in 900 mL of intestinal fluid simulating fasting conditions at 37 ± 0.5°C, A 100 mg tablet or capsule of the formulation contains at least 65% by weight of metaxalone, 70%, 75%, or 80% by weight is released within 300 minutes.

[0035] In a particularly preferred subembodiment, the speed is increased at 50 rpm in a USP Apparatus Type 2 (paddle) and When tested in 900 mL of intestinal fluid simulating fasting conditions at 37 ± 0.5°C, The 100 mg tablets or capsules of the formulation contain at least 75% by weight of metaxalone. Release within 00 minutes.

[0036] In another subembodiment, the rotational speed is adjusted to 100 rpm and 37±100 rpm in a USP Apparatus Type 2 (paddle). When tested in 900 mL of acetate buffer solution at pH 4.5 at 0.5°C, 6 of the formulations The 40 mg tablets or capsules contain 65%, 60%, or 55% metaxalone by weight. , 50% by weight, or 45% by weight or less is released in 90 minutes.

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

[0038] In yet another subembodiment, the mixture is mixed in a USP Apparatus Type 2 (paddle) at 100 rpm and When tested in 900 mL of pH 6.0 phosphate buffer solution at 37±0.5°C, The formulation, a 640 mg tablet or capsule, contains 65% by weight of metaxalone, 60% by weight of metaxalone, and 5% by weight of 5%, 50%, or 45% or less by weight is released in 90 minutes.

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

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

[0041] In one subembodiment, when the formulation is characterized based on metaxalone particle size, When tested according to the Byrne method (i.e., laser diffraction), a small number of micronized particles of metaxalone At least 50%, 70%, or 90% are smaller than 200, 100, or 75 microns Alternatively or additionally, at least 10% of the micronized particles, when tested according to the Malvern Method, At least 30%, 40%, or 50% are less than 50, 30, or 20 microns.

[0042] In another subembodiment, 10%, 5%, or less of the non-micronized particles when tested by sieving method. Not more than 2% is retained on the #30 sieve, and at least 15% of the non-micronized particles of metaxalone , 25%, 35%, or 45% are retained on the #120 sieve. In addition, at least 10% or 20% of the non-micronized particles are micronized when tested by the sieve method. % is retained on the #325 sieve.

[0043] In yet a further embodiment, the formulations of the present invention comprise: Thus, in one subembodiment, the formulation of the present invention comprises 640 parts by weight of Metaxalone and 10 to 30 parts by weight or 15 to 25 parts by weight of propylene glycol alginate Includes recalls.

[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 or 1 5 to 25 parts by weight of alginic acid, 40 to 60 parts by weight or 45 to 55 parts by weight of povidone, and and 2 to 8 parts by weight or 4 to 6 parts by weight of a lubricant. A preferred lubricant is maltodextrin. It is magnesium. [Example]

[0045] In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.). Although the present invention has been made with a view to achieving the above results, some errors and deviations are to be expected. A complete disclosure of how the methods claimed herein were made and evaluated It is intended to provide a thorough understanding of the present invention and its application to those skilled in the art and is intended to be purely exemplary of the present invention. It is not intended to limit the scope of what the inventors regard as their invention. It's not that.

[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 show the micronized and non-micronized metaxalone used in the formulations in Table 1. Representative particle sizes for the particles are given.

[0049] [Table 2a]

[0050] [Table 2b]

[0051] [Example 3] Typical manufacturing method This example demonstrates the efficacy of metaxalone in the treatment of rheumatoid arthritis using the formulations and metaxalone described in Tables 1 and 2. Contains detailed information describing the method for manufacturing Taxalone tablets 640 mg. Granulation solution: Slowly add purified water while mixing using a mixer at the required speed. The povidone was dissolved by adding Premix: Micronized metaxalone, metaxalone, FD&C Yellow #6, alginate propionate The propylene glycol and alginic acid were mixed at an appropriate head speed. Wet granules: Add the above premix blend to the blender while mixing at an appropriate head speed. The granule solution was added. Drying: The wet granules were dried in an oven to achieve the desired moisture content. Upon completion of the process, the dried granules were milled using a commuting mill. Final blend: Add magnesium stearate and grind the blend in a suitable blender. It was lubricated using. 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 show the 640 Dissolution test results for 800 mg tablets and 800 mg Skelaxin® tablets It describes the following.

[0053] [Table 4a]

[0054] [Table 4b]

[0055] [Example 5] Dissolution test results / SLS and pH buffer Tables 5a and 5b and Figure 1 show the 640 mg tablets produced by the method of Example 3 and Additional dissolution test results for 800 mg Skelaxin® tablets are described. is doing.

[0056] [Table 5a]

[0057] [Table 5b]

[0058] [Example 6] Bioequivalence study results Randomized, single dose comparison of 640 mg metaxalone tablets produced by the method of Example 3 A quadruplicate, open-label, crossover experiment, fasted and fed, was enumerated. 47 healthy adults were randomly assigned to receive the reference drug, Skelaxin® tablets 800 mg. Volunteers (29 men and 18 women) completed the experiment in both fasted and fed states. Data from 47 subjects were used to calculate pharmacokinetic results using SAS. The 90% confidence interval for the mean test-to-reference area and peak concentration ratio is 0.80 to 1.2 The bioequivalence interval for the 640 mg tablets was within 5.5. It has been proven bioequivalent to Laxin® tablets 800 mg.

[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 are incorporated herein by reference in their entirety. The present application is hereby incorporated by reference in its entirety in order to more fully describe the state of the art relating to Various modifications and variations may be made without departing from the scope or spirit of the present invention. It will be apparent to one skilled in the art that variations can be made in the present invention. The embodiments will be readily apparent to those skilled in the art upon consideration of the specification and practice of the invention disclosed herein. It is clear that the specification and examples are to be considered as exemplary only and do not limit the true scope of the invention. It is intended that the scope and spirit be indicated by the following claims.

Claims

1. A solid oral pharmaceutical formulation comprising metaxalone and one or more pharmaceutically acceptable excipients. So, a. 900 m in a USP Apparatus Type 2 (paddle) at 100 rpm and 37 ± 0.5°C When tested in 0.5% SLS in water at 1 L, the 640 mg tablet or capsule of the formulation The agent is at least 50%, 55%, 60%, 65%, or more by weight of metaxalone. or 70% by weight of the active ingredient is released within 60 minutes, and / or b. 900 mL in a USP Apparatus Type 2 (paddle) at 50 rpm and 37±0.5°C When tested in intestinal fluid simulating fasting conditions, 100 mg tablets or The capsules contain at least 65%, 70%, 75%, or more by weight of metaxalone. Releases approximately 80% by weight within 300 minutes. Solid oral pharmaceutical formulations.

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

3. 900 mL of water was added to a USP Apparatus Type 2 (paddle) at 50 rpm and 37±0.5°C. When tested in intestinal fluid simulating fasting conditions, the formulations, 100 mg tablets or capsules, The capsule contains at least 65%, 70%, 75%, or 8% by weight of metaxalone.

2. The solid oral pharmaceutical formulation of claim 1, wherein 0% by weight of the active ingredient is released within 300 minutes.

4. a. 900°C in a USP Apparatus Type 2 (paddle) at 100 rpm and 37±0.5°C 640 mg tablets or capsules of the formulation when tested in 0.5% SLS in 1 mL of water the agent releases at least 60% by weight of metaxalone within 60 minutes; b. 900 mL in a USP Apparatus Type 2 (paddle) at 50 rpm and 37±0.5°C When tested in intestinal fluid simulating fasting conditions, 100 mg tablets of the formulation or The capsule releases at least 75% by weight of metaxalone within 300 minutes.

2. The solid oral pharmaceutical formulation of claim 1.

5. 900 mL in USP Apparatus Type 2 (paddle) at 100 rpm and 37±0.5°C When tested in acetate buffer solution at pH 4.5, the 640 mg tablets or capsules of the formulation The cellulosic agent is 65%, 60%, 55%, 50%, or 4% by weight of metaxalone.

10. The solid oral pharmaceutical formulation of claim 1, which releases 5% by weight or less in 90 minutes.

6. 900 mL in USP Apparatus Type 2 (paddle) at 100 rpm and 37±0.5°C When tested in a phosphate buffer solution at pH 6.0, the 640 mg tablets or capsules of the formulation The cellulosic agent is 65%, 60%, 55%, 50%, or 4% by weight of metaxalone.

10. The solid oral pharmaceutical formulation of claim 1, which releases 5% by weight or less in 90 minutes.

7. 40-80% by weight micronized particles of metaxalone and 20-60% by weight metaxalone comprising non-micronized particles of a. 90% of the micronized particles of metaxalone have a particle size of 200 mm or less when tested according to the Malvern method. Smaller than a micron b. At least 35% of the non-micronized particles of said metaxalone are # when tested by sieving method Retained on 120 sieve 2. The solid oral pharmaceutical formulation of claim 1.

8. 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:

9. 40-80% by weight micronized particles of metaxalone and 20-60% by weight metaxalone 1. A solid oral pharmaceutical formulation selected from tablets and capsules comprising non-micronized particles of a. 90% of the micronized particles of metaxalone have a particle size of 500 nm when tested according to the Malvern method. , 350, 200, 100, 75, or 50 microns; b. Less than 10%, 5%, or 2% of the non-micronized particles are #3 when tested by sieving method. 1.0 sieve and at least 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, %, or 35% is retained on the #120 sieve; Solid oral pharmaceutical formulations.

10. a. 90% of the micronized particles of metaxalone are 20% or less when tested according to the Malvern method. Less than 0 microns b. when tested by Sieving Method, less than 5% of the non-micronized particles are retained on a #30 sieve; at least 35% of the non-micronized particles of the metaxalone are retained on a #120 sieve; 10. The solid oral pharmaceutical formulation of claim 9.

11. a. 900°C in a USP Apparatus Type 2 (paddle) at 100 rpm and 37±0.5°C 640 mg tablets or capsules of the formulation when tested in 0.5% SLS in 1 mL of water the agent releases at least 60% by weight of its metaxalone within 60 minutes; b. 900 m in a USP Apparatus Type 2 (paddle) at 50 rpm and 37 ± 0.5°C When tested in intestinal fluid simulating the fasting state of L., the 100 mg tablet or The capsule releases at least 75% by weight of metaxalone within 300 minutes.

10. The solid oral pharmaceutical formulation of claim 9.

12. a. 900°C in a USP Apparatus Type 2 (paddle) at 100 rpm and 37±0.5°C When tested in 1 mL of acetate buffer solution at pH 4.5, the 640 mg tablet of the formulation or The capsules release up to 65% of the metaxalone in 90 minutes. b. 900°C in a USP Apparatus Type 2 (paddle) at 100 rpm and 37±0.5°C When tested in 1 mL of pH 6.0 phosphate buffer solution, the 640 mg tablet of the formulation or The capsule releases 65% or less of the metaxalone in 90 minutes.

10. The solid oral pharmaceutical formulation of claim 9.

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

14. 640 mg of metaxalone in the formulation of claim 1 administered in a fasted state where it is needed. or a method for treating musculoskeletal pain, comprising administering to a patient in a fed state.

15. The method of claim 14 , wherein the administration is performed in the fed state.

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