Oral preparation and use thereof

文档序号：1159814 发布日期：2020-09-15 浏览：22次中文

阅读说明：本技术 经口制剂及其用途 (Oral preparation and use thereof ) 是由 P·万坎 A·萨萨曼 G·B·威尔姆布里克于 2019-02-01 设计创作，主要内容包括：公开了包含特定的基于取代吡啶的化合物的治疗性经口制剂、它们的生产,以及所述制剂针对适应症治疗所述脑中P物质介导途径诸如颅内压升高或所述脑中(超)磷酸化tau蛋白(τ)表达改变的方法与用途,所述适应症诸如但不限于脑震荡、脑震荡后的(或脑震荡后)综合征(PCS)、慢性外伤性脑病(CTE)、外伤性脑损伤(TBI)和中风。(Therapeutic oral formulations comprising specific substituted pyridine-based compounds, their manufacture, and methods and uses of the formulations for treating substance P-mediated pathways in the brain, such as increased intracranial pressure or altered expression of (hyper) phosphorylated tau protein (τ) in the brain, for indications such as, but not limited to, concussion, post-concussion (or post-concussion) syndrome (PCS), Chronic Traumatic Encephalopathy (CTE), Traumatic Brain Injury (TBI), and stroke are disclosed.)

1. A pharmaceutical composition in the form of a tablet, comprising:

(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein R is₁Is H or C_1-4An alkyl group; and is

Wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof within the composition has a D (0.5) particle size distribution of less than about 60 μ ι η;

(ii) at least one diluent selected from the group consisting of: lactose, sorbitol, dibasic calcium phosphate dihydrate, calcium sulfate dihydrate, calcium carbonate, croscarmellose sodium, calcium phosphate, dibasic calcium phosphate dihydrate, crospovidone, ferric oxide, magnesium carbonate, magnesium oxide, sucrose, or sodium chloride, wherein the at least one diluent is present in the composition in an amount of about 35% to about 70% wt/wt based on the total weight of the composition;

(iii) at least one lubricant selected from the group consisting of: magnesium stearate, stearic acid, calcium stearate, paraffin, sodium lauryl sulfate, sodium benzoate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, mineral oil, poloxamer, PEG400, PEG 600, or PEG8000, wherein said at least one lubricant is present in said composition in an amount of about 0.1% to about 2% wt/wt based on the total weight of said composition;

(iv) at least one disintegrant selected from the group consisting of: microcrystalline cellulose, alginic acid, citric acid, croscarmellose sodium, carboxymethylcellulose calcium, cysteine hydrochloride, methylcellulose, polyoxyl stearate, sodium starch glycolate, sodium alginate, or carboxymethylcellulose sodium, wherein the at least one disintegrant is present in the composition in an amount of about 20% to about 30% wt/wt, based on the total weight of the composition;

(v) at least one binder selected from the group consisting of: starch, gelatin, glucose, polyvinylpyrrolidone (povidone), carboxymethylcellulose, acacia, candelilla wax, carnauba wax (carnuba wax), corn starch, glyceryl behenate, hypromellose, or polyethylene oxide, wherein the at least one binder is present in the composition in an amount of about 5% to about 15% wt/wt based on the total weight of the composition; and

(vi) at least one anti-caking agent selected from the group consisting of: fumed silica, or talc, wherein said at least one anti-caking agent is present in said composition in an amount of from about 0.2% to about 2% wt/wt based on the total weight of the composition.

2. The pharmaceutical composition of claim 1, wherein R₁Selected from H, methyl, ethyl, n-propyl or isopropyl.

3. The pharmaceutical composition according to claim 1 or 2, wherein at least one diluent is selected from the group consisting of: lactose, sorbitol or sucrose.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein at least one lubricant is selected from the group consisting of: magnesium stearate, stearic acid, calcium stearate, PEG400, PEG 600, or PEG 8000.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein at least one disintegrant is selected from the group consisting of: microcrystalline cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, methyl cellulose, or sodium carboxymethyl cellulose.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein at least one binder is selected from the group consisting of: starch, gelatin, glucose, acacia, candelilla, carnauba, or corn starch.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the anti-caking agent is fumed silica.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the diluent is lactose.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the lubricant is magnesium stearate.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the disintegrant is microcrystalline cellulose.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the binder is starch.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, is present in the composition in an amount of about 0.1% to about 50% wt/wt based on the total weight of the composition.

13. The pharmaceutical composition according to any one of claims 1 to 12, further comprising at least one coating selected from the group consisting of: hydroxypropyl cellulose, hypromellose phthalate, methylcellulose, methacrylic acid copolymer, tetraiodofluorescein sodium, or sodium propionate.

14. A pharmaceutical composition in the form of a tablet, comprising:

(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein R is₁Is H or C_1-4An alkyl group; and is

Wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof within the composition has a D (0.5) particle size distribution of less than about 60 μ ι η;

(ii) lactose, wherein lactose is present in the composition in an amount of about 35% to about 70% wt/wt based on the total weight of the composition;

(iii) magnesium stearate, wherein magnesium stearate is present in the composition in an amount of about 0.1% to about 2% wt/wt based on the total weight of the composition;

(iv) microcrystalline cellulose, wherein microcrystalline cellulose is present in the composition in an amount of about 20% to about 30% wt/wt based on the total weight of the composition;

(v) a starch, wherein starch is present in the composition in an amount of about 5% to about 15% wt/wt based on the total weight of the composition; and

(vi) fumed silica, wherein fumed silica is present in the composition in an amount of about 0.2% to about 2% wt/wt based on the total weight of the composition.

15. The composition according to any one of claims 1 to 14, wherein the compound of formula (I) is:

16. a method of treating hyperphosphorylated tau protein (τ) overexpression, postconcussive syndrome (PCS), Chronic Traumatic Encephalopathy (CTE) or increased intracranial pressure in the brain of a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition in the form of a tablet comprising:

(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein R is₁Is H or C_1-4An alkyl group; and is

Wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof within the composition has a D (0.5) particle size distribution of less than about 60 μ ι η;

17. A pharmaceutical composition in the form of a tablet for treating hyperphosphorylated tau protein (τ) overexpression, postconcussive syndrome (PCS), Chronic Traumatic Encephalopathy (CTE) or increased intracranial pressure in the brain of a subject in need thereof, the pharmaceutical composition comprising:

(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein R is₁Is H or C_1-4An alkyl group; and is

Wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof within the composition has a D (0.5) particle size distribution of less than about 60 μ ι η;

(v) at least one binder selected from the group consisting of: starch, gelatin, glucose, polyvinylpyrrolidone (povidone), carboxymethylcellulose, acacia, candelilla wax, carnauba wax, corn starch, glyceryl behenate, hypromellose, or polyethylene oxide, wherein the at least one binder is present in the composition in an amount of about 5% to about 15% wt/wt based on the total weight of the composition; and

18. The method according to claim 16 or 17, said method for treating increased intracranial pressure is a method for treating traumatic brain injury.

19. The method according to claim 16 or 17, said method for treating increased intracranial pressure is a method for treating stroke.

20. The method according to claim 16 or 17, for treating increased intracranial pressure is a method for treating PCS.

Technical Field

The present invention relates generally to therapeutic oral formulations comprising specific substituted pyridine-based compounds, their manufacture, and methods and uses of the formulations for treating substance P mediated pathways in the brain, such as increased intracranial pressure or altered expression of (hyper) phosphorylated tau protein (τ) in the brain, for indications such as, but not limited to, concussion, post-concussion (or post-concussion) syndrome (PCS), Chronic Traumatic Encephalopathy (CTE), Traumatic Brain Injury (TBI), and stroke.

Background

Traumatic Brain Injury (TBI), also known as intracranial injury, occurs when an external force damages the brain. TBI can be classified according to severity, mechanism (occlusive or penetrating brain injury), or other characteristics (e.g., occurring in a specific location or broad area). TBI can lead to physical, cognitive, social, emotional, and behavioral symptoms, with fatalities possibly reverting from complete to permanent disabilities or death.

Brain trauma occurs as a result of sudden acceleration or deceleration within the skull, or from a complex combination of motion and sudden impact. In addition to the damage caused at the time of injury, various events from minutes to days following injury may also lead to secondary injury. These processes include changes in cerebral blood flow and intracranial pressure and expression of (hyper) phosphorylated tau protein (tau) in the brain,

the most common causes of TBI include violence, traffic accidents, construction and sports. Motorcycles are a major cause, and the importance in developing countries is increasing with the decrease of other causes. It is estimated that between 160 and 380 million traumatic brain injuries are the result of physical and recreational activities in the united states each year. In children 2 to 4 years of age, falls are the most common cause of TBI, whereas in older children traffic accidents are comparable to falls in this location. TBI is the third most common injury caused by child abuse. Abuse causes 19% of pediatric brain trauma cases, and mortality is higher in these cases.

Lack of effective drugs that can reduce TBI or intracranial pressure elevation (ICP) in stroke, nor any drug that can prevent hyperphosphorylated tau overexpression has been associated with poor clinical outcome for indications such as TBI and alzheimer's disease. Therefore, there is a need for a drug that can cure or ameliorate ICP elevation in TBI or stroke or prevent hyperphosphorylated tau protein overexpression.

Even though Active Pharmaceutical Ingredients (APIs) have been identified, there are still a number of obstacles to overcome in formulating pharmaceuticals. In formulating a medicament suitable for human administration, the skilled person will appreciate that formulation techniques are unpredictable. Various factors need to be carefully investigated and adjusted to at least maintain, if not enhance, the pharmacokinetic properties of the API and/or to impart stability to the drug so that it has an acceptable shelf life. In this sense, careful study and investigation of the physical properties of the API, the mode of delivery, the flowability of the composition, excipient compatibility, manufacturing uniformity and release profile is required.

If not properly formulated, the API may not be effective in providing bioavailability to the patient. For example, while calcium salts may be used as bulking agents, they have also been found to interfere with the absorption of tetracycline (an example of an API) in the gastrointestinal tract. This example emphasizes that the components added in the formulation, as one may perceive, may not always be inert and may interact with the API.

Further, the addition of diluents to the formulation may also alter the physicochemical properties of the formulation, which may destabilize the product and may cause problems in production. This is further exacerbated by the need for Good Manufacturing Practice (GMP) standards, as in pharmaceutical formulations for use as pharmaceuticals, each ingredient must meet a certain level of compliance with existing standards and regulations.

The present invention seeks to overcome or ameliorate at least one of the disadvantages of the art with respect to the formulation of particular compounds.

Disclosure of Invention

The present invention provides therapeutic oral formulations comprising an effective amount of a particular substituted pyridine-based compound and other excipients, and optionally a coating. In particular, the formulation is provided in the form of a tablet. The tablets are characterized by consistent weight and content uniformity, good dissolution profiles, and acceptable hardness. Thus, the tablet is capable of achieving an immediate release dissolution profile. In this aspect, the formulation would be able to benefit a subject in need thereof by providing immediate relief of substance P-mediated processes, such as hyperphosphorylated tau overexpression or elevation of intracranial pressure (ICP), and accordingly immediate relief of conditions and/or symptoms of indications such as, but not limited to, PCS, CTE, TBI and stroke.

In a first aspect, the present invention provides a pharmaceutical composition in the form of a tablet comprising:

(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein R is₁Is H or C_1-4An alkyl group; and is

Wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof within the composition has a D (0.5) particle size distribution of less than about 60 μm;

(iii) at least one lubricant selected from the group consisting of: magnesium stearate, stearic acid, calcium stearate, paraffin, sodium lauryl sulfate, sodium benzoate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, mineral oil, polaxamer, PEG400, PEG 600, or PEG8000, wherein at least one lubricant is present in the composition in an amount of about 0.1% to about 2% wt/wt based on the total weight of the composition;

(vi) at least one anti-caking agent selected from the group consisting of: fumed silica, or talc, wherein the at least one anti-caking agent is present in the composition in an amount of about 0.2% to about 2% wt/wt based on the total weight of the composition.

In one embodiment, the present invention provides a pharmaceutical composition as described herein, wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is present in the composition in an amount of from about 0.1% to about 50% based on the total weight of the composition.

In a second aspect, the present invention provides a method of preventing the overexpression of hyperphosphorylated tau protein after concussion in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition in the form of a tablet as described herein.

In a third aspect, the present invention provides a pharmaceutical composition in the form of a tablet for use in preventing hyperphosphorylated tau overexpression after a concussion in a subject in need thereof, the pharmaceutical composition as described herein.

In a fourth aspect, the present invention provides a method of treating elevated intracranial pressure in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition in the form of a tablet as described herein.

In a fifth aspect, the present invention provides a pharmaceutical composition in the form of a tablet for use in treating elevated intracranial pressure in a subject in need thereof, the pharmaceutical composition as described herein.

In one embodiment, the method for preventing hyperphosphorylated tau protein overexpression is a method for treating concussion or post-concussion syndrome (PCS).

In one embodiment, the method for treating increased intracranial pressure is a method for treating traumatic brain injury.

In another embodiment, the method for treating increased intracranial pressure is a method for treating stroke.

Detailed Description

In this specification and in the claims which follow, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The terms "about" or "approximately" as used herein mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which error range will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that the prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For purposes of the present invention, the following terms are defined below.

"alkyl" means a radicalA monovalent alkyl group, which may be linear or branched, and has 1 to 4 carbon atoms or more preferably 1 to 3 carbon atoms. As used herein, C_1-4Alkyl refers to an alkyl selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

An "excipient" is a pharmaceutically inactive substance that acts as a vehicle or medium for a drug or other active substance. In the pharmaceutical industry, it is a comprehensive term that includes various subgroups including diluents or fillers, binders or binders, disintegrants, lubricants, glidants, flavoring agents, coloring agents, coatings and sweeteners. Such components will generally be present in the formulation as a mixture. The skilled artisan will appreciate that some excipients may serve multiple functions in the formulation. For example, croscarmellose sodium may act as a sweetener and/or diluent when added to a formulation. In another example, microcrystalline cellulose may act as a diluent and/or disintegrant. Talc has been used as an anti-caking agent, glidant, diluent, and/or lubricant.

A "diluent" is an inert substance that is capable of acting as a filler in a formulation. The addition of a diluent to the formulation serves to supplement the volume of the formulation. Due to the increased volume, the formulation may therefore be easier to handle.

The "binder" serves to hold or bring together the different components of the formulation. In this sense, the binder provides cohesive strength to the formulation. The binder may be added in dry or wet form.

The "lubricant" serves to reduce friction between the die wall and the formulation, preventing the formulation from adhering to the die or punch. For example, if the formulation is to be used to form a tablet, the lubricant reduces friction between the die wall and the formed tablet. Thus, the lubricant helps to make the tablet easier to eject from the die cavity. The lubricant may be soluble or insoluble in the formulation.

"glidants" aid in the flowability of the formulation. This is desirable because it reduces waste and improves control when, for example, transferring the formulation from a hopper to a mold cavity. Glidants work by reducing friction between particles within a formulation.

A "disintegrant" is a substance included in the formulation to facilitate penetration of moisture and dispersion of the matrix of the dosage form in the dissolution fluid. For example, in an oral formulation such as a tablet formulation or a hard shell capsule formulation, the solid dosage form should ideally be dispersed within the primary particles from which it is made.

"anti-caking agents" are also known as anti-agglomeration agents. They are used to prevent lump formation in the pelletized blend or API. Agglomeration can be a problem with respect to flow, particle size and general processability. In the presence of small amounts of moisture, the API will dissolve, and the dissolved API will act as a binder and form a mass within the API itself or the blend. The anti-caking agent covers the API particles and prevents caking due to its high surface area. In addition, the anti-caking agent should not chemically react with the API or other excipients.

In a first aspect, the present invention provides a pharmaceutical oral composition. When administered orally, the pharmaceutical compositions are generally formulated in unit dosage forms, such as tablets, caplets, cachets, powders, granules, beads, chewable lozenges, capsules, liquids, aqueous suspensions or solutions, or the like, using conventional equipment and techniques known in the art. For example, the pharmaceutical oral composition may be in liquid form or solid form. In some embodiments, the pharmaceutical composition is in the form of a tablet. The tablet may be of any suitable size or suitable shape. In another embodiment, the pharmaceutical composition is in liquid form. In another embodiment, the pharmaceutical composition is in the form of a powder. In another embodiment, the pharmaceutical composition is in the form of a capsule. In another embodiment, the pharmaceutical composition is in the form of a gel.

In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

wherein R is₁Is H or C_1-4An alkyl group.

In one embodiment, R₁Is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. In another embodiment, R₁Is H, methyl, ethyl, n-propyl or isopropyl. In another embodiment, R₁Is H. In another embodiment, R₁Is methyl. In another embodiment, R₁Is ethyl. In another embodiment, R₁Is n-propyl. In another embodiment, R₁Is isopropyl. In another embodiment, R₁Is n-butyl. In another embodiment, R₁Is sec-butyl. In another embodiment, R₁Is an isobutyl group. In another embodiment, R₁Is a tert-butyl group.

Thus, in some embodiments, the pharmaceutical composition comprises a compound of formula (I) selected from:

specifically, in some embodiments, the pharmaceutical composition comprises a compound of formula (I) below, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

in one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is provided as a salt. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof is a hydrochloride salt. In another embodiment, the compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a dihydrochloride salt. Thus, in some embodiments, the pharmaceutical composition comprises a compound of formula (I) selected from:

with respect to the present invention, when formulating pharmaceutical compositions, the inventors found that the problem was agglomeration when the API was mixed with excipients. This results in poor formulation appearance, such as spots observed on the tablet surface. Another problem is that when formulating tablets, the formulation is found to stick to the punches during compression. Further, the API content of the tablets was found to be non-uniform throughout the batch and the recovery was also low. In this regard, although the inventors have conducted experiments in various ways to solve the above-described problems. For example, various combinations and ratios of excipients were tested, but none significantly improved these problems. Unexpectedly, the inventors have found that micronization of APIs can help to significantly alleviate these problems.

Thus, the particle size of the API is believed to have a fundamental impact on both the uniformity and dissolution rate of the formulation blend and thus aid in the selection of the appropriate excipients for the final tablet formulation. As mentioned above, it was found to be difficult to screen before blending to make the formulation. It was further observed that various colored particles (yellowish, orange and brown) remained on the screen. Further, when tabletted, undesirably noticeable speckles were observed. It has been found advantageous to have the D (0.5) particle size of the API less than about 70 μm. Specifically, when the D (0.5) particle size of the API is less than about 60 μm, the hardness, weight and content uniformity of the tablet and the dissolution profile remain consistent from batch to batch.

The skilled person will understand that D (0.5) particle size distribution (or alternatively, D (50)) refers to a particle size distribution at which 50% of the particles in the cumulative distribution are trapped at the stated values. Thus, D (0.5) is the cumulative particle size distribution where 50% of the sample particle sizes are smaller than the specified value and 50% of the sample particle sizes are larger than the specified value. For example, if D (0.5) ═ 5.8 μm, then 50% of the particles in the sample are larger than 5.8 μm and 50% are smaller than 5.8 μm. D (0.5) is also referred to as the median particle diameter or median value of the particle size distribution.

Thus, in some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, within the pharmaceutical composition has a D (0.5) particle size distribution of less than about 70 μm. In another embodiment, the D (0.5) is less than about 60 μm. In another embodiment, the D (0.5) is less than about 50 μm. In another embodiment, the D (0.5) is less than about 40 μm. In another embodiment, the D (0.5) is less than about 30 μm. In another embodiment, the D (0.5) is less than about 20 μm. In another embodiment, the D (0.5) is less than about 10 μm. In another embodiment, the D (0.5) is less than about 5 μm. In another embodiment, the D (0.5) is from about 5 μm to about 70 μm. In another embodiment, the D (0.5) is from about 5 μm to about 60 μm. In another embodiment, the D (0.5) is from about 10 μm to about 60 μm. In another embodiment, the D (0.5) is from about 20 μm to about 60 μm. In another embodiment, the D (0.5) is from about 30 μm to about 60 μm. In another embodiment, the D (0.5) is from about 40 μm to about 60 μm. In another embodiment, the D (0.5) is from about 5 μm to about 50 μm. In another embodiment, the D (0.5) is from about 10 μm to about 50 μm. In another embodiment, the D (0.5) is from about 20 μm to about 50 μm. In another embodiment, the D (0.5) is from about 30 μm to about 50 μm. In another embodiment, the D (0.5) is from about 40 μm to about 50 μm.

Tablets will generally comprise one or more excipients. The excipients should be compatible with the other ingredients of the formulation and not physiologically deleterious to the recipient thereof. Examples of suitable Excipients are well known to those skilled in the art of tablet formulation and may be found, for example, in Handbook of Pharmaceutical Excipients (eds.: Rowe, Sheskey & Quinn) 6 th edition 2009.

In one embodiment, the pharmaceutical composition comprises at least one diluent. The diluent may be selected from the group consisting of: lactose, sorbitol, dibasic calcium phosphate dihydrate, calcium sulfate dihydrate, calcium carbonate, croscarmellose sodium, calcium phosphate, dibasic calcium phosphate dihydrate, crospovidone, ferric oxide, magnesium carbonate, magnesium oxide, sucrose or sodium chloride. In another embodiment, the at least one diluent may be selected from the group consisting of: lactose, sorbitol, croscarmellose sodium, crospovidone, ferric oxide, magnesium carbonate, magnesium oxide or sucrose. In another embodiment, the at least one diluent may be selected from the group consisting of: lactose, sorbitol or sucrose. In another embodiment, the at least one diluent is lactose. Lactose can be used in anhydrous or hydrated form (e.g. monohydrate) and is usually prepared by spray drying, fluid bed granulation or drum drying. In another embodiment, the at least one diluent is sorbitol. In another embodiment, the at least one diluent is sucrose.

In one embodiment, the at least one diluent is present in the composition in an amount of about 10% to about 90% wt/wt based on the total weight of the composition. In another embodiment, the at least one diluent is present in the composition in an amount of about 20% to about 80% wt/wt based on the total weight of the composition. In another embodiment, the at least one diluent is present in the composition in an amount of about 30% to about 70% wt/wt based on the total weight of the composition. In another embodiment, the at least one diluent is present in the composition in an amount of about 35% to about 70% wt/wt based on the total weight of the composition. In another embodiment, the at least one diluent is present in the composition in an amount of about 40% to about 70% wt/wt based on the total weight of the composition. In another embodiment, the at least one diluent is present in the composition in an amount of about 45% to about 70% wt/wt based on the total weight of the composition. In another embodiment, the at least one diluent is present in the composition in an amount of about 50% to about 70% wt/wt based on the total weight of the composition.

In one embodiment, the pharmaceutical composition comprises at least one lubricant. The lubricant may be selected from the group consisting of: magnesium stearate, stearic acid, calcium stearate, paraffin, sodium lauryl sulfate, sodium benzoate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, mineral oil, poloxamer, PEG400, PEG 600 or PEG 8000. In another embodiment, the at least one lubricant may be selected from the group consisting of: magnesium stearate, stearic acid, calcium stearate, sodium lauryl sulfate, sodium benzoate, glyceryl monostearate, sodium stearyl fumarate, poloxamer, PEG400, PEG 600 or PEG 8000. In another embodiment, the at least one lubricant may be selected from the group consisting of: magnesium stearate, stearic acid, calcium stearate, PEG400, PEG 600, or PEG 8000. In another embodiment, the lubricant is magnesium stearate. In another embodiment, the lubricant is stearic acid. In another embodiment, the lubricant is calcium stearate. In another embodiment, the lubricant is PEG 400. In another embodiment, the lubricant is PEG 600. In another embodiment, the lubricant is PEG 8000.

In one embodiment, the at least one lubricant is present in the composition in an amount of about 0.01% to about 4% wt/wt based on the total weight of the composition. In another embodiment, the at least one lubricant is present in the composition in an amount of about 0.05% to about 3.5% wt/wt based on the total weight of the composition. In another embodiment, the at least one lubricant is present in the composition in an amount of about 0.1% to about 3% wt/wt based on the total weight of the composition. In another embodiment, the at least one lubricant is present in the composition in an amount of about 0.1% to about 2.5% wt/wt based on the total weight of the composition. In another embodiment, the at least one lubricant is present in the composition in an amount of about 0.1% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one lubricant is present in the composition in an amount of about 0.3% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one lubricant is present in the composition in an amount of about 0.5% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one lubricant is present in the composition in an amount of about 0.7% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one lubricant is present in the composition in an amount of about 1% to about 2% wt/wt based on the total weight of the composition.

In one embodiment, the pharmaceutical composition comprises at least one disintegrant. The disintegrant may be selected from the group consisting of: microcrystalline cellulose, alginic acid, citric acid, croscarmellose sodium, carboxymethylcellulose calcium, cysteine hydrochloride, methylcellulose, polyoxyl stearate, carboxymethyl starch sodium, sodium alginate or carboxymethylcellulose sodium. In another embodiment, the at least one disintegrant may be selected from the group consisting of: microcrystalline cellulose, alginic acid, citric acid, croscarmellose sodium, carboxymethylcellulose calcium, cysteine hydrochloride, methylcellulose, polyoxyl stearate, sodium starch glycolate or carboxymethylcellulose sodium. In another embodiment, the at least one disintegrant may be selected from the group consisting of: microcrystalline cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, methyl cellulose, or sodium carboxymethyl cellulose. In another embodiment, the at least one disintegrant may be selected from the group consisting of: microcrystalline cellulose, carboxymethylcellulose calcium, methylcellulose, or carboxymethylcellulose sodium. In another embodiment, the disintegrant is microcrystalline cellulose. In another embodiment, the disintegrant is sodium starch glycolate. In another embodiment, the disintegrant is carboxymethylcellulose calcium. In another embodiment, the disintegrant is methylcellulose. In another embodiment, the disintegrant is sodium carboxymethyl cellulose.

In one embodiment, the at least one disintegrant is present in the composition in an amount of about 10% to about 40% wt/wt based on the total weight of the composition. In another embodiment, the at least one disintegrant is present in the composition in an amount of about 15% to about 35% wt/wt based on the total weight of the composition. In another embodiment, the at least one disintegrant is present in the composition in an amount of about 18% to about 33% wt/wt based on the total weight of the composition. In another embodiment, the at least one disintegrant is present in the composition in an amount of about 20% to about 30% wt/wt based on the total weight of the composition. In another embodiment, the at least one disintegrant is present in the composition in an amount of about 22% to about 28% wt/wt based on the total weight of the composition.

In one embodiment, when the disintegrant is microcrystalline cellulose, the disintegrant is present in the composition in an amount of about 10% to about 40% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 15% to about 35% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 18% to about 33% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 20% to about 30% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 22% to about 28% wt/wt based on the total weight of the composition.

In one embodiment, when the disintegrant is sodium starch glycolate, the disintegrant is present in the composition in an amount of about 2% to about 7% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 2% to about 6.5% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 2% to about 6% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 2.5% to about 5.5% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 3% to about 5% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 3% to about 4.5% wt/wt based on the total weight of the composition. In another embodiment, the disintegrant is present in the composition in an amount of about 3% to about 4% wt/wt based on the total weight of the composition.

In one embodiment, the pharmaceutical composition comprises at least one binder. The binder may be selected from the group consisting of: starch, gelatin, glucose, polyvinylpyrrolidone (povidone), carboxymethylcellulose, acacia, candelilla wax, carnauba wax, corn starch, glyceryl behenate, hypromellose, or polyethylene oxide. In another embodiment, the at least one binder may be selected from the group consisting of: starch, gelatin, glucose, polyvinylpyrrolidone (povidone), acacia, candelilla wax, carnauba wax, corn starch, glyceryl behenate, or hypromellose. In another embodiment, the at least one binder may be selected from the group consisting of: starch, gelatin, glucose, acacia, candelilla, carnauba, or corn starch. In another embodiment, the binder is starch. In another embodiment, the binding agent is gelatin. In another embodiment, the binder is glucose. In another embodiment, the binder is gum arabic. In another embodiment, the binder is candelilla wax. In another embodiment, the binder is carnauba wax. In another embodiment, the binder is corn starch.

In one embodiment, the at least one binder is present in the composition in an amount of about 2% to about 20% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 3% to about 19% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 4% to about 18% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 5% to about 17% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 5% to about 16% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 5% to about 15% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 5% to about 14% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 5% to about 13% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 5% to about 12% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 5% to about 11% wt/wt based on the total weight of the composition. In another embodiment, the at least one binder is present in the composition in an amount of about 5% to about 10% wt/wt based on the total weight of the composition.

As mentioned above, problems of spotting, sticking to punches and consistency of tablet batches can be mitigated by micronization of the API. It has been found that the combination of micronization of the API with the use of an anti-caking agent can further alleviate these problems. In particular, the combination of micronization of the API with the use of a specific anti-caking agent can produce a tablet formulation that is spot-free, non-sticking to the punches, and consistent from batch to batch.

Thus, in one embodiment, the at least one anti-caking agent may be selected from the group consisting of: fumed silica, or talc. In another embodiment, the anti-caking agent is fumed silica. In another embodiment, the anti-caking agent is silicon dioxide. In another embodiment, the anti-caking agent is talc.

In one embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.05% to about 4% wt/wt, based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.1% to about 3.5% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.15% to about 3% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.2% to about 2.5% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.2% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.25% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.3% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.35% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.4% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.45% to about 2% wt/wt based on the total weight of the composition. In another embodiment, the at least one anti-caking agent is present in the composition in an amount of from about 0.5% to about 2% wt/wt based on the total weight of the composition.

The tablets provided herein may be uncoated or coated (in which case they include a coating). Although uncoated tablets may be used, it is more common to provide coated tablets, in which case a conventional non-enteric coating may be used. Film coatings are known in the art and may be composed of hydrophilic polymeric materials, not limited to polysaccharide materials, such as Hypromellose (HPMC), methylcellulose, Hydroxyethylcellulose (HEC), Hydroxypropylcellulose (HPC), poly (vinyl alcohol-co-ethylene glycol), and other water-soluble polymers. Although the water soluble material included in the film coating of the present invention may include a single polymeric material, it may also be formed using a mixture of more than one polymer. The coating may be white or colored, e.g., gray. Suitable coatings include, but are not limited to, polymeric film coatings, such as those comprising polyvinyl alcohol, e.g.'

II' (which includes partially hydrolyzed PVA, titanium dioxide, polyethylene glycol 3350 and talc, and optionally a coloring agent such as iron oxide or indigo carmine or yellow iron oxide (iron oxide yellow) or FD&C yellow No. 6). The amount of coating will generally be between about 2-4% by weight of the tablet core, and in certain specific embodiments, about 3%. Unless otherwise specifically stated, where dosage forms are coated, it is understood that reference to% by weight of a tablet means the weight of the entire tablet, i.e., including the coatingAnd (4) weight.

Accordingly, the pharmaceutical composition may further comprise at least one coating selected from the group consisting of: hydroxypropyl cellulose, hypromellose phthalate, methylcellulose, methacrylic acid copolymer, tetraiodofluorescein sodium, or sodium propionate. In another embodiment, the at least one coating may be selected from hydroxypropyl cellulose, hypromellose phthalate, methylcellulose, or methacrylic acid copolymers. In another embodiment, the coating is hydroxypropyl cellulose. In another embodiment, the coating is hypromellose. In another embodiment, the coating is hypromellose phthalate. In another embodiment, the coating is methylcellulose. In another embodiment, the coating is a methacrylic acid copolymer.

Suitable pharmaceutical compositions contain, for example, from about 0.1% to about 99.9% of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof (active ingredient). In one embodiment, the active ingredient may be present in the composition in an amount of about 0.1% to about 90% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 0.1% to about 80% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 0.1% to about 70% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 0.1% to about 60% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 0.1% to about 50% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 1% to about 80% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 5% to about 80% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 10% to about 80% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 15% to about 80% wt/wt based on the total weight of the composition. In another embodiment, the active ingredient may be present in the composition in an amount of about 20% to about 80% wt/wt based on the total weight of the composition.

In some embodiments, the pharmaceutical composition in tablet form comprises:

(i) a compound of formula (I) as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof;

(ii) lactose;

(iii) magnesium stearate;

(iv) microcrystalline cellulose;

(v) starch; and

(vi) sodium starch glycolate.

In other embodiments, the pharmaceutical composition in tablet form comprises:

(i) a compound of formula (I) as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof; wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof within the composition has a D (0.5) particle size distribution of less than 60 μ ι η;

(ii) lactose;

(iii) magnesium stearate;

(iv) microcrystalline cellulose;

(v) starch; and

(vi) sodium starch glycolate.

In other embodiments, the pharmaceutical composition in tablet form comprises:

(ii) lactose, wherein the lactose is present in the composition in an amount of about 35% to about 70% wt/wt based on the total weight of the composition.

(iii) Magnesium stearate; wherein magnesium stearate is present in the composition in an amount of about 0.1% to about 2% wt/wt based on the total weight of the composition;

(iv) microcrystalline cellulose, wherein the microcrystalline cellulose is present in the composition in an amount of about 20% to about 30% wt/wt based on the total weight of the composition;

(v) a starch, wherein the starch is present in the composition in an amount of about 5% to about 15% wt/wt based on the total weight of the composition; and

(vi) sodium starch glycolate, wherein the sodium starch glycolate is present in the composition in an amount of about 2% to about 7% wt/wt based on the total weight of the composition.

In some embodiments, the pharmaceutical composition comprises:

(i) a compound of formula (I) as described herein or a pharmaceutically acceptable salt, solvate or prodrug thereof;

(ii) lactose;

(iii) magnesium stearate;

(iv) microcrystalline cellulose;

(v) starch; and

(vi) fumed silica.

In some embodiments, the pharmaceutical composition in tablet form comprises:

(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof as described herein, wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof within the composition has a D (0.5) particle size distribution of less than 60 μ ι η;

(ii) lactose;

(iii) magnesium stearate;

(iv) microcrystalline cellulose;

(v) starch; and

(vi) fumed silica.

In other embodiments, the pharmaceutical composition in tablet form comprises:

(ii) lactose, wherein the lactose is present in the composition in an amount of about 35% to about 70% wt/wt based on the total weight of the composition;

(iii) magnesium stearate, wherein magnesium stearate is present in the composition in an amount of about 0.1% to about 2% wt/wt based on the total weight of the composition;

(iv) microcrystalline cellulose, wherein the microcrystalline cellulose is present in the composition in an amount of about 20% to about 30% wt/wt based on the total weight of the composition;

(v) a starch, wherein the starch is present in the composition in an amount of about 5% to about 15% wt/wt based on the total weight of the composition; and

(vi) fumed silica, wherein the fumed silica is present in the composition in an amount of about 0.2% to about 2% wt/wt based on the total weight of the composition.

Pharmaceutically acceptable salts include those obtained by reacting a main compound functioning as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid. Pharmaceutically acceptable salts also include those salts in which the principal compound acts as an acid and is formed by reaction with an appropriate base, for example, the salts of sodium, potassium, calcium, magnesium, ammonium and choline. One skilled in the art will further recognize that acid addition salts may be prepared by reacting the compounds with the appropriate inorganic or organic acid by any of a variety of known methods. Alternatively, alkali metal salts and alkaline earth metal salts can be prepared by reacting the compounds with an appropriate base by a variety of known methods. The following are further examples of acid salts that may be obtained by reaction with inorganic or organic acids: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, digluconate, cyclopentylpropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate (palmoate), pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, methanesulfonate, and undecanoate.

It will be appreciated that in addition to the ingredients particularly mentioned above, the compositions of the invention may also include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents, disintegrants, coating agents, preservatives, lubricants and/or time delay agents. Suitable sweetening agents include aspartame or saccharin. Suitable flavoring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavoring agents. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable time delays include glyceryl monostearate or glyceryl distearate.

The composition may contain any other suitable carrier, diluent or excipient. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, skin penetration agents, surfactants, isotonic and absorption agents, and the like. It will be appreciated that the compositions of the invention may also comprise other supplementary physiologically active agents.

For example, the pharmaceutical composition may further comprise preservatives, buffers, stabilizers and/or viscosity enhancers. Examples of suitable preservatives are benzoic acid esters of p-hydroxybenzoic acid, propylene glycol, phenol, phenethyl alcohol or benzyl alcohol. Examples of suitable buffers are sodium phosphate salts, citric acid, tartaric acid, and the like. Examples of suitable stabilizers are antioxidants such as alpha-tocopheryl acetate, alpha-thioglycerol, sodium metabisulphite, ascorbic acid, acetylcysteine, 8-hydroxyquinoline, chelating agents such as disodium edetate. Examples of suitable viscosity enhancing agents, suspending or dispersing agents are polyvinyl alcohol, carbomer, polyoxypropylene glycol, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene hydrogenated castor oil 60.

For example, the pharmaceutical composition may further comprise a pH controlling agent and/or an isotonic agent. Examples of suitable pH control agents include hydrochloric acid, sodium hydroxide, and the like. Examples of suitable isotonicity agents are glucose, D-sorbitol or D-mannitol, sodium chloride.

The carrier must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

In some embodiments, it was observed that the pharmaceutical composition adhered to the die tablet press during compression into tablets. Advantageously, it was observed that by varying the nominal weight of the tablet, the blocking effect could be further minimized and/or eliminated.

Thus, in one embodiment, the pharmaceutical composition in tablet form has a weight of about 50mg to about 500 mg. In another embodiment, the tablet is about 50mg to about 450 mg. In another embodiment, the tablet is about 50mg to about 400 mg. In another embodiment, the tablet is about 50mg to about 350 mg. In another embodiment, the tablet is about 50mg to about 300 mg. In another embodiment, the tablet is about 100mg to about 300 mg. In another embodiment, the tablet is about 50 mg. In another embodiment, the tablet is about 75 mg. In another embodiment, the tablet is about 100 mg. In another embodiment, the tablet is about 150 mg. In another embodiment, the tablet is about 200 mg. In another embodiment, the tablet is about 250 mg. In another embodiment, the tablet is about 300 mg. In another embodiment, the tablet is about 350 mg. In another embodiment, the tablet is about 400 mg. In another embodiment, the tablet is about 450 mg. In another embodiment, the tablet is about 500 mg.

Compositions of the present invention suitable for oral administration may be presented as discrete units, such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., an inert diluent, preservative, disintegrant (e.g., sodium carboxymethyl starch, crospovidone, croscarmellose sodium), surfactant or dispersing agent.

Compositions suitable for topical application in the oral cavity include: lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of the active ingredient as described herein above.

In one embodiment, the pharmaceutical composition in tablet form is an immediate release pharmaceutical composition. In this aspect, the pharmaceutical composition is formulated to release the API immediately upon oral administration. Immediate release products generally result in relatively rapid drug absorption and concomitant onset of pharmacodynamic effects. Providing a subject in need with a rapid relief of the increase in ICP is advantageous for the pharmaceutical composition of the invention, as the subject's condition may worsen because of the longer he/she is in such an abnormal state. Elevated ICP is likely to cause serious injury, and if sustained, is often fatal. For example, elevated ICP can crush brain tissue, alter brain structure, cause hydrocephalus, cause a brain hernia, and limit blood supply to the brain. Thus, the compositions of the present invention may provide relief from conditions and/or symptoms caused by elevated ICP, such as, but not limited to, headache, vomiting without nausea, ocular paralysis, altered level of consciousness, elevated blood pressure, back pain, double vision, optic papillary edema, or further damage to the brain or spinal cord, or a combination thereof.

In one embodiment, the compound of formula (I) is released immediately after oral administration. In another embodiment, the compound of formula (I) is released 1 minute after oral administration. In another embodiment, the compound of formula (I) is released 5 minutes after oral administration. In another embodiment, the compound of formula (I) is released 10 minutes after oral administration. In another embodiment, the compound of formula (I) is released 15 minutes after oral administration. In another embodiment, the compound of formula (I) is released 20 minutes after oral administration. In another embodiment, the compound of formula (I) is released 25 minutes after oral administration. In another embodiment, the compound of formula (I) is released 30 minutes after oral administration. In another embodiment, the compound of formula (I) is released 40 minutes after oral administration. In another embodiment, the compound of formula (I) is released 50 minutes after oral administration. In another embodiment, the compound of formula (I) is released 60 minutes after oral administration. In another embodiment, the compound of formula (I) is released 90 minutes after oral administration.

In a second aspect, the present invention provides a method for treating elevated intracranial pressure in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition in the form of a tablet comprising:

(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

wherein R is₁Is H or C_1-4An alkyl group; and is

Wherein the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof within the composition has a D (0.5) particle size distribution of less than about 60 μm;

(iii) at least one lubricant selected from the group consisting of: magnesium stearate, stearic acid, calcium stearate, paraffin wax, sodium lauryl sulfate, sodium benzoate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, sodium stearyl fumarate, mineral oil, poloxamer, PEG400, PEG 600, or PEG8000, wherein the at least one lubricant is present in the composition in an amount of about 0.1% to about 2% wt/wt based on the total weight of the composition;

In a third aspect, the present invention provides a pharmaceutical composition in the form of a tablet for use in treating increased intracranial pressure in a subject in need thereof, the pharmaceutical composition as described herein.

In one embodiment, the dosage of the pharmaceutical composition administered to the subject in various embodiments of the invention is such that the compound of formula (I) administered is in the range of 0.1mg/kg to 100 mg/kg. In one embodiment, the dosage of the pharmaceutical composition administered to the subject in various embodiments of the invention is such that the compound of formula (I) administered is in the range of 0.1mg/kg to 100 mg/kg. For example, the dose may be 0.1mg/kg, 0.2mg/kg, 0.5mg/kg, 1.0mg/kg, 2.0mg/kg, 3.0mg/kg, 4.0mg/kg, 5.0mg/kg, 6.0mg/kg, 7.0mg/kg, 8.0mg/kg, 9.0mg/kg, 10.0mg/kg, 11.0mg/kg, 12.0mg/kg, 13.0mg/kg, 14.0mg/kg, 15.0mg/kg, 16.010 mg/kg, 17.0mg/kg, 18.0mg/kg, 19.0mg/kg, 20.0mg/kg, 21.0mg/kg, 22.0mg/kg, 23.0mg/kg, 24.0mg/kg, 25.0mg/kg, 26.0mg/kg, 27.0mg/kg, 28.0mg/kg, 29.0mg/kg, 30.0mg/kg, 31.0mg/kg, 0mg/kg, 31.0mg/kg, 34.0mg/kg, 35.0mg/kg, 36.0mg/kg, 37.0mg/kg, 38.0mg/kg, 39.0mg/kg, 40.0mg/kg, 41.0mg/kg, 42.0mg/kg, 43.0mg/kg, 44.0mg/kg, 45.0mg/kg, 46.0mg/kg, 47.0mg/kg, 48.0mg/kg, 49.0mg/kg, 50.0mg/kg, 51.0mg/kg, 52.0mg/kg, 53.0mg/kg, 54.0mg/kg, 55.0mg/kg, 56.0mg/kg, 57.0mg/kg, 58.0mg/kg, 59.0mg/kg, 60.0mg/kg, 61.0mg/kg, 62.0mg/kg, 63.0mg/kg, 64.0mg/kg, 65.0mg/kg, 66.0mg/kg, 67.0mg/kg, 0mg/kg, 0.0mg/kg, 67.0mg/kg, 0mg/kg, 50.0mg/, 71.0mg/kg, 72.0mg/kg, 73.0mg/kg, 74.0mg/kg, 75.0mg/kg, 76.0mg/kg, 77.0mg/kg, 78.0mg/kg, 79.0mg/kg, 80.0mg/kg, 81.0mg/kg, 82.0mg/kg, 83.0mg/kg, 84.0mg/kg, 85.0mg/kg, 86.0mg/kg, 87.0mg/kg, 88.0mg/kg, 89.0mg/kg, 90.0mg/kg, 91.0mg/kg, 92.0mg/kg, 93.0mg/kg, 94.0mg/kg, 95.0mg/kg, 96.0mg/kg, 97.0mg/kg, 98.0mg/kg or 99.0 mg/kg.

In one embodiment, the pharmaceutical composition should be administered as a treatment for an injury associated with concussion following an injury event.

In one embodiment, the method for treating increased intracranial pressure is a method for treating traumatic brain injury.

In another embodiment, the method for treating increased intracranial pressure is a method for treating stroke.

In one embodiment, the effective amount is an amount capable of maintaining a blood concentration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, within a therapeutic range for at least 3 days, e.g., at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, or at least 20 days.

In one embodiment, the effective amount is administered in a single or multiple doses. In one embodiment, the effective amount is administered in a single or multiple oral doses.

The terms "treatment (treat)", "treatment (treatment)" and "treating (treating)" refer to one or more of:

(a) alleviating or reducing at least one symptom of a disorder in a subject, including, for example, reducing intracranial pressure in a TBI patient or preventing post-concussion PCS;

(b) alleviating or reducing the intensity and/or duration of manifestation of a condition experienced by a subject, including, but not limited to, those in response to a given stimulus (e.g., pressure, tissue damage, hypothermia, etc.); and

(c) suppress, delay onset (i.e., the period prior to clinical manifestation of the disorder) and/or reduce the risk of developing or worsening the disorder.

The subject or patient receiving administration of a therapeutic compound as an effective treatment for a disease or condition is preferably a human.

It will be understood that any compound that is a prodrug of the compound of formula (I) is also within the scope and spirit of the invention. The term "prodrug" is used in its broadest sense and includes those derivatives that are converted in vivo to the compounds of the invention. Such derivatives will readily occur to those skilled in the art and include, for example, phosphonic acid derivatives.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope of the invention. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

Certain embodiments of the present invention will now be described with reference to the following examples, which are intended for illustrative purposes only and are not intended to limit the scope of the generality of the foregoing description.

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