MX2008000963A - High drug load formulations and dosage forms - Google Patents

Abstract

The invention relates to high drug load formulations containing (R)-2-(2-fluoro-4-biphenylyl)propionic acid as an active pharmaceutical ingredient.

Description

FORMULATIONS WITH HIGH DRUG CHARGE AND DOSAGE FORMS CROSS REFERENCE WITH RELATED REQUESTS This request claims priority according to 35 U.S.C. § 119 (e) to US Provisional Applications Nos. 60/701, 710, filed July 22, 2005 and 60 / 706,344 filed August 8, 2005, both are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION The invention relates to pharmaceutical formulations and dosage forms, particularly pharmaceutical formulations having a high drug loading.

BACKGROUND OF THE INVENTION A particularly difficult problem faced by the pharmaceutical and medical communities is patient compliance with dosing regimens. Lack of adherence to a dosing regimen can be disastrous. Generally speaking, depending on the pharmacokinetic and pharmacodynamic behavior of a therapeutic specific, and the nature of the disease, a profile of drug concentration in a target tissue must be obtained to produce a therapeutic effect. Effective drug concentration profiles are obtained through patient compliance with dosing regimens that were shown to produce a clinically relevant effect during controlled clinical trials. Non-compliance (not attachment) with a prescribed dosing regimen has negative clinical consequences. Failure to comply may result in lower levels of drug in the target tissue and the disease may "escape" the effects of the drug since it is not present at inhibitory concentrations. For example, non-compliance with the prescribed treatment regimen for antiretroviral medication has produced drug-resistant strains of HIV that have been transmitted throughout the population (Boden et al., JAMA 282: 1135-1141 (1999)). In fact, there is an excessive decline in sustaining the viral load as compliance goes from 95% to 70% (Paterson et al Ann. Int. Med. 133: 21-30 (2000)), resulting in more problems for the patient. The pharmaceutical / medical community has concentrated clinical trials of drug development on simple dosing regimens to promote compliance. Drugs that require complex dosing regimens are now routinely abandoned because patients will not meet or can not comply with the required dosing regimen. An interesting example of how tablet compliance and size affect Drug development is the history of the protease inhibitors amprenavir and fosamprenavir. Amprenavir was approved by the FDA in 1999 as an HIV protease inhibitor but never gained widespread use because it was found to be significantly less effective than indinavir. In fact, the current guidelines recommend against the use of amprenavir due to a high tablet load and its potential effect on compliance (Discussion on Clinical Practices for the Treatment of HIV Infection, convened by the Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents infected with HIV See www.Aidsinfo.nih.gov). Recently, fosamprenavir was approved by the FDA for the treatment of HIV-1. Fosamprenavir is a prodrug of amprenavir that has improved oral solubility and bioavailability, allowing dosing once or twice a day with smaller tablets and fewer tablets than amprenavir, resulting in increased patient acceptance of the dosing regimen of fosamprenavir and the greater compliance and expected clinical efficacy. A particular problem in creating acceptable dosing regimens is when large quantities of a drug need to be delivered to a patient: there is a limit to the size of a tablet that a patient is able to swallow and the more tablets a patient has to take It will be that he commits an error, resulting in non-compliance. There is a need for useful formulations for the delivery of large amounts of drug, with a manageable tablet (pill) load and an acceptable tablet size. The pharmaceutical tablet formulation typically involves mixing the active pharmaceutical ingredient (API, the drug) with one or more inactive ingredients (ie, excipients). Tablets containing low doses (eg, less than 50 mg of drug per dose) will often be formulated with more excipient on a weight basis than the API to facilitate the manufacturing process (eg, compaction), but still give As a result small tablets that are easy to swallow for the patient. Because the excipient comprises a substantial portion of the total tablet weight, the processing and fabricability of the tablets are easily adjusted regardless of the properties of the drug agent. Conversely, with high-dose drugs, the characteristics of the tablet are profoundly influenced by the properties of the API. If these properties are not compatible with commercial manufacturing requirements, the formulator is faced with producing tablets that are larger in size (adding excipients to solve manufacturing problems), or requiring the administration of multiple tablets, each containing a percentage Reduced API, both situations have a negative impact on patient compliance. There is a need for dosage forms containing (R) -2- (2-fluoro-4-biphenylyl) propionic acid containing a high charge of drug wherein the drug comprises a high percentage of the weight of the total dosage form to provide dosage forms of a size that facilitate patient compliance with common dosage regimens.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to formulations with high drug loading having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as the active pharmaceutical ingredient. The inventors have discovered formulations of (R) -2- (2-fluoro-4-biphenylyl) propionic acid which allow the production of tablets containing (R) -2- (2-fluoro-4-biphenylyl) propionic acid having each 200 mg or more of API, excellent mechanical properties and dissolution profiles, and pharmacokinetically desirable profiles. The inventively high drug loading formulations allow the production of tablets having 55% or more (by weight) of (R) -2- (2-fluoro-4-biphenylyl) propionic acid. The inventive compositions also have desirable manufacturing characteristics. Formulations with high drug loading are suitable for use under conditions that require the dosing of high levels of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, such as Alzheimer's disease. In a first embodiment, the invention provides a pharmaceutical composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid or a pharmaceutically acceptable salt thereof mixed with one or more excipients pharmaceutically acceptable, wherein the weight of the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is 55% or more of the total weight of the unit dosage form. In some aspects of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid may be 57% or more, 60% or more, or 63% or more of the total weight of the dosage form unitary In some aspects of this embodiment, the unit dosage form has approximately 200 mg, 200 or more mg, 300 mg, 300 or more mg, 400 mg, 400 or more mg, 500 mg, 500 or more mg, 600 mg, 600 or more mg, 700 mg, 700 or more mg, 800 mg, or 800 or more mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid. In one aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation has a disintegrant as an ingredient (eg, microcrystalline cellulose and / or croscarmellose sodium). In another aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation has a binder as an ingredient (e.g., hydroxypropylmethylcellulose). In another aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation has a diluent as an ingredient (e.g., lactose). In another aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation has a slipping agent as an ingredient (eg, colloidal silicon dioxide). In another aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation has a lubricant as an ingredient (eg, magnesium stearate). The formulations and unit dosage forms of this embodiment of the invention, optionally, may have coatings, coloring agents, stabilizers, preservatives, and / or flavoring agents. Formulation of this modality may be provided as a unit dosage form suitable for oral administration (e.g., a tablet). The first embodiment of the invention further provides a (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation having from 55% to 90% by weight of (R) -2- (2-fluoro) acid -4-biphenylyl) propionic and from 10% to 45% by weight of inactive pharmaceutical ingredients. In one aspect, the formulation has from 55% to 85% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid and 15% -45% by weight of inactive pharmaceutical ingredients. In one aspect, the formulation has from 55% to 75% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid and from 25% to 45% by weight of inactive ingredients. In one aspect, the formulation has from 60% to 70% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid and from 30% to 40% by weight of inactive pharmaceutical ingredients. In a second embodiment, the invention provides a tablet dosage form having between 320 and 480 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, or a pharmaceutically acceptable salt thereof, wherein the The long axis of the tablet is about 1.52 cm to 2.03 cm, and the tablet width is about 0.76 cm to 1.01 cm. In one aspect of this embodiment, the unit dosage form has a length no greater than 2.08 cm, no greater than 2.03 cm, no greater than 1.95 cm, no greater than 1.82 cm, or no greater than 1.77 cm. In one aspect of this modality, the form of unit dosage has a width no greater than 1.04 cm, no greater than 1.01 cm, no greater than 0.96 cm, or no greater than 0.88 cm. In some aspects of the invention, the total volume of the unit dosage form is less than 0.70 cm3, less than 0.65 cm3, less than 0.60 cm3, less than 0.55 cm3, less than 0.50 cm3, or less than 0.45 cm3. In some aspects of this embodiment, each tablet has one or more excipients chosen from disintegrants, binders, diluents, slipping agents, lubricants, coloring agents, stabilizers, preservatives, and / or flavoring agents. In some aspects of this embodiment, each tablet has (R) -2- (2-fluoro-4-biphenylyl) propionic acid and one or more binders, one or more diluents, one or more disintegrants, one or more slipping agents, one or more lubricants, and if desired, one or more optional ingredients. In one aspect of this embodiment, the tablet unit dosage form is coated. In a third embodiment, the invention provides a unit dosage form of tablet having 55% or more by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, or a pharmaceutically acceptable salt thereof, and which produces a dissolution profile substantially similar to one or more of those shown in Figures 1 and 2. The unit dosage form of this embodiment is suitable for oral administration. In a related embodiment, the unit dosage form is a capsule dosage form. In one aspect of this third embodiment, the unit dosage form has (R) -2- (2-fluoro-4-biphenylyl) propionic acid and one or more pharmaceutically acceptable excipients. With a way of tablet dosage, the excipient (s) may be chosen from disintegrants, binders, diluents, sliders, lubricants, coloring agents, stabilizers, preservatives, and / or flavoring agents. In one aspect of this embodiment, the unit dosage form is a coated tablet. In other aspects of this embodiment, the unit dosage form has (R) -2- (2-fluoro-4-biphenylyl) propionic acid and one or more pharmaceutically acceptable excipients in sufficient amounts to produce a dissolution profile substantially similar to one. or more than those shown in Figures 1 and 2. In one aspect of this embodiment, a dosage form is provided having between 320 to 480 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid which produces a dissolution profile substantially similar to one or more of those shown in Figures 1 and 2. In a fourth embodiment, the invention provides a unit dosage form of tablet containing approximately 400 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, or a pharmaceutically acceptable salt thereof, and having 55% or more by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid in the tablet. According to this embodiment, the unit dosage form of 400 mg produces a pharmacokinetic profile that is substantially similar (bioequivalent) to that shown in Figure 3A-3C and Table A after oral administration of the indicated dose to an individual in fasting state (eg, two tablets, each containing 400 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid for 800 mg total API). The The unit dosage form of this modality is suitable for oral administration. In a related embodiment, the unit dosage form is a capsule dosage form. In one aspect of this fourth embodiment, the unit dosage form has (R) -2- (2-fluoro-4-biphenylyl) propionic acid and one or more pharmaceutically acceptable excipients as components. With a tablet dosage form the excipient (s) can be chosen from disintegrants, binders, diluents, sliders, lubricants, coloring agents, stabilizers, preservatives, and / or flavoring agents. In one aspect of this fourth embodiment, the unit dosage form is a coated tablet. In another aspect of this embodiment, the unit dosage form has (R) -2- (2-fluoro-4-biphenylyl) propionic acid and one or more pharmaceutically acceptable excipients in sufficient amounts to produce a substantially similar pharmacokinetic profile (bioequivalent) to that shown in Figure 3A-3C and Table A when orally administered to an individual in a fasted state. In one aspect of this embodiment, a dosage form is provided having between 320 and 480 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid which produces a substantially similar (bioequivalent) pharmacokinetic profile to that shown in Figure 3A-3C and Table A for the BID dose group of 800 mg (e.g., 2 tablets each having approximately 400 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid) .

In one aspect, the unit dosage form according to any of the embodiments of the invention, when tested in a pH regulator of potassium phosphate pH 7.2 at 37 ° C using a USP 2 apparatus (paddles), at a rotation speed of 75 rpm, has a dissolution profile so that less than 85, 80, 75, 70, 65, or 60 percent by weight of the acid (R) -2- (2-fluoro-4-biphenylyl) Propionic is released at 15 minutes. In one aspect, the unit dosage form according to any of the embodiments of the invention, when tested in a pH regulator of potassium phosphate pH 7.2 at 37 ° C using a USP 2 apparatus (blades) at a speed rotation of 75 rpm, has a dissolution profile so that not less than 3, 5, 10, 15, 20, 30, 40, 50, 60, 70, or 80 percent by weight of the acid (R) -2 - (2-fluoro-4-biphenylyl) propionic is released at 15 minutes. In another aspect, the unit dosage form according to any of the embodiments of the invention, when tested in a pH regulator of potassium phosphate pH 7.2 at 37 ° C using a USP 2 device (paddles) at a speed of rotation of 75 rpm, has a dissolution profile so that more than 80, 85, 90, or 95 percent by weight of the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is released at 45 minutes In another aspect, the unit dosage form according to any of the embodiments of the invention, when tested in a pH regulator of potassium phosphate pH 7.2 at 37 ° C using a USP 2 device (paddles) at a speed rotation of 75 rpm, has a dissolution profile so that more than 70, 80, 90, 92, 94, or 96 weight percent of the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is released at 60 minutes. In another embodiment, the invention provides compositions and methods useful for preparing unit dosage forms having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient. . According to one aspect of this embodiment of the invention, the composition is a premixing composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, and one or more other agents sliders as ingredients. In some aspects of this embodiment, (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in the premix composition in amounts of 50-95%, 60-95%, or 70-95% of the total weight of the premix composition. The diluent is present in an amount sufficient to allow adequate mixing with the other ingredients of the formulation and / or allow adequate flowability during manufacture. In some aspects of this embodiment, the premix composition has one or more diluents present in amounts of 1-30%, 3-25%, or 5-20% of the total weight of the premix composition. The slipping agent is present in an amount sufficient to ensure the proper flow qualities of the powder mixture (premix composition). In some aspects of this embodiment, the premix composition has one or more slipping agents present in amounts of 0.01-5%, 0.1-5%, or 0.1-3% of the total weight of the premix composition. In some aspects of this embodiment, optional ingredients are present in amounts of 0-20%, 1-20%, or 1-10% of the total weight of the premix composition. In one aspect, the method includes charging (R) -2- (2-fluoro-4-biphenylyl) propionic acid, the diluent (s), the slipping agent (s) and any optional ingredients in a mixer followed by mixing for a sufficient time to provide a substantially uniform pre-mix composition. The premix composition can then be used in the next process step, grinding. According to one aspect of the invention, the premix composition is then milled through a screen having a size sufficient to reduce the particle size of the larger particles of the premix composition to give a milled composition. The milled composition can then be used to form a wet granulation. In an alternative aspect, the materials can be loaded directly into the high shear granulator and blended in the high shear granulator before the wet granulation step. In another embodiment, the invention provides a wet granulation composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, one or more binders, one or more slipping agents, one or more more wetting agents and optionally, one or more additional ingredients. In addition, this embodiment provides a method for wet granulation of the wet granulation composition. In one aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in the wet granulation composition in amounts of 40-95%, 45-95%, or 50-90% of the total weight of the wet granulation composition. In one aspect of this embodiment, the diluent (s) are present in the wet granulation composition in amounts of 1-30%, 1-20%, or 5-15% of the total weight of the wet granulation composition. In one aspect of this embodiment, the slipping agent (s) are present in the wet granulation composition in amounts of 0.01-10%, 0.01-5%, or 0.1-5% of the total weight of the wet granulation composition. The binder is present in an amount sufficient to impart an immediate release dissolution profile for the unit dosage form of coated tablet. In one aspect of this embodiment, the binder (s) are present in the wet granulation composition in amounts of 1-30%, 1-20%, or 1-15% of the total weight of the wet granulation composition. The wetting agent is present in an amount sufficient to prevent the formation of granules that are hard enough to require excessive pressure to tablet (and / or prevent the formation of tablets having a mottled appearance) and / or result in granules that they are excessively soft causing difficulties during compression (and / or disintegration during lubrication). In one aspect of this embodiment, the wetting agent (s) are present in the wet granulation composition in amounts of 1-40%, 1-25%, or 5-25% of the total weight of the wet granulation composition. In some aspects of this modality, optional ingredients are present in amounts of 0-20%, 1-20%, or 1- % of the total weight of the wet granulation composition. According to one aspect of this embodiment, the binder and milled composition are loaded in a granulator and mixed dry for a sufficient time to adequately mix / bond the ground composition and the binder (e.g., provide a substantially uniform mixture). followed by high shear granulation with the wetting agent for a sufficient time to result in the formation of different granules.The wet granulation is then ground through a sufficient screen size to reduce the average particle size. The wet granulation is then dried by means of an appropriate form of method by removing the wetting agent The "dried" wet granulation can then be milled through a sufficient screen size to produce a granulation composition (component) having a size of adequate particle In another modality, the invention provides a pre-tablet composition having a granulation component and one or more disintegrants. The pre-tablet composition has (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, one or more binders, one or more slipping agents, one or more disintegrants, and optionally, one or more optional ingredients. In one aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in the previous tablet composition in amounts of 50-95%, 55-90%, or 55-85 % of the total weight of the previous tablet composition. In one aspect of this modality, he or she diluents are present in the previous tablet composition in amounts of 1-30%, 1-20%, or 5-15% of the total weight of the previous tablet composition. In one aspect of this embodiment, the binder (s) are present in the prior tablet composition in amounts of 1-30%, 1-20%, or 1-15% of the total weight of the previous tablet composition. In one aspect of this embodiment, the sliders or agents are present in the previous tablet composition in amounts of 0.01-10%, 0.01-5%, or 0.1-5% of the total weight of the previous tablet composition. The disintegrant is present in an amount sufficient to produce an immediate release dissolution profile of the unit dosage form. In one aspect of this embodiment, the disintegrant (s) are present in the prior tablet composition in amounts of 1-40%, 5-25%, or 5-20% of the total weight of the previous tablet composition. In one aspect of this embodiment, one or more optional ingredients are present in the previous tablet composition in amounts of 1-20%, 1-25%, or 5-25% of the total weight of the previous tablet composition. According to one aspect of this embodiment, the dried granulation is charged in a mixer together with the disintegrant (s) and any optional / additional ingredients followed by mixing for a time to provide a substantially uniform mixture. In one embodiment, the invention provides a tableting composition having the tabletting composition and one or more lubricants. Accordingly, this embodiment refers to formulations having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as an API, one or more diluents, one or more binders, one or more slipping agents, one or more disintegrants, and one or more lubricants, and methods for preparing such compositions. The composition of this mode is suitable for compression tabletting. In one aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in the tabletting composition in amounts of 50-95%, 55-90%, or 55-85 % of the total weight of the tabletting composition. In one aspect of this embodiment, the diluent (s) are present in the tableting composition in amounts of 1-30%, 1-20%, or 5-15% of the total weight of the tabletting composition. In one aspect of this embodiment, the binder (s) are present in the tableting composition in amounts of 1-30%, 1-20% or 1-15% of the total weight of the tableting composition. In one aspect of this embodiment, the slider agent (s) are present in the tabletting composition in amounts of 0.01-10%, 0.01-5%, or 0.1-5% of the total weight of the tabletting composition. In one aspect of this embodiment, the disintegrant (s) are present in the tabletting composition in amounts of 1-40%, 5-25%, or 5-20% of the total weight of the tabletting composition. The lubricant is present in an amount sufficient to allow ejection of the tablet in clean form from the die with minimal effort to the tablet. In one aspect of this embodiment, the lubricant (s) are present in amounts of 0.01-10%, 0.1-10%, or 0.1-5% of the total weight of the composition of this embodiment. In some aspects of this modality, the composition is prepared by loading the lubricant (s) in the diffusion mixer with the others components (for example, those in mode three) and mixing for a sufficient time to produce a substantially uniform mixture. The composition prepared according to this embodiment can then be compressed into tablets with an appropriate press. The composition is compressed sufficiently to produce a tablet which, when coated, produces an immediate release dissolution profile that is substantially similar to one or more of those shown in Figure 1 and Figure 2. In another embodiment, the invention refers to preparing a coated tablet having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as an API. The tablet (ie, those prepared according to the above embodiment) is coated with a coating sufficient to produce an immediate release dissolution profile of the unit dosage form of coated tablet and / or impart sufficient stability to the unit dosage form (e.g. complies with the standards of the United States Pharmacopeia (USP)). According to one aspect of this embodiment, a film coating suspension is prepared with a suitable coating agent and water. The film coating suspension can then be used to coat the tablets in, for example, a perforated coating tray to produce a coated tablet. In some aspects of this embodiment, the coating represents 0.1-15%, 0.1-10%, or 1-7% of the total weight of the tablet.

In another embodiment, the invention provides a unit dosage form of (R) -2- (2-fluoro-4-biphenylyl) propionic acid tablet produced in accordance with the methods of the invention which produces a dissolution profile substantially similar to one or more of those shown in Figures 1 and 2. In another aspect of this embodiment, the invention provides a unit dosage form of (R) -2- (2-fluoro-4-biphenylyl) propionic acid tablet produced from according to the methods of the invention which produces a pharmacokinetic profile substantially similar to that shown in Figure 3A-3C and Table A for the indicated dose. In some aspects of the invention, the method for making the tablet unit dosage forms of the invention involves a high shear wet granulation process. In a specific aspect of the invention, the general scheme for the process for making the unit dosage form of the invention involves a premixing composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, and one or more slipping agents, which is mixed long enough to give a uniform pre-milling composition. The pre-grinding composition is then used in the next step of the milling process. The milled composition is then used to form a wet granulation. One or more binders and milled composition are then loaded in a granulator and mixed dry, followed by granulation with the wetting agent to give the wet granulation. The wet granulation is then ground, dried, then milled again to give the intragranular portion of the unit dosage form. Next, one or more disintegrants are added to the intragranular component and mixed in a diffusion mixer. Next, the composition is prepared by loading one or more lubricants into the diffusion mixer with the other components. This composition is then ready for tableting with a compression tablet press. After the formation of the tablets, they can then be coated to give the unit dosage form. An exemplary method of this aspect of the invention is explained in summarized form in Figure 4. In some aspects of the above described embodiments, the unit dosage form of the invention can be manufactured using a high shear granulation procedure in wherein (R) -2- (2-fluoro-4-biphenylyl) propionic acid is premixed and pre-ground with one or more binders such as lactose (eg, anhydrous) and one or more slipping agents such as silicon dioxide colloidal The premix can be processed in a drum mixer followed by milling to reduce the average particle size of the large particles of the (R) -2- (2-fluoro-4-biphenylyl) propionic acid premix before the high shear granulation. Once granulated, the premix can be dried, milled, mixed, compressed in a high speed rotary press and coated on a perforated tray. The formulations and unit dosage forms of the invention are useful for treating diseases and conditions where levels High levels of (R) -2- (2-fluoro-4-biphenylyl) propionic acid need to be delivered to the patient. In some aspects, the invention provides a method for using the unit dosage form as in any of the embodiments of the invention which comprises identifying an individual in need of treatment and administering to said individual a therapeutically effective amount of the unit dosage form. In some aspects of the invention, the individual in need of treatment has a neurodegenerative disorder. In some aspects of the invention, the neurodegenerative disorder is chosen from Alzheimer's disease, dementia, mild cognitive impairment, Parkinson's disease, Huntington's disease and symptoms thereof. In some aspects of the invention the individual in need of treatment has a form of Alzheimer's disease that is chosen from prodromal Alzheimer's disease, mild Alzheimer's disease, mild to moderate Alzheimer's disease, moderate Alzheimer's disease, moderate to severe Alzheimer's disease. , severe Alzheimer's disease, dementia and / or vascular dementia. In some aspects of the invention, the individual in need of treatment has a form of Alzheimer's disease that is mild Alzheimer's disease. In some aspects of this modality, the individual in need of treatment is at risk of developing Alzheimer's disease or wishes prophylaxis against the onset of Alzheimer's disease. In some aspect of the invention, the unit dosage form is administered twice a day (eg, two 400 mg tablets in the morning and two 400 mg tablets in the evening). In some aspects of In the invention, the unit dosage form comprises from about 320 to 480 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid or molar equivalent of a pharmaceutically acceptable salt thereof and two forms are administered to the individual. of unit dosage twice a day (for example, two unit dosage forms in the morning and two unit dosage forms at night). In some aspects of the invention, the individual in need of treatment has Alzheimer's disease or wishes prophylaxis against the development of the symptoms of Alzheimer's disease. In some aspects of the invention, the individual in need of treatment has cancer. In some aspects of the invention, the individual in need of treatment has a cancer (or is looking for cancer prevention) that is chosen from brain, lung, liver, spleen, kidney, lymph node, small intestine, pancreatic, blood cancer. , colon, stomach, breast, endometrial, prostate, testicle, ovary, skin, and cancer of the head and neck, esophageal cancer and bone marrow cancer. In one aspect, the individual who needs treatment has prostate cancer. Those skilled in the art are capable of identifying individuals in need of treatment. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, examples of suitable methods and materials are described in FIG. continuation. In case of conflict, it will control the present specification, including definitions. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the dissolution profiles of various tablets containing (R) -2- (2-fluoro-4-biphenylyl) propionic acid having a PVP binder. See example 3 for experimental details. Figure 2 illustrates the dissolution profiles of various tablets containing (R) -2- (2-fluoro-4-biphenylyl) propionic acid having an HPMC binder. See example 3 for experimental details. Figure 3A-3C and Table A represent a favorable PK profile for the treatment of disorders where the concentration of (R) -2- (2-fluoro-4-biphenylyl) propionic acid should be maintained at a therapeutic level for sustained periods. These profiles were obtained under conditions where the individuals had been in a BID dosing regimen (eg, 800_BID refers to 800 mg of API twice a day) for a sufficient period of time to obtain steady-state drug concentrations before take the indicated dose (200 mg of API, 400 mg of API, or 800 mg of API) after the fasting state.

Figure 4 is an exemplary flow chart illustrating a method of the invention.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to a pharmaceutical formulation with high drug loading having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as the active pharmaceutical ingredient. The invention includes oral compositions that provide pharmacological, pharmacokinetic and therapeutic characteristics particularly useful in the treatment and prevention of Alzheimer's disease, prostate cancer, as well as other disorders. The composition of the invention is formulated with one or more pharmaceutically acceptable excipients (inactive pharmaceutical ingredients). The pharmaceutical composition of the invention is formulated for oral administration (eg, a tablet dosage form). The (R) -2- (2-fluoro-4-biphenylyl) propionic acid-containing composition of the invention can be used in methods for treating, preventing (delaying the onset of one or more symptoms of a disease), and prophylaxis against neurodegenerative disorders such as Alzheimer's disease, or neoplastic diseases such as prostate cancer. The inventors have discovered formulations of (R) -2- (2-fluoro-4-biphenylyl) propionic acid which allow the production of (R) -2- (2-fluoro-4-biphenyl) propionic acid tablets having 200 mg or more of API, manufacturing properties, mechanical properties, dissolution profiles excellent, and pharmacokinetically desirable profiles. The inventive formulations allow the production of tablets having 55% or more by weight of the active pharmaceutical ingredient. Also, the invention relates to a composition and methods for making pharmaceutical compositions having one or more superior properties relative to other compositions comprising (R) -2- (2-fluoro-4-biphenylyl) propionic acid. These superior properties include, but are not limited to, one or more of the following: improved bioavailability, improved solubility of the pharmaceutical composition, improved disintegration times for immediate release oral dosage forms, improved dissolution times for oral dosage forms immediate release, reduced tablet friability, increased tablet hardness, improved safety for oral dosage forms, reduced moisture content and / or hygroscopicity for oral dosage forms, improved composition wettability, improved particle size distribution of acid (R) -2- (2-fluoro-4-biphenylyl) propionic, compressibility of the improved composition, improved composition properties of the composition, improved chemical stability of the final oral dosage form, improved physical stability of the dosage form oral finish, reduced tablet size, or uniformity of the improved cla, improved dose uniformity, increased granule density for wet granulated compositions, reduced water requirements for wet granulation, reduced wet granulation time, and / or reduced drying time for wet granulated mixtures. The formulations and unit dosage forms of the invention contain (R) -2- (2-fluoro-4-biphenylyl) propionic acid as an active pharmaceutical ingredient. (R) -2- (2-Fluoro-4-biphenylyl) propionic acid is the "R" enantiomer of flurbiprofen ((f, S) -2- (2-fluoro-4-biphenylyl) propionic acid). The (R) -2- (2-fluoro-4-biphenylyl) propionic acid can be obtained from resolving racemic flurbiprofen or through enantioselective and enantiospecific synthesis. The R enantiomer of flurbiprofen ((R) -2- (2-fluoro-4-biphenylyl) propionic acid), or a desired enantiomeric excess of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, is it can be obtained by resolving the racemic flurbiprofen according to well known methods, and it is also commercially available (for example, Caymen Chemical, Ann Arbor, Ml). Methods for resolving (R) -2- (2-fluoro-4-biphenylyl) propionic acid from the racemate are described in US Pat. No. 5,599,969 to Hardy et al. which describes reacting racemic flurbiprofen with α-methylbenzylamine to form an isolable salt of (R) -2- (2-fluoro-4-biphenylyl) propionic acid. US Patent 4,209,638 to Boots Co. discloses a process for resolving 2-arylpropionic acids, including flurbiprofen, by mixing the racemate with a chiral organic nitrogenous base under certain conditions followed by recovery and separation of the diastereomeric salts. Other patents that disclose methods for resolving racemic arylpropionic acids include U.S. Patent Nos. 4,983,765 to PAZ; 5,015,764 to Ethyl Corp .; 5,235,100 to Ethyl Corp .; 5,574,183 to Albemarle Corp .; and 5,510,519 to Sumitomo Chemical Company. The oral unit dosage forms of the present invention may contain any of the following inactive ingredients, or compounds of a similar nature: a diluent such as lactose; a binder such as hydroxypropylmethylcellulose; a disintegrating agent (disintegrant) such as croscarmellose sodium, or microcrystalline cellulose; a lubricant such as magnesium stearate or stearic acid; a slipping agent such as colloidal silicon dioxide; and optional ingredients such as coloring agents, stabilizers, preservatives and / or flavoring agents. further, the dosage forms of the invention may contain other miscellaneous materials which modify the physical form of the dosage unit, for example, polymer coatings (eg, cellulose compounds, methacrylates or acrylates), sugar coatings, shellac coatings, color coatings, wax coatings, or other types of coatings. The invention provides pharmaceutical compositions having (R) -2- (2-fluoro-4-biphenylyl) propionic acid and one or more pharmaceutically acceptable excipients, wherein the (R) -2- (2-fluoro-4-biphenylyl) acid propionic comprises 55% or more of the total weight of the unit dosage form. The unit dosage form of this embodiment is suitable for oral administration (e.g., a tablet). In some aspects of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is 57% or more, 60% or more, or 63% or more of the total weight of the unit dosage form. In some aspects of this embodiment, the unit dosage form has approximately 200 mg, 200 or more mg, 300 mg, 300 or more mg, 400 mg, 400 or more mg, 800 mg, and 800 or more mg of acid (R ) -2- (2-fluoro-4-biphenylyl) propionic acid in the free acid form. The (R) -2- (2-fluoro-4-biphenylyl) propionic acid may be present in the formulation as the free acid form, or as a salt form of the free acid (percentages and weights given in reference to the free acid unless otherwise mentioned, the weights and percentages of the salt form are calculated based on having the same molar equivalent as the free acid). In a specific aspect of this embodiment, approximately 400 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid free acid is present in a tablet formulation and comprises 65% to 68% of the total weight of the tablet. The invention provides a pharmaceutical formulation of (R) -2- (2-fluoro-4-biphenylyl) propionic acid having from 55% to 90% by weight of (R) -2- (2-fluoro-4-biphenylyl) acid. ) propionic and from 10% to 45% by weight of inactive pharmaceutical ingredients. The formulation may be a unit dosage form suitable for oral administration (e.g., a tablet). In one aspect of the invention, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation has from 55% to 85% by weight of (R) -2- (2-fluoro-4) acid. -biphenylyl) propionic and from 15% to 45% by weight of inactive pharmaceutical ingredients. In another aspect of the invention, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation has from 55% to 75% by weight of (R) -2- (2-fluoro-4) acid. - biphenylyl) propionic and from 25% to 45% of inactive ingredients. In another aspect, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid formulation has from 60% to 70% by weight of (R) -2- (2-fluoro-4-biphenylyl) acid. propionic and from 30% to 40% of inactive pharmaceutical ingredients. According to a specific aspect of this embodiment, the formulation has from 55% to 90% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 1% to 20% by weight of lactose ( calculated on the basis of anhydrous lactose), 1% to 20% by weight of hydroxypropylmethylcellulose, 5% to 45% by weight of microcrystalline cellulose, and optional ingredients if desired. The pharmaceutical formulations containing (R) -2- (2-fluoro-4-biphenylyl) propionic acid of the present invention generally have 55% or more of the total weight of the unit dosage form as (R) -2- ( 2-fluoro-4-biphenylyl) propionic, where the remaining weight is composed of one or more pharmaceutically acceptable excipients. The excipients for use in the formulations and unit dosage forms of the invention include one or more excipients that are chosen from disintegrants, binders, diluents, sliders, and lubricants, as well as any desired optional ingredients. Accordingly, in one aspect of the invention, the unit dosage form has an excipient which is a disintegrant (eg, microcrystalline cellulose and / or croscarmellose). The amount of disintegrant in the pharmaceutical formulation can be 45% or less, 40% or less, 35% or less, 30% or less, or less than 25% of the total weight of the unit dosage form. In another aspect of the invention, the dosage form unit has an excipient which is a binder (e.g., hydroxypropylmethylcellulose). The amount of binder in the pharmaceutical formulation can be 20% or less, 15% or less, 10% or less, or less than 8% of the total weight of the unit dosage form. In another aspect of the invention, the unit dosage form has an excipient which is a diluent such as lactose. The amount of diluent in the pharmaceutical formulation can be 20% or less, 17% or less, 15% or less, or less than 12% of the total weight of the unit dosage form. In another aspect of the invention, the unit dosage form has an excipient which is a slipping agent such as colloidal silicon dioxide. The amount of slipping agent in the pharmaceutical formulation can be 7% or less, 5% or less, 3% or less, or less than 2% of the total weight of the unit dosage form. In another aspect of the invention, the unit dosage form has an excipient which is a lubricant such as magnesium stearate. The amount of lubricant in the pharmaceutical formulation can be 10% or less, 5% or less, 3% or less, or less than 2% of the total weight of the unit dosage form. In another aspect of the invention, the unit dosage form, which contains (R) -2- (2-fluoro-4-biphenylyl) propionic acid and one or more excipients, is coated. In one aspect of the invention, the weight of the coating (eg, Rosa Opadry) is from 0.1% to 10% of the total weight of the unit dosage form. In one aspect, the weight of the coating is from 0.1% to 8% of the total weight of the unit dosage form. In other aspect of this embodiment, the weight of the coating is from 0.1% to 5% of the total weight of the unit dosage form. Also, the invention provides a dosage form having between 320 and 480 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid wherein the unit dosage form has a length not greater than 2.08 cm, greater than 2.03 cm, no greater than 1.95 cm, no greater than 1.82 cm, or no greater than 1.77 cm. The formulation of this embodiment may be a unit dosage form suitable for oral administration (e.g., a tablet). In one aspect of this embodiment, the unit dosage form has a width no greater than 1.04 cm, no greater than 1.01 cm, no greater than 0.96 cm, or no greater than 0.88 cm. In some aspects of the invention, the total volume of the unit dosage form is less than 0.70 cm3, less than 0.65 cm3, less than 0.60 cm3, less than 0.55 cm3, less than 0.50 cm3, or less than 0.45 cm3. In addition, the invention provides a unit dosage form having 55% or more by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid that produces a dissolution profile that is substantially similar to one or more of those shown in Figures 1 and 2. The unit dosage form of this modality is suitable for oral administration. For the purpose of comparing dissolution profiles, the method described in example 3 can be used. In one aspect of this embodiment, the unit dosage form has approximately 400 mg of (R) -2- (2-fluoro) acid. -4-biphenylyl) propionic and has a dissolution profile substantially similar to that shown for formulation 1 in Figure 2.

The invention also provides a formulation having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more disintegrants, one or more binders, one or more diluents, and, if desired, optional ingredients. In one aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in an amount of 55% to 90% by weight, disintegrant of 5% to 45% by weight, binder from 1% to 20% by weight, diluent from 1% to 20% by weight, and any optional ingredients. The unit dosage form of this modality is suitable for oral administration. According to one aspect of the invention, the formulation has from 55% to 90% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 1% to 20% by weight of lactose, % to 20% by weight of hydroxypropylmethylcellulose, 5% to 45% by weight of microcrystalline cellulose, and if desired, optional ingredients. According to another aspect of this embodiment, the formulation has from 55% to 85% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 3% to 17% by weight of lactose, % to 15% by weight of hydroxypropylmethylcellulose, 5% to 25% by weight of microcrystalline cellulose, and if desired, optional ingredients. According to another aspect of this embodiment, the formulation has from 55% to 80% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 5% to 15% by weight of lactose, % to 10% by weight of hydroxypropylmethylcellulose, 10% to 20% by weight of microcrystalline cellulose, and if desired, optional ingredients. According to another aspect of this embodiment, the formulation has from 60% to 70% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 8% to 12% by weight of lactose, % to 8% by weight of hydroxypropylmethylcellulose, 12% to 16% by weight of microcrystalline cellulose, and, if desired, optional ingredients. The invention further provides an orally available composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, lactose, colloidal silicon dioxide, hydroxypropylmethylcellulose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. According to a specific aspect of this embodiment, the formulation has from 55% to 90% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 1% to 20% by weight of lactose, 0.1% to 7% by weight of colloidal silicon dioxide, 1% to 20% by weight of hydroxypropylmethylcellulose, 5% to 45% by weight of microcrystalline cellulose, 0.1% to 10% by weight of croscarmellose sodium, 0.1% to 10% by weight of magnesium stearate, and optional ingredients as desired. According to a more specific aspect of this embodiment, the formulation has from 55% to 85% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 3% to 17% by weight of lactose , 0.1% to 5% by weight of colloidal silicon dioxide, 1% to 15% by weight of hydroxypropylmethylcellulose, 5% to 25% by weight of microcrystalline cellulose, 0.1% to 5% by weight of croscarmellose sodium, 0.1% to 5% by weight. Weight% of magnesium stearate, and optional ingredients as desired. In an even more specific aspect of this embodiment, the formulation has from 55% to 80% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 5% to 15% by weight of lactose, 0.1% to 3% by weight of colloidal silicon dioxide, 2% to 10% by weight of hydroxypropylmethylcellulose, 10% to 20% by weight of microcrystalline cellulose, 0.1% to 3% by weight of croscarmellose sodium, 0.1% to 3% in Weight of magnesium stearate, and optional ingredients as desired. According to another specific aspect of this embodiment, the formulation has from 60% to 70% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 8% to 12% by weight of lactose, 0.5% to 2% by weight of colloidal silicon dioxide, 5% to 8% by weight of hydroxypropylmethylcellulose, 12% to 16% by weight of microcrystalline cellulose, 0.2% to 2% by weight of croscarmellose sodium, 0.2% to 2% by weight of magnesium stearate, and optional ingredients as desired. In one embodiment, the invention provides a unit dosage form having 55% or more by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid wherein the acid (R) -2- (2- fluoro-4-biphenylyl) propionic is obtained from flurbiprofen. In one aspect of this embodiment, flurbiprofen is prepared from 4-bromo-2-fluorobiphenyl. In another aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid in the unit dosage form is obtained by chiral recrystallization from the racemate. The invention also relates to unit dosage forms of (R) -2- (2-fluoro-4-biphenylyl) propionic acid having 55% or more by weight of (R) -2- (2-fluoro-4) acid. β-biphenylyl) propionic producing a pharmacokinetic profile that is substantially bioequivalent to that shown in Figure 3A-3C and Table A. As used herein, substantially bioequivalent refers to the parameters Cmax (maximum concentration in plasma) and AUC ( area under the curve, drug exposure) within 80% to 125% of the reference parameter. The unit dosage form of this embodiment is suitable for oral administration (e.g., a tablet).

In some aspects of this embodiment, the unit dosage form is a coated tablet.

TABLE A PK analysis of an average value compartment In one embodiment, oral administration of a single dose (eg, two tablets each having 400 mg of API) of the formulation of the invention to a subject in a fasted state, provides a Cmax of about 25-200 μg per mL per dose, preferably 25-150 μg per mL per dose, and more preferably, between 30-95 μg per mL per dose. In some aspects of the invention, the oral administration of a single dose of the formulation of the invention to a subject in a fasted state, provides a Cmax, per dose, greater than 25 μg per mL, 30 μg per mL, 35 μg per mL, 40 μg per mL, 45 μg per mL, 50 μg per mL, 55 μg per mL, or 60 μg per mL. The administration of a single dose of the compositions of the invention to a subject in a fasted state provides an AUC (area under the curve of concentration against time; total drug exposure) of approximately 200 hr «μg / mL to approximately 600 hr» μg / mL. The person skilled in the art understands that pharmacokinetic parameters can vary substantially depending on the subject (patient taking the drug) and these values are representative of parameters obtained from a group of subjects, rather than from an individual. See US Patent Publication No. 20050042284 (USSN 10/889971 to Zavitz et al, filed July 12, 2004) which is incorporated herein by reference for a description of methods for obtaining these pharmacokinetic parameters. Desirably, the formulations of the invention are substantially free of (S) -2- (2-fluoro-4-biphenylyl) propionic acid. In one aspect, at least 90% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid at 10% by weight or less of (S) -2- (2-fluoro-4) acid biphenylyl) 2- (2-fluoro-4-biphenylyl) propionic acid (S + R) propionic is found in the pharmaceutical composition. In another aspect, at least 95% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid at 5% by weight or less of (S) -2- (2-fluoro-4) acid biphenylyl) 2- (2-fluoro-4-biphenylyl) propionic acid (S + R) propionic is found in the pharmaceutical composition. In another aspect, at least 99% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid at 1% by weight or less of (S) -2- (2-fluoro-4) acid biphenylyl) 2- (2-fluoro-4-biphenylyl) propionic acid (S + R) propionic is found in the pharmaceutical composition. In another aspect, at least 99.9% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid at 0.1% by weight or less of (S) -2- (2-fluoro-4) acid biphenylyl) propionic acid 2- (2-fluoro-4-biphenylyl) propionic acid (S + R) total is found in the pharmaceutical composition. In one aspect, the unit dosage form is a tablet. In another aspect, the unit dosage form is a capsule. In a specific embodiment of the invention, a unit dosage form of tablet is provided having from about 380 mg to 420 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, of about 50 mg a 70 mg of lactose, from about 3 mg to 7 mg of colloidal silicon dioxide, from about 30 mg to 50 mg of hydroxypropylmethylcellulose, from about 70 mg to 105 mg of microcrystalline cellulose, from about 1 mg to 5 mg of croscarmellose sodium, from about 4 mg to 8 mg of magnesium stearate, and optional ingredients as desired. According to a more specific aspect of this embodiment, the formulation has from about 385 mg to 415 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, from about 55 mg to 65 mg of lactose, from about 3.5 mg to 6.5 mg of colloidal silicon dioxide, from about 32 mg to 48 mg of hydroxypropylmethylcellulose, from about 75 mg to 100 mg of microcrystalline cellulose, from about 1.5 mg to 4.5 mg of croscarmellose sodium, of about 4.5 mg a 7.5 mg of magnesium stearate, and optional ingredients as desired. According to an even more specific aspect of this embodiment, the formulation has from about 390 mg to 410 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, of about 56 mg a 64 mg of lactose, from about 4.0 mg to 6.5 mg of colloidal silicon dioxide, from about 34 mg to 46 mg of hydroxypropylmethylcellulose, from about 80 mg to 95 mg of microcrystalline cellulose, from about 2.0 mg to 4.0 mg of croscarmellose sodium, from about 5.0 mg to 7.0 mg of magnesium stearate, and optional ingredients as desired. In an even more specific aspect of this embodiment, the formulation has from about 395 mg to 405 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, from about 56 mg to 64 mg of lactose, about 4.0 mg to 6.0 mg of colloidal silicon dioxide, from about 34 mg to 46 mg of hydroxypropylmethylcellulose, from about 82 mg to 93 mg of microcrystalline cellulose, from about 2.0 mg to 4.0 mg of croscarmellose sodium, from about 5.0 mg to 7.0 mg of magnesium stearate, and optional ingredients as desired.

Definitions As used herein, the term "(R) -2- (2-fluoro-4-biphenylyl) propionic acid" refers to the free acid form of (R) -2- (2-fluoro- 4-biphenylyl) propionic and molar equivalents of various salt forms, substantially free of (S) -2- (2-fluoro-4-biphenylyl) propionic acid. When the term "(R) -2- (2-fluoro-4-biphenylyl) propionic acid" is used herein, it should also be construed as including the pharmaceutically acceptable salts thereof. In the context of specific amounts and ranges of pharmaceutically acceptable salts, it should be interpreted as an equivalent molar amount of the free acid. That is, if a pharmaceutically acceptable salt is used in the formulation, it must provide the same molar amount of the free acid form as specified in the particular embodiment. As used herein, the term "dose" or "dosage" refers to the amount of active pharmaceutical ingredient that an individual takes or is administered at one time. For example, a dose of (R) -2- (2-fluoro-4-biphenylyl) propionic acid of 800 mg refers to, in the case of a dosing regimen of twice a day, a situation where, for example, , the individual takes 800 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid in the morning and 800 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid in the night. The (R) -2- (2-fluoro-4-biphenylyl) propionic acid dose of 800 mg can be divided into two or more dosage units, for example, two tablets of (R) -2- (2-fluoro-4-biphenylyl) propionic acid of 400 mg or two capsules of (R) -2- (2-fluoro-4-biphenylyl) propionic acid of 400 mg. As used herein, the term "unit dosage form" refers to a physically discrete unit, such as a capsule or tablet suitable as a unit dosage for a human patient. Each unit contains a predetermined amount of (R) -2- (2-fluoro-4-biphenylyl) propionic acid which was discovered as a result of this invention which produces the desired pharmacokinetic profile which produces the desired therapeutic effect. As used herein "a similar substantial dissolution profile" refers to one that gives within ± 50, 40, 30, 20, 10, or 5% of indicated release of the API when it is tested according to the procedure set forth in example 3 at specific time points.

Methods for preparing unit dosage forms In general, there are three general methods of tablet preparation: (1) the wet granulation method; (2) the dry granulation method; and (3) direct compression. These methods are well known to those skilled in the art. See, Reminqton's Pharmaceutical Sciences, 16 and 18 Eds., Mack Publishing Co., Easton, Pa. (1980 and 1990). See, also, U.S. Pharmacopeia XXI, U.S. Pharmacopeial Convention, Inc., Rockville, Md. (1985). In one embodiment, (R) -2- (2-fluoro-4-biphenylyl) propionic acid tablets can be manufactured using a high shear wet granulation method that incorporates preblending and pre-milling to reduce the size of the tablets. large particles in the drug substance. Once granulated, the material can be dried, ground and mixed again. The final powder mixture can be compressed into tablets in a high speed rotary press and the resulting tablets coated in a perforated tray. Soft gelatin capsules containing a mixture of the active pharmaceutical ingredient and vegetable oil or water miscible, non-aqueous materials such as, for example, polyethylene glycol and the like can be prepared. Hard gelatin capsules may contain ingredient granules active pharmaceutical in combination with a solid, powdery carrier, such as, for example, lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. The tablets are typically made by molding, by compression or by generally accepted tabletting methods. Accordingly, compressed tablets are usually prepared by large-scale production methods while molded tablets often involve small-scale operations. Tablets for oral use are typically prepared as follows, although other techniques may be employed. The solid substances are milled or sieved to a desired particle size, and the binder is homogenized and suspended in a suitable solvent. The active pharmaceutical ingredient and auxiliary agents are mixed with the binder solution. The resulting mixture is moistened to form a uniform suspension. The wetting typically causes the particles to aggregate slightly, and the resulting mass is pressed smoothly through a stainless steel screen having a desired size. The layers of the mixture are then dried in controlled drying units for a given period of time to obtain a desired particle size and consistency. The granules of the dried mixture are gently sieved to remove any dust. Disintegrants, antifriction and anti-adhesion agents are added to this mixture. Finally, the mixture is pressed into tablets using a machine with dies and dice appropriate to obtain the desired tablet size. The operating parameters of the machine can be selected by the person skilled in the art. Various tablet formulations can be made according to the present invention. These include tablet dosage forms such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, multiple-compression tablets, long-acting tablets and the like. Sugar coated tablets (SCT) are compressed tablets that contain a sugar coating. Such a coating can be colored and are useful for covering drug substances that have unpleasant tastes or odors and for protecting materials sensitive to oxidation. Film-coated tablets (FCT) are compressed tablets that are covered with a thin film or film of a water soluble material. Many polymeric substances with film-forming properties can be used. The film coating imparts the same general characteristics as the sugar coating with the added advantage of a considerably reduced period of time required for the coating operation. Enteric coated tablets are also suitable for use in the present invention. Enteric coated tablets (ECT) are compressed tablets coated with substances that resist dissolution in the gastric fluid but disintegrate in the intestine. The enteric coating can be used for tablets containing drug substances that are inactivated or destroyed in the stomach, for those that irritate the mucosa or as a delayed release medium of the medication. Multiple compression tablets (MCT) are compressed tablets made by more than one compression cycle, such as layered tablets or press-coated tablets. Layered tablets are prepared by compressing additional tablet granulation in a previously compressed granulation. The operation can be repeated to produce multilayer tablets of two, three or more layers. Typically, special tablet presses are required to make tablets in layers. See, for example, the U.S. patent. No. 5,213,738, incorporated herein by reference in its entirety. Press-coated tablets are another form of multiple compression tablets. Such tablets, also called dry-coated tablets, are prepared by feeding tablets previously compressed in a tabletting machine and compressing another layer of granulation around the preformed tablets. These tablets have all the advantages of compressed tablets, ie, grooving, monogramming, disintegration speed, etc., while retaining the attributes of the sugar-coated tablets by hiding the flavor of the drug substance in the core tablet. Press-coated tablets can also be used to separate incompatible drug substances. In addition, they can be used to provide an enteric coating to the core tablets. Both types of tablets (ie, layered tablets and pressed-coated tablets) are they can be used, for example, in the design of long-acting dosage forms of the present invention. In practical use, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid can be combined as the active pharmaceutical ingredient in intimate admixture with a pharmaceutically acceptable carrier according to conventional pharmaceutical mixing techniques. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media or excipients may be employed. These include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as suspensions, elixirs and solutions; or aerosols; or excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, capsules, tablets and tablets. Solid oral preparations are generally preferred over liquid ones. Because of their ease of administration, tablets and capsules represent the most favorable oral dosage unit forms, in which case solid pharmaceutically acceptable excipients are obviously employed. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. Preferred solid oral preparations are tablets and capsules. Pharmaceutical stabilizers can be used to stabilize compositions comprising (R) -2- (2-fluoro-4-biphenylyl) propionic acid, or pharmaceutically acceptable salts, solvates or clathrates thereof. Acceptable stabilizers include, but are not limited to, L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid, and L-cysteine dihydrochloride. See, for example, U.S. patents. 5,731,000 numbers; 5,763,493; 5,541, 231; and 5,358,970, all of which are incorporated herein by reference. In general, the compositions are prepared by uniformly and intimately admixing the active pharmaceutical ingredient with a liquid pharmaceutically acceptable carrier or a finely divided solid pharmaceutically acceptable carrier, or both, and then, if necessary, shaping the product into the desired presentation . For example, a tablet can be prepared by compression or molding, optionally with one or more additional ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active pharmaceutical ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, disintegrating agent, and / or surface active agent. or dispersing agent. The molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The invention relates to the preparation of formulations with high drug loading having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as the active ingredient. The inventors have discovered formulations of (R) -2- (2-fluoro-4-biphenylyl) propionic acid which allows the production of unit dosage forms of (R) -2- (2-fluoro-4-biphenylyl) propionic acid having 200 mg or more of API, excellent mechanical properties, and a therapeutically desirable pharmacokinetic profile (and dissolution profile). The inventive formulations also allow the production of tablets having 55% or more of active ingredient (by weight). In particular, the invention relates to methods and compositions useful in the preparation of unit dosage forms containing (R) -2- (2-fluoro-4-biphenylyl) propionic acid. The invention provides compositions and methods useful for preparing unit dosage forms having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as the active pharmaceutical ingredient. According to one embodiment of the invention, the composition is a pre-mix composition having (R) -2- (2-fluoro-4-biphenyl) propionic acid, one or more diluents, and one or more slipping agents as ingredients . In some aspects of this embodiment, (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in the premix composition in amounts of 50-95%, 60-95%, or 70-95 % of the total weight of the premix composition. In some aspects of this embodiment, the premix composition has one or more diluents present in amounts of 1-30%, 3-25%, or 5-20% of the total weight of the premix composition. In some aspects of this embodiment, the premix composition has one or more slipping agents present in amounts of 0.01-5%, 0.1-5%, or 0.1-3% of the total weight of the composition. pre-mix composition. In some aspects of this embodiment optional ingredients are present in amounts of 0-20%, 1-20%, or 1-10% of the total weight of the premix composition. The methods of this embodiment include charging (R) -2- (2-fluoro-4-biphenylyl) propionic acid, the diluent (s), the slipping agent (s) and any optional ingredients in a mixer followed by mixing for a sufficient time to provide a substantially uniform mixture. The premixed milling composition can be used in the next process step, milling. Accordingly, the pre-grinding composition is then ground through a sufficient screen to reduce the particle size of the previous grinding composition. The milled composition can then be used to form a wet granulation. The invention provides a wet granulation composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, one or more slipping agents, one or more binders, one or more wetting agents and optionally, one or more additional ingredients. In addition, in one embodiment, the invention provides a method for wet granulation of the wet granulation composition. In one aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in the wet granulation composition in amounts of 40-95%, 45-95%, or 50-90. % of the total weight of the wet granulation composition. In one aspect of this embodiment, the diluent (s) are present in the wet granulation composition in amounts of 1-30%, 1-20%, or 5-15% of the total weight of the wet granulation composition. In one aspect of this embodiment, the slipping agent (s) are present in the wet granulation composition in amounts of 0.01-10, 0.01-5%, or 0.1-5% of the total weight of the wet granulation composition. In one aspect of this embodiment, the binder (s) are present in the wet granulation composition in amounts of 1-30%, 1-20%, or 1-15% of the total weight of the wet granulation composition. In one aspect of this embodiment, the wetting agent (s) are present in the wet granulation composition in amounts of 1-40%, 1-25%, or 5-25% of the total weight of the wet granulation composition. In some aspects of this modality, optional ingredients are present in amounts of 0-20%, 1-20%, or 1-10% of the total weight of the wet granulation composition. According to this embodiment, the binder (s), milled composition, and any optional ingredients are charged to the granulator and mixed dry for a sufficient time followed by granulation with the wetting agent for a sufficient time. The wet granulation is then ground through a sieve. The wet granulation is then dried by means of an appropriate method to remove the wetting agent to produce a dried granulation. In another embodiment, the invention provides a pre-tabletting composition having a dried granulation component and one or more disintegrants. Therefore, this embodiment provides a pre-tabletting composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, one or more binders, one or more slipping agents, one or more disintegrants, and optionally, one or more optional ingredients, and methods for preparing the tabletting composition. In one aspect of this embodiment, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in the tabletting composition in amounts of 50-95%, 55-90%, or 55-85 % of the total weight of the intragranular composition. In one aspect of this embodiment, the diluent (s) are present in the tabletting composition in amounts of 1-30%, 1-20%, or 5-15% of the total weight of the tabletting composition. In one aspect of this embodiment, the slipping agent (s) are present in the tabletting composition in amounts of 0.01-10%, 0.01-5%, or 0.1-5% of the total weight of the tabletting composition. In one aspect of this embodiment, the binder (s) are present in the tabletting composition in amounts of 1-30%, 1-20%, or 1-15% of the total weight of the tabletting composition. In one aspect of the embodiment, the disintegrant (s) are present in amounts of 1-40%, 5-25%, or 5-20% of the total weight of the tabletting composition. In one aspect of this embodiment, the optional ingredient (s) is present in the tabletting composition in amounts of 1-20%, 1-25%, or 5-25% of the total weight of the tabletting composition. According to the method of this embodiment, the pre-tabletting composition is made by mixing (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more binders, one or more slipping agents, and any optional ingredients in a mixer for a sufficient time followed by grinding the resulting mixture through a sieve of sufficient mesh size to reduce the size of the particles containing API. The milled composition is then placed or discharged in a high shear granulator with one or more disintegrants, and any sectional ingredients where these components are mixed dry for a sufficient time to provide a uniform mixture. Then the dry blended material is granulated with purified water (5-30% of the dry weight of the material, or 5-25% of the dry weight of the material, or 10-22% of the dry weight of the material), during enough time to produce a wet granulation. Next, the wet granulation is milled through a sieve of appropriate size followed by drying of the milled wet granulation. Finally, the dried ground granulation is milled through a sieve of appropriate size to produce a dry granulation (pre-tabletting composition). In another embodiment, the invention provides a method for preparing a tabletting composition having the tabletting composition and one or more lubricants. Therefore, this embodiment refers to formulations having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as an API, one or more diluents, one or more binders, one or more slipping agents, one or more disintegrants, and one or more lubricants, and methods for preparing such compositions. The composition of this mode is suitable for compression tabletting. In one aspect of this mode, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is present in the tabletting composition in amounts of 50-95%, 55-90%, or 55-85% of the total weight of the composition of tabletting. In one aspect of this embodiment, the diluent (s) are present in the tableting composition in amounts of 1-30%, 1-20%, or 5-15% of the total weight of the tabletting composition. In one aspect of this embodiment, the binder (s) are present in the tabletting composition in amounts of 1-30%, 1-20%, or 1-15% of the total weight of the tabletting composition. In one aspect of this embodiment, the slider agent (s) are present in the tabletting composition in amounts of 0.01-10., 0.01-5%, or 0.1-5% of the total weight of the tabletting composition. In one aspect of this embodiment, the disintegrant (s) are present in the tabletting composition in amounts of 1-40%, 5-25%, or 5-20% of the total weight of the tabletting composition. The lubricant is present in an amount sufficient to allow ejection of the tablet in clean form from the die with minimal effort to the tablet. In one aspect of this embodiment, the lubricant (s) are present in amounts of 0.01-10%, 0.1-10%, or 0.1-5% of the total weight of the composition of this embodiment. According to the method of this embodiment, the composition is prepared by loading the lubricant (s) in the diffusion mixer with the other components (eg, those in mode four) and mixing for a sufficient time to provide a uniform mixture. The composition prepared according to this embodiment can then be compressed into tablets with an appropriate press. The composition is compressed in the form sufficient to produce a tablet which, when coated, produces an immediate release dissolution profile similar to one or more of those shown in Figures 1 and 2. In another embodiment, the invention relates to preparing a coated tablet having acid (R) -2- (2-fluoro-4-biphenylyl) propionic as an API. The tablet (ie, those prepared according to the fourth embodiment) is coated with a coating sufficient to produce an immediate release dissolution profile of the unit dosage form of coated tablet and / or impart sufficient stability to the form of unit dosage. According to this embodiment, a film coating suspension is prepared with a suitable coating agent and water. The film coating suspension can then be used to coat the tablets in, for example, a perforated coating tray to produce a coated tablet. In some aspects of this embodiment, the coating represents 0.1-15%, 0.1-10%, or 1-7% of the total weight of the tablet. In another embodiment, the invention provides a unit dosage form of (R) -2- (2-fluoro-4-biphenylyl) propionic acid tablet produced according to the methods of the invention which produces a dissolution profile similar to one. or more than those shown in Figures 1 and 2 and / or a pharmacokinetic profile bioequivalent to one or more of those shown in Figure 3A-3C and Table A.

In a specific embodiment, tablets of (R) -2- (2-fluoro-4-biphenylyl) propionic acid can be manufactured using a high shear granulation method, which incorporates pre-mixing and pre-milling to reduce the size of the large particles in the drug substance. Once granulated, the material was dried, ground and mixed again. The final powder mixture was compressed into tablets in a high speed rotary press and the resulting tablets were coated in a perforated tray. The bulk coated tablets were packed in bulk for shipping before clinical packaging. In some aspects of the above described embodiments, the unit dosage form of the invention can be manufactured using a high shear granulation process in which the (R) -2- (2-fluoro-4-biphenyl) propionic acid it is previously premixed and ground with one or more binders such as anhydrous lactose and one or more slurry agents such as colloidal silicon dioxide. The premix can be processed in a drum mixer followed by milling to reduce the average particle size of the large particles of the (R) -2- (2-fluoro-4-biphenylyl) propionic acid premix before the high shear granulation. Once granulated, the premix can be dried, milled, mixed, compressed in a high speed rotary press and coated on a perforated tray.

In one aspect, the invention provides a method for manufacturing a unit dosage form of a tablet having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as an active pharmaceutical ingredient comprising: (a) loading the lactose, (R) -2- (2-fluoro-4-biphenylyl) propionic acid drug substance, colloidal silicon dioxide, and hydroxypropylmethylcellulose in the high shear granulator; (b) mixing (e.g., dry blending) the lactose, (R) -2- (2-fluoro-4-biphenylyl) propionic acid drug substance, colloidal silicon dioxide, and hydroxypropylmethylcellulose in the high effort granulator cutting; (c) granulate the material using purified water; (d) grinding the wet granulation through a sieve of appropriate size; (e) drying the milled granulation; (f) grinding the dried granulation through a sieve of appropriate size; (g) loading the dried granulation together with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide in a diffusion mixer and mixing the material for an appropriate time; (h) loading the magnesium stearate into the diffusion mixer and mixing for an appropriate time; (i) compressing the mixed powders in a high speed rotary press; Y (j) film coating the tablets.

Inactive pharmaceutical ingredients The formulations and unit dosage forms of the invention can have many different ingredients. Depending on the concentration of the dosage, a unit dosage form has an amount of active pharmaceutical ingredient (API) sufficient to obtain a therapeutic effect in a target population. Additionally, "inactive pharmaceutical ingredients" need to be present to achieve a therapeutically effective release of the API. Therefore, the amount and type of inactive ingredients help to obtain a therapeutically effective release of the therapeutic agent. one or more disintegrants in an amount sufficient to facilitate the decomposition (disintegration) of the tablet after administration (eg, providing: In one aspect of the invention, a unit dosage tablet having the following inactive ingredients is provided a dissolution profile immediate release), one or more binders in an amount sufficient to impart sufficient cohesiveness to the tablet and / or provide sufficient qualities of free flow through the formulation of granules of size / hardness desired, one or more diluents in an amount sufficient to impart satisfactory compression characteristics, one or more lubricants in an amount sufficient to provide an adequate flow rate of the granulation and / or prevent adhesion of the material to the die / die, reduce the friction between particles, and / or facilitate the ejection of the die, and if desired, optional ingredients. The rate of disintegration, and often the rate of dissolution of a solid pharmaceutical formulation compacted in an aqueous environment (eg, the stomach of the patient) can be increased by the addition of a disintegrant to the formulation. Disintegrants include, but are not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (eg Ac-Di-Sol® Primellose), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon, Polyplasdone ), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, starch sodium glycocholate (e.g. Explotab) and starch. Solid pharmaceutical formulations that are compacted in a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active pharmaceutical ingredient and other excipients after compression. Binders for solid pharmaceutical formulations include, but are not limited to, acacia, alginic acid, carbomer (eg carbopol), carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ®), hydroxypropylmethylcellulose (eg Methocel®), lactose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (for example, Kollidon®, Plasdone®), pregelatinized starch, sodium alginate and starch. Sliding agents can be added to improve the flowability of a solid non-compacted formulation and improve the accuracy of the dosage. Excipients that can function as slippery agents include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate. When a dosage form such as a tablet is made by compaction of a powder formulation, the formulation is subjected to die and die pressure. Some excipients and active pharmaceutical ingredients have a tendency to adhere to die and die surfaces, which can cause the product to have pitting and other irregularities on the surface. A lubricant can be added to the formulation to reduce adhesion and facilitate release of the product from the die. Lubricants include, but are not limited to, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. Examples of diluents include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, powdered sugar, dextrates, dextrin, dextrose, ethylcellulose, fructose, fumaric acid, palmito-stearate. glyceryl, oil hydrogenated vegetable, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium chain glyceride, microcrystalline cellulose, polydextrose, polymethylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, starch pregelatinized, sterilizable corn, sucrose, sugar spheres, talc, tragacanth, trehalose and xylitol. Examples of disintegrants include, but are not limited to, alginic acid, calcium phosphate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, powdered cellulose, chitosan, crospovidone, docusate sodium, guar gum, hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, povidone, alginate of sodium, sodium starch glycolate, starch and pregelatinized starch. Examples of binders (binders) include, but are not limited to, acacia, alginic acid, carbomers, sodium carboxymethylcellulose, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, powdered sugar, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, poloxamer, polydextrose, polyethylene oxide , polymethylacrylates, povidone, sodium alginate, starch, pregelatinized starch, stearic acid, sucrose, sunflower oil and zein. Examples of lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, palmito-stearate of glyceryl, hydrogenated resin oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, fumarate sodium stearyl, stearic acid, talc and zinc stearate. Examples of slipping agents include, but are not limited to, calcium phosphate, calcium silicate, powdered cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch and talc. Examples of suitable pharmaceutically acceptable salts of APIs include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. In addition, organic salts including, but not limited to, salts of lysine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine and tris can also be used. Optional ingredients in the formulations of the invention include, but are not limited to, flavors, coloring agents and stabilizers. The flavoring and flavoring agents make the dosage form more palatable to the patient. Flavoring agents and flavor enhancers common for pharmaceuticals that can be included in the formulation of the present invention include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethylmaltol and tartaric acid.

The solid and liquid formulations can also be stained using any pharmaceutically acceptable dye to improve their appearance and / or facilitate patient identification of the product and unit dosage level. In one embodiment, the tablet unit dosage form has a hardness of about 5 kp (kilopond) or more, about 7 kp or more, about 9 kp or more, about 11 kp or more, and about 13 kp or more to avoid excessive friability, and a hardness of about 20 kp or less, about 19 kp or less, about 18 kp or less, about 17 kp or less, and about 16 kp or less, it is advisable to avoid the subsequent difficulty in hydrating the tablet when expose to gastric fluid. In some aspects of this modality, the hardness of the tablet unit dosage form is from 9 kp to 18 kp, 11 kp to 17 kp, and 13 kp to 17 kp. When the hardness is in an acceptable range, tablet friability is typically less than about 1.0%, preferably less than about 0.8% and more preferably less than about 0.5% in a standard test. Although the person skilled in the art recognizes that there are many techniques available to determine hardness, for comparison purposes, the method used to determine the tablet hardness of the unit dosage forms of the invention (as described in the example) should be used. 6). Some problems that can cause variations in tablet hardness are inconsistent tablet weight, variations in particle size, poor dust compressibility and insufficient binder level. A problem encountered with the unit tablet dosage forms is that they can often exhibit high friability. Friability is a physical parameter of a solid dosage form that refers to the ability of tablets to withstand physical disturbance. Friability is the tendency of a tablet to crumble, break or break. Dosage forms that have high friability will dissolve or disintegrate rapidly. An optimal unit dosage form will dissolve or disintegrate rapidly and have a low level of friability. The present invention provides this combination of desirable characteristic qualities in a high drug loading formulation. Specifically, the (R) -2- (2-fluoro-4-biphenylyl) propionic acid dosage forms of the invention have excellent dissolution profiles and desirable friabilities. The tablets of the invention have a friability of less than about 1%, which means that the tablets meet the standard of the United States Pharmacopoeia for tablet friability (which requires a friability of less than 1%). Although the person skilled in the art recognizes that there are many techniques available to determine tablet friability, for comparison purposes, the method used to determine the friability of the unit dosage forms of the invention (as described in the example) should be used. 7). Friable tablets can be caused by low moisture content, insufficient binder, tablet configuration (for example, sharp edges against beveled edges). In some aspects, the tablet unit dosage forms of the invention have a friability of less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, and less than about 0.4% (all at 100 rev). Poor disintegration can be derived from tablets that are compressed too hard, insufficient disintegrant levels, or too much binder. In some aspects of the invention, the total volume of the unit dosage form is less than 0.7 cm3, less than 0.65 cm3, less than 0.60 cm3, less than 0.55 cm3, less than 0.50 cm3, or less than 0.45 cm3. The present invention is illustrated below by reference to the following examples which particularly disclose preferred embodiments. However, it should be mentioned that these modalities are illustrative and should not be interpreted as limiting the invention in any way.

EXAMPLES EXAMPLE 1 Components of a tablet formulation containing (R) -2- (2-fluoro-4-biphenylyl) propionic acid The components of this tablet formulation are given in Table 1 below. The quantitative composition in both the batch preparation and the individual tablets is given in Table 2 while an exemplary method for preparing the tablets is given in Example 2.

TABLE 1 Components of 400 mg tablets Component Specification / grade Substance of drug - acid (R) -2- (2-fluoro-4- Specification of biphenylyl) propionic manufacturer Lactose, anhydrous1 EP, USP Colloidal silicon dioxide (Cab-O) -Sil M5P) EP, USP Hydroxypropylmethylcellulose E-5 EP, USP Microcrystalline cellulose (Avicel PH 302) EP, USP Croscarmellose sodium Type A (Ac-Di-Sol) EP, USP Magnesium stearate, non-bovine1 EP, USP Water, purified EP, USP Rosa Opadry 03K94003 Internal Specification2 TABLE 2 Quantitative composition of 400 mg tablets of (R) -2- (2-fluoro-4-biphenylyl) propionic acid Component Weight Lot (mg / tablet) representative (grams / lot) Substance of drug - (R) -2- (2- 400.00 300,000 fluoro-4-biphenylyl) propionic acid Lactose, anhydrous 59.60 44,700 Colloidal silicon dioxide (Cab-O-Sil M5P) 2.70 2.025 Hydroxypropylmethylcellulose E-5 39.00 29,250 Water, purified Essential 70.2001 withdrawn during drying Granulation of (R) -2- (2-fluoro-4,375,975 biphenylyl) propionic acid: Granulation of acid (R) -2- (2-fluoro-4,375,975) biphenylyl) propionic microcrystalline cellulose (Avicel PH 302) 87.00 65,250 Croscarmellose sodium (Ac-Di-Sol) 3.00 2,250 Component Weight Lot (mg / tablet) representative (grams / lot) Colloidal silicon dioxide (Cab-O-Sil M5P) 2 70 2,025 Magnesium stearate, non-bovine 6 00 4,500 Mixture of (R) -2- (2-fluoro-4-biphenyl) propionic acid 450,000 total for compression: Acid tablet core (R) -2- (2-fluoro-4-b? Phen? L? l) 450,000 propionico Rosa Opadry 03K94003 18 56 13,920 Water, purified Essential102,075 withdrawn during drying Total: 618 6 463,920 Mixing properties of formulation 1 Density 0.51 g / ml Vibrated density 0.62 g / ml volumetric rate of 4,664 kg / sec flow rate: Screen analysis Mesh size size /% retained mesh / retained% Mesh 40: 22% Mesh 80: 45% Mesh 100: 6% Mesh 140: 8% Mesh 2 00: 6% Mesh 325: 7% Tray: 6% Physical properties of the tablet of formulation 1 Weight variation 0.598 g average (1.11% RSD) Hardness 15.2 kp average (3.8% RSD) Thickness 5.30 average (0.54% RSD) Disintegration (mimseg) 22:55, 24:15, 26 : 30 Friability: 100 rev 0.28% 400 rev. 0.82% Dissolution of the coated tablet of formulation 1 Actual film coating 2.2% 15 min: 51.9% (8.0) 30 min .: 96.1% (1.2) 45 min .: 98.5% (1.5) 60 min .: 99.0% (1.4) 90 min .: 99.4% (1.2) The unit dosage form of Example 1 is a preferred unit dosage form of the invention. Accordingly, the unit dosage form can, for example, have at 15 minutes more than 50% release of the API, at 30 minutes more than 60% release of the API, at 45 minutes more than or equal to 80% release of the API, 60 minutes more than or equal to 80% of the API release, and 90 minutes more than or equal to 80% of the API release.

EXAMPLE 2 Procedure for preparing tablet formulations containing (R) -2- (2-fluoro-4-biphenylyl) propionic acid The tablet unit dosage form in example 1 can be manufactured according to the following protocol. The manufacturing process was a high shear granulation process that incorporated pre-blending and pre-milling to reduce the size of the large particles in the drug substance. Once granulated, the material was dried, ground and mixed again. The final powder mixture was compressed into tablets in a high speed rotary press and the resulting tablets were coated in a perforated tray. The summary explanation of the manufacture is given below: 1. Load anhydrous lactose, acid drug substance (R) -2- (2-fluoro-4-biphenylyl) propionic, and colloidal silicon dioxide in a drum type mixer. 2. Mix the components together for long enough (for example, 5 minutes) and discharge into a mill (for example, Cornil U20 or equivalent). 3. Grind through a sieve of sufficient size (eg, 0.045 cm) to reduce the particle size of the large particles in the drug substance. Download in a high granulator Shear stress (for example, Fielder PMA300 (Eastleigh, Hampshire, United Kingdom) or equivalent). 4. Charge the hydroxypropylmethylcellulose in the high shear granulator and mix dry (approximately 3 minutes). 5. Granulate the material using purified water (for example, 14. 5% to 18.9% of dry weight materials; granulate in Setting 1 for approximately 10 minutes). 6. Grind the wet granulation through a sieve of appropriate size (for example, Comil U20 or equivalent, 0.635 cm sieve). 7. Dry ground granulation (eg, fluid bed) Aeromatic T5 (Eastleigh, Hampshire, United Kingdom) or equivalent; approximately 70 ° C inlet, approximately 30 ° C outlet; dry to LOD < 2.0%; approximately 20-25 minutes). 8. Grind the dried granulation through a sieve of appropriate size (for example, Comil U20 (available from Quadro, Waterloo, Ontario, Canada) or equivalent; 0.13 cm screen). Note: Steps 1-8 can be carried out as sub-pot granulations to allow batch size adjustment. 9. Charge the dried granulation together with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide in a diffusion mixer (eg, Bohle PM1000 or equivalent). Mix the material for an appropriate time (eg, 25 minutes at 6 rpm).

. Charge the magnesium stearate in the diffusion mixer. Mix during appropriate time (for example, 5 minutes at 6 rpm), 11. Compress the mixed powders in a high speed rotary press in modified oval tablets of 600 mg (total tablet weight) smoothed with MY4. 12. Prepare the coating suspension with film by mixing Rosa Opadry in purified water for a solids concentration of 12% by weight. 13. Apply film coating to tablets with Rosa Opadry in a perforated coating tray (eg, Lodige LHC130 Hi-Coater) at a theoretical weight gain of approximately 3%. Note: Steps 12-13 can be carried out as sublime linings, in which case step 14 (consolidation of sublots) is required. 14. Consolidate the sublots as necessary.

EXAMPLE 3 Dissolution The dissolution test of 400 mg tablets of (R) -2- (2-fluoro-4-biphenylyl) propionic acid is carried out in 900 mL of pH 7.2 potassium phosphate buffer at 37 ° C using a USP device 2 (pallets) at a rotation speed of 75 rpm. At appropriate time intervals, a aliquot is removed and the amount of dissolved (R) -2- (2-fluoro-4-biphenylyl) propionic acid is determined by means of LCR Socratic analysis. The CLAR system consists of a Zorbax 5 μm column, SB C18, 250 mm x 4.6 mm i.d. with pH phosphate potassium pH regulator mobile phase: acetonitrile (30:70). The flow rate is adjusted to 1.0 mL / min and the detection is by UV absorption at 247 nm. See US Patent Publication No. 2005042284 for a description of the reference tablets used in obtaining the dissolution profiles in Figure 1 and Figure 2.

EXAMPLE 4 Uniformity of content The uniformity of the content of (R) -2- (2-fluoro-4-biphenylyl) propionic acid tablets is determined by means of reverse phase HPLC. The (R) -2- (2-fluoro-4-biphenylyl) propionic acid is extracted from ten individual tablets by stirring in methanol for thirty minutes. Aliquots of the resulting solutions are then diluted with water: acetonitrile (55:45) and filtered through 0.45 μm nylon Acrodisc syringe filters. The solutions are then injected into a CLAR system using a Waters Nova-Pak C18 column, 150 x 3.9 mm, 4 μm maintained at 30 ° C. The injection volume is 10 μL and the mobile phase consists of water: acetonitrile: glacial acetic acid (55: 40: 5). The flow rate is 1.5 μL / min and detection is by UV absorption at 254 nm.

EXAMPLE 5 Disintegration rates The disintegration times of the unit dosage forms of the invention were measured using a USP XXIV disintegration apparatus (See page 1941 of the United States Pharmacopeia XXIV, commission of the United States Pharmacopeia, Rockville, MD, USA).

EXAMPLE 6 Hardness of the tablet A hardness tester Key International (Cottage Grove, OR) was used to measure the hardness of the tablet.

EXAMPLE 7 Friability of the tablet A Vanderkamp Shrink Tablet Tester (Vankel Industries, Inc., Cary, NC) was used to measure the friability of the unit dosage forms of the invention (American Pharmaceutical Association Publication vol. XLV, No. 2 (February 1956 ).

EXAMPLE 8 Flow rate The flow rate index was obtained using a flow properties meter J.R. Johanson (J.R. Johanson, Inc. San Luis Obispo, CA) which estimates the flow rate, feed and density of the container, and the rate of recovery based on the parameters of the container.

EXAMPLE 9 Formulations The following formulations exemplify the formulations and unit dosage forms used to determine the dissolution profiles shown in Figures 1 and 2. A method that can be used to prepare such tablets is described in Example 2.

Formulation 2 Formulation 2 has a high shear granulation with 1.5% by weight intragranular PVP and 0.5% by weight extragranular AcDiSol. The formulation has the following components: Intragranular components Extragranular components Mixing properties of the formulation 2 Volumetric density: 0.56 g / ml Vibrated density: 0.73 g / ml Flow rate index: 0.913 kg / sec Screen analysis Mesh size /% retained Mesh size /% withheld Mesh 40: 23.5% Mesh 80: 35.7% Mesh 100: 6.1% Mesh 140: 8.6% Mesh 200: 6.8% Mesh 325: 8.7% Tray: 10.6% Properties of the formulation tablet 2 Weight variation 0.600 g average (0.67% RSD) Hardness 15.2 kp average (7.0% RSD) Thickness 5.38 average (0.53% RSD) Disintegration (my sec) 23:07, 24:40, 25 : 19 Friability: 100 rev 0.26% 400 rev. 0.87% Solution of the coated tablet of formulation 2 Actual film coating 2.3% 15 min: 41.0% (4.3) 30 min .: 93.8% (1.5) 45 min .: 98.3% (0.7) 60 min .: 99.2% (0.6) 90 min .: 99.5% (0.6) Formulation 3 Formulation 3 has a high shear granulation with 1.5% by weight PVP, and 1.5% by weight AcDiSol, both intragranular, with 5% by weight of extragranular StaRx 1500. Formulation 3 has the following components: Intraqranular components Extraqranular components Mixing properties of formulation 3 Volumetric density: 0.50 g / ml Vibrated density: 0.65 g / ml flow rate index: 2.619 kg / sec Screen analysis Mesh size /% retained Mesh size /% retained Mesh 40: 5.4% Mesh 80: 42.5% Mesh 100: 8.0% Mesh 140: 14.4% Mesh 200: 11.9% Mesh 325: 13.0% Tray: 10.6% Properties of the tablet of formulation 3 Weight variation 0.604 g average (0.68% RSD) Hardness 14.4 kp average (5.2% RSD) Thickness 5.41 average (0.34% RSD) Disintegration (mi sec) 11: 45, 12:00, 12 : 29 Friability: 100 rev 0.27% 400 rev. 0.95% Dissolution of the coated tablet of formulation 3 Actual film coating 2.4% 15 min: 70.0% (3.2) 30 min .: 99.5% (0.7) 45 min .: 99.7% (0.5) 60 min .: 99.7% (0.7) 90 min .: 99.9% (0.5) Formulation 4 Formulation 4 has a high shear granulation with 1.5 wt.% PVP binder and 1.5 wt.% Intragranular AcDiSol disintegrating weight. Formulation 4 has the following components: Intraqranular components Extraqranular components Mixing properties of the formulation 4 Volumetric density: 0.52 g / cc Vibrated density: 0.66 g / cc Flow rate index: 2.86 kg / sec Screen analysis Mesh size /% retained Mesh size /% retained 40 23.6% 80 33.2% 100 6.8% 140 10.5% 200 7.6% 325 8.6% Tray: 9.7% Properties of the formulation tablet 4 Weight variation 0.604 g (0.75% RSD) Hardness 14.4 kp (5.3% RSD) Thickness 5.42 mm (0.69% RSD) Disintegration (min: sec) 10:42, 11: 00, 11: 15 Friability: 100 revs. 0.3509% loss 400 revs. 1.0461% loss Dissolution of the coated tablet of the formulation 4 Actual film coating 1.6% by weight min 30 min 45 min 60 min 90 min 63.8 (2.4%) 96.8 (2.1%) 98.2 (1.1%) 98.4 (1.0%) 98.6 (0.9%) Formulation 5 Formulation 5 has a high shear granulation with 1.5 wt% binder PVP and 0 wt% intragranular disintegrant weight, and 1.5 wt% extragranular pregelatinized starch. The components of formulation 5 are the following: Intragranular components Extragranular components Mixing properties of the formulation 5 Volumetric density: 0.56 g / cc Vibrated density: 0.74 g / cc Flow rate index: 0.844 kg / sec Screen analysis Mesh size /% retained Mesh size /% retained 40 10.5% 80 33.4% 100 6.0% 140 9.6% 200 10.0% 325 13.7% Tray: 16.8% Properties of the tablet of the formulation 5 Weight variation 0.5992 g (0.4% RSD) Hardness 15.8 kp (5.4% RSD) Thickness 5.31 mm (0.4% RSD) Disintegration (mi sec) 37:15, 38:22, 38:29 Friability: 100 rev. 0.33% 400 rev. 1.6% Dissolution of the coated tablet of the formulation 5 Actual film coating 1.8% min 30 min 45 min 60 min 90 min 7.7 (27.4%) 23.6 (19.9%) 41.4 (24.3%) 66.8 (28.3%) 96.9 (2.0%) Formulation 6 Formulation 6 has a high shear granulation with 6.5% by weight HPMC, 1.5% by weight intragranular disintegrant, and 5% by weight extragranular pregelatinized starch. The components of formulation 6 are the following: Intragranular components Extraqranular components Volumetric density: 0.47 g / cc Vibrated density: 0.59 g / cc flow rate index: 4.4 kg / sec Screen analysis Mesh size /% retained Mesh size /% retained 40 4.1% 80 27.7% 100 10.5% 140 24.5% 200 16.6% 325 11.9% Tray: 4.9% Properties of the formulation tablet 6 Weight variation 0.601 g (0.48% RSD) Hardness 14.8 kp (5.0% RSD) Thickness 5.35 mm (0.45% RSD) Disintegration (min: sec) 11: 28, 11: 40, 12: 45 Friability: 100 rev. 0.33% 400 rev. 1.6% Dissolution of the coated tablet of the formulation 6 Actual film coating 2.0% by weight min 30 min 45 min 60 min 90 min 5.8 (22.7%) 17.5 (21.0%) 33.1.4 (22.4%) 64.2 (26.7%) 94.6 (5.6%) Formulation 7 Formulation 7 has a high shear granulation with 5 wt% HPMC binder and 0 wt% disintegrant. The components of formulation 7 are the following: Intraqranular components Extragranular components Mixing properties of the formulation 7 Volumetric density: 0.54 g / cc Vibrated density: 0.68 g / cc Flow rate index: 3.14 kg / sec Screen analysis Mesh size /% retained Mesh size /% withheld 40 22.8% 80 37.2% 100 6.8% 140 9.9% 200 6.9% 325 8.9% Tray: 7.4% Properties of the formulation tablet 7 Weight variation 0.604 g (0.793% RSD) Hardness 14.9 kp (6.3% RSD) Thickness 5.27 mm (0.81% RSD) Disintegration (min: sec) 46:21, 51: 22, 54: 20 Friability: 100 rev. 0.2988% 400 rev. 0.8675% Dissolution of the coated tablet of the formulation 7 Actual film coating 2.2% by weight min 30 min 45 min 60 min 90 min 3. 1 (21.7%) 9.8 (40.8%) 32.9 (50.9%) 82.7 (12.4%) 96.7 (3.1%) Formulation 8 Formulation 8 has a high shear granulation with 8 wt% HPMC binder and 0 wt% disintegrant weight. The components of formulation 8 are the following: Intraqranular components Extragranular components Mixing properties of the formulation 8 Volumetric density: 0.56 g / cc Vibrated density: 0.71 g / cc Flow rate index: 1.78 kg / sec Screen analysis Mesh size /% retained T Taarmraño mesh /% retained 40 30.0% 80 26.8% 100 6.6% 140 9.5% 200 7.4% 325 9.2% Tray: 19.4% Properties of the tablet of the formulation 8 Weight variation 0.602 g (0.398% RSD) Hardness 14.6 kp (4.1% RSD) Thickness 5.33 mm (0.1% RSD) Disintegration (min: sec) 52:31, 54:50, 56: 33 Friability: 100 rev. 0.3099% 400 rev. 0.8804% Dissolution of the coated tablet of the formulation 8 Actual film coating 2.3% min 30 min 45 min 60 min 90 min . 8 (22.7%) 17.5 (21.0%) 33.1 (22.4%) 64.2 (26.7%) 94.6 (5.6%) Formulation reference tablet 9 Core tablet components Coated tablet All publications and patent applications mentioned in the specification indicate the level of those skilled in the art to which this invention relates. All publications and patent applications are hereby incorporated by reference to the same extent as if it were specifically and individually indicated that each publication or individual patent application is incorporated by reference. Just mentioning the publications and patent applications does not necessarily constitute admitting that they are the prior art to the present application. Although the above invention has been described in some detail by way of illustration and example for purposes of clarity of understandingIt will be obvious that certain changes and modifications may be made within the scope of the appended claims.

Claims (48)

NOVELTY OF THE INVENTION CLAIMS

1. - A unit dosage form comprising 55-90% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, of 10-45% by weight excipient, wherein the dosage form unit has 200 mg or more of (R) -2- (2-fluoro-4-biphenylyl) propionic acid.

2. The unit dosage form according to claim 1, further characterized in that it has 200-800 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid.

3. The unit dosage form according to claim 1, further characterized in that it has 300-500 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid.

4. The unit dosage form according to claim 3, further characterized in that the total weight of the dosage form is not more than 800 mg.

5. The unit dosage form according to claim 3, further characterized in that the total weight of the dosage form is not more than 700 mg.

6. The unit dosage form according to claim 1, further characterized in that the excipient comprises microcrystalline cellulose.

7 '.- The unit dosage form according to claim 1, further characterized in that the (R) -2- (2-fluoro-4-biphenylyl) propionic acid is the free acid form of the acid (R) -2 - (2-fluoro-4-biphenylyl) propionic.

8. The unit dosage form according to claim 1, further characterized in that the dosage form is a tablet or a capsule.

9. The unit dosage form according to claim 1, further characterized in that the dosage form is a tablet.

10. A unit dosage form comprising 380-420 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid and 200-260 mg of excipient.

11. A unit dosage form comprising 200-600 mg of (R) -2- (2-fIuoro-4-biphenyl) propionic acid which is more than 55% by weight of acid (R) -2- ( 2-fluoro-4-biphenylyl) propionic.

12. The unit dosage form according to claim 11, further characterized in that it has 350-450 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid and less than 300 mg of excipient.

13. The unit dosage form according to claim 12, further characterized in that when administered orally to a subject in a fasted state it provides a Cmax of about 30 to about 95 μg / ml.

14. - The unit dosage form according to claim 13, further characterized in that it is suitable for oral administration.

15. The unit dosage form according to claim 14, further characterized in that it is a tablet or a capsule.

16. The unit dosage form according to claim 15, further characterized in that it is a tablet.

17. A unit dosage form comprising 55-80% by weight of (R) -2- (2-fluoro-4-biphenylyl) propionic acid and of about 20-45% by weight of excipient having a weight total of less than 800 mg.

18. The unit dosage form according to claim 17, further characterized in that it has 380-420 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid.

19. The unit dosage form according to claim 17, further characterized in that the excipient comprises microcrystalline cellulose.

20. The unit dosage form according to claim 19, further characterized in that it also comprises hydroxypropylmethylcellulose.

21. The unit dosage form according to claim 17, further characterized in that it also comprises lactose, colloidal silicon dioxide, hydroxypropylmethylcellulose, croscarmellose sodium and magnesium stearate.

22. The unit dosage form according to claim 21, further characterized in that it is a coated tablet.

23. The unit dosage form according to claim 21, further characterized in that it has from about 380 mg to 420 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, from about 50 mg to 70 mg of lactose, from about 3 mg to 7 mg of dioxide of colloidal silicon, from about 30 mg to 50 mg of hydroxypropylmethylcellulose, from about 70 mg to 105 mg of microcrystalline cellulose, from about 1 mg to 5 mg of croscarmellose sodium, from about 4 mg to 8 mg of magnesium stearate, and ingredients optional as desired.

24. The unitary dosage form according to claim 21, further characterized in that it has from approximately 385 mg to 415 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, of about 55 mg a 65 mg of lactose, from about 3.5 mg to 6.5 mg of colloidal silicon dioxide, from about 32 mg to 48 mg of hydroxypropylmethylcellulose, from about 75 mg to 100 mg of microcrystalline cellulose, from about 1.5 mg to 4.5 mg of croscarmellose sodium, from about 4.5 mg to 7.5 mg of magnesium stearate, and optional ingredients as desired.

25. - The unit dosage form according to claim 21, further characterized in that it has from about 390 mg to 410 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, from about 56 mg to 64 mg of lactose, from about 4.0 mg to 6.5 mg of colloidal silicon dioxide, from about 34 mg to 46 mg of hydroxypropylmethylcellulose, from about 80 mg to 95 mg of microcrystalline cellulose, from about 2.0 mg to 4.0 mg of croscarmellose sodium, of about 5.0 mg to 7.0 mg of magnesium stearate, and optional ingredients as desired.

26. The unit dosage form according to claim 21, further characterized in that it has from about 395 mg to 405 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid, of about 56 mg a 64 mg of lactose, from about 4.0 mg to 6.0 mg of colloidal silicon dioxide, from about 34 mg to 46 mg of hydroxypropylmethylcellulose, from about 82 mg to 93 mg of microcrystalline cellulose, from about 2.0 mg to 4.0 mg of croscarmellose sodium, from about 5.0 mg to 7.0 mg of magnesium stearate, and optional ingredients as desired.

27. A method for manufacturing a unit dosage form of a tablet having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as an active pharmaceutical ingredient comprising: (a) loading lactose, a substance of (R) -2- (2-fluoro-4-biphenylyl) propionic acid and colloidal silicon dioxide drug in a drum-type mixer; (b) mix the components together for long enough and unload in a mill; (c) milling through a sieve of sufficient size to reduce the particle size of the large particles in the drug substance and discharge into a high shear granulator; (d) loading the hydroxypropylmethylcellulose into the high shear granulator and dry mixing; (e) granulating the material using purified water; (f) milling the wet granulation through a sieve of appropriate size; (g) drying the milled granulation; (h) milling the dried granulation through a sieve of appropriate size; (i) loading the dried granulation together with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide in a diffusion mixer and mixing the material for an appropriate time; (j) loading the magnesium stearate into the diffusion mixer and mixing for an appropriate time; (k) compressing the mixed powders in a high speed rotary press; and (I) coating the tablets with film.

28. A composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, and one or more slipping agents as ingredients.

29. The composition according to claim 28, further characterized in that it has 50-95% of the total weight as (R) -2- (2-fluoro-4-biphenylyl) propionic acid; 1-30% of the total weight as one or more diluents present; and 0.01-5% of the total weight as one or more sliders.

30. - The composition according to claim 28, further characterized in that it has 60-95% of the total weight as (R) -2- (2-fluoro-4-biphenylyl) propionic acid; 3-25% of the total weight as one or more diluents present; and 0.1-5% of the total weight as one or more sliders.

31. The composition according to claim 28, further characterized in that it has 70-95% of the total weight as (R) -2- (2-fluoro-4-biphenylyl) propionic acid; 5-20% of the total weight as 1 or more diluents present; and 0.1-3% of the total weight as 1 or more sliders.

32.- A composition having (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, one or more slipping agents, one or more binders, one or more wetting agents and optionally , one or more additional ingredients.

33.- A composition that has 40-95% (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 1-30% of one or more diluents, 0.01-10% of one or more slipping agents, 1-30% of one or more binders, of 1-40% of one or more wetting agents and 0-20% of one or more optional ingredients.

34.- A composition that has 45-95% (R) -2- (2-fluoro-4-biphenylyl) propionic acid, of 1-20% of one or more diluents, of 0.01-5% of one or more more slipping agents, 1-20% of one or more binders, of 1-25% of one or more wetting agents and 1-20% of one or more optional ingredients.

35. - A composition having 50-90% (R) -2- (2-fluoro-4-biphenylyl) propionic acid, 5-15% of one or more diluents, 0.1-5% of one or more agents sliders, 1-15% of one or more binders, 5-25% of one or more wetting agents and 1-10% of one or more optional ingredients.

36.- A composition having a dried granulation component and one or more disintegrants wherein the dried granulation has (R) -2- (2-fluoro-4-biphenylyl) propionic acid, one or more diluents, one or more binders , and one or more sliders.

37.- The composition according to claim 36, further characterized in that the disintegrant (s) are 1-40% of the total weight of the composition.

38.- The composition according to claim 36, further characterized in that the disintegrant (s) are 5-25% of the total weight of the composition.

39.- The composition according to claim 36, further characterized in that the disintegrant (s) are 5-20% of the total weight of the composition.

40.- The use of the unit dosage form of claim 1, for the manufacture of a medicament useful for treating a neurodegenerative disorder in an individual.

41. The use as claimed in claim 40, wherein the neurodegenerative disorder is chosen from Alzheimer's disease, dementia, mild cognitive impairment, Parkinson's disease, Huntington's disease and symptoms thereof.

42. The use as claimed in claim 41, wherein the Alzheimer's disease is chosen from prodromal Alzheimer's disease, mild Alzheimer's disease, mild to moderate Alzheimer's disease, moderate Alzheimer's disease, moderate to severe Alzheimer's disease. , and severe Alzheimer's disease.

43. The use as claimed in claim 41, wherein the Alzheimer's disease is mild Alzheimer's disease.

44.- The use as claimed in claim 40, wherein the medicament is adapted to be administrable twice a day.

45. The use as claimed in claim 40, wherein the medicament comprises from about 320 to 480 mg of (R) -2- (2-fluoro-4-biphenylyl) propionic acid or molar equivalent of a pharmaceutically acceptable salt thereof and wherein the medicament is adapted to be administrable in the form of two unit dosage forms twice a day

46. The use as claimed in claim 45, wherein the individual has Alzheimer's disease or wishes prophylaxis against the development of the symptoms of Alzheimer's disease.

47. The use as claimed in claim 40, wherein the medicament is also useful for treating cancer.

48. - The use as claimed in claim 47, wherein the cancer is selected from cancer of brain, lung, liver, spleen, kidney, lymph nodes, small intestine, pancreas, blood cells, colon, stomach, breast, endometrial, prostate , testicle, ovary, skin, and head and neck, esophagus and bone marrow. 49.- The use as claimed in claim 47, wherein the cancer is prostate cancer. 50.- A method for manufacturing a unit dosage form of tablet having (R) -2- (2-fluoro-4-biphenylyl) propionic acid as an active pharmaceutical ingredient comprising: (a) loading lactose, a substance of (R) -2- (2-fluoro-4-biphenylyl) propionic acid drug, colloidal silicon dioxide, and hydroxypropylmethylcellulose in the high shear granulator; (b) mixing the lactose, (R) -2- (2-fluoro-4-biphenylyl) propionic acid drug substance, colloidal silicon dioxide, and hydroxypropyl methylcellulose in the high shear granulator; (c) granulate the material using purified water; (d) grinding the wet granulation through a sieve of appropriate size; (e) drying the milled granulation; (f) grinding the dried granulation through a sieve of appropriate size; (g) loading the dried granulation together with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide in a diffusion mixer and mixing the material for an appropriate time; (h) loading the magnesium stearate into the diffusion mixer and mixing for an appropriate time; (i) compressing the mixed powders in a high speed rotary press; and (j) film coating the tablets.