WO2014159814A1

WO2014159814A1 - Formulations and tablets for treatment or prevention of neurological disorders

Info

Publication number: WO2014159814A1
Application number: PCT/US2014/025226
Authority: WO
Inventors: Patricia Oliver; Anh Thu Pham; Akaash Kumari SINGH
Original assignee: Patricia Oliver; Anh Thu Pham; Singh Akaash Kumari
Priority date: 2013-03-13
Filing date: 2014-03-13
Publication date: 2014-10-02

Abstract

Disclosed are pharmaceutical formulations of (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid and its pharmaceutically acceptable salts, tablets comprising such formulations, methods of making the formulations and tablets, and methods of treating a neurological disorder such as Alzheimer's disease with same.

Description

FORMULATIONS AND TABLETS FOR TREATMENT OR PREVENTION OF

NEUROLOGICAL DISORDERS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Serial No. 61/780,693, filed March 13, 2013, the entire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The invention relates to tablets and pharmaceutical formulations, more specifically to tablets and pharmaceutical formulations of (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid and salts thereof.

BACKGROUND OF THE INVENTION

[0003] (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid, described in U.S. Pat. No. 8,217,064, which is incorporated by reference herein, as well as a pharmaceutical acceptable salt thereof, is a gamma secretase modulator.

[0004] However, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl- 3-yl)-3-cyclobutylpropanoic acid and its salts are difficult to formulate as they are prone to aggregation or gelling. Accordingly, substantial effort was expanded to discover a formulation of a pharmaceutically acceptable salt of (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoic acid.

SUMMARY OF THE INVENTION

[0005] The present invention is based, in part, upon the surprising discovery that (R)-2- (5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or salts thereof, can be formulated in a pharmaceutical formulation in which their tendencies to gel or aggregate are substantially reduce or eliminated.

[0006] It is understood that any of the embodiments described below can be combined in any desired way, and any embodiment or combination of embodiments can be applied to each of the aspects described below, unless the context indicates otherwise. [0007] These and other aspects and embodiments of the invention will be apparent to one of ordinary skill in the art based upon the following detailed description of the invention.

[0008] In one aspect, a pharmaceutical composition is described, comprising: (a) (R)-2- (5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof; (b) colloidal silicon dioxide; and (c) cross- linked polyvinylpolypyrrolidone (crospovidone).

[0009] In some embodiments, the pharmaceutical composition further includes micro crystalline cellulose.

[0010] In some embodiments, the colloidal silicon dioxide is present in the composition in an amount of about 5% to about 20% by weight.

[0011] In some embodiments, cross-linked polyvinylpolypyrrolidone (crospovidone) is present in the composition in an amount of about 5% to about 20% by weight.

[0012] In some embodiments, colloidal silicon dioxide is present in the composition in an amount of about 10%> by weight.

[0013] In some embodiments, cross-linked polyvinylpolypyrrolidone (crospovidone) is present in the composition in an amount of about 10% by weight.

[0014] In some embodiments, microcrystalline cellulose is present in the composition in an amount of about 20% to about 50% by weight.

[0015] In some embodiments, the pharmaceutical composition does not include a poloxamer.

[0016] In some embodiments, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is substantially crystalline.

[0017] In some embodiments, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 10 mg to about 200 mg by weight.

[0018] In some embodiments, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof does not substantially agglomerate. [0019] In some embodiments, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof does not substantially gel.

[0020] In some embodiments, the pharmaceutically acceptable salt is potassium salt.

[0021] In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0022] In some embodiments, the pharmaceutical composition is in the form of a tablet, a capsule or a powder.

[0023] In some embodiments, the pharmaceutical composition is in the form of a tablet.

[0024] In another aspect, a method of treating or preventing Alzheimer's disease in a patient is described, comprising administering to the patient in need thereof the

pharmaceutical composition of any one of embodiments described herein.

[0025] In some embodiments, the pharmaceutical composition is administered once daily.

[0026] In some embodiments, the pharmaceutical composition is administered twice daily.

[0027] In some embodiments, the patient is a mammal.

[0028] In some embodiments, the mammal is a human.

[0029] In yet another aspect, an oral solid dosage form is described, comprising: (a) a core comprising (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)- 3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof and an excipient; and (b) an enteric coating.

[0030] In some embodiments, the enteric coating includes a methacrylic acid copolymer.

[0031] In some embodiments, the enteric coating includes polyethylene glycol (PEG).

[0032] In some embodiments, the methacrylic acid copolymer is methacrylic acid copolymer type C.

[0033] In some embodiments, the core includes from about 45% to about 70% of micro crystalline cellulose.

[0034] In some embodiments, the core does not include a poloxamer.

[0035] In some embodiments, the core includes about 10%> of cross-linked

polyvinylpolypyrrolidone (crospovidone) .

[0036] In some embodiments, the enteric coating is present in the amount of about 10% to about 20% of the weight of the core. [0037] In some embodiments, the coating begins to dissolve at pH between about 4 to about 7.

[0038] In some embodiments, the coating begins to dissolve at pH between about 4.5 to about 6.5.

[0039] In some embodiments, the coating begins to dissolve at pH about 5.5.

[0040] In some embodiments, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is substantially crystalline.

[0041] In some embodiments, the core includes from about 10 mg to about 200 mg of

(R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the pharmaceutically acceptable salt is potassium salt.

[0043] In some embodiments, the oral dosage form is suitable for once or twice daily administration.

[0044] In yet another aspect, a method of treating or preventing Alzheimer's disease in a patient is described, comprising administering to the patient in need thereof the oral dosage form of any one of the embodiments described herein.

[0045] In some embodiments, the oral dosage form is administered once daily.

[0046] In some embodiments, the oral dosage form is administered twice daily.

[0047] In some embodiments, the patient is a mammal.

[0048] In some embodiments, the mammal is a human.

[0049] In yet another aspect, an oral pharmaceutical composition is described, comprising: (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof and an excipient, wherein the formulation provides a maximum blood level concentration of (R)-2-(5-chloro-6- (2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or its anion at about 3 to about 5 hours after dosing when administered without food.

[0050] In some embodiments, the composition provides a maximum blood level concentration of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)- 3-cyclobutylpropanoic acid or its anion at about 6 to about 7 hours after dosing when administered with food. [0051] In some embodiments, the composition includes about 5% to about 20% by weight of colloidal silicon dioxide.

[0052] In some embodiments, the composition includes about 5% to about 20% by weight of cross-linked polyvinylpolypyrrolidone (crospovidone).

[0053] In some embodiments, the composition includes about 20%> to about 50%> by weight of microcrystalline cellulose.

[0054] In some embodiments, the pharmaceutical composition does not include a poloxamer.

[0055] In some embodiments, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is substantially crystalline.

[0056] In some embodiments, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 10 mg to about 200 mg by weight.

[0057] In some embodiments, the pharmaceutically acceptable salt is potassium salt.

[0058] In some embodiments, the pharmaceutical composition is suitable for once-daily administration.

[0059] In some embodiments, the pharmaceutical composition is suitable for twice-daily administration.

[0060] In some embodiments, the pharmaceutical composition is in the form of a tablet, a capsule or a powder.

[0061] In some embodiments, the pharmaceutical composition is in the form of a tablet.

[0062] In yet another aspect, a method of treating or preventing Alzheimer's disease in a patient is described, comprising administering to the patient in need thereof an effective amount of the pharmaceutical composition of any one of the embodiments described herein.

[0063] In some embodiments, the pharmaceutical composition is administered once or twice daily.

[0064] In some embodiments, the patient is a mammal.

[0065] In some embodiments, the mammal is a human. BRIEF DESCRIPTION OF THE FIGURES

[0066] Figure 1 illustrates an embodiment of a manufacturing process for enteric coated tablets.

[0067] Figure 2 is a graphic representation of the food effect on the blood levels of (R)-2- (5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoate anion.

[0068] Figures 3A and 3B are graphic representations of dose proportionality of (R)-2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate.

[0069] Figures 4A-4H are graphic representations of pharmacokinetic characteristics of various doses and dosing regimens of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate.

[0070] Figures 5A-5B are graphic representations of the effects of 200 mg single dosing (SD) and multiple dosing (MD) of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate anion in non-elderly and elderly (ELD) subjects.

[0071] Figures 6A and 6B are graphic representations of the maximum blood

concentrations of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3- yl)-3-cyclobutylpropanoate anion in non-elderly and elderly (ELD) with multiple dosing (MD) and single dosing.

[0072] Fig. 6C is a graphic representation of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate anion AUCo-24 in elderly (ELD) and non-elderly subjects for single dosing (SD) and multiple dosing (MD).

DETAILED DESCRIPTION OF THE INVENTION

1. References and Definitions

[0073] The patent and scientific literature referred to herein establishes knowledge that is available to those of skill in the art. The issued U.S. patents, allowed U.S.

applications, published U.S. applications, published foreign applications, foreign patents, and references, including database entries, that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. [0074] The recitation of "about" preceding a range of values is intended to modify both endpoints in the range, e.g., "about 83-89°C" is equivalent to "about 83°C to about 89°C".

[0075] As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable can be equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable can be equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 can take the values 0, 1 or 2 if the variable is inherently discrete, and can take the values 0.0, 0.1, 0.01, 0.001, or any other real values > 0 and≤ 2 if the variable is inherently continuous.

[0076] As used herein, unless specifically indicated otherwise, the word "or" is used in the inclusive sense of "and/or" and not the exclusive sense of "either/or."

[0077] As used herein, "Pharmaceutically Acceptable Salt" refers to a pharmaceutically acceptable salt of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3- yl)-3-cyclobutylpropanoic acid.

[0078] As used herein, "Potassium Salt" refers to potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate.

[0079] As used herein, "Free Acid" refers to (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-

(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoic acid.

[0080] The following abbreviations are used herein: MCC is microcrystalline cellulose, EC is enteric coating, PVA is polyvinyl alcohol, API is active pharmaceutical ingredient.

2. (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid ("Free Acid")

[0081] (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifiuoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid ("Free Acid") is a non-solvated crystalline material with a melting point with an onset of about 91°C. It is essentially insoluble in deionized water. The thermodynamic aqueous solubility of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid was determined to be less than 0.0001 mg/ml. [0082] Synthesis of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifiuoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid is described in U.S. Pat. No. 8,217,064, which is incorporated by reference herein.

[0083] The Free Acid is very hydrophobic. It has a tendency to agglomerate and forms a gel.

3. Pharmaceutically Acceptable Salts of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid ("Pharmaceutically Acceptable Salts")

[0084] Some pharmaceutically acceptable salts of (R)-2-(5-chloro-6-(2,2,2- trifiuoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoic acid

("Pharmaceutically Acceptable Salts") have more favorable chemical and physical properties (e.g., increased solubility) for formulation as drugs for human therapy than the Free Acid. The Free Acid can be readily converted to a Pharmaceutically Acceptable Salt using techniques known in the art.

[0085] Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts of the Free Acid can be prepared by treatment with inorganic bases, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, tromethamine, 2-ethylamino ethanol, histidine, procaine, and the like.

[0086] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al.,

"Pharmaceutical Salts," J. Pharm. Sci., 1977:66: 1-19.

4. Potassium (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3- yl)-3-cyclobutylpropanoate ("Potassium Salt")

[0087] The potassium Salt is significantly more soluble in water than Free Acid.

[0088] Potassium Salt can be prepared as follows: 200 mg of (R)-2-(5-chloro-6-(2,2,2- trifiuoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3 -cyclobutylpropanoic acid as a free acid is dissolved in tBuOH (5 ml) at 60°C and treated with 0.95 equivalents of KOH (395 μΐ, 1M in H₂0). After 30 minutes at 60°C the solution is dried via lyophilization to provide a white solid. This material is then treated with toluene (4 ml, 20 volumes) and brought to reflux and then allowed to cool to room temperature. The solid produced is filtered off and dried under vacuum overnight. An exemplary yield of the Potassium Salt produced by this process is about 79% (171 mg).

5. Formulations of Pharmaceutically Acceptable Salts

[0089] It has been surprisingly discovered that colloidal silicon dioxide can substantially reduce or prevent a Pharmaceutically Acceptable Salt from agglomerating, gelling or sticking. Generally, silicone dioxide is present in the formulation in the amount of at least 5% or at least 10% substantially reduces or prevents a Pharmaceutically Acceptable Salt from agglomerating. In some embodiments, the amount of silicon dioxide used is more than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, or 40%. In some embodiments, the amount of silicon dioxide used is less than 5%. In some embodiments, the amount of silicon dioxide used is more than 20%>. In some embodiments, the amount of silicon dioxide used is 5%- 20%) by weight of the formulation or by weight of the solid dosage. In some embodiments, the amount of silicon dioxide used is about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13% about 14%, about 15% or about 15%-20% by weight of the formulation or by weight of the solid dosage. Without being bound by any theory, it is believed that colloidal silicon dioxide acts as an anti-gellant in the formulation and prevents sticking during manufacturing. This is in contrast with the conventional use of silicon dioxide in pharmaceutical formulations, where it is normally used as a glidant to assist in the flow powder during manufacturing.

[0090] It has also been surprisingly discovered that crospovidone (cross-linked polyvinylpyrrolidone), when used in combination with that colloidal silicon dioxide, can substantially reduce or prevent A Pharmaceutically Acceptable Salt from agglomerating or gelling. Generally, crospovidone is present in the formulation in the amount of at least 5% or at least 10% substantially reduces or prevents A Pharmaceutically Acceptable Salt from agglomerating. In some embodiments, the amount of crospovidone used is 5%-20% by weight of the formulation or by weight of the solid dosage. In some embodiments, the amount of crospovidone used is about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13% about 14%, about 15% or about 15%-20% by weight of the formulation or by weight of the core of the solid dosage. In some

embodiments, the amount of crospovidone used is more than 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%), 25%), 30%), or 40%>. In some embodiments, the amount of crospovidone used is less than 5%. In some embodiments, the amount of crospovidone used is more than 20%>. Crospovidone is generally used as a disintergrant in pharmaceutical solid dosage forms, but in an amount of less than 3% w/w.

[0091] Poloxamer is a commonly used excipient in pharmaceutical formulations as a surfactant. Its generally accepted role is to prevent the active pharmaceutical ingredient (API) from gelling or to increase solubility of the API. When poloxamer was added to the formulation of the Potassium Salt, it was unexpectedly observed that poloxamer caused some degree of racemization of the Potassium Salt. This racemization was surprising as it did not occur under basic conditions, where it is generally expected to occur. In general,

pharmaceutical excipients are inert and do not cause racemization of an API. Removal of poloxamer eliminated the racemization. Therefore, in some embodiments, the formulations described herein are free of poloxamer.

[0092] In some embodiments, MCC can be used as a filler or a diluent in the

formulations. In some embodiments, the amount of MCC ranges from 28.5% to 66.25% w/w. In some embodiments, the amount of MCC ranges from 10% to 20%, from 20% to 30%, from 30% to 40%, from 40% to 50%, or from 50% to 60%.

6. Enteric coating

[0093] In some embodiments, the solid dosage forms described herein (e.g., tablets) are coated with an enteric coating. The enteric coating is used to prevent protonation of a Pharmaceutically Acceptable Salt (e.g., of Potassium Salt) while the dosage form in an acid environment (e.g., in the stomach) and generate the Free Acid, which less soluble than the Potassium Salt in water.

[0094] Suitable polymers for the enteric coating are generally insoluble in acidic environments (e.g., gastric fluid) but are soluble at pH 5.5 and higher. Such polymers include, but are not limited to, cellulose acetate phthalate, methacrylate-base polymers, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, anionic phthalate polymers based on methacrylic acid and methacrylic acid esters. These compounds can either used alone or in combinations in an organic solvent. Generally, these polymers are dissolved in organic solvents before being used in the coating process. Exemplary organic solvents include methyl alcohol, ethyl alcohol, ethyl alcohol/water, isopropyl alcohol, isopropyl alcohol/water, n-butyl alcohol, propylene glycol, ethyleneglycol monobutyl ether, acetone,

acetone/isopropyl alcohol, and the like. Aqueous based polymeric dispersions are preferred for enteric coating applications in pharmaceutical industries. Suitable plasticizers impart sufficient tensile strength to the coating to prevent film cracking. Such plasticizers include triethyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethylphthalate, acetyl triethyl citrate, and the like. The coating procedures can be performed in a suitable coating machine.

[0095] Examples of commercially available enteric coatings are Sureteric®, Nutrateric® II, Opadry® and Acryl-EZE®, each of which is commercially available from Colorcon, Inc. (Harleysville, PA and West Point, PA). In addition, aqueous enteric coatings based on methacrylic acid - ethyl acrylate copolymer (Kollicoat® MAE 30 DP) are known to provide excellent gastric resistance and are available from BASF AG (Ludwigshafen, Germany).

[0096] Enteric coatings can also include polyethylene glycol (PEG). Suitable

polyethylene glycols include PEG 4,000, PEG 6,000, PEG 8,000 and PEG 10,000. Other excipients known in the art may be used.

[0097] Enteric coating useful in the formulations described herein have a dissolution trigger point at pH from about 4.5 to about 6.5. In some embodiments, the dissolution trigger point of the enteric coating is at pH of about 4.5, about 5.0, about 5.5, about 6.0, or about 6.5.

[0098] The amount of enteric coating on a solid dosage (e.g., a tablet) can vary. In some embodiments, the enteric coating is present on the solid dosage in an amount of 5-25% by weight of the core, or in a amount of about 10-20% by weight of the core.

7. Moisture Barrier Coating (Seal Coating)

[0099] In some embodiment, the formulations described herein include a moisture barrier coating. This coating can be applied on the solid dosage (e.g., a tablet) before enteric coating is applied. Thus, the moisture barrier coating is generally underneath, although not necessarily directly underneath, the enteric coating if such enteric coating is present. In other embodiments, the seal coating can be applied on the tablet after the enteric coating.

[0100] U.S. Pat. No. 5,885,617 discloses a moisture barrier film coating composition for forming a moisture barrier film coating for pharmaceutical tablets which comprises polyvinyl alcohol (PVA), lecithin, and optionally, a flow aid, and/or a colorant, and/or suspending agent. This coating composition is sold by Colorcon, Inc. (West Point, PA) as Opadry® amb. Opadry® amb coating produces film coatings having excellent moisture barrier properties.

[0101] Polyethylene glycol (PEG) can be used as a plasticizer in film coatings to reduce the glass transition temperature of the film forming polymer and to make the polymer less brittle.

[0102] Insoluble materials such as pigments, glidants, and flow aids can be used in film coating compositions. For instance, pigment is used to provide a color to the film coating and talc is used as a glidant and a filler to reduce the percentage of the amount of other more costly components in the film coating composition.

[0103] U.S. Pat. No. 4,432,965 discloses a sustained release oral dosage form comprising a tablet core containing a pharmaceutically effective amount of quinidine which is coated with a sustained released polymeric coating which contains about 5 to about 20% by weight polyethylene glycol and from about 80 to 95% by weight polyvinyl alcohol (PVA). This sustained release polymeric coating dissolves slowly in gastric and intestinal fluids.

[0104] The amount of a seal coating on a solid dosage (e.g., a tablet) can vary. In some embodiments, the seal coating is present on the solid dosage in an amount of 5-25% by weight of the core, or in an amount of about 10-20% by weight of the core.

8. Pharmaceutical Compositions of Pharmaceutically Acceptable Salts and Their

Administration

[0105] Due to its inclusion of a Pharmaceutically Acceptable Salt, a composition described herein is useful in human medicine. As described above, a composition described herein is useful for treating or preventing a neurological disorder in a subject in need thereof. Neurological disorders include, but are not limited to, Alzheimer's disease (including early onset Alzheimer's disease) and schizophrenia.

[0106] A Pharmaceutically Acceptable Salt can be administered in amounts that are effective to treat or prevent a neurological disorder (e.g., Alzheimer's disease) in a subject in need thereof.

[0107] When administered to a subject, a Pharmaceutically Acceptable Salt can be administered as a component of a composition that comprises a physiologically acceptable carrier or vehicle. The present compositions, which comprise a Pharmaceutically Acceptable Salt, can be administered orally. [0108] In some embodiments, a composition described herein is administered orally.

[0109] In some embodiments, a composition described herein can be delivered in an immediate drug-release system. In other embodiments, a composition described herein can be delivered in a controlled-release system or sustained release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled or sustained release systems discussed in the review by Langer, Science 249: 1527- 1533 (1990) can be used. In one embodiment a pump can be used (Langer, Science

249: 1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); and Saudek et al., N. Engl. J Med. 321 :574 (1989)). In another embodiment polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 2:61 (1983); Levy et al, Science 228: 190 (1935); During et al, Ann. Neural. 25:351 (1989); and Howard et al, J. Neurosurg. 71 : 105 (1989)).

[0110] The present compositions optionally comprise a suitable amount of a

pharmaceutically acceptable excipient so as to provide the form for proper administration to the subject.

[0111] Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0112] In one embodiment, a composition described herein is formulated in accordance with routine procedures as a composition adapted for oral administration to human beings. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Alternatively, a tablet or pill form can be used in an immediate drug-release system. Selectively permeable membranes surrounding an osmotically active driving a Pharmaceutically Acceptable Salt are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0113] Pharmaceutical preparations for oral use can be obtained through combination of a Pharmaceutically Acceptable Salt with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients in addition to those previously mentioned are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0114] Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0115] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0116] Pharmaceutically Acceptable Salts or free acid can be administered by immediate- release, controlled-release or sustained release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719;

5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and

5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing immediate, controlled, or sustained release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled or sustained release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled or sustained release. In some embodiments, the tablets are coated with an enteric coating.

[0117] In one embodiment a controlled or sustained release composition comprises a minimal amount of a Pharmaceutically Acceptable Salt to treat or prevent a neurological disorder (e.g., Alzheimer's disease) over a period of time. Advantages of controlled or sustained release compositions include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled or sustained release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of active pharmaceutical ingredient, and can thus reduce the occurrence of adverse side effects.

[0118] Controlled or sustained release compositions can initially release an amount of a Pharmaceutically Acceptable Salt that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the active pharmaceutical ingredient to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the Pharmaceutically Acceptable Salt or the Free Acid in the body, the active pharmaceutical ingredient can be released from the dosage form at a rate that will replace the amount of the Pharmaceutically Acceptable Salt or the Free Acid being metabolized and excreted from the body. Controlled or sustained release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0119] The amount of the active pharmaceutical ingredient that is effective in the treatment or prevention of a neurological disorder (e.g., Alzheimer's disease) can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, and the seriousness of the condition being treated and can be decided according to the judgment of the practitioner and each subject's circumstances in view of, e.g., published clinical studies. Suitable effective dosage amounts, however, range from about 10 micrograms to about 5 grams about every 4 hours, although they are typically about 500 mg or less per every 4 hours. In one embodiment, the effective dosage is about 0.01 mg, 0.5 mg, about 1 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, and about 5.0 g, every 4 hours. Equivalent dosages can be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months.

[0120] The effective dosage amounts described herein refer to total amounts administered by weight of the Free Acid; that is, if more than one Pharmaceutically Acceptable Salt is administered, the effective dosage amounts correspond to the total amount administered.

[0121] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99%; and in another embodiment from about 1% to about 70% of Pharmaceutically Acceptable Salt by weight or volume.

[0122] The dosage regimen utilizing a composition described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of

administration; the renal or hepatic function of the subject; and the specific Pharmaceutically Acceptable Salt employed. A person skilled in the art can readily determine the effective amount of the Pharmaceutically Acceptable Salt useful for treating or preventing the

Alzheimer's disease, including early onset Alzheimer's disease.

[0123] A Pharmaceutically Acceptable Salt can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. In some embodiments, the formulations of a Pharmaceutically Acceptable Salt are formulated for once daily dosing. In some embodiments, the formulations of a Pharmaceutically Acceptable Salt are formulated for twice daily dosing.

[0124] The amount of the Pharmaceutically Acceptable Salt in the formulation can be from about 5 mg to about 500 mg, for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 80 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 450 mg or 500 mg. In some embodiments, these amounts indicate the amount of the Free Acid or its anion in the formulation.

[0125] A composition described herein can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.

[0126] The present methods for treating or preventing neurological disorder (e.g., Alzheimer's disease or early onset Alzheimer's disease) in a subject in need thereof can further comprise administering another prophylactic or therapeutic agent to the subject being administered a Pharmaceutically Acceptable Salt. In one embodiment, the other prophylactic or therapeutic agent is administered in an effective amount. The other prophylactic or therapeutic agent includes, but is not limited to, an anti-inflammatory agent, an anti-renal failure agent, an anti-diabetic agent, and anti-cardiovascular disease agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anxiolytic agent, and an analgesic agent. [0127] In one embodiment, the other prophylactic or therapeutic agent is an agent useful for reducing any potential side effect of a Pharmaceutically Acceptable Salt. Such potential side effects include, but are not limited to, nausea, vomiting, headache, low white blood cell count, low red blood cell count, low platelet count, headache, fever, lethargy, a muscle ache, general pain, bone pain, pain at an injection site, diarrhea, neuropathy, pruritis, a mouth sore, alopecia, anxiety or depression.

[0128] In one embodiment, a composition described herein can be administered prior to, concurrently with, or after an anti-inflammatory agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.

[0129] Effective amounts of the other prophylactic or therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other prophylactic or therapeutic agent's optimal effective amount range. In one embodiment of the invention, where another prophylactic or therapeutic agent is administered to a subject, the effective amount of a composition described herein is less than its effective amount would be where the other prophylactic or therapeutic agent is not administered. In this case, without being bound by theory, it is believed that a

Pharmaceutically Acceptable Salt and the other prophylactic or therapeutic agent act synergistically to treat or prevent a neurological disorder (e.g., Alzheimer's disease or early onset Alzheimer's disease).

9. Food Effect

[0130] The term "food effect" refers to a somewhat unpredictable phenomenon that can influence the absorption of drugs from the gastrointestinal tract following oral administration. A food effect can be designated as "negative" when absorption is decreased, or as "positive" when absorption of a drug is increased and manifested as an increase in oral bioavailability (as reflected by total exposure, usually defined as AUC₀__∞). Alternatively, "food effect" can refer to changes in maximum concentration (Cmax), or the time to reach maximum

concentration (Tmax), independently of the overall absorption of the drug. As a result, some drugs need to be taken in either fasted or fed conditions to achieve the optimum

pharmacological effect. For example, patients may be instructed to take a drug with a meal, before a meal (e.g., one hour, two hours, or three ours before a meal), or after a meal (e.g., one hour, two hours, or three hours after a meal). Many drugs, however, are unaffected by presence or absence of food, and can be taken in either a fasted or a fed state.

[0131] As described more fully below, it has been discovered that administration of a Pharmaceutically Acceptable Salt without food decreases the time to achieve maximum blood concentration or Tmax for the Free Acid. In one experiment, the administration of the Pharmaceutically Acceptable Salt without food resulted in achieving Tmax of the Free Acid about three hours more quickly than when the Pharmaceutically Acceptable Salt was administered with food. As another example, it has been discovered that administration of Pharmaceutically Acceptable Salt with food increases the overall bioavailability of the Free Acid and results in a higher maximum concentration (Cmax) of the Free Acid. For example, administration of the Pharmaceutically Acceptable Salt with food resulted in an increase in bioavailability (AUCo-_∞) and approximately 50% increase in Cmax compared to

administration in a fasted state.

[0132] As discussed above, administration of the Pharmaceutically Acceptable Salt without food or in a fasted state can result in shortening the time required to achieve a maximum plasma concentration (Tmax) of the Free Acid. Achieving a shorter Tmax can be desirable since onset of drug action can be more rapid and the duration of drug action may be shortened. Some embodiments relate to methods of shortening the time required to achieve a maximum plasma concentration or a Tmax of the Free Acid in a patient being treated for a neurological disorder (e.g., Alzheimer's disease), which methods can include administering to the patient a therapeutically effective amount of a Pharmaceutically Acceptable Salt in a pharmaceutical composition without food.

[0133] Other embodiments relate to methods of increasing the time required to achieve a maximum concentration of the Salt in a patient by administering the Pharmaceutically Acceptable Salt with food.

[0134] Some embodiments relate to methods of preventing a Pharmaceutically

Acceptable Salt food effect in order to minimize the time required for onset of action of the drug. The methods can include administering the Pharmaceutically Acceptable Salt to a patient in need thereof, wherein the patient is in a fasted state or has not eaten or will not eat within a particular time period. The methods further can include providing instructions to take the Pharmaceutically Acceptable Salt without food or in a fasted state. [0135] As illustrated in Fig. 2, the food effect with the Salt increases the Tmax and decreases its Cmax.

10. Elderly Patient Effect

[0136] Elderly patients metabolize the Free Acid differently than non-elderly patients. This is believed to be due differences in weight or renal clearance between the non-elderly and elderly patients. It is believed that elderly patients have a decreased clearance of acyl glucuronide, which is a metabolite of the Pharmaceutically Acceptable Salt and the Free Acid.

11. Kits

[0137] The invention provides kits that can simplify the administration of a

Pharmaceutically Acceptable Salt to a subject. A typical kit of the invention comprises a unit dosage form comprising a Pharmaceutically Acceptable Salt. In some embodiment, the Pharmaceutically Acceptable Salt is present in the unit dosage in a pharmaceutically effective amount.

[0138] In one embodiment, the unit dosage form is a container, which can be sterile, containing an effective amount of an Pharmaceutically Acceptable Salt and a physiologically acceptable carrier or vehicle. The kit can further comprise a label or printed instructions instructing the use of a composition described herein to treat or prevent a Alzheimer's disease, including early onset Alzheimer's disease. The kit can also further comprise a unit dosage form of another prophylactic or therapeutic agent, for example, a container containing an effective amount of the other prophylactic or therapeutic agent. In one embodiment, the kit comprises a container containing an effective amount of a Pharmaceutically Acceptable Salt and an effective amount of another prophylactic or therapeutic agent. Examples of other prophylactic or therapeutic agents include, but are not limited to, those listed above.

EXAMPLES

[0139] This invention is further illustrated by the following examples, which should not be construed as limiting. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are intended to be encompassed in the scope of the claims that follow the examples below.

EXAMPLE 1

Enteric coated tablets

[0140] Enteric Coated (EC) tablets were prepared in three strengths (10, 50, and 100 mg) and were formulated as enteric coated tablets. The enteric coating had a trigger pH of 5.5. The active pharmaceutical ingredient was potassium (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate ("Potassium Salt"). The tablet compositions for two sets of Tablets, Composition A ("Comp. A") and Composition B ("Comp. B") are provided in Tables 1 and 2 below. Dosages of the active ingredient in Tables 1 and 2 refer to the weight of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)- 4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid ("Free Acid"), not the Potassium Salt.

TABLE 1

4 Mannitol 200 SD 5.0 25 5.0 25

5 Crospovidone (BASF) 5.0 25 5.0 25

6 Sodium Lauryl Sulphate 4.0 20 4.0 20

7 Poloxamer 407 4.0 20 - -

8 Colloidal Silicon dioxide 10.0 50 10.0 50

9 PRUV 1.0 5 - -

10 Magnesium stearate - - 0.25 1.25

Subtotal (Granulation) 80.75 403.75 80.00 400

EXTRAGRANULAR

1 1 MCC PH 200 LM 10.25 51.25 12.50 62.5

12 Crospovidone (BASF) 5.0 25 5.0 25

13 Talc 2.0 10 2.0 10

14 Pruv 2.0 10 - -

15 Magnesium stearate - - 0.5 2.5

Total Core Tablet 100.0 500 100.0 500

COATING

16 Opadry AMB 80W68912 5 25 5 25

17 Purified Water - - - -

18 Acryleze 93A18597 10.72 53.6 10.72 53.6

19 PEG 8000 0.84 4.2 0.84 4.2

20 Purified Water - - - -

Total Coated Tablet 1 16.56 582.8 1 16.56 582.8

As base for % w/w and mg/tab.

Table 2 provides the summary of compositions described in Table 1.

TABLE 2

dioxide

9 and 14 PRUV^® (Sodium 3.0 - 15 - 27.00 mg

Stearyl Fumarate)

10 and Magnesium stearate - 0.75 - 3.75 400.74 mg 15

13 Talc 2.0 2.0 10 10 220.40 mg

16 Opadry AMB 5.0 5.0 25 25 34.10 mg

80W68912

18 Acryleze 93A18597 10.72 10.72 53.6 53.6 160.00 mg

19 PEG 8000 0.84 0.84 4.2 4.2 167.60 mg

As base for %w/w and mg/tab

** For similar dosage form (i.e. oral tablet or capsule).

[0141] The manufacturing of the enteric coated (EC) tablets began with dry granulation of the micronized drug substance with a subset of the diluents (microcrystalline cellulose and powdered mannitol), the surfactant (sodium lauryl sulfate) and colloidal silicon dioxide. The granulation was then milled and poloxamer, additional diluent (microcrystalline cellulose), crospovidone and a portion of the lubricant (sodium stearyl fumarate) were added. The granules were then processed using a roller compactor until a bulk density of NLT0.4 g/mL was achieved. After an IPC for potency was performed, the remaining diluent

(microcrystalline cellulose), crospovidone, glidant (talc) and lubricant (sodium stearyl fumarate) were added.

[0142] The final blend was assessed for content uniformity and the cores tableted.

During the tableting, the cores were checked for weight, hardness, thickness, disintegration and friability. Following tableting, the cores were then seal coated and enteric coated. For the 100 mg tablets, the silicon dioxide was added in two portions, once before roller compaction and once after. The process used to manufacture the enteric coated tablets in this example is illustrated in Fig. 1.

EXAMPLE 2

Pharmacokinetic Studies

[0143] Pharmacokinetic studies were performed with the tablets of Composition A described in Example 1. In addition, tablets of 200 mg and 400 mg dosages were made.

[0144] Figure 2 illustrates the food effect for a 100 mg dosage. As can be seen From Fig. 2, the 100 mg tablets provide the maximum blood concentration (Cmax) of (R)-2-(5-chloro- 6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate anion at Tmax of about 3.5 hours when administered without food and at about 6.5 hours when administered after a meal. The uptake of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid was delayed by about 3 hours and its maximum blood concentration (Cmax) reduced when administered with food.

[0145] Figures 3A and 3B illustrate dose proportionality of (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoic acid.

[0146] Figures 4A-4H illustrate pharmacokinetic characteristics of (R)-2-(5-chloro-6- (2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid.

[0147] Pharmacokinetic characteristics were similar across observed across a wide dose range following single dosing (SD) or multiple daily dosing (MD). Figs. 4A-4D provide the blood levels of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)- 3-cyclobutylpropanoate anion for 20 mg, 50 mg, 100 mg and 200 mg dose on a linear scale, while Figs. 4E-4H provide the drug concentration for the same doses on a logarithmic scale.

[0148] Figures 5A-5B illustrate the effects of 200 mg single dosing (SD) and multiple dosing (MD) in non-elderly and elderly (ELD) subjects.

[0149] Although the general pharmacokinetic characteristics are similar in non-elderly and elderly subjects, both single dose (SD) and multiple dose (MD) daily dose AUCo-24 values are greater in elderly subjects than non-elderly subjects.

[0150] Figs. 6A and 6B illustrate the maximum blood concentrations in non-elderly and elderly (ELD) with multiple dosing (MD) and single dosing. As can be seen in Figs. 6A and 6B, (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid exposure increased in elderly subjects (ELD) with repeat daily dosing (MD) relative to single dose administration (SD). This effect was not observed in non-elderly subjects. Both single (SD) and repeat (MD) daily dose (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4 ' -(trifluoromethyl)biphenyl-3 -yl)-3 -cyclobutylpropanoate anion AUCo-24 values are greater in elderly subjects than non-elderly subjects, as illustrated in Fig. 6C.

Claims

What is claimed is:

1. A pharmaceutical composition comprising:

(a) (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3- cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof;

(b) colloidal silicon dioxide; and

(c) cross-linked polyvmylpolypyrrolidone (crospovidone).

2. The pharmaceutical composition of claim 1, further comprising microcrystalline cellulose.

3. The pharmaceutical composition of any one of claims 1-2, wherein colloidal silicon dioxide is present in the composition in an amount of about 5% to about 20% by weight.

4. The pharmaceutical composition of any one of claims 1-3, wherein cross-linked polyvmylpolypyrrolidone (crospovidone) is present in the composition in an amount of about 5% to about 20% by weight.

5. The pharmaceutical composition of any one of claims 1-4, wherein colloidal silicon dioxide is present in the composition in an amount of about 10% by weight.

6. The pharmaceutical composition of any one of claims 1-5, wherein cross-linked polyvmylpolypyrrolidone (crospovidone) is present in the composition in an amount of about 10% by weight.

7. The pharmaceutical formulation of any one of claims 2-6, wherein microcrystalline cellulose is present in the composition in an amount of about 20% to about 50% by weight.

8. The pharmaceutical composition of any one of claims 1-7 which does not comprise a poloxamer.

9. The pharmaceutical composition of any one of claims 1-8, wherein (R)-2-(5-chloro- 6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is substantially crystalline.

10. The pharmaceutical formulation of any one of claims 1-9, wherein (R)-2-(5-chloro-6- (2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 10 mg to about 200 mg by weight.

11. The pharmaceutical composition of any one of claims 1-10, wherein (R)-2-(5-chloro- 6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof does not substantially agglomerate.

12. The pharmaceutical composition of any one of claims 1-11, wherein (R)-2-(5-chloro- 6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof does not substantially gel.

13. The pharmaceutical composition of any one of claims 1-12, wherein the

pharmaceutically acceptable salt is potassium salt.

14. The pharmaceutical composition of any one of claims 1-13 formulated for oral administration.

15. The pharmaceutical composition of claim 14 in the form of a tablet, a capsule or a powder.

16. The pharmaceutical composition of claim 15 in the form of a tablet.

17. A method of treating or preventing Alzheimer's disease in a patient comprising administering to the patient in need thereof the pharmaceutical composition of any one of claims 1-16.

18. The method of claim 17, wherein the pharmaceutical composition is administered once daily.

19. The method of claim 17, wherein the pharmaceutical composition is administered twice daily.

20. The method of any one of claims 17-19, wherein the patient is a mammal.

21. The method of claim 20, wherein the mammal is a human.

22. An oral solid dosage form comprising:

(a) a core comprising (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof and an excipient; and

(b) an enteric coating.

23. The oral dosage form of claim 22, wherein the enteric coating comprises a methacrylic acid copolymer.

24. The oral dosage form of any one claims 22-23, wherein the enteric coating comprises polyethylene glycol (PEG).

25. The oral dosage form of any one claims 23-24, wherein the methacrylic acid copolymer is methacrylic acid copolymer type C.

26. The oral dosage form of any one of claims 21-25, wherein the core comprises from about 45% to about 70% of microcrystalline cellulose.

27. The oral dosage form of any one of claims 22-26, wherein the core does not comprise a poloxamer.

28. The oral dosage form of any one of claims 22-27, wherein the core comprises about 10%) of cross-linked polyvinylpolypyrrolidone (crospovidone).

29. The oral dosage form of any one of claims 22-28, wherein the enteric coating is present in the amount of about 10% to about 20% of the weight of the core.

30. The oral dosage form of any one of claims 22-29, wherein the coating begins to dissolve at pH between about 4 to about 7.

31. The oral dosage form of any one of claims 22-29, wherein the coating begins to dissolve at pH between about 4.5 to about 6.5.

32. The oral dosage form of any one of claims 22-29, wherein the coating begins to dissolve at pH about 5.5.

33. The pharmaceutical composition of any one of claims 21-32, wherein (R)-2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is substantially crystalline.

34. The oral dosage form of any one of claims 21-33, wherein the core comprises from about 10 mg to about 200 mg of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof.

35. The oral dosage form of any one of claims 21-34, wherein the pharmaceutically acceptable salt is potassium salt.

36. The oral dosage form of any one of claims 21-35, suitable for once or twice daily administration.

37. A method of treating or preventing Alzheimer's disease in a patient comprising administering to the patient in need thereof the oral dosage form of any one of claims 21-36.

38. The method of claim 37, wherein the oral dosage form is administered once daily.

39. The method of claim 37, wherein the oral dosage form is administered twice daily.

40. The method of any one of claims 37-39, wherein the patient is a mammal.

41. The method of claim 40, wherein the mammal is a human.

42. An oral pharmaceutical composition comprising: (R)-2-(5-chloro-6-(2,2,2- trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof and an excipient, wherein the formulation provides a maximum blood level concentration of (R)-2-(5-chloro-6- (2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate anion at about 3 to about 5 hours after dosing when administered without food.

43. The pharmaceutical composition of claim 42, wherein the composition provides a maximum blood level concentration of (R)-2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4'- (trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoate anion at about 6 to about 7 hours after dosing when administered with food.

44. The pharmaceutical composition of any one of claims 42-43, wherein the composition comprises about 5% to about 20% by weight of colloidal silicon dioxide.

45. The pharmaceutical composition of any one of claims 42-44, wherein the

composition comprises about 5% to about 20% by weight of cross-linked

polyvinylpolypyrrolidone (crospovidone) .

46. The pharmaceutical formulation of any one of claims 42-45, wherein the composition comprises about 20%> to about 50%> by weight of microcrystalline cellulose.

47. The pharmaceutical composition of any one of claims 42-46, which does not comprise a poloxamer.

48. The pharmaceutical composition of any one of claims 42-47, wherein (R)-2-(5- chloro-6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is substantially crystalline.

49. The pharmaceutical formulation of any one of claims 42-48, wherein (R)-2-(5-chloro- 6-(2,2,2-trifluoroethoxy)-4'-(trifluoromethyl)biphenyl-3-yl)-3-cyclobutylpropanoic acid or a pharmaceutically acceptable salt thereof is present in the composition in an amount of about 10 mg to about 200 mg by weight.

50. The pharmaceutical composition of any one of claims 42-49, wherein the

pharmaceutically acceptable salt is potassium salt.

51. The pharmaceutical composition of any one of claims 42-50 suitable for once-daily administration.

52. The pharmaceutical composition of any one of claims 42-50 suitable for twice-daily administration.

53. The pharmaceutical composition of any one of claims 42-52 in the form of a tablet, a capsule or a powder.

54. The pharmaceutical composition of claim 53 in the form of a tablet.

55. A method of treating or preventing Alzheimer's disease in a patient comprising administering to the patient in need thereof an effective amount of the pharmaceutical composition of any one of claims 42-54.

56. The method of claim 55, wherein the pharmaceutical composition is administered once or twice daily.

57. The method of any one of claims 55-56, wherein the patient is a mammal.

58. The method of claim 57, wherein the mammal is a human.

59. The pharmaceutical composition of claim 1 , wherein wherein colloidal silicon dioxide is present in the composition in an amount of about 10% by weight and cross-linked polyvmylpolypyrrolidone (crospovidone) is present in the composition in an amount of about 10% by weight.

60. The pharmaceutical composition of claim 1 , wherein wherein colloidal silicon dioxide is present in the composition in an amount of about 10% by weight and cross-linked polyvmylpolypyrrolidone (crospovidone) is present in the composition in an amount of about 5% by weight.