HK1176300A - Pharmaceutical formulations comprising 1- (beta-d-glucopyranosyl) -2 -thienyl-methylbenzene derivatives as inhibitors of sglt - Google Patents

Description

Pharmaceutical formulation comprising 1- (beta-D-glucopyranosyl) -2-thienyl-methylbenzene derivative as SGLT inhibitor

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application 61/333,495 filed on 11/5/2010, which is incorporated herein by reference in its entirety.

Statement regarding federally sponsored research or development

The research and development of the invention described below was not federally sponsored.

Technical Field

The present invention relates to novel pharmaceutical compositions comprising a compound of formula (I), a prodrug thereof, or a pharmaceutically acceptable salt thereof, as disclosed herein, which are useful for treating diabetes, obesity, diabetic complications, and related diseases.

Background

WO 2005/012326, the disclosure of which is incorporated herein by reference in its entirety, discloses a class of compounds that are sodium-dependent glucose transporter (SGLT) inhibitors and therapeutic uses of these compounds, such as the treatment of diabetes, obesity, diabetic complications, and the like. WO 2005/012326 discloses the compound 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene). 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) hemihydrate and certain crystalline forms thereof are disclosed in WO 2008/069327, the disclosure of WO 2008/069327 also being incorporated herein by reference in its entirety.

Disclosure of Invention

In its many embodiments, the present invention provides novel pharmaceutical compositions of compounds of formula (I), prodrugs thereof, or pharmaceutically acceptable salts thereof, and methods of using such pharmaceutical compositions to treat, prevent, inhibit, or ameliorate one or more diseases associated with sodium-dependent glucose transporters.

One aspect of the invention features an orally-administrable pharmaceutical formulation comprising:

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

wherein

R₁Is halogen, cyano, optionally substituted lower alkyl or optionally substituted lower alkoxy; and is

R₂Is an optionally substituted aryl group or an optionally substituted heterocyclic group;

(b) at least one diluent or filler;

(c) optionally at least one disintegrant;

(d) optionally at least one binder; and

(e) optionally at least one lubricant;

wherein

The compound of formula (I) is present in an amount ranging from about 1% to about 80% by weight;

the diluent or filler is present in an amount in the range of about 10% to about 95% by weight;

the disintegrant, if present, is present in an amount ranging from about 0.1% to about 20% by weight;

the binder, if present, is present in an amount ranging from about 0.1% to about 20% by weight; and

the lubricant, if present, is present in an amount ranging from about 0.1% to about 5% by weight, all of the above% by weight being based on the weight of the formulation.

In certain embodiments, the compound of formula (I) is a compound of formula (I-S) as described herein.

In certain embodiments, the present invention relates to an orally administrable pharmaceutical formulation comprising a compound of formula (I) as described herein in combination with a bioavailability facilitator.

In certain embodiments, the bioavailability facilitator increases the bioavailability of the compound and includes excipients known in pharmaceutical formulations. Preferably, the compound of formula (I) is formulated with the bioavailability facilitator, resulting in a measurable increase in the bioavailability of the compound after administration of the formulation.

Preferably the present invention further relates to a bioavailability facilitator which comprises a composition of excipients such as binders, fillers, disintegrants, lubricants or combinations thereof.

In certain embodiments, the formulations of the present invention are solid oral dosage forms that provide increased bioavailability of the compound contained therein as compared to an oral suspension containing the same amount of the compound as the solid oral dosage form.

Additional embodiments and advantages of the invention will be apparent from the detailed discussion, schemes, examples and claims that follow.

Drawings

FIGS. 1A and B provide linear and logarithmic plasma concentration profiles of the compounds of formula (I-S) after oral administration of different formulations of the compounds of formula (I-S) to dogs.

FIG. 2 provides plasma concentration profiles of compound (I-S) following oral administration of different formulations of the compound of formula (I-S) to human subjects.

Detailed Description

The present invention relates in part to an orally administrable pharmaceutical formulation comprising:

(a) a compound of formula (I-S) or a prodrug or pharmaceutically acceptable salt thereof:

(b) at least one diluent or filler;

(c) optionally at least one disintegrant;

(d) optionally at least one binder; and

(e) optionally at least one lubricant;

wherein

The compound of formula (I-S) is present in an amount ranging from about 1% to about 80% by weight;

the diluent or filler is present in an amount in the range of about 10% to about 95% by weight;

the disintegrant, if present, is present in an amount ranging from about 0.1% to about 20% by weight;

the binder, if present, is present in an amount ranging from about 0.1% to about 20% by weight; and

the lubricant, if present, is present in an amount ranging from about 0.1% to about 5% by weight, all of the above% by weight being based on the weight of the formulation.

In certain embodiments, the present invention relates to an orally administrable pharmaceutical formulation comprising:

(a) a compound of formula (I-S) or a prodrug or pharmaceutically acceptable salt thereof, present in an amount ranging from about 40% to about 60% by weight;

(b) at least one diluent or filler present in an amount ranging from about 30% to about 50% by weight;

(c) at least one disintegrant present in an amount ranging from about 3% to about 10% by weight;

(d) at least one binder present in an amount ranging from about 0.5% to about 5% by weight; and

(e) at least one lubricant present in an amount ranging from about 0.5% to about 2% by weight;

wherein the wt% is based on the weight of the formulation.

The compound of formula (I-S) may also be referred to as 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene).

In certain preferred embodiments, the compound of formula (I-S) is a hemihydrate of the compound of formula (I-S), also known as 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) hemihydrate.

In certain embodiments, the invention relates to a pharmaceutical composition as described herein for use in the manufacture of a pharmaceutical dosage form for oral administration to a mammal in need of treatment, characterized in that the dosage form can be administered at any time of day independently of the ingestion by the mammal.

In certain embodiments, the invention relates to a method of treatment of the human or non-human animal body comprising administering to said body a therapeutically effective dose of a pharmaceutical composition as described herein.

In certain embodiments, the present invention relates to a pharmaceutical pack suitable for commercial sale, the pack comprising a container, an oral dosage form as described herein, and the pack being accompanied by written material that is not limited with respect to whether the dosage form can be administered fed or fasted.

A) Term(s) for

Some terms are defined below and used throughout this disclosure.

"administration" or "administering" means providing a drug to a patient in a pharmacologically effective manner.

By "patient" or "subject" is meant an animal, preferably a mammal, more preferably a human, in need of therapeutic intervention.

"dosage form" refers to one or more compounds in a medium, carrier, vehicle, or device suitable for administration to a patient. By "oral dosage form" is meant a dosage form suitable for oral administration.

"dose" refers to one unit of drug. Typically, the dosage is provided in a dosage form. The patient may be given a dosage according to a variety of dosing regimens. Typical dosing regimens include once daily oral (qd), twice daily oral (bid), and three times daily oral (tid).

"terminal half-Life" (t)¹/₂) The calculation was 0.693/k, where "k" refers to the apparent clearance rate constant, which was estimated by linear regression of log-transformed plasma concentrations in the terminal log-linear decay phase.

Plasma half-life (t) of drug¹/₂) Is the time required to halve the plasma concentration (e.g., from 100mg/L to 50 mg/L). Knowledge of the half-life can be used to determine the frequency of administration (number of intakes per day) required to obtain the desired plasma concentration. Generally, the half-life of a particular drug is independent of the dose administered. In some particular cases, it varies with the dose: it may increase or decrease with, for example, saturation of the mechanism (elimination, catabolism, binding of plasma proteins, etc.).

The "area under the curve" or "AUC" is the area measured under the plasma drug concentration curve (also called plasma concentration profile). Generally, AUC refers to the integral of the plasma drug concentration curve over a time interval, e.g., AUC start-end. Thus, AUC0-48h refers to the AUC obtained from integrating the plasma concentration profile over a period of 0-48 hours, where 0 is conventionally the time at which the drug or drug-containing dosage form is administered to the patient. AUCt refers to the area under the plasma concentration curve from 0 hours to the time t of the last detectable concentration, calculated by the trapezoidal rule. AUCinf refers to the AUC value extrapolated to infinity (calculated as the sum of AUCt) and the area extrapolated to infinity (calculated as the concentration at time t (Ct) divided by k). (if t cannot be estimated for the subject¹/₂Value, mean t usable for the treatment¹/₂Value calculation AUCinf).

By "mean area under the plasma concentration profile" is meant the mean AUCinf obtained in several patients (following a single administration of the dosage form to each patient) or given multiple doses to the same patient at different times (with sufficient clearance between doses to allow the drug level to drop to pre-dose levels, etc.).

"C" refers to the concentration of a drug in the plasma or serum of a subject, usually expressed as mass per unit volume, typically nanograms per milliliter. For convenience, this concentration is referred to herein as "drug plasma concentration", "plasma drug concentration" or "plasma concentration". The plasma drug concentration at any time after administration is designated C_{Time of day}As in C_9hOr C_24hAnd the like. The maximum plasma concentration obtained after administration of the dosage form, obtained directly from the experimental data without interpolation, is called C_max. The mean plasma concentration obtained over the target period is called Cx_Average. "mean single dose maximum plasma concentration C_maxBy "is meant the mean C obtained in several patients (after a single administration of the dosage form to each patient) or by multiple administrations to the same patient (with sufficient clearance between administrations to allow the drug level to drop to the pre-administration level, etc.)_max。

The "plasma concentration profile" represents a curve obtained by plotting the plasma concentration of the drug compound against time. In general, the convention is as follows: the zero point on the time scale (conventionally on the x-axis) is the time at which the drug compound or dosage form containing the drug compound is administered to the patient.

By "mean time to maximum plasma concentration" is meant the time from administration of a dosage form comprising a drug to the patient to the C at which the drug is obtained, in several patients (after a single administration of the dosage form to each patient) or multiple administrations to the same patient (with sufficient clearance between administrations to allow the drug level to drop to the pre-administration level, etc.)_maxThe average time elapsed over time and is obtained directly from the experimental data without interpolation.

Bioavailability indicates the percentage of drug administered that reaches the central compartment. It is typically measured as follows: for example, AUC obtained after intravenous administration and after oral administration are compared. The AUC obtained after intravenous administration corresponds to the bioavailability, defined as 100%; after oral administration, the AUC corresponds to the same bioavailability at best. It is usually lower and sometimes zero. In contrast, in the present application, the maximum plasma concentration C reached after administration is used_maxIndicating bioavailability. Higher C of the pharmaceutical dosage form_maxIndicating that better bioavailability of the drug can be achieved by administration of the dosage form.

A cavity refers to the imaginary volume in which the drug is dispensed. It may or may not correspond to a real volume, for example a volume of blood called the first or central cavity, or the whole body other than blood called the second cavity. The central cavity typically includes plasma and those tissues or organs in tissues where drug concentrations rapidly equilibrate with plasma. The real anatomical part in which the drug is distributed in different concentrations is represented as 1, 2, rarely 3 virtual cavities, where the concentration of the drug is considered uniform. The concept of lacunae thus makes it possible to mimic the fate of a drug.

The term "halogen" refers to chlorine, bromine, iodine and fluorine, with chlorine and fluorine being preferred.

The term "alkyl" denotes a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms. Preferred is a linear or branched alkyl group having 1 to 6 carbon atoms, and more preferred is a linear or branched alkyl group having 1 to 4 carbon atoms. Examples thereof are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl and various branched isomers thereof. Further, the alkyl group may be optionally and independently substituted with 1 to 5 substituents as described below, if necessary.

An "alkoxy" group is an oxygen ether formed from a straight or branched chain alkanyl radical as described previously. In some embodiments, alkoxy groups may be optionally and independently substituted with 1 to 5, preferably 1 to 3 substituents as defined below.

The term "alkylene" denotes a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms. A linear or branched alkylene group having 1 to 6 carbon atoms is preferable, and a linear or branched alkylene group having 1 to 4 carbon atoms is more preferable. Examples thereof are methylene, ethylene, propylene, trimethylene and the like. If necessary, the alkylene group may be optionally substituted in the same manner as the above-mentioned "alkyl group". Where alkylene groups as defined above are attached to two different carbon atoms of the phenyl ring, they together with the attached carbon atoms form a fused five-, six-or seven-membered carbocyclic ring and may be optionally substituted by one or more substituents as defined below.

The term "alkenyl" refers to a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond. Preferred alkenyl groups are straight or branched chain alkenyl groups having 2 to 6 carbon atoms, and more preferred are straight or branched chain alkenyl groups having 2 to 4 carbon atoms. Examples thereof are vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4, 8, 12-tetradecatrienyl and the like. The alkenyl group may be optionally and independently substituted with 1 to 4 substituents as described below, if necessary.

"alkenylene" means a straight or branched divalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond. A linear or branched alkenylene group having 2 to 6 carbon atoms is preferable, and a linear or branched alkenylene group having 2 to 4 carbon atoms is more preferable. Examples thereof are vinylidene group, propenylene group, butadienylene group and the like. The alkenylene group may be optionally substituted with 1 to 4 substituents as described below, if necessary. When alkenylene groups as defined above are attached to two different carbon atoms of the phenyl ring, they form together with the attached carbon atoms a fused five-, six-or seven-membered carbocyclic ring (e.g. a fused phenyl ring) and may be optionally substituted by one or more substituents as defined below.

"alkynyl" means a straight or branched monovalent hydrocarbon chain having at least one triple bond. Preferred alkynyl groups are straight or branched chain alkynyl groups having 2 to 6 carbon atoms, and more preferred straight or branched chain alkynyl groups having 2 to 4 carbon atoms. Examples thereof are 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecyynyl, 4-dodecenyl and the like. The alkynyl group may be optionally and independently substituted with 1 to 4 substituents as described below, if necessary.

The term "cycloalkyl" denotes a monocyclic or bicyclic monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and more preferably a monocyclic saturated hydrocarbon group having 3 to 7 carbon atoms. Examples thereof are monocyclic alkyl and bicyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. These groups may be optionally and independently substituted with 1 to 4 substituents as described below, if necessary. The cycloalkyl group may be optionally condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be cyclicOptionally containing oxygen, nitrogen, sulfur, SO or SO atoms₂) And the condensed saturated hydrocarbon ring or the condensed unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents as described below.

The term "cycloalkylene" denotes a monocyclic or bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon atoms, and preferably a monocyclic saturated hydrocarbon ring having 3 to 6 carbon atoms. Examples thereof are a monocyclic alkylene group and a bicyclic cycloalkylene group, such as a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group and the like. These groups may be optionally and independently substituted with 1 to 4 substituents as described below, if necessary. Further, the cycloalkylene group may be optionally condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) And the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents as described below.

"cycloalkenyl" means a monocyclic or bicyclic monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms and having at least one double bond. Preferred cycloalkenyl groups are monocyclic unsaturated hydrocarbon groups having 4 to 7 carbon atoms. Examples thereof are monocyclic alkenyl groups such as cyclopentenyl group, cyclopentadienyl group, cyclohexenyl group and the like. These groups may be optionally and independently substituted with 1 to 4 substituents as described below, if necessary. Further, the cycloalkenyl group may be optionally condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (if necessary, the saturated hydrocarbon ring and the unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring₂) And the condensed saturated hydrocarbon ring or unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents as described below.

The term "cycloalkynyl" refers to a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms and at least one triple bond. Preferred cycloalkynyl groups are monocyclic unsaturated hydrocarbon groups having 6 to 8 carbon atoms. Examples thereof are monocyclic alkynyl groups such as cyclooctynyl, cyclodecynyl. These groups may be optionally substituted with 1 to 4 substituents described below, if necessary. Further, the cycloalkynyl group may be optionally and independently fused with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (which may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 in the ring, if necessary), and the fused saturated hydrocarbon ring or unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described below.

The term "aryl" refers to a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof are phenyl group, naphthyl group (including 1-naphthyl group and 2-naphthyl group). These groups may be optionally and independently substituted with 1 to 4 substituents described below, if necessary. Further, the aryl group may be optionally fused with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (which may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO, or SO2 within the ring, if necessary), and the fused saturated hydrocarbon ring or unsaturated hydrocarbon ring may be optionally and independently substituted with 1 to 4 substituents described below.

The term "unsaturated monocyclic heterocyclic ring" means an unsaturated hydrocarbon ring containing 1 to 4 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms, and preferably a 4-to 7-membered saturated or unsaturated hydrocarbon ring containing 1 to 4 heteroatoms independently selected from nitrogen atoms, oxygen atoms and sulfur atoms. Examples thereof are pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole,Oxazole, isoAzole, 4, 5-dihydroOxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, and the like. Among them, pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, and the like are preferably used,Oxazole and thiazole. If necessary, the "unsaturated monocyclic heterocycle" may be optionally and independently substituted by 1 to 4 groups ofThe substituent is substituted.

The term "unsaturated fused heterobicyclic ring" means a hydrocarbon ring composed of a saturated or unsaturated hydrocarbon ring condensed with the above-mentioned unsaturated monocyclic heterocyclic ring, wherein said saturated hydrocarbon ring and said unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO in the ring, if necessary₂. "unsaturated fused and heterobicyclic ring" includes, for example, benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, dihydroisoquinoline, and the like. Furthermore, "heterocycle" also includes their possible N-or S-oxides.

The term "heterocyclyl" refers to the monovalent radicals of the unsaturated monocyclic heterocycles or unsaturated fused heterobicycles mentioned above, as well as the monovalent radicals of the saturated forms of the unsaturated monocyclic heterocycles or unsaturated fused heterobicycles mentioned above. The heterocyclic group may be optionally and independently substituted with 1 to 4 substituents described below, if necessary.

The term "alkanoyl" refers to formyl and the group formed by bonding an "alkyl" group to a carbonyl group.

The term "substituted" refers to groups in which one or more hydrogen atoms are each independently replaced by the same or different substituents.

The term "independently" when used in conjunction with a substituent means that when more than one such substituent is possible, such substituents may be the same or different from each other.

The definition of any substituent or variable at a particular position in a molecule is intended to be independent of its definitions elsewhere in that molecule. It is to be understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art and those methods set forth herein.

Substituents for each of the above groups include, for example, halogen atoms (fluorine, chlorine, bromine), nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, sulfo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylidenemethyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloalkynyloxy, aryloxy, heterocyclyloxy, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloalkynylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkoxy-carbonyl, alkenyloxy-carbonyl, alkynyloxy-carbonyl, cycloalkoxy-carbonyl, cycloalkenyl-oxy-carbonyl, cycloalkynyl-oxy-carbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkanoyloxy, alkenyl-carbonyloxy, alkynyl-carbonyloxy, Cycloalkyl-carbonyloxy, cycloalkenyl-carbonyloxy, cycloalkynyl-carbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono-or di-alkylamino, mono-or di-alkanoylamino, mono-or di-alkoxycarbonylamino, mono-or di-arylcarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfinylamino, carbamoyl, mono-or di-alkylcarbamoyl, mono-or di-arylcarbamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, alkoxycarbonylamino, alkylsulfinylamino, alkylsulfonylamino, arylsulfony, Cycloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl, arylsulfonyl and heterocyclylsulfonyl. Each of the above groups may be optionally substituted with these substituents.

Further, terms such as haloalkyl, halogenated lower alkyl, halogenated alkoxy, halogenated lower alkoxy, halogenated phenyl or halogenated heterocyclic group mean that alkyl, lower alkyl, alkoxy, lower alkoxy, phenyl or heterocyclic group (hereinafter referred to as alkyl and the like) are respectively substituted with one or more halogen atoms. Preferred are alkyl groups substituted with 1 to 7 halogen atoms and the like, and more preferred are alkyl groups substituted with 1 to 5 halogen atoms and the like. Likewise, terms such as hydroxyalkyl, hydroxy-lower alkyl, hydroxyalkoxy, hydroxy-lower alkoxy, and hydroxyphenyl refer to alkyl groups substituted with one or more hydroxy groups, and the like. Preferred are alkyl groups substituted with 1 to 4 hydroxyl groups and the like, and more preferred are alkyl groups substituted with 1 to 2 hydroxyl groups and the like. Further, terms such as alkoxyalkyl, lower alkoxyalkyl, alkoxy-lower alkyl, lower alkoxy-lower alkyl, alkoxyalkoxy, lower alkoxyalkoxy, alkoxy-lower alkoxy, lower alkoxy-lower alkoxy, alkoxyphenyl, and lower alkoxyphenyl refer to alkyl groups substituted with one or more alkoxy groups, and the like. Preferred are alkyl groups substituted with 1 to 4 alkoxy groups and the like, and more preferred are alkyl groups substituted with 1 to 2 alkoxy groups and the like.

The terms "aralkyl" and "arylalkoxy" used alone or as part of another group refer to alkyl and alkoxy groups described above having an aryl substituent.

Unless otherwise defined, the term "lower" used in the definition of chemical formula in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms. More preferably, the term refers to a straight or branched carbon chain having 1 to 4 carbon atoms.

The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The term "prodrug" denotes an ester or carbonate formed as follows: one or more of the hydroxyl groups of the compound of formula (I) are reacted with an acylating agent substituted with an alkyl, alkoxy or aryl group according to a conventional method to produce an acetate, pivalate, methyl carbonate, benzoate and the like. In addition, prodrugs also include esters or amides, which are likewise formed by reacting one or more of the hydroxyl groups of the compound compounds of formula (I) with an α -amino acid or β -amino acid, etc., using a condensing agent by conventional methods. In addition, prodrugs also include ethers, which are likewise formed by reacting one or more of the hydroxy groups of the compounds of formula (I) with a condensing agent by conventional methods.

By "pharmaceutically acceptable" is meant that the molecular entities and compositions are of sufficient purity and quality to be useful in the preparation of the compositions or medicaments of the present invention. As both human (clinical and over-the-counter) and veterinary are equally included within the scope of the present invention, formulations may include compositions or medicaments for human or veterinary use.

The term "pharmaceutically acceptable salts" includes, for example, salts with alkali metals (e.g., lithium, sodium, potassium, etc.); salts with alkaline earth metals (e.g., calcium, magnesium, etc.); salts with zinc or aluminum; salts with organic bases (e.g., ammonium, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris (hydroxymethyl) aminomethane, N-methylglucamine, triethanolamine, dehydroabietylamine); salts with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like); or salts with organic acids (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.); or salts with acidic amino acids (e.g., aspartic acid, glutamic acid, etc.).

The compounds of formula (I) of the present invention also include mixtures of stereoisomers, or each pure or substantially pure isomer. For example, the compounds of the present invention may optionally have one or more asymmetric centers at a carbon atom that contains any of the substituents. Thus, the compounds of formula (I) may exist as enantiomers or diastereomers or mixtures thereof. When the compound of formula (I) of the present invention contains a double bond, the compound of the present invention may exist in the form of geometric isomers (cis-compound, trans-compound), and when the compound of formula (I) of the present invention contains an unsaturated bond such as carbonyl group, the compound of the present invention may exist in the form of tautomers, and the compound of the present invention also includes these isomers or mixtures thereof. In the preparation of the compounds of the present invention, the starting compounds may be used in the form of racemic mixtures, enantiomers or diastereomers. When the compounds of the present invention are obtained in diastereoisomeric or enantiomeric forms, they can be separated using conventional methods (e.g., chromatography or fractional crystallization).

Further, the compound of formula (I) of the present invention includes an intramolecular salt, hydrate, solvate or polymorph thereof.

To provide a more concise description, some of the quantitative representations given herein are not modified by the term "about". It is understood that each quantity given herein is meant to refer to the actual given value, whether or not the term "about" is used explicitly, and also to refer to the approximation to such given value that would reasonably be inferred according to the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

To provide a more concise description, some quantitative expressions are described herein as ranges from about amount X to about amount Y. It should be understood that where a range is described, the range is not limited to the upper and lower bounds described, but includes the entire range from about X to about Y, or any amount or range therein.

B) Compound (I)

The compounds of formula (I) exhibit excellent inhibitory activity against sodium-dependent glucose transporters and excellent glucose-lowering effect. Thus, the formulations of the invention are useful for treating or delaying the progression or onset of a sodium-dependent glucose transporter-mediated disorder. In particular, the formulations of the invention may be used to treat or delay the progression or onset of: diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, or hypertension. In particular, the formulation of the present invention may be used for the treatment or prevention of diabetes (type I and type II diabetes, etc.), diabetic complications (such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) or obesity, or may be used for the treatment of postprandial hyperglycemia.

In certain preferred embodiments, R is shown in formula (I)₁Is a halogen atom or a lower alkyl group; and R shown in formula (I)₂The phenyl group is optionally substituted with 1 to 3 substituents selected from: halogen atom, cyano group, lower alkyl group, halo-lower alkyl group, lower alkoxy group, halo-lower alkoxy group, methylenedioxy group, ethyleneoxy group, mono-or di-lower alkylamino group, carbamoyl group and mono-or di-lower alkylcarbamoyl group.

The pharmaceutical compounds of formula (I) preferably used in the disclosed formulations generally have slight to weak aqueous solubility in their crystalline or amorphous forms and thus poor bioavailability, but the present invention is not necessarily limited to compounds having little or no aqueous solubility.

Preferred representative compounds for use in the formulations of the present invention include: 1- (beta-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) or a prodrug or a pharmaceutically acceptable salt thereof. In certain more preferred embodiments, the compound used in the formulations of the present invention is 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) hemihydrate.

Preferably, 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) or a prodrug or pharmaceutically acceptable salt thereof is included in the formulation of the invention in an amount from about 25mg to about 600mg, preferably from about 50mg to about 400 mg.

In certain more preferred embodiments, 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) or a prodrug or pharmaceutically acceptable salt thereof is included in the formulation of the invention in an amount of about 25mg, about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg or about 400 mg. In certain more preferred embodiments, 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) or a prodrug or pharmaceutically acceptable salt thereof is included in the formulation of the invention in an amount of about 100mg or about 300 mg. In certain embodiments, wherein the 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) is in the form of a hemihydrate, preferably 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) hemihydrate is included in the formulation in an amount of about 25.5mg, about 51mg, about 102mg, about 204mg, or about 306mg, preferably in an amount of about 102mg or about 306 mg.

C) Preparation

In an embodiment of the invention, the compound is formulated into an oral dosage form suitable for administration to a patient in need thereof.

The oral dosage form may be provided in the form of any pharmaceutically acceptable solid dosage form. Preferably, the solid dosage form includes, for example, solid articles such as tablets, pills, granules, capsules, powders, and others. More preferably, the solid dosage form is an oral tablet or capsule formulation. Most preferably, the solid dosage form is an oral tablet.

In certain embodiments of the invention, the formulation includes a filler or diluent in an amount of from about 10% to about 95% by weight of the formulation, preferably from about 25% to about 90% by weight of the formulation, more preferably from about 30% to about 50% by weight of the formulation, or from about 35% to about 45% by weight of the formulation.

In certain embodiments of the invention, the formulation includes a disintegrant in an amount from about 0.1% to about 20% by weight of the formulation, preferably from about 0.25% to about 10% by weight of the formulation, more preferably from about 3% to about 10% by weight of the formulation, or from about 5% to about 7% by weight of the formulation.

In certain embodiments of the invention, the formulation includes a binder in an amount of from about 0.1% to about 20% by weight of the formulation, preferably from about 0.1% to about 10% by weight of the formulation, more preferably from about 0.5% to about 5% by weight of the formulation, or from about 1% to about 4% by weight of the formulation.

In certain embodiments of the invention, the formulation includes a lubricant in an amount of from about 0.1% to about 5% by weight of the formulation, preferably from about 0.1% to about 2% by weight of the formulation, more preferably from about 0.5% to 2% by weight of the formulation, or from 0.5% to 1.5% by weight of the formulation.

In certain embodiments of the present invention, the formulation optionally includes a surfactant in an amount of from about 0% to about 10% by weight of the formulation, preferably from about 0% to about 5% by weight of the formulation.

The solid dosage forms may comprise the compound in combination with various pharmaceutically acceptable excipients, and preferably the dosage forms are adapted to provide increased bioavailability of the compound in a particular manner to achieve a desired clinical effect by oral administration to a patient.

The bioavailability facilitator of the present invention includes any combination of excipients described herein, such that the formulation will provide increased bioavailability of the compounds contained within the formulation. In certain preferred embodiments, the bioavailability facilitator includes 2 or more excipients as described herein.

Pharmaceutically acceptable excipients are known in the art and may be provided in view of the desired functionality and processing ability. The role of excipients in the oral dosage form includes, but is not limited to: fillers, binders, disintegrants, release controlling agents, glidants, lubricants, coating agents, and the like.

For example, in one embodiment of the present invention, it is desirable to have the immediate release characteristics of the dosage form. To help achieve this property in a solid dosage form, the dosage form preferably comprises a disintegrant in the amounts indicated herein. In another embodiment of the invention, wherein a controlled release or sustained release formulation of the compound is desired. Such formulations can be achieved by varying the amount, concentration and ratio of certain release-controlling polymers.

In one embodiment, the formulation of the invention comprises the following amounts of the compound: from about 1% to about 80%, preferably from about 5% to about 60% by weight of the formulation, more preferably from about 40% to about 60% by weight of the formulation, or from about 45% to about 55% by weight of the formulation. One or more of the dosage forms may be administered depending on the desired dosage of the compound.

For example, in a preferred embodiment of the present invention, an oral release formulation is provided in the form of a tablet comprising about 100mg1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene), microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, anhydrous lactose, and magnesium stearate.

In another preferred embodiment of the invention, the oral release formulation is provided in the form of a tablet comprising about 300mg1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene), microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, anhydrous lactose and magnesium stearate.

In another preferred embodiment of the invention, the oral release formulation is provided in the form of a tablet comprising about 102mg1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) hemihydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, anhydrous lactose and magnesium stearate.

In another preferred embodiment of the invention, the oral release formulation is provided in the form of a tablet comprising about 306mg1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) hemihydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, anhydrous lactose and magnesium stearate.

Fillers or diluents for use in the formulations of the present invention include fillers or diluents commonly used in pharmaceutical formulations. Examples of fillers or diluents used in accordance with the present invention include, but are not limited to: sugars such as lactose, glucose, sucrose, cellulose, starch and carbohydrate derivatives, polysaccharides(including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, calcium carbonate, magnesium carbonate, microcrystalline cellulose, combinations thereof, and the like. In certain preferred embodiments, the filler or diluent is lactose, microcrystalline cellulose, or a combination thereof. Several classes of microcrystalline cellulose are suitable for use in the formulations described herein, such as microcrystalline cellulose selected from the group consisting of:types PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose. Several classes of lactose are suitable for use in the formulations described herein, for example, lactose selected from the group consisting of: anhydrous lactose, lactose monohydrate, lactose fasting flo, directly compressible anhydrous lactose and modified lactose monohydrate. In one embodiment of the invention, the filler or diluent is a combination of microcrystalline cellulose and lactose.

Binders useful in the formulations of the present invention include binders commonly used in pharmaceutical formulations. Examples of adhesives for use according to the present invention include, but are not limited to: cellulose derivatives (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose), glycols, sucrose, glucose, corn syrup, polysaccharides (including acacia, tragacanth, guar gum, alginates, and starch), corn starch, pregelatinized starch, modified corn starch, gelatin, polyvinylpyrrolidone, polyethylene glycol, combinations thereof, and the like. Preferably, the binder, if present, is hydroxypropyl cellulose.

Disintegrants for use in the formulations of the invention include disintegrants commonly used in pharmaceutical formulations. Examples of disintegrants for use in accordance with the invention include, but are not limited to: starches, clays, celluloses, alginates and gums and cross-linked starches, celluloses and polymers, combinations thereof, and the like. Representative disintegrants include: microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginates, crospovidone, cellulose, agar and related gums, sodium starch glycolate, corn starch, potato starch, sodium starch glycolate, Veegum HV, methylcellulose, agar, soap clay, carboxymethylcellulose, alginic acid, guar gum, combinations thereof, and the like. Preferably, the disintegrant, if present, is cross-linked cellulose, more preferably cross-linked sodium carboxymethyl cellulose or cross-linked sodium carboxymethyl cellulose.

Lubricants used in the formulations of the present invention are those commonly used in pharmaceutical formulations. Examples of lubricants used according to the present invention include, but are not limited to: magnesium carbonate, magnesium lauryl sulfate, calcium silicate, talc, fumed silica, combinations thereof, and the like. Other useful lubricants include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, sodium benzoate, colloidal silicon dioxide, magnesium oxide, microcrystalline cellulose, starch, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium acetate, sodium chloride, combinations thereof, and the like. Preferably, the lubricant, if present, is magnesium stearate or stearic acid, more preferably magnesium stearate.

Surfactants useful in the formulations of the present invention include surfactants commonly used in pharmaceutical formulations. Examples of surfactants for use according to the present invention include, but are not limited to: ionic and non-ionic surfactants or wetting agents commonly used in pharmaceutical formulations such as ethoxylated castor oil, polydiolated glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, docusate sodium, sodium lauryl sulfate, cholic acid or derivatives thereof, lecithin, phospholipids, combinations thereof and the like.

Other polymers often used as excipients include, but are not limited to: methylcellulose (MC), Ethylcellulose (EC), Hydroxyethylcellulose (HEC), Methylhydroxyethylcellulose (MHEC), Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and the like. These polymers, alone or in different combinations, can be used for a variety of purposes, including but not limited to controlling the release of the compounds of the formulations of the present invention.

In any event, the appropriate excipients should be selected so that they are compatible with the other excipients and do not bind to the pharmaceutical compound or cause degradation of the drug.

The pharmaceutical formulations disclosed herein may additionally comprise an antioxidant and a chelating agent. For example, the pharmaceutical formulation may comprise Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), Propyl Gallate (PG), sodium metabisulfite, ascorbyl palmitate, potassium metabisulfite, disodium EDTA (ethylenediaminetetraacetic acid; also known as disodium edetate), EDTA, tartaric acid, citric acid monohydrate, and sodium sulfite.

In another embodiment, the tablet or capsule of the present invention has a protective outer layer. The protective outer layer of the tablet or capsule, when present, may comprise from about 10% to about 95% polymer, based on the weight of the coating layer, and may be prepared using conventional procedures. In one embodiment, the outer layer of the tablet or capsule comprises from about 20% to about 90% polymer, based on the weight of the coating layer. The formulation may contain at least one coating polymer and a coating solvent (e.g., water) which is used for processing and removed by drying. Suitable examples of polymers for the coating layer include, but are not limited to: hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), ethylcellulose, methacrylic acid polymers, hydroxypropyl cellulose, and starch. In one embodiment, the coating polymer is PVA. In another embodiment, the coating polymer is hydroxypropyl cellulose.

The coating may also optionally include from about 0% to about 30% by weight plasticizer, based on the weight of the coating layer. In one embodiment, the plasticizer is about 15% to about 25% by weight of the coating layer. Suitable plasticizers include, but are not limited to, for example, triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol (PEG), glycerin, triacetin, and triethyl citrate.

In another embodiment, the coating may also optionally include an anti-adherent or glidant, such as talc, fumed silica, or magnesium stearate.

In another embodiment, the coating may also optionally include an opacifier, such as titanium dioxide.

In another embodiment, wherein the formulation is a tablet, the tablet may be further coated with a coating layer that will provide a decorative benefit to the dosage form. In certain embodiments, such coatings help protect the tablet. In certain embodiments, such coatings comprise hydroxypropyl methylcellulose, polyethylene glycol, polydextrose, titanium dioxide, and triacetin. In certain other embodiments, such coatings comprise hydroxypropylmethylcellulose 2910, polyethylene glycol 400, polydextrose, titanium dioxide, camuba wax, and yellow iron oxide. In at least one embodiment, such a coating layer comprises an amount of from about 0% to about 10% by weight of the tabletII (white); in certain other embodiments, the amount is from about 0% to about 6% by weight of the tablet; in other embodiments, the amount is from about 0% to about 3% by weight of the tablet; in other embodiments, the amount is from about 2 to about 4% by weight of the tablet.

D) Other therapeutic agents

In another embodiment, the formulation of the present invention additionally comprises one or more other therapeutic agents to provide the desired therapeutic effect.

Other therapeutic agents suitable for combination with the formulations of the present invention include, but are not limited to, known therapeutic agents useful in the treatment of the aforementioned disorders associated with SGLT2 activity, including: antidiabetic agents, antihyperglycemic agents, hypolipidemic agents or lipid lowering agents, anti-obesity agents, antihypertensive agents and appetite suppressants.

The present invention further provides a method for treating or delaying the progression or onset of a disease or disorder associated with SGLT2 activity, the method comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the present invention and one or more of: antidiabetic agents, antihyperglycemic agents, hypolipidemic agents or lipid lowering agents, anti-obesity agents, antihypertensive agents and appetite suppressants.

In one embodiment, the present invention provides a method for treating type II diabetes, the method comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the present invention and one or more antidiabetic agents. In another embodiment, the present invention provides a method for prolonging the progression or onset of type II diabetes, comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the present invention and one or more antidiabetic agents.

In another embodiment, the invention provides a method for treating or delaying the progression or onset of type II diabetes, the method comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the present invention and one or more of: antihyperglycemic agents, hypolipidemic or lipid lowering agents, anti-obesity agents, antihypertensive agents, and appetite suppressants. For example, the present invention provides a method for treating or delaying the progression or onset of type II diabetes, the method comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of the pharmaceutical formulation of the present invention and an antihyperglycemic agent. In another embodiment, the invention provides a method for treating or delaying the progression or onset of type II diabetes, the method comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of the pharmaceutical formulation of the present invention and a hypolipidemic agent. In another embodiment, the invention provides a method for treating or delaying the progression or onset of type II diabetes, the method comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the present invention and an anti-obesity agent. In another embodiment, the invention provides a method for treating or delaying the progression or onset of type II diabetes, the method comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the present invention and an antihypertensive agent. In another embodiment, the invention provides a method for treating or delaying the progression or onset of type II diabetes, the method comprising: administering to a mammalian species in need of such treatment a therapeutically effective amount of a pharmaceutical formulation of the invention and an appetite suppressant.

Examples of antidiabetic agents suitable for use in combination with the formulations of the present invention include, but are not limited to: biguanides (e.g., metformin or phenformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulin (including insulin secretagogues or insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide, and glipizide), biguanide/glyburide combinations (e.g.,) Thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, glycogen phosphorylase inhibitors, inhibitors of fatty acid binding proteins (aP2), glucagon-like peptide-1 (GLP-1) and other agonists of the GLP-1 receptor and dipeptidyl peptidase IV (DPP4) inhibitors.

Other suitable thiazolidinediones include, but are not limited to: MCC-555, faraglitazar, englitazone or darglitazone; isaglitazone, reglitazar, rivoglitazone, liraglutide and (Z) -1, 4-bis-4- [ (3, 5-dioxo-1, 2, 4-Oxazolidin-2-yl-methyl)]Phenoxy but-2-ene.

Examples of PPAR-alpha agonists, PPAR-gamma agonists, and PPAR alpha/gamma dual agonists include, but are not limited to: moglicata, peliglitazar, tesaglitazar AR-HO39242, GW-501516, and IRP 297.

Suitable DPP4 inhibitors include, but are not limited to: sitagliptin and saxagliptin.

Examples of antihyperglycemic agents suitable for use in combination with the formulations of the present invention include, but are not limited to: glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-37), exenatide, LY-315902, MK-0431, liraglutide, ZP-10, and CJC-1131.

Examples of lipid lowering agents/lipid lowering agents suitable for use in combination with the formulations of the present invention include one or more MTP inhibitors, HMGCoA reductase inhibitors (e.g., mevastatin, lovastatin, pravastatin, simvastatin, fluvastatin, cerivastatin, atorvastatin, atavistin, rosuvastatin), squalene synthetase inhibitors, fibric acid derivatives (e.g., fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like), probucol, bile acid sequestrants (such as cholestyramine, colestipol, and cholestaphylamine, and also liposoms), ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na +/bile acid co-inhibitors, upregulators of LDL receptor activity, bile acid sequestrants, cholesterol ester transfer proteins (e.g., CETP inhibitors such as Tochester and JTT-705, PPAR agonists (as described above), and/or niacin and derivatives thereof. Preferred hypolipidemic agents include, for example: pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin and rosuvastatin.

Examples of antihypertensive agents suitable for use in combination with the formulations of the present invention include, but are not limited to: beta adrenergic blockers, calcium channel blockers (L-and T-forms; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlorthiazide, polythiazide, benzthiazide, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan) and ET receptor antagonists (e.g., sitaxsentan and atxen).

Examples of anti-obesity agents suitable for use in combination with the formulations of the present invention include, but are not limited to: beta 3 adrenergic agonists, lipase inhibitors, 5-hydroxytryptamine (and dopamine) reuptake inhibitors, thyroid receptor beta drugs, 5HT2C agonists; MCHR1 antagonists such as synaptic SNAP-7941 and Takeda T-226926, melanocortin receptor (MC4R) agonists, melanin-containing hormone receptor (MCHR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, NPY1 or NPY5 antagonists, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, 11- β -HSD-1 inhibitors, desmoid receptor modulators, monoamine reuptake inhibitors or releases, ciliary neurotrophic factor, BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, cannabinoid-1 receptor antagonists, and anorectic agents.

Examples of lipase inhibitors that may be used in combination with the formulations of the present invention include, but are not limited to: orlistat and ATL-962 (Alizyme).

5-hydroxytryptamine (and dopamine) reuptake inhibitors (or 5-hydroxytryptamine receptor agonists) that may be used in combination with the formulations of the present invention include, but are not limited to: BVT-933, sibutramine, topiramate and axokine.

Examples of monoamine reuptake inhibitors that may be used in combination with the formulations of the present invention include, but are not limited to: fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, parachlorophentermine, clofosfamide, clotermine, pisereib, sibutramine, dextroamphetamine, phentermine, phenylpropanolamine, and mazindol.

Anorexics agents that may be used in combination with the formulations of the present invention include, but are not limited to, topiramate, dextroamphetamine, phentermine, phenylpropanolamine, and mazindol.

Where any of the formulations of the present invention is used in combination with other therapeutic agents, the other therapeutic agents may be used in amounts indicated, for example, in the physicians' Desk Reference, or in other amounts known and used by those of ordinary skill in the art.

Where any of the formulations of the invention is used in combination with other therapeutic agents, each compound in the combination may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination in jointly therapeutically effective amounts, e.g., in the daily dosages as set forth herein. In one embodiment of the invention, the fixed combination of the invention may be prepared as follows: dry granules of the compound of formula (I) or (I-S) or the formulation of the invention and other therapeutic agents are mixed and the mixture is filled into capsules of the desired size, shape, color, or other characteristics or compressed to form tablets.

E) Production of the formulations

In certain embodiments, the formulations of the present invention are prepared by preparing a mixture of the pharmaceutical compound and the bioavailability facilitator. This may most directly be achieved by dissolving these components in their liquid solvent and subsequently removing the solvent. Thus viewed from another aspect the invention provides a process for the preparation of a pharmaceutical composition comprising: dissolving a pharmaceutical compound and a pharmaceutically acceptable excipient in a solvent; removing the solvent from the resulting solution; optionally forming the resulting product into a desired shape; and optionally coating the resulting product with a physiologically tolerable coating material.

The products according to the invention are preferably produced by standard techniquesA dosage form of the embodiments described herein. For example, the dosage form may be produced by wet granulation techniques. In wet granulation techniques, the drug and carrier are mixed using an aqueous or organic solvent (such as denatured absolute ethanol) as the granulation fluid. The remaining ingredients may be dissolved in a portion of the granulation fluid (such as the solvent described above) and the latter prepared wet mixture slowly added to the drug mixture with continuous mixing in a blender. The granulation fluid is added until a wet mixture is produced, which is then forced through a predetermined screen and dried in a fluid bed dryer. The dried granules were then sized. Next, magnesium stearate or another suitable lubricant and other excipient materials are added to the drug particles, the particles are placed in milling jar sand and mixed on a milling jar for 10 minutes. Pressing the composition into a layer, e.g. inPress or KorschLCT press. For a three layer core, the drug layer composition and the granules or powder of the compressed layer composition are placed sequentially into an appropriately sized die, an intermediate compression step is applied to each of the first 2 layers, and then after the last layer is added to the die, a final compression step is performed to form a three layer core. Intermediate pressing typically occurs at a force of about 50-100 newtons. Final stage compression typically occurs at a force of 3500 newtons or greater (often 3500-. Feeding the compressed cores to a dry coating press, e.g.Dry Coater press, followed by coating with the wall material described herein.

Pan coating may be conveniently used to provide the finished dosage form. In a pan coating system, the wall-forming composition of the inner or outer wall (as the case may be) is deposited by continuously spraying a suitable wall composition onto the compressed core while tumbling in a rotating coating pan. Pan coaters are used because of their availability on a commercial scale. Other techniques may be used to coat the compressed core. Once coated, the walls are dried in a forced air oven or in an oven with controlled temperature and humidity to release the dosage form of the solvent used in the production. Drying conditions are conventionally selected based on available equipment, ambient conditions, solvents, coating materials, coating thickness, and the like.

Other coating techniques may also be used. For example, one alternative technique uses an air levitation operation. The operation includes: the compressed cores are suspended and tumbled in air until a coating is applied to the cores. Air suspension operations are described in the following documents: U.S. patent nos. 2,799,241; J.am.pharm.Assoc., vol.48, page 451-459 (1959); and the literature, volume 49, pages 82-84 (1960). Use ofAir suspension coaters, for example using methylene chloride methanol as a co-solvent for the wall forming material, may also coat the dosage form. Aeromatic air suspension coaters can be applied using co-solvents.

In another embodiment, drug layers comprising drug and other ingredients are blended and compressed into a solid layer. The layer has dimensions corresponding to the internal dimensions of the area that the layer is to occupy in the dosage form, and it also has dimensions corresponding to the compressed layer (if included) for forming an arrangement in contact with each other. The drug and other ingredients may also be blended with the solvent by conventional methods such as ball milling, calendering, stirring or rolling, and mixed into a solid or semi-solid form, and then pressed into a preselected shape. The compressed core may then be coated with an inner wall material and a semipermeable wall material as described herein.

Another production method that can be used includes: the powdered ingredients were blended in a fluid bed granulator. After dry blending the powdered ingredients in the granulator, a granulation fluid (e.g., polyvinylpyrrolidone in water) is sprayed on the powder. The coated powder is then dried in a granulator. The process may granulate all ingredients present therein while adding the granulation fluid. After drying the granules, a lubricant (such as stearic acid or magnesium stearate) is mixed into the granules using a blender (e.g., a V-blender or back blender). The granules are then compressed and coated in the manner described above.

Exemplary solvents suitable for producing the components of the dosage form include: aqueous or inert organic solvents that do not adversely damage the materials used in the system. The solvent broadly includes a member selected from the group consisting of: aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic compounds, aromatic compounds, heterocyclic solvents, and mixtures thereof. Typical solvents include: acetone, diacetone alcohol, methanol, ethanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene chloride, ethylene dichloride, propylene dichloride, carbon tetrachloride nitroethane, nitropropane tetrachloroethane, diethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1, 4-diacetone alcohol, methyl ethyl acetate, n-butyl acetate, methyl isobutyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene chloride, ethylene dichloride, propylene dichlorideAlkanes, tetrahydrofuran, diglyme, water, aqueous solvents containing inorganic salts (such as sodium chloride, calcium chloride, etc.), and mixtures thereof, such as acetone and water, acetone and methanol, acetone and ethanol, dichloromethane and methanol, and dichloroethane and methanol.

Exemplary liquid carriers of the invention include: lipophilic solvents (such as oils and lipids), surfactants, and hydrophilic solvents. Exemplary lipophilic solvents, for example, include, but are not limited to: capmul PG-8, Caprol MPGO, Capryol 90, Plurol Oleique CC497, Capmul MCM, Labrafac PG, N-decanol, Caprol 10G100, oleic acid, vitamin E, Maisine 35-1, Gelucire33/01, Gelucire 44/14, lauryl alcohol, Captex 355EP, Captex 500, Cappyric/Caplic triglyceride, Peceol, Caprol ET, Labrafil M2125CS, Labrafac CC, Labrafil M201944 CS, Captex 8277, Myvacet 9-45, Isopropyl Nyrolate, Caprol PGE860, olive oil, Plurol Oleique, peanut oil, Captex 300Low C6, and capric acid.

Exemplary surfactants, for example, include, but are not limited to: vitamin E TPGS, Cremophor (EL, EL-P and RH40 grades), Labrasol, Tween (20, 60, 80 grades), Pluronic (L-31, L-35, L-42, L-64 and L-121 grades), Acconon S-35, Solutol HS-15 and Span (20 and 80 grades).

Exemplary hydrophilic solvents, for example, include, but are not limited to: dimethyl isosorbide, polyethylene glycol (grades PEG 300, 400, 600, 3000, 4000, 6000 and 8000) and Propylene Glycol (PG).

In general, substantially complete solvent removal is preferred because the resulting product can be readily shaped. The shaping can be achieved as follows: by spray drying the solution (to provide the product in particulate form), by evaporating the solvent from the solution disposed in the mold, by molding (e.g., injection molding), by extrusion, and the like. Generally, when hot, a product may be formed and allowed to cool to solidify. The shaped product can likewise be produced in the form of a film or sheet by evaporation, or by pouring the heated substance onto a plate and evaporating off the solvent.

F) Formulation examples

The following formulation examples are merely illustrative and are not intended to limit the scope of the invention in any way. Tablets were prepared using the ingredients listed in tables 1.1-1.6 and the procedures described below.

In the following examples in tables 1.1-1.6, the exemplified compounds, lactose anhydrous, microcrystalline cellulose and croscarmellose sodium were sieved and placed in a fluidized bed.

Hydroxypropyl cellulose and purified water were mixed to prepare a granulation solution.

The granulation solution is sprayed into a fluidized bed to granulate the dried ingredients.

When the granulation solution is exhausted, the granules in the fluidized bed are dried.

The dried granules are passed through a suitable mill equipped with a suitable sieve.

The milled granules are placed in a suitable blender and mixed with the sieved magnesium stearate.

The mixture is blended for a suitable period of time.

The final blend was compressed into tablets using a suitable rotary tablet press.

In case a film coating (e.g. Opadry II) is used, the film coating powder is mixed with purified water to obtain a film coating suspension.

The tablets are film coated in a suitable coating pan and dried.

Table 1.1: 100mg tablet formulation

¹The amount of hemihydrate corresponds to 100mg of 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl)]Benzene)

Table 1.2: 25mg tablet formulation

¹The amount of hemihydrate corresponds to 25mg of 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl)]Benzene)

Table 1.3: 200mg tablet formulation

¹The amount of hemihydrate corresponds to 200mg of 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl]Benzene)

Table 1.4: 50mg tablet formulation

¹The amount of hemihydrate corresponds to 50mg of 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl]Benzene)

Table 1.5: 300mg coated tablet formulation

¹The amount of hemihydrate corresponds to 300mg of 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl)]Benzene)

²Coating tablets with Opadry II to 3% weight gain

Table 1.6: 100mg coated tablet formulation

¹The amount of hemihydrate corresponds to 100mg of 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl)]Benzene)

²Coating tablets with Opadry II to 4% weight gain

G) Biological examples

In vivo pharmacokinetic data from dog studies

Different orally administrable formulations were used to compare the exposure of 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) in dogs. 11 male beagle dogs were selected for this study, which had a body weight of 8.0-10.0kg at the time of administration and exhibited good overall health. The dogs were divided into 3 groups according to their weight. After an overnight fast, each dog received a single dose of oral suspension or tablet formulation. 3 dosage forms for co-administration of the pharmaceutical compound 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene): 5mg/mL nanosuspension, 100mg tablet formulation, and 25mg tablet formulation. 3 fasted dogs in group 1 received 20mL of 5mg/mL nanosuspension; the 4 fasted dogs assigned to group 2 received 100mg tablet formulation (1 tablet/dog; ingredients are listed in table 1.1); the 4 fasted dogs assigned to group 3 received 25mg tablet formulation (4 tablets/dog; ingredients are listed in table 1.2).

After each dose, dogs received 10mL of tap water to ensure delivery of the entire dose. Approximately 3mL blood samples were collected into K2EDTA tubes by jugular puncture or other suitable sites at 0 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours after the initial administration and placed on wet ice. Plasma was harvested by centrifugation and frozen at-20 ℃. All samples were placed in amber vials to protect from white light and processed 2 hours after collection.

Analysis of the drug compound 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl) in plasma samples using liquid chromatography-triple or quadruple mass spectrometry (LC-MS/MS) assay procedure (lower limit of quantitation 50ng/mL)]Benzene) was added. Electronically transferring plasma concentration data to Watson^TMLIMS computer system. The Watson^TMThe system assigns a value of 0.00 to those concentrations below the lower limit of quantitation.

TABLE 2

The nanosuspension used as a control in this study included 0.5%Suspension, measured in weight percent.Is a hydroxypropyl methylcellulose (HPMC) polymer that exhibits high viscosity and is used as a thickener for suspensions. The drug concentration was 5mg drug per 1mL suspension volume. A total of 20mL of suspension was administered to each dog in the nanosuspension group.

The pharmaceutical compound 1- (. beta. -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl) was carried out using a computer program validated by WinNonlin Version 4.0.1(Pharsight)]Benzene) to determine: maximum plasma concentration (C)_max) Time to maximum plasma concentration (t)_max) Area under plasma concentration versus time curve extrapolated to infinity (AUC)_infAnd AUC_0-48h) Terminal half-life (t)_1/2) And plasma clearance (CL/F).

TABLE 3

After a single oral administration of 20mL of a 5mg/mL nanosuspension of the compound to male beagle dogs, based on the average t at 1.17 hours_maxThe absorption of the compound is rapid and is based on an average t of 9.23 hours_1/2Value, its elimination is slow. Administration of an oral single dose of 100mg tablet formulation or 4 doses of 25mg tablet formulation of the compound showed delayed absorption of the compound, e.g. average t of 2.25 and 3.50 hours, respectively_maxThe values indicate.

However, after application of 2 tablet formulations, the elimination of the compound remained slow with an average t of 9.13 and 9.97 hours, respectively_1/2The value is obtained. Maximum plasma concentration (C) of the compound after oral administration of 1 dose of 100mg tablet formulation and 4 doses of 25mg tablet formulation compared to 5mg/mL nanosuspension based on mean plasma pharmacokinetic parameters normalized to 1mg/kg_max) Higher (fig. 1A and B).

Furthermore, the bioavailability (as measured by AUC) after administration of either a 100mg tablet formulation or a 25mg tablet formulation of the compound compared to the corresponding value after administration of 5mg/mL nanosuspension_infIndicated) is higher.

In vivo pharmacokinetic data from human studies

Healthy human subjects receive a single oral administration of a liquid nanosuspension or tablet formulation under fed and/or fasted conditions at 3 different dosage levels of the pharmaceutical compound 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene). The 3 dose levels included: 25mg (representative formulation listed in Table 1.2), 200mg (representative formulation listed in Table 1.3) and 400mg of the pharmaceutical compound. Specifically, a 400mg tablet dose is achieved by administering 2 doses of 200mg tablet formulation.

The mean plasma concentration profile of the compound after oral administration of 200mg tablet formulation (in fasted and fed conditions) and 40mL of 5mg/mL liquid nanosuspension (fed condition) is shown in figure 2. Similar profiles of tablet formulation versus nanosuspension were obtained at doses of 25mg and 400 mg.

As shown in Table 4, inUnder fed conditions, after 25 and 200mg doses, maximum plasma concentrations (t) of the compound were reached for the tablet formulation_max) The median time of (a) is about 1-1.5 hours, and in the case of nanosuspensions 4 hours. At a 400mg dose level, for 2 doses of 200mg tablet formulation, the median t_maxIs about 1.75 hours and in the case of nanosuspensions is 2.25 hours.

Mean C of the nanosuspension formulations under fed conditions for all doses (25mg, 200mg, 400mg)_maxLower than tablet formulations.

Mean C under fasting conditions after administration of tablet formulations at doses of 25 and 200mg_maxHigher than in fed conditions. Mean AUC of the compounds for all doses (25mg, 200mg and 400mg) with fed or fasted (only 25mg and 200mg tablet formulations)_infThe values are comparable.

TABLE 4

These data suggest that food does not significantly affect the extent of bioavailability of a pharmaceutical compound, however, it decreases the rate of absorption, e.g., C_maxDecrease sum of t_maxAs evidenced by the delay of (c).

After administration of tablets at a dose of 400mg (2X200mg tablets), varying the meal time (30 min dosing before breakfast compared to 10 min dosing before breakfast) did not seem to affect t_max、t_1/2、C_maxOr AUC_∞。

For all treatment regimens (regardless of formulation and food intake), pharmaceutical compoundsAverage t of_1/2Is in the range of about 8 to about 12 hours.

Claims (17)

1. An orally-administrable pharmaceutical formulation comprising:

(a) a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof

(I)

Wherein

R₁Is halogen, cyano, orOptionally substituted lower alkyl or optionally substituted lower alkoxy; and is

R₂Is an optionally substituted aryl group or an optionally substituted heterocyclic group;

(b) at least one diluent or filler;

(c) optionally at least one disintegrant;

(d) optionally at least one binder; and

(e) optionally at least one lubricant;

wherein

The compound of formula (I) is present in an amount ranging from about 1% to about 80% by weight;

the diluent or filler is present in an amount in the range of about 10% to about 95% by weight;

the disintegrant, if present, is present in an amount ranging from about 0.1% to about 20% by weight;

the binder, if present, is present in an amount ranging from about 0.1% to about 20% by weight; and is

The lubricant, if present, is present in an amount ranging from about 0.1% to about 5% by weight, all of the above% by weight being based on the weight of the formulation.

2. The pharmaceutical composition of claim 1, wherein

R₁Is a halogen atom or a lower alkyl group; and is

R₂Is phenyl optionally substituted with 1 to 3 substituents selected from: halogen atom, cyano group, lower alkyl group, halo-lower alkyl group, lower alkoxy group, halo-lower alkoxy group, methylenedioxy group, ethyleneoxy group, mono-or di-lower alkylamino group, carbamoyl group and mono-or di-lower alkylcarbamoyl group.

3. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is a compound of formula (I-S):

(I-S)；

or a prodrug or pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition of claim 3, wherein the compound is present in an amount of about 25mg to about 600 mg.

5. The pharmaceutical composition of claim 3, wherein the compound is present in an amount of about 50mg to about 300 mg.

6. The pharmaceutical composition of claim 3, wherein the compound is present in an amount of about 100 mg.

7. The pharmaceutical composition of claim 3, wherein the compound is present in an amount of about 300 mg.

8. The pharmaceutical composition of claim 1, wherein the compound is 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) hemihydrate.

9. The pharmaceutical composition of claim 1, wherein the formulation is a tablet.

10. A method for treating a sodium-dependent glucose transporter mediated disorder, the method comprising: administering to a patient in need thereof a pharmaceutical composition according to claim 3.

11. The method of claim 10, wherein the compound is administered 1 time per day at a dose of about 50mg to about 300 mg.

12. The method of claim 10, wherein the compound is administered at a dose of about 100 mg/day.

13. The method of claim 10, wherein the compound is administered at a dose of about 300 mg/day.

14. An orally-administrable pharmaceutical formulation comprising:

(a) a compound of formula (I-S) or a prodrug or pharmaceutically acceptable salt thereof,

(I-S)，

present in an amount ranging from about 40% to about 60% by weight;

(b) at least one diluent or filler present in an amount ranging from about 30% to about 50% by weight;

(c) at least one disintegrant present in an amount ranging from about 3% to about 10% by weight;

(d) at least one binder present in an amount ranging from about 0.5% to about 5% by weight; and

(e) at least one lubricant present in an amount ranging from about 0.5% to about 2% by weight;

wherein the wt% is based on the weight of the formulation.

15. The pharmaceutical composition of claim 14, wherein the compound is 1- (β -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl ] benzene) hemihydrate.

16. The pharmaceutical composition of claim 14, wherein the formulation is a tablet.

17. The pharmaceutical composition of claim 15, wherein the formulation is a tablet.