WO2009091663A1 - Stable pharmaceutical formulation of a dpp-iv inhibitor with metformin - Google Patents

Abstract

A dosage form is provided for an anti-diabetic DPP-IV inhibitor of formula (I) as its tartrate salt compound of formula (IT), in combination with a metformin salt, wherein the purity of the active pharmaceutical ingredients are maintained over a prolonged storage period under conditions similar to those likely encountered in home storage of the medication by a diabetic patient. A formulation free of calcium salts such as calcium phosphate, but including, for example, microcrystalline cellulose, copovidone, crospovidone, colloidal silicon dioxide, and magnesium stearate, when compacted into a tablet with the tartrate salt compound of formula (IT) was shown to be more stable than for a tablet formulation including a calcium salt. Methods for preparation of the dosage form, and methods for use of the dosage form, are also provided.

Description

STABLE PHARMACEUTICAL FORMULATION OF A DPP-IV INHIBITOR WITH METFORMIN

Related Applications

This application claims priority under 35 U.S.C. §119(e) to U.S. Application Serial No. 61/020,978, filed January 14, 2008, and to U.S. Application Serial No. 61/022,227, filed January 18, 2008, both of which are incorporated herein by reference in their entireties.

Background of the Invention

The enzyme dipeptidyl peptidase IV (DPP-IV) is a member of the dipeptidyl peptidase family, which cleaves N-terminal dipeptide residues from proteins, particularly where the dipeptide includes an N-terminal penultimate proline or alanine residue. DPP-IV is believed to be involved in glucose control, as its peptidolytic action inactivates the insulotropic peptides glucagon-like peptide I (GLP-I) and gastric inhibitory protein (GJJP). Inhibition of DPP-IV, such as with synthetic inhibitors in vivo, can serve to increase plasma concentrations of GLP-I and GIP, and thus improve glycemic control in the body. Such synthetic inhibitors would therefore be useful in the treatment of diabetes mellitus and related conditions.

However, there exist other members of this dipeptidyl peptidase (DPP) enzyme family including DPP-XII, DPP-XIII, DPP-IX, and FAP (fibroblast activation protein), which have similar substrate specificities to DPP-IV.

Inhibition of certain of these enzymes, for example, DPP-XIII, is known to cause toxic effects in mammals. Therefore, to be medicinally useful, inhibitors of DPP-IV must also exhibit selectivity for DPP-IV relative to at least some other members of the DPP enzyme family. Certain such selective DPP-IV inhibitors have been developed, as is disclosed in the PCT Patent Application Publication No. WO 2005/047297 and in U.S. Patent Application Publication Nos. 2006/0258621, 2006/0264400, and 2006/0264401. Inhibition of DPP-IV by compounds of the structure of the formula:

wherein R^a and R^b are OH providing a boronic acid, its salt, or a protected form, is disclosed therein. The compound is referred to as a pyrrolidin-3-yl-glycyl- έøro-proline, or more generally, a pyrrolidin-3-ylglycylaminoalkylboronate. U.S. Patent Application Publication No. 2006/0264400, published Nov. 23,

2006, specifically claims a compound of this structure and its use for selectively inhibiting DPP-IV, such as in a mammal with a malcondition that can be regulated or normalized by inhibition of DPP-IV, such as diabetes.

The DPP-IV inhibitor can be given as a combination with the known anti-diabetes drug, metformin. Metformin (also known by trade names METIGUANIDE, GLUCOPHAGE, and others), is a salt of 3- (diaminomethylidene)-l,l-dimethylguanidine, also known as 1,1,- dimethylbiguanide. Metformin is typically provided as the hydrochloride salt. In order to obtain the benefits of administration of a selective DPP-IV inhibitor, such as in a combination medication with metformin, particularly by oral ingestion, a patient must ingest the inhibitor compound in a form adapted to facilitate absorption of the active pharmaceutical ingredient into the blood stream where it can be transported to the site of action within the body. The dosage form, which in some applications will likely be adapted for home use on a daily or other regular basis by diabetic patients, must also provide for stability of the bioactive compound under the storage conditions typically encountered in patients' homes, for example, in a home medicine cabinet where exposure to warmth and humidity is expected. Summary of the Invention

The invention is directed to a dosage form for a DPP-IV inhibitor in combination with metformin that provides for a surprisingly high degree of storage stability, particularly under warm or humid conditions. An embodiment of the present invention is directed to a tablet dosage form for the active pharmaceutical ingredient, a DPP-IV inhibitor having formula (I):

_^

(I) as its tartrate salt compound of formula (IT), corresponding to the formula shown above wherein R^a and R^b are both OH and a salt is formed with tartaric acid. This is understood to include any solvates, hydrates, tautomers, or stereoisomers, thereof. Any stereoisomeric form of a compound of formula (I), and optical isomeric mixtures, are included. The dosage form includes a tartrate salt (IT) of the compound of formula (I); metformin, such as a salt thereof; optionally, a diluent including a microcrystalline cellulose; a binder including copovidone; a disintegrant including crospovidone; a lubricant including magnesium stearate; and a glidant including colloidal silicon dioxide. The tartrate salt of the compound of formula (IT) can include any stereoisomeric form of tartaric acid such as a monotartrate, an L-tartrate, or a mono-L-tartrate. The dosage form is free of a calcium salt. More specifically, the dosage form is free of calcium phosphate. As is described in U.S. Application Ser. No. 60/939,292, filed May 21, 2007 by the inventor herein, it was surprisingly found that the presence of calcium salts led to high rates of decomposition of the compound of formula (IT); herein, the unexpected instability of the compound of formula (IT) and metformin in the presence of calcium salts is disclosed.

The compound of formula (I) is an inhibitor of the enzyme dipeptidyl peptidase IV (DPP-IV). More particularly, a specific stereoisomer of this compound, a compound of formula (II)

(H) is an inhibitor of DPP-IV, and in the form of a tartrate salt is likewise an inhibitor of DPP-IV. An embodiment of the present invention is directed to the dosage form recited above including the specific stereoisomer of formula (II) as a tartrate salt.

An embodiment of the present invention, directed to a method of preparation of the inventive dosage form, involves milling the tartrate salt compound of formula (IT) to provide a milled compound; then, blending the milled compound with an optional diluent including microcrystalline cellulose and with the metformin hydrochloride to provide a blended milled compound; then, in a fiuidized bed granulator, granulating the blended milled compound with a solution of the binder including copovidone in water to provide granules; then drying the granules; then milling and screening the granules to provide dried, milled granules; then blending the dried, milled granules with the dispersant including crospovidone, the glidant including colloidal silicon dioxide, and the lubricant including magnesium stearate, to provide a lubricated blend; then compressing the lubricated blend in a tablet press to provide the inventive dosage form. The dosage form is free of a calcium salt. More specifically, the dosage form is free of calcium phosphate.

Another embodiment of a method of preparation of the inventive dosage form involves dry mixing the tartrate compound of formula (IT) , and metformin hydrochloride, the optional diluent including microcrystalline cellulose, and the binder including copovidone, in a high shear granulator to provide a dry mix; then adding water to the dry mix to provide granules; then drying and milling the granules; then adding the dispersant including crospovidone, the glidant including colloidal silicon dioxide and the lubricant including magnesium stearate; then mixing all these together to provide a lubricated blend; then compressing the lubricated blend in a tablet press to provide the inventive dosage form. Again the dosage form is free of a calcium salt; more specifically, the dosage form is free of calcium phosphate. The inventive dosage form can include from about 50 mg to about 500 mg of the tartrate compound of formula (IT) on a free base basis. Specifically, the inventive dosage form can include about 50 mg, 100 mg, 200 mg, or 400 mg of the inventive compound on a free base basis. The dosage form can contain any acceptable amount of the metformin hydrochloride. For example, the dosage form can contain about 150 mg to about 1500 mg metformin hydrochloride.

The present invention further provides the use of the dosage forms disclosed herein for medical therapy. Also provided is the use of dosage forms disclosed herein to prepare a medicament for treating diabetes mellitus.

To better illustrate the invention described herein, a non-limiting list of exemplary aspects and embodiments of the invention is provided here:

Aspect 1. A tablet dosage form for an active pharmaceutical ingredient comprising a compound of formula (I)

(I) as a tartrate salt of formula (IT), including a solvate, hydrate, tautomer, or stereoisomer, thereof; metformin or a pharmaceutically acceptable salt thereof; a diluent comprising macrocrystalline cellulose; a disintegrant comprising crospovidone; a binder comprising copolyvidone; a lubricant comprising magnesium stearate; and a glidant comprising colloidal silicon dioxide; wherein the dosage form is free of a calcium salt.

Aspect 2. A tablet dosage form for an active pharmaceutical ingredient comprising a compound of formula (I)

(I) as a tartrate salt of formula (IT), including a solvate, hydrate, tautomer, or stereoisomer, thereof; metformin or a pharmaceutically acceptable salt thereof; a disintegrant comprising crospovidone; a binder comprising copolyvidone; a lubricant comprising magnesium stearate; and a glidant comprising colloidal silicon dioxide; wherein the dosage form is free of a calcium salt.

Aspect 3. The dosage form of aspect 1 or 2, wherein the active pharmaceutical ingredient comprising a tartrate salt of the compound of formula (I) is substantially anhydrous.

Aspect 4. The dosage form of aspect 1 or 2, comprising about 50 mg to about 500 mg of the tartrate salt of the compound of formula (I) on a free base basis. Aspect 5. The dosage form of aspect 1 or 2, comprising about 50 mg,

100 mg, 200 mg, or 400 mg of the tartrate salt of the compound of formula (I) on a free base basis.

Aspect 6. The dosage form of aspect 1 or 2, wherein the compound of Formula (I) is a compound having the stereochemical configuration (2R)-I -{2- [(3R)-pyrrolidin-3-yl]-acetyl}-pyrrolidine-2-boronic acid.

Aspect 7. The dosage form of aspect 1 or 2, wherein the active pharmaceutical ingredient comprises a compound of formula (II)

(H) as a tartrate salt of formula (HT), including a solvate, hydrate, tautomer, or stereoisomer, thereof.

Aspect 8. The dosage form of aspect 7, comprising about 50 mg to about 500 mg of the compound of formula (HT) on a free base basis.

Aspect 9. The dosage form of aspect 7, comprising about 50 mg, 100 mg, 200 mg, or 400 mg of the compound of formula (HT) on a free base basis. Aspect 10. The dosage form of aspect 1 or 2, wherein the tartrate salt of formula (IT) is a monotartrate salt, an L-tartrate salt, or both. Aspect 11. The dosage form of aspect 1 or 2, wherein the metformin comprises about 150 mg to about 1500 mg metformin hydrochloride.

Aspect 12. The dosage form of aspect 1 or 2, wherein the dosage form comprises about 3-8 wt% crospovidone, about 1% colloidal silicon dioxide, and about 0.5% magnesium stearate.

Aspect 13. The dosage form of aspect 1 or 2, wherein the tablet is capsule-shaped.

Aspect 14. The dosage form of aspect 1 or 2, wherein the tablet is coated with a moisture-repelling coating material. Aspect 15. The dosage form of aspect 14, wherein the moisture-repelling coating material comprises a polymer.

Aspect 16. The dosage form of aspect 15, wherein the polymer comprises polyvinyl alcohol or polyvinyl acetate.

Aspect 17. The dosage form of aspect 1 or 2, wherein the dosage form is free of calcium phosphate.

Aspect 18. The dosage form of aspect 1 or 2, wherein at a temperature of 25⁰C and a relative humidity of about 60%, less than about 0.5% impurities derived from the compound of formula (IT) are formed over a period of about 3 months. Aspect 19. The dosage form of aspect 1 or 2, wherein at a temperature of

25⁰C and a relative humidity of about 60%, less than about 1% impurities derived from the compound of formula (IT) are formed over a period of about 6 months.

Aspect 20. The dosage form of aspect 1 or 2, wherein at a temperature of 4O⁰C and a relative humidity of about 75%, less than about 0.5% impurities derived from the compound of formula (IT) are formed over a period of about 3 months.

Aspect 21. The dosage form of aspect 1 or 2, wherein at a temperature of 4O⁰C and a relative humidity of about 75%, less than about 1% impurities derived from the compound of formula (IT) are formed over a period of about 6 months.

Aspect 22. The dosage form of aspect 1 or 2, formed by a process including a step of fluidized bed granulation, a step of high shear granulation, or both. Aspect 23. A method of preparing the dosage form of aspect 1 or 2, comprising:

(a) milling the tartrate salt compound of formula (IT) to provide a milled compound; then, (b) blending the milled compound with, optionally, the diluent, and with a metformin salt to provide a blended milled compound; then

(c) in a fluidized bed granulator, granulating the blended milled compound with a solution of the binder in water to provide granules; then

(d) drying the granules to provide dried granules; then (e) milling and screening the dried granules to provide dried, milled granules; then

(f) blending the dried, milled granules with the dispersant, the glidant, and the lubricant to provide a lubricated blend; then

(g) compressing the lubricated blend in a tablet press to provide the dosage form; wherein the dosage form is free of a calcium salt.

Aspect 24. The method of aspect 23, further comprising, after milling the tartrate salt compound of Formula (IT), passing the milled compound through a 0033 screen. Aspect 25. The method of aspect 23, wherein the solution of the binder in water is about a 25% solution of copovidone in water.

Aspect 26. The method of aspect 23, wherein the granules are dried to about 2% to about 8% moisture content.

Aspect 27. The method of aspect 23, wherein the step of granulation comprises top spray granulation.

Aspect 28. The method of aspect 23, wherein the step of blending comprises blending together the dried milled granules, the disintegrant, and the glidant, and then, adding the lubricant and blending in the lubricant.

Aspect 29. The method of aspect 23, wherein the tartrate salt compound of formula (IT) is a monotartrate salt.

Aspect 30. The method of aspect 23, wherein the dosage form is free of calcium phosphate.

Aspect 31. The method of aspect 23, wherein the tablet press is a rotary tablet press fitted with modified capsule shaped tooling at a target tablet weight. Aspect 32. The method of aspect 23, further comprising coating the tablets with a moisture-repelling coating material.

Aspect 33. The method of aspect 32, wherein the moisture-repelling coating material comprises a polymer. Aspect 34. The method of aspect 33, wherein the polymer comprises polyvinyl alcohol or polyvinyl acetate.

Aspect 34a. The method of aspect 22, wherein in step (f), additional milled compound of formula (IT) and, optionally, additional diluent, is blended with the dried, milled, granules. Aspect 35. A method of preparing the dosage form of aspect 1, comprising: in a high shear granulator,

(a) dry mixing the tartrate compound of formula (IT), a metformin salt, optionally the diluent, and the binder to provide a dry mix; then (b) adding water to the dry mix to provide granules; then

(c) drying and milling the granules; then

(d) adding the dispersant, the glidant and the lubricant; then

(e) mixing to provide a lubricated blend; then

(f) compressing the lubricated blend in a tablet press to provide the dosage form; wherein the dosage form is free of a calcium salt.

Aspect 36. The method of aspect 35, further comprising adding an additional quantity of the tartrate compound of formula (I) during the step of adding the dispersant, the glidant, and the lubricant. Aspect 37. The method of aspect 36, wherein the additional quantity of the tartrate compound of formula (IT) is about 10% of the weight of an amount of the tartrate compound of formula (IT) dry mixed with the diluent and the binder.

Aspect 38. The method of aspect 35, wherein the tartrate compound of formula (IT) is a monotartrate.

Aspect 39. The method of aspect 35, wherein the dosage form is free of calcium phosphate.

Aspect 40. The method of aspect 35, wherein the tablet press is a rotary tablet press fitted with modified capsule shaped tooling at a target tablet weight. Aspect 41. The method of aspect 35, further comprising coating the tablets with a moisture-repelling coating material, preferably a material comprising a polymer.

Aspect 41a. The method of claim 35 further comprising adding, in step (d), additional milled compound of formula (IT) and, optionally, additional diluent.

Aspect 42. A method of treating a malcondition in a patient wherein inhibition of DPP-IV is indicated, comprising administering the dosage form of aspect 1 or 2 at a frequency and over a period of time sufficient to provide a beneficial effect to the patient.

Aspect 43. A method of treating a malcondition in a patient wherein inhibition of DPP-IV is indicated, comprising administering the dosage form prepared by the method of aspect 23 at a frequency and over a period of time sufficient to provide a beneficial effect to the patient. Aspect 44. A method of treating a malcondition in a patient wherein inhibition of DPP-IV is indicated, comprising administering the dosage form prepared by the method of aspect 35 at a frequency and over a period of time sufficient to provide a beneficial effect to the patient.

Aspect 45. Use of a tablet dosage form for an active pharmaceutical ingredient comprising a compound of Formula (I)

(I) as a tartrate salt of formula (IT), including a solvate, hydrate, tautomer, or stereoisomer, thereof; metformin or a pharmaceutically acceptable salt thereof; optionally, a diluent comprising macrocrystalline cellulose; a disintegrant comprising crospovidone; a binder comprising copolyvidone; a lubricant comprising magnesium stearate; and a glidant comprising colloidal silicon dioxide; wherein the dosage form is free of a calcium salt, for use in medical therapy. Aspect 46. The use of aspect 45, wherein the medical therapy is the treatment of diabetes mellitus.

Aspect 47. The use of aspect 46, wherein diabetes mellitus is in a mammal. Aspect 48. The use of aspect 47, wherein the mammal is a human.

Aspect 49. Use of a tablet dosage form for an active pharmaceutical ingredient comprising a compound of formula (I)

(I) as a tartrate salt of formula (IT), including a solvate, hydrate, tautomer, or stereoisomer, thereof; metformin or a pharmaceutically acceptable salt thereof; optionally, a diluent comprising microcrystalline cellulose; a disintegrant comprising crospovidone; a binder comprising copolyvidone; a lubricant comprising magnesium stearate; and a glidant comprising colloidal silicon dioxide; wherein the dosage form is free of a calcium salt, to prepare a medicament for treatment of diabetes mellitus.

Aspect 50. The use of aspect 49, wherein diabetes mellitus is in a mammal.

Aspect 51. The use of aspect 50, wherein the mammal is a human.

Detailed Description of the Invention

One of ordinary skill in the art would readily appreciate that the pharmaceutical formulations and methods described herein can be prepared and practiced by applying known procedures in the pharmaceutical arts. These include, for example, unless otherwise indicated, conventional techniques of pharmaceutical sciences including pharmaceutical dosage form design, drug development, pharmacology, of organic chemistry, and polymer sciences. See generally, for example, Reminfiton: The Science and Practice of Pharmacy, 21^st edition, Lippincott, Williams & Wilkins, (2005). Methods recited herein may be earned out in any order of the recited events, which is logically possible, as well as the recited order of events. Furthermore, where a range of values is provided, it is understood that every intervening value, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. Also, it is contemplated that any optional feature of the inventive variations described may be set forth and claimed independently, or in combination with any one or more of the features described herein.

Definitions

Reference will now be made in detail to certain claims of the disclosed subject matter, examples of which are illustrated in the accompanying structures and formulas. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that they are not intended to limit the disclosed subject matter to those claims. On the contrary, the disclosed subject matter is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the presently disclosed subject matter as defined by the claims.

References in the specification to "one embodiment" indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described.

Unless otherwise indicated, the words and phrases presented in this document have their ordinary meanings to one of skill in the art. Such ordinary meanings can be obtained by reference to their use in the art and by reference to general and scientific dictionaries, for example, Webster's Third New International Dictionary, Merriam- Webster Inc., Springfield, MA, 1993, The American Heritage Dictionary of the English Language, Houghton Mifflin, Boston MA, 1981, and Hawley's Condensed Chemical Dictionary, 14^th edition, Wiley Europe, 2002.

The following explanations of certain terms are meant to be illustrative rather than exhaustive. These terms have their ordinary meanings given by usage in the art and in addition include the following explanations.

As used herein, the term "about" refers to a variation of 10 percent of the value specified, for example, about 50 percent carries a variation from 45 to 55 percent.

As used herein, the term "and/or" refers to any one of the items, any combination of the items, or all of the items with which this term is associated.

As used herein, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise.

As used herein, the term "active pharmaceutical ingredient," or API, refers to a molecular entity adapted for treatment of a malcondition in a patient in need thereof. The present active pharmaceutical ingredient in an inhibitor of the enzyme DPP-IV, which can be useful in the treatment of diabetes and other conditions involving the need for improvement in glycemic control. The active pharmaceutical ingredient of the present invention is an aminoboronic acid, which is present in the inventive dosage form as its tartrate salt. By a "tartrate" is meant herein a salt of tartaric acid. The tartaric acid can be of any stereochemical configuration, or any mixture thereof. For example, a tartrate salt of the invention can be a salt of D-tartaric acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, or any combination thereof.

As used herein, the term "binder" refers to a pharmacologically inert substance, suitable for human consumption, which serves to hold the constituents of a tablet together after compression forming of the tablet has occurred. Copovidone is a binder in the inventive dosage form. By "copovidone," also known as "copolyvidone," is meant a copolymer of vinyl pyrrolidone and vinyl alcohol, as is well-known in the art. The copolymer can be a graft copolymer. When used as a binder, the copovidone provides good adhesion, elasticity, and hardness, and may assist in repelling moisture from the tablets, once formed.

As used herein, the term "dosage form" refers to a physical and chemical composition of an active pharmaceutical ingredient (API) that is adapted for administration to a patient in need thereof. The inventive dosage form is a tablet. By a tablet is meant a relatively hard, compact object, suitable for oral ingestion, prepared by compression of a powder including an active pharmaceutical ingredient and, usually, excipients. As used herein, the term "excipicnt" refers to an ingredient of the dosage form that is not medicinally active, but serves to dilute the active pharmaceutical ingredient, assist in dispersion of the tablet in the patient's stomach, bind the tablet together, and serve other functions like stabilizing the active pharmaceutical ingredient against decomposition. The inventive tablet can be coated or uncoated. By "coated" is meant that the tablet is covered with a layer, usually a continuous layer, of a substance such as a polymer that can serve to preserve tablet integrity, reduce dusting, and repel moisture. An uncoated tablet lacks the covering layer, thus exposing the core to environmental conditions. The processes of preparing the inventive dosage form including milling, screening, drying, blending, granulation, etc. are carried out as is well-known in the art, as described in Remington: The Science and Practice of Pharmacy, 21 ^st edition, Lippincott, Williams & Wilkins, (2005). Terms as are used in the compounding arts, such as granulation and fluidized bed granulation (also known as fluid bed granulation), are described in detail therein. As used herein, "high shear" granulation refers to a dry granulation process carried out with a relatively high degree of shear forces being applied to the solids during the granulation process, for example, during mixing prior to addition of the water in the formation of granules from a mixed powder including the active pharmaceutical ingredient and excipients. High shear forces aid in dispersion of the active pharmaceutical ingredient, usually as a powder of relatively fine texture, with the excipients.

As used herein, the term "diluent" refers to a pharmacologically inert substance that is nevertheless suitable for human consumption, which serves as an excipient in the inventive dosage form. A diluent serves to dilute the active pharmaceutical ingredient in the inventive dosage form, such that tablets of a typical size can be prepared incorporating a wide range of actual doses of the active pharmaceutical ingredient. A diluent need not be included if the content per dosage form of one or both pharmaceutical ingredients is desired to be maximized for a particular dosage unit size. A diluent can comprise a microcrystalline cellulose, for example, AVICEL. Lactose and isomalt are other common diluents. AVICEL, a form of microcrystalline cellulose, is a commercially available product that is formed of acid-treated cellulose, which treatment tends to dissolve more amorphous regions of the cellulose and to leave more crystalline regions of the cellulose. Microcrystalline cellulose can be a diluent in the inventive dosage form.

Other diluents well-known to those skilled in the art include monobasic calcium phosphate, dibasic calcium phosphate and tribasic calcium phosphate. Almost completely water-insoluble, calcium phosphates are particularly well- known pharmacologically inert diluents or fillers that are compatible with a wide range of active pharmaceutical ingredients. By the term "calcium phosphate" is meant herein calcium phosphate in any of its forms, including, for example, monobasic calcium phosphate (Ca(H₂PO₄)₂), dibasic calcium phosphate (CaHPO₄), and tricalcium phosphate (Ca₂(PO₄)S), including any orthophosphates, pyrophosphates, or superphosphates, or other polymeric phosphates wherein the counterion includes calcium. By a "calcium salt" is meant any ionic compound including calcium, specifically including the above- listed calcium phosphates, and calcium sulfate. As used herein, the term "disintegrant" refers to a substance that assists in dissolution of the dosage form after oral ingestion. It is believed to assist in hydration and to avoid the formation of gels in the stomach of the patient as the tablet dissolves, thus assisting in the release of the active pharmaceutical ingredient into the gastric juices so that it can be absorbed into the bloodstream. The disintegrant of the inventive dosage form includes crospovidone, a cross- linked polyvinylpyrrolidone.

As used herein, the term "an effective amount" refers to an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Determination of an effective amount for a given administration is well within the ordinary skill in the pharmaceutical arts.

As used herein, the term "free base" refers to the molecular form of an amine, wherein the amine is not in salt form. When it is stated that an inventive dosage form contains some quantity of the compound of Formula (I) tartrate "on a free base basis," what is meant is that the quantity of the tartrate salt form of the active pharmaceutical ingredient that is included is equivalent to the stated quantity of the active pharmaceutical ingredient in its free base form; i.e., that actual quantity of active pharmaceutical ingredient tartrate in the dosage form is normalized for the difference in molecular weight between the free base and the tartrate salt of the free base of the compound of Formula (I). Thus, for a monotartrate, non-hydrated form, the actual weight of the tartrate salt will be about 162% of the weight of the active pharmaceutical ingredient on a free base basis, the ratio of the sum of the molecular weights of the compound of Formula (I) and tartaric acid to the molecular weight of the compound of Formula (I), i.e., about 390/240.

The stability of an active pharmaceutical ingredient in a dosage form can be expressed by providing data concerning the percent decomposition of the active pharmaceutical ingredient that occurs over a certain time period, when the dosage form is stored at a stated temperature and relative humidity (RH). This value can be expressed as the percent of remaining active pharmaceutical ingredient, or as the ratio of the purity of the active pharmaceutical ingredient at the given time point over the purity of the active pharmaceutical ingredient at the beginning of the time period ending in that time point. By relative humidity is meant the percent of water saturation of the air at the stated temperature.

As used herein, the term "glidant" refers to a substance that assists in maintaining favorable powder flow properties of the powder materials that are compressed to form the inventive tablet. The glidant of the present invention includes colloidal silicon dioxide, which is a fumed silica with a particle size of about 15 nm.

As used herein, the term "hydrate" refers to the complex where the solvent molecule is water.

As used herein, the term "lubricant" refers to a substance that is useful in the tablet compression process, serving to lubricate metal parts of the tablet die. The lubricant of the present invention includes magnesium stearate.

As used herein, the term "mammal" refers to any of a class of warmblooded higher vertebrates that nourish their young with milk secreted by mammary glands and have skin usually more or less covered with hair, and non- exclusively includes humans and non-human primates, their children, including neonates and adolescents, both male and female, livestock species, such as horses, cattle, sheep, and goats, and research and domestic species, including dogs, cats, mice, rats, guinea pigs, and rabbits.

As used herein, the term "patient" refers to a warm-blooded animal, and preferably a mammal, for example, a cat, dog, horse, cow, pig, mouse, rat, or primate, including a human.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio. Several pharmaceutically acceptable ingredients are known in the art and official publications, for example, The United States Pharmacopeia describe the analytical criteria to assess the pharmaceutical acceptability of numerous ingredients of interest.

As used herein, the terms "preferred" and "preferably" refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.

As used herein, the term "prodrug" refers to any pharmaceutically acceptable form of a compound, which upon administration to a patient, provides the compound. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example, hydrolyzed or oxidized, in the host to form a compound of the formula (I) or formula (II). Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs may include, for example, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.

The prodrug can be readily prepared from the compounds of formula (I) or formula (II) using methods known in the art. See, for example, Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309 323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6(3): 165 182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985); Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172- 178, 949-982 (1995).

As used herein, the term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three- dimensional structures, which are not interchangeable.

As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or formula (II), or a salt or physiologically functional derivative thereof) and a solvent. Such solvents, for the purpose of the invention, should not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Non- limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. As used herein, the term "subject" refers to animals, for example, mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In certain embodiments, the subject is a human.

As used herein, the terms "anhydrous" and "substantially anhydrous" refers to a moisture content of less than about 0.1 % by weight and preferably less than about 0.05% by weight.

As used herein, the term "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule.

As used herein, the term "therapeutic composition" refers to an admixture with an organic or inorganic carrier or excipient, and can be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, or other form suitable for use. As used herein, the terms "treating" or "treat" or "treatment" refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. As used herein, the term "treatment," covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject, which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.

As used herein, "μg" denotes microgram, "mg" denotes milligram, "g" denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar, and "nm" denotes nanometer; "min" denotes minutes.

As used herein, the term "L.O.D." means "loss on drying", a measure of the degree of dryness of a solid, as is well-known in the art.

The "Hausner ratio" (Hausner HH. Friction conditions in a mass of metal powders. Int J Powder Metall. 1967;3:7-13) and the "Carr index" (Carr RL. Classifying flow properties of solids. Chem Eng 1965;72:69-72) are widely used to estimate the flow properties of powders. The Carr index is also called "percent compressibility." It is calculated by the formula:

where V_B is the freely settled volume of a given mass of powder, and V_τ is the tapped volume of the same mass of powder. It can also be expressed as:

C = IOO x (I - -) PT where p_# is the freely settled bulk density of the powder, and pγ is the tapped bulk density of the powder.

According to Carr (see above), a value between 5 and 15, 12and 16, 18 and 21 , and 23 and 28 indicates excellent, good, fair, and poor flow properties of the material, respectively. In other words, a Carr index greater than 25% is considered to be an indication of poor flowability, and below 15%, of good flowability (Kanig, Joseph L.; Lachman, Leon; Lieberman, Herbert A. (1986). The Theory and Practice of Industrial Pharmacy (3 ed.). Philadelphia: Lea & Febiger. ISBN 0-8121-0977-5).

The Carr index is related to the Hausner ratio, another indication of flowability, by the formula: C = 100 x (1 - 1///)_.

According to Wells (Wells JI. Pharmaceutical preformulation: the physicochemical properties of drug substances. New York, NY: Wiley; 1988:p. 210), a Hausner ratio value of less than 1.20 is indicative of good flowability of the material, whereas a value of 1.5 or higher suggests a poor flow display by the material.

Detailed Description

The present invention is directed to a dosage form for an active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a mixture of tartrate salt (formula (IT) of a compound of formula (I) as defined herein, and metformin, such as metformin hydrochloride. The compound of formula (I) is an aminoboronic acid analog of a peptide that inhibits the bioactivity of the enzyme DPP-IV. The compound of formula (I) is a selective inhibitor of DPP-IV that can be used for treatment of a malcondition involving glycemic control, such as takes place in diabetes. Other malconditions involving glycemic control include hyperglycemia and hypoglycemia. The inventive dosage form has been unexpectedly found to provide for greater active pharmaceutical ingredient stability than would a dosage form for the active pharmaceutical ingredient that a person of ordinary skill in the art would likely select.

The compound of formula (I) is disclosed and claimed in U.S. Patent Application Publication No. 2006/0264400 by the inventors herein. The tartrate salt of a compound of formula (I) and formulations thereof are disclosed and claimed in U.S. Application Serial No. 60/841,097 by the inventors herein.

The present invention discloses and claims a dosage form adapted for administration of the tartrate salt of the compound of formula (I), wherein the inventors have surprisingly found that the active pharmaceutical ingredient is more stable on prolonged storage under typical storage conditions than is the same active pharmaceutical ingredient when formulated in a Standard manner. This was unexpectedly found to be the case even when the active pharmaceutical ingredient is in an uncoated tablet dosage form, provided that the excipients include the ingredients claimed herein and exclude calcium salts. Common calcium salts used as excipients include calcium phosphates and calcium sulfate.

Table 1 shows the storage stability under the indicated conditions of formulations including the tartrate salt compound of formula (IT) and metformin in composition prepared by fluidized bed mixing as described in Examples 1 and 2 below. Analyses were performed by HPLC and show changes in active pharmaceutical ingredient content over time. AU the formulations of Table 1 lack calcium salts, such as calcium phosphate. As can be seen, even out to 12 weeks, at 4O⁰C and 75% relative humidity (RH), in a formulation of the present invention, no significant change in purity of compound IT was observed.

In contrast, a control formulation, including calcium salts, showed significant decomposition of the compound of formula (IT) over the time period tested, as discussed below.

Table 1

Table 2 shows the relative storage stabilities of formulations of Compound IT prepared by dry blending, as described in Examples 3 and 4, described below. One formulation (Example 3), carried out as a control experiment, contains dibasic calcium phosphate, the other (Example 4) is free of calcium salts. As can be seen, in the formulation containing the calcium salt (Example 3), after 2 weeks at 60⁰C, substantial decomposition of Compound IT has taken place, wherein in the formulation lacking the calcium salt (Example 4), both Compound IT and metformin are stable.

Table 2

It is generally understood in the art that microcrystalline cellulose and dibasic calcium phosphate are about equally suitable for use as diluents or fillers in pharmaceutical compositions. Both are generally regarded as inert substances that are suitable for formation of tablets containing active pharmaceutical ingredient substances by compression in tablet presses. For example, in

Remington: The Science and Practice of Pharmacy, 21^st edition, Lippincott, Williams & Wilkins, (2005), it is stated (page 902), that "[d]irect-compression vehicles or carriers must have good flow and compressible characteristics . . . The vehicles include processed forms of most of the common diluents including dicalcium phosphate dihydrate, tricalcium phosphate, calcium sulfate, anhydrous lactose, spray-dried lactose, pregelatinizcd starch, compressible sugar, mannitol, and microcrystalline cellulose." Thus, if a person of ordinary skill were consulting a well-known and well-respected formulation encyclopedia such as Remington, above, the person would be led to the conclusion that calcium phosphate and microcrystalline cellulose, along with lactose or mannitol, would be equally suitable as carriers for their active pharmaceutical ingredient.

Furthermore, as the inhibitor of DPP-IV is adapted for treatment of malconditions involving glycemic control, such as diabetes, a person of ordinary skill would be expected to select a diluent that was other than a sugar, sugar alcohol, or a substance like a sugar that can act as a substrate either for human sugar-transporting or metabolizing enzymes or for gastro-intestinal bacterial populations. Diabetic patients typically need to maintain strict control of carbohydrates in their diet, which would lead a person of ordinary skill to select compounds like dicalcium phosphate dihydrate, tricalcium phosphate, calcium sulfate, or microcrystalline cellulose, rather than any of the usual metabolizable carbohydrate excipients like lactose or mannitol.

However, the inventors herein have surprisingly discovered that calcium phosphate has a markedly detrimental effect on the storage stability of the active pharmaceutical ingredient, Compound IT, in combination with metformin, in formulations adapted for oral ingestion. As shown above, the presence of calcium phosphate causes massive decomposition of the compound of formula (I) tartrate, Compound IT, including over periods of time and under conditions similar to those that would be expected to be encountered on storage of self- administered anti-diabetes drugs in patients' medicine cabinets. Particularly as the inventive drugs are expected to be useful for the oral treatment of diabetes, wherein diabetic patients will keep substantial reserves of the drug on hand and would also be expected to self-administer the drug, for example, on a daily basis (so it would be stored in home environments), this discovery of the active pharmaceutical ingredient's instability in the presence of a common excipient is significant.

The dosage form can be prepared to contain about 50 mg to about 500 mg of the active pharmaceutical ingredient on a free base basis. For example, the dosage form can contain about 50 mg, 100 mg, 200 mg, or 400 mg of the active pharmaceutical ingredient on a free base basis. Examples of 200 mg and 400 mg dosage forms are provided below in the Examples. The dosage form can contain any acceptable amount of the metformin hydrochloride. For example, the dosage form can contain about 150 mg to about 1500 mg metformin hydrochloride. Certain non-limiting examples, for example such as are shown in

Examples 1-4, and Examples 5 and 6, are provided below to illustrate various embodiments of the inventive formulations and methods. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

Concentrations, amounts, etc., of various components are often presented in a range format throughout this disclosure. The description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the claimed invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as 1 % to 8% should be considered to have specifically disclosed subranges such as 1% to 7%, 2% to 8%, 2% to 6%, 3% to 6%, 4% to 8%, 3% to 8% etc., as well as individual numbers within that range, such as, 2%, 5%, 7% etc. This construction applies regardless of the breadth of the range and in all contexts throughout this disclosure.

Similarly, except as explicitly required by claim language, a single substance or component may meet more than a single functional requirement, provided that the single substance fulfills the more than one functional requirement as specified by claim language.

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

Examples

Example 1

Formulation (50 mg Compound IT/250 mg Metformin HCl prepared by Fluid bed Granulation)

Example 2

Formulation (150 mg Compound IT/1000 mg Metformin HCl prepared by Fluid

Bed Granulation)

Equipment List for Fluidized Bed Granulation for Examples 1 and 2

• KG5 High Shear Granulator

• Niro MP-I Fluid Bed

• Quadro Comil 197

• 4 quart V-Blender

• IKA Mixer

• B3B Tablet Press

Manufacturing Process for Examples 1 and 2

Example 3

Formulation for Dry Blend using 10% Dibasic Calcium Phosphate (control)

Example 4

Formulation for Dry blend by using 10% Lactose

Process Flow Diagram for the Dry Blend Compositions Examples 3 and 4

Example 5

Formulations for Compound IT in Combination with Metformin HCl:

100 mg Compound IT /1000 mg Metformin HCl Combinations (Formulations L

2, 3. and 4)

Formulation 1

Equipment List

1 - KG5 High Shear Granulator

2 - Quadro Comil 197S

3 - 8qt. V-Blender

4 - IKA paddle mixer / glass beaker

5 - Rotary tablet press (Mendel Tablet pres and size D tooling - fully tooled w/ paddle feeder) Method of Manufacture

Step 1 Charge Metformin HCl in high shear granulator.

Step 2 Prepare 15% Copovidone solution into water, mix until dissolved.

Step 3 Granulate step #1 with binder solution.

Step 4 Dry in Vacuum Oven @ 50 ± 1O⁰C until LOD is 2.0 ± 1%.

Step 5 Mill granules through # 16 mesh screen.

Step 6 Blend granules with Crospovidone and Compound IT for 5 min.

Step 7 Screen Magnesium Stearate through a # 20 mesh screen.

Step 8 Blend Magnesium Stearate with step # 7 for 2 min.

Step 9 Compress.

Results

Final blend in process tests table

Formulation 2

Equipment List 1-KG5 High Shear Granulator 2-Quadro Comil 197 3- 8 qt. V-Blender

4- IKA paddle mixer w/ glass beaker

5- Rotary tablet press (Mendel Tablet pres and size D tooling - fully tooled w/ paddle feeder)

Method of Manufacture

Step 1 Mix Compound IT and Metformin HCl in high shear for 2 min.

Step 2 Prepare 15% Copovidone solution into water, mix until dissolved.

Step 3 Granulate step #1 with binder solution.

Step 4 Dry in Vacuum Oven @ 50 ± 10⁰C until LOD is 2.0 ± 1.0%. Step 5 Mill granules through # 16 mesh screen.

Step 6 Blend granules with Crospovidone and Avicel PHl 12 for 5 min.

Step 7 Screen Magnesium Stearate through a # 20 mesh screen.

Step 8 Blend Magnesium Stearate with step # 7 for 2 min.

Step 9 Compress.

Results

Final blend in process tests table

Formulation 3.0

Equipment List

1-KG5 High Shear Granulator 2-Quadro Comil 197

3- 4qt. V-Blender

4- IKA Mixer 5- Rotary Tablet Press (Mendel Tablet pres and size D tooling - fully tooled w/ paddle feeder)

Method of Manufacture

Step 1 Mix Metformin HC, Vi Avicel PHl 12 and Vi Compound IT in high shear for 2 min. Step 2 Prepare 15% Copovidone solution into water until dissolved.

Step 3 Granulate step # 1 with binder solution.

Step 4 Dry in Vacuum Oven @ 50 ± 10⁰C until LOD is 2.0 ± 1%.

Step 5 Mill granules through # 16 mesh screen.

Step 6 Blend granules with Crospovidone, Vi Avicel PHl 12 and Vi Compound

IT for 5 min.

Step 7 Screen Magnesium Stearate through a # 20 mesh screen.

Step 8 Blend Magnesium Stearate with step # 7 for 2 min.

Step 9 Compress.

Results

Final blend in process tests table

Wei^ δht (g) Bulk Volume Tapped volume Taps (time) LOD (%)

(ml) (ml)

44.4 80 (0 .55 g/mL) 62 (0.72 g/mL) 544 2.29

Formulation 3.1

Equipment List

1 - 4qt. V-Blender

2 - Rotary tablet press (Mendel Tablet pres and size D tooling - fully tooled w/ paddle feeder)

Method of Manufacture

Step 1 - Blend 119.39 g (theoretical equivalent) of MCC PHl 12 with remaining powder blend from formulation 3 for two minutes.

Step 2 - Compress.

Formulation 3.2

Equipment List

1 - 4qt. V-Blender

2 - Rotary tablet press (Mendel Tablet pres and size D tooling - fully tooled w/ paddle feeder)

Method of Manufacture

Step 1 - Blend 170.77 g (theoretical equivalent) of Emcompress with remaining powder blend from formulation 3.1 for two minutes. Step 2 - Compress.

The 1550 mg weight tablets had a hardness of 13-15 kp and a thickness of 8.60 mm.

Formulation 4.0

Equipment List

1 - High Shear Granulator

2 -Quadro Comil 197S (fitted with 0.055"R (14#) round-hole screen) 3- 8 qt. V-Blender

4- IKA Paddle Mixer w/ glass or SS beaker

5- Rotary Tablet Press (Mendel Tablet pres and size D tooling - 2-station tooled w/ paddle feeder)

Method of Manufacture

Step 1 Prepare 20% PVP solution into water, mix until dissolved

Step 2 .High-shear mix Compound IT, Metformin HCl and Corn Starch in granulator for 2 min.

Step 3 Gradually add binder solution while high-shear mixing with impeller @ 200 RPM chopper @1800 RPM.

Step 4 Once granules are formed, continue wet-massing for 2 min.

Step 5 Dry in Vacuum Oven @ 50 ± 1O⁰C until LOD is 2.5 ± 0.5%.

Step 6 Mill granules through # 14 mesh round-hole screen at low speed.

Step 7 Partition dried, sized granulation into 3 subparts. Step 8 Blend granules with Avicel PHl 02, Crospovidone and colloidal silicon dioxide for 5 min.

Step 9 Screen Magnesium Stearate through a # 20 mesh screen.

Step 10 Lube blend with Mag for 2 min.

Step 9 Compress (Target 17-20 kp hardness, 1650 mg weight)

Example 6

Formulations for Compound IT in Combination with Metformin HCl:

200 mg Compound IT / 750 mg Metformin HCl Formulation 5.0

NOTE: Due to capacity limitations, this batch was processed as two separate batches (batch A and batch B)

Equipment List

1 - High Shear Granulator

2 -Quadro Comil 197S (fitted with 10-mesh round-hole screen)

3- 3.5 qt. V-Blender

10 4- IKA Paddle Mixer w/ glass or SS beaker

5- Rotary Tablet Press (Mendel Tablet press and size D tooling - 2-station tooled w/ forced feeder)

Method of Manufacture 15 Step 1 Prepare 20% PVP solution into water, mix until dissolved.

Step 2 Mix Compound IT, Metformin HCl, Avicel PHl 02 and Corn Starch in granulator for 2 min.

Step 3 Gradually add binder solution while mixing with impeller @ 200 RPM chopper ® 1800 RPM. Step 4 Once granules are formed, continue wet-massing for 2 min.

Step 5 Dry in Vacuum Oven @ 50 + 10⁰C until LOD is 3.0 + 0.5%.

Step 6 Mill granules through # 10 mesh round-hole screen at medium speed

(2000 RPM ).

Step 7 Blend granules with Avicel PHl 02, Crospovidone and colloidal silicon dioxide for 5 min.

Step 8 Screen magnesium stearate through a # 20 mesh screen.

Step 9 Lube blend with magnesium stearate for 2 min.

Step 10 Compress (target 17-20 kp hardness, 1500 mg weight).

Formulation 6.0

Equipment List

1 - High Shear Granulator - TK Fielder 25

2 -Quadro Comil 197S (fitted with 10# or 12# round-hole screen) 3- 1 cu.ft. V-Blender

5- Rotary Tablet Press (Mendel Tablet press and size D tooling w/ paddle feeder) Method of Manufacture

Step 1 Dispense approximately 1,000 g of purified water into an appropriate container

Step 2 .High-shear mix Compound IT, Metformin HCl, corn starch, microcrystalline cellulose and povidone in granulator for approximately 3 min.

Step 3 Gradually add purified water (via spray nozzle) at a constant rate while high-shear mixing with impeller and chopper at medium speed until small granules are observed and dry powder is absent.

Step 4 Once small granules are formed, continue wet-massing for 2 min to further densify existing granules and fully hydrate and disperse dry binder.

Measure the LOD of the wet granulation.

Step 5 Dry in Vacuum Oven @ 50 ± 10⁰C until LOD is 2.75 ± 0.5%.

Step 6 Size granules through # 10 mesh round-hole screening mill at low speed.

Step 7 Pass colloidal silicon dioxide through a 16-mesh screen. Step 8 Blend dried, sized granules with crospovidone and colloidal silicon dioxide for 5 min in 1 cu.ft v-blender.

Step 9 Pass magnesium stearate through a 20-mesh screen.

Step 10 Lube blend with magnesium stearate for 3 min.

Step 11 Compress (target 15-20 kp hardness, 1512 mg weight).

All patents, patent applications, publications, scientific articles, web sites, and other documents and materials referenced or mentioned herein are indicative of the levels of skill of those skilled in the art to which the invention pertains, and each such referenced document and material is hereby incorporated by reference to the same extent as if it had been incorporated by reference in its entirety individually or set forth herein in its entirety. Additionally, all claims in this application, and all priority applications, including but not limited to original claims, are hereby incorporated in their entirety into, and form a part of, the written description of the invention. Applicants reserve the right to physically incorporate into this specification any and all materials and information from any such patents, applications, publications, scientific articles, web sites, electronically available information, and other referenced materials or documents. Applicants reserve the right to physically incorporate into any part of this document, including any part of the written description, the claims referred to above including but not limited to any original claims.

Claims

ClaimsWhat is claimed is:

1. A tablet dosage form for an active pharmaceutical ingredient comprising a compound of formula (I)

(I) as a tartrate salt compound of formula (IT), including a solvate, hydrate, tautomer, or stereoisomer, thereof; metformin or a pharmaceutically acceptable salt thereof; optionally, a diluent comprising microcrystalline cellulose; a disintegrant comprising crospovidone; a binder comprising copolyvidone; a lubricant comprising magnesium stearate; and a glidant comprising colloidal silicon dioxide; wherein the dosage form is free of a calcium salt.

2. The dosage form of claim 1, wherein the active pharmaceutical ingredient comprising a tartrate salt compound of formula (IT) is substantially anhydrous.

3. The dosage form of claim 1, comprising about 50 mg to about 500 mg of the tartrate salt compound of formula (IT) on a free base basis.

4. The dosage form of claim 1, comprising about 50 mg, 100 mg, 200 mg, or 400 mg of the tartrate salt compound of formula (IT) on a free base basis.

5. The dosage form of claim 1, wherein the compound of formula (I) is a compound having the stereochemical configuration (2R)-l-{2-[(3R)-pyrrolidin-

3-yl]-acetyl}-pyrrolidine-2-boronic acid.

6. The dosage form of claim 1, wherein the active pharmaceutical ingredient comprises a compound of formula (II)

(H) as a tartrate salt of formula (HT), including a solvate, hydrate, tautomer, stereoisomer, or prodrug thereof.

7. The dosage form of claim 6, comprising about 50 mg to about 500 mg of the compound of formula (HT) on a free base basis.

8. The dosage form of claim 6, comprising about 50 mg, 100 mg, 200 mg, or 400 mg of the compound of formula (HT) on a free base basis.

9. The dosage form of claim 1 , wherein the tartrate salt is a monotartrate salt, an L-tartrate salt, or both.

10. The dosage form of claim 1, wherein the metformin comprises about 150 mg to about 1500 mg metformin hydrochloride.

11. The dosage form of claim 1 , wherein the dosage form comprises about 3- 8 wt% crospovidone, about 1% colloidal silicon dioxide, and about 0.5% magnesium stearate.

12. The dosage form of claim 1, wherein the tablet is capsule-shaped.

13. The dosage form of claim 1 , wherein the tablet is coated with a moisture- repelling coating material.

14. The dosage form of claim 13, wherein the moisture-repelling coating material comprises a polymer.

15. The dosage form of claim 14, wherein the polymer comprises polyvinyl alcohol or polyvinyl acetate.

16. The dosage form of claim 1, wherein the dosage form is free of calcium phosphate.

17. The dosage form of claim 1 , wherein at a temperature of 25⁰C and a relative humidity of about 60%, less than about 0.5% impurities derived from the compound of formula (IT) are formed over a period of about 3 months.

18. The dosage form of claim 1 , wherein at a temperature of 25⁰C and a relative humidity of about 60%, less than about 1 % impurities derived from the compound of formula (IT) are formed over a period of about 6 months.

19. The dosage form of claim 1 , wherein at a temperature of 4O⁰C and a relative humidity of about 75%, less than about 0.5% impurities derived from the compound of formula (IT) are formed over a period of about 3 months.

20. The dosage form of claim 1 , wherein at a temperature of 4O⁰C and a relative humidity of about 75%, less than about 1% impurities derived from the compound of formula (IT) are formed over a period of about 6 months.

21. The dosage form of claim 1 formed by a process including a step of fluidized bed granulation, a step of high shear granulation, or both.

22. A method of preparing the dosage form of claim 1, comprising:

(a) milling the tartrate salt compound of formula (IT) to provide a milled compound; then,

(b) blending the milled compound with the optional diluent and with a metformin salt to provide a blended milled compound; then

(c) in a fluidized bed granulator, granulating the blended milled compound with a solution of the binder in water to provide granules; then

(d) drying the granules to provide dried granules; then (e) milling and screening the dried granules to provide dried, milled granules; then

(f) blending the dried, milled granules with the dispersant, the glidant, and the lubricant to provide a lubricated blend; then (g) compressing the lubricated blend in a tablet press to provide the dosage form; wherein the dosage form is free of a calcium salt.

23. The method of claim 22, further comprising, after milling the tartrate salt compound of formula (IT) , passing the milled compound through a #16 mesh screen.

24. The method of claim 22, wherein the solution of the binder in water is about a 25% solution of copovidone in water.

25. The method of claim 22, wherein the granules are dried to about 2% to about 8% moisture content.

26. The method of claim 22, wherein the step of granulation comprises top spray granulation.

27. The method of claim 22, wherein the step of blending comprises blending together the dried milled granules, the disintegrant, and the glidant, and then, adding the lubricant and blending in the lubricant.

28. The method of claim 22, wherein the tartrate salt compound of Formula (IT) is a monotartrate salt.

29. The method of claim 22, wherein the dosage form is free of calcium phosphate.

30. The method of claim 22, wherein the tablet press is a rotary tablet press fitted with modified capsule shaped tooling at a target tablet weight.

31. The method of claim 22, further comprising coating the tablets with a moisture-repelling coating material.

32. The method of claim 31 , wherein the moisture-repelling coating material comprises a polymer.

33. The method of claim 32, wherein the polymer comprises polyvinyl alcohol or polyvinyl acetate.

34. The method of claim 22, wherein in step (f), additional milled compound of formula (IT) and, optionally, additional diluent, is blended with the dried, milled, granules.

35. A method of preparing the dosage form of claim 1, comprising: in a high shear granulator,

(a) dry mixing the tartrate salt compound of formula (IT), a metformin salt, the optional diluent, and the binder to provide a dry mix; then

(b) adding water to the dry mix to provide granules; then

(c) drying and milling the granules; then (d) adding the dispersant, the glidant and the lubricant; then

(e) mixing to provide a lubricated blend; then

(f) compressing the lubricated blend in a tablet press to provide the dosage form; wherein the dosage form is free of a calcium salt.

36. The method of claim 35, further comprising adding an additional quantity of the tartrate compound of formula (IT) during the step of adding the dispersant, the glidant, and the lubricant.

37. The method of claim 36, wherein the additional quantity of the tartrate compound of formula (IT) is about 10% of the weight of an amount of the tartrate compound of formula (IT) dry mixed with the diluent and the binder.

38. The method of claim 35, wherein the tartrate compound of formula (IT) is a mono tartrate.

39. The method of claim 35, wherein the dosage form is free of calcium phosphate.

40. The method of claim 35, wherein the tablet press is a rotary tablet press fitted with modified capsule shaped tooling at a target tablet weight.

41. The method of claim 35 , further comprising coating the tablets with a moisture-repelling coating material, preferably a material comprising a polymer.

42. The method of claim 35 further comprising adding, in step (d), additional milled compound of formula (IT) and, optionally, additional diluent.

43. A method of treating a malcondition in a patient wherein inhibition of DPP-IV is indicated, comprising administering the dosage form of claim 1 at a frequency and over a period of time sufficient to provide a beneficial effect to the patient.

44. A method of treating a malcondition in a patient wherein inhibition of DPP-IV is indicated, comprising administering the dosage form prepared by the method of claim 22 at a frequency and over a period of time sufficient to provide a beneficial effect to the patient.

45. A method of treating a malcondition in a patient wherein inhibition of DPP-IV is indicated, comprising administering the dosage form prepared by the method of claim 35 at a frequency and over a period of time sufficient to provide a beneficial effect to the patient.

46. Use of a tablet dosage form for an active pharmaceutical ingredient comprising a compound of Formula (I)

(I) as a tartrate salt of formula (IT), including a solvate, hydrate, tautomer, stereoisomer, or prodrug thereof; metformin or a pharmaceutically acceptable salt thereof; optionally, a diluent comprising microcrystalline cellulose; a disintegrant comprising crospovidone; a binder comprising copolyvidone; a lubricant comprising magnesium stearate; and a glidant comprising colloidal silicon dioxide; wherein the dosage form is free of a calcium salt, for use in medical therapy.

47. The use of claim 46, wherein the medical therapy is the treatment of diabetes mellitus.

48. The use of claim 47, wherein diabetes mellitus is in a mammal.

49. The use of claim 48, wherein the mammal is a human.

50. Use of a tablet dosage form for an active pharmaceutical ingredient comprising a compound of Formula (I)

(I) as a tartrate salt compound of formula (IT), including a solvate, hydrate, tautomer, stereoisomer, or prodrug thereof; metformin or a pharmaceutically acceptable salt thereof; optionally, a diluent comprising microcrystalline cellulose; a disintegrant comprising crospovidone; a binder comprising copolyvidone; a lubricant comprising magnesium stearate; and a glidant comprising colloidal silicon dioxide; wherein the dosage form is free of a calcium salt; to prepare a medicament for treatment of diabetes mellitus.

51. The use of claim 50, wherein diabetes mellitus is in a mammal.

52. The use of claim 51, wherein the mammal is a human.