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WO2009091663A1 - Forme posologique stable d'un inhibiteur de la dpp-iv avec de la metformine - Google Patents

Forme posologique stable d'un inhibiteur de la dpp-iv avec de la metformine

Info

Publication number
WO2009091663A1
WO2009091663A1 PCT/US2009/030470 US2009030470W WO2009091663A1 WO 2009091663 A1 WO2009091663 A1 WO 2009091663A1 US 2009030470 W US2009030470 W US 2009030470W WO 2009091663 A1 WO2009091663 A1 WO 2009091663A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
compound
formula
salt
tartrate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2009/030470
Other languages
English (en)
Inventor
Zhen-Ping Wu
Jr. Richard Alexander Moore
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Phenomix Corp
Original Assignee
Phenomix Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Phenomix Corp filed Critical Phenomix Corp
Publication of WO2009091663A1 publication Critical patent/WO2009091663A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the enzyme dipeptidyl peptidase 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.
  • DPP dipeptidyl peptidase
  • DPP-XIII 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:
  • 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- ⁇ ro-proline, or more generally, a pyrrolidin-3-ylglycylaminoalkylboronate.
  • 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
  • METIGUANIDE is a salt of 3- (diaminomethylidene)-l,l-dimethylguanidine, also known as 1,1,- dimethylbiguanide.
  • Metformin is typically provided as the hydrochloride salt.
  • a patient 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.
  • 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):
  • 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.
  • 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
  • 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.
  • 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.
  • a tablet dosage form for an active pharmaceutical ingredient comprising a compound of formula (I)
  • a tablet dosage form for an active pharmaceutical ingredient comprising a compound of formula (I)
  • 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,
  • 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)
  • 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 25 0 C 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
  • Aspect 20 The dosage form of aspect 1 or 2, wherein at a temperature of 4O 0 C 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 4O 0 C 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:
  • 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,
  • 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.
  • 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.
  • 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 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 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.
  • 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.
  • 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.
  • a “tartrate” is meant herein a salt of tartaric acid.
  • the tartaric acid can be of any stereochemical configuration, or any mixture thereof.
  • 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.
  • 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.
  • copovidone also known as “copolyvidone”
  • the copolymer can be a graft copolymer.
  • the copovidone provides good adhesion, elasticity, and hardness, and may assist in repelling moisture from the tablets, once formed.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • AVICEL 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.
  • 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.
  • calcium phosphate is meant herein calcium phosphate in any of its forms, including, for example, monobasic calcium phosphate (Ca(H 2 PO 4 ) 2 ), dibasic calcium phosphate (CaHPO 4 ), and tricalcium phosphate (Ca 2 (PO 4 )S), including any orthophosphates, pyrophosphates, or superphosphates, or other polymeric phosphates wherein the counterion includes calcium.
  • a “calcium salt” is meant any ionic compound including calcium, specifically including the above- listed calcium phosphates, and calcium sulfate.
  • disintegrant refers to a substance that assists in dissolution of the dosage form after oral ingestion.
  • the disintegrant of the inventive dosage form includes crospovidone, a cross- linked polyvinylpyrrolidone.
  • 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.
  • the term “free base” refers to the molecular form of an amine, wherein the amine is not in salt form.
  • 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).
  • 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.
  • relative humidity is meant the percent of water saturation of the air at the stated temperature.
  • 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.
  • hydrate refers to the complex where the solvent molecule is water.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • solvents for the purpose of the invention, should not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid.
  • 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.
  • mammals including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like.
  • the subject is a human.
  • 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.
  • tautomer refers to a proton shift from one atom of a molecule to another atom of the same molecule.
  • 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.
  • 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.
  • 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.
  • ⁇ g denotes microgram
  • mg denotes milligram
  • g denotes gram
  • ⁇ L denotes microliter
  • mL denotes milliliter
  • L denotes liter
  • nM denotes nanomolar
  • ⁇ M denotes micromolar
  • mM denotes millimolar
  • M denotes molar
  • nm denotes nanometer
  • min denotes minutes.
  • 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 ⁇ is the tapped volume of the same mass of powder. It can also be expressed as:
  • Carr 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 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 4O 0 C and 75% relative humidity (RH), in a formulation of the present invention, no significant change in purity of compound IT was observed.
  • RH relative humidity
  • 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.
  • the formulation containing the calcium salt (Example 3) after 2 weeks at 60 0 C, 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.
  • 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
  • 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.”
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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 ⁇ 1O 0 C 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.
  • 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 ⁇ 10 0 C 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.
  • 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 ⁇ 10 0 C 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
  • Step 7 Screen Magnesium Stearate through a # 20 mesh screen.
  • Step 8 Blend Magnesium Stearate with step # 7 for 2 min.
  • Step 9 Compress.
  • Step 1 Blend 119.39 g (theoretical equivalent) of MCC PHl 12 with remaining powder blend from formulation 3 for two minutes.
  • 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.
  • 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 ⁇ 1O 0 C 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)
  • 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 + 10 0 C until LOD is 3.0 + 0.5%.
  • Step 6 Mill granules through # 10 mesh round-hole screen at medium speed
  • 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).
  • 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.
  • Step 5 Dry in Vacuum Oven @ 50 ⁇ 10 0 C 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).

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Abstract

L'invention porte sur une forme posologique pour un inhibiteur de la DPP-IV antidiabétique représenté par la formule (I) comme son composé de sel de tartrate représenté par la formule (IT), en combinaison avec un sel de metformine, la pureté des ingrédients pharmaceutiques actifs étant maintenue pendant une période de stockage prolongée dans des conditions similaires à celles susceptibles d'être rencontrées lors d'un stockage domestique de la médication par un patient diabétique. Une formulation exempte de sels de calcium, tels que le phosphate de calcium, mais comprenant, par exemple, de la cellulose microcristalline, la copovidone, la crospovidone, le dioxyde de silicium colloïdal et le stéarate de magnésium, lorsqu'elle est compactée en un comprimé avec le composé de sel de tartrate représenté par la formule (IT), a été montrée être plus stable que pour une formulation de comprimé comprenant un sel de calcium. L'invention porte également sur des procédés de préparation de la forme posologique et sur des procédés d'utilisation de la forme posologique.
PCT/US2009/030470 2008-01-14 2009-01-08 Forme posologique stable d'un inhibiteur de la dpp-iv avec de la metformine Ceased WO2009091663A1 (fr)

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US61/020,978 2008-01-14
US2222708P 2008-01-18 2008-01-18
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011064352A1 (fr) 2009-11-27 2011-06-03 Boehringer Ingelheim International Gmbh Traitement de patients diabétiques génotypés par des inhibiteurs de dpp-iv tels que la linagliptine
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
WO2011138421A1 (fr) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combinaison thérapeutique
WO2011161161A1 (fr) 2010-06-24 2011-12-29 Boehringer Ingelheim International Gmbh Thérapie du diabète
WO2013174767A1 (fr) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh Dérivé de xanthine en tant qu'inhibiteur de la dpp-4 à utiliser dans la modification de l'apport alimentaire et dans la régulation des préférences alimentaires
WO2014101986A1 (fr) * 2012-12-27 2014-07-03 Zentiva Sağlik Ürünleri San. Ve Tic. A.Ş. Procédé de granulation à sec pour la production de compositions de comprimés de metformine et compositions associées
WO2021045706A1 (fr) * 2019-09-06 2021-03-11 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Combinaison comprenant de la vildagliptine et de la metformine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060258621A1 (en) * 2003-11-12 2006-11-16 Campbell David A Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv
US20060264400A1 (en) * 2003-11-12 2006-11-23 Campbell David A Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv
US20070148252A1 (en) * 2005-11-28 2007-06-28 Marinus Pharmaceuticals Solid ganaxolone formulations and methods for the making and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060258621A1 (en) * 2003-11-12 2006-11-16 Campbell David A Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv
US20060264400A1 (en) * 2003-11-12 2006-11-23 Campbell David A Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv
US20070148252A1 (en) * 2005-11-28 2007-06-28 Marinus Pharmaceuticals Solid ganaxolone formulations and methods for the making and use thereof

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011064352A1 (fr) 2009-11-27 2011-06-03 Boehringer Ingelheim International Gmbh Traitement de patients diabétiques génotypés par des inhibiteurs de dpp-iv tels que la linagliptine
EP3646859A1 (fr) 2009-11-27 2020-05-06 Boehringer Ingelheim International GmbH Traitement de patients diabétiques génotypés avec des inhibiteurs de dpp-iv tels que la linagliptine
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
WO2011138421A1 (fr) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combinaison thérapeutique
WO2011161161A1 (fr) 2010-06-24 2011-12-29 Boehringer Ingelheim International Gmbh Thérapie du diabète
WO2013174767A1 (fr) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh Dérivé de xanthine en tant qu'inhibiteur de la dpp-4 à utiliser dans la modification de l'apport alimentaire et dans la régulation des préférences alimentaires
WO2014101986A1 (fr) * 2012-12-27 2014-07-03 Zentiva Sağlik Ürünleri San. Ve Tic. A.Ş. Procédé de granulation à sec pour la production de compositions de comprimés de metformine et compositions associées
RU2647421C2 (ru) * 2012-12-27 2018-03-15 Зентива Саглык Урунлеры Сан. Ве Тыдж. А.Ш. Способ сухого гранулирования для получения композиций метформина в виде таблеток и его композиции
WO2021045706A1 (fr) * 2019-09-06 2021-03-11 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Combinaison comprenant de la vildagliptine et de la metformine

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