WO2005021524A1 - Procede pour la preparation d'une forme amorphe de repaglinide - Google Patents

Procede pour la preparation d'une forme amorphe de repaglinide Download PDF

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Publication number
WO2005021524A1
WO2005021524A1 PCT/IB2004/002776 IB2004002776W WO2005021524A1 WO 2005021524 A1 WO2005021524 A1 WO 2005021524A1 IB 2004002776 W IB2004002776 W IB 2004002776W WO 2005021524 A1 WO2005021524 A1 WO 2005021524A1
Authority
WO
WIPO (PCT)
Prior art keywords
repaglinide
amoφhous
amoφhous form
process according
patient
Prior art date
Application number
PCT/IB2004/002776
Other languages
English (en)
Inventor
Yatendra Kumar
Purna Chandra Ray
Jayachandra Suresh Babu
Original Assignee
Ranbaxy Laboratories Limited
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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to EP04769193A priority Critical patent/EP1664008A1/fr
Publication of WO2005021524A1 publication Critical patent/WO2005021524A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • repaglinide is S(+)-2-ethoxy-4-[N-(l-(2-piperidino-phenyl)-3-methyl- l-butyl)-aminocarbonylmethyl]benzoic acid, which belongs to a new class of hypoglycemic benzoic acid derivatives.
  • 5,216,167 discloses enantiomers, diastereomers, non-toxic salts and non-toxic acid addition salts of repaglinide.
  • repaglinide which has a melting point of 102 to 104 °C, is prepared by recrystallizing from petroleum ether/toluene.
  • U.S. Patent No. 6,143,769 discloses a process for preparing repaglmide, which has a melting point of 126 to 131 °C, by recrystallizing from ethanol/water.
  • repaglinide that is available in other physical forms, such as, for example, amorphous form.
  • the present invention also encompasses repaglinide in an amorphous form.
  • the amorphous form of repaglinide is characterized by a differential scanning calorimetry curve having a single melting endotherm with a peak temperature of about 52.98 °C and an extrapolated onset temperature of about 47.23 °C.
  • the present invention further encompasses a method of treating a disease related to hypoglycemic activity comprising administering a therapeutically effective amount of an amo ⁇ hous form of repaglinide to a patient in need thereof.
  • the present invention also encompasses a method of treating diabetes mellitus comprising administering a therapeutically effective amount of an amo ⁇ hous form of repaglinide to a patient in need thereof.
  • the patient is a human.
  • the present invention encompasses a process for the preparation of an amo ⁇ hous form of repaglinide, which comprises recovering amo ⁇ hous repaglinide from a repaglinide solution by spray drying.
  • the repaglinide solution can be obtained directly from a reaction mixture, i another embodiment, the repaglinide solution can be obtained by dissolving crystalline repaglinide in a suitable solvent.
  • suitable solvents can be alcohols, ketones, ethers, chlorinated hydrocarbons, esters, nitriles, dipolar aprotic solvents, cyclic ethers, and mixtures thereof.
  • the suitable solvents can be methanol, ethanol, isopropanol, dichloromethane, dichloroethane, acetonitrile, tetrahydrofuran, dioxane, diethylether, diisopropylether, tertiary butylethylether, and mixtures thereof.
  • the air inlet temperature of the spray drier can be from about 40 °C to about 100 °C and outlet temperature of the spray drier can be from about 20°C to about 80 °C.
  • the present invention also encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an amo ⁇ hous form of repaglinide and at least one pharmaceutical acceptable excipient, carrier, or diluent.
  • the amo ⁇ hous form of repaglinide is characterized by a differential scanning calorimetry curve having a single melting endotherm with a peak temperature of about 52.98 °C and an extrapolated onset temperature of about 47.23 °C.
  • Fig. 1 is an X-ray diffraction spectrum of an amo ⁇ hous form of repaglinide.
  • Fig.2 is an IR spectrum of an amo ⁇ hous form of repaglinide obtained by using potassium bromide pellets.
  • the present invention encompasses a new form of repaglinide, and in particular, an amo ⁇ hous form of repaglinide.
  • the present invention encompasses a process for preparing an amo ⁇ hous form of repaglinide is provided comprising spray drying of a solution of repaglinide.
  • the present invention encompasses a pharmaceutical composition comprising an amo ⁇ hous form of repaglinide, along with pharmaceutically acceptable excipients.
  • the amo ⁇ hous form of repaglinide that is utilized in the pharmaceutical compositions is formed by recovering amo ⁇ hous repaglinide from a repaglinide solution by spray drying.
  • the present invention encompasses a method for treating or preventing diabetes mellitus, which comprises administering an effective amount of amo ⁇ hous form of repaglinide, is provided.
  • the amo ⁇ hous form of repaglinide is characterized by its non-crystalline nature.
  • the amo ⁇ hous form of repaglimde can be characterized by X-ray powder diffraction spectrum, or IR spectrum, as shown in Figures 1, and 2.
  • the amo ⁇ hous form of repaglinide also can be characterized by a differential scanning calorimetry (DSC) curve, which exhibits a single melting endotherm with a peak temperature of about 52.98°C and an extrapolated onset temperature of about 47.23°C.
  • DSC differential scanning calorimetry
  • the present invention also is directed to a process for preparing an amo ⁇ hous form of repaglinide comprising recovering amo ⁇ hous repaglinide from a solution in a suitable solvent by spray drying.
  • the solution of repaglinide can be obtained by dissolving crystalline repaglinide in a suitable solvent, or alternatively, such a solution may be obtained directly, from a reaction in which repaglinide is formed.
  • Any known forms of crystalline repaglinide can be used as a starting material, such as forms disclosed in U.S. Patent Nos. 5,216,167 and 6,143,769.
  • a solution of repaglinide obtained in-situ during the preparation process can be used as such for spray drying.
  • Repaglinide can be obtained by known methods, such as methods disclosed in U.S. Patent Nos. 5,216,167 and 6,143,769, and WO 03/027072.
  • suitable solvents include any solvent or solvent mixture in which repaglinide is soluble, hi particular, suitable solvents include, for example, alcohols, such as methanol, ethanol and isopropanol; ketones, such as acetone and methyl isobutyl ketone; ethers, such as diethylether, diisopropylether and tertiary butylethylether; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride and ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide and dimethylformamide; esters, such as ethylacetate and isopropylacetate; cyclic ethers, such as dioxane and tetrahydrofuran and mixtures
  • Spray drying can be accomplished by using a spray dryer, which operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction.
  • the drying gas can be air, one or more inert gases, or a mixture thereof.
  • the inert gases can be nitrogen, argon or carbon dioxide.
  • the air inlet temperature of the spray drier can be from about 40 °C to about 100 °C and the outlet temperature can be from about 20 °C to about 80 °C.
  • the amo ⁇ hous form of repaglinide exhibits hypoglycemic activity.
  • the present invention encompasses a method of treating or preventing a disease related to hypoglycemic activity comprising administering amo ⁇ hous form of repaglinide to a patient in need of such treatment.
  • the present invention encompasses a method of treating or preventing diabetes mellitus comprising administering amo ⁇ hous form of repaglinide to a patient in need of such treatment.
  • the patient is human.
  • the amo ⁇ hous form of repaglinide can be administered as part of a pharmaceutical composition.
  • the present invention encompasses a pharmaceutical composition that comprises an effective amount of an amo ⁇ hous form of repaglinide along with a pharmaceutically acceptable carrier, diluent or excipient, and optionally one or more other therapeutic ingredients.
  • a pharmaceutically acceptable carrier diluent or excipient
  • the amo ⁇ hous form of repaglinide can be conventionally formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms. Any suitable route of administration may be employed, such as, for example, peroral or parental.
  • the pharmaceutical carrier can be a conventional solid or liquid carrier.
  • solid carriers include, but are not limited to, lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, corn and or potato starch, amylose, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, magnesium stearate, secondary calcium phosphate, polyoxyethylenepolyoxypropylene polymer, microcrystalline cellulose, N-methylglucamine, L-lysine and stearic acid.
  • liquid carriers include, but are not limited to, salt solutions, syrup, alcohols, polyethylene glycols, polyhydroxy ethoxylated castor oil, peanut oil, olive oil and water.
  • the carrier or diluent may include any time delay material well known to the art, such as, for example, glyceryl monostearate, glyceryl distearate, hydroxymethylcellulose and polyvinylpyrrolidone alone or mixed with a wax.
  • a solid carrier for oral administration the preparation can be formed into a tablet, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.
  • the preparation may be a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non- aqueous liquid suspension.
  • compositions of this invention can be made following the conventional techniques of the pharmaceutical industry involving mixing, granulating and compressing or variously mixing and dissolving the ingredients as appropriate to give the desired end product.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as diluents, binders, lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers, coloring agents, flavoring agents and the like, which do not deleteriously react with the active compound.
  • auxiliary agents such as diluents, binders, lubricants, preservatives, disintegrants, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers, coloring agents, flavoring agents and the like, which do not deleteriously react with the active compound.
  • FT-LR Instrument Perkin Elmer, 16 PC SCAN: 16scans, 4.0 cm "1 Run in accordance to the USP 25, general test methods, page 1920, infrared abso ⁇ tion spectra were obtained by potassium bromide pellet method.
  • Example 2 Crystalline repaglinide (lOg) was dissolved in 150 mL of acetone at room temperature. The clear solution thus obtained was subjected to spray drying in a mini spray dryer (Buchi Model 190).
  • the spray drier was configured to utilize a nitrogen gas inlet at 700mm of Hg and flow rate was set at 10.0 mL/minute. The inlet temperature was maintained at 56 °C and accordingly, the outlet temperature was 35 °C.
  • Repaglinide was charged in the spray drier for 15 minutes and 7.0 g of white fluffy powder was collected.

Abstract

La présente invention concerne une nouvelle forme amorphe de répaglinide et un procédé pour sa préparation. Elle concerne également des compositions pharmaceutiques contenant cette forme amorphe, ainsi que son utilisation dans le traitement du diabète sucré.
PCT/IB2004/002776 2003-08-28 2004-08-27 Procede pour la preparation d'une forme amorphe de repaglinide WO2005021524A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP04769193A EP1664008A1 (fr) 2003-08-28 2004-08-27 Procede pour la preparation d'une forme amorphe de repaglinide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1049/DEL/2003 2003-08-28
IN1049DE2003 2003-08-28

Publications (1)

Publication Number Publication Date
WO2005021524A1 true WO2005021524A1 (fr) 2005-03-10

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/002776 WO2005021524A1 (fr) 2003-08-28 2004-08-27 Procede pour la preparation d'une forme amorphe de repaglinide

Country Status (2)

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EP (1) EP1664008A1 (fr)
WO (1) WO2005021524A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2177221A1 (fr) 2008-10-20 2010-04-21 Krka Tovarna Zdravil, D.D., Novo Mesto Procedure de préparation de répaglinide essentielment optiquement pur et ses précurseurs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000337A1 (fr) * 1991-06-21 1993-01-07 Dr. Karl Thomae Gmbh Acides (s)(+)-2-ethoxy-4-[n-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoique
WO2004018442A1 (fr) * 2002-08-23 2004-03-04 Dr. Reddy's Laboratories Limited Formes cristalline et amorphe de (s)-repaglinide et procedes de preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000337A1 (fr) * 1991-06-21 1993-01-07 Dr. Karl Thomae Gmbh Acides (s)(+)-2-ethoxy-4-[n-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoique
WO2004018442A1 (fr) * 2002-08-23 2004-03-04 Dr. Reddy's Laboratories Limited Formes cristalline et amorphe de (s)-repaglinide et procedes de preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. BERNSTEIN: "Polymorphism in molecular crystals", 2002, OXFORD UNIVERSITY PRESS, XP002308143 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2177221A1 (fr) 2008-10-20 2010-04-21 Krka Tovarna Zdravil, D.D., Novo Mesto Procedure de préparation de répaglinide essentielment optiquement pur et ses précurseurs

Also Published As

Publication number Publication date
EP1664008A1 (fr) 2006-06-07

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