WO2007130064A1 - Acide 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione)butanedioique, procedes de preparation et compositions a base de maleate de rosiglitazone - Google Patents

Acide 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione)butanedioique, procedes de preparation et compositions a base de maleate de rosiglitazone Download PDF

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Publication number
WO2007130064A1
WO2007130064A1 PCT/US2006/017994 US2006017994W WO2007130064A1 WO 2007130064 A1 WO2007130064 A1 WO 2007130064A1 US 2006017994 W US2006017994 W US 2006017994W WO 2007130064 A1 WO2007130064 A1 WO 2007130064A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
rosiglitazone maleate
formula
sealed package
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PCT/US2006/017994
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English (en)
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WO2007130064A8 (fr
Inventor
Yehudit Dolitzky
Yoseph Avezov
Dina Spivak
Minutza Leibovici
Ben-Zion Solomon
Original Assignee
Teva Pharmaceutical Industries, Ltd.
Teva Pharmaceuticals Usa, Inc.
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
Priority to BRPI0621551A priority Critical patent/BRPI0621551A2/pt
Priority to JP2009509523A priority patent/JP2009536643A/ja
Priority to MX2008014298A priority patent/MX2008014298A/es
Priority to PCT/US2006/017994 priority patent/WO2007130064A1/fr
Priority to CNA2006800543976A priority patent/CN101426789A/zh
Priority to CA002647829A priority patent/CA2647829A1/fr
Application filed by Teva Pharmaceutical Industries, Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries, Ltd.
Publication of WO2007130064A1 publication Critical patent/WO2007130064A1/fr
Priority to IL188175A priority patent/IL188175A0/en
Publication of WO2007130064A8 publication Critical patent/WO2007130064A8/fr
Priority to NO20085124A priority patent/NO20085124L/no
Priority to NO20092362A priority patent/NO20092362L/no
Priority to IL199822A priority patent/IL199822A0/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a rosiglitazone maleate impurity and its use as a reference marker and reference standard.
  • Rosiglitazone is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity.
  • Chemically, rosiglitazone maleate is ( ⁇ ) -5- [ [4- [2- (methyl- 2- pyridinylamino) ethoxy] phenyl] methyl] -2,4- thiazolidinedione, (Z) -2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base).
  • the molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable.
  • Rosiglitazone Maleate is marketed in the United States under the trade name AVANDIA® in 2 mg, 4 mg, and 8 mg tablets.
  • Rosiglitazone Maleate in combination with Metformin HCl under the trade name AVANDAMET® in tablets with the following dosages: 1 mg/ 500 mg; 2 mg/ 500 mg; 4 mg/ 500 mg; 2 mg/ 1000 mg; 4 mg/ 1000 mg.
  • Rosiglitazone and its maleate salt are disclosed in the following United States patents, hereby incorporated by reference: 5,002,953; 5,741,803; 6,288,095.
  • the regulatory agencies generally require a manufacturing specification that sets the maximum amount of each identified impurity as well as the maximum amount for all remaining unidentified impurities.
  • stability testing is performed on the pharmaceutical composition to insure that it does not substantially change over time.
  • the subject invention provides an isolated compound of the formula :
  • the subject invention also provides a composition comprising a compound of the formula:
  • composition is free of rosiglitazone maleate.
  • the subject invention also provides a composition comprising a compound having the formula(I):
  • composition in an amount of at least 0.2% based on the weight of the composition, and a carrier.
  • the subject invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a granulate of a mixture of: a) rosiglitazone maleate; b) at least one pharmaceutically acceptable carrier; and c) less than 0.1% of the compound of the formula (I):
  • the subject invention also provides a sealed package comprising: a pharmaceutical composition comprising rosiglitazone maleate and at least one pharmaceutically acceptable carrier; and a desiccant.
  • the subject invention also provides a process for preparing a pharmaceutical composition comprising rosiglitazone maleate and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises less than 1.2% of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl]methyl] -2, 4-thiazolidinedione ⁇ -butanedioic acid, based on the combined weight of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -2, 4- thiazolidinedione ⁇ -butanedioic acid ⁇ and rosiglitazone maleate, comprising: a. obtaining rosiglitazone maleate drug substance; b. determining the total amount of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl] methyl] -
  • the subject invention also provides a process for validating a batch of a pharmaceutical composition containing rosiglitazone maleate and at least one pharmaceutically acceptable carrier for distribution comprising: a. determining the total amount of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy]phenyl]methyl] - 2, 4-thiazolidinedione ⁇ -butanedioic acid in a sample of the batch after stability testing; and b.
  • step a) validating the batch for distribution only if the sample of the batch is determined in step a) to contain less than 1.2% by weight of 2-N- ⁇ 5-[[4- [2- (methyl-2-pyridinylamino) ethoxy]phenyl]methyl] -2, 4-thiazolidinedione ⁇ butanedioic acid.
  • the subject invention provides a isolated compound of the formula :
  • the subject invention also provides a composition comprising a compound of the formula:
  • composition is free of rosiglitazone maleate.
  • the subject invention also provides a composition comprising a compound having the formula (I):
  • composition in an amount of at least 0.2% based on the weight of the composition, and a carrier.
  • the composition comprises at least 1.5% of the compound of the formula (I) , based on the weight of the composition.
  • the composition comprises at least 50% of the compound of the formula (I) , based on the weight of the composition.
  • the composition comprises from more than 0 to 99.8% by weight of rosiglitazone maleate, based on the combined weight of the compound of the formula (I) and the rosiglitazone maleate.
  • the composition comprises from more than 0 to 98.5% by weight of rosiglitazone maleate, based on the combined weight of the compound of the formula (I) and the rosiglitazone maleate.
  • composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.
  • the compound of formula (I) is present in an amount between 0.20% and 5.0% based on the combined weight of the compound of formula (I) and rosiglitazone maleate in the composition.
  • 0.20% to 5.0% it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, 0.25%, 0.30%, 0.35% ... 4.95% unit amounts are included as embodiments of this invention.
  • the compound of formula (I) is present in an amount between 0.20% and 3.0% based on the combined weight of the compound of formula (I) and rosiglitazone maleate in the composition.
  • 0.20% to 3.0% it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, 0.25%, 0.30%, 0.35% ... 2.95% unit amounts are included, as embodiments of this invention.
  • the compound of formula (I) is present in an amount between 0.25% and 2.0% based on the combined weight of the compound of formula (I) and rosiglitazone maleate in the composition.
  • 0.25% to 2.0% it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, 0.30%, 0.35%, 0.40% ... 1.95% unit amounts are included as embodiments of this invention.
  • the compound of formula (I) is present in an amount between 0.70% and 2.0% based on the combined weight of the compound of formula (I) and rosiglitazone maleate in the composition.
  • 0.70% to 2.0% it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, 0.75%, 0.80%, 0.85% ... 1.95% unit amounts are included as embodiments of this invention.
  • the compound of formula (I) is present in an amount between 1.10% and 2.0% based on the combined weight of the compound of formula (I) and rosiglitazone maleate in the composition.
  • 1.10% to 2.0% it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, 1.15%, 1.20%, 1.25% ... 1.95% unit amounts are included as embodiments of this invention.
  • the subject invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a granulate of a mixture of: a) rosiglitazone maleate; b) at least one pharmaceutically acceptable carrier; and c) less than 0.1% of the compound of the formula (I):
  • the compound of formula (I) is present in an amount less than 0.1% based on the combined weight of the compound and rosiglitazone maleate.
  • the granulate is a product of wet granulation in an aqueous solution.
  • the granulate is a milled granulate.
  • the pharmaceutical composition further comprises at least one disintegrant and at least one binder .
  • the disintegrant is croscarmellose sodium
  • the binder is povidone 1 .
  • the pharmaceutical composition further comprises a biguanide antidiabetic compound.
  • the biguanide antidiabetic compound is a pharmaceutically acceptable salt of metformin.
  • the pharmaceutically acceptable salt of metformin is metformin hydrochloride.
  • the pharmaceutical composition further comprises a sulfonyl urea antidiabetic compound.
  • the sulfonyl urea antidiabetic compound is glimepride or glipizide.
  • the pharmaceutical composition is in the form of a tablet.
  • the tablet comprises a tablet core, the tablet core comprising, by weight, between 1% and 4% rosiglitazone maleate, 6% croscarmellose sodium, 2% povidone, between 0.5% and 1% magnesium stearate and between 87% and 90% filler, the filler consisting of lactose and microcrystalline cellulose.
  • the tablet comprises a tablet core, the tablet core comprising, by weight, between 75% and 76% metformin HCl, between 0.2% and 1% rosiglitazone maleate, between 5% and 6% povidone, between 1% and 2% croscarmellose sodium, between 4% and 5% starch, and between 0.5% and 1% magnesium stearate.
  • the subject invention also provides a sealed package comprising the composition described herein or the pharmaceutical composition described herein.
  • the sealed package further comprises a desiccant .
  • the desiccant is silica gel.
  • the sealed package is a HDPE bottle.
  • the sealed package comprises the pharmaceutical composition described herein, wherein the pharmaceutical composition contains less than 1.0% of a compound of the formula (I) :
  • the subject invention also provides a sealed package comprising: a pharmaceutical composition comprising rosiglitazone maleate and at least one pharmaceutically acceptable carrier; and a desiccant.
  • the pharmaceutical composition further comprises a compound of the formula (D:
  • the pharmaceutical composition is present in the pharmaceutical composition in an amount of less than 0.1%, based on the combined weight of the compound of the formula (I) and rosiglitazone maleate.
  • the pharmaceutical composition contains less than 1 . 0% of a compound of the formula (I) :
  • the pharmaceutical composition further comprises at least one disintegrant and at least one binder.
  • the disintegrant is croscarmellose sodium
  • the binder is povidone .
  • the pharmaceutical composition further comprises a biguanide antidiabetic compound.
  • the biguanide antidiabetic compound is a pharmaceutically acceptable salt of metformin.
  • the pharmaceutically acceptable salt of metformin is metformin HCl.
  • the pharmaceutical composition further comprises a sulfonyl urea antidiabetic compound.
  • the sulfonyl urea antidiabetic compound is glimepride or glipizide.
  • the pharmaceutical composition is in the form of a tablet.
  • the tablet comprises a tablet core, the tablet core comprising, by weight, between 1% and 4% rosiglitazone maleate, 6% croscarmellose sodium, 2% povidone, between 0.5% and 1% magnesium stearate and between 87% and 90% filler, the filler consisting of lactose and microcrystalline cellulose .
  • the tablet comprises a tablet core, the tablet core comprising, by weight, between 75% and 76% metformin HCl, between 0.2% and 1% rosiglitazone maleate, between 5% and 6% povidone, between 1% and 2% croscarmellose sodium, between 4% and 5% starch, and between 0.5% and 1% magnesium stearate.
  • the desiccant is silica gel.
  • the pharmaceutical composition is prepared by wet granulation with water.
  • the sealed package is a HDPE bottle .
  • the subject invention also provides a process for making the pharmaceutical composition described herein, comprising a) granulating in the presence of water a mixture of rosiglitazone maleate, croscarmellose sodium, povidone and a filler to obtain a granualte; b) drying the granulate; c) milling the granulate to obtain a milled granulate; d) mixing the milled granulate with magnesium stearate to obtain a final blend; and e) compressing the final blend into a tablet core.
  • steps c) - e) are performed in an atmosphere having a relative humidity of 30% or less.
  • the subject invention also provides another process for making the pharmaceutical composition described herein, comprising a) granulating in the presence of an aqueous povidone solution a mixture comprising rosiglitazone maleate and metformin to obtain a granulate; b) drying the granulate; c) milling the granulate to obtain a milled granulate; d) mixing the milled granulate with croscarmellose sodium and starch to obtain an first blend; e) mixing the first blend with magnesium stearate to obtain a final blend; and f) compressing the final blend into a tablet core.
  • steps c) - f) are performed in an atmosphere having a relative humidity of 30% or less.
  • the process further comprises coating the tablet core with a film coating.
  • the subject invention also provides another process for preparing the pharmaceutical composition described herein or the sealed package described herein, comprising: a. obtaining rosiglitazone maleate drug substance; b. determining the total amount of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl]methyl] -
  • the pharmaceutical composition is prepared by wet granulation in an aqueous solution.
  • the subject invention also provides process for preparing a pharmaceutical composition comprising rosiglitazone maleate and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition comprises less than 1.2% of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy]phenyl]methyl] - 2, 4-thiazolidinedione ⁇ -butanedioic acid, based on the combined weight of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy]phenyl]methyl] -2, 4-thiazolidinedione ⁇ -butanedioic acid and rosiglitazone maleate, comprising: a. obtaining rosiglitazone maleate drug substance; b. determining the total amount of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy]phenyl]methyl] -
  • the pharmaceutical composition is prepared by wet granulation in an .aqueous solution.
  • the subject invention also provides a process for validating a batch of a pharmaceutical composition containing rosiglitazone maleate and at least one pharmaceutically acceptable carrier for distribution comprising: a. determining the total amount of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy]phenyl]methyl] - 2, 4-thiazolidinedione ⁇ -butanedioic acid in a sample of the batch after stability testing; and b.
  • step a) validating the batch for distribution only if the sample of the batch is determined in step a) to contain less than 1.2% by weight of 2-N- ⁇ 5-[[4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl]methyl] -2, 4-thiazolidinedione ⁇ butanedioic acid.
  • the batch is validated for distribution only if the sample of the batch is determined in step a) to contain less than 1.0% by weight of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy]phenyl]methyl] - 2, 4-thiazolidinedione ⁇ -butanedioic acid.
  • the batch is validated for distribution only if the sample of the batch is determined in step a) to contain less than 0.5% by weight of 2-N- ⁇ 5- [ [4- [2- (methyl-2-pyridinylamino) ethoxy] phenyl]methyl] -2, 4-thiazolidinedione ⁇ -butanedioic acid.
  • the subject invention also provides a process for making the isolated compound described herein, comprising: a. contacting rosiglitazone maleate with water at a temperature of 40-100 0 C, and b. isolating the compound from the reaction mixture of step a) .
  • the compound is isolated from the mixture via chromatography.
  • the compound is isolated from the mixture via recrystallization.
  • the subject invention also provides a method for increasing insulin sensitivity in a human subject comprising administering to the human subject the pharmaceutical composition described herein.
  • the subject invention also provides use of the composition described herein or the pharmaceutical composition described herein for manufacturing a medicament for increasing insulin sensitivity in a human subject.
  • the subject invention also provides a the pharmaceutical composition described herein for increasing insulin sensitivity in a human subject.
  • Step (c) Determining the amount of Compound 1 in the sample by comparing the area of Step (a) to the area of Step (b) and taking into account the relative response factor between Compound 1 and rosiglitazone.
  • drug substance refers to the active ingredient in a drug product, which provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.
  • drug product or “DP” refers to the finished dosage form containing the drug substance as well as at least one pharmaceutically acceptable carrier.
  • a "sealed" package, container or coating substantially prevents the atmosphere from coming in contact with the contents of the package or container or with the material coated by the coating.
  • a "HDPE” bottle refers to a bottle constructed of high density polyethylene plastic.
  • Impurities can be present in the active pharmaceutical ingredient (API) or in the pharmaceutical dosage form, for example, in tablets.
  • API active pharmaceutical ingredient
  • the excipients in the dosage form cause the degradation of rosiglitazone maleate and thereby bring about the presence of impurities . It is possible that these impurities only come into being after time and are found as a result of long term or accelerated stability studies .
  • impurities are defined spectroscopically and or with another physical method, and then associated with a peak position, such as that in a chromatogram or a spot on a TLC plate.
  • a peak position such as that in a chromatogram or a spot on a TLC plate.
  • the impurity can be identified by its position in the chromatogram where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector.
  • the retention time can vary based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the "Relative retention time,” (RRT) to identify impurities. (Strobel p. 922)
  • RRT Relative retention time
  • the RRT of an impurity is defined as the retention time of the impurity divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column and to use that compound as the reference marker for determination of the RRT .
  • a reference standard is a compound in a relatively pure state, used to quantify the amount of the compound in an unknown mixture.
  • a reference standard can be used as either an external standard or as an internal standard.
  • An external standard is employed when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique.
  • the amount of the compound in the mixture can be determined by comparing the magnitude of the detector responses .
  • An internal standard is employed when an unknown mixture contains a detectable amount of the reference standard compound without addition of the reference standard.
  • the amount of internal standard is determined by preparing at least two samples by adding known and differing amounts of the internal standard.
  • the proportion of the detector response due to the reference standard present in the mixture can be determined by plotting the detector response attained for each of the samples against the amount of the reference standard added to each of the samples and extrapolating the plot to zero.
  • compositions may be prepared as medicaments to be administered orally, parenterally, rectally or transdermally.
  • suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or soft gelatin capsules, sublingual tablets, syrups and suspensions; for parenteral administration the invention provides ampoules or vials that include an aqueous or non-aqueous solution or emulsion; for rectal administration there are provided suppositories with hydrophilic or hydrophobic vehicles; and for topical application as ointments and transdermal delivery there are provided suitable delivery systems as known in the art .
  • Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like.
  • Example 1 Isolation of Compound 1 by Preparative HPLC
  • Ig of rosiglitazone maleate was mixed with Ig of water in a reaction vessel with screw cap. The mixture was kept at 70° C for 5 days.
  • 24 mL of methanol: water solution of trifluoroacetic acid (with a pH of about 2.8) (3:2) were added.
  • the rosiglitazone base concentration of the solution was 40mg/mL.
  • Example 2 Isolation of Compound 1 by Crystallization 1.3g of rosiglitazone maleate was mixed with 1.3g of water in a reaction vessel with screw cap. The mixture was kept at 70° C for 5 days. 4 ml of methanol: water solution of trifluoroacetic acid with a pH of about 2.8 (3:2) were added to the mixture .
  • the sample was stored at 2-8°C for 5 days. Crystals of rosiglitazone maleate enriched with Compound 1 precipitated spontaneously from the sample. These crystals were vacuum- filtered and washed with cold water and methanol . These crude crystals were then dissolved in hot isopropyl alcohol and cooled in an ice bath until crystals of Compound 1 appeared. The crystals were vacuum-filtered then washed with cold isopropyl alcohol, methanol and dried to yield 40 mg. Purity: about 97-98%.
  • Detector UV at 245nm, 10mm flow cell path length Injection Volume: 20 ⁇ L Standard Solution preparation: Rosiglitazone maleate analytical standard was dissolved in diluent to make a solution with a concentration of approximately 0.2 ⁇ g/mL in terms of rosiglitazone. Sample preparation:
  • the standard and samples were injected and the peak due to Compound 1 was monitored and calculated in the relevant sample .
  • the peak which corresponded to Compound 1 was found to elute at approximately a Relative Retention Time of 0.7, when compared to the rosiglitazone maleate peak.
  • Example 4 HPLC Method for Determining Presence of Compound 1 in Formulation of Rosiglitazone Maleate Tablets or in Combined Formulation of Rosiglitazone Maleate and Metformin HCl Tablets
  • Solution B 75% Solution A and 25% acetonitrile.
  • Rosiglitazone maleate analytical standard was diluted with diluent to a concentration of 0.1 ⁇ g/mL.
  • Tablets were dissolved and diluted based on the declared strengths .
  • the quantifiable limit of this method was determined to be 0.1% based on the combined weight of Compound 1 and rosiglitazone .
  • Example 5a Preparation of Tablets Comprising Rosiglitazone Maleate and Metformin Tablets were prepared using the excipients in Table 1.
  • Metformin HCl & Povidone (PVP K-30) of Part I were transferred to a high shear mixer and mixed.
  • Macrocrystalline cellulose and Colloidal Silicon Dioxide of part II were screened and mixed in a Y-cone mixer with Rosiglitazone and Microcrystalline cellulose of Part III and with Microcrystalline cellulose of part IV.
  • Povidone (PVP K-90) solution in hot purified water was added to the high shear mixer from Step 3 & was mixed to attain a wet granulate.
  • Steps 6 to 10 which follow were performed in an atmosphere with lower than 30% relative humidity.
  • the dried granulate was milled and transferred to a Flow bin or Y-cone .
  • the cores were coated using OPADRY®, which consists of HPMC2910/HYPROMELLOSE 6 cP, Titanium dioxide, Macrogol / PEG 400, Iron Oxide yellow/ iron oxide red; using a coating machine .
  • OPADRY® which consists of HPMC2910/HYPROMELLOSE 6 cP, Titanium dioxide, Macrogol / PEG 400, Iron Oxide yellow/ iron oxide red; using a coating machine .
  • Part I The components of Part I were transferred to a high 0 shear mixer and mixed.
  • Purified water (granulation solution) was added to the high shear mixer from Step 1 and mixed, and a wet granulate was attained.
  • Steps 4 to 7 which follow were performed in an atmosphere with lower than 30% relative humidity.
  • the dried granulate was milled and transferred to a flow bin or Y-cone and mixed.
  • Magnesium stearate was screened through a sieve, transferred to the flow bin or Y-cone from Step 4 and mixed to attain the final blend. 6.
  • the final blend from Step 5 was compressed in to cores in a tableting machine .
  • the cores were coated in a coating machine using Opadry® which consists of: HPMC2910/HYPROMELLOSE 6 cP, Titanium dioxide, Macrogol / PEG 3350, Triacetin/Glycerol, Triacetate, Talc, Iron Oxide yellow/ red/black, FD&C Blue#2/Indigo Carmine Aluminum Lake.
  • Opadry® which consists of: HPMC2910/HYPROMELLOSE 6 cP, Titanium dioxide, Macrogol / PEG 3350, Triacetin/Glycerol, Triacetate, Talc, Iron Oxide yellow/ red/black, FD&C Blue#2/Indigo Carmine Aluminum Lake.
  • drug product 500 mg metformin/ 4 mg rosiglitazone base
  • Example 5a drug product prepared as in Example 5a made from two different batches of the rosiglitazone maleate drug substance was analyzed for presence of Compound 1 before and after thermodegradation using the method described in Example 4.
  • thermodegradation was performed by subjecting the samples to 65°C heat and 100% relative humidity for 5 days.
  • the content of Compound 1 is listed in the table below.
  • the peaks were measured and the area percent (area of Compound 1 peak/ area of all rosiglitazone related peaks) of the Compound 1 peak is listed below.
  • Rosiglitazone maleate was mixed with various excipients and with metformin in the same proportions as present in the 500mg/4mg (base strength) metformin/ rosiglitazone maleate tablets. 0.5 ml of water was added to each mixture, and the samples were kept at 65 0 C for 4 days. The amount of Compound 1 was determined in each of the samples using the method in Example 4. The results are summarized in the table below. The peaks were measured and the area percent (area of Compound 1 peak/ area of all rosiglitazone related peaks) of the Compound 1 peak is listed below.
  • Placebo mix A refers to a mixture of excipients as indicated in Example 5a, with the exception of rosiglitazone maleate.
  • Placebo mix B refers to a mixture of excipients as indicated in Example 5b, with the exception of rosiglitazone maleate.
  • This Example indicates that the presence of moisture and some excipients, especially starch, enhances the production of Compound 1 in accelerated conditions.
  • Tablets were prepared as described in Example 5. 100 tablets were packed into high density polyethylene (HDPE) bottles ' either with or without silica gel and were stored at 75% RH and 4O 0 C for 3 months. The tablets were then tested for Compound 1. The results, in terms of percentage of Compound 1 are listed in the table below. The percentage of compound in all of the dosages in the table below before the stability testing was less than 0.1%.
  • HDPE high density polyethylene
  • Example 4 The amount of Compound 1 in commercially available AVANDAMET ® tablets 1000/2 mg was analyzed using Example 4. Compound 1 was present in an amount that was less than quantifiable .

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  • Health & Medical Sciences (AREA)
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  • Endocrinology (AREA)
  • Hematology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un composé isolé de formule (I), ainsi que des procédés permettant de le détecter et de minimiser sa présence dans des compositions pharmaceutiques améliorées à base de maléate de rosiglitazone.
PCT/US2006/017994 2006-05-09 2006-05-09 Acide 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione)butanedioique, procedes de preparation et compositions a base de maleate de rosiglitazone WO2007130064A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
JP2009509523A JP2009536643A (ja) 2006-05-09 2006-05-09 ２−ｎ−｛５−［［４−［２−（メチル−２−ピリジニルアミノ）エトキシ］フェニル］メチル］−２，４−チアゾリジンジオン｝−ブタン二酸、製造方法、および、ロシグリタゾンマレアートとの組成物
MX2008014298A MX2008014298A (es) 2006-05-09 2006-05-09 Ácido 2-n-{5-[[4-[2-(metil-2-piridinilamino)etoxi]fenil]metil]-2,4 -tiazolidindiona}butanodioico, metodos de preparacion y composiciones con maleato de rosiglitazona.
PCT/US2006/017994 WO2007130064A1 (fr) 2006-05-09 2006-05-09 Acide 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione)butanedioique, procedes de preparation et compositions a base de maleate de rosiglitazone
CNA2006800543976A CN101426789A (zh) 2006-05-09 2006-05-09 2－n－{5－[[4－[2－(甲基－2－吡啶氨基)乙氧基]苯基]甲基]－2，4－噻唑烷二酮}丁二酸、其制备方法以及具有马来酸罗格列酮的组合物
CA002647829A CA2647829A1 (fr) 2006-05-09 2006-05-09 Acide 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione)butanedioique, procedes de preparation et compositions a base de maleate de rosiglitazone
BRPI0621551A BRPI0621551A2 (pt) 2006-05-09 2006-05-09 composto isolado, composição, embalagem vedada, processos para produzir a composição farmacêutica, para preparar a composição farmacêutica ou a embalagem vedada, para validar uma batelada de uma composição farmacêutica e para produzir o composto isolado, método para aumentar a sensibilidade à insulina em um indivíduo humano, e, uso da composição
IL188175A IL188175A0 (en) 2006-05-09 2007-12-17 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy] phenyl] methyl]-2,4-thiazolidinedione)butanedioic acid, methods of preparation and compositions with rosiglitazone maleate
NO20085124A NO20085124L (no) 2006-05-09 2008-12-09 2-n-(-5-[[4-(2-(methyl-2-pyridinylamino)ethoxy]phenly]methyl]-2,4-thaizolidinedione)butanedioic acid, methods of preparation and compositions whit rosiglitazone
NO20092362A NO20092362L (no) 2006-05-09 2009-06-19 2-N-(5-[{4-(2-(metyl-2-pyridinylamino) etoksy] fenyl]metyl}2,4-tiazolidinedion) butanedisyre, fremgangsmater for fremstilling og sammensetninger med rosiglitazon maleat
IL199822A IL199822A0 (en) 2006-05-09 2009-07-13 Sealed package of pharmaceutical composition comprising 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy] phenyl] methyl]-2,4-thiazolidinedione)butanedioic acid, methods of preparation and compositions with rosiglitazone maleate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2006/017994 WO2007130064A1 (fr) 2006-05-09 2006-05-09 Acide 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione)butanedioique, procedes de preparation et compositions a base de maleate de rosiglitazone

Publications (2)

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WO2007130064A1 true WO2007130064A1 (fr) 2007-11-15
WO2007130064A8 WO2007130064A8 (fr) 2008-11-13

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PCT/US2006/017994 WO2007130064A1 (fr) 2006-05-09 2006-05-09 Acide 2-n-(5-[[4-(2-methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione)butanedioique, procedes de preparation et compositions a base de maleate de rosiglitazone

Country Status (8)

Country Link
JP (1) JP2009536643A (fr)
CN (1) CN101426789A (fr)
BR (1) BRPI0621551A2 (fr)
CA (1) CA2647829A1 (fr)
IL (2) IL188175A0 (fr)
MX (1) MX2008014298A (fr)
NO (2) NO20085124L (fr)
WO (1) WO2007130064A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010013141A3 (fr) * 2008-08-01 2010-06-17 Actavis Group Ptc Ehf Hydrogénosulfate de rosiglitazone essentiellement pur

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102863436B (zh) * 2012-06-19 2018-02-09 重庆医科大学 噻唑烷二酮类衍生物及其制备和用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5741803A (en) * 1992-09-05 1998-04-21 Smithkline Beecham Plc Substituted thiazolidinedionle derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5741803A (en) * 1992-09-05 1998-04-21 Smithkline Beecham Plc Substituted thiazolidinedionle derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010013141A3 (fr) * 2008-08-01 2010-06-17 Actavis Group Ptc Ehf Hydrogénosulfate de rosiglitazone essentiellement pur

Also Published As

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IL199822A0 (en) 2011-07-31
CN101426789A (zh) 2009-05-06
BRPI0621551A2 (pt) 2016-08-16
MX2008014298A (es) 2008-11-26
IL188175A0 (en) 2008-03-20
WO2007130064A8 (fr) 2008-11-13
NO20085124L (no) 2009-02-04
JP2009536643A (ja) 2009-10-15
NO20092362L (no) 2009-02-04
CA2647829A1 (fr) 2007-11-15

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