Title:
CYCLODEXTRIN INCLUSIONS COMPLEXES OF PYRIMIDINE-2,4,6-TRIONES
Document Type and Number:
WIPO Patent Application WO2005097058
Kind Code:
A3
Abstract:
It was surprisingly found that a-trioxopyrimidine-cyclodextrin-complex formed of a trioxopyrimidine derivative represented by the below-described formula (I) and a water-soluble cyclodextrin (further abbreviated as CD) exhibits enhanced water solubility, excellent stability, and low topical stimulation and is useful as a therapeutic agent. Accordingly, the present invention provides a trioxopyrimidine-cyclodextrin complex formed of a trioxopyrimidine derivative or a salt thereof and a cyclodextrin, preferably a-, ß- or ?-cyclodextrin or a water-soluble cyclodextrin derivative (water-soluble being defined as a solubility of at least 0.5 gr/100ml water at 25°C), wherein the trioxopyrimidine derivative is represented by formula (I). It was furthermore found that such a trioxopyrimidine complex with cyclodextrin and an adjuvant such as L-lysine or L-arginine show improved water solubility and bioavailability, excellent stability, and low topical stimulation and is useful as a therapeutic agent.
Inventors:
BARTSCH PIERRE (BE)
CATALDO DIDIER (BE)
ENDELE RICHARD (DE)
EVRARD BRIGITTE (BE)
FOIDART JEAN-MICHEL (BE)
KRELL HANS-WILLI (DE)
ZIMMERMANN GERD (DE)
CATALDO DIDIER (BE)
ENDELE RICHARD (DE)
EVRARD BRIGITTE (BE)
FOIDART JEAN-MICHEL (BE)
KRELL HANS-WILLI (DE)
ZIMMERMANN GERD (DE)
Application Number:
PCT/EP2005/003348
Publication Date:
August 17, 2006
Filing Date:
March 31, 2005
Export Citation:
Assignee:
HOFFMANN LA ROCHE (CH)
UNIV LIEGE (BE)
BARTSCH PIERRE (BE)
CATALDO DIDIER (BE)
ENDELE RICHARD (DE)
EVRARD BRIGITTE (BE)
FOIDART JEAN-MICHEL (BE)
KRELL HANS-WILLI (DE)
ZIMMERMANN GERD (DE)
UNIV LIEGE (BE)
BARTSCH PIERRE (BE)
CATALDO DIDIER (BE)
ENDELE RICHARD (DE)
EVRARD BRIGITTE (BE)
FOIDART JEAN-MICHEL (BE)
KRELL HANS-WILLI (DE)
ZIMMERMANN GERD (DE)
International Classes:
A61K47/48; A61K9/00; A61K31/198; A61K31/515; A61K47/18; A61P11/06
Domestic Patent References:
| WO2001025217A1 | 2001-04-12 | |||
| WO1997023465A1 | 1997-07-03 | |||
| WO2002089824A1 | 2002-11-14 | |||
| WO2000040962A1 | 2000-07-13 | |||
| WO2000037109A2 | 2000-06-29 |
Foreign References:
| EP1018340A1 | 2000-07-12 |
Other References:
GRAMS F ET AL: "PYRIMIDINE-2,4,6-TRIONES: A NEW EFFECTIVE AND SELECTIVE CLASS OF MATRIX METALLOPROTEINASE INHIBITORS", BIOLOGICAL CHEMISTRY, vol. 382, no. 8, August 2001 (2001-08-01), pages 1277 - 1285, XP008009641, ISSN: 1431-6730
FOLEY L H ET AL: "Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 11, no. 8, 23 April 2001 (2001-04-23), pages 969 - 972, XP002271775, ISSN: 0960-894X
MASAHIKO SUZUKI ET AL: "A STUDY OF 1:1 PLUS 1:2 COMPLEXES BETWEEN BARBITURATE AND CYCLODEXTRIN USING THE FREEZING POINT DEPRESSION METHOD", CHEMICAL AND PHARMACEUTICAL BULLETIN, TOKYO, JP, vol. 41, no. 8, 1 August 1993 (1993-08-01), pages 1444 - 1447, XP000395593, ISSN: 0009-2363
JOZSEF SZEJTLI: "CYCLODEXTRIN TECHNOLOGY", 1988, KLUWER ACADEMIC PUBLISHERS, DORDRECHT, NL, XP001194813
KOIZUMI K ET AL: "[Comparison between interactions of alpha- and beta-cyclodextrin with barbituric acid derivatives]", YAKUGAKU ZASSHI. JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN. DEC 1974, vol. 94, no. 12, December 1974 (1974-12-01), pages 1515 - 1519, XP008034887, ISSN: 0031-6903
LOUKAS YANNIS L: "Quantitative structure-binding relationships (QSBR) and artificial neural networks: Improved predictions in drug: Cyclodextrin inclusion complexes", INTERNATIONAL JOURNAL OF PHARMACEUTICS (KIDLINGTON), vol. 226, no. 1-2, 11 September 2001 (2001-09-11), pages 207 - 211, XP002297397, ISSN: 0378-5173
AKI HATSUMI ET AL: "Multimodal inclusion complexes between barbiturates and 2-hydroxypropyl-beta-cyclodextrin in aqueous solution: Isothermal titration microcalorimetry, 13C NMR spectrometry, and molecular dynamics simulation", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 90, no. 8, August 2001 (2001-08-01), pages 1186 - 1197, XP002297398, ISSN: 0022-3549
LOPATA A ET AL: "Quantitative structure-stability relationships among inclusion complexes of cyclodextrins I: Barbituric acid derivatives", JOURNAL OF PHARMACEUTICAL SCIENCES 1985 UNITED STATES, vol. 74, no. 2, 1985, pages 211 - 213, XP001194803
IWAOKU R ET AL: "Enhanced absorption of phenobarbital from suppositories containing phenobarbital-[beta]-cyclodextrin inclusion complex", CHEMICAL AND PHARMACEUTICAL BULLETIN 1982 JAPAN, vol. 30, no. 4, 1982, pages 1416 - 1421, XP001194804
CSABAI KATALIN ET AL: "Interaction of some barbituric acid derivatives with hydroxypropyl-beta-cyclodextrin", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 91, no. 1, 1993, AMSTERDAM, NL, pages 15 - 22, XP001202117, ISSN: 0378-5173
LEIN, MICHAEL ET AL: "The new synthetic matrix metalloproteinase inhibitor (roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model", ONCOGENE, vol. 21, no. 3, 2002, pages 2089 - 2096, XP002297399, ISSN: 0950-9232
PIEL G ET AL: "Study of the influence of both cyclodextrins and L-Lysine on the aqueous solubility of nimesulide; isolation and characterization of nimesulide-L-Lysine-Cyclodextrin complexes", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 86, no. 4, 1997, pages 475 - 480, XP002383359, ISSN: 0022-3549
MURA P ET AL: "Ternary systems of naproxen with hydroxypropyl-[beta]-cyclodextrin and aminoacids", INTERNATIONAL JOURNAL OF PHARMACEUTICS 24 JUL 2003 NETHERLANDS, vol. 260, no. 2, 24 July 2003 (2003-07-24), pages 293 - 302, XP002383360, ISSN: 0378-5173
MURA P ET AL: "Solid-state characterization and dissolution properties of Naproxen-Arginine-Hydroxypropyl-[beta]-cyclodextrin ternary system", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 59, no. 1, 2005, pages 99 - 106, XP002383361, ISSN: 0939-6411
FOLEY L H ET AL: "Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 11, no. 8, 23 April 2001 (2001-04-23), pages 969 - 972, XP002271775, ISSN: 0960-894X
MASAHIKO SUZUKI ET AL: "A STUDY OF 1:1 PLUS 1:2 COMPLEXES BETWEEN BARBITURATE AND CYCLODEXTRIN USING THE FREEZING POINT DEPRESSION METHOD", CHEMICAL AND PHARMACEUTICAL BULLETIN, TOKYO, JP, vol. 41, no. 8, 1 August 1993 (1993-08-01), pages 1444 - 1447, XP000395593, ISSN: 0009-2363
JOZSEF SZEJTLI: "CYCLODEXTRIN TECHNOLOGY", 1988, KLUWER ACADEMIC PUBLISHERS, DORDRECHT, NL, XP001194813
KOIZUMI K ET AL: "[Comparison between interactions of alpha- and beta-cyclodextrin with barbituric acid derivatives]", YAKUGAKU ZASSHI. JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN. DEC 1974, vol. 94, no. 12, December 1974 (1974-12-01), pages 1515 - 1519, XP008034887, ISSN: 0031-6903
LOUKAS YANNIS L: "Quantitative structure-binding relationships (QSBR) and artificial neural networks: Improved predictions in drug: Cyclodextrin inclusion complexes", INTERNATIONAL JOURNAL OF PHARMACEUTICS (KIDLINGTON), vol. 226, no. 1-2, 11 September 2001 (2001-09-11), pages 207 - 211, XP002297397, ISSN: 0378-5173
AKI HATSUMI ET AL: "Multimodal inclusion complexes between barbiturates and 2-hydroxypropyl-beta-cyclodextrin in aqueous solution: Isothermal titration microcalorimetry, 13C NMR spectrometry, and molecular dynamics simulation", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 90, no. 8, August 2001 (2001-08-01), pages 1186 - 1197, XP002297398, ISSN: 0022-3549
LOPATA A ET AL: "Quantitative structure-stability relationships among inclusion complexes of cyclodextrins I: Barbituric acid derivatives", JOURNAL OF PHARMACEUTICAL SCIENCES 1985 UNITED STATES, vol. 74, no. 2, 1985, pages 211 - 213, XP001194803
IWAOKU R ET AL: "Enhanced absorption of phenobarbital from suppositories containing phenobarbital-[beta]-cyclodextrin inclusion complex", CHEMICAL AND PHARMACEUTICAL BULLETIN 1982 JAPAN, vol. 30, no. 4, 1982, pages 1416 - 1421, XP001194804
CSABAI KATALIN ET AL: "Interaction of some barbituric acid derivatives with hydroxypropyl-beta-cyclodextrin", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 91, no. 1, 1993, AMSTERDAM, NL, pages 15 - 22, XP001202117, ISSN: 0378-5173
LEIN, MICHAEL ET AL: "The new synthetic matrix metalloproteinase inhibitor (roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model", ONCOGENE, vol. 21, no. 3, 2002, pages 2089 - 2096, XP002297399, ISSN: 0950-9232
PIEL G ET AL: "Study of the influence of both cyclodextrins and L-Lysine on the aqueous solubility of nimesulide; isolation and characterization of nimesulide-L-Lysine-Cyclodextrin complexes", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 86, no. 4, 1997, pages 475 - 480, XP002383359, ISSN: 0022-3549
MURA P ET AL: "Ternary systems of naproxen with hydroxypropyl-[beta]-cyclodextrin and aminoacids", INTERNATIONAL JOURNAL OF PHARMACEUTICS 24 JUL 2003 NETHERLANDS, vol. 260, no. 2, 24 July 2003 (2003-07-24), pages 293 - 302, XP002383360, ISSN: 0378-5173
MURA P ET AL: "Solid-state characterization and dissolution properties of Naproxen-Arginine-Hydroxypropyl-[beta]-cyclodextrin ternary system", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 59, no. 1, 2005, pages 99 - 106, XP002383361, ISSN: 0939-6411
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