WO2009127059A1 - Complexes d’isogranulatimide et de granulatimide avec une cyclodextrine, formulations et utilisation pour le traitement du cancer - Google Patents

Complexes d’isogranulatimide et de granulatimide avec une cyclodextrine, formulations et utilisation pour le traitement du cancer Download PDF

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Publication number
WO2009127059A1
WO2009127059A1 PCT/CA2009/000495 CA2009000495W WO2009127059A1 WO 2009127059 A1 WO2009127059 A1 WO 2009127059A1 CA 2009000495 W CA2009000495 W CA 2009000495W WO 2009127059 A1 WO2009127059 A1 WO 2009127059A1
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cyclodextrin
group
pharmaceutical composition
formula
compound
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PCT/CA2009/000495
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English (en)
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Gilles Tremblay
Aida Kalbakji
Mario Filion
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Alethia Biotherapeutics Inc.
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Publication of WO2009127059A1 publication Critical patent/WO2009127059A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • BACKGROUND PCT WO 99/47522 describes novel granulatimide compounds, isogranulatimide compounds, derivatives thereof and pharmaceutical formulations thereof.
  • This invention is based, in part, on the discovery that a complexation of granulatimide and/or isogranulatimide and/or derivatives thereof may be made with a cyclodextrin. Furthermore, it was discovered that such complexations have improved solubility and bioavailability. Such complexation may take place in the presence of dextrose. The efficacy of such compounds and complexes may be improved by the formulations and the methods described herein.
  • a pharmaceutical composition including a compound of formula I complexed with at least one cyclodextrin selected from: a hydrophilic ⁇ -cyclodextrin derivative; a hydrophobic ⁇ -cyclodextrins derivative; an ionaizable ⁇ -cyclodextrins derivative; an ⁇ -cyclodextrin; and a ⁇ -cyclodextrin, wherein the compound of formula I has the structure:
  • W may be selected from the group consisting of formula (i) or (ii) wherein the structures may be as follows:
  • K, E and T may be independently selected from the group consisting of: N, CR, and CZ, and wherein R and Z may be as defined below:
  • K and E may be independently selected from the group consisting of: N, CR and CZ, and wherein R, Z and Q may be as defined below.
  • R 1 may be selected from the group consisting of: R; RCO-; ArCO-; and, ArCH 2 -, wherein Ar may be an aromatic substituent selected from the group consisting of: phenyl, napthyl, anthracyl, phenanthryl, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, imidazole, thiazole, oxazole, and pyridine, and Ar may be optionally substituted with R or Z and R and Z may be defined as below.
  • Ar may be an aromatic substituent selected from the group consisting of: phenyl, napthyl, anthracyl, phenanthryl, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, imidazole, thiazole, oxazole, and pyridine, and Ar may be optionally substituted with R or Z
  • R 2 may be selected from the group consisting of: H; a saturated or unsaturated linear, branched or cyclic, skeleton containing one to ten carbon atoms, in which the carbon atoms may be optionally substituted with a substituent selected from the group consisting of: -OH; -OR 3 ; -O 2 CR 3 ; -SH; -SR 3 ; -SOCR 3 ; -NH 2 ; -NHR 3 ; -NH(R 3 ) 2 ; -NHCOR 3 ; NRCOR 3 ; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CHO; -COR 3 ; -CONH 2 ; -CONHR 3 ; -CON(R 3 ) 2 ; -COSH; -COSR 3 ; -NO 2 ; -SO 3 H; -SOR 3 ; and - SO 2 R 3 , wherein each R 3
  • Each R may be independently selected from the group consisting of: H; and, a structural fragment having a saturated or unsaturated linear, branched or cyclic, skeleton containing one to ten carbon atoms, in which the carbon atoms may be optionally substituted with a substituent selected from the group consisting of: -OH; -OR 3 ; -O 2 CR 3 ; -SH; -SR 3 ; -SOCR 3 ; -NH 2 ; -NHR 3 ; -NH(R 3 ) 2 ; -NHCOR 3 ; NRCOR 3 ; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CO 2 R 3 ; -CHO; -COR 3 ; -CONH 2 ; -CONHR 3 ; -CON(R 3 ) 2 ; -COSH; -COSR 3 ; -NO 2 ; -SO 3 H; -SOR 3
  • Each Z may be independently selected from the group consisting of: H; -OH; -OR; -O 2 CR; -SH; -SR; -SOCR; -NH 2 ; -NHR; -NH(R) 2 ; -NHCOR; NRCOR; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CO 2 R; -CHO; -COR; -CONH 2 ; -CONHR; -CON(R) 2 ; -COSH; -COSR; -NO 2 ; -SO 3 H; -SOR; and, -SO 2 R.
  • Q may be selected from the group consisting of: NR 2 ; O; S; and C(R) 2 .
  • X and Y may be independently selected from the group consisting of: O; H; OH; and H 2 .
  • R 1 may be H or CH 3 .
  • Q may be NH.
  • X and Y may be oxygen.
  • W may be a five membered ring of formula (i) or (ii) comprising at least one nitrogen atom. Where E, K and T are present, they may be N or CH.
  • a pharmaceutical composition that includes a compound of the formula:
  • cyclodextrin selected from: a hydrophilic ⁇ -cyclodextrin derivative; a hydrophobic ⁇ -cyclodextrins derivative; an ionaizable ⁇ -cyclodextrins derivative; a ⁇ -cyclodextrin; and a ⁇ -cyclodextrin.
  • a pharmaceutical composition that includes a compound of the formula: complexed with at least one cyclodextrin selected from: a hydrophilic ⁇ -cyclodextrin derivative; a hydrophobic ⁇ -cyclodextrins derivative; an ionaizable ⁇ -cyclodextrins derivative; a ⁇ -cyclodextrin; and a ⁇ -cyclodextrin.
  • a pharmaceutical composition that includes a compound of the formula:
  • cyclodextrin selected from: a hydrophilic ⁇ -cyclodextrin derivative; a hydrophobic ⁇ -cyclodextrins derivative; an ionaizable ⁇ -cyclodextrins derivative; a ⁇ -cyclodextrin; and a ⁇ -cyclodextrin.
  • a pharmaceutical composition that includes a compound of the formula:
  • cyclodextrin selected from: a hydrophilic ⁇ -cyclodextrin derivative; a hydrophobic ⁇ -cyclodextrins derivative; an ionaizable ⁇ -cyclodextrins derivative; a ⁇ -cyclodextrin; and a ⁇ -cyclodextrin.
  • a pharmaceutical composition that includes a compound of the formula:
  • cyclodextrin selected from: a hydrophilic ⁇ -cyclodextrin derivative; a hydrophobic ⁇ -cyclodextrins derivative; an ionaizable ⁇ -cyclodextrins derivative; a ⁇ -cyclodextrin; and a ⁇ -cyclodextrin.
  • the pharmaceutical compositions may include a further pharmaceutically acceptable carrier.
  • the pharmaceutical compositions may be for treating cancer.
  • the pharmaceutical compositions may be for treating cancer wherein the cancer may be selected from: colon and ovarian.
  • the pharmaceutical compositions may be for use in a method of treatment of the human or animal body.
  • the pharmaceutical compositions may have a volume-weighted mean particle size of less than 5 ⁇ m.
  • the pharmaceutical compositions may have a volume-weighted mean particle size within the range of 0.1 ⁇ m and 50 ⁇ m.
  • the pharmaceutical compositions may have a volume-weighted mean particle size of less than 10 ⁇ m.
  • the pharmaceutical compositions may have a volume-weighted mean particle size of less than 25 ⁇ m.
  • Particle size may be measured using one or more of the methods known in the art.
  • Particle size may be measured using laser diffraction.
  • compositions may contain a hydrophilic ⁇ -cyclodextrin derivative selected from: methylated ⁇ -cyclodextrin; hydroxyalkylated ⁇ -cyclodextrin; and branched ⁇ -cyclodextrin.
  • a hydrophilic ⁇ -cyclodextrin derivative selected from: methylated ⁇ -cyclodextrin; hydroxyalkylated ⁇ -cyclodextrin; and branched ⁇ -cyclodextrin.
  • the pharmaceutical compositions may contain a hydrophobic ⁇ -cyclodextrin derivative selected from: alkylated ⁇ -cyclodextrin; and acylated ⁇ -cyclodextrin.
  • the ionaizable ⁇ -cyclodextrin derivative may be anionic ⁇ -cyclodextrin.
  • the at least one cyclodextrin may comprise 2-hydroxypropyl- ⁇ -cyclodextrin (HPCD) .
  • the pharmaceutical compositions may comprise a water-soluble compound for inducing osmosis.
  • the water-soluble compound for inducing osmosis may be selected from: sodium chloride, mannitol, dextrate, and dextrose.
  • the water-soluble compound for inducing osmosis may be selected from: 0.9% sodium chloride and 5% dextrose.
  • the pharmaceutical compositions may be used in the manufacture of a medicament for the treatment of cancer.
  • the medicament may sensitize cancer cells to the effects of DNA damaging agents on cancer cells.
  • the pharmaceutical compositions may be used wherein the cancer may be colon or ovarian.
  • the pharmaceutical compositions may be used for the treatment of cancer.
  • the pharmaceutical compositions may be used wherein the cancer may be colon or ovarian.
  • a complexation product wherein a cyclodextrin may be complexed with a compound of formula I having the structure:
  • W may be selected from the group consisting of formula (i) or (ii) wherein the structures may be as follows:
  • K, E and T may be independently selected from the group consisting of: N, CR, and CZ, and wherein R and Z may be as defined below;
  • R 1 may be selected from the group consisting of: R; RCO-; ArCO-; and, ArCH 2 -, wherein Ar may be an aromatic substituent selected from the group consisting of: phenyl, napthyl, anthracyl, phenanthryl, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, imidazole, thiazole, oxazole, and pyridine, and Ar may be optionally substituted with R or Z and R and Z may be defined as below.
  • R 2 may be selected from the group consisting of: H; a saturated or unsaturated linear, branched or cyclic, skeleton containing one to ten carbon atoms, in which the carbon atoms may be optionally substituted with a substituent selected from the group consisting of: -OH; -OR 3 ; -O 2 CR 3 ; -SH; -SR 3 ; -SOCR 3 ; -NH 2 ; -NHR 3 ; -NH(R 3 ) 2 ; -NHCOR 3 ; NRCOR 3 ; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CHO; -COR 3 ; -CONH 2 ; -CONHR 3 ; -CON(R 3 ) 2 ; -COSH; -COSR 3 ; -NO 2 ; -SO 3 H; -SOR 3 ; and - SO 2 R 3 , wherein each R 3
  • Each R may be independently selected from the group consisting of: H; and, a structural fragment having a saturated or unsaturated linear, branched or cyclic, skeleton containing one to ten carbon atoms, in which the carbon atoms may be optionally substituted with a substituent selected from the group consisting of: -OH; -OR 3 ; -O 2 CR 3 ; -SH; -SR 3 ; -SOCR 3 ; -NH 2 ; -NHR 3 ; -NH(R 3 ) 2 ;
  • each R 3 may be independently selected from the group consisting of: a linear, branched or cyclic, one to ten carbon saturated or unsaturated alkyl group.
  • Each Z may be independently selected from the group consisting of: H; -OH; -OR; -O 2 CR; -SH; -SR; -SOCR; -NH 2 ; -NHR; -NH(R) 2 ; -NHCOR; NRCOR; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CO 2 R; -CHO; -COR; -CONH 2 ; -CONHR; -CON(R) 2 ; -COSH; -COSR; -NO 2 ; -SO 3 H; -SOR; and, -SO 2 R.
  • Q may be selected from the group consisting of: NR 2 ; O; S; and C(R) 2 .
  • X and Y may be independently selected from the group consisting of: O; H; OH; and H 2 .
  • R 1 may be H or CH 3 .
  • Q may be NH.
  • X and Y may be oxygen.
  • W may be a five membered ring of formula (i) or (ii) comprising at least one nitrogen atom. Where E, K and T are present, they may be N or CH.
  • composition that includes a cyclodextrin complexed with a compound of formula I having the structure:
  • W may be selected from the group consisting of formula (i) or (ii) wherein the structures may be as follows:
  • K, E and T may be independently selected from the group consisting of: N, CR, and CZ, and wherein R and Z may be as defined below;
  • K and E may be independently selected from the group consisting of: N, CR and CZ, and wherein R, Z and Q may be as defined below.
  • R 1 may be selected from the group consisting of: R; RCO-; ArCO-; and, ArCH 2 -, wherein Ar may be an aromatic substituent selected from the group consisting of: phenyl, napthyl, anthracyl, phenanthryl, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, imidazole, thiazole, oxazole, and pyridine, and Ar may be optionally substituted with R or Z and R and Z may be defined as below.
  • Ar may be an aromatic substituent selected from the group consisting of: phenyl, napthyl, anthracyl, phenanthryl, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, imidazole, thiazole, oxazole, and pyridine, and Ar may be optionally substituted with R or Z
  • R 2 may be selected from the group consisting of: H; a saturated or unsaturated linear, branched or cyclic, skeleton containing one to ten carbon atoms, in which the carbon atoms may be optionally substituted with a substituent selected from the group consisting of: -OH; -OR 3 ; -O 2 CR 3 ; -SH; -SR 3 ; -SOCR 3 ; -NH 2 ; -NHR 3 ; -NH(R 3 ) 2 ; -NHCOR 3 ; NRCOR 3 ; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CHO; -COR 3 ; -CONH 2 ; -CONHR 3 ; -CON(R 3 ) 2 ; -COSH; -COSR 3 ; -NO 2 ; -SO 3 H; -SOR 3 ; and - SO 2 R 3 , wherein each R 3
  • Each R may be independently selected from the group consisting of: H; and, a structural fragment having a saturated or unsaturated linear, branched or cyclic, skeleton containing one to ten carbon atoms, in which the carbon atoms may be optionally substituted with a substituent selected from the group consisting of: -OH; -OR 3 ; -O 2 CR 3 ; -SH; -SR 3 ; -SOCR 3 ; -NH 2 ; -NHR 3 ; -NH(R 3 ) 2 ; -NHCOR 3 ; NRCOR 3 ; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CO 2 R 3 ; -CHO; -COR 3 ; -CONH 2 ; -CONHR 3 ; -CON(R 3 ) 2 ; -COSH; -COSR 3 ; -NO 2 ; -SO 3 H; -SOR 3
  • Each Z may be independently selected from the group consisting of: H; -OH; -OR; -O 2 CR; -SH;
  • Q may be selected from the group consisting of: NR 2 ; O; S; and C(R) 2 .
  • X and Y may be independently selected from the group consisting of: O; H; OH; and H 2 ; wherein the weight ratio of the compound to cyclodextrin ranges from 1 :10 to 1 :1000, preferably from 1 :50 to 1 :1000, and more preferably from 1 :50 to 1 :500.
  • R 1 may be H or CH 3 .
  • Q may be NH.
  • X and Y may be oxygen.
  • W may be a five membered ring of formula (i) or (ii) comprising at least one nitrogen atom. Where E, K and T, where present, they may be N or CH.
  • a method of producing a water soluble amorphous pharmaceutical composition involves combining a cyclodextrin and a compound of formula I having the structure:
  • W may be selected from the group consisting of formula (i) or (ii) wherein the structures may be as follows:
  • K, E and T may be independently selected from the group consisting of: N, CR, and CZ, and wherein R and Z may be as defined below;
  • K and E may be independently selected from the group consisting of: N, CR and CZ, and wherein R, Z and Q may be as defined below.
  • R 1 may be selected from the group consisting of: R; RCO-; ArCO-; and, ArCH 2 -, wherein Ar may be an aromatic substituent selected from the group consisting of: phenyl, napthyl, anthracyl, phenanthryl, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, imidazole, thiazole, oxazole, and pyridine, and Ar may be optionally substituted with R or Z and R and Z may be defined as below.
  • Ar may be an aromatic substituent selected from the group consisting of: phenyl, napthyl, anthracyl, phenanthryl, furan, pyrrole, thiophene, benzofuran, benzothiophene, quinoline, isoquinoline, imidazole, thiazole, oxazole, and pyridine, and Ar may be optionally substituted with R or Z
  • R 2 may be selected from the group consisting of: H; a saturated or unsaturated linear, branched or cyclic, skeleton containing one to ten carbon atoms, in which the carbon atoms may be optionally substituted with a substituent selected from the group consisting of: -OH; -OR 3 ; -O 2 CR 3 ; -SH; -SR 3 ; -SOCR 3 ; -NH 2 ; -NHR 3 ; -NH(R 3 ) 2 ; -NHCOR 3 ; NRCOR 3 ; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CHO; -COR 3 ; -CONH 2 ; -CONHR 3 ; -CON(R 3 ) 2 ; -COSH; -COSR 3 ; -NO 2 ; -SO 3 H; -SOR 3 ; and - SO 2 R 3 , wherein each R 3
  • Each R may be independently selected from the group consisting of: H; and, a structural fragment having a saturated or unsaturated linear, branched or cyclic, skeleton containing one to ten carbon atoms, in which the carbon atoms may be optionally substituted with a substituent selected from the group consisting of: -OH; -OR 3 ; -O 2 CR 3 ; -SH; -SR 3 ; -SOCR 3 ; -NH 2 ; -NHR 3 ; -NH(R 3 ) 2 ; -NHCOR 3 ; NRCOR 3 ; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CO 2 R 3 ; -CHO; -COR 3 ; -CONH 2 ; -CONHR 3 ; -CON(R 3 ) 2 ; -COSH; -COSR 3 ; -NO 2 ; -SO 3 H; -SOR 3
  • Each Z may be independently selected from the group consisting of: H; -OH; -OR; -O 2 CR; -SH; -SR; -SOCR; -NH 2 ; -NHR; -NH(R) 2 ; -NHCOR; NRCOR; -I; -Br; -Cl; -F; -CN; -CO 2 H; -CO 2 R; -CHO; -COR; -CONH 2 ; -CONHR; -CON(R) 2 ; -COSH; -COSR; -NO 2 ; -SO 3 H; -SOR; and, -SO 2 R.
  • Q may be selected from the group consisting of: NR 2 ; O; S; and C(R) 2 .
  • X and Y may be independently selected from the group consisting of: O; H; OH; and H 2 and wherein the weight ratio of the compound to cyclodextrin ranges from 1:10 to 1:1000, preferably from 1 :50 to 1:1000, and more preferably from 1 :50 to 1 :500.
  • R 1 may be H or CH 3 .
  • Q may be NH.
  • X and Y may be oxygen.
  • W may be a five membered ring of formula (i) or (ii) comprising at least one nitrogen atom. Where E, K and T, where present, they may be N or CH.
  • the method may include the pharmaceutical composition comprising a compound of the formula:
  • the method may include the pharmaceutical composition comprising a compound of the formula:
  • the method may include the pharmaceutical composition comprising a compound of the formula:
  • the method may include the pharmaceutical composition comprising a compound of the formula:
  • the method may include the pharmaceutical composition comprising a compound of the formula:
  • the method may include the pharmaceutical composition comprising a further pharmaceutically acceptable carrier.
  • the method may include the pharmaceutical composition formulated for intravenous administration.
  • the method may include the pharmaceutical composition wherein the particles have a volume-weighted mean particle size of less than 5 ⁇ m.
  • the method may include the pharmaceutical composition wherein the particles have a volume-weighted mean particle size within the range of 0.1 ⁇ m and 50 ⁇ m.
  • the method may include the pharmaceutical composition wherein the particles have a volume-weighted mean particle size of less than 10 ⁇ m.
  • the method may include the pharmaceutical composition wherein the particles have a volume-weighted mean particle size of less than 25 ⁇ m.
  • Particle size may be measured using one or more of the methods known in the art.
  • Particle size may be measured using laser diffraction.
  • the method may include cyclodextrin selected from one or more of the following: a hydropnilic ⁇ -cyclodextrin derivative; a hydrophobic ⁇ -cyclodextrin; an ionaizable ⁇ -cyclodextrin derivative; an ⁇ -cyclodextrin; and a ⁇ -cyclodextrin.
  • cyclodextrin selected from one or more of the following: a hydropnilic ⁇ -cyclodextrin derivative; a hydrophobic ⁇ -cyclodextrin; an ionaizable ⁇ -cyclodextrin derivative; an ⁇ -cyclodextrin; and a ⁇ -cyclodextrin.
  • the method may include cyclodextrin selected from one or more of the following: methylated ⁇ -cyclodextrin; hydroxyalkylated ⁇ -cyclodextrin; branched ⁇ -cyclodextrin; alkylated ⁇ -cyclodextrin; acylated ⁇ -cyclodextrin; anionic ⁇ -cyclodextrin; ⁇ -cyclodextrin; and a ⁇ -cyclodextrin.
  • the method may include 2-hydroxypropyl- ⁇ -cyclodextrin (HPCD).
  • the method may include the addition of a water-soluble compound for inducing osmosis.
  • the water-soluble compound or inducing osmosis may be isotonic.
  • the water-soluble compound for inducing osmosis may be comprised of one or more of the following: sodium chloride, mannitol, dextrate, and dextrose.
  • the water-soluble compound for inducing osmosis may be selected from: 0.9% sodium chloride and 5% dextrose.
  • the method may include a solution formed in an aqueous medium.
  • the method may comprise stabilizing the water soluble amorphous pharmaceutical composition with one or more of: ultrasound energy; heat; elevated pressure; and mechanical agitation.
  • stabilizing the water soluble amorphous pharmaceutical composition may include the use of ultrasound energy.
  • stabilizing the water soluble amorphous pharmaceutical composition may include elevation of the water soluble amorphous pharmaceutical composition to a temperature of between about 4O 0 C and about 70 0 C.
  • the mechanical agitation may include stirring.
  • Figures IA and IB are illustrations displaying the chemical structures of isogranulatimide (IA); and the chemical structures of granulatimide (IB).
  • Figure 2 are graphs displaying the effect of isogranulatimide and topotecan on cell lines TOV-21G and TOV-112D.
  • Figure 3 is a graph displaying the effect of isogranulatimide and topotecan on the cell line TOV-21G in the presence of DMSO and HPCD.
  • Figure 4 is a graph displaying the effect of isogranulatimide and irinotecan on the cell line HCT-116 in the presence of DMSO and HPCD.
  • Figure 5 is a graph displaying the effect of isogranulatimide and topotecan on the cell line TOV-21G.
  • Figure 6 is a graph displaying the effect of isogranulatimide and topotecan on the cell line HCT-116.
  • Granulatimide, isogranulatimide, derivatives thereof and pharmaceutical formulations thereof are described in PCT WO 99/47522.
  • These compounds include the naturally occurring compounds, granulatimide and isogranulatimide, which may be in purified or partially purified form, including extracts containing these compounds taken from naturally occurring sources (for example, Didemnum granulatum). Alternatively, these compounds may be synthesized or partially synthesized from purified extracts.
  • These compounds may be useful as a cytotoxic agents, as a protein kinase inhibitors, or as G2 checkpoint inhibitors.
  • the compounds may be used to sensitize cells to the effects of DNA damaging agents; and the use of such compounds in the formulation of agents, including medicaments.
  • Cyclodextrins are a family of cyclic oligosaccharides, which are linked via ⁇ -1,4 linkages. Depending upon the number of units, cyclodextrins can be classified as ⁇ -cyclodextrin, a six- membered oligosaccharide; ⁇ -cyclodextrin, a seven-membered oligosaccharide; and ⁇ - cyclodextrin, an eight-membered oligosaccharide. As described generally in Davis, M.E. and
  • cyclodextrins may include glucosyl- ⁇ -cyclodextrin, maltosyl- ⁇ -cyclodextrin, dimaltosyl- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, 2- hydroxypropyl- ⁇ -cyclodextrin, sulphobutylether- ⁇ -cyclodextrin, randomly methylated- ⁇ - cyclodextrin, and 2-hydroxypropyl- ⁇ -cyclodextrin.
  • skeleton refers to a group of atoms that make up the main atomic chain or ring of a chemical moiety.
  • the main atomic chain or ring does not include atoms that are substituents on those atoms.
  • methane has a main atomic chain consisting of 1 carbon atom and 4-methyl-pentane has main atomic chain consisting of 5 carbon atoms.
  • a skeleton containing one to ten carbon atoms contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the main atomic chain or ring, but the chemical moiety that comprises the skeleton, may have more than 10 atoms in total.
  • the chemical moiety may have more than 10 carbon atoms in total.
  • 1 -ethyl, 5-chloro-cyclodecane are all examples of chemical moieties that each comprise a skeleton having 1 to 10 carbon atoms.
  • the functional groups conjugated to the compound may be a biological delivery and targeting molecule.
  • biological delivery and targeting molecules are those that bind to a specific biological substance or site.
  • the biological substance or site is the intended target of the biorecognition molecule that binds to it, enabling the delivery of the compound to the tissue or cells of interest (for example, neoplastic colon or neoplastic ovary).
  • Targeting of the compound may be accomplished by conjugating it to a biological delivery and targeting molecule. Examples of biological delivery and targeting molecules are described below.
  • a ligand may function as a biological delivery and targeting molecule by selectively binding or having a specific affinity for another substance.
  • a ligand is recognized and bound by a specific binding body or binding partner, or receptor.
  • ligands suitable for targeting are antigens, haptens, biotin, biotin derivatives, lectins, galactosamine and fucosylamine moieties, receptors, substrates, coenzymes and cofactors among others.
  • a ligand may include cancer and tumor antigens such as alpha-fetoproteins, prostate specific antigen (PSA) and CEA, cancer markers and oncoproteins, among others.
  • Other substances that can function as ligands for delivery and targeting are certain steroids, prostaglandins, carbohydrates, lipids, certain proteins or protein fragments (i.e. hormones, toxins), and synthetic or natural polypeptides with cell affinity.
  • Ligands may also include various substances with selective affinity for ligators that may be produced through recombinant DNA, genetic and molecular engineering.
  • Another type of delivery and targeting molecule may be an antibody, which is defined to include all classes of antibodies, monoclonal antibodies, chimeric antibodies, Fab fractions, fragments and derivatives thereof.
  • Other delivery and targeting molecules include enzymes, especially cell surface enzymes such as neuraminidases, plasma proteins, avidins, streptavidins, chalones, cavitands, thyroglobulin, intrinsic factor, globulins, chelators, surfactants, organometallic substances, staphylococcal protein A, protein G, cytochromes, lectins, certain resins, and organic polymers.
  • Delivery and targeting molecules may also include various substances such as any proteins, protein fragments or polypeptides with affinity for the surface of any cells or tissues to be targeted by the compound. These proteins may be produced through recombinant DNA, genetic and molecular engineering techniques know in the art. Any suitable membrane transfer proteins to facilitate the transfer of the compound to the target cell interior may be of particular use.
  • Delivery and targeting molecules may not only be desirable for delivery to a target cell or tissue but may also to facilitate the transport of the compound into a cell.
  • U.S. Pat. No 6,204,054 describes the use of transcytosis vehicles and enhancers capable of transporting physiologically-active agents across epithelia, endothelia and mesothelia containing the GP60 receptor.
  • the GP60 receptor has been implicated in receptor-mediated transcytosis of albumin across cell barriers.
  • U.S. Pat. No 6,204,054 exploits GP60 receptor-mediated transcytosis for the transport of physiologically-active agents which do not naturally pass through epithelia, endothelia and mesothelia via the GP60 system.
  • a compound can be coupled to albumin, albumin fragments, anti-GP60 polyclonal and monoclonal antibodies, anti-GP60 polyclonal and monoclonal antibody fragments, and GP60 peptide fragments to facilitate transport into the cell.
  • the conjugation to a functional group may also improve other properties of the compound.
  • Such functional groups are often termed drug carriers and can improve the stability, solubility or biocompatibility of the drug being carried.
  • 4,675,381 describes a polyaspartate and/or polyglutamate polymer as a drug carrier.
  • This patent suggests the use of polyaspartate and/or polyglutamate polymers as drug carriers wherein the drug is encapsulated or incorporated in the matrix of the polymer.
  • U.S. Pat. No. 5,087,616 describes the use of a biodegradable polymeric carrier to which one or more cytotoxic molecules, such as daunomycin is conjugated.
  • the biodegradable polymeric carrier is specified to be, for example, a homopolymer of polyglutamic acid.
  • U.S. Pat. No. 4,960,790 describes the anti-tumor agent taxol covalently conjugated to an amino acid (glutamic acid).
  • U.S. Pat. No. 5,420,105 describes the use of polypeptide carriers that are capable of binding one drug or multiple drugs.
  • the polypeptide carrier may be further attached to a targeting or delivery protein, such as an antibody or ligand capable of binding to a desired target site in vivo.
  • U.S. Pat. No. 6,127,349 describes the use of phospholipids to improve the solubility of the therapeutic agents (steroids, peptides, antibiotics and other biologically active agents and pharmaceutical formulations) and to improve their bio-availability.
  • fatty acids could be conjugated to the compound in order to stabilize the activity of the anti-angiogenic substances.
  • U.S. Pat. No. 6,380,253 describes the conjugation of anti-angiogenic substances (proteins - angiostatin and endostatin etc.) to cis unsaturated fatty acids or polyunsaturated fatty acids to potentiate and stabilize the activity of the anti-angiogenic substances.
  • Other suitable drug carriers include Polyethylene glycol (PEG) and related polymer derivatives.
  • EP 1082105 (WO9959548) describes the use of biodegradable polyester polymers as a drug delivery system to facilitate controlled release of the conjugated drug.
  • the compound may be conjugated to another pharmaceutically active compound to enhance the therapeutic effect on the target cell or tissue by delivering a second compound with a similar anti-mitotic effect or a different activity altogether.
  • US 6,051,576 describes the use of co-drug formulations by conjugating two or more agents via a labile linkage to improve the pharmaceutical and pharmacological properties of pharmacologically active compounds.
  • conjugation can be through noncovalent or attractive binding as with an antigen and antibody or biotin and avidin.
  • Noncovalent coupling is binding between substances through ionic or hydrogen bonding or van der waals forces, and/or their hydrophobic or hydrophilic properties.
  • conjugation may be through covalent, electron-pair bonds or linkages.
  • Many methods and agents for covalent conjugation (or crosslinking) are known and, with appropriate modification, can be used to conjugate the desired substances to the compound.
  • linkages may be amide bonds, peptide bonds, ether bonds, and thio ether bonds, among others.
  • Topoisomerase I is an essential human enzyme that is required for the unwinding of double-stranded DNA during processes such as DNA synthesis or transcription.
  • the alkaloid captothecin from which the clinically approved derivatives topotecan and irinotecan were derived, is a potent inhibitor of topoisomerase I that causes double-stranded DNA breaks.
  • Topotecan and irinotecan are used as anti-cancer agents in several solid tumor indications (Pommier, Y. (2006) Nat. Rev. Cancer 6, 789 802).
  • DNA damaging agents include topoisomerase II inhibitors such as etoposide and doxorubicin also function by inhibiting proper DNA unwinding (Nitiss, J.L (2002) Curr. Opin. Investig. Drugs 3, 1512 1516), DNA alkylating agents such as mitomycin C (Tomasz, M. and Palom, Y. (1997) Pharmacol. Ther. 76, 73 87); and DNA damage by UV or gamma irradiation.
  • topoisomerase II inhibitors such as etoposide and doxorubicin also function by inhibiting proper DNA unwinding
  • DNA alkylating agents such as mitomycin C (Tomasz, M. and Palom, Y. (1997) Pharmacol. Ther. 76, 73 87)
  • DNA damage by UV or gamma irradiation include UV or gamma irradiation.
  • compositions and conjugations set out herein may be made as set out below to enhance the properties of the pharmaceutical compositions.
  • Humans, and other animals, in particular, mammals, suffering from proliferative diseases, and other similar conditions may be treated by administering an effective amount of one or more of the above- identified pharmaceutical compositions or a pharmaceutically acceptable derivative or salt thereof in a pharmaceutically acceptable carrier or diluent.
  • the active materials may be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, or subcutaneously.
  • salts or complexes may refer to salts or complexes that retain the desired biological activity of the above-identified compounds and exhibit minimal undesired toxicological effects.
  • Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount suffcient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
  • a dose of the active compound for the above-mentioned conditions may be in the range from about 0.5 to 500 mg/kg, or 1 to 100 mg/kg per day.
  • the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 1 to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form.
  • An oral dosage of 25-250 mg is often convenient.
  • the active ingredient may be administered to achieve peak plasma concentrations of the active compound of about 0.1 to 100 ⁇ M, or about 1-10 ⁇ M. This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient.
  • the concentration of active compound in the drug composition may depend on absorption, distribution, inactivation/metabolism, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of toxicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents such as
  • carriers may be physiological saline or phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the active compound can also be administered through a transdermal patch.
  • Methods for preparing transdermal patches are known to those skilled in the art. For example, see Brown L., and Langer R., Transdermal Delivery of Drugs, Annual Review of Medicine, 39:221-229 (1988).
  • the active compounds may be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in US patent 4,522,811.
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine stearoyl phosphatidyl choline, arachadoyl phosphatidy choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, and/or triphosphate derivatives are then introduced into the container. The container is then swirled by hand to free the lipid aggregates, thereby forming the liposomal suspension.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine stearoyl phosphatidyl choline, arachadoyl phosphatidy
  • Oral compositions may include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • compositions such as in a coating of hard gelatin
  • Suitable pharmaceutically acceptable carriers for parenteral application include sterile water, physiological saline, bacteriostatic saline (saline containing 0.9 mg/ml benzyl alcohol) and phosphate-buffered saline.
  • the active compound or pharmaceutically acceptable salt or derivative thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active compound or pharmaceutically acceptable derivatives or salts thereof can also be administered with other active materials that do not impair the desired action, or with materials that supplement the desired action.
  • Particle size spectrophotometry uses visible and ultra-violet light to differentiate between very similar particle sizes in multi-modal distributions. Particle size spectrophotometry measures light scattered at a fixed angle as a function of its wavelength. By using a wide range of wavelengths of ultra-violet to visible light (for example, 190 run to 1100 nm) it is possible to measure a wide range of particles from 5 nm to 15 ⁇ m.
  • Dynamic light scattering (DLS) or photon correlation spectroscopy (PCS) is capable of precision particle size measurements from 0.5 nm to 6 ⁇ m.
  • This method measures the intensity of light scattered in a particular direction by particles in a sample. The intensity of scattered light changes with time, due to the Brownian motion of particles in the suspension.
  • instruments obtain a correlation factor from the intensity versus time profile.
  • the exponentially decaying correlation function is related to diffusion coefficients, and using the Stokes-Einstein equation and these coefficients the instrument can calculate the particle radius. It is an absolute measurement (i.e. knowledge of the particle composition is not needed) and can measure particles ranging in size from 0.5 nm to 6 ⁇ m.
  • Laser Diffraction is a method for measuring particle sizes in a suspension. This method is usually used to measure the sizes of particles of a few ⁇ m to 1000's of ⁇ m. A laser is used to scatter light off particles in a dilute suspension. A lens focuses the scattered light on a detector and the intensity of light at various angles on the detector can be correlated using the Mie scattering effect to determine the particle size.
  • Single particle optical sizing SPOS
  • OPC optical particle counting
  • the size of a particle determined by a given technique may vary from another technique, due to the use of the equivalent sphere approximation.
  • Equivalent sphere approximation is often used to derive a single diameter that is indicative of the size, and depending on the technique may provide different size distributions.
  • Different techniques measure different particle properties (for example, sedimentation rate, light scattering patterns, or projected image size) and it is accordingly important to consider the non-sphericity and statistical representations when comparing the results of different methods.
  • a non-spherical particle may affect a measurement in different ways depending on the physical property being measured in order to derive the particle size.
  • particle sizing standard reference materials (which tend to be spherical) may be used so that similar results can then be generated by multiple techniques or alternatively, particle sizing standard reference materials may be used to optimize settings and analysis.
  • the statistical representations will likely vary when different techniques are used. Such statistical representations may apply different weightings to the particles within the distribution. For example, one technique may measure the number of particles of a given size whereas another may measure the mass of particles and may affect the shape reported size distribution and the technique's sensitivity to changes in the distribution width.
  • EXAMPLE 1 The ability of isogranulatimide to enhance the cytotoxic effect of topotecan was measured in ovarian cancer cells.
  • Two human ovarian cancer cell lines derived from chemotherapy-naive patients were utilized that have been previously characterized in terms of their morphology, tumorigenicity, and global expression profiles.
  • these analyses revealed that these cell lines were excellent models for in vivo behavior of ovarian tumors in humans (Provencher D.M. et al, (2000) In Vitro Cell. Dev. Biol Anim. 36, 357 361; Samouelian V. et ah, (2004) Cancer Chemother. Pharmacol. 54, 497 504).
  • These cell lines are designated TOV-21G and TOV-112D.
  • a lO mg/ml stock solution of isogranulatimide was prepared in 100% DMSO.
  • 4,000 cells/well TOV-21G or TOV-112D cells were seeded in 48-well plates and allowed to adhere overnight at 37°C in 5% CO 2 .
  • the cells were treated with 10 or 5 nM topotecan for 16 hours to induce DNA damage.
  • the cells were incubated for 3 days in the presence of 5 ⁇ M isogranulatimide after which the cell number was determined spectrophotometrically by MTT assay at 570 nm (Mosmann, T. (1983) J. Immunol. Methods 65, 55 63).
  • a comparative study was performed to ascertain the efficacy of isogranulatimide formulated in HPCD compared to isogranulatimide resuspended in DMSO.
  • the complexation reaction that resulted in the formulation of isogranulatimide in cyclodextrins can be accomplished as follows: 5 grams of solid HPCD (SigmaTM #H107) was resuspended in sterile water containing 5% dextrose (D5W, Baxter CorporationTM #JB0062) until complete dissolution after which the volume was increased to exactly 50 ml. This solution was filter sterilized through a 0.22 micron filter.
  • the chemosensitizing activity of the isogranulatimide-HPCD formulation was tested in ovarian cancer cells and directly compared with isogranulatimide resuspended in DMSO.
  • 4,000 cells/well TOV-21G cells were seeded in 48-well plates and allowed to adhere overnight at 37°C in 5% CO 2 .
  • the cells were treated with 10 nM topotecan for 16 hours. Following this treatment, the cells were incubated for 3 days in the presence of isogranulatimide at the indicated concentrations after which the cell number was determined spectrophotometrically by MTT assay at 570 nm.
  • the isogranulatimide that was complexed with HPCD was significantly more active than the compound resuspended in DMSO.
  • the maximum percentage of inhibition by isogranulatimide was achieved at the lowest concentration used in this example.
  • the data represents the mean of at least 2 experiments conducted separately ⁇ SEM.
  • isogranulatimde was also assessed in a colon carcinoma cell line (ATCC #CCL-247).
  • the experiment of Example 2 was repeated with the colon cancer cell line under very similar conditions except irinotecan replaced topotecan as the DNA damaging agent.
  • isogranulatimide was more active when formulated in cyclodextrin (see Figure 4).
  • the data represents the mean of at least 2 experiments conducted separately ⁇ SEM.

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Abstract

La présente invention concerne des formulations de complexes amorphes de composés de formule (I), tels que l’isogranulatimide ou la granulatimide, avec au moins une cyclodextrine. Lesdites formulations renferment en outre un composé hydrosoluble destiné à induire une osmose, tel que le dextrose et/ou le chlorure de sodium. L’invention a également pour objet des procédés  de préparation des formulations mentionnées précédemment et des procédés de délivrance dans des applications in vitro et in vivo. Les formulations peuvent être appropriées pour des indications cancéreuses où l’on souhaite amplifier l’efficacité cytotoxique de médicaments anticancéreux tels que des agents endommageant l’ADN ou antimitotiques. En outre, ces formulations peuvent être appropriées pour des indications cancéreuses où l’on souhaite augmenter l’efficacité de la radiothérapie. Dans les composés de formule (I), W est défini comme étant un groupe de formule (i) ou (ii) dans laquelle K, E et T représentent indépendamment N, CR ou CZ ; Q représente NR2, O, S ou C(R)2 ; R1 représente R, RCO- ou ArCO- ; X et Y représentent O, H, OH ou H2 et R, Z, R2 et Ar sont tels que définis dans la revendication 1.
PCT/CA2009/000495 2008-04-15 2009-04-15 Complexes d’isogranulatimide et de granulatimide avec une cyclodextrine, formulations et utilisation pour le traitement du cancer WO2009127059A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827307A (zh) * 2011-06-17 2012-12-19 首都医科大学 β-环糊精修饰的四氢-β-咔啉羧酸衍生物及其制备方法和应用
CN103450371A (zh) * 2012-06-01 2013-12-18 首都医科大学 四氢-β-咔啉-3-甲酰基-二乙烯三胺-β-环糊精，其制备，抗血栓活性和应用

Citations (1)

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WO1999047522A1 (fr) * 1998-03-13 1999-09-23 The University Of British Columbia Derives de granulatimide utilises dans le traitement du cancer

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WO1999047522A1 (fr) * 1998-03-13 1999-09-23 The University Of British Columbia Derives de granulatimide utilises dans le traitement du cancer

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827307A (zh) * 2011-06-17 2012-12-19 首都医科大学 β-环糊精修饰的四氢-β-咔啉羧酸衍生物及其制备方法和应用
CN103450371A (zh) * 2012-06-01 2013-12-18 首都医科大学 四氢-β-咔啉-3-甲酰基-二乙烯三胺-β-环糊精，其制备，抗血栓活性和应用

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