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WO2009060218A1 - Nouveaux complexes et procédé de préparation de ces derniers - Google Patents

Nouveaux complexes et procédé de préparation de ces derniers Download PDF

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Publication number
WO2009060218A1
WO2009060218A1 PCT/GB2008/003770 GB2008003770W WO2009060218A1 WO 2009060218 A1 WO2009060218 A1 WO 2009060218A1 GB 2008003770 W GB2008003770 W GB 2008003770W WO 2009060218 A1 WO2009060218 A1 WO 2009060218A1
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Prior art keywords
complex
polymer
active ingredient
group
hydrolysis
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English (en)
Inventor
Stephen Brocchini
Antony Godwin
Karola Les
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Abzena UK Ltd
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Polytherics Ltd
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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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel soluble complexes of insoluble active ingredients and a process for making them.
  • WO 2005/065712 discloses novel complexes comprising a narrow molecular weight distribution polymer that includes units derived from an acrylic acid or a salt thereof, and (i) a substance that has pharmacological activity against a pathogenic organism, or (ii) a substance that has pharmacological activity against a cancer, or (iii) one or more agents selected from antigens and immunogens.
  • the invention of WO 2005/065712 rests upon the fact that such complexes demonstrate improved biological efficacy by generating an unusual immune response.
  • the present invention provides a process for the solubilisation of an active ingredient having a solubility in water of pH 6 or greater, of less than 5mg/ml, which comprises complexing said active ingredient with a polymer which comprises units derived from an acrylic acid or a salt thereof; provided that the active ingredient is not amphotericin B.
  • the complexes prepared by the process according to the invention are novel, and the invention therefore provides these complexes per se.
  • the invention also provides a pharmaceutical or cosmetic preparation which comprises a complex of the present invention in admixture or conjunction with a pharmaceutically or cosmetically suitable carrier; a complex of the present invention for use as a medicament; and a method of treating a patient which comprises administering an effective amount of a complex according to the present invention to a patient in need of treatment.
  • the active ingredients to be solubilised by the present invention have a solubility in water having a neutral or basic pH, of less than 5 mg/ml, preferably less than lmg/ml.
  • the present invention has been found to be particularly useful for certain classes of highly insoluble active ingredients. In particular, it is useful for the solubilisation of insoluble materials having a molecular weight of less than 900Da.
  • the active ingredient does not contain free primary amine groups, and preferably it also does not contain free secondary amine groups.
  • One preferred active ingredient for use in the present invention is 7-ethyl-10- hydroxycamptothecin, also known as SN38, a cancer drug, which has the structure:
  • a further preferred active ingredient for use in the present invention is imatinib mesylate (available under the Trade Mark Gleevec), (a cancer drug) which has the structure:
  • a further preferred active ingredient for use in the present invention is artemisinin, (a cancer drug also having anti-malarial properties) which has the structure:
  • a further preferred active ingredient for use in the present invention is coenzyme QlO, (a food supplement and immunogen) which has the structure:
  • active ingredients which may be used with benefit in the present invention include progesterone, dextazoxone, hydroxytaxenones e.g. taxol, beclamethasone, fiumethasone, diethylstilbestrol, and the compounds of the following formulae:
  • the polymer used in the present invention preferably has a narrow molecular weight distribution, preferably corresponding to a polydispersity of 1.7 or less, for example 1.6 or less, for example 1.5 or less, for example 1.4 or less, for example 1.2 or less, for example less than 1.7, for example less than 1.6, for example less than 1.5, for example less than 1.4, for example, less than 1.2.
  • a polydispersibility of less than 1.2 is generally preferred.
  • the polymer preferably has a number average molecular weight of less than 100,000.
  • the exact molecular weight should be such that, when present in the blood, the polymer remains substantially in the circulating blood after passage through the kidney, with little or none of the polymer undergoing filtration through the glomerular apparatus, but can readily leave the blood circulation into the tissue.
  • Renal filtration also known as glomerular filtration
  • of large molecules is a function inter alia of the size and shape of the molecule, which is dependent in part on the molecular weight.
  • the threshold molecular weight for any particular polymer may be determined by standard tests, for example, using a radiolabeled polymer.
  • the molecular weight of the polymer may for example be 80,000 or less, for example 75,000 or less, for example 65,000 or less, for example 55,000 or less, for example 45,000 or less.
  • the polymer generally has a molecular weight of 4,000 or more, for example, 5,000 or more, for example, 10,000 or more, for example, 20,000 or more, for example, 30,000 or more, for example, 40,000 or more.
  • a polymer may have a molecular weight within a range that combines any of the upper molecular weight values given above with any of the lower molecular weight values given above. Examples of such ranges include but are not limited to ranges of from 80,000 to 4,000, 75,000 to 5,000, 65,000 to 10,000, 55,000 to 10,000, and 45,000 to 10,000. Further examples include the ranges from 50,000 to 4,000, for example, from 40,000 to 25,000. Molecular weights in the range of from 10,000 to 45,000 may be preferred.
  • a complex is an association between a polymer and an active ingredient, the association between the components being non-covalent. It may for example involve any one or more of ionic, electrostatic and van der Waals forces. Although a complex predominantly involves non-covalent association between the components, there may nevertheless be some covalent bonding.
  • the term "complexing" should be construed accordingly, i.e. as the reaction between a polymer and an active ingredient under conditions such that a complex (as opposed to a covalently-bonded conjugate) is formed.
  • the term "active ingredient" should be understood to include any relevant biologically active material intended for pharmaceutical, nutraceutical or cosmetic use.
  • the active ingredient may be a drug intended for pharmaceutical use, a nutritional supplement, a vitamin, or an ingredient for a cosmetic preparation.
  • the insoluble active ingredient is a drug, it may be for example a substance that has pharmacological activity against a pathogenic organism, or a substance that has pharmacological activity against a cancer, or an antigen or immunogen.
  • the complex of the invention may be administered by any suitable means known in the art.
  • a pharmaceutical preparation of the invention may be in a form suitable for administration intravenously, intra-arterially, into the lymphatic circulation, into a lymph node, orally, intraperitoneally, topically, buccally, rectally, to the surface of the skin, transdermally, subcutaneously, intramuscularly, into the joint space, intranasally, intravitreally, or pulmonarily, directly to an organ, around an organ, by injection into an organ, or by direct infusion through an organ.
  • the present invention includes administration of a complex in accordance with the invention by any of such routes.
  • a pharmaceutical preparation of the invention may be in the form of a depot or reservoir preparation, or an aerosol preparation.
  • Suitable formulations for that above and other routes of administration are known in the art, see for example, Remington's Pharmaceutical Sciences by E. W. Martin. See also Wang, Y. J. and Hanson, M. A., Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S, 1988.
  • a complex of the invention may be "particulate associated". Such particulates may be produced by emulsion, homogenisation and spray drying processes, which are known in the art. For a review of such formulations see for example, Hanes J, Cleland JL & Langer R, Advanced Drug Delivery Reviews 28 (1997) 97-119. Pharmaceutical compositions comprising such particulate associated complexes of the invention may be administered mucosally by a pulmonary or nasal route, by ingestion, or by a non-mucosal parenteral route, especially subcutaneously or intramuscularly.
  • the concentration of the complex may be, for example, from 0.1 to 100 mg/ml, for example, from 1 to 50 mg/ml.
  • the loading of the active drug may be, for example, from 5 to 80%, for example from 10 to 50%, e.g. from 30 to 60%, by weight.
  • Other formulations may comprise the polymer in analogous amounts, for example, calculated on the basis of the liquid preparations.
  • Topical preparations may for example be in the form of solutions, suspensions, emulsions, lotions, creams, gels or foams. Any suitable solid, liquid or unit dosage form may be used when oral administration is required.
  • the polymer used in the present invention may be either a homopolymer or copolymer of an acrylic acid, for example, of acrylic acid or methacrylic acid or a salt thereof. It may be a polymer comprising a unit (I)
  • R is selected from the group consisting of hydrogen and Ci-Ci 8 alkyl, C 2 -Ci 8 alkenyl, C 7 -Ci 8 aralkyl, C 7 -Ci 8 alkaryl, C 6 -Ci 8 aryl, -CO 2 H, C 2 -Ci 8 alkoxycarbony, C 2 - Cisalkaminocarbonyl, or any one of Ci-Ci 8 alkyl, C 2 -Ci 8 alkenyl, C 7 -Ci 8 aralkyl, C 7 - Cisalkaryl, C 6 -Ci 8 aryl, C 2 -Ci 8 alkoxycarbony, C 2 -Ci 8 alkaminocarbonyl, substituted with a heteroatom within, or attached to, the carbon backbone; and R 1 is selected from the group consisting of hydrogen and Ci-C 6 alkyl groups; and salts thereof, for example, alkali metal salts, for example, sodium salts, or am
  • R is selected from the group consisting of hydrogen, Ci-C ⁇ alkyl, Ci-C 6 alkenyl, Ci-Qaralkyl, Ci-C 6 alkaryl, Ci-C 6 alkylamido, d-C 6 alkylimido and -CO 2 H.
  • R is hydrogen, methyl or -CO 2 H, especially hydrogen or -CO 2 H.
  • R 1 is, independently of R, hydrogen, methyl or ethyl. In particular R is hydrogen and R 1 is methyl.
  • block copolymers that include units derived from an acrylic acid or a salt thereof include block copolymers comprising the unit (II)
  • R, R 1 are defined as above and R 2 is a bond
  • R 3 is selected from the group consisting of Ci-C 18 alkylene, C 2 -Ci 8 alkenylene, C 7 -C
  • L is a divalent linker joining the blocks
  • m and n is each an integer 1 or greater than 1.
  • R and R 1 have the meanings given above.
  • the groups R 3 which may be the same or different, are selected from the group consisting of Ci-C 8 alkylene groups, preferably 1,2-alkylene, and C 6 -Ci 2 arylene groups, most preferably methylene, ethylene, 1,2-propylene and 1,3 -propylene.
  • all groups R 3 are the same, most preferably all are 1,2-ethylene or 1,2-propylene.
  • L preferably comprises a C]-C 18 alkylene or C 6 -Ci 8 arylene group which may be substituted and/or interrupted with one or more heteroatoms.
  • L comprises a group selected from the group consisting Of Ci-C 6 alkylene, C 6 -C 12 arylene, C 1 -C 12 oxyalkylene and C 1 -C 6 acyl.
  • L comprises an alkylene group, it can be branched, linear or cyclical, substituted or unsubstituted with one or more alkyl groups, and is preferably methylene, 1,2-ethylene, 1,2-propylene, 1,3-propylene, tert butylene, see butylene, hexylene or octylene.
  • L comprises an arylene group, it is preferably benzylene, tolylene or xylylene. Most preferably L comprises a - COR a group, wherein R a is selected from the group consisting of C 1 -C 6 alkylene or C 6 -C 12 arylene, preferably methylene, 1,2-ethylene, 1,2-propylene, 1, 3 -propylene, tert butylene and sec butylene.
  • a polymer may be a homopolymer incorporating unit (I) or may be a copolymer or block copolymer incorporating other polymeric, oligomeric or monomelic units, for example, a block copolymer comprising units (II) as described above.
  • further polymeric units incorporated in a homopolymer or copolymer or block copolymer may comprise acrylic polymers, alkylene polymers, urethane polymers, amide polymers, polypeptides, polysaccharides and ester polymers.
  • additional polymeric components comprise polyethylene glycol, polyaconitic acid or polyesters.
  • a polymer having units (I) or (II) may also comprise further units that enable, for example, solubilisation of the precursor polymer and/or that enable control of the number of free acrylate acid groups (and hence salt-forming groups) in the polymer to be used according to the invention.
  • a polymer comprising units (I) may have the structure (III) or (IV)
  • R, R 1 , R 2 and R 3 , L, m and n are defined as above, R 4 , R 5 and R 6 are selected, independently, from the same groups as R, R 1 and R 2 , respectively;
  • Q denotes a group that is not cleaved or is not substantially cleaved under the conditions used to produce the polymer; and
  • p denotes an integer 1 or greater than 1.
  • Q may be a targeting group, i.e. a group that targets the polymer to a cell type, eg macrophages, or to an organ eg the liver.
  • Q may be, for example, selected from the group consisting of Ci-Ci 2 alkyl, C 2 -C 12 alkenyl, C 7 -Ci 2 aralkyl, C 7 -Ci 2 alkaryl, Ci-Ci 2 alkoxy, Ci-Ci 2 hydroxyalkyl, Ci- Ci 2 alkylamino, Ci-Ci 2 alkanoyl, Cj-C] 2 aminoalkyl or any one OfCi-Ci 2 alkyl, C 2 -Cj 2 alkenyl, C 7 -Ci 2 aralkyl, C 7 -Ci 2 alkaryl, Ci-Ci 2 alkocxy, Ci-Ci 2 hydroxyalkyl, C 1 - C 12 alkylamino, Ci-Ci 2 alkanoyl substituted with an amine, hydroxyl or thiol group.
  • Q comprises an amine group, for example, a Ci-Ci 2 hydroxyalkylamino group, for example, a
  • the group Q may be a solubilising group for the polymer in aqueous solutions.
  • the polymer may be a water soluble polyacrylamide homo-or copolymer, preferably a polymethacrylamide or polyethacrylamide homo- or copolymer.
  • the presence of the groups Q enables control of the number of free acrylate acid groups (and hence salt- forming groups) in the polymer.
  • the proportion of the Q-containing units relative to the number of leaving group X-containing units in the precursor polymer may be selected.
  • the relative proportion of the Q-containing units relative to the number of leaving group X-eontaining units will determine the number of acrylate acid or salt groups in the polymer product.
  • the polyanionic nature of the polymer may influence its biological activity. The ability to manipulate the ionic nature of the polymer is therefore useful in producing a polymer having desired properties.
  • the polymer preferably includes units derived from methacrylic acid or a salt thereof, for example, a polymethacrylic acid or a salt thereof, for example a sodium salt thereof.
  • the polymer may, for example, be a polymethacrylic acid having a polydispersibility and molecular weight as given above.
  • the polymer used in a complex of the invention is a polymethacrylic acid (PMAA) or a salt thereof, for example, a sodium salt, having a polydispersity of less than 1.4, preferably less than 1.2.
  • the polymer used in the Examples herein is polymethacrylic acid, sodium salt, which was produced in Examples 1 to 4 by hydrolysis of poly(N-methacryloxysuccinimide) (PMOSu) using sodium hydroxide.
  • PMAA polymethacrylic acid
  • a salt thereof for example, a sodium salt
  • the polymer used in the Examples herein is polymethacrylic acid, sodium salt, which was produced in Examples 1 to 4 by hydrolysis of poly(N-methacryloxysuccinimide) (PMOSu) using sodium hydroxide.
  • PMOSu poly(N-methacryloxysuccinimide)
  • a polymer for use according to the invention may be produced by a method involving hydrolysis of a precursor polymer using a basic agent, for example, an alkali metal or alkaline earth metal base, for example, a sodium, potassium, caesium, calcium, magnesium, or lithium base.
  • a basic agent for example, an alkali metal or alkaline earth metal base, for example, a sodium, potassium, caesium, calcium, magnesium, or lithium base.
  • a base may be, for example, a hydroxide, carbonate or hydrogen carbonate, for example, sodium hydroxide.
  • the precursor polymer may be PMOSu, or it may be another suitable precursor polymer, for example, a precursor polymer as described below.
  • the hydrolysis is suitably carried out in the presence of a suitable solvent.
  • Aqueous/organic systems for example using an organic solvent in which the precursor polymer is soluble, and aqueous base, are generally preferred.
  • Suitable organic solvents include, for example, DMF, DMSO, DMPU or dimethylactamide. Mixtures of organic solvents, for example DMSO/acetone, may be used.
  • the hydrolysis may be carried out under mild conditions, for example, ambient temperature and pressure and gentle heating, for example, 40 to 6O 0 C, for example for 2 to 16 hours, or stronger conditions may be used.
  • the PMOSu used as the precursor polymer in the production of PMAA-Na may for example be produced as described in WO 01/18080 and WO 2005/065712 by homogeneous polymerisation of methacryloxysuccinimide using an atom transfer radical polymerisation method, for example a copper mediated method.
  • a polymer for use in the invention may be produced by hydrolysis of a corresponding precursor polymer that has, in place of the hydrogen atom of the acrylate carboxylic acid in the units derived from an acrylic acid, a group that can be cleaved by hydrolysis to give the acid, for example, cleaved by mild hydrolysis.
  • a group that can be cleaved by hydrolysis is, for example, an appropriate leaving group, for example, an electron withdrawing group, for example, an acylating group, which is preferably a carboxylate activating, generally selected from the group consisting of N-succinimidyl, pentachlorophenyl, pentafluorophenyl, para-nitrophenyl, dinitrophenyl, N-phthalimido, N-bornyl, cyanomethyl, pyridyl, trichlorotriazine, 5-chloroquinolino, and imidazolyl goups, preferably an N-succinimidyl or imidazolyl group, and especially an N- succinimidyl group.
  • an appropriate leaving group for example, an electron withdrawing group
  • an acylating group which is preferably a carboxylate activating, generally selected from the group consisting of N-succinimidyl, pentachlorophenyl, pent
  • Hydrolysis may be carried out using a basic agent, for example, as described above, for example, using sodium hydroxide, and may be carried out under mild conditions, for example, ambient temperature and pressure and gentle heating, for example, 40 to 6O 0 C, for example for 2 to 16 hours.
  • a basic agent for example, as described above, for example, using sodium hydroxide
  • mild conditions for example, ambient temperature and pressure and gentle heating, for example, 40 to 6O 0 C, for example for 2 to 16 hours.
  • a polymer comprising units (I) or (II) as described above may be produced from a polymer (a "precursor polymer") described in WO 01/18080 or from a similar polymer, or from a polymer described in WO 03/059973 or a similar polymer.
  • precursor polymers include polymers comprising the unit (Ia) and polymers comprising the unit (Ha)
  • R, R 1 , R 2 , R 3 , L, m and n are as defined above
  • X denotes a leaving group, for example, an acylating group, which is preferably a carboxylate activating, generally selected from the group consisting of N-succinimidyl, pentachlorophenyl, pentafluorophenyl, para-nitrophenyl, dinitrophenyl, N-phthalimido, N-bornyl, cyanomethyl, pyridyl, trichlorotriazine, 5-chloroquinolino, and imidazolyl goups
  • X preferably denotes an N-succinimidyl or imidazolyl group.
  • a polymer comprising a unit that comprises the group Q ie a polymer comprising the unit (III) or a polymer comprising the unit (IV) may be produced from a corresponding precursor polymer (Ilia) or (FVa)
  • R, R 1 , R 2 and R 3 , R 4 , R 5 and R 6 , L, Q, X, m, n and p are defined as above, m, n and p may each represent an integer of up to 500, and preferably the total of m, n and p is not greater than about 500.
  • a precursor polymer especially a precursor polymer that comprises a leaving group suitable for cleavage by hydrolysis to give a polymer for use according to the invention may be produced by any appropriate method.
  • a polymer precursor having the desired polydispersity may be produced by atom transfer radical polymerisation method, for example, a copper mediated atom transfer radical polymerisation, or other methods including free radical polymerisation, may be used. Such methods are described in WO 01/18080 and in WO 03/059973.
  • a suitable radical initiator is utilised.
  • Such initiators commonly comprise alkylhalides, preferably alkylbromides.
  • the initiator is 2-bromo-2-methyl-(2- hydroxyethyl)propanoate.
  • the polymerization is also carried out in the presence of a polymerization mediator comprising a Cu(I) complex.
  • complexes are usually Cu(I)Br complexes, complexed by a chelating ligand.
  • Typical mediators are Cu(I)Br (Bipy) 2 , Cu(I)Br(Bipy), Cu(I)Br (Pentamethyl diethylene), Cu(I)Br[methyl] 6 tris(2- aminoethyl)amine] and Cu(I)Br(N,N',N",N'"-pentamethyldiethylenetriamine).
  • solvents are generally aprotic solvents, for example, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulphoxide and sulpholane and mixtures thereof.
  • water may be used.
  • Particularly preferred solvents are dimethylsulphoxide and dimethylformamide and mixtures thereof.
  • a complex of the invention is prepared by hydrolysing a polymer precursor as defined above, especially under mild conditions, to form the polymer in the presence of the insoluble ingredient, rather than to form a complex between a preformed polymer and the insoluble active ingredient.
  • the hydrophobic precursor polymer is converted to a hydrophilic polymer in the presence of the active ingredient, which facilitates complex formation.
  • the hydrolysis of the polymer precursor in the presence of the insoluble active ingredient should generally be carried out under conditions such that the insoluble active ingredient is not substantially affected adversely, for example, the hydrolysis should generally be carried out under mild conditions. Suitable conditions are given above.
  • a precursor polymer preferably a precursor polymer of polymethacrylic acid, for example a precursor polymer having an N-succinimide leaving group, is hydrolysed under the above mild conditions, for example using sodium hydroxide, in the presence of the insoluble active ingredient.
  • a suitable organic solvent for example DMSO
  • adding that solution to an aqueous solution of a suitable base, for example sodium hydroxide.
  • the complexes of the invention are polyelectrolytes having acidic groups.
  • the extent of deprotonation may vary according to the environment of the complex.
  • a complex of the invention may be in the form of a salt.
  • a salt may be, for example, with a monovalent, bivalent, trivalent or quadrivalent counter ion.
  • a monovalent counter ion may be, for example, an alkali metal ion, for example, a sodium or potassium ion, or an ammonium ion.
  • a bivalent counter ion may be, for example, an alkaline earth metal ion, for example, a calcium or magnesium ion.
  • Other counter ions include ions of transition metals, for example, iron, tin etc.
  • More than one type of counter ion may be present and associated with the polymer.
  • the number and proportion of salt-forming groups may be controlled, for example, by the use of appropriate polymer precursors, for example, as described above.
  • the substance or agent that is to form a complex with the polymer should generally be capable of sustaining a positive charge to enable direct formation of the complex by means of non-covalent interactions including electrostatic forces due to opposing charges.
  • the substance or agent used for complex formation may having basic, cationic or zwitterionic properties or may be adapted to have such properties.
  • Figures 1, 2, 3 and 4 show the diagnostic signals for the complexes prepared in Examples 1, 2, 3 and 4 respectively in the proton nuclear magnetic resonance spectroscopy spectrum of the complex.
  • Figure 5 shows the results of the cell toxicity testing of Example 6.
  • Figures 6, 7 and 8 show the results of Example 7, that it, the IFN- ⁇ production by PBMCs following a 48 h incubation with free active agent (solid bar) and complexed active agent (hashed bar), for the complexes of Examples 1 to 3.
  • Examples 1 to 3 show the diagnostic signals for the complexes prepared in Examples 1, 2, 3 and 4 respectively in the proton nuclear magnetic resonance spectroscopy spectrum of the complex.
  • Figure 5 shows the results of the cell toxicity testing of Example 6.
  • Figures 6, 7 and 8 show the results of Example 7, that it, the IFN- ⁇ production by PBMCs following a 48 h incubation with free active agent (solid bar) and complexed active agent (hashed bar), for the complexes of Examples 1 to 3.
  • imatinib mesylate, artemisinin, coenzyme QlO and 7-ethyl- 10-hydroxycamptothecin were investigated for the effects of complexation with polymethacrylic acid sodium salt, PMAA-Na, having a molecular weight of about 30,000 and a polydispersity of less than 1.7.
  • the dialysed sample was passed through a 0.2 ⁇ m filter and the filtrate freeze- dried to give a yellow solid product (80 mg, 33 wt% 7-ethyl-lO-Hydroxycamptothecm).
  • the wt% of active ingredient in the product was determined by dissolving the complex in 0.1 N NaOH and reading the absorbance at 265 nm against a calibration curve of free active ingredient. The presence of active ingredient was confirmed by a diagnostic signal for the active ingredient at 7.25 ppm (Figure 1) in the proton nuclear magnetic resonance spectroscopy spectrum of the complex obtained in deuterated water.
  • Example 5 7-Ethyl-lO-hydroxycamptothecin complex preparation starting with a mixture of PMOSu and PMAA
  • the dialysed solutions were then filtered (0.2 ⁇ m) filter and the filtrate freeze-dried to afford 64.7 mg of a yellow solid product.
  • the wt% of drug in the product was determined by dissolving the complex in 0.1 N NaOH and reading the absorbance at 280 nm against a calibration curve of free drug and was determined to be 15 wt%.
  • the ratio of PMOSu to PMAA was varied. Using 25 mg of each polymer gave 63.7 mg of product containing 21 wt% of the drug. Using 10 mg of PMOSu and 40 mg of PMAA gave 62.5 mg of product containing 17 wt%.
  • the dialysed solutions were then filtered (0.2 ⁇ m) filter and the filtrate freeze- dried to afford 49.4 mg of a yellow solid product.
  • the wt% of drug in the product was determined by dissolving the complex in 0.1 N NaOH and reading the absorbance at 280 nm against a calibration curve of free drug and was determined to be 17 wt%.
  • Example 7 7-Ethyl-10-Hydroxycamptothecin complex starting with PMAA and without using DMSO
  • the reaction mixture was then dialysed using Visking dialysis membrane (MWCO 12-14 kDa, Medicell International) for 24 h against 1 L of water with 6 changes of water.
  • the dialysed solutions were then filtered (0.2 ⁇ m) filter and the filtrate freeze-dried to afford 47 mg of a yellow solid product.
  • the wt% of drug in the product was determined by dissolving the complex in 0.1 N NaOH and reading the absorbance at 280 nm against a calibration curve of free drug and was determined to be 15 wt%.
  • Example 8 7-Ethyl-lO-hydroxycamptothecin complex with polyvinyl pyrollidone) (PVP) as an additional carrier
  • the dialysed solution was filtered (0.2 ⁇ m) and the filtrate freeze-dried to afford 52.2 mg of a yellow solid product.
  • the wt% of drug in the product was determined by dissolving the complex in 0.1 N NaOH and reading the absorbance at 280 nm against a calibration curve of free drug and was determined to be 12 wt%.
  • the dialysed sample was filtered (0.2 ⁇ m) and the filtrate freeze-dried to afford 8.7 mg of a yellow solid product.
  • the wt% of drag in the product was determined by dissolving the complex in 0.1 N NaOH and reading the absorbance at 280 nm against a calibration curve of free drag and was determined to be 16 wt%.
  • HT-29 cells (ECACC, Cat no. 91072201) were first prepared in DMEM/10% FCS (10 6 cells/ml) and plated on a 96-well flat-bottomed tissue culture plate at 100,000 cells/well (100 ⁇ l/well). Cells were allowed to adhere overnight.
  • the 7-ethyl- 10-hydroxycamptothecin complex was prepared as a two-fold dilutional series in DMEM/10% FCS (twice desired concentration) and 100 ⁇ l added per well. Samples were prepared in duplicates. A two-fold dilution series was also prepared for free, non- complexed 7-ethyl-lO-hydroxycamptothecin (2 mg/ml in DMSO). Similarly, DMSO was added as control to ensure that the toxicity of 7-ethyl-10-hydroxycamptothecin was not due to the amount of DMSO present. After samples were added, HT-29 cells were incubated for 72h at 37 0 C (5% CO 2 ).
  • MTT 5 mg/ml in DMEM, filtered; Sigma- Aldrich, Cat no. M5655
  • the amount of conversion of soluble MTT to insoluble purple formazan crystals is proportional to the level of proliferation.
  • the plate was then centrifuged at 1,500 rpm for 5 min and the supernatant was carefully aspirated.
  • DMSO was then added at 50 ⁇ l/well to dissolve the formazan crystals.
  • the resulting purple solution was then measured by UV spectroscopy at an absorbance of 570 nm.
  • Figures 5Al, 5A2, 5Bl and 5B2 The results of the 3-day HT-29 proliferation assay are shown in Figures 5Al, 5A2, 5Bl and 5B2.
  • Figure 5Al represents the uncomplexed active agent, with additional data for the uncomplexed active agent being represented in Figure 5A2, while
  • Figure 5Bl represents the complex, with additional data for the complex being represented in Figure 5B2.
  • the dose for the complex was adjusted to the 7-ethyl-10-hydroxycamptothecin loading.
  • 7-ethyl-l O-hydroxycamptothecin showed a toxicity level whose LD 50 was 0.02 ⁇ g/ml.
  • LD 50 of the 7-ethyl-10-hydroxycamptothecin complex was 0.09 ⁇ g/ml.
  • the imatinib mesylate complex induced MIP-I ⁇ release at 100 ⁇ g/ml whose level was over 8-fold higher than the basal MIP-I ⁇ level ( Figure 6).
  • the equivalent dose of free imatinib mesylate could not be tested due to the toxicity of the solvent.
  • Free imatinib mesylate did not elicit MIP- l ⁇ release from PBMCs.
  • the coenzyme QlO complex showed a dose-dependent release of MIP-I ⁇ that was more potent at a lower range of doses (Figure 8).
  • the level of MIP-I ⁇ released into the supernatant was 2.5-fold higher than the basal level. Free coenzyme QlO did not elicit any MIP-I ⁇ release from PBMCs.

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Abstract

L'invention concerne un nouveau complexe qui comprend : un ingrédient actif possédant une solubilité dans l'eau d'un pH supérieur ou égal à 6, pour une concentration inférieure à 5mg/ml; et un polymère comprenant des unités dérivées d'un acide acrylique ou d'un sel de ce dernier, à condition que l'ingrédient actif ne soit pas l'amphotéricine B. Les complexes de l'invention sont utiles pour solubiliser des ingrédients actifs hautement insolubles.
PCT/GB2008/003770 2007-11-09 2008-11-07 Nouveaux complexes et procédé de préparation de ces derniers Ceased WO2009060218A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004017940A2 (fr) * 2002-08-20 2004-03-04 Neopharm, Inc. Preparations de sn38 pharmaceutiquement active a base de lipides
WO2004075921A1 (fr) * 2003-02-26 2004-09-10 Vrije Universiteit Brussel Complexe d'inclusion d'artemisinine ou de derives de celle-ci et de cyclodextrines
US20040214829A1 (en) * 2000-07-14 2004-10-28 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
WO2005013930A1 (fr) * 2003-08-02 2005-02-17 Lrc Products Limited Composition antiparasite
WO2005065712A2 (fr) * 2004-01-07 2005-07-21 Polytherics Limited Complexes presentant une activite d'adjuvant
US20060210511A1 (en) * 2005-03-21 2006-09-21 Stone Violetta I Methods of treating skin and mucosal tissue atrophy using compositions including tensioning polymers

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040214829A1 (en) * 2000-07-14 2004-10-28 Allergan, Inc. Compositions containing alpha-2-adrenergic agonist components
WO2004017940A2 (fr) * 2002-08-20 2004-03-04 Neopharm, Inc. Preparations de sn38 pharmaceutiquement active a base de lipides
WO2004075921A1 (fr) * 2003-02-26 2004-09-10 Vrije Universiteit Brussel Complexe d'inclusion d'artemisinine ou de derives de celle-ci et de cyclodextrines
WO2005013930A1 (fr) * 2003-08-02 2005-02-17 Lrc Products Limited Composition antiparasite
WO2005065712A2 (fr) * 2004-01-07 2005-07-21 Polytherics Limited Complexes presentant une activite d'adjuvant
US20060210511A1 (en) * 2005-03-21 2006-09-21 Stone Violetta I Methods of treating skin and mucosal tissue atrophy using compositions including tensioning polymers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SANT V P ET AL: "Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization", JOURNAL OF CONTROLLED RELEASE, ELSEVIER, AMSTERDAM, NL, vol. 97, no. 2, 18 June 2004 (2004-06-18), pages 301 - 312, XP004515649, ISSN: 0168-3659 *

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