EP1210093A1 - Polymeres degradables - Google Patents

Polymeres degradables

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Publication number
EP1210093A1
EP1210093A1 EP00961523A EP00961523A EP1210093A1 EP 1210093 A1 EP1210093 A1 EP 1210093A1 EP 00961523 A EP00961523 A EP 00961523A EP 00961523 A EP00961523 A EP 00961523A EP 1210093 A1 EP1210093 A1 EP 1210093A1
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EP
European Patent Office
Prior art keywords
group
polymer
integer
polymers
groups
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EP00961523A
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German (de)
English (en)
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EP1210093A4 (fr
Inventor
Steven James School of Pharmacy BROCCHINI
Marie-Claude Dubois School of Pharmacy CLOCHARD
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Abzena UK Ltd
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School of Pharmacy University of London
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Priority to EP00961523A priority Critical patent/EP1210093A4/fr
Publication of EP1210093A1 publication Critical patent/EP1210093A1/fr
Publication of EP1210093A4 publication Critical patent/EP1210093A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/26—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from polyamines and polycarboxylic acids
    • C08G69/34—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from polyamines and polycarboxylic acids using polymerised unsaturated fatty acids

Definitions

  • the present invention is concerned with degradable polymers and the production of materials therefrom. These polymers and materials find utility in polymer therapeutics and pharmaceutical compositions for the treatment of disease. Background of the Invention
  • Polymer Therapeutics are developed for biomedical applications requiring physiologically soluble polymers and include biologically active polymers, polymer-drug conjugates, polymer-protein conjugates, and other covalent constructs of bioactive molecules.
  • An exemplary class of a polymer-drug conjugate is derived from copolymers of hydroxypropyl methacrylamide (HPMA) which have been extensively studied for the conjugation of cytotoxic drugs for cancer chemotherapy (Duncan R: Drug- polymer conjugates: potential for improved chemotherapy. Anti-Cancer Drugs, 1992, 3, 175-210. Putnam D, Kopecek J: Polymer conjugates with anticancer activity.
  • PK-1 displayed reduced toxicity compared to free doxorubicin in the Phase I studies (Vasey P, Twelves C, Kaye S, Wilson P, Morrison R, Duncan R, Thomson A, Hilditch T, Murray T, Burtles S, Cassidy J: Phase I clinical and pharmacokinetic study of PKI (HPMA copolymer doxorubicin): first member of a new class of chemotherapeutic agents : drug-polymer conjugates. Clin. Cancer Res., 1999, 5, 83-94). The maximum tolerated dose of PK-1 was 320 mg/m 2 which is 4-5 times higher than the usual clinical dose of free doxorubicin.
  • the polymers used to develop Polymer Therapeutics may also be separately developed for other biomedical applications where the polymer can form aggregates such as polymeric micelles and complexes.
  • Another important set of medical applications include those that require the polymer be used as a material, rather than as a physiologically soluble molecule.
  • drug release matrices including microspheres and nanoparticles
  • hydrogels including injectable gels and viscious solutions
  • hybrid systems e.g. liposomes with conjugated poly(ethylene glycol) (PEG) on the outer surface
  • devices including rods, pellets, capsules, films, gels
  • Polymers are also clinically widely used as excipients in drug formulation.
  • biomedical polymers provide a broad technology platform for optimising the efficacy of an active therapeutic drug.
  • Covalent conjugation of a drug to a soluble, biocompatible polymer can result in improved efficacy of the drug.
  • polymer-drug conjugates exhibit this improvement for the following main reasons: (1 ) altered biodistribution, (2) prolonged circulation, (3) release of the drug in the proteolytic and acidic environment of the secondary lysosome after cellular uptake of the conjugate by pinocytosis and (4) more favourable physicochemical properties imparted to the drug due to the characteristics of large molecules (e.g. increased drug solubility in biological fluids).
  • EPR enhanced permeability and retention
  • albumin has been investigated as a protein used to conjugate a bioactive molecule (Balboni P, Minia A, Grossi M, Barbanti- Brodano G, Mattioli A, Fiume L: Activity of albumin conjugates of 5- fluorodeoxyuridine and cytosine arabinoside on poxviruses as a lysosomotropic antiviral chemotherapy. Nature, 1976, 264, 181-183. Trouet A, Masquelier M, Baurain R, Campaneere D: A covalent linkage between daunorubicin and proteins that is stable in serum and reversible by lysosomal hydrolases as required for a lysosomotropic drug-carrier conjugate.
  • the major limitations for using a protein to conjugate a bioactive compound include the propensity for inducing immunogenicity and non-specific degradation of the protein in vivo, and denaturation and irreversible alteration of the protein during preparation of the conjugate.
  • transferrin which binds to the tranferrin receptor and thus have the potential to undergo receptor-mediated uptake
  • transferrin which binds to the tranferrin receptor and thus have the potential to undergo receptor-mediated uptake
  • transferrin-mitomycin C conjugate in HL60 cells as a receptor- mediated drug targeting system.
  • various immuno-conjugates Gaal D, Hudecz F: Low toxicity and high antitumour activity of daunomycin by conjugation to an immunopotential amphoteric branced polypeptide.
  • transferrin which binds to the tranferrin receptor and thus have the potential to undergo receptor-mediated uptake
  • transferrin-mitomycin C conjugate in HL60 cells as a receptor- mediated drug targeting system.
  • various immuno-conjugates Gaal D, Hudecz F: Low toxicity and high antitumour activity of daunomycin by conjugation to an immunopotential amphoteric branced polypeptide. Eur. J. Cancer
  • Trail P Willner D, Hellestrom K: Site-directed delivery of anthracyclines for the treatment of cancer. Drug Dev. Res., 1995, 34. 196-209. Eno-Amooquaye E, Searle F, Boden J, harma S, Burke P: Altered biodistribution of an antibody - enzyme conjugate modified with polyethylene glycol. Br. J. Cancer, 1996, 73. 1323-1327. Flanagan P, Duncan R, Subr V, Ulbrich K, Kopeckova P, Kopecek J: Evaluation antibody-[N-(2-hydroxypropyl)methacrylamide] copolymer conjugates as targetable drug-carriers. 2.
  • Monodisperse molecular weight distribution is often claimed to be a significant advantage for using proteins to conjugate drugs, but this can only be useful if a single species of the protein-drug conjugate can be reproducibly prepared on adequate scale which is stable on storage. This is generally not economically or technologically possible to achieve in practice.
  • degradable synthetic polymers developed for biomedical application, and specifically for conjugation applications which can address the limitations inherent in the use of natural polymers for these applications.
  • Synthetic polymers which have been prepared and studied that are potentially degradable include polymers derived from amino acids (e.g. poly(glutamic acid) , poly[ 5 N-(2-hydroxyethyl)-L-glutamine), ⁇ -poly(2- hydroxyethyl aspartamide), poly(L-glutamic acid) and polylysine). These polymers when prepared for conjugation applications that require physiological solubility do not degrade in vivo to any extent within a time period of 10-100 hours. Additionally polymers and copolymers including pseudo-poly(amino acids) (James K, Kohn J: Pseudo-poly(amino acid)s: Examples for synthetic materials derived from natural metabolites.
  • the three main parts of a polymer-drug conjugate (1 ) polymer, (2) linker and (3) conjugated drug all have defined biological function. Together these components produce a distinct profile of pharmacological, pharmacokinetic and physicochemical properties typical of polymer-drug conjugates.
  • the polymer is not a mere carrier for the pharmacologically active drug.
  • the properties of the polymer are directly responsible for defining the circulation half-life, rate of cellular uptake, minimising toxicity of potent cytotoxic drugs and imparting favourable physicochemical properties (e.g. increasing the solubility of lipophilic drugs).
  • Lysosomes also contain a vast array of hydrolytic enzymes including proteases, esterases, glycosidases, phosphates and nucleases. Drugs have been conjugated to polymers using conjugation linkers that degrade in the lysosome while remaining intact in the bloodstream. Since many drugs are not pharmacologically active while conjugated to a polymer, this results in drastically reduced toxicity compared to the free drug in circulation.
  • linkages have been used to covalently bind a drug to the polymeric carrier.
  • linkages include, amide, ester, hydrazide, urethane, carbonate, imine, hydroxyl, thioether, azo and C-C.
  • pendent chain linkers designed to be stable in the bloodstream, but degradable by lysosomal enzymes and thus able to release the drug intracellularly.
  • Acid-labile, pH dependent linkers which are designed to remain stable in plasma at neutral pH (7.4), but release drug intracellularly by hydrolysis in the more acidic environment of the endosome and lysosome (pH 5.5 to 6.5).
  • Peptide linkers have been shown to mediate lysosomotropic drug delivery (wherein the drug preferentially accumulates in the lysosome). It has become apparent that one of the successful methods of control of the rate and location of drug release from pendent chain polymers has occurred favourably when a drug is bound to the polymer backbone via a peptidyl side-chain.
  • Dilman, et al (Cancer res., 1988, 48, 6097-6102) have conjugated daunorubicin to the anti-T-cell monaclonal antibody T101 using a cis-aconityl group. The pH sensitivity of the linkage was confirmed.
  • a similar study using a monaclonal antibody conjugated to doxorubicin has been shown to suppress the growth of established tumour xenografts in nude mice (Yang and Ricefelt Proc. Natl. Acad. Sci., 1988, 85, 1189-1193).
  • GB 2,270,920 discloses a therapeutically useful alginate-bioactive agent conjugate, wherein the alginate and bioactive agent are connected covalently via an acid labile linkage, preferably a cis-aconityl group.
  • An advantage of conjugating a drug via an acid-labile linker is that free drug alone can be released from the pendent chain rather than amino acid or peptide drug derivatives which can occur with peptidyl linkers.
  • One object of the present invention is to provide pH dependant degradeable polymers.
  • a further object of the present invention is to provide biocompatible, degradable polymers that will hydrolytically degrade at faster rates at acidic pH values than at neutral pH values
  • a further object of the present invention is to provide degradable polymers that degrade in the endosome or lysosome, while enabling conjugation to a lysosomally labile bioactive agent.
  • One embodiment of the invention provides a polymer comprising: a polymeric backbone comprising at least one unit having the structure (I),
  • R-R 4 comprise groups selected from the group consisting of H, C r C 12 alkyl, C 6 -C 18 aryl, C 7 -C 18 aralkyl, C 6 -C 18 cycloalkyl or any of the group consisting of C r C 12 alkyl, C 6 -C 18 aryl, C 7 -C 18 aralkyl, C 6 -C 18 cycloalkyl substituted, within the carbon chain or appended thereto, with one or more heteroatoms;
  • R and R 2 or R and R 4 or R and R 1 or R 2 and R 3 may be joined so that with the carbon atom(s) to which they are attached they together form a saturated, partially unsaturated or unsaturated ring system respectively, may have a pendent group which may incorporate a linker unit, (for example a peptide linkage) or a unit having the structure (I);
  • A comprises a proton donating moiety selected from the group consisting of
  • B comprises a hydrolytically labile group and is selected from the group consisting of
  • each R 5 is individually selected from the group consisting of H, 0,-0, 2 alkyl, C 6 -C 18 aryl, C 7 -C 18 aralkyl, C 6 -C 18 cycloalkyl; wherein groups A and B are in a cis-configuration about bond C a -C b ; m is an integer of 0 to 100, n, p and q are each an integer of 0 or 1 ; Q comprises 1 or more structures selected from the group consisting of
  • R 6 -R 11 are individually selected from the same group as defined for group R above and r is an integer between 1 and 5000, preferably 1 to 10, most preferably 1 to 6.
  • C a -C b may be a double bond, in which case p and q are 0 and groups A and B are in a cis-configuration across the double bond.
  • R and R 2 or R and R 4 or R and R 1 or R 2 and R 3 , preferably R and R 2 may be joined to oneanother to form part of a C 3 - C 12 ring system which may have none one or more than one unsaturated bond and may be aromatic.
  • a and B are in a cis- configuration about bond C a -C b .
  • a ring system is a C 3 -C 7 ring system
  • the ring system may incorporate any of the groups defined for R or may include one or more Q groups.
  • C a -C b is a single bond
  • p and q are 1 and R
  • R 1 , R 4 and A are selected from sterically bulky groups in such a way as to maintain a cis- configuration of A and B about bond C a -C b .
  • C a -C b is a double bond.
  • R-R 4 are individually selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl and hexyl and isomers thereof, acyl, alkoxy and acyloxy or mixtures thereof. Most preferably R, R 2 and R 3 are hydrogen.
  • each R 5 is individually selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl and hexyl, preferably hydrogen.
  • A preferably comprises a group or a protected carboxylic acid group.
  • B preferably comprises an amide bond, and is most preferably a wherein R 5 has been hereinbefore defined.
  • Q may comprise more than one or a mixture of the structures defined above.
  • Q comprises a carbonyl group, -NR 12 -, -O- or -CH 2 - group, wherein R 12 is selected from the group consisting of hydrogen, C, .6 - alkyl, preferably methyl, ethyl, propyl, butyl, pentyl and hexyl and isomers thereof.
  • R 12 is a hydrogen atom.
  • Q comprises a carbonyl functionality or a -CH 2 - group, especially a carbonyl functionality.
  • bond C a -C b is a double bond
  • R is hydrogen
  • R 2 and R 3 are hydrogen
  • n is 1
  • m is 1
  • p and q are 0,
  • A is a carboxylic acid group
  • B comprises an amide bond
  • Q comprises an carbonyl group.
  • the groups A, B, Q, R-R 4 , m, n, p and q in each individual moiety are the same.
  • the other components of the polymeric backbone may be other groups having the structure (I), peptide units or other degradeable polymeric, oligomeric or monomeric units.
  • the polymeric backbone may comprise acrylic polymers, alkylene polymers, urethane polymers, amide polymers, polypeptides, polysaccharides and ester polymers.
  • the backbone components comprise derivatised polyethyleneglycol or copolymers of hydroxyalkyl(meth)acrylamide, most preferably amine derivatised polyethyleneglycol or hydroxypropylmethacrylamide-methacrylic acid copolymers, or derivatives thereof.
  • a further embodiment of the present invention provides a polymer comprising a polymeric backbone comprising the structure (II)
  • L is a polymeric, oligomeric or copolymeric bridging group which comprises groups selected from the group consisting of acrylic polymers, alkylene polymers, urethane polymers, polyethylene glycols, polyamides(including polypeptides).
  • polysaccharides and polyesters a is an integer of 1 to 100000, b and c are integers of 0 to 100000 and s is an integer of 0 to 100;
  • D comprises one or more structures individually selected from the group consisting of,
  • R 14 and R 14 ' comprise groups individually selected from the same groups as defined for Ror may comprise a structure selected from the group consisting of
  • n is an integer of 0-100
  • R 15 is selected from the group consisting of hydrogen and C C 6 alkyl
  • R 16 to R 18 are individually selected from the group consisting of H, C C 12 alkyl, C C 12 alkenyl, C 6 -C 18 aryl, C 7 -C 18 aralkyl, C 5 -C 18 cycloalkyl or is selected from the group consisting of C C 12 alkyl, C,-C 12 alkenyl, C 6 -C 18 aryl, C 7 -C 18 aralkyl, C 6 -C 18 cycloalkyl substituted, within the carbon chain or appended thereto, with one or more heteroatoms, a pendent group comprising a linker unit, for example a peptide linkage or a unit having the structure (I) or a leaving group;
  • R 13 is selected from the group consisting of H, C r C 12 alkyl, C r C 12 alkenyl, C 6 -C
  • L comprises a compound selected from the group comprising derivatised polyethyleneglycol and (hydroxyalkyl(meth)acrylamide-methacrylic acid copolymer or amide or ester derivative thereof, most preferably amine derivatised polyethyleneglycol.
  • L comprises a structure comprising a group selected from the group consisting of wherein PEG is polyethyleneglycol
  • R 19 -R 24 may be a pendent group comprising a cleavable linker unit, and comprise groups individually selected from the same groups as defined for R or may comprise a structure selected from the group consisting of
  • n and R 16 to R 18 have been defined hereinbefore.
  • s is preferably an integer of 1 to 10.
  • L is a group incorporating one of groups R 19 to R 24 , b is preferably 0.
  • R 14 to R 24 should incorporate a pendent group.
  • a pendent group incorporates a cleavable bond.
  • R 14 to R 24 comprise a cleavable group (I) as hereinbefore defined, or a peptidic bond capable of being cleaved by lysosomal enzymes.
  • R 16 -R 18 are H, tosylate, Fmoc, halogen, methyl, ethyl, propyl, butyl, pentyl or isomers thereof.
  • a pendent group as defined hereinbefore may incorporate a bioactive agent to form a conjugate.
  • the bioactive agent is an anti-cancer agent, for example doxorubicin, daunomycin, taxol and the like. This permits both cleavage of the linker unit, thus releasing drug to the desired site, and biodegradation of the macromolecular carrier, thus reducing side effects associated with the difficulty of clearing such molecules from the system.
  • the molecular weight of L is less than 220 kDa, more preferably less than 100 kDa, most preferably less than 30 kDa.
  • the polymer has a weight of 500D-400 kDa.
  • a further embodiment of the invention provides prepolymer comprising the structure (III)
  • A, B, Q, R-R 4 , R 13 , L, m, n, p and q are as defined herein before;
  • A', B', Q' R 1 '-R 4 ', m', n', p', and q' are selected from the groups as defined for A, B, Q, R 1 - R 4 m, n, p and q respectively;
  • E and K are selected from the group consisting of hydrogen, a protecting group or an activating group and may be the same or different;
  • z is an integer of of 1 to 100, y is an integer of 0 to 10 and x is an integer of 0 to 100.
  • z is preferably 1
  • y is preferably 1 or
  • x is preferably 1 or 0.
  • B and/or B' comprise a carboxylic acid group
  • E and K are an activating group selected from the group consisting of N- succinimidyl, pentachlorophenyl, pentaflourophenyl, para-nitrophenyl, dinitrophenyl, N-phthalimido, N-norbornyl, cyanomethyl, pyridyl, trichlorotriazine, 5-chloroquinolino.
  • groups E and K are known as an "active esters ".
  • E and K are N-succinimidyl.
  • activating moieties that can act as an acylation reagent, such as the mixed anhydrides.
  • A, B, Q, R-R 4 , D, m, n, p and q are as defined above, G and M are selected from the group consisting of hydrogen, an activating group or a protecting group and may be the same or different, i and j are integers of 1 to 10. i is preferably 1 and j is preferably 1.
  • G and M are an activating group as defined above.
  • G and M are hydrogen or N-succinimidyl.
  • a further embodiment provides process for preparing a polymer, copolymer or prepolymer comprising reacting at least one compound having the structure (V)
  • R 25 , R 26 and R 27 are selected from the group as defined for R;
  • Q" is selected from the group consisting of carboxylic acid, primary or secondary amine and carbonyl;
  • u is an integer of 0 or 1 ,
  • v is an integer of 1 to 100,
  • R 27 and R 25 may be attached to form part of a C 3 - C 12 ring system which may have more than one unsaturated bond and may be aromatic; with at least one compound selected from the group consisting of J and R 13 LNHR 28 , wherein L and R 13 groups are as defined above and R 28 is selected from the same group as defined for R and may be the same or different,
  • J is a compound having at least one primary or secondary amine and a carboxylic acid group and a pendent group incorporating a cleavable bond.
  • Q is a carboxylic acid group
  • R 27 is hydrogen
  • u and v are 1
  • R 25 and R 26 are hydrogen or methyl.
  • R 13 LNHR 28 comprises a NHR 29 group, wherein R 29 is individually selected from the same group as defined for R 28 .
  • a further embodiment provides a method of selectively degrading a polymer comprising the steps of: a) introducing a polymer as defined by structure (i) or (II) to an environment having a pH of less than 6.5, b) cleaving said polymer.
  • a further embodiment provides a method for releasing a bioactive agent comprising the steps of a) introducing a conjugate as described hereinbefore to an environment having a pH of less than 6.5, c) cleaving the bioactive agent from the linker group by acid or enzymic hydrolysis, d) optionally additionally cleaving the polymer by acid or enzymic hydrolysis.
  • compositions which comprise at least one polymer or polymer-bioactive agent conjugate and a carrier.
  • compositions may be administered orally, by injection, or topically and may comprise a pharmaceutically acceptable excipient.
  • a further embodiment of the invention includes the use of the novel polymer as a pharmaceutical excipient. As it degrades very quickly at low pH ranges it has application as an excipient for drug formulations prepared for oral administration (i.e. for rapid degradation in the gut or gastro intestinal tract where there are regions of very low pH).
  • novel polymers of the present invention may be water soluble or insoluble depending on size and the nature of its components.
  • the degradation products of the polymer are preferably soluble.
  • the present invention provides a polymer comprising an acid labile, pH dependent backbone incorporating a cis- aconityl group therein, more specifically a group having the structure (VI).
  • This group is designed to remain stable in plasma at neutral pH (-7.4), but degrade intracellularly by hydrolysis in the more acidic environment of the endosome or lysosome ( ⁇ pH 5.5 - 6.5).
  • the group (vi) is incorporated into a polymer backbone comprising a polymeric, oligomeric or copolymeric group which comprises functionalised or unfunctionalised polyethyleneglycol, ethyleneglycol copolymers, poly(hydroxyalkyl(meth)acrylamide), for instance hydroxypropylmethacrylamide-methacrylic acid copolymer (or amide or ester derivative thereof) and copolymers of styrene and maleic anhydride, polyurethanes, polyalkylenes and polyamides or amino acid residues.
  • the polymeric backbone should incorporate a functionalised polyethyleneglycol (PEG) polymer or copolymer most preferably an amine functionalised PEG polymer.
  • PEG polyethyleneglycol
  • the molecular weight of the polymer of the present invention is in the range of 30-400 kDa, while the weight of the prepolymer (III) is preferably less than about 220 kDa in order to ensure that the degraded polymer subunits are cleared from the lysosome and the kidney glomerulus. Most preferably the polymer degradation products have a molecular weight in the range of 0.5 kDa-30 kDa.
  • One preferred polymer of the present invention is a water soluble polyamide having the formula 3 and is made by the general reaction scheme summarised below: wherein PEG is a polyethylene glycol group having a molecular weight in the range 500 Da-100kDa or derivative thereof and u is an integer in the range of 1-10000.
  • the preferred polymer may be prepared by a 2 step, and optionally 3 step process.
  • an equivalent of cis-aconitic anhydride, 1 is reacted with a compound containing two primary or secondary amine groups.
  • Suitable solvents include non-protic solvents including acetonitrile, dimethylformamide, dimethylsulphoxide, DMA, tetrahydrofuran, ethyl acetate, dioxane, acetone etc. Preferably acetonitrile is used.
  • the product is isolated by a suitable method such as solvent separation and the resultant macromonomer 2 is then used as a prepolymer for the production of the acid labile polymer backbone.
  • Macromonomer (2) may be reacted with two equivalents of an activating group as described hereinbefore (N-hydroxysuccinimide shown) to produce an active monomer.
  • an activating group as described hereinbefore (N-hydroxysuccinimide shown) to produce an active monomer.
  • the reason for this is that the unprotected carboxylic acid moieties would otherwise compete in the polymerization reaction, resulting in potential incomplete degradation of the polymer backbone. This situation could, however, be used in the production or enablement of cross-linking and gel formation.
  • compound 3_ is produced.
  • This compound (3) or compound 2 may then be reacted further with a compound R 13 LNHR 28 as defined hereinbefore.
  • R 3 LNHR 28 is simply a amine-difunctionalised PEG molecule.
  • Other compounds that are suitable for use as R 13 LNHR 28 are
  • R 19 -R 24 have been defined hereinbefore.
  • the above defined R 14 -R 19 groups contain a group that is capable of conjugation to a drug, or a precursor thereof, for example, the group R 19 -R 24 should preferably contain a primary or secondary amine.
  • Suitable methods of attaching a linker molecule or a drug to the polymer backbone are as follows:
  • x is a leaving group such as tosylate, Br and the like.
  • the conditions for the step to the final product 4 of the reaction are different than the first, and involve the use of a condensation or coupling reagent type of compound such as a carbodiimide (e.g. dicyclohexyl carbodiimide, diisopropylcarbodiimide, 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide, mixed anhydride reagents (e.g. 2-ethoxy-1- ethoxycarbonyl-1-1 , 2-dihydroquinoline, 2-isobutoxy-1-isobutoxycarbonyl-2, 2-dihydroquinoline, isobutyl chloroformate), phosphonium salts (e.g.
  • a condensation or coupling reagent type of compound such as a carbodiimide (e.g. dicyclohexyl carbodiimide, diisopropylcarbodiimide, 1 -(3-dimethylaminopropy
  • benzotriazole-l-yl-oxy-tris-(dimethylamino)- phosphoniumhexafluorophosphate (Castro's reagent), bromo-tris-pyrrolidino- phosphonium hexafluorophospate, benzotriazole-1-yl-oxy-tris-pyrrolidino- phosphonium hexafluorophosphate), uronium salts (e.g.
  • carbonates e.g. 1 ,1'- carbonyl-diimidazole, N,N'-disuccininimidyl carbonate.
  • the particularly preferred solvents and conditions for this reaction are that molecule 2 is allowed to react in acetonitrile (with DIPC and hydroxysuccinimide) to give the macromonomer 3.
  • the macromonomer 3 is isolated then allowed to react in aqueous carbonate (Na 2 CO 3 ) at pH 9, 24 h at ambient temperature to give the polymer such as 4.
  • Another particularly preferred embodiment of the present invention is the production of the water soluble polyamide having the formula 7 and is made by the general reaction scheme summarised below:
  • PEG is a polyethylene glycol group having a molecular weight in the range 500 Da-100kDa or derivative thereof, and v is an integer in the range of 1-10000.
  • the preferred polymer may be prepared by a 2 step, and optionally 3 step process. In the first step an equivalent of cis- aconitic anhydride, 1, is reacted with a compound containing an amine group and a carboxylic acid group (8) wherein R 33 is selected from the same group of compounds as defined for R 19 -R 24 .
  • Suitable solvents again include non-protic solvents, preferably acetonitrile.
  • Macromonomer (2) may be reacted with two equivalents of a protecting group (N-hydroxysuccinimide shown) to produce an active monomer. If protection is carried out as shown, compound 6_ is produced.
  • This compound (6) or compound 5 may then be reacted further with a compound R 13 LNHR 28 as defined hereinbefore.
  • R 13 LNHR 28 is simply a amine-difunctionalised PEG molecule.
  • Other compounds that are envisaged for use as R 13 LNHR 28 are as shown above.
  • Another embodiment of the present invention is the production of the water soluble polyamide having the formula H and is made by the general reaction scheme summarised below: wherein n is an integer of 1-10000.
  • X is a halogen, preferably bromine and PEG is polyethyleneglycol.
  • Dimethylanhydride is reacted with a suitable halogenating agent to produce a halogenated dimethylanhydride.
  • Diamino- PEG is reacted with the halogenated anhydride to produce the polymer.
  • Suitable solvents for this method again include non-protic solvents, preferably dichloromethane. Since there is the free carboxylate (C-4) there is an equilibrium with the zwitterionic structure 12.
  • N-bromosuccinimide is used as the brominating agent. Since there is the free carboxylate (C-4) there is an equilibrium with the zwitterionic structure 12.
  • Figure 1 shows the degradation study of the preferred polyamide 4 of the invention at pH 7.4, 5.5 and 2 in phosphate buffer at 37 C as described in the Examples.
  • Figure 2 shows a continued degradation profile for polyamide 4 over a
  • Figure 3 shows the red blood cell lysis assay incubated for 24 h; 0, indicates polyamide 4; ⁇ indicates positive control, poly(ethylene imine); LJ indicates negative control, dextran.
  • the decrease in lysis observed with increasing concentration of poly(ethylene imine) is due to the partial precipitation of haemoglobin with this polymeric control.
  • Figure 4 shows B16 F10 cell viability (cytotoxicity) assay;0 indicates polymer 4; ⁇ indicates positive control, polylysine;U indicates negative control, dextran.
  • Figure 5 shows the in vitro degradation profile for poly(amido amine)
  • a 50 ml three neck round bottom flask was fitted with a condenser, thermometer and a dropping funnel.
  • the flask was cooled using a water ice bath and PEG NH2 500 Jeffamine (1.6 g, 3.2 mmol, 1 eq.) and acetonitrile (5.0 ml) were added to the flask.
  • PEG NH2 500 Jeffamine 1.6 g, 3.2 mmol, 1 eq.
  • acetonitrile 5.0 ml
  • To the dropping funnel was added c/s-aconitic anhydride 1 (2.0 g, 12.8 mmol, 4.0 eq.) and acetonitrile (10 ml). Under nitrogen atmosphere, the c/s-aconitic anhydride solution was slowly added over a 30 minute period to the Jeffamine solution which turned a light yellow coiour during the addition.
  • the reaction was exothermic and the risk of possible decarboxylation was minimised by ensuring that the temperature of the reaction mixture remained in the range of 0-3 °C through out the addition of the anhydride solution.
  • the ice water bath was the removed and the reaction mixture allowed to stir for 1 hour at ambient temperature.
  • Diethyl ether (30 ml) was then added to the solution and the reaction mixture poured into a separatory funnel. More ether was added and the macromonomer 2 separated as an oil which settled to the bottom of the separatory funnel and was isolated. Excess solvent was first evaporated from the crude macromononer 2 under flowing nitrogen and then the oil dried in vacuum at 40 °C. Preparation of polyamide 4.
  • PEG NH2 3400 (5,00g, 1.47 mmol, 1eq.) was dissolved in acetonitrile (35 ml) in a 100 ml round bottomed flask, placed in an argon atmosphere and kept cold by an ice bath. A two-fold excess of c/s-aconitic anhydride (0.92g, 5.88 mmol, 4eq) was dissolved in acetonitrile (5 ml) under argon atmosphere. C/s- aconitic anhydride solution was slowly added into the cold solution of PEG NH2 3400 over an hour, ensuring that addition was slow enough not to cause a colour change in the reaction mixture. The reaction was left to stir in the fridge overnight.
  • the macromonomer was precipitated from the solution with about three times the volume of chilled diethyl ether (120 ml). The precipitate was filtered with vacuum using a glass filter (porosity 3) and further dried in a dissector in vacuum for 30 minutes. The macromonomer 2 was obtained with an isolated yield of 88.1 %.
  • the IR and 1 H NMR data for macromonomer 2 is as follows:
  • the macromonomer 2 (2.00g, 0.54 mmol, 1 eq) was dissolved in acetonitrile (25 ml) in a 100 ml round bottom flask, placed in an argon atmosphere and kept cold with an ice bath. A two-fold excess for N- hydroxysuccinimide (NHS) (0.25g, 2.16 mmol, 4 eq.) was dissolved in acetonitrile (2 ml) and added to the cold macromonomer solution. Diisopropyl carbodiimide (DIPC) (0.14g, 1.08 mmol, 2 eq) was also dissolved in acetonitril (2 ml) and slowly added into the reaction solution.
  • DIPC Diisopropyl carbodiimide
  • the reactions was stirred overnight in the fridge. More acetonitrile (25 ml) was added the next day to dissolve the Diisopropyl urea DIPC precipitate that had been formed during the reaction.
  • the activated macromonomer 3 was then precipitated from the solution with about five times the volume of diethyl ether (250 ml) pre-chilled in an ice bath. The precipitate was filtered with vacuum using a glass filter (porosity 3) and further dried in a dissector in vacuum for 30 minutes. The activated macromonomer 3 was obtained with an isolated yield of 78.5%.
  • the IR and 1 H NMR data for activated macromonomer 3 is as follows:
  • PEG NH2 3'400 (0.7g, 0.20 mmol) was dissolved in pH 9 sodium carbonate solution (17 ml). The resultant solution was added to the activated macromonomer 3 (0.80g, 0.20 mmol) which had been weighted out in a 50 ml round bottom flask and placed in an ice bath. The pH of the final reaction mixture was checked with universal paper and adjusted slowly to pH 9 with sodium carbonate if necessary. The polymerisation was allowed to take place in the fridge. Aliquots were removed periodically and analysed by SEC to observe the conversion of polymerisation. After 25 hours, the polymer was precipitated into a chilled stirred solution of tetrahydrofuran (THF)-diethyl ether (2:3, 250 ml).
  • THF tetrahydrofuran
  • the precipitate was then filtered with vacuum using a glass filter (porosity 3) and further dried in a dissector in vacuum for 30 minutes.
  • the large polydispersity indicates that in the unfractionate or crude polymer mixture there was also some unreacted prepolymer, dimers, trimers and oligimers in addition to the desired 60 kDa material that was prepared.
  • the polymer 4 has also been prepared directly from the macromonomer 2 in organic solvent using a coupling reagent only without activating with N- hydroxysuccinimide.
  • the macromonmer 2 (2.00g, 0.54 mmol, 1 eq.) was dissolved in acetonitrile (25 ml) in a 100 ml round bottom flask, placed in an argon atmosphere and kept cold with an ice bath.
  • PEG NH2 3400 (1.83g, 0.54 mmol, 1 eq.) was dissolved in acetonitrile (25 ml) and added to the cold macromonomer solution.
  • DIPC (0.17 ml, 1.08 mmol, 2 eq.) was then slowly added and the polymerisation was allowed to take place in the fridge. Aliquots were removed periodically and analysed by SEC to observe the conversion of polymerisation.
  • the polymer was precipitated after 212 h with six times the volumes of ether (300 ml) pre-chilled in an ice bath. The precipitate was filtered under vacuum with glass filter (porosity 3) and further dried in a dissector under continuous vacuum for 30 minutes. Mw:..7O00 ⁇ 50'000 Da Degradation study.
  • biocompatibility assays are as follows: Cell Viability Assay. Adherent cells were seeded into separate, sterile, o flat-bottomed 96 well, tissue culture treated plates at a density of 5x10 4 cells/well
  • Red blood cell (RBC) lysis Fresh blood was obtained from male Wistar 5 rats (-250 g body weight) through cardiac puncture after carbon dioxide asphyxiation, and collected in a heparin/lithium blood tube. Erythrocytes were isolated by centrifugation (Heraeus Instruments, Varifuge 3.0RS) at 1530 ' g for 10 minutes at 4 °C. The supernatant was discarded along with the top 3-5 mm of the pellet. The erythrocytes were re-suspended in pH 7.4 phosphate buffer 0 solution (PBS) and the suspension was centrifuged as before and the supernatant was discarded. This washing process was repeated.
  • PBS pH 7.4 phosphate buffer 0 solution
  • a 2% w/v RBC suspension in PBS was then prepared.
  • Various concentrations of the polymers in PBS were added to 96-well plates, followed by the RBC suspension.
  • the negative control was dextran which does not cause haemolysis.
  • the positive 5 control was polyethylenimine (PEI) which causes RBC membranes to lyse.
  • the polymer concentrations tested were 0.75, 1.25, 2.5, 3.75 and 5 mg/ml.
  • the final volume in each well was 200 ml containing a 1 % w/v suspension of RBC.
  • Four wells were used for each concentration.
  • four wells were loaded with PBS instead of polymer as a negative control.
  • Eight wells on a separate plate 0 were loaded with 1 % v/v Triton-X 100 solution and RBC suspension to enable
  • Example 3 Synthesis of polyamide 7. o
  • the amino acid aconityl derivative 5 was synthesized from a reaction between c/s-aconitic anhydride 1 and Glycine 8.
  • Glycine 8 (1.299 g, 17.32 mmol) and 30 mL anhydrous acetonitrile were added to a 100 mL round bottom flask equipped with a magnetic stir bar and a pressure equilising dropping funnel.
  • Cis- Aconitic anhydride 1 4.322 g, 27.71 mmol
  • 10 mL anhydrous acetonitrile was added via the dropping funnel and the heterogeneous reaction mixture stirred at ambient temperature for 48 h.
  • the product 5 was filtered under vacuum with a glass filter (porosity 4), rinsed with chilled acetonitrile and dried in a dessicator in a vacuum and weighed to give an an isolated yield of 91 %.
  • the product 5 and was found to be soluble in water, methanol and ethanol.
  • the IR and 1 H NMR data for product 5 is as follows:
  • Amino acid aconityl derivative 5 (0.1 g, 0.433 mmol, 1 eq) and acetonitrile (5.0 ml) were placed into a 50 mL round bottom flask equipped with a magnetic stir bar and pressure equilising dropping funnel. The solution was cooled using a dry ice bath. Into another 50 mL round bottom flask equipped with a magnatic stirr bar was added pentachlorphenol (0.69 g, 2.598 mmol, 6 eq.) in anhydrous acetonitrile (10 ml). This solution was also cooled in an ice bath.
  • the activated monomer 6 obtained with an isolated yield of 62 %.
  • the activated monomer 6 0.2 g, 0.275 mmol, 1 eq
  • dichloromethane 10 ml
  • Polymer H is a poly(amido amine). Since there is the free carboxylate (C-4) there is an equilibrium with the zwitterionic structure 12.

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Abstract

On décrit un polymère qui comprend: un squelette polymère comportant au moins une unité représentée par la structure (I), dans laquelle R-R4 comprennent des groupes sélectionnés dans le groupe formé par H, alkyle C¿1?-C12, aryle C6-C18, aralkyle C7-C18, cycloalkyle C6-C18 ou n'importe quel groupe faisant partie du groupe formé par alkyle C1-C12, aryle C6-C18, aralkyle C7-C18, cycloalkyle C6-C18 substitué, situé dans la chaîne carbone ou pendant de ce dernier, avec un ou plusieurs hétéroatomes; R et R?2¿ ou R et R4 ou R et R?1 ou R2 et R3¿ peuvent être liés, pour qu'ils forment, avec le ou les atomes de carbone auxquels ils sont attachés, un système d'anneau respectivement saturé, partiellement saturé ou non saturé, et ils peuvent avoir un groupe pendant pouvant comprendre une unité de liaison (par exemple une liaison peptide) ou une unité représentée par la structure (I); A comprend une fraction donneuse de protons sélectionnée dans le groupe formé par les éléments de formule (1). B comprend un groupe hydrolytiquement labile et se trouve sélectionné dans le groupe formé de composés de formule (2), dans laquelle chaque R5 est individuellement sélectionné dans le groupe formé par H, alkyle C¿1?-C12, aryle C6-C18, aralkyle C7-C18, cycloalkyle C6-C18; lesdits groupes A et B étant dans une configuration cis- autour de la liaison Ca-Cb; m représente un entier compris entre 0 et 100, n, p et q représentent chacun un entier tel que 0 ou 1; Q comprend une ou plusieurs structures sélectionnées dans le groupe de formule (3) dans laquelle R?6-R11¿ sont individuellement sélectionnés dans le même groupe que le groupe R ci-dessus et r représente un entier compris entre 1 et 5000, de préférence compris entre 1 et 10 et plus préférablement encore compris entre 1 et 6. On décrit également des procédés de production et d'utilisation de ce polymère.
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US8697074B2 (en) 2008-07-10 2014-04-15 Esbatech, An Alcon Biomedical Research Unit Llc Methods and compositions for enhanced delivery of macromolecules
EP3130603A1 (fr) 2008-06-30 2017-02-15 ESBATech, an Alcon Biomedical Research Unit LLC Polypeptides fonctionnalisés

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GB0131112D0 (en) * 2001-12-31 2002-02-13 Univ London Pharmacy Block copolymers
GB0316294D0 (en) 2003-07-11 2003-08-13 Polytherics Ltd Conjugated biological molecules and their preparation
US20060263328A1 (en) * 2005-05-19 2006-11-23 Sang Van Hydrophilic polymers with pendant functional groups and method thereof
DK2306986T3 (en) * 2008-06-26 2018-06-18 Prolynx Llc PRODRUGS AND PHARMACEUTICAL Macromolecule Conjugates with Controlled Drug Release Rates
WO2017110918A1 (fr) * 2015-12-25 2017-06-29 東レ株式会社 Résine polyamide à extrémité modifiée et son procédé de production
CA3095644A1 (fr) * 2018-03-29 2019-10-03 Nof Corporation Conjugue de polyethylene glycol degradable
WO2022244690A1 (fr) * 2021-05-19 2022-11-24 国立大学法人筑波大学 POLY(ÉTHYLÈNE GLYCOL)-b-POLY (4-NYLON) ET NANOPARTICULES CORRESPONDANTES

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EP3130603A1 (fr) 2008-06-30 2017-02-15 ESBATech, an Alcon Biomedical Research Unit LLC Polypeptides fonctionnalisés
US8697074B2 (en) 2008-07-10 2014-04-15 Esbatech, An Alcon Biomedical Research Unit Llc Methods and compositions for enhanced delivery of macromolecules
EP2769711A1 (fr) 2008-07-10 2014-08-27 ESBATech, an Alcon Biomedical Research Unit LLC Procédés et compositions favorisant l'administration de macromolécules

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