US2005220880A1PendingUtilityA1
Drug carriers comprising amphiphilic block copolymers
Est. expiryMar 7, 2022(expired)· nominal 20-yr term from priority
C08F 293/005C08L 53/00A61P 35/00A61K 9/1075
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Claims
Abstract
An aqueous composition comprises an amphiphilic block copolymer, having a hydrophilic block comprising pendant zwitterionic groups and a hydrophobic block, and a biologically active compound associated with the polymer. The polymer is preferably in the form of micelles, and preferably the biological active is a hydrophobic drug, for instance having a calculated or experimentally determined logP of at least 1.0, where P is the octanol:water partition coefficient. The hydrophilic block is preferably formed from acrylic monomer including phosphoryicholine groups. The hydrophobic group is suitably formed from monomer which has groups which can be ionised at useful pH's, especially tertiary amine groups. Micelles may be formed by dissolving the block copolymer in aqueous solvent at a pH at which the amine groups are protonated then raising the pH to a value at which the amine groups are substantially deprotonated, whereupon micelles spontaneously form. The preformed micelles are then contacted with active, under conditions such that solubilisation of the active occurs. The active may be a water-insoluble drug, for instance for tumour treatment.
Claims
exact text as granted — not AI-modified1 . An aqueous composition comprising an amphiphilic block copolymer having a hydrophilic block and a hydrophobic block, dispersed in the solution, and a biologically active compound associated with the polymer, wherein the hydrophilic block has pendant zwitterionic groups.
2 . A composition according to claim 1 in which the biologically active molecule is associated by hydrophobic interactions with the copolymer.
3 . A composition according to claim 2 in which the biologically active compound has a measured and/or calculated partition coefficient between octanol and water, of at least 1.0.
4 . A composition according to claim 1 in which the copolymer is dispersed in the form of micelles.
5 . A composition according to claim 1 wherein the hydrophilic block is formed by radical polymerisation of ethylenically unsaturated monomers.
6 . A composition according to claim 5 in which the monomers comprise a zwitterionic monomer.
7 . A composition according to claim 6 in which the zwitterionic monomer has the general formula
Y B X I
in which Y is an ethylenically unsaturated group selected from the group consisting of H 2 C═CR—CO-A-, H 2 C═CR—C 6 H 4 -A 1 -, H 2 C═CR—CH 2 A 2 , R 20 —CO—CR═CR—CO—O, RCH═CH—CO—O—, RCH═C(COOR 2 )CH 2 —CO—O,
A is —O— or NR 1 ;
A 1 is selected from the group consisting of a bond, (CH 2 ) I A 2 and (CH 2 ) I SO 3 — in which I is 1 to 12 ;
A 2 is selected from the group consisting of a bond, —O—, O—CO—, CO—O, CO—NR 1 —, —NR 1 —CO, O—CO—NR 1 —, and NR 1 —CO—O—;
R is hydrogen or C 1-4 alkyl;
R 1 is hydrogen, C 1-4 alkyl or BX;
R 2 is hydrogen or C 1-4 , alkyl;
B is selected from the group consisting of a bond, straight and branched alkanediyl groups, alkylene oxaalkylene groups, and alkylene (oligooxalkylene) groups, optionally containing one or more fluorine substituents; and
X is a zwitterionic group.
8 . A composition according to claim 7 in which X is a group of the general formula II
in which the moieties A 3 and A 4 , which are the same or different, are —O—, —S—, —NH— or a valence bond, and W + is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which is a C 1-12 -alkanediyl group.
9 . A composition according to claim 7 in which X has the general formula III
where the groups R 5 are the same or different and each is hydrogen or C 1-4 alkyl, and m is from 1 to 4.
10 . A composition according to claim 7 in which Y is H 2 C═CR—CO-A- in which R is H or methyl and -A- is —O— or —NH—.
11 . A composition according to claim 7 in which B is a C 2-6 -alkanediyl group.
12 . A composition according to claim 7 in which the zwitterionic monomer is 2-methacryloyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt.
13 . A composition according to claim 1 in which the hydrophobic block comprises pendant groups which are ionisable, having a pK A or pK B in the range 4 to 10.
14 . A composition according to claim 13 in which the hydrophobic block is formed by radical polymerisation of ethylenically unsaturated monomers.
15 . A composition according to claim 14 in which the monomers from which the hydrophobic block is formed have the general formula VII
Y 1 B 1 Q VII
in which Y 1 is an ethylenically unsaturated group selected from the group consisting of H 2 C═CR 40 —CO-A 8 -, H 2 C═CR 14 —C 6 H 4 -A 9 -, H 2 C═CR 14 —CH 2 A 10 , R 16 O—CO—CR 14 ═CR 14 —CO—O, R 14 CH═CH—CO—O—, R 14 CH═C(COOR 16 )CH 2 —CO—O,
A 8 is —O— or NR 15 ;
A 9 is selected from the group consisting of a bond, (CH 2 ) q A 10 and (CH 2 ) q SO 3 — in which q is 1 to 12;
A 10 is selected from the group consisting of a bond, —O—, O—CO—, CO—O—, CO—NR 41 —, —NR 41 —CO, O—CO—NR 15 —, and NR 15 —CO—O—;
R 14 is hydrogen or C 1-4 , alkyl;
R 15 is hydrogen, C 1-4 — alkyl or B 1 Q;
R 16 is hydrogen or C 1-4 alkyl;
B 1 is seletected from the group consisting of a bond, or a straight and branched alkanediyl groups, alkylene oxaalkylene groups, and alkylene (oligooxalkylene) groups, optionally containing one or more fluorine substituents; and
Q is a cationic or cationisable group of the formula —NR 17 P , —PR 17 p or SR 17 l , in which p is 2 or 3, r is 1 or 2, the groups R 17 are the same or different and each is selected from the group consisting of hydrogen, C 1-24 alkyl and aryl, or two of the groups R 17 together with the heteroatom to which they are attached from a 5 to 7 membered heterocyclic ring or three R 17 groups together with the heteroatom to which they are attached form a 5 to 7 membered heteroaromatic ring, either of which rings may be fused to another 5 to 7 membered saturated or unsaturated ring, and any of the R 17 groups may be substituted by amino or hydroxyl groups or halogen.
16 . A composition according to claim 15 in which Q is NR 17 2 in which each R 17 is H or C 1-4 -alkyl.
17 . A composition according to claim 5 in which the ethylenically unsaturated monomers include comonomer.
18 . A composition according to claim 17 in which the comonomer has the general formula VIII
in which R 18 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl and groups COOR 22 in which R 22 is hydrogen and C 1-4 alkyl;
R 19 is selected from the group consisting of hydrogen, halogen and C 1-4 alkyl;
R 20 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl and groups COOR 22 provided that R 18 and R 20 are not both COOR 22 ; and
R 21 is selected from the group consisting of C 1-10 alkyl, C 1-20 alkoxycarbonyl, mono- or di-(C 1-20 alkyl)amino carbonyl, C 6-20 aryl (including alkaryl) C 7-20 aralkyl, C 6-20 aryloxycarbonyl, C 1-20 -aralkyloxycarbonyl, C 6-20 arylamino carbonyl, C 7-20 aralkyl-amino, a hydroxyl and C 2-10 acyloxy groups, any of which may have one or more substituents selected from the group consisting of halogen atoms, and alkoxy, oligo-alkoxy, aryloxy, acyloxy, acylamino, amine, carboxyl, sulphonyl, phosphoryl, phosphino, zwitterionic, hydroxyl, vinyloxycarbonyl, and reactive silyl and silyloxy groups;
or R 21 and R 20 or R 21 and R 19 may together form —CONR 23 CO in which R 23 is a C 1-20 alkyl group.
19 . A composition according to claim 18 in which the comonomer is selected from the group consisting of a C 1-24 alkyl(alk)-acrylates C 1-24 -alkyl(alk)-acrylamides, mono- and di-hydroxy-C 1-6 -alkyl(alk)-acrylates, mono- and di-hydroxy-C 1-6 -alkyl(alk)acrylamides, oligo(C 2-3 alkoxy) C 2-18 alkyl(alk)-acrylates, C 2-18 alkyl(alk)acrylamides, styrene, vinylacetate and N-vinyllactam.
20 . A composition according to claim 1 in which the polydispersity of molecular weight of each of the blocks is less than 2.0.
21 . A composition according to claim 5 in which the degree of polymerisation of the hydrophilic block is in the range 2 to 1000.
22 . A composition according to claim 14 in which the degree of polymerisation of the hydrophobic block is in the range 5 to 2000.
23 . A composition according to claim 21 or 22 in which the ratio of the degrees of polymerisation of the hydrophobic to hydrophilic blocks is in the range 1:5 to 10:1.
24 . A composition according to claim 5 in which the radical polymerisation is a controlled radical polymerisation.
25 . A composition according to claim 24 in which the polymerisation is an atom transfer radical polymerisation or group transfer polymerisation.
26 . A composition according to claim 25 in which the initiator for the radical transfer polymerisation process is a polymer compound in which the polymeric moiety is hydrophobic which forms the hydrophobic block of the copolymer.
27 . A composition according to claim 25 in which the hydrophobic block is also formed from ethylenically unsaturated monomers by a radical transfer polymerisation process.
28 . A composition according to claim 1 in which the biologically active molecule is a cytotoxic compound.
29 . A method of forming an aqueous composition comprising an amphiphilic block copolymer and a biologically active compound, in which the copolymer comprises a hydrophilic block and a hydrophobic block in which process an aqueous dispersion of empty copolymer micelles is formed and the micellar dispersion is contacted with biologically active compound under conditions such that the biologically active compound becomes associated with the copolymer in the micelles, wherein the hydrophilic block has pendant zwitterionic groups.
30 . A method according to claim 29 in which the biologically active compound has a partition coefficient between octanol and water of at least 1.0.
31 . A method according to claim 29 in which the hydrophobic block of the copolymer comprises ionisable groups, and in which the empty copolymer micelles are formed by a process comprising:
a) a first copolymer dissolution step in which the block copolymer, with the groups of hydrophobic block in at least partially ionised form, is dissolved in an aqueous liquid, and b) a second micelle forming step in which the conditions in the solution are adjusted so that the ionised groups are converted at least partially to their ionisable form, whereby the copolymer is above the critical micelle concentration in the aqueous liquid and micelles are formed.
32 . A method according to claim 31 in which the conditions which are adjusted are of temperature and/or pH.
33 . A method according to claim 31 in which the ionisable groups are primary, secondary or tertiary amine groups and in which the micelle forming step involves raising the pH whereby the ionised groups become deprotonated.
34 . A method according to claim 29 in which the biologically active compound is in solid form when it is contacted with the aqueous dispersion of empty micelles.
35 . A method according to claim 29 in which the biologically active compound is in solution in an organic solvent when it is contacted with the aqueous dispersion of empty micelles.
36 . (canceled)
37 . A composition according to claim 3 in which the said partition coefficient is at least 1.5.
38 . A composition according to claim 8 in which W + is a group of formula —W 1 —N + R 3 3 , —W 1 —P + R 4 3 , —W 1 —S + R 4 2 or —W 1 -Het + in which:
W 1 is selected from the group consisting of alkanediyl of 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene and alkylene cycloalkyl alkylene, which group W 1 optionally contains one or more fluorine substituents and/or one or more functional groups; and either the groups R 3 are the same or different and each is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and aryl or two of the groups R 3 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R 3 together with the nitrogen atom to which they are attached as heteroaromatic ring having 5 to 7 atoms, either of which rings may be fused with another saturated or unsaturated ring to form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R 3 is substituted by a hydrophilic functional group, and the groups R 4 are the same or different and each is R 3 or a group OR 3 , where R 3 is as defined above; and Het is an aromatic nitrogen-, phosphorus- or sulphur-containing ring.
39 . A composition according to claim 14 in which the ethylenically unsaturated monomers include comonomer.
40 . A composition according to claim 39 in which the comonomer has the general formula VIII
in which R 18 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl and groups COOR 22 in which R 22 is hydrogen or C 1-4 alkyl;
R 19 is selected from the group consisting hydrogen, halogen and C 1-4 alkyl;
R 20 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl and groups COOR 22 provided that R 18 and R 20 are not both COOR 22 ;
R 21 is selected from the group consisting of C 1-10 alkyl, C 1-20 alkoxycarbonyl, mono- or di-(C 1-20 alkyl)amino carbonyl, C 6-20 aryl, C 7-20 aralkyl, C 6-20 aryloxycarbonyl, C 1-20 -aralkyloxycarbonyl, C 6-20 arylamino carbonyl, C 7-20 aralkyl-amino, hydroxyl and C 2-10 acyloxy group, any of which may have one or more substituents selected from the group consisting of halogen atoms and alkoxy, oligo-alkoxy, aryloxy, acyloxy, acylamino, amine, carboxyl, sulphonyl, phosphoryl, phosphino, zwitterionic, hydroxyl, vinyloxycarbonyl, and reactive silyl and silyloxy groups, or R 21 and R 20 or R 21 and R 19 may together form —CONR 23 CO in which R 23 is a C 1-20 alkyl group.
41 . A composition according to claim 40 in which the comonomer is selected from the group consisting of C 1-24 alkyl(alk)acrylates, C 1-24 alkyl(alk)acrylamides, mono- and di-hydroxy-C 1-6 alkyl(alk)acrylates, mono- and di-hydroxy-C 1-6 -alkyl(alk)acrylamides, oligo(C 2-3 alkoxy) C 2-18 -alkyl(alk)acrylates, C 2-18 alkyl(alk)acrylamides, styrene, vinylacetate and N-vinyllactam acrylamides, mono- and di-hydroxy-C 1-6 -alkyl(alk)acrylates, and acrylamides, oligo(C 2-3 alkoxy) C 2-18 -alkyl(alk)acrylates, and acrylamides, styrene, vinylacetate and N-vinyllactam.
42 . A composition according to claim 20 in which the said polydispersity is in the range 1.1 to 1.4.
43 . A composition according to claim 21 in which the said degree of polymerisation is in the range 10 to 100.
44 . A composition according to claim 22 in which the said degree of polymerisation is in the range 20 to 250 .
45 . A method according to claim 29 in which the biologically active molecule is a cytotoxic compound.
46 . A method according to claim 29 wherein the hydrophilic block is formed by radical polymerisation of ethylenically unsaturated monomers.
47 . A method according to claim 46 in which the monomers comprise a zwitterionic monomer.
48 . A method according to claim 47 in which the zwitterionic monomer has the general formula
Y B X I
in which Y is an ethylenically unsaturated group selected from the group consisting of H 2 C═CR—CO-A-, H 2 C═CR—C 6 H 4 -A 1 -, H 2 C═CR—CH 2 A 2 , R 20 —CO—CR═CR—CO—O, RCH═CH—CO—O—, RCH═C(COOR 2 )CH 2 —CO—O,
A is —O— or NR 1 ;
A 1 is selected from the group consisting of a bond, (CH 2 ) I A 2 and (CH 2 ) I SO 3 — in which I is 1 to 12;
A 2 is selected from the group consisting of a bond, —O—, O—CO—, CO—O, CO—NR 1 —, —NR 1 —CO, O—CO—NR 1 — and NR 1 —CO—O—;
R is hydrogen or C 1-4 alkyl;
R 1 is hydrogen, C 1-4 -alkyl or BX;
R 2 is hydrogen or C 1-4 alkyl; and
B is selected from the group consisting of a bond, straight and branched alkanediyl groups, alkylene oxaalkylene groups, and alkylene (oligooxalkylene) groups, optionally containing one or more fluorine substituents.
49 . A method according to claim 49 in which W + is a group of formula —W 1 —N + R 3 3 , —W 1 —P + R 4 3 , —W 1 —S + R 4 2 or —W 1 -Het + in which:
W 1 is selected from the group consisting of alkanediyl of 2-6 carbon atoms optionally containing one or more ethylenically unsaturated double or triple bonds, disubstituted-aryl (arylene), alkylene arylene, arylene alkylene, alkylene aryl alkylene, cycloalkanediyl, alkylene cycloalkyl, cycloalkyl alkylene and alkylene cycloalkyl alkylene, which group W 1 optionally contains one or more fluorine substituents and/or one or more functional groups; and either the groups R 3 are the same or different and each is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and aryl or two of the groups R 3 together with the nitrogen atom to which they are attached form an aliphatic heterocyclic ring containing from 5 to 7 atoms, or the three groups R 3 together with the nitrogen atom to which they are attached as heteroaromatic ring having 5 to 7 atoms, either of which rings may be fused with another saturated or unsaturated ring to form a fused ring structure containing from 5 to 7 atoms in each ring, and optionally one or more of the groups R 3 is substituted by a hydrophilic functional group, and the groups R 4 are the same or different and each is R 3 or a group OR 3 , where R 3 is as defined above; and Het is an aromatic nitrogen-, phosphorus- or sulphur-containing ring.
50 . A method according to claim 49 in which X is a group of the general formula II
in which the moieties A 3 and A 4 , which are the same or different, are —O—, —S—, —NH— or a valence bond and W + is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which is a C 1-12 -alkanediyl group.
51 . A method according to claim 48 in which X has the general formula III
where the groups R 5 are the same or different and each is hydrogen or C 1-4 alkyl, and m is from 1 to 4.
52 . The method according to claim 48 in which the zwitterionic monomer is 2-methacryloyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt.
53 . A method according to claim 29 in which the hydrophobic block comprises pendant groups which are ionisable, having a pK A or pK B in the range 4 to 10.
54 . A method according to claim 53 in which the hydrophobic block is formed by radical polymerisation of ethylenically unsaturated monomers including monomers having the general formula VII
Y 1 B 1 Q VII
in which Y 1 is an ethylenically unsaturated group selected from the group consisting of H 2 C═CR 40 —CO-A 8 -, H 2 C═CR 14 —C 6 H 4 -A 9 -, H 2 C═CR 14 —CH 2 A 10 , R 16 O—CO—CR 14 ═CR 14 —CO—O, R 14 CH═CH—CO—O—, R 14 CH═C(COOR 16 )CH 2 —CO—O,
A 8 is —O— or NR 15 ;
A 9 is selected from the group consisting of a bond, (CH 2 ) q A 10 and (CH 2 ) q SO 3 — in which q is 1 to 12;
A 10 is selected from the group consisting of a bond, —O—, O—CO—, CO—O—, CO—NR 41 —, —NR 41 —CO, O—CO—NR 15 — and NR 15 —CO—O—;
R 14 is hydrogen or C 1-4 alkyl;
R 15 is hydrogen, C 1-4 -alkyl or B 1 Q;
R 16 is hydrogen or C 1-4 alkyl;
B 1 is selected from the group consisting of a bond, straight and branched alkanediyl groups, alkylene oxaalkylene groups, and alkylene (oligooxalkylene) group, optionally containing one or more fluorine substituents; and
Q is a cationic or cationisable group of the formula —NR 17 P , —PR 17 P or SR 17 r , in which p is 2 or 3, r is 1 or 2, the groups R 17 are the same or different and each is selected from the group consisting of hydrogen, C 1-24 alkyl and aryl, or two of the groups R 17 together with the heteroatom to which they are attached from a 5 to 7 membered heterocyclic ring or three R 17 groups together with the heteroatom to which they are attached form a 5 to 7 membered heteroaromatic ring, either of which rings may be fused to another 5 to 7 membered saturated or unsaturated ring, and any of the R 17 groups may be substituted by amino or hydroxyl groups or halogen.
55 . A method according to claim 54 in which Q is NR 17 2 in which each R 17 is H or C 1-4 alkyl.
56 . A method according to claim 46 in which the radical polymerisation is a controlled radical polymerisation.Join the waitlist — get patent alerts
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