DRUG DELIVERY
Formulations of drugs and crystalline side chain polymers to provide controlled and/or sustained release drug formulations.
1 - 63 . (canceled)
49 . A pharmaceutical formulation which (i) comprises a drug and at least one crystalline side chain polymer (CYSC polymer) and (ii) has a crystalline melting point, Tp, above 37° C., the CYSC polymer being a polymer which
(A) has a backbone comprising
(1) a plurality of repeating units having formula (1) below, the units of formula (1) being the same or different,
where Y ch is a trivalent moiety forming part of the backbone of the CYSC polymer,
b is a bond or a divalent moiety which links the Cy moiety to the polymer backbone and which is not an anhydride linkage, and
Cy is a monovalent moiety which is capable of associating with other moieties to provide the CYSC polymer with crystallinity; and
(2) a plurality of units having formula (2) below, the units of formula (2) being the same or different, and the weight of the units of formula (2) being 5 to 25%, based on the weight of the polymer,
where Z is a moiety forming part of the backbone of the CYSC polymer, and
Rz is a hydrophilic moiety which is not a Cy moiety; and
(B) has a crystalline melting point, Tp, of 22 to 70° C., an onset of melting point, To, such that Tp−To is less than 15° C., and a heat of fusion of at least 10 J/g which results from the association of the Cy moieties;
(C) is free of main chain crystallinity;
(D) has a number average molecular weight, Mn, of 1000 to 20,000 Daltons;
(E) is not cross-linked or otherwise rendered non-flowable; and
(F) is a random copolymer or a block copolymer or block copolymer other than an elastomer.
50 . A composition according to claim 49 wherein Cy is a moiety containing 16-22 linear carbon atoms.
51 . A composition according to claim 49 wherein Cy is a moiety containing a polyoxyalkylene moiety.
52 . A composition according to claim 49 wherein the backbone of the CYSC polymer consists essentially of carbon atoms which are linked to each other directly by covalent bonds.
53 . A composition according to claim 49 wherein the CYSC polymer is a poly(meth)acrylate.
54 . A composition according to claim 49 wherein the Rz moiety comprises a carboxylic acid or hydroxyl moiety.
55 . A composition according to claim 49 wherein the Rz moiety comprises a ligand group which will bind to a target receptor site.
56 . A composition according to claim 49 which contains a first CYSC polymer having a first melting point Tp1 and a second CYSC polymer having a second melting point Tp2 which is at least 2° C. different from Tp1.
57 . A composition according to claim 49 which contains at least 5% by weight of the drug.
58 . A composition according to claim 49 wherein the drug is associated with the CYSC polymer through hydrogen bonding, ionic bonding or ligand attachment with the repeating units of formula (2) in the CYSC polymer.
59 . A composition according to claim 49 wherein the drug is covalently bound to the repeating units of formula (2) in the CYSC polymer.
60 . A composition according to claim 52 wherein the covalent bond between the drug and the CYSC polymer is pH-sensitive.
61 . A composition according to claim 49 wherein the drug is covalently bound to a moiety forming part of the polymer backbone.
62 . A composition according to claim 49 which is a solid and which has been treated with an aqueous or aqueous and organic solvent solution.
63 . A composition according to claim 49 which, when tested in vitro (elution into 1 L PBS, pH 7.2 at 37° C., stirred at 100 rpm), releases the drug in a way which has one or more of the following characteristics:
(a) an average rate of release no greater than 50 milligrams per day averaged over any 24 hour period during the first 168 hours of elution;
(b) an average rate no greater than 25 milligrams per day averaged over any 24 hour period during a period from 12 hours to 168 hours following inception of elution;
(c) continuously releases between 1 milligram and 60 milligram of the drug per day over a period of at least 30 days;
(d) continuously releases between 1 milligram and 60 milligrams of the drug per day averaged over any 24 hour period during a period from 12 hours to 168 hours following inception of elution;
(e) releases no more than 10% by weight of the drug present in the formulation over a period of 24 hours; and
(f) continuously releases a therapeutic dose of drug over a period of at least 30 days wherein the average 24 hour drug release rate is within one standard deviation of the 30 day mean.
64 . A pharmaceutical formulation which (i) comprises a drug and at least one crystalline side chain polymer (CYSC polymer) and (ii) has a crystalline melting point, Tp, above 37° C., the CYSC polymer being a polymer which
(A) has a backbone comprising
(1) a plurality of repeating units having formula (1) below, the units of formula (1) being the same or different,
where Y ch is a trivalent moiety forming part of the backbone of the CYSC polymer,
b is a bond or a divalent moiety which links the Cy moiety to the polymer backbone and which is not an anhydride linkage, and
Cy is a monovalent moiety which is capable of associating with other moieties to provide the CYSC polymer with crystallinity; and
(2) a plurality of units having formula (2) below, the units of formula (2) being the same or different, and the weight of the units of formula (2) being 5 to 25%, based on the weight of the polymer,
where Z is a moiety forming part of the backbone of the CYSC polymer, and
Rz is a hydrophilic moiety which is not a Cy moiety; and
(B) has a crystalline melting point, Tp, of 22 to 70° C., an onset of melting point, To, such that Tp−To is less than 15° C., and a heat of fusion of at least 10 J/g which results from the association of the Cy moieties; him
and which has at least one of the following characteristics:
(1) Cy contains a polyoxyalkylene moiety,
(2) the Rz moiety includes a ligand group which will bind to a target receptor site,
(3) the composition contains a first CYSC polymer having a first melting point Tp1 and a second CYSC polymer having a second melting point Tp2 which is at least 2° C. different from Tp1,
(4) the drug is associated with the CYSC polymer through hydrogen bonding, ionic bonding or ligand attachment with the repeating units of formula (2) in the CYSC polymer,
(5) the drug is covalently bound to the repeating units of formula (2) in the CYSC polymer, and
(6) the drug is covalently bound to a moiety forming part of the polymer backbone.
65 . A composition according to claim 64 which is a solid and which has been treated with an aqueous or aqueous and organic solvent solution.
66 . A composition according to claim 64 which, when tested in vitro (elution into 1 L PBS, pH 7.2 at 37° C., stirred at 100 rpm), releases the drug in a way which has one or more of the following characteristics:
(a) an the average rate of release no greater than 50 milligrams per day averaged over any 24 hour period during the first 168 hours of elution;
(b) an average rate no greater than 25 milligrams per day averaged over any 24 hour period during a period from 12 hours to 168 hours following inception of elution;
(c) continuously releases between 1 milligram and 60 milligram of the drug per day over a period of at least 30 days;
(d) continuously releases between 1 milligram and 60 milligrams of the drug per day averaged over any 24 hour period during a period from 12 hours to 168 hours following inception of elution;
(e) releases no more than 10% by weight of the drug present in the formulation over a period of 24 hours; and
(f) continuously releases a therapeutic dose of drug over a period of at least 30 days wherein the average 24 hour drug release rate is within one standard deviation of the 30 day mean.
67 . A method of treating a subject which comprises administering to the subject a pharmaceutical formulation which (i) comprises a drug and least one crystalline side chain polymer (CYSC polymer) and (ii) has a crystalline melting point, Tp, above 37° C., the CYSC polymer being a polymer which
(A) has a backbone comprising
(1) a plurality of repeating units having formula (1) below, the units of formula (1) being the same or different,
where Y ch is a trivalent moiety forming part of the backbone of the CYSC polymer,
b is a bond or a divalent moiety which links the Cy moiety to the polymer backbone and which is not an anhydride linkage, and
Cy is a monovalent moiety which is capable of associating with other moieties to provide the CYSC polymer with crystallinity; and
(2) a plurality of units having formula (2) below, the units of formula (2) being the same or different, and the weight of the units of formula (2) being 5 to 25%, based on the weight of the polymer,
where Z is a moiety forming part of the backbone of the CYSC polymer, and
Rz is a hydrophilic moiety which is not a Cy moiety; and
(B) has a crystalline melting point, Tp, of 22 to 70° C., an onset of melting point, To, such that Tp−To is less than 15° C., and a heat of fusion of at least 10 J/g which results from the association of the Cy moieties;
the drug being released from the formulation by a change in one or more of the following: (i) exposing the formulation to an enzyme, (ii) changing the pH of the environment surrounding the formulation, (iii) hydration of the formulation, (iv) oxidation of the formulation, (v) reduction of the formulation, and (vi) heating the formulation.
68 . A method according to claim 67 wherein the composition has at (a least one of the following characteristics:
(1) Cy contains a polyoxyalkylene moiety,
(2) the Rz moiety includes a ligand group which will bind to a target receptor site,
(3) the composition contains a first CYSC polymer having a first melting point Tp1 and a second CYSC polymer having a second melting point Tp2 which is at least 2° C. different from Tp1,
(4) the drug is associated with the CYSC polymer through hydrogen bonding, ionic bonding or ligand attachment with the repeating units of formula (2) in the CYSC polymer,
(5) the drug is covalently bound to the repeating units of formula (2) in the CYSC polymer, and
(6) the drug is covalently bound to a moiety forming part of the polymer backbone.