Biodegradable low molecular weight triblock poly (lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
First Claim
1. A biodegradable ABA- or BAB-type triblock polymer, said ABA triblock having the formula:
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space="preserve" listing-type="equation">PL(G).sub.z-1 A-PEG-PL(G).sub.z-1 Aand said BAB triblock having the formula;
space="preserve" listing-type="equation">PEG-PL(G).sub.z-1 A-PEGwherein z is an integer of 1 or 2, wherein the A-block is represented by PL(G)z-1 A such that when z is 2 the A-block is a poly(lactide-co-glycolide) or PLGA copolymer, and when z is 1 the A-block is a poly(lactide) or PLA polymer and wherein the B-block is represented by PEG which is a hydrophilic polyethylene glycol polymer, said block copolymer having a weight average molecular weight of between about 2000 to 4990 and possessing reverse thermal gelation properties, and wherein said PL(G)z-1 A A-block comprises about 51 to 83% by weight of said polymer and the PEG B-block comprises about 17 to 49% by weight of said polymer.
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Abstract
A water soluble biodegradable ABA- or BAB-type triblock polymer is disclosed that is made up of a major amount of a hydrophobic polymer made of a poly(lactide-co-glycolide) copolymer or poly(lactide) polymer as the A-blocks and a minor amount of a hydrophilic polyethylene glycol polymer B-block, having an overall weight average molecular weight of between about 2000 and 4990, and that possesses reverse thermal gelation properties. Effective concentrations of the triblock polymer and a drug may be uniformly contained in an aqueous phase to form a drug delivery composition. At temperatures below the gelation temperature of the triblock polymer the composition is a liquid and at temperatures at or above the gelation temperature the composition is a gel or semi-solid. The composition may be administered to a warm-blooded animal as a liquid by parenteral, ocular, topical, inhalation, transdermal, vaginal, transurethral, rectal, nasal, oral, pulmonary or aural delivery means and is a gel at body temperature. The composition may also be administered as a gel. The drug is released at a controlled rate from the gel which biodegrades into non-toxic products. The release rate of the drug may be adjusted by changing various parameters such as hydrophobic/hydrophilic componenet content, polymer concentration, molecular weight and polydispersity of the triblock polymer. Because the triblock polymer is amphiphilic, it functions to increase the solubility and/or stability of drugs in the composition.
223 Citations
69 Claims
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1. A biodegradable ABA- or BAB-type triblock polymer, said ABA triblock having the formula:
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space="preserve" listing-type="equation">PL(G).sub.z-1 A-PEG-PL(G).sub.z-1 Aand said BAB triblock having the formula;
space="preserve" listing-type="equation">PEG-PL(G).sub.z-1 A-PEGwherein z is an integer of 1 or 2, wherein the A-block is represented by PL(G)z-1 A such that when z is 2 the A-block is a poly(lactide-co-glycolide) or PLGA copolymer, and when z is 1 the A-block is a poly(lactide) or PLA polymer and wherein the B-block is represented by PEG which is a hydrophilic polyethylene glycol polymer, said block copolymer having a weight average molecular weight of between about 2000 to 4990 and possessing reverse thermal gelation properties, and wherein said PL(G)z-1 A A-block comprises about 51 to 83% by weight of said polymer and the PEG B-block comprises about 17 to 49% by weight of said polymer. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
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9. An aqueous biodegradable polymeric drug delivery composition possessing reverse thermal gelation properties comprised of an aqueous phase having uniformly contained therein:
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(a) an effective amount of a drug; and (b) a biodegradable ABA- or BAB-type triblock polymer said ABA triblock having the formula;
space="preserve" listing-type="equation">PL(G).sub.z-1 A-PEG-PL(G).sub.z-1 Aand said BAB triblock having the formula;
space="preserve" listing-type="equation">PEG-PL(G).sub.z-1 A-PEGwherein z is an integer of 1 or 2, wherein the A block is represented by PL(G)z-1 A such that when z is 2 the A block is a poly(lactide-co-glycolide) or PGLA copolymer, and when z is 1 the A block is a poly(lactide) or PLA polymer and wherein the B block is represented by PEG which is a hydrophilic polyethylene glycol polymer, said triblock polymer having a weight average molecular weight of between about 2000 to 4990, and wherein, in the triblock polymer, the PL(G)z-1 A A-block comprises about 51 to 83% by weight of said polymer and the PEG B-block comprises about 17 to 49% by weight of said polymer. - View Dependent Claims (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)
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24. A method for the administration of a drug to a warm blooded animal in a controlled release form which comprises:
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(1) providing an aqueous biodegradable polymeric drug delivery composition possessing reverse thermal gelation properties comprised of an aqueous phase having uniformly contained therein; (a) an effective amount of a drug; and (b) a biodegradable ABA- or BAB-type triblock polymer said ABA triblock having the formula;
space="preserve" listing-type="equation">PL(G).sub.z-1 A-PEG-PL(G).sub.z-1 Aand said BAB triblock having the formula;
space="preserve" listing-type="equation">PEG-PL(G).sub.z-1 A-PEGwherein z is an integer of 1 or 2, wherein the A block is represented by PL(G)z-1 A such that when z is 2 the A block is a poly(lactide-co-glycolide) or PLGA copolymer and when z is 1 the A block is a poly(lactide) or PLA polymer and wherein the B block is represented by PEG which is a hydrophilic polyethylene glycol polymer, said block copolymer having a weight average molecular weight of between about 2000 to 4990, and wherein, in the triblock polymer, the PL(G)z-1 A A-block comprises about 51 to 83% by weight of said polymer and the PEG B-block comprises about 17 to 49% by weight of said polymer, (2) maintaining said composition as a liquid at a temperature below the gelation temperature of said triblock polymer; and (3) administering said composition as a liquid to said warm blooded animal with the subsequent formation of a gel as the temperature of said composition is raised by the body temperature of said animal to be above the gelation temperature of said triblock polymer. - View Dependent Claims (25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)
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40. A method for enhancing the solubility of a drug comprising uniformly admixing an effective amount of said drug in an aqueous biodegradable polymeric drug delivery composition possessing reverse thermal gelation properties said aqueous composition being comprised of an aqueous phase having uniformly contained therein a biodegradable ABA- or BAB-type triblock polymer said ABA triblock having the formula:
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space="preserve" listing-type="equation">PL(G).sub.z-1 A-PEG-PL(G).sub.z-1 Aand said BAB triblock having the formula;
space="preserve" listing-type="equation">PEG-PL(G).sub.z-1 A-PEGwherein z is an integer of 1 or 2, wherein the A-block is represented by PL(G)z-1 A such that when z is 2 the A-block is a poly(lactide-co-glycolide) or PLGA copolymer, and when z is 1 the A-block is a poly(lactide) or PLA polymer and wherein the B-block is represented by PEG which is a hydrophilic polyethylene glycol polymer, said triblock polymer having a weight average molecular weight of between about 2000 to 4990, and wherein, in the tri-block polymer, the PL(G)z-1 A A-block comprises about 51 to 83% by weight of said polymer and the PEG B-block comprises about 17 to 49% by weight of said polymer. - View Dependent Claims (41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)
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55. A method for enhancing the stability of a drug comprising uniformly admixing an effective amount of said drug in an aqueous biodegradable polymeric drug delivery composition possessing reverse thermal gelation properties said aqueous composition being comprised of an aqueous phase having uniformly contained therein a biodegradable ABA- or BAB-type triblock polymer said ABA triblock having the formula:
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space="preserve" listing-type="equation">PL(G).sub.z-1 A-PEG-PL(G).sub.z-1 Aand said BAB triblock having the formula;
space="preserve" listing-type="equation">PEG-PL(G).sub.z-1 A-PEGwherein z is an integer of 1 or 2, wherein the A-block is represented by PL(G)z-1 A such that when z is 2 the A-block is a poly(lactide-co-glycolide) or PLGA copolymer, and when z is 1 the A-block is a poly(lactide) or PLA polymer and wherein the B-block is represented by PEG which is a hydrophilic polyethylene glycol polymer, said triblock polymer having a weight average molecular weight of between about 2000 to 4990, and wherein, in the triblock Polymer, the PL(G)z-1 A A-block comprises about 51 to 83% by weight of said polymer and the PEG B-block comprises about 17 to 49% by weight of said polymer. - View Dependent Claims (56, 57, 61, 62, 63, 64, 65, 66, 67, 68, 69)
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- 58. A method according to claim 58 wherein the triblock polymer is a ABA type.
Specification