Biodegradable block copolymeric compositions for drug delivery

Abstract

An improved drug delivery composition and method of use is disclosed. The composition comprises one or more biodegradable block copolymer drug carriers; and a reconstitution enhancing and enabling agent comprising polyethylene glycol (PEG), a PEG derivative or a mixture of PEG and a PEG derivative. The composition can be administered as is or after being be dissolved or rapidly reconstituted in an aqueous vehicle to afford a homogeneous solution or uniform colloidal systems.

1 - 34 . (canceled) 
     
     
         35 . A method of preparing an improved drug delivery formulation comprising the steps of:
 A) providing a drug delivery composition comprising
 (i) one or more biodegradable block copolymer drug carriers comprising A-B, A-B-A or B-A-B block copolymers having a total weight average molecular weight of 1000 to 100,000 Daltons, wherein the A block is a biodegradable polyester or poly(ortho ester) and the B block is polyethylene glycol(PEG), and the weight percentage of the A block is between 20 to 99% and the weight percentage of the B block is between 1 to 80%, wherein said block copolymer, when formed as an aqueous polymer solution, remains a free flowing liquid upon parenteral administration; and 
 (ii) a liquid polyethylene glycol(PEG), a PEG derivative, or a mixture of PEG and a PEG derivative, said PEG or PEG derivative having a molecular weight of 150 to 1100 Daltons; and wherein the biodegradable block copolymeric drug carriers is soluble in the liquid PEG, PEG derivatives, or mixtures of PEG and PEG derivatives; and wherein the weight ratio of the biodegradable block copolymeric drug carrier and the PEG, PEG derivative or mixtures thereof is within the range of 5:1 to 1:99, and 
   B) formulating the composition as an injectable liquid which is without water, or mixing the water or mixing an aqueous solution with the composition to form a homogeneous aqueous solution or a uniform colloidal system.   
     
     
         36 . The method according to  claim 35  wherein the ratio of the composition to water or aqueous solution is within the range of 2:1 to 1:10,000. 
     
     
         37 . The method according to  claim 35  wherein the composition can be reconstituted in water or an aqueous solution to form a homogeneous solution or an uniform colloidal system within 0.01 minutes to 180 minutes. 
     
     
         38 . A method of preparing an improved drug delivery formulation comprising the steps of:
 A) providing a drug delivery composition comprising
 (i) one or more biodegradable block copolymer drug carriers comprising A-B. A-B-A or B-A-B block copolymers having a total weight average molecular weight of 2000 to 8000 Daltons, wherein the A block is a biodegradable polyester or poly(ortho ester) and the B block is polyethylene glycol(PEG), and the weight percentage of the A block is between 50.1% to 83% and the weight percentage of the B block is between 17% to 49.9%, wherein said block copolymer, when formed as an aqueous polymer solution, remains a free flowing liquid upon parenteral administration; and 
 (ii) a polyethylene glycol(PEG), a PEG derivative, or a mixture of PEG and a PEG derivative, said PEG or PEG derivative having a molecular weight of 150 to 1100 Daltons; and wherein at least one of the biodegradable block copolymeric drug carriers is soluble in an aqueous solution and miscible with the PEG, PEG derivatives, or mixtures thereof, and wherein the weight ratio of the biodegradable block copolymeric drug carrier and the PEG. PEG derivative or mixtures thereof is within the range of 5:1 to 1:99; and 
   B) formulating the composition as an injectable liquid which is without water, or mixing water or mixing an aqueous solution with the composition to form a homogeneous aqueous solution or a uniform colloidal system.   
     
     
         39 . The method according to  claim 38  wherein the ratio of the composition to water or aqueous solution is within the range of 2:1 to 1:10,000. 
     
     
         40 . The method according to  claim 38  wherein the composition can be reconstituted in water or an aqueous solution to form a homogeneous solution or an uniform colloidal system within 0.01 minutes to 180 minutes. 
     
     
         41 . A method of preparing an improved drug delivery formulation comprising the steps of:
 A) providing a drug delivery composition comprising
 (i) one or more biodegradable block copolymer drug carriers comprising A-B, A-B-A or B-A-B block copolymers having a total weight average molecular weight of 1000 to 100,000 Daltons, wherein the A block is a biodegradable polyester or poly(ortho ester) and the B block is polyethylene glycol(PEG), and the weight percentage of the A block is between 20 to 99% and the weight percentage of the B block is between 1 to 80%, wherein said block copolymer, when formed as an aqueous polymer solution, remains a free flowing liquid upon parenteral administration; and 
 (ii) a liquid polyethylene glycol(PEG), a PEG derivative, or a mixture of PEG and a PEG derivative, said PEG or PEG derivative having a molecular weight of 150 to 1100 Daltons; and wherein the biodegradable block copolymeric drug carriers is soluble in the liquid PEG. PEG derivatives, or mixtures of PEG and PEG derivatives, and wherein the weight ratio of the biodegradable block copolymeric drug carrier and the PEG, PEG derivative or mixtures thereof is within the range of 5:1 to 1:99; and 
   B) formulating the composition as an injectable liquid without adding water.   
     
     
         42 . The method according to  claim 35  wherein the PEG derivative is an ester derivatized PEG wherein the PEG is derivatized from a member selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, and mixtures thereof. 
     
     
         43 . The method according to  claim 35  wherein the PEG derivative is an ortho ester derivatized PEG. 
     
     
         44 . The method according to  claim 35  wherein the PEG derivative is represented by R 1 —CO—O—(CH 2 —CH 2 —O) n —CO—R 2  or R 1 —O—(CH 2 —CH 2 —O) n —R 2  wherein R 1  and R 2  are independently members selected from the group consisting of H and C 1  to C 10  alkyl and n is an integer between 3 and 20. 
     
     
         45 . The method according to  claim 35  further comprising a drug. 
     
     
         46 . The method according to  claim 38  wherein the PEG derivative is an ester derivatized PEG wherein the PEG is derivatized from a member selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxy butyric acid, ε-valerolactone, δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, and mixtures thereof. 
     
     
         47 . The method according to  claim 38  wherein the PEG derivative is an ortho ester derivatized PEG. 
     
     
         48 . The method according to  claim 38  wherein the PEG derivative is represented by R 1 —CO—O—(CH 2 —CH 2 —O) n —CO—R 2  or R 1 —O—(CH 2 —CH 2 —O), —R 2  wherein R 1  and R 2  are independently members selected from the group consisting of H and C I  to C 10  alkyl and n is an integer between 3 and 20. 
     
     
         49 . The method according to  claim 38  further comprising a drug. 
     
     
         50 . The method according to  claim 38 , wherein the biodegradable ABA-type, BAB- or AB-type block copolymer comprising:
 i) 50.1 to 65% by weight of a biodegradable, hydrophobic A block comprising a biodegradable polyester or poly(ortho ester), and   ii) 35 to 49.9% by weight of a hydrophilic B block comprising a polyethylene glycol (PEG), and wherein the block copolymer has a weight average molecular weight of between 2400 to 4999 daltons, with the proviso that said block copolymer, when formed as an aqueous polymer solution, is a free flowing liquid at temperatures of between at least 35 to 42° C.   
     
     
         51 . The method according to  claim 50 , wherein the PEG derivative is an ester derivatized PEG wherein the PEG is derivatized from a member selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, E-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, and mixtures thereof. 
     
     
         52 . The method according to  claim 50  wherein the PEG derivative is an ortho ester derivatized PEG. 
     
     
         53 . The method according to  claim 50  wherein the PEG derivative is represented by R 1 —CO—O—(CH 2 —CH 2 —O) n —CO—R 2  or R 1 —O—(CH 2 —CH 2 —O) n —R 2  wherein R 1  and R 2  are independently members selected from the group consisting of H and C 1  to C 10  alkyl and n is an integer between 3 and 20. 
     
     
         54 . The method according to  claim 50  further comprising a drug. 
     
     
         55 . The method according to  claim 41  wherein the PEG derivative is an ester derivatized PEG wherein the PEG is derivatized from a member selected from the group consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic acid, ε-caprolactone, 1,4-dioxan-2-one, ε-hydroxy hexanoic acid, γ-butyrolactone, γ-hydroxy butyric acid, δ-valerolactone, δ-hydroxy valeric acid, hydroxybutyric acids, malic acid, and mixtures thereof. 
     
     
         56 . The method according to  claim 41  wherein the PEG derivative is an ortho ester derivatized PEG. 
     
     
         57 . The method according to  claim 41  wherein the PEG derivative is represented by R 1 —CO—O—(CH 2 —CH 2 —O) n —CO—R 2  or R 1 —O—(CH 2 —CH 2 —O) n —R 2  wherein R 1  and R 2  are independently members selected from the group consisting of H and C I  to C 10  alkyl and n is an integer between 3 and 20. 
     
     
         58 . The method according to  claim 41  further comprising a drug.