Semi-solid delivery systems
The invention provides semi-solid systems for delivering biologically active materials that include a polymer comprising 1) one or more polycaprolactone (PCL) units and 2) at least one or more polyethylene glycol (PEG) units; wherein at least one of said polycaprolactone units is conjugated to a PEG forming an acetal group.
1. A polymer comprising 1) one or more polycaprolactone (PCL) units and 2) at least one or more polyethylene glycol (PEG) units; wherein at least one of said polycaprolactone units is conjugated to a PEG unit forming an acetal group, wherein said polymer comprises one or more units of formula (I):
wherein:
A is an acid-labile, hydrolytically cleavable acetal group; and PCL/PEG is either a polycaprolactone or a polyethylene glycol chain, or is a chain containing polycaprolactone and polyethylene glycol groups.
2. The polymer of claim 1 , wherein each PCL is a homopolymer of caprolactone.
3. The polymer of claim 1 which comprises one or more units of formula II:
wherein:
R in each occurrence is independently (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 10 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 3 -C 8 )cycloalkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-(C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, or (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl; and
m in each occurrence is an integer from 1 to 50.
4. The polymer of claim 3 wherein R is (C 2 -C 10 )alkyl.
5. The polymer of claim 1 which comprises one or more units of formula (III):
wherein
R in each occurrence is independently (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 10 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 3 -C 8 )cycloalkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-(C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, or (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl;
m in each occurrence is an integer from 1 to 50; and
p is an integer from 1 to 50.
6. The polymer of claim 1 which comprises one or more units of formula (IV)
wherein:
R in each occurrence is independently (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 10 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 3 -C 8 )cycloalkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-(C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, or (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl; and
m in each occurrence is an integer from 1 to 50;
n in each occurrence is an integer from 1 to 50.
7. The polymer of claim 1 which comprises one or more units of formula (V)
wherein
R in each occurrence is independently (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 10 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 3 -C 8 )cycloalkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-(C 3 -C 8 )cycloalkyl-(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, or (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl;
m in each occurrence is an integer from 1 to 50;
n is an integer from 1 to 50; and
o is an integer from 1 to 50.
8. The polymer of claim 1 which has a molecular weight of at least about 2000.
9. The polymer of claim 1 which has a molecular weight of at least about 10,000.
10. The polymer of claim 1 which has a molecular weight of less than about 50,000.
11. The polymer of claim 1 which has a molecular weight of 15,000±10,000.
12. The polymer of claim 1 comprising one or more units of the formula:
wherein: R 1 is (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkenyl containing 1 to 3 double bonds; R 2 is hydrogen, (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkenyl containing 1 to 3 double bonds, wherein the position at which R 2 is connected to R 1 can be at the α, β, γ, δ, ε, ζ carbon of R 1 ; m is an integer from 1-20; and n is an integer from 1-20.
13. The polymer of claim 1 comprising polyethyleneoxide having a molecular weight of no more than about 2000.
14. The polymer of claim 1 comprising polyethyleneoxide having a molecular weight of no more than about 1000.
15. A pharmaceutical composition comprising a polymer as described in claim 1 and a biologically active agent.
16. The composition of claim 15 wherein the biologically active agent is selected from small molecular drugs, large molecular drugs, proteins, antibodies, peptides, polysaccharides, nucleic acids.
17. The composition of claim 16 wherein the biologically active agent is a tumor antigen or immunostimulatory adjuvant.
18. The composition of claim 15 wherein the biologically active agent is a tumor cell, a tumor-associated peptide, a tumor neoantigen from genetic mutation in somatic tumor cells, an aberrantly glycolsylated tumor protein, tumor cell membrane, or DNA encoding any of the above.
19. The composition of claim 15 , wherein the biologically active agent is CpG oligodeoxynucleotide, polyinosinic-polycytidylic acid (polyIC), imiquimod, an imidazoquinoline-derivative of imiquimod, resiquimod, or flagellin.