Controlled release system
The present invention relates to controlled release systems that may be administered other than intravenously. The controlled release system is directed to active ingredients, entrapped in or otherwise incorporated in or coupled to polymer carriers or polymeric devices, such as micelles, nanoparticles, microspheres and other types of polymer devices for controlled release; the active ingredients are covalently bonded to the polymer carriers or polymeric devices. The controlled release systems may suitably be used to treat diseases.
1. Method to provide the bloodstream of a vertebrate subject with an intact nanoparticulate control release system comprising at least one active ingredient for systemic treatment of a disease which method comprises administering the nanoparticulate control release system via a subcutaneous or intraperitoneal route, and
wherein the control release system is obtained by
(i) mixing active ingredient comprising a first reactive moiety with an aqueous solution or dispersion comprising polymer chains, said polymer chains comprising at least one second reactive moiety capable of reacting with said first reactive moiety of said at least one active ingredient, the polymer chains further being capable of cross-linking intra- or intermolecularly; and
(ii) subjecting this mixture to cross-linking forming a 3D-matrix under such conditions that simultaneously with the formation of the 3D-matrix, said at least one active ingredient is entrapped;
wherein the polymer chains comprise polymers of hydrophobically modified esters of N-hydroxyalkyl-(meth)acrylamide and N-(meth)acryloyl amino acids; and wherein said at least one active ingredient is covalently coupled to the 3D matrix.
2. Method according to claim 1 , wherein polymer chains include monomers derived from N-isopropylacrylamide and/or alkyl-2-oxazalines.
3. Method according to claim 1 , wherein said control release system comprises micelle, hydrogel and/or coating forming polymers based on said polymers.
4. Method according to claim 1 , wherein the polymer chains are di- or triblock copolymers with PEG.
5. Method according to claim 1 , wherein the control release system has a hydrodynamic diameter that is smaller than 100 nm.
6. Method according to claim 1 , wherein the control release system has a neutral surface charge.
7. Method according to claim 1 , wherein said at least one active ingredient is a drug molecule, a peptide, a protein, an imaging agent, genetic material or a combination thereof.
8. Method according to claim 1 , wherein the polymer chains and said at least one active ingredient contain polymerisable moieties.
9. Method according to claim 1 , wherein the polymer chains comprise terminal double bonds or are linear chains containing carbon-carbon double bonds.
10. Method according to claim 1 , wherein the active ingredient is coupled to the 3D-matrix via a degradable bond.
11. Method according to claim 1 , wherein the 3D-matrix is coupled to the active ingredient via
HOQ-(C n H 2n )—S(R 1 )(R 2 )—(C m H 2m )—CH 2 -A,
wherein n and m are integers from 0 to 20;
wherein each R 1 and R 2 is independently selected from an electron lone pair, an oxygen moiety, and a nitrogen moiety;
wherein A is a conjunction moiety; and
wherein Q is a direct bond, C═O, C═NH or C=NRp, wherein Rp is a C1-C3 alkyl.
12. Method according to claim 1 , wherein the control release system comprises targeted ligands.
13. Method according to claim 1 , wherein the treatment is of a disease selected from the group consisting of cancer, infection, ophthalmological diseases, viral infection, bacterial infection, fungal infection, mycoplasma infection, parasite infection, inflammation, dermatological diseases, cardiovascular diseases, diseases of the central nerve system, auto-immune disease, proliferative diseases, arthritis, psychotic diseases, psoriasis, diabetes, metabolic disorders, lung diseases, respiratory diseases, pulmonary diseases, COPD, diseases of the muscoskeletal system, emphysema, edema, dementia, and hormonal diseases.
14. Method according to claim 1 , wherein the at least one active ingredient is an anesthetic or therapeutic or preventive vaccine.
15. Method according to claim 1 , wherein said polymer chains are (co)polymers of N-hydroxyalkyl methacrylamide-oligolactates.
16. Method according to claim 15 wherein said polymer chains are (co)polymers of (oligo)lactate esters of HPMAm (hydroxypropyl methacrylamide) or HEMAm (hydroxyethylmethacrylamide).
17. Method according to claim 5 wherein the control release system has a hydrodynamic diameter that is between 30-90 nm.
18. Method according to claim 1 wherein the polymer chain comprises vinyl groups, (meth)acrylate groups and/or (meth)acrylamide groups.
19. Method according to claim 1 wherein the vertebrate is a mammal.
20. Method according to claim 1 wherein the vertebrate is a human.
21. Method according to claim 8 wherein the polymerisable moieties are free-radical polymerisable moieties.