Drug delivery systems

• US 5,482,719 A
• Filed: 10/30/1992
• Issued: 01/09/1996
• Est. Priority Date: 10/30/1992
• Status: Expired due to Fees

• Current Assignee: Medipro Sciences Ltd.
• Original Assignee: Medipro Sciences Ltd.
• Inventors: Bakhtiyari, Hamid, Guillet, James E.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US07/971,996
• Time in Patent Office: 1,166 Days
• Field of Search: 424/486, 424/485, 424/78.38, 424/451, 424/78.08, 424/78.37, 424/78.31
• US Class Current: 424/486
• CPC Class Codes: A61K 41/0042 Photocleavage of drugs in vivo, e.g. cleavage of photolabile linkers in vivo by UV radiation for releasing the pharmacologically-active agent from the administered agent; photothrombosis or photoocclusion
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61N 5/0601 Apparatus for use inside the body
• CPC Class Codes: A61N 5/062 Photodynamic therapy, i.e. excitation of an agent

Abstract

A photoactivatable drug delivery system is provided, in which a drug is combined e.g. by covalent bonding, incorporation in a matrix or encapsulation, with a photosensitive macromolecule. In combination, the drug is inert. The macromolecule is large enough to prevent migration of the combination within the body, so that the combination can be implanted at a location of maximum effectiveness. The drug is released from the combination, in therapeutically active form, upon appropriate irradiation.

Claims

1. A macromolecular complex of a therapeutically effective amount of a therapeutic substance and a biologically acceptable polymer, covalently chemically bonded thereto through the intermediary of a photolabile covalent chemical bond, said complex being effectively therapeutically inert and biologically acceptable for administration to a mammal, the complex being capable upon incidence of radiation of appropriately chosen characteristics to release the therapeutic substance therefrom in a therapeutically active form.

2. The complex of claim 1 wherein the photolabile covalent chemical bond derives from a photolabile peptide blocker compound.

3. The complex of claim 1 wherein the photolabile covalent chemical bond is a chemical grouping of an oxy-methylene bond with the oxygen thereof covalently bound through its second valence link to the therapeutic substance group, and the methylene group bound through its second valence link to an aromatic nucleus at a position adjacent to a nitro substituent.

4. The complex of claim 3 wherein the aromatic nucleus of the grouping is benzene.

5. The complex of claim 4 wherein benzene nucleus is unsubstituted otherwise than by said nitro substituent, and is convalently chemically linked to said polymer at the position para to that of the methylene group.

6. The complex of claim 1 wherein the photolabile covalent chemical bond is derived from reaction of 3-nitro-4-bromomethylbenzoic acid coupled to the polymer at its position para to the bromo-methyl group, with a nucleophilic group on the therapeutic substance.

7. The complex of claim 1 wherein the photolabile chemical bond is derived from reaction of a compound of general formula:

##STR21## in which X is halogen, R is H or C1-C4 lower alkyl and R1 is C1-C4 alkylene, with a polymer through its carboxyl group and with the drug through its halo group.

8. The complex of claim 1 wherein said compound is [4-(2-chloropropionyl)phenyl]acetic acid.

9. The complex of claim 6 wherein the nucleophilic group on the therapeutic substance is a carboxylic acid group.

10. The complex of claim 1 wherein the polymer has a plurality of hydroxyl groups per molecule.

11. The complex of claim 10 wherein the polymer is selected from the group consisting of starch, starch derivatives, cyclodextrin, polyvinyl alcohol, polyethylene glycol and poly(hydroxyethylmethacrylate) and copolymers thereof.

12. The complex of claim 11 wherein the therapeutic substance is an anti-inflammatory agent.

13. The complex of claim 11 wherein the therapeutic substance is an anti-tumor agent.

14. The complex of claim 1 wherein the photolabile covalent chemical bond is a carbamate linkage from an amino group of the therapeutically active substance.

15. The complex of claim 14 including a nitrobenzene group interposed between the polymer and the carbamate linkage.

16. The complex of claim 1 wherein the photolabile covalent chemical bond is a keto aromatic group.

17. The complex of claim 16 wherein the keto aromatic group is linked to the therapeutic substance through an ether linkage, which on photolysis reforms a hydroxyl group on the therapeutically active substance.

22. The complex of claim 1 wherein the therapeutic substance is enclosed in a capsule of photodegradable polymeric material.

23. The complex of claim 22 wherein the photodegradable polymeric material is a copolymer containing polymerized groups derived from methyl vinyl ketone or methyl isopropenyl ketone, phenyl vinyl ketone or phenyl isopropenyl ketone.

24. The complex of claim 23 wherein the photodegradable polymeric material is a copolymer of methacrylic acid or methyl methacrylate with one of methylvinyl ketone and methylisopropenyl ketone, phenyl vinyl ketone and phenyl isopropenyl ketone.

18. A macromolelcular complex of a therapeutically effective amount of a therapeutic substance and a biologically acceptable polymer, the therapeutic substance and a biologically acceptable polymer, the therapeutic substance being diffused into a hydrogel of the biologically acceptable polymer, the hydrogel being susceptible to dimensional change upon exposure to light of appropriate wavelength, to release the therapeutic substance therefrom during such exposure.

19. The complex of claim 18 wherein the dimensional change is reversible.

20. The complex of claim 19 wherein the polymer of the hydrogel has attached thereto malachite green derivative groups.

21. The complex of claim 20 wherein the polymer of the hydrogel is derived form polymerization of acrylamide, 2-hydroxyethyl methacrylamide, dihydroxypropyl methacrylate, methylene bisacrylamide, tetraethyleneglycol dimethacrylate or triethyleneglycol dimethacrylate.