Process for the preparation of azo-and /or disulfide polymer mat

Details Process for the preparation of azo-and /or disulfide polymer mat Process for the preparation of azo-and /or disulfide polymer mat

1992-09-09

1995-04-18

Page, Thurman K.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

424426, 424468, 424486, 424482, 424497, A61K 922, A61K 4734

Patent

active

054076820

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a process for the preparation of azo- and/or disulfide- containing polymers to be used in the preparation of drug delivery systems providing a site specific delivery of the active agent in the colon.
The novel azo and disulfide containing polymers can be applied for preparing drug delivery systems that result in a site specific release of the drug in the lower part of the intestine.
It has been mentioned in the literature that the colon is a reductive medium and that enzymes are present which are able to cleave azo and disulfide bonds in organic molecules.
Peppercorn et al. published in Journal of Pharmacology and Experimental Therapy, 181, 555, 1972 that salicylazosulfapyridine (a drug applied for the therapeutic treatment of ulcerative colitis) (azuflidine, sulfasalazine) can be cleaved by microflora in the colon with release of 5-aminosalicylic acid.
U.S. Pat. Nos. 4,190,716 and 4,298,595 describe polymers having 5-aminosalicylic acid linked to a polymer backbone via an aromatic azo linkage which can be used for the site specific release of 5-aminosalicylic acid in the colon.
U.S. Pat. No. 4,663,308 describes the synthesis of a potentially crosslinked polymer obtained by radical copolymerization of vinyl monomers with an azo-containing comonomer which functions as a crosslinker during polymerization. A typical example of such an azo-containing crosslinker is 4,4'-divinylazobenzene. The resulting polymers were tested for the preparation of site selective drug delivery systems enabling the release of drug in the colon. Drug delivery systems can consist of systems coated by the azopolymer. The release of the enclosed drug is caused by enzymatic degradation of polymeric coating.
These systems have been proposed as a means to deliver drugs (e.g. peptides) via rectal and oral application to the colon.
Preliminary in vivo experiments with vasopressin containing dosage forms, coated with the azo-containing polymers, demonstrated the release of the peptide following oral administration of the novel dosage form. (Saffran, Journal of Pharmaceutical Sciences, 1988; Polymer Preprints, 1988; Science, 1986).
The azo-containing polymer systems described by Saffran all have in common their preparation via a copolymerization of vinyl-type monomers with substituted or nonsubstituted divinylazobenzene. This will ultimately lead to crosslinked polymers. ##STR1## The disadvantage of this procedure is the possibility for crosslinkage of the polymer.
The polymers obtained after copolymerization of vinylmonomers with divinylazobenzene are to some extent crosslinked. Crosslinked polymers are insoluble and infusable. The reproducibility of preparing low degree crosslinked and still soluble polymers is anticipated to be very low.
The available literature learns that, not only azobonds but also disulfide bonds can be cleaved in the reductive medium that exists in the lower part of the G.I. tract, i.e. the colon.
The reductive potential in caecal contents has been reported in the literature, e.g. by H. Schroder and A. Johanssson (Xenobiotica, 3,4, 233-246, 1973). The potentials recorded ranged from -100 to -400 mV. This reductive medium is anticipated to be able to reduce disulfide bonds in organic compounds.
The disulfide bond in glutathione drug conjugates can be reduced in the colon and lead to liberation of the glutathion-linked thiol (G. L. Larsen, J. P. Larson, J. A. Gustarson, Fusobacterium necrophorum, Xenobiotica, 13, 689, 1983).
The objective of the presently described invention is the preparation of a series of azo- and disulfide-containing polymers which are susceptible to reductive cleavage in the gastro intestinal tract, i.e. in the colon, and which will be used for the preparation of colon specific drug delivery systems.
The method by which these reduction clearable polymers are prepared is the polycondensation or polyaddition of an .alpha.,.omega.-difunctional reagent with an appropriate .alpha.,.omega.-difunctional comonomer.
The reduction sensitive polymers are prepared according to

REFERENCES:
patent: 3909497 (1975-09-01), Hendry et al.
patent: 4298595 (1981-11-01), Parkinson et al.
patent: 4663308 (1987-05-01), Saffran
patent: 5225514 (1993-07-01), Kimura et al.

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