Tailored Polymeric Materials for Controlled Delivery Systems

Chapter 9

Injectable Absorbable Gel-Formers for the Controlled Release of Bioactive Agents-Drugs

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 16, 2015 | http://pubs.acs.org Publication Date: September 24, 1998 | doi: 10.1021/bk-1998-0709.ch009

Shalaby W. Shalaby R&D Laboratories, Poly-Med, Inc., Westinghouse Road, Pendleton, SC 29625

The concept of hydrogel-forming, self-solvating absorbable polyester copolymers and typical examples are noted. Application of representative gel formulations for the controlled release of a number of bioactive agents, including antibiotics, immunosuppressants, and a vaccine are presented. On-going studies and future perspectives on the broad-based applications of this new family of drug carriers are briefly discussed.

Growing interest in developing absorbable pharmaceutical and surgical products which degrade in the biological environment to safe by-products and leave no residual mass at the application site (7-9), justified the search for novel, absorbable gels. In a recent disclosure (10), novel gel formers were described to be based on absorbable copolymers which, upon hydration, result in hydrogels that are stabilized by pseudocrosslinks provided by hydrophobic polyester components covalently linked to hydrophilic ones made of pharmaceutically acceptable polymer, such as polyoxyethylene. The polyester component is made of safe monomers, such as pdioxanone, e-caprolactone, glycolide, lactide, and mixtures thereof. Contrary to a related study (77), which describes in-situ formation of biodegradable, microporous, solid implants in a living body through coagulation of a solution of a polymer in an organic solvent such as N-methyl-2-pyrrolidine, the new hydrogel formers do not require the use of solvents. Such solvents did include low molecular organic ones that can migrate from the application site and cause damage to living tissue, such as cell dehydration and necrosis. Equally important is the fact that previously known systems are solid implants which can elicit mechanical incompatibility and, hence, patient discomfort as compared with the new compliant, swollen, mechanically compatible hydrogels (10). Meanwhile, potential applications of the w-s#f/-forming implants, and the more recent gel-formers, have been described to entail their use for tissue regeneration and release of growth factors (72). Depending on the composition of the

©1998 American Chemical Society

In Tailored Polymeric Materials for Controlled Delivery Systems; McCulloch, I., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

125


126 gel-formers used in the present study, these absorbable matrices can be used for the controlled release of antibiotics over a period of 1 to 6 weeks (JO). The use of absorbable gel-formers may very well lead to some of the most important applications of absorbable polymers in the pharmaceutical and biomedical industries. These would include use of the gel-formers in (1) periodontal application of antibiotics; (2) antibiotics formulations for osteomyelitis; (3) intraocular drug delivery; (4) wound healing and hemostasis; (5) controlling the release of insulin; and (6) controlling the bioavailability of ricin Α-chain. These uses are discussed in the following paragraphs. Explored Application of Gel-Formers in Controlled Release Systems Periodontal Application. This entails the use of injectable gel-forming formulations for controlled delivery of antibiotics, such as tetracycline or doxycycline, for combating periodontal infections for periods of one to four weeks (10). Antibiotic Formulations for Bone Infection. In a Phase I study of an NIH-SBIR program addressing osteomyelitis, available results indicate that (1) selected gelformers are capable of controlling the in vitro release of gentamicin and vancomycin for at least two weeks; (2) two types of gel-formers can be formulated, with clinically relevant doses of vancomycin, into injectable forms; (3) injection of the vancomycin formulation about the periosteum of the goat tibia for localized drug delivery; and (4) controlled release of the vancomycin formulation is feasible without leading to toxic blood levels. Injectable Intraocular Delivery Systems. In an SBIR (Phase I) supported by the DoD, the feasibility of using tailored gel-formers to develop an injectable, controlled release system for intraocular delivery of key drugs is being investigated. Available data indicate that (1) injectable gel-formers containing pilocarpine, naproxen, cyclosporin and ganciclovir in clinically relevant doses can be prepared; (2) a continued release in a buffered medium for at least one week can be achieved; and (3) active formulations of the four drugs and a placebo can be readily injected into the vitreous cavity of the rabbit eye without eliciting unacceptable, gross tissue reactions. Wound Healing and Hemostatic Application. Preliminary results of a study supported by a DoD grant on wound healing and hemostatic agents (using hairless rats and rabbits) indicate that (1) certain gel-forming formulations can be used for the controlled delivery of antibiotics to incisional and burn wounds in hairless rats; (2) incisional wound strength regain in hairless rats can be improved when placebo gelformers are used; and (3) selected gel-forming formulations can induce hemostasis in a rabbit animal model. Insulin Controlled Release Systems. Preliminary study on the use of certain gelformers for the controlled release of insulin demonstrate the feasibility of this concept.



127 Controlled Release of Ricin Α-chain. This has been the subject of a Phase I SBIR program supported by the DoD and available results (13,14) on subcutaneously (SC) administered active formulations do verify that (1) gel formulations can be easily prepared and appear suitable for scale-up; (2) one SC formulation is capable of releasing sufficient amounts of ricin Α-chain (RAC) to elicit IgG formation at protective levels over a period of 4-6 weeks; (3) one formulation provides persistent protection at least 6 weeks post-immunization; and (4) a correlation can be established between IgG formation and the composition of the polymeric carriers. Available Phase I results suggest that (1) a single-dose, absorbable SC formulation, GF-Π, exhibits potentially unique in vivo performance as it comprises a microparticulate cation-exchanger; (2) upon comparing commercial R A C solution (RAC-L) with GF-Π, the latter elicits a more gradual antibody response that peaks at 10 weeks and it exceeds a fast-decaying, initially higher response to RAC-L; (3) in terms of antibody response, GF-Π is associated with higher durability over the 10- to 20-week period; and (4) GF-Π elicits a higher response of IgG-2A than R A C - L at 6 weeks. On-Going Studies—Future Perspective Preliminary results of on-going studies on the use of selected members of the gelformers family of copolymers indicate their potential use for accelerating wound healing, in treating burn wounds, and in hemostatic formulations. In this context, it is reasonable to suggest that suitable bioactive agents/drugs can be used in conjunction with the aforementioned systems to modulate their performance through the controlled release of the desired agents required for the corresponding biological events, such as tissue regeneration and hemostasis. Success in treating burn wounds can very well be extrapolated to effective treatment of chronic skin ulcers. Demonstrated feasibility studies on the intraocular administration of gelforming formulations can open a new area in eye therapy. The use of the gelformers is likely to find use as sealants in vascular and soft-tissue repair as well as carriers of living cells and growth factors in tissue engineering. Literature Cited 1. Shalaby, S.W., Chap. 3 in High Technology Fibers (Lewin & Preston, Eds.), Dekker, New York, 1985. 2. Shalaby, S.W., in Encyclopedia ofPharmaceutical Technology (J.C. Boylan & J. Swarbrick, eds.), Vol. 1, Dekker, New York, 1988, p. 465. 3. Shalaby, S.W., in Water-Soluble Polymers, (Shalaby et al., Eds.), Vol. 467, Chapt. 33, ACS Symp. Ser., Amer. Chem. Soc., Washington, DC, 1991a. 4. Shalaby, S.W., Polym. News, 16, 238 (1991b). 5. Shalaby, S.W., J. Appl. Biomater., 3, 73 (1992). 6. Shalaby, S.W. (Ed.), Biomedical Polymers: Designed to Degrade Systems, Hanser Publ., New York 1994a. 7. Shalaby, S.W. et al, Polymers ofBiological & Biomedical Significance, Vol. 540, ACS Symp. Ser., Amer. Chem. Soc., Washington 1994b.


128


8. 9. 10. 11. 12. 13.

Shalaby, S.W. et al, Irish Patent (to Kinerton, Ltd.) S-61251 (1994c). Shalaby, S.W. and Shalaby, W.S.-W., Indian J. Tech., 31, 464 (1993). Shalaby, S.W., U.S. Patent (to Poly-Med, Inc.) 5,610,052 (1997). Dunn, R.L. et al, U.S. Pat. 4,938,763 (1990). Dunn, R.L. et al, Polym. Prepr., 35(2), 437 (1994). Corbett, J.T. et al, Ninth International Conference on Antiviral Research, Fukusima, Japan, 1996. 14. Corbett, J.T. et al, Ninth International Conference on Antiviral Research, Fukusima, Japan, 1996b.


Tailored Polymeric Materials for Controlled Delivery Systems

Recommend Documents