The basic hypothesis underlying the proposed studies is that oral mucosal (transbuccal) administration provides an advantageous route for systemic and local drug delivery. The oral mucosal route avoids the adverse environment of intestinal absorption and th risk of infection of parenteral delivery. The non-keratinized oral mucosa is more permeable than the skin and has a better blood supply so that it may be the optimum route to deliver bioactive peptides or peptide hormones. In order to gain basic information required for the rational design of oral mucosal drug delivery systems, three specific aims are proposed; To establish physicochemical characteristics of a candidate drug for oral mucosal delivery, the permeability of porcine oral mucosa will be determined for a series of test compounds. The test compounds have been chosen to include a wide range of polarities, molecular sizes and charge characteristics. The information gained in this study should permit prediction of the rates at which pharmaceutical agents could diffuse through oral mucosa. In order to increase the rate of diffusion of drugs through the mucosa and to extend the range of drugs that could be effectively administered via this route, a series of permeability enhancers will be studied. A number of substances known to fluidize membrane lipids will be examined for similar effects on oral mucosa. In addition, structural analogues of endogenous mucosal lipids designed to increase membrane fluidity will be prepared and studied. Finally, the distribution of radioactively or fluorescently labelled compounds within the mucosa will be determined by means of cryosectioning and counting and by image analysis of fluorescence micrographs. The effects of permeability enhancers on tissue distribution will be examined. These tissue distribution studies will provide fundamental information regarding drug binding and reservoir effects, the possible existence of secondary barriers within the mucosa and the mechanisms of action of permeability enhancers. The research will be strengthened by collaboration with two other sites, UCSF and SFSU. The development of oral mucosal drug delivery systems would provide an advantagous means of administering a range of pharmaceutical agents. The ability to deliver bioactive peptides and peptide hormones, such as insulin, would represent a major breakthrough in drug delivery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011273-02
Application #
2414699
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1996-05-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Iowa
Department
Dentistry
Type
Schools of Dentistry
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Senel, S; Kremer, M J; Kas, S et al. (2000) Enhancing effect of chitosan on peptide drug delivery across buccal mucosa. Biomaterials 21:2067-71
Du, X; Squier, C A; Kremer, M J et al. (2000) Penetration of N-nitrosonornicotine (NNN) across oral mucosa in the presence of ethanol and nicotine. J Oral Pathol Med 29:80-5
Squier, C A; Kremer, M J; Bruskin, A et al. (1999) Oral mucosal permeability and stability of transforming growth factor beta-3 in vitro. Pharm Res 16:1557-63
Kuempel, D; Swartzendruber, D C; Squier, C A et al. (1998) In vitro reconstitution of stratum corneum lipid lamellae. Biochim Biophys Acta 1372:135-40
Squier, C A; Kremer, M; Wertz, P W (1997) Continuous flow mucosal cells for measuring the in-vitro permeability of small tissue samples. J Pharm Sci 86:82-4
Whittle, S; Swartzendruber, D C; Kremer, M et al. (1997) Lipids of hamster cheek pouch epithelium. Lipids 32:961-4