Postmenopausal osteoporosis affects 1.5 million women each year in the United States. The spine is frequently involved, but the most serious manifestation of osteoporosis is hip fracture. Some 250,000 hip fractures occur each year in the United States, with a mortality rate of 12 to 20%. The direct and indirect costs for caring of these patients is 7 to 12 billion $/year. Calcitonin (CT) is an effective therapeutic agent used in the management of several disorders with accelerated bone resorption. In a recent clinical trial, it was demonstrated that rectally administered CT is well tolerated and has a beneficial effect on bone mass in osteoporotic women. Development of an oral delivery system is of great importance, because it is expected, that for the treatment of chronic disorders in non-life threatening situations, such as postmenopausal osteoporosis, parenteral administration will lead to poor patient compliance and thus restricted utility. Due to its size and a wide therapeutic index, CT is an excellent candidate for oral delivery. The synthesis of novel tailor-made hydrogels suitable for colon-specific CT delivery and the development of a delivery device containing penetration enhancers is the aim of this proposal. Preliminary studies demonstrated that: a) Hydrogels can be designed which degrade in the colon. Rates of degradation have been achieved that are consistent with the transit time. b) By protecting the carboxylic groups of the ionizable comonomer the kinetics of swelling in the small intestine (SI) can be controlled. Consequently, hydrogels can be designed which are degraded very fast in the colon. At the same time the release in the SI is minimized. c) A model protein (insulin) retains its biological activity during the preparation of a delivery device (hydrogel coated gelatin capsule). d) Degradation of model proteins in vitro clearly indicated that both in the lumen and at the brush border the proteolytic activity in the colon is considerably lower than in the SI. e) Concentrations of penetration enhancer (medium chain glycerides) have been identified which do minimal damage the intestinal tissue in vitro. f) Bioavailability of CT after intracolonic administration to rats can be considerably increased by coadministration of medium chain glycerides. Based on these results, novel pH sensitive hydrogels will be synthesized containing azoaromatic crosslinks susceptible to degradation by microbial enzymes in the colon. In the SI their swelling kinetics is controlled by incorporation of hydrophobic hydrolyzable side-chains. In the low pH range of the stomach, the gels have a low degree of swelling and the protein is protected against digestion by enzymes. In the SI controlled swelling takes place. Upon arrival in the colon a degree of swelling is reached that makes the crosslinks accessible to azoreductase activity. The gel is degraded and CT released. Coadministration of penetration enhancers will modify the transepithelial permeability. The toxicity of individual parts of the formulation will be determined. Based on these results a delivery device for oral CT delivery will be designed and the bioavailability of CT as well as the biocompatibility of the device determined. Based on in vivo animal data criteria will be established for the design of an oral calcitonin delivery system to treat postmenopausal osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM050839-03S1
Application #
2873419
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1995-04-01
Project End
1999-12-31
Budget Start
1998-07-01
Budget End
1999-12-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Gao, Song-Qi; Sun, Yongen; Kopecková, Pavla et al. (2009) Antitumor efficacy of colon-specific HPMA copolymer/9-aminocamptothecin conjugates in mice bearing human-colon carcinoma xenografts. Macromol Biosci 9:1135-42
Gao, Song-Qi; Sun, Yongen; Kopeckova, Pavla et al. (2008) Pharmacokinetic modeling of absorption behavior of 9-aminocamptothecin (9-AC) released from colon-specific HPMA copolymer-9-AC conjugate in rats. Pharm Res 25:218-26
Gao, Song-Qi; Lu, Zheng-Rong; Kopeckova, Pavla et al. (2007) Biodistribution and pharmacokinetics of colon-specific HPMA copolymer--9-aminocamptothecin conjugate in mice. J Control Release 117:179-85
Lu, R H; Kopeckova, P; Kopecek, J (1999) Degradation and aggregation of human calcitonin in vitro. Pharm Res 16:359-67
Akala, E O; Kopeckova, P; Kopecek, J (1998) Novel pH-sensitive hydrogels with adjustable swelling kinetics. Biomaterials 19:1037-47
Ghandehari, H; Smith, P L; Ellens, H et al. (1997) Size-dependent permeability of hydrophilic probes across rabbit colonic epithelium. J Pharmacol Exp Ther 280:747-53