The development of a dosage form for the buccal administration of ergotamine tartrate was undertaken to overcome the poor absorption encountered with oral administration. Polyvinyl alcohol, a non-ionic polymer, was chosen as the main excipient for this mucoadhesive gel formulation. The adhesive force and the physical strength of the gels were measured using a rheometer. The adhesive force increased when a small amount of polyoxyethylene octylphenyl ether was added to the polyvinyl alcohol gels, and strengthened with an increase in the effective surface area between the gels and the adherents. The in vitro release rate of ergotamine tartrate from the gels was lowered with increasing concentration of polyvinyl alcohol in the gel.

Low molecular weight heparin (LMWH), a glycosaminoglycan of approximately 6000 molecular weight, is currently used in the prevention of postsurgical thrombosis and in the treatment of deep vein thrombosis. Current dosing regimens entail subcutaneous injections of 2500–5000 anti-factor Xa units per day. Transbuccal delivery of LMWH may provide significant advantages over the current injectable dosage forms. The kinetics and extent of LMWH absorption from prototype buccal dosage forms were evaluated. Based on pharmacokinetic analysis, over 3000 anti-factor Xa units (i.e., 20 mg) could be delivered from a single application. These results demonstrate the feasibility of administering macromolecular drugs, such as LMWH, via the buccal route.

This work proposes a method to study mechanisms of action of permeation enhancers and demonstrates that it is possible to effectively, transiently and reversibly increase mucosal permeability without causing any visible mucosal irritation and damaging the permeation barrier. Permeation enhancers have been used to increase mucosal permeability in buccal, sublingual and nasal drug delivery. However, it is unclear whether they act by transiently altering the mucosa or by damaging it. When an enhancer increases mucosal permeability, the permeability to glucose, which is extremely low without an enhancer, is also increased. Glucose in the submucosal interstitial fluid can thus permeate across the mucosa (back permeation) and be collected. For transient mucosal alteration, the permeation barrier will begin to recover after the enhancer is removed, resulting in a gradual decrease in glucose back permeation flux. If the mucosa is damaged, it is assumed that the flux will not decrease for some time. The effectiveness of sodium cholate (C), sodium taurocholate (TC) and lysophosphatidylcholine (LPC) as enhancers was demonstrated in the buccal administration of insulin in anesthetized dogs. Recovery kinetics were studied in the same animals by measuring glucose back permeation fluxes following exposure to these enhancers. Glucose back permeation flux showed no decrease following exposure to C, but began to decrease immediately following exposure to TC and LPC, and decreased by 80% in 5–8 h. No visible mucosal irritation was observed in any case. These results suggest that under the given conditions, TC and LPC transiently altered the mucosal barrier function while C altered the mucosal barrier function for prolonged times which may be the result of either extended enhancer stay in the mucosa or mucosa damage.

A novel heterogeneous interpenetrating polymer networks system has been developed to provide versatile drug release. This system consists of two chemically independent crosslinked polymers in which the proportions and properties of both polymers can be independently varied. The first network is a hydrophobic polyurethane network while the other consists of a hydrophilic/hydrophobic balanced vinyl network. Two critical parameters, the crosslinking density of the polyurethane network and the hydrophilicity of the vinyl network, can be varied to generate desired release kinetics for a given drug from disk-shaped devices. By varying these two parameters, first-order, pseudo-zero order release kinetics, or bimodal release patterns could be obtained. It is hypothesized that the balancing of the network elasticity and the osmotic swelling pressure induced by water soluble drugs (osmotically active solutes) incorporated into the matrices is involved in the unusual release properties observed with these matrices. However, with drugs of low aqueous solubility, other effects, such as microphase separation and network hydration kinetics, may also be involved.

A new transdermal device design is presented in which the system is fabricated with the drug in an impermeable, pre-active state. The system is activated by the user immediately prior to application, thereby converting the impermeable drug into a permeable form. The new design can provide significant improvements in safety, stability and performance of transdermal drug delivery systems.

The adsorption of antithrombin III (AT III) onto polystyrene surfaces preadsorbed with albumin or albuminheparin conjugates was studied using a two step enzyme immuno assay. When AT III-buffer solutions were used, the highest adsorption values were measured on high affinity albumin-heparin conjugate pretreated surfaces. Less AT III adsorption was found on nonfractionated albumin-heparin conjugate preadsorbed surfaces. AT III adsorption could also be detected on low affinity conjugate and albumin coated surfaces. When AT III was adsorbed from plasma or plasma dilutions with buffer, only AT III on surfaces preadsorbed with high affinity or nonfractionated albumin-heparin conjugate was found. These results demonstrate that the heparin moiety of the conjugate is directed to the solution phase whereas the albumin moiety contacts the polystyrene surfaca

Annals of the New York Academy of SciencesVolume 416, Issue 1 p. 513-524 THE BIOLOGICAL ACTIVITY OF ANTITHROMBOTIC AGENTS IMMOBILIZED ON POLYMER SURFACESa Sung Wan Kim, Sung Wan Kim Department of Pharmaceutics University of Utah Salt Lake City, Utah 84112Search for more papers by this authorCharles D. Ebert, Charles D. Ebert Department of Pharmaceutics University of Utah Salt Lake City, Utah 84112Search for more papers by this authorJames C. McRea, James C. McRea Department of Pharmaceutics University of Utah Salt Lake City, Utah 84112Search for more papers by this authorColin Briggs, Colin Briggs Department of Pharmacy The University of Manitoba Winnipeg, Canada R3T 2N2Search for more papers by this authorSi Myung Byun, Si Myung Byun Department of Bioengineering Korean Advanced Institute of Science and Technology Seoul, KoreaSearch for more papers by this authorHyun Pyo Kim, Hyun Pyo Kim Department of Bioengineering Korean Advanced Institute of Science and Technology Seoul, KoreaSearch for more papers by this author Sung Wan Kim, Sung Wan Kim Department of Pharmaceutics University of Utah Salt Lake City, Utah 84112Search for more papers by this authorCharles D. Ebert, Charles D. Ebert Department of Pharmaceutics University of Utah Salt Lake City, Utah 84112Search for more papers by this authorJames C. McRea, James C. McRea Department of Pharmaceutics University of Utah Salt Lake City, Utah 84112Search for more papers by this authorColin Briggs, Colin Briggs Department of Pharmacy The University of Manitoba Winnipeg, Canada R3T 2N2Search for more papers by this authorSi Myung Byun, Si Myung Byun Department of Bioengineering Korean Advanced Institute of Science and Technology Seoul, KoreaSearch for more papers by this authorHyun Pyo Kim, Hyun Pyo Kim Department of Bioengineering Korean Advanced Institute of Science and Technology Seoul, KoreaSearch for more papers by this author First published: December 1983 https://doi.org/10.1111/j.1749-6632.1983.tb35209.xCitations: 15 a This work was supported by National Institutes of Health Grant HL-20251. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 R. L. Varco, Ed. 1971. Mechanical Surfaces and Gas Layer Effects on Moving Blood. Fed. Proc. 30. 2 L. Vroman & E. F. Leonard, Eds. 1977. Ann. N.Y. Acad. Sci. 283. 3 S. L. Cooper & N. A. Peppas, Eds. 1982. ACS Adv. Chem. Ser. 199. 4 Kim, S. W., C. D. Ebert, J. Lin & J. C. McRea. 1983. ASAIO Journal 6: 76. 5 McRea, J. C. & S. W. Kim. 1978. Trans. Am. Soc. Artif. Int. Org. 24: 746. 6 McRea, J. C, C. D. Ebert & S. W. Kim. 1981. Trans. Am. Soc. Artif. Int. Org. 27: 511. 7 Ebert, C., J. C. McRea & S. W. Kim. 1980. In Controlled Release of Bioactive Materials. J. Baker, Ed.: 107. Academic Press. 8 Kim, S. W., J. Lin, J. C. McRea, C. D. Ebert & J. Feijen. Manuscript in preparation. 9 Grode, G. A., R. D. Falb & C. Crowley. 1972. J. Biomed. Mater. Res. Symp. 3: 77. 10 Merril, E. W., E. W. Salzman, P. S. L. Wong, T. P. Ashford, A. H. Brown & W. G. Austen. 1970. J. Appl. Physiol. 29: 723. 11 Eriksson, J. C., G. Berger, G. Hultquist, R. Larsson, D. Olsson & H. Lagergren. 1979. J. Colloid. Interface Sci. 72: 142. 12 Schmer, G. 1972. Trans. Am. Soc. Artif. Int. Org. 18: 321. 13 Labarre, D., M. C. Boffa & M. Jozefowicz. 1977. J. Biomed. Mater. Res. 11: 283. 14 Danishefsky, I. & F. Tzeng. 1974. Thromb. Res. 4: 237. 15 Goosen, M. F. A. & M. V. Sefton. 1980. Thromb. Res. 20: 543. 16 Miyura, Y., S. Aoyugi, Y. Kusada & K. Miyamoto. 1980. Biomed. Mater. Res. 14: 619. 17 Ebert, C. D., E. S. Lee, J. Deneris & S. W. Kim. 1982. In Interfacial Phenomena and Applications. S. L. Cooper & N. A. Peppas, Eds. AC. Adv. Chem. Series 199: 161. 18 Ebert, C. D. & S. W. Kim. 1982. Thromb. Res. 26: 43. 19 Wilman, B. & P. Wallen. 1973. J. Biochem. 36: 25. 20 Ohshiro, T., A. Sugitachi, S. D. Hong, K. Mukai, F. Murakami, G. Kosaki & S. Motoi. 1978. Blood and Vessel (Japan) 9: 72. 21 Sugitachi, A., T. Kawahara, J. Kodama, Y. Kikkawa & K. Takagi. 1978. Blut 37: 31. 22 Ohshiro, T. & G. Kosaki. 1980. Artif. Org. 4: 58. 23 Sugitachi, A., K. Takagi, S. Imaoka & G. Kosagi. 1978. Thromb. Haemostas. 39: 426. 24 Sugitachi, A. & K. Takagi. 1978. Int. J. Artif. Org. 1: 88. 25 Kim, H. P., S. M. Byun, Y. I. Yeom & S. W. Kim. 1983 J. Pharm. Sci. 72: 225. 26 Johnson, A. J., D. L. Kline & N. Alkjaersig. 1969. Thromb. Diath. Haemorrh. 21: 259. 27 Lowry, D. H., W. J. Rosenbrough, A. L. Farr & R. J. Randall. 1951. J. BIol. Chem. 193: 265. 28 Cuatrecasas, P. 1970. J. Biol. Chem. 245: 3059. 29 Steers, E., P. Cuatrecasas & H. Pollard. 1971. J. Biol. Chem. 246: 196. 30 Lowe, C. R., M. J. Harvey, D. B. Craven & P. D. G. Dean. 1973. Biochem. J. 133: 499. 31 Grode, G. A., J. Pitmann, J. P. Growley, R. I. Leininger & R. D. Falb. 1974. Trans. Am. Soc. Artif. Int. Org. 20: 38. 32 Sinha, A. K. & R. W. Coleman. 1978. Science 200: 202. 33 Lee, S. Unpublished data. 34 Ebert, C. D., E. S. Lee & S. W. Kim. 1982. J. Biomed. Mater. Res. 16: 629. Citing Literature Volume416, Issue1Surface Phenomena in Hemorheology: Their Theoretical, Experimental, and Clinical AspectsDecember 1983Pages 513-524 ReferencesRelatedInformation

The self-association of insulin monomers into oligomers and macromolecular aggregates leads to complications in the administration of insulin, both in conventional administration and in the development of long-term insulin delivery systems.These problems are aggravated by the tendency of insulin to adsorb onto the surface of solution containers and infusion devices.Furthermore, with insulin infusion devices, shear rates can be generated which can accelerate the self-association and surface adsorption processes.The effects of urea on shear-induced insulin self-association and surface adsorption were investigated.It was found that the addition of a certain concentration range of urea to insulin so- lutions greatly reduces both insulin self-association and surface adsorption.Circular dichroic studies established that these concentrations of urea also preserve insulin conformation under high shear rates, where conformations are altered without urea.Higher urea concentrations lead to insulin denaturation and accelerated'self-association.

Covalently bound conjugates of human serum albumin and heparin were prepared as compounds which could improve the blood-compatibility of polymer surfaces either by preadsorption or by covalent coupling of the conjugates onto blood contacting surfaces. The conjugates (10–16 weight % of heparin) were obtained by a condensation reaction between albumin and heparin using 1-ethyl-3-(dimethylaminopropyl)-carbodiimide. Unreacted albumin and heparin were removed by diethylaminoethyl (DEAE)-cellulose and Cibacron Blue Sepharose chromatography respectively. The activity of the heparin component incorporated in the albumin-heparin conjugates (Ac) was compared with that of the heparin used for the synthesis of the conjugates (Anat) by thrombin time, inhibition of Factor Xa and the activated partial thromboplastin time (APTT) assays. The Ac/Anat ratio for the above assays was as follows': Thrombin time 1.25, Factor Xa inhibition 0.5. and APTT 0.5. Gel filtration chromatography showed broad-molecular weight distributions. The conjugates were fractionated using immobilized antithrombin III (ATIII). High ATIII and low ATIII affinity conjugate fractions showed the same behavior as ATIII fractionated heparin with respect to thrombin times and Factor Xa inhibition.

Owing to the chemical instability of prostacyclin, the direct immobilization of this prostaglandin has not been successful. A new procedure is described for the preparation of immobilized prostacyclin based on the conversion of immobilized prostaglandin F2 alpha to immobilized prostaglandin I2-Materials thus prepared show dramatic antiplatelet effects with regard to platelet aggregation and platelet adhesion. Radioimmunoassays of plasmas used in in vitro platelet tests and of buffers used in prostacyclin leakage studies established that these effects are not due to the release of prostacyclin from the respective immobilization substrates.

Heparin anticoagulant activity decreases as the degree of carboxylic derivatization increases; however, partially derivatized heparin, both carboxylic and hydroxyl derivatives, retains anticoagulant activity. Heparin was immobilized via carboxylic groups to diaminoalkane agarose gels to provide coupling spacer groups of various lengths. Anticoagulant activity increased precipitously beginning with 10-carbon unit spacer groups, but heparin coupled with less than 10 spacer groups demonstrated only minimal anticoagulant activity.

Heparin immobilized to polymer surfaces via different length diaminoalkane spacer arms was evaluated for anticoagulant activity and for platelet interactions. The anticoagulant activity of the immobilized heparin, as determined by APTT assays, was found to increase with increasing spacer arm length. Variations in spacer arm length produced no affect on platelet retention or PF 4 release for heparin immobilized materials. To investigate immobilized heparin-adsorbed plasma protein interactions, XPS analysis of heparinized surfaces, before and after plasma contact, was conducted. Immobilized heparin was not able to penetrate adsorbed plasma protein layers with any spacer arm length evaluated, indicating that immobilized heparin does not directly interact with platelets.