Lymphatic delivery

Lactic acid oligomer microspheres containing aclarubicin have been studied for selective lymphatic delivery. Low (less than 10,000 molecular weight oligomers were used to produce microspheres designed to release drug over a 30-day period (99). Additives have been used to alter the release rate of aclarubicin-loaded poly(lactide) microspheres (100). Mitomycin C was incorporated into poly(lactic... 

H., and Muranishi, S., Lactic acid oligomer microspheres containing an anticancer agent for selective lymphatic delivery. 

It appears that activated carbon might be a potential carrier for lymphatic delivery, or to peritoneal or pleural cavities, the most common sites in cancer metastasis. Minimal side effects are expected, since constant low concentrations of drug are maintained in the general circulation. 

Yoshikawa, H., et al. 1985. Comparison of disappearance from blood and lymphatic delivery of human fibroblast interferon in rat by different administration route. J Pharmacobiodyn 8 206. 

Takada, K., et al. 1986. Effect of administration route on the selective lymphatic delivery of cyclosporin A by lipid-surfactant mixed micelles. J Pharmacobiodyn 9 156. 

K. Takada, H. Yoshimura, H. Yoshikawa, S. Muranishi, T. Yasumura, and S. Oka, Enhanced selective lymphatic delivery of cyclosporin A by solubilisers and intensified immunosuppressive activity against mice skin allograft, Pharm. Res. 3 48-51 (1986). 

In addition to the treatment of diseases of the lymphatics, drag targeting to the lymphatics may be used to facilitate sustained release effects, as the drag must distribute from the lymphatics into the general circulation. Delivery into the systemic circulation following oral lymphatic delivery is also a means of avoiding first-pass liver metabolism. 

The small intestine is drained by the hepatic portal vein, making the liver the first port of call for orally absorbed drugs. Therefore, high hepatic metabolism will compromise systemic availability. Formulation to enhance lymphatic absorption offers the potential for avoiding such first-pass metabolism. It could also target anticancer agents to lymphatic carcinomas. Table 1 lists various materials and associated therapeutic agents that have been formulated for lymphatic delivery. 

Takada K, Furuya Y, Yoshikawa H, Muranishi S. Biological and pharmaceutical factors affecting the absorption and lymphatic delivery of cyclosporin A from gastrointestinal tract. ] Pharmaco-biodyn 1988 11 80-87. 

Kim CK, Han JH (1995) Lymphatic delivery and pharmacokinetics of methotrexate after intramuscular injection of differently charged liposome-entrapped methotrexate to rats. J Microencapsul 12 437-4 46... 

Approaches to stabilize or avoid instability Prodrugs Enteric coating (protection in stomach) Lipid vehicles (micelles or emulsions/microemulsions) Enzyme inhibitor Lymphatic delivery (to avoid first-pass metabolism) Lipid prodrugs P-gp efflux pump inhibitors ... 

Wada R, Hyon S-H, Ikada Y, Nakao Y, Yoshikawa H, Muranishi S. Lactic acid oligomer microspheres containing an anticancer agent for selective lymphatic delivery I. in vitro studies. Journal of Bioactive and Compatible Polymers. 1988 3 126-136. 

O Driscoll CM. Lipid-based formulations for intestinal lymphatic delivery. European Journal of Pharmaceutical Sciences. 2002 15(5) 405-415. 

The absorption of drugs from the rectal [32] cavity has been studied in some detail. Muranishi et al. [34] have shown that a significant increase in the absorption and lymphatic uptake of soluble and colloidal macromolecules can be achieved by pretreating the rectal mucosal membrane with lipid-nonionic surfactant mixed micelles. They found no evidence of serious damage of the mucosal membrane. Davis [30] suggested that the vaginal cavity could be an effective delivery site for certain pharmaceuticals, such as calcitonin, used for the treatment of postmenopausal osteoporosis. 

M. Murakami, Enhanced absorption and lymphatic transport of macromolecules via the rectal route, in Delivery Systems for Peptide Drugs (S. S. Davis, L. Ilium, and E. Tomlinson, eds.), Plenum Press, New York, 1986, p. 177. 

Drug molecules that have traversed the physieal and enzymatic barriers of the colonic mucosa may enter the blood-eapillary bed or the lymphatic sinuses. Intact drug that reaches the venous capillaries from the submucosa is transported to the liver via the hepatic-portal system where they may undergo significant metabolism. On the other hand, uptake into the lymphatie sinuses of the colon results in direct delivery into the systemic circulation that causes less metabolic breakdown of the absorbed drug [3]. 

Yoshikawa, H., K. Takada, S. Muranishi, Y. Satoh, and N. Naruse, A method to potentiate enteral absorption of interferon and selective delivery into lymphatics. J Phar-macobiodyn, 1984. 7(1) 59-62. 

Hussain, N., Jaitley, V., Florence, A.T. (2001). Recent advances in the understanding of uptake of microparticulates across the gastrointestinal lymphatics. Advanced Drug Delivery Reviews, 50, 107-142. 

Hauss, D.J., Fogal, S.E., Ficorilli, J.V., Price, C.A., Roy, T., Jayara, A.A., and Keirns, J.J. (1998) Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J. Pharm. Sci., 87 164-169. 

Holm, R., Porter, C.J.H., Edwards, GA., Mullertz, A., Kristensen, H.G, and Charman, W.N. (2003) Examination of oral absorption and lymphatic transport of halofantrine in a tripie-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides.Eur. J. Pharm. Sci., 20 91-97. 

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