Site-specific delivery

One element that is often ignored in this evaluation though is the extent of the mechanism. For example, if enzymatic activity is to be used to release drug at the site of action, even if the activity/time/volume is one hundred times higher at the desired site than elsewhere (not unreasonable), but the volume of nonspecific activity is one thousand times as great (also not unreasonable), the system does not stand any chance of achieving site-specific delivery. 

Finally, site-specific delivery also depends on the extent of competing processes in the biological system as well as the interaction of the drug itself with the biological system. Therefore successful design of polymeric drug delivery approaches requires a comprehensive appreciation of the pharmacology, pharmacokinetics, and pharmacodynamics involved. 

Table 1 Reasons for Site-Specific Delivery of Drugs Pharmaceutical...

Fig. 2 Anatomical and physiological pathways for site-specific delivery. (From Ref. 5.)...

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

As noted in the patent for this system, pulsatile systems are expected to have numerous applications in drug delivery, including site-specific delivery in the GI tract and bid (twice-a-day) dosing of two pulsatile systems that simulates qid (four times a day) dosing of immediately available products. The latter concept is expected to have a particular advantage for those drugs that have high first-pass metabolism. 

To provide for prolonged, site-specific delivery of NGF to the tissue in a convenient manner without affecting the properties of the conduit, biodegradable polymer microspheres of poly(L-lactide)co-glycolide... 

Rouge N, Buri P, Doelker E (1996) Drug absorption sites in the gastrointestinal tract and dosage forms for site-specific delivery. Int J Pharm 136 117-139... 

Tissue-selective activation of classical prodrugs Site-specific delivery of ad hoc chemical systems... 

J. Takata, Y. Karube, M. Hanada, K. Matsunaga, Y. Matsushima, T. Sendo, T. Aoyama, Vitamin K Prodrugs 1. Synthesis of Amino Acid Esters of Menahydroquinone-4 and Enzymatic Reconversion to an Active Form , Pharm. Res. 1995, 12, 18-23 J. Takata, Y. Karube, M. Hanada, K. Matsunaga, Y. Matsushima, T. Sendo, R. Oishi, Vitamin K Prodrugs 2. Water-Soluble Prodrugs of Menahydroquinone-4 for Systemic Site-Specific Delivery , Pharm. Res. 1995, 12, 1973- 1979. 

Site-specific delivery liposomes, drug monoclonal antibody... 

In the context of the development of new contrast agents for medical diagnostic imaging, the nanoparticulate carriers have indeed drawn special attention. These systems allow for an efficient site-specific delivery of targeted contrast agents and, due to their size, provide some relaxivity enhancement with respect to the isolated paramagnetic molecules. 

In 1980, Stella and Himmelstein [5] introduced the principles of pharmacokinetic modelling into the field of pro-drugs and site-specific delivery. In 1986, Hunt et al. [6] extended the model of Stella and Himmelstein by taking into account a specific area where toxicity occurs. Their work may be considered as the frame of reference for later work in this area. 

Because the size and surface net charge of liposomes can also influence the rate and extent of tissue distribution, these characteristics could be used for target-specific delivery of liposome-encapsulated proteins and drugs. These issues will be discussed later in the context of Site-specific delivery strategies. ... 

Site-specific delivery will require the use of a self-locating system, typically a bioadhesive formulation, although an IVR, due to its elastomeric nature, will remain located high in the vaginal space. Conversely, for rapid distribution throughout the space, semisolid or fast-dissolving solid systems will be required. For semisolids, flow properties and viscoelastic character will be the critical determinants of their ability to spread rapidly from their point of application. 

Site-specific delivery to the back of the eye, including the vitreous, the choroid and particularly the retina, is the most challenging objective facing researchers in the field of therapeutic ophthalmology. There is a growing but unmet need for drug carriers that reach the retina at appropriate therapeutic levels following topical application. 

This time controlled release tablet with a designated lag time followed by a rapid release may provide an alternative to site-specific delivery of drugs with optimal absorption windows or colonic delivery of drugs that are sensitive to low pH or enzyme action for the treatment of localized conditions such as ulcerative colitis, Crohn s disease, and irritable bowel syndrome (IBS). Also, by controlling a predetermined lag time of drug from dosage form, the release behavior can be matched with the body s circadian rhythm pattern in chronotherapy. 

P.C. Rensen, R.M. Schiffelers, A.J. Versluis, M.K. Bijsterbosch, M.E. Van Kuijk-Meuwissen and T.J. Van Berkel, Human recombinant apolipoprotein E-enriched liposomes can mimic low-density lipoproteins as carriers for the site-specific delivery of antitumor agents, Mol. Pharmacol. 52 (1997) 445-455. 

Site-specific delivery and release of drugs will not only be useful to achieve systemic therapeutic effects (after absorption), but also topical applications, for instance for the treatment of inflammatory bowel disease, ulcerative colitis, and colon cancer, to name the most prevalent. 

M. K. Bijsterbosch and T. J. C. Van Berkel, Lactosylated high density lipoprotein a potential carrier for the site-specific delivery of drugs to parenchymal liver cells, Mol. Pharmacol. 47 404-411 (1992). 

Kitamura, M., Taylor, S., Unwin, R., Burton, S., Shimizu, F. and Fine, L. G. (1994). Gene transfer into the rat renal glomerulus via a mesangial cell vector Site-specific delivery, in situ amplification, and sustained expression of an exogenous gene in vivo. J. Clin. Invest. 94, 497-505. 

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