Parenteral peptide and protein drug delivery systems include non-degradable ·and degradable polymeric systems, osmotic pumps andliposomes. A typical non-degradable polymeric system consists of adispersion of protein particles embedded .. inah EVAc matrix in the form of either films or miGrosp.Oeres. The protein is released by diffusion through a network of pores and channels created by the diss:9lvingprotein particles . A duration of release of over 100 days has been observed . The rate and extent of protein release from EVAc matrices are controlled by factors such as the pmtein'ssblubility, particle size and its degree of loading in the matrix. Protein release is most rapid and cOlTlplete when the particle size is large and the degree of loading is high. The fabrication method and mpl.ecular weight of the matrix also affect drug release , Degr~d~ble polymeric systems are attractive when compared with non-degradable systems, explained Dr. Lee"pecause they needn't be surgically implanted or removed. The mechanism of drug release depends on the type of system. In a study in which insulin was incorporated into crosslinked albumin beads, :for instance, about two-thirds of the entrapped protein wasrelea.sed 3 to 7 weeks before the matrixconipletely degraded . Osmotic pumps operate on osmotic imbibition of water from the implantation site, which generates an internal'pressure that discharges the drug at a predetermined rate. This system has been used extensively tQstudy the physiological and pharmacological effects of Insulin, IlJteinising hormone, lutein ising hormone-releasing hormone and its analogues, prolactin, parathyroid hormone, vasopressin, and otherpeptides and proteins . Thus far, the clinical utility of the pump has not been proven. Lipdsomes have been considered for controlled drug delivery for almost 20 years. Peptides and protein? studied include insulin, human growth hormone, interferons, and other immunomodulators. Liposomes have the ability to protect the entrapped peptide or protein ·from degradation by proteolytic enzymes. They can also reduce the clearance of the entrapped substance from the site of intramuscular or subcut,;meous administration, thus prolonging its systemic activity. Despite these advantages as protein and peptide carriers, warned Dr Lee, the widespread use ofliposomes in peptide and protein delivery may be.Jimited by their capacity as immunoadjuvants and by the tendency of their constituent phospholipids to interact with the peptides and proteins being encapsulated. This interaction can affect the release kinetics of the peptide from theliposomes as well as theJormulation's shelf life. Non-parenteral peptide and protein drug delivery systems, including the nasal, transdermal, rectal, vaginat! t>uccal, and oral routes, are also being actively studied. The nasal route has received much attenti~n~Jhe most popular d0 9age form has been theaQueous90lution, although gels,powders, .and microsR.heres have also been investigated. Tran9qermal delivery ~uccessfully delivers small drug molecules such- as scopolamine, nitroglycerin, c1onidine, and estradiol. However, compared with the mucosal routes, the transdermal route offers greater resistance to peptide and protein absorption, primarily because of the impermeability of the stratumcorneurn. Iontophoresis may overcome this resistance, although results from studies using this technique have beenequivocal. Rectal and vaginal delivery systems ·take the form of solutions, gels, and supp,Ositories. Gels are the most efficient form because they offer a proper balance between retention ·at the administration site and the Jate of peptide release. Buccal .delivery of proteins and peptides has been underinvestigated, said Dr Lee. Compared with the nas~t cavity, the buccal mucosa offers a much larger and more easily accessed area for placing adhesiY!=l)p.blets, gels, and patches. However, in at leastone study, sodium glycocholate, a penetration enhanqer, was needed to produce absorption ofdetectablea.rnounts of insulin . Oraf delivery, though generally ·unsuccessful at present, offers potential therapeutic and comm~rcial benefits. Recently, insulin has been encapsulated with an impervious azopolymer film that remai~c~intact until it reaches the large intestine.

Drug targeting in cancer chemotherapy Richard Kirsch, PhD, of Smith, Kline & French, Philadelphia, presented a provocative paper on the challenges of drug targeting in cancer chemotherapy. There is a growing debate, said Dr Kirsch, on the limitedctherapeuticbenefit of some ofthenewdelivery systems. He predictsthat the introduction of successful targeting systems for current cancer agents may not be accompanied by the dramatic theraPi:l(.1tic;;gains hoped for . .In addition, the new delivery systems will have to prove themselves in terms }?tcost containment and patient acceptance. He pOinted out that many of the proposed efforts to achiev!=lcell-specific targeting have ignored knowledgeof .th~ .pathogenesis of the target disease and host plirysiology and .anatomy. Regardihg .monoc.lonal. antibodies, Dr Kirsch .stated that. researchers have made excessive and premature claims regarding clinical utility. They have also neglected to consider such factors as the antigehic heterogeneity of tumour cells , the microvascular permeability to immunoglobulins and antibody fragments, nonspecific tissue localisation,ands~nsitisation to xenogeneic antibodies. Dr Kirsch concluded by summarising thecha.llenges of developing improved drug delivery systems: • Drug delivery must ·be targeted to specific .organs and individual centypes. • The use of microenvironmental stimuli for controlled-release systems must be expanded. • Mgr,~. complex drug rel.easeprofil~sand applications .• tqmultidrugcombinations .must be engineered. • D~li\,~ry systems for new drug classes (such as peptides and proteins, lipids and highly lipophilic molecu.l~s, and genes) must be furtheLdeveloped. J\n,c:!r:n;t~ro INPHARMA '!> 2 July 1988

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