pled to neocarzinostatin (SMANCS)into the hepatic artery peutics,it is vital that novel technologies be developed to for to treat liver cancer is another example of a polymer drug an be achieved b et al 2001;Tor e202w PP otein hepa id. wh ute.8 for the cutaneous injection (Okada et 1982)Emphasis has been bicin for treating in B for fu aposi's s coma and lip placed on increasing the pends on or protein s appeared in the pharmace perties of th ry formulations.The se formulations ve due to its ise of tion.Howe ver.there ar ugh the li r the on in th rst pa the st ach and be de been much attention on chrono tiss stems are inte incre with the ogical rh syste d in dal ield of r given new ways to treat a nun 198 th the (Le e,1991).More must re Clearly,the distinc ties of each individual ition.them sal lining that u ally prot cts organs fron abra eae Thus, and protein should b ften involves amsof polymer che ount for the drug's unigue pharma codvnamics and pharma aceutical scientists (Robinson 1997) oral ro a subject o nuous intensive arch efforts i hat can re d to a ph chang eand,at the san among th are th rug sucn as na outes with nistration being con line pH of the (Figure 3).One of th no eltic tein from degradation in the small in ine and tempor instability and rmeability of these dru En Morishita et al 2002.Fig e 4 sh s the nain ellular bar activity in the int rs to drug or prote mech cant advances in the creation of protein and peptide thera AIChE Journal December 2003 Vol.49.No.12 2995
pled to neocarzinostatin SMANCS into the hepatic artery Ž . to treat liver cancer is another example of a polymer drug targeting strategy Maeda, 1991 . Ž . Specific targeting to specific tissues can be achieved by coupling the polymer-drug with a molecule such as antibody Ž or a carbohydrate recognized by tissue cell surface recep- . tors. One challenge has been discovering appropriate targeting molecules. Galactose which is recognized by the hepatocyte cell surface asialoglycoprotein receptor is one example where successful targeting has been achieved Duncan, 2003 . Ž . Liposomes have been used both for targeting and to create safer intravenous drug formulations for drugs such as doxorubicin for treating HIV-associated Kaposi’s sarcoma and liposomal amphotericin B for fungal infections in cancer Park et Ž al., 1997; Torchilin, 1994 . Liposomes provide a way of alter- . ing a drugs pharmacokinetics and can make them less toxic by changing their biodistribution in the body. Nonin©asi©e deli©ery of proteins A significant opportunity has appeared in the pharmaceutical sciences over the past 35 years with the development of advanced drug delivery formulations. These formulations do not simply release the drug, peptide, or protein at some characteristic rate, but do so in a way that the pharmaceutical scientist and molecular designer wants Peppas et al., 2000 . Ž . For example, insulin may be delivered only when needed, calcitonin may be directed to bypass the stomach and be delivered only in the upper small intestine, and large molecular weight, genetically-engineered molecules are delivered across tissues at acceptable rates Peppas and Huang, 2002 . Ž . The increased availability of large molecular weight protein- and peptide-based drugs with the recent advances in the field of molecular biology has given new ways to treat a number of diseases Silbart and Keren, 1989 . The structure, Ž . physicochemical properties, stability, pharmacodynamics, and pharmacokinetics of these new biopharmaceuticals place stringent demands on the way they are delivered into the body Ž . Lee, 1991 . More specifically, peptides and proteins must retain their structural integrity until they reach their delivery site and cannot be degraded upon enzymatic interactions. In addition, the mucosal lining that usually protects organs from mechanical and abrasive damage poses a main obstacle for the successful penetration of such drugs to the appropriate delivery site. Thus, each peptide and protein should be administered in an optimal temporal pattern that would account for the drug’s unique pharmacodynamics and pharmacokinetics. Alternative delivery methods to the traditional intravenous route are a subject of continuous intensive research efforts in both industry and academia. Prominent among these are the nasal, transdermal, pulmonary, buccal, ocular, vaginal, rectal and oral delivery routes with oral administration being considered the most convenient Lehr, 1994 . Ž . The oral delivery route is the most challenging for complex drugs such as peptides or proteins from a technical perspective due to the extremely low bioavailability associated with the instability and low permeability of these drugs. Enzyme activity in the intestine or stomach also contributes significantly to the overall instability of such drugs. With the significant advances in the creation of protein and peptide therapeutics, it is vital that novel technologies be developed to formulate and deliver these drugs. Important challenges relate to the problems of stability, low bioavailability, the degree and rate at which a substance as a drug is absorbed into a Ž . living system or is made available at the site of physiological activity and short half-life of proteins and peptides Peppas Ž et al., 2001; Torres-Lugo et al., 2002b .. For example, the bioavailability of leuprolide, a luteinizing hormone-releasing hormone LHRH analog, is only 0.05% Ž . through the oral route, 3% for the nasal route, 8% for the rectal route, 38% for the vaginal route, and 65% for the subcutaneous injection Okada et al., 1982 . Emphasis has been Ž . placed on increasing the bioavailability of peptides and proteins for various administration routes by designing novel drug delivery systems tailored specifically for a specific application Ž . Lowman et al., 1999; Kim and Peppas, 2002; Peppas, 2003 . Typically, the selection of the route of administration depends on Intended therapeutic use of a peptide or protein Desired duration of service-life Physicochemical properties of the protein or peptide. For example, oral delivery of peptides and proteins is attractive due to its ease of application. However, there are many problems that need to be addressed, such as the harsh gastric environment, permeability through the lipophilic epithelial cellular membrane andror the tight junction in the upper small intestine, as well as first pass metabolism by the liver. Recently, there also has been much attention on chronopharmacological drug delivery systems. These drug delivery systems are intended to match the delivery of the therapeutic agents with the biological rhythm. These systems are important especially in the area of endocrinology and in delivery of vaccines. For example, it has been shown that the treatment of hypopituitary dwarfism by administration of human growth hormone releasing hormone GHRH is more effective when Ž . the GHRH is administered in a pulsatile manner Chappel, Ž 1999 .. Clearly, the distinct properties of each individual peptide and protein combined with the physiological peculiarities of each delivery route prevent the design of a generic controlled-release system for even a general subset of peptides or proteins. Furthermore, the complexity involved in the design of a controlled-release device is very interdisciplinary and often involves teams of polymer chemists, chemical engineers, pharmacokineticists, pharmacologists, clinicians, and pharmaceutical scientists Robinson, 1997 . Ž . In the oral route, Peppas and co-workers Lowman et al., Ž 1999a,b; Torres-Lugo et al., 2002a,b have used bioadhesives . that can respond to a pH change and, at the same time, protect protein drugs such as insulin and calcitonin from the acidic pH of the stomach and then release it into the more alkaline pH of the intestine Figure 3 . One of the novelties Ž . of these particular bioadhesive polymers is that they are also able to protect the protein from degradation in the small intestine and temporarily open connections between intestinal cells to allow proteins to penetrate into the intestine Ž . Morishita et al., 2002 . Figure 4 shows the main cellular barriers to drug or protein transport. Several mechanisms are involved in protein cellular transport including paracellular, transcellular and transcytotic transport Figure 5 . As Ž . AIChE Journal December 2003 Vol. 49, No. 12 2995
Transcellular Transcytosi Low pH Carrier-Mediated Paracellula Fgure5.etenaool,eeo8tspPehtope2hrougn igure 3 beha gastrointe Torres-Lugo et al.(202a)pointed out,it is possible using aco-2 o make -Bay et al,1996;Milstein et al into the an imn of biomaterials.The rate r for trar These patches can deliver c nber of drugs bein ed Anpr tricity such 5)I ure 4.Potentia to solute rt in a ng electr culture system A)Cell monolayer syste th amounts of drug f 2996 December 2003 Vol.49.No.12 AIChE Journal
Figure 3. Swelling behavior of poly methacrylic ( acid-g-ethylene glycol hydrogels ) P MAA-g-EG as a function of the pH of the ( ) gastrointestinal tract. Torres-Lugo et al. 2002a pointed out, it is possible using Ž . Caco-2 cell lines to identify the main mechanisms of solute transport across tissues and, therefore, improve the solute bioavailability. Mathiowitz and co-workers have used certain types of polyanhydrides that have bioadhesive properties. By Figure 4. Potential barriers to solute transport in a cell culture system. Ž . A Cell monolayer system grown onto a microporous system; B concentration profile system for the solute with the Ž . largest concentration drop within the cell monolayer. C , o original concentration of the solute, C , concentration of the d solute in the donor chamber, C , concentration of the solute r in the receiver chamber. Figure 5. Protein or drug transport pathways through the cell monolayer courtesy: J. Lopez . ( ) exposing carboxylic groups on the polymer’s exterior surface, they are able to bind to the gut. In particular, polyfumaric sebacic acid anhydride exhibits strong adhesive forces. Nanospheres made of these polymers were able to deliver drugs like insulin in diabetic rats Mathiowitz et al., 1997 . Ž . This type of approach has also been used to deliver genes in rats. Another approach has been to combine protein drugs with small molecules that are molecular carriers that appear to make the protein smaller and enable them to cross the intestine. This approach is being used to deliver insulin and heparin in animals Leone-Bay et al., 1996; Milstein et al., Ž 1998 . Another method has been to couple proteins to . molecules that target receptors in the gastrointestinal tract. For example, Russell-Jones et al. 2000 have coupled pro- Ž . teins to vitamin B-12 , which has receptors in the intestine. By doing this, protein along with the vitamin, is transported into the intestine where subsequent cleavage takes place, releasing the intact protein Alsenz et al., 2000 . Ž . Transdermal patch technology represents an important area of biomaterials. The rate limiting barrier for transdermal patches are made up of substances such as ethylene vinyl-acetate or other polymers. These patches can deliver drugs from one to seven days. Currently, 11 drugs or drug combinations are delivered through the body via this method. Scientists are also exploring various physical forces to enhance the transport of drugs through the skin to expand the number of drugs being delivered. Approaches involve electricity such as iontophoresis Merino et al., 1997 or electro- Ž . poration Prausnitz et al., 1993; Langer, 1998 . Ultrasound is Ž . also being studied. In the latter case, the permeability of some drugs can be increased several thousand fold Mitragotri et Ž al., 1995 . In addition, it is not only possible to deliver drugs . using electrical or ultrasonic approaches, but also to extract intestinal fluid and actually sense particular analytes such as glucose in that fluid Kost et al., 2000 . Ž . A variety of strategies have been used to deliver drugs into the lung. However, it has been difficult to get significant amounts of drug from an inhaler into the lung. 10% is often an upper limit. One of the reasons for this has been the ag- 2996 December 2003 Vol. 49, No. 12 AIChE Journal