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African Journal of Biotechnology Vol. 4 (13), pp. 1591-1597, December 2005 Available online at http://www.academicjournals.org/AJB ISSN 1684–5315 2005 Academic Journals Optimising oral systems for the delivery of therapeutic
proteins and peptides
Ikhuoria M. ARHEWOH, Edith I. AHONKHAI and Augustine O. OKHAMAFE
Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of Benin, Benin City Therapeutic proteins/peptides are mostly administered as parenteral (injectable) preparations as a
result of their poor oral bioavailability which is due to degradation by proteolytic enzymes, poor
membrane permeability and large molecular size. However, the oral route would be preferred to the
parenteral administration because it is more convenient for self-administration, non-invasive and more
patient friendly. Consequently, efforts have intensified over the past two decades to maximize the
extent of absorption of protein and peptide drugs in order to achieve optimum bioavailability via the
oral route. A suitable oral delivery system should retain the drug and maintain its integrity until it gets
to the region of maximum absorption where the protein/peptide is released. It would be advantageous
for such a delivery system to be capable of attaching itself to the absorptive cells in that region during
the course of drug release by means of specific interactions with the tissue components. Furthermore,
movement of drug should be independent of prevailing factors in the gut during passage. This review
examines the various efforts and strategies that have been used to pursue the goals of effective oral
peptide delivery, progress made so far, as well as current trends and future prospects. Relevant issues
and phenomena such as membrane permeability control, intestinal absorption, paracellular pathway
and targeting have also been discussed.

Key words: Protein and peptide delivery, delivery systems, oral administration, targeting, intestinal absorption.

INTRODUCTION
Over the last two decades, the field of biomedical in the form of haemoglobin, myoglobin and various research has witnessed dramatic advances in the lipoproteins, they effect the transport of oxygen and other understanding, diagnosis, and treatment of human chemical substances within the body (Schwendeman et diseases. These developments have been fueled by an al., 1996; Adessi and Sotto., 2002). The increasing increased awareness of the essential roles played by importance of proteins and peptides can be attributed to endogenous proteins and peptides in the regulation and three main developments. First, improved analytical integration of life processes (Samonen, 1985). For methods have fostered the discovery of numerous example, in the form of skin, hair, cartilage and muscle, hormones and peptides that have found applications as proteins hold together, protect, and provide structure to biopharmaceuticals. Second, molecular biology and the body of a multicel ular organism. In the form of genetic engineering have enabled the large-scale enzymes, hormones, antibodies and globulins, they production of polypeptides previously available only in catalyze, regulate and protect the body chemistry while smal quantities. Third, there is now a better understanding of the role of regulatory proteins/peptides *Corresponding authors E-mail: okhamafe@uniben.edu, Consequently, pharmaceutical scientists are now okhamafe@uniben.edu.ng. Tel: +234-8022905981. Fax: +234-
routinely using specific peptide sequences as lead structures for drug development. (Adessi and Sotto, Despite the high level of activity in peptide-based drug Rather than administering the protein itself, the DNA research, several obstacles hinder the development of plasmid that codes for it is swal owed. This then attaches peptides into useful therapeutical y deliverable agents, to the cel s in the smal intestine where it manufactures the most important of which is imparting good the required protein drug using available materials in the bioavailability while maintaining pharmacological efficacy cel . The protein is thereafter absorbed into the blood (Humphrey and Ringrose, 1986). This problem stems stream. The gene has a short half-life and hence must be from the unique structural features of peptides which are administered regularly to be effective. The advantage is directly linked to their high instability in biological milieu, that it provides for safe, easily managed treatment unlike rapid elimination from plasma, poor transportability most gene-based therapies currently available. It is also across membranes and ease of metabolism either within hoped that this system wil be relatively free from ectopic the gastrointestinal tract or within the cel s lining the tract expressions usual y experienced with gene therapies (Davis et al., 1986; Schwendeman et al, 1996). since the bulk of the administered genes remain within the intestine and is passed out with feaces along with sloughed cel s of the intestinal epithelium. ORAL DELIVERY OF PROTEINS AND PEPTIDES
A primary objective of oral delivery systems is to protect
MEMBRANE PERMEABILITY CONTROL
protein and peptide drugs from acid and luminal proteases in the GIT. More recent efforts seem to focus It is important that a successful oral delivery system on site-specific delivery systems. The site could be an incorporating a membrane would exhibit a permeability, organ, a cel subset or even an intracel ular region with which can be modulated control ed by factors favourable the objective of restricting the distribution of the peptide to the targeting of the drug to the specific site of to the specific target site. This should al ow for an absorption. To achieve this, suitable polymer additives increase in efficacy with an attendant decrease in toxicity may be used. The benefits of this approach have been highlighted by Okhamafe and Goosen (1993). Membrane Various systems for achieving site-specific delivery of permeability control is also a critical factor in living cel oral y administered protein/peptide drugs have been encapsulation technology and in the development of addressed in recent years including coating systems bioartificial organs. Furthermore, membrane modulation based on pH changes and enzymatic activity of intestinal is often employed to improve the strength and stability of microflora (Macloid et al., 1999; Stubbe et al., 2001), the microcapsule itself (Okhamafe and Goosen, 1999). nanoparticles, (Shinji et al., 1997), liposomes (Kimura Ahonkhai et al. (2005) recently found that by and Saishin, 1985), matrix devices (Krishnaiah et al., incorporating polymers or solid fil ers in the core of 2001) and conjugate (degradable prodrug) formation chitosan-alginate microcapsule, the release of a model (Yano et al., 2002; Arhewoh and Okhamafe, 2004). Al of protein, bovine serum albumin (BSA) can be modulated these have produced variable release profiles, often such that 70% of the protein is delivered to the desired because the transit time through the colon can vary absorption site in the gut 9 h later (see Figure 1). Related substantial y from as low as 6 to as high as 30 h. Several applications include the pre-purification and concentration of these approaches are somewhat complex and if they of products of cel encapsulation, release into the were to be translated into actual manufacture of oral circulatory system of hormonal and enzymatic products delivery systems, the products would be expensive and, generated by bioartificial organs which are protected from therefore, unaffordable in most developing countries. In components of the immune system, principal y our laboratories, preliminary studies on microcapsules of immunoglobulins. Some relevant parameters to be chitosan-alginate modified with selected excepients such considered in membrane permeability control are as HPMCAS, talc, microcrystal ine cel ulose, polymeta- crylates and pectins were carried out. Protein release was determined at different pH media spanning the pH range of the gut (Figure 1). It was observed that PROTEIN/PEPTIDE ABSORPTION
microcapsules modified with talc and microcrystal ine cel ulose had higher protein retention in the core in al the Intestinal absorption
pH tested (Okhamafe et al., 1996; Ahonkhai et al., 2005; Arhewoh et al., 2005). This shows that modification of the The primary function of the intestine is the digestion and core of chitosan-alginate microcapsules could facilitate absorption of food substances including proteins. Within the intestinal lumen, pancreatic endopeptidases chiefly trypsin, elastase and chymotrypsin together with the ORAL GENE DELIVERY
exopeptidases, carboxyl peptidase A and B, produce amino acids and peptides typical y 2 to 6 residues in In vivo production of proteins through oral gene therapy length. The efficient absorption of an intact peptide, has also been investigated (Rothman et al., 2005). therefore, is the exception rather than the rule. Examples Table 1. Critical factors affecting microcapsule membrane permeability.
Capsule wall
Process factor
Figure 1. Protein (BSA) release at pH 1.2 from microcapsules modified with different additives – Talc
(T), Eudragit L100 (L), Eudragit RSPM (RS), HPMCAS (H), microcrystal ine cel ulose (M) and Control oral y absorbed, biological y active peptides are rare. absorbed in the colon, usual y leaving less than 100 ml of However, both thyrotrophin-releasing hormone (TRH) fluid to be excreted in the feces. Most of the absorption in (Yokohama et al., 1984) and the luteinizing hormone- the large intestine occurs in the proximal one half of the releasing hormone (LHRH) analogue, leuprolide colon, giving this portion the name, absorbing colon. The (Gonzalez-Barcena et al., 1975) were reported to exert mucosa of the large intestine, like that of the smal biological activity when given oral y in rat and man. The intestine, has a high capability for active absorption of activity of these two proteins is a reflection of their sodium (Guyton and Hal , 1996). Numerous bacteria, extreme potency as only a smal portion of TRH was especial y colon bacil i, are present normal y in the actual y absorbed in rat and man. It was further observed absorbing colon (Wilson and Basit, 2005). They are that in the rat, absorption is limited to the upper region of capable of digesting smal amounts of cel ulose, in this the intestine and is mediated by a Na+ dependent, way providing a few calories of nutrition to the body each peptide transport system (Yokohama et al., 1984). day. Substances formed as a result of bacterial activity Remarkably, absorption of DN-1417, a close structural are vitamin K, vitamin B12, thiamin, riboflavin and various analog of TRH, is not active, but occurs by passive gases that contribute to flatus in the colon, especial y diffusion in al parts of the intestine. Furthermore, only carbon dioxide, hydrogen and methane. It is based on 1% is absorbed in rat and 10% in dog. This example this bacterial activity that the colon can be used as a site il ustrates the sensitivity of transport proteins to structural of drug delivery whereby polymer-coated drugs are modifications in their substrates (Kimura 1984). targeted to the colon. The bacteria in the colon degrade the polymer thus releasing the drug where it can either exert local action or be absorbed into systemic circulation Colonic absorption
(Stubbe at al., 2001; Wilson and Basit, 2005).
Most of the water and electrolytes in chyme, which pass
Colonic transit is an important factor in the absorption through the ileocecal valve into the large intestine, are of drugs that either act local y in the colon or are absorbed into systemic circulation from the colon. The time at which a delivery system arrives at the colon Targeting the drug to specific cel s along the lining of depends mainly on the gastric emptying rate (Davies et the intestine may be useful in facilitating protein/peptide al., 1991). The arrival time for a tablet or capsule in the absorption, for instance, M-cel s located on the dome colon can range from about 5 h in the fasted condition to epithelium of gut-associated lymphoid tissues are known 13 h or longer in the fed condition. In healthy volunteers, to be capable of sampling macromolecular antigen from the colonic transit of tablet or capsules releasing drug the lumen through an endocytic pathway (Keljo and over a prolonged period probably delivers most of its Hamilton, 1983; Kompel a and Lee, 2001). The M-cel s active ingredients to the colon rather than to the upper GI are located on Peyer’s patches and the possibility of administering microparticles oral y to target this site has been suggested (Eldridge et al., 1990). The researchers
Lymphatic absorption
administered 20 mg of microspheres containing the fluorescent dye, coumarin-6 to non-anesthesized mice. At Drugs administered through the gastro-intestinal tract are 48 h, the mice were kil ed and three representative normal y transported into systemic circulation via the Peyer’s patches, together with the first mesenteric lymph portal vein. As a consequence, compounds can node proximal to the appendix and spleen, were excised sometimes undergo extensive metabolism during the first for microscopic observation. The number of absorbed pass through the liver. Some wel -known drugs, such as microspheres was counted in frozen sections using a lignocaine, are almost total y metabolized by this process florescence microscope. The percentage of ingested with a consequence that little or none is available to the dose was not determined; however, of the microspheres general circulation. Other routes, such as rectal, buccal, investigated, only those composed of polystyrene, poly nasal and transdermal, avoid the first pass effect but do (methylmethacrylate), poly ( hydroxylbutyrate), poly (D, L- not provide the convenience of oral delivery. If a drug is lactide), poly (L-lactide) and poly (D, L-lactide- absorbed through the lymphatic system rather than by coglycolides) were absorbed into the Peyer’s patches of the portal circulation, it wil find its way into the blood via the smal intestine, while those composed of ethyl the thoracic duct and wil , therefore, avoid the first pass cel ulose, cel ulose acetate hydrogen phthalate and effect. A drug absorbed lymphatical y is incorporated into cel ulose triacetate were not. Microsphere uptake chylomicrons (and other lipoproteins) produced by the fat occurred only in Peyer’s patches and was restricted to digestion process. Various surfactant solubilised systems those microspheres up to 10 µm in diameter. Absorptive and other enhancing agents would appear to direct drugs cel s located on the ideal epithelium are known to be to the lymphatic route and there are even claims that capable of sampling luminal peptide growth factors particulates can be taken up this way (Leferve and Joel., (Gonnela et al., 1987) bile acids (Ho, 1987) and cyanocobalamine (Doscherholmen et al., 1971) The conjugation of large molecular weight drugs with From recent advances in protein absorption studies polymers, such as dextran, appears to be an interesting have emerged a new system termed ‘Active Peptide strategy for enhancing the lymphatic uptake of anticancer Transport’ (APT) (Stevenson and Keon, 1998). APT agents (Muranishi et al., 1987). In this case the describes a new formulation that is designed to “actively” lymphatics could wel be the target site (e.g., for open alternative absorptive pathways in the body. These treatment of metastatic spread) rather than the systemic alternative pathways make transporting proteins to body cel s and the muscles faster and more efficient. APT is important because it is designed to al ow the body to absorb peptides faster and more efficiently. The body has PATHWAY FOR PROTEIN/PEPTIDE ABSORPTION
three different protein transport systems that it uses for Identifying a region in the intestine that favours muscle growth. The first system uses free-form amino protein/peptide absorption is a crucial step in the design acids. This is a very inefficient system because the free- of oral delivery systems for protein drugs. The intestinal form amino acids must compete with one another for barrier is of major importance. Furthermore, regional absorption. The second system involves smal , short peptide chains of 2 to 3 amino acids linked together. variations in the penetration barriers to peptides may result in regional differences in their absorption (Kompel a These are cal ed di- and tri-peptides. Di- and tri-peptides and Lee, 2001). There are certain factors that affect the are absorbed into the blood stream through the permeability of molecules through the intestinal barrier transcel ular pathways. The third system involves large molecular weight peptides and is unique to whey protein. This is not used when casein, egg white or soy proteins are digested. It should be noted that not al proteins Physicochemical properties of the drug molecules Characteristics of the intestinal barrier stimulate al three protein transport systems. In fact, only special y made designer proteins stimulate the pathways. APT with ful spectrum whey peptides is designed to facilitate the stimulation of al three transport systems and molecular delivery vehicle contains a carrier - adapter can only be found in designer protein. These APT ful conjugate, which bound non-covalently to a recognition spectrum whey peptides are a complete spectrum of very tag fused to the targeting protein (Gaidamakova et al., low, low, medium and high molecular weight whey Another approach towards delivering drugs into cel s is the concept of loligomers. Loligomers are synthetic peptides composed of a branched polylysine case Paracellular pathway
harboring identical arms, each carrying peptide signals guiding their import and localization into cel s. The most The paracel ular pathway is found along the intestinal important advantages of loligomers include: wal and is used by the second and third transport The multivalent presentation of targeting signals systems as an alternative pathway for peptide absorption. resulting from a tentacular arrangement. Multivalency This pathway is normal y closed off to entry of peptides increases the efficiency of import and intracel ular routing and nutrients by a special cel cal ed “tight junction” signals as compared to similar linear peptides. (Stevenson and Koan 1998). In a current model of a tight Another advantage is that it reduces and delays the junction, two major integral membrane proteins are found impact of peptide degradation in terms of cel ular - occludin and claudin - each with four membrane processing and compartmentalization (Borkx et al., spanning alpha-helices. The junction depends upon extra cel ular calcium to maintain integrity. The permeability The vectorial delivery of nucleus – directed loligomers properties of tight junctions vary considerably in different into cel s has recently been confirmed by microscopy and epithelia and epithelial cel s can transiently alter their tight flow cytometry studies (Borkx et al., 2002). Practical uses junctions in order to al ow increased flow of solutes and of loligomers include photosenstizers for use in water through breaches in the junction barriers photodynamic therapy and the incorporation of cytotoxin (doscherholmen et al., 1971; Fanning et al., 1998). The T-lymphocyte epitopes with a view to creating synthetic tight junctions usual y prevent the transport of protein vaccines. Branched peptide such as loligomers through the paracel ular pathway. However, research has represents simple and versatile molecular vehicles with shown that specific amounts of key ingredients, the same potential applications in a wide variety of drug design ingredients found in designer protein’s APT, help the tight junctions to open (Fanning et al., 1998). Natural y, with both the transcel ular and paracel ular pathways opened, protein is potential y absorbed faster and in greater Delivery to cancer cells
amounts. Furthermore, unique protein with molecular weight larger than the di- or tri-peptides absorbed by the Cancer treatment has always posed a problem. The second transport system may be able to pass through effectiveness of conventional solid tumor treatment is intact (Stevenson and Koan, 1998; Muranishi and limited by the systemic toxicity and lack of specificity of chemotherapeutic agents. Barriers are also frequently hampering targeting of drugs and toxins to solid tumors and their microenvironment. Present treatment modalities TARGETING
are frequently insufficient to eliminate viable cancer cel s without exceeding the limits of toxicity to normal tissue. Existing methods for selective targeting are based on The coming generation of cancer therapeutics depends chemical conjugation of therapeutic and diagnostic on the precise targeting and sustained release of anti- agents or their carriers to cel specific targeting molecules tumor agents to overcome their limitations. (Gaidamakova et al., 2001; Pastorino et al., 2001). These Phage-derived peptides for targeting of doxorubicin methods are limited by potential damage to targeting conjugates to solid tumors have been designed molecules that can be inflicted by the conjugation (Schatzlein et al., 2001). Nano-conjugates are low procedure. In addition, conjugation procedures have to molecular weight conjugates of a smal drug or toxin and be developed on case - by - case basis (Amidon, 1995). a targeting ligand coupled through a cleavable linker In order to avoid this problem, a new approach has been group. They offer potential advantages for tumor specific developed to constructing molecular vehicles for target- delivery in diffusion – limited situations. As a model, a mediated delivery of therapeutics and diagnostic agents. doxorubicin conjugate targeted to the transferring In this approach, the targeting molecule is expressed as receptor (TFR) was chosen. A library of phage a fusion protein containing a recognition tag. The expressing a cyclic nanopeptide was panned against recognition tag is defined as a protein or peptide that can TFR. The apparent affinity of phages determined by bind non-covalently with another peptide or protein surface plasmon resonance (SPR) increased with each (adapter). In turn, the adapter is chemical y conjugated to cycle of the panning procedure. After five rounds, a carrier of therapeutics or diagnostics. The assembled approximately 80% of phages expressed the same peptide, which mediated a 30 to 50-fold increased of peptide drugs because of slow transit, low volume and receptor specific cel ular uptake of the phages. The a lack of vigorous stirring, leading to an ability to create corresponding peptide was synthesized using solid local conditions favourable to stabilization and absorption phage peptide chemistry on a sulphonamide based enhancement. In addition, the colonic region has a high safety catch resin. Crude mixtures of the peptide, as wel presence of microbial anaerobic organisms providing as transferrin itself, were able to inhibit the phage uptake reducing conditions and sufficient area to partial y compensate for low peptide mucosal permeability and a Chitosan nanoparticles encapsulating dextran – doxorubicin conjugate has been used as carrier for It is expected that in the foreseeable future more focus targeting tumors (Mitra, 2001). Doxorubicin (DXR) wil be on the colon as a region for site-specific delivery of commonly used in cancer therapy is known to produce therapeutic substances (proteins, peptides, genes, etc) undesirable side effects such as cardiotoxicity. To that are unstable in the other regions of the GIT in order minimize these, attempts were made to couple the drug to optimize convenience, therapeutic benefits and safety. with dextran (DEX) and then to encapsulate this drug conjugate in hydrogel nanoparticles. By encapsulation of the drug conjugate in biodegradable, biocompatible long REFERENCES
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