Current Challenges in Non-Invasive Insulin Delivery Systems A Comparative Review

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Advanced Drug Delivery Reviews 59 (2007) 1521 1546 www.elsevier.com/locate/addr
Current challenges in non-invasive insulin delivery systems: A comparative review

El-Sayed Khafagy, Mariko Morishita , Yoshinori Onuki, Kozo Takayama
Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan Received 23 March 2007; accepted 16 August 2007 Available online 22 August 2007
Abstract The quest to eliminate the needle from insulin delivery and to replace it with non- or less-invasive alternative routes has driven rigorous pharmaceutical research to replace the injectable forms of insulin. Recently, various approaches have been studied involving many strategies using various technologies that have shown success in delivering insulin, which are designed to overcome the inherent barriers for insulin uptake across the gastrointestinal tract, mucosal membranes and skin. This review examines some of the many attempts made to develop alternative, more convenient routes for insulin delivery to avoid existing long-term dependence on multiple subcutaneous injections and to improve the pharmacodynamic properties of insulin. In addition, this article concentrates on the successes in this new millennium in developing potential noninvasive technologies and devices, and on major new milestones in modern insulin delivery for the effective treatment of diabetes. 2007 Elsevier B.V. All rights reserved.
Keywords: Non-invasive delivery system; Modern insulin delivery; Administration routes; Marketed products; Formulation technologies; Future patents
Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . Routes of insulin administration . . . . . . . . . . 2.1. Oral administration . . . . . . . . . . . . . 2.1.1. Background . . . . . . . . . . . . 2.1.2. Absorption enhancers . . . . . . . 2.1.3. Enzyme inhibitors . . . . . . . . . 2.1.4. Mucoadhesive polymeric systems . 2.1.5. Particulate carrier delivery systems 2.1.6. Targeted delivery systems . . . . . 2.2. Buccal administration . . . . . . . . . . . . 2.3. Nasal administration . . . . . . . . . . . . . 2.4. Pulmonary administration . . . . . . . . . . 2.4.1. Background . . . . . . . . . . . . 2.4.2. Dry powder inhalation . . . . . . . 2.4.3. Absorption enhancers . . . . . . . 2.4.4. Particulate carrier systems . . . . . 2.5. Ocular administration . . . . . . . . . . . . 2.6. Rectal administration . . . . . . . . . . . . 2.7. Transdermal administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1522 1522 1522 1522 1523 1524 1524 1525 1526 1526 1528 1529 1529 1530 1530 1531 1532 1533 1534
Corresponding author. Tel./fax: +81 3 5498 5783. E-mail address: morisita@hoshi.ac.jp (M. Morishita). 0169-409X/$ - see front matter 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2007.08.019
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2.7.1. Background . . . . . . . . . . . . . 2.7.2. Absorption enhancers . . . . . . . . 2.7.3. Transdermal drug delivery systems . 2.7.4. Iontophoresis . . . . . . . . . . . . 2.7.5. Sonophoresis (ultrasound) . . . . . . 2.7.6. Microneedles . . . . . . . . . . . . 3. Recent marketed and developed formulations for 4. Conclusion . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction Advances in biotechnology have meant that a wide variety of peptide drugs are now produced on a commercial scale. With the advent of biotechnology, particularly advances in recombinant protein technology, the therapeutic roles of peptides and proteins have received a great deal of attention [13]. Protein and peptide drug delivery has been an area of intensive research because of their efficacy in several disease conditions. However, despite rapid progress in the large-scale manufacture of therapeutic proteins, the convenient and effective delivery of these drugs to the body remains a major challenge. Most of these therapeutic peptides are still administered by the parenteral route because of their poor bioavailability when delivered via other routes. Peptide drugs are usually indicated for chronic conditions, and the use of injections on a daily basis during long-term treatment has obvious drawbacks [4]. The past decade saw increased interest in the formulation and delivery of biological drugs for a range of diseases. Unlike conventional drugs, the clinical development of these types of drugs has not been possible without some sort of sophisticated pharmaceutical technology. Among the most important therapeutic proteins and peptides being explored is insulin. Insulin was isolated from bovine pancreas in 1922 by Frederick Banting and Charles Best, who received the 1923 Nobel Prize for Medicine with John McLeod. Conventional insulin treatment is basically a replacement therapy, in which exogenous insulin is administered subcutaneously to mimic, as closely as possible, the insulin secretion of the healthy pancreas. The subcutaneous route has been the mainstay of insulin delivery until now. Although these parenteral routes are satisfactory in terms of efficacy in the great majority of cases, they can result in peripheral hyperinsulinemia, the stimulation of smooth muscle cell proliferation, and the incorporation of glucose into the lipid of arterial walls, and they might therefore be the causative factor in diabetic micro- and macroangiopathy [5]. Moreover, the burden of daily injections, physiological stress, pain, inconvenience, cost, risks, infection, inability to handle insulin, and the localized deposition of insulin, leading to local hypertrophy and fat deposition at the injection sites remain problems [6]. The synthesis of insulin by recombinant DNA technology represented an important scientific milestone and made large quantities of the protein available at an affordable price, a factor that led insulin to become one of the most popular proteins to be studied for non-parenteral delivery. Consequently, the results of research into several
aspects of the delivery of the insulin are available. In recent years, there has been a great deal of interest in the exploitation of non-invasive routes for insulin delivery, and their development by the pharmaceutical industry, including oral, nasal, buccal, pulmonary, transdermal, rectal, and ocular drug delivery systems [79]. The objective of this review is to provide an update on the most promising advances in non-invasively delivery systems for insulin that may overcome the barriers to its absorption. 2. Routes of insulin administration 2.1. Oral administration 2.1.1. Background The gastrointestinal tract (GIT) is the route of choice for the administration of most drugs, regardless of their molecular structure or weight. The manufacture of an oral dosage form does not have to meet specialized regulatory requirements relating to such issues as sterility, pyrogenicity, and particulate contamination. Insulin has an important place in drug therapies for insulin-dependent diabetes mellitus (type I) and for many patients with non-insulin-dependent diabetes mellitus (type II). However, it is still generally delivered via injections. It would be highly advantageous if insulin could be administered orally [10], because the oral delivery of insulin can mimic the physiological fate of insulin and may provide better glucose homeostasis. This would also lessen the incidence of peripheral hyperinsulinemia, which is associated with neuropathy, retinoendopathy, and so forth [11]. Various challenges are usually evaluated by determining the fate of insulin in the GIT. The main challenges reported involve overcoming the enzymatic degradation of insulin and the insufficient permeation of insulin through the GIT [12]. Success in the oral delivery of therapeutic insulin would improve the quality of life of many people who must routinely receive injections of this drug. In the last few decades, various attempts have been made to overcome the limitations and drawbacks of conventional oral insulin therapy. The successful oral delivery of insulin involves overcoming the barrier of enzymatic degradation, achieving epithelial permeability, and conserving the bioactivity of the drug during formulation processing. Pharmaceutical strategies have been proposed to maximize oral insulin bioavailability in insulin delivery systems, to overcome barriers, and to develop safe and effective therapies. Table 1 presents a summary of recent oral insulin delivery systems.
E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546 Table 1 Oral insulin delivery systems System Absorption enhancers Bile salt/fatty acid mixed micellar system Insulin solution/N-lauryl--D-maltopyranoside W/O/W emulsion/DHA or EPA Enteric-coated capsule/Witepsol W35 + NaSal Insulin solution/AP, SGC, SC or Na2EDTA Enzyme inhibitors Drugcarrier matrix/BBI and elastatinal Insulin solution/AP, SGC, STI, CM or BAC Insulin solution/SGC, BTT, LPT, CTT or BAC Insulin solution/CkOVM or DkOVM Insulin solution/hyaluronidase Mucoadhesive polymeric systems P(MAA-g-EG) hydrogel microparticles Lectin-conjugated alginate microparticles Chitosan NPs ChitosanTBAinsulin tablets Particulate carrier delivery systems Lecithin-based microemulsion Double liposomes Fusogenic liposomes Eudragit S100 microspheres Insulinphospholipid complex NPs Targeted delivery systems Colon-targeted delivery system (CODES) Colon-targeted delivery system (Azopolymer-coated pellets) Insulintransferrin conjugate Application In vivo/rats In vitro/Ussing chamber In situ/rat intestine In vivo/dogs In situ/rat intestine Observation Improved paracellular absorption Enhanced colon permeability PAa was 43.2% PAa was 12.6% PAb was 0.1%5.5%
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Refs. [13] [14] [15] [16] [17]
In vitro/artificial intestinal fluid In situ/rat intestine In situ/rat intestine In vitro/diffusion chamber In situ/rat intestine
Significant reduction in enzymatic degradation PAb was 0.1%5.1% PAb was 0.1%2.3% Two fold increase in insulin stability and flux values Significant reduction in blood glucose levels
[20] [21] [22] [25] [27]
In vivo/rats In vivo/rats In vivo/rats In vivo/rats
PAa was 9.5% Hypoglycemic effect lasted for 8 h PAa was 14.9% PAa was 1.69%
[47] [48] [49] [61]
In vivo/rats In vivo/rats In situ/rat intestine In vivo/rabbits In vivo/rats
30% reduction in blood glucose levels PAb was 0.39%5.5% PAa was 10.1%15.7% 24% reduction in blood glucose levels PAa was 7.7%
[74] [76] [78] [82] [84]
In vivo/dogs In vivo/rats In vivo/rats
BA was 0.5% PAb was 0.89%3.38% 70% reduction in blood glucose levels
[90] [91] [96]
Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; PA, pharmacological availability; NaSal, sodium salicylate; RH, relative hypoglycemia; AP, aprotinin; SGC, sodium glycocholate; SC, sodium caprate; Na2EDTA, ethylenediaminetetraacetic acid disodium salt; BBI, BowmanBirk inhibitor; STI, soybean trypsin inhibitor; CM, camostat mesilate; BAC, bacitracin; BTT, bestatin; LPT, leupeptin; CTT, cystatin; CkOVM, chicken ovomucoid; DkOVM, duck ovomucoid; P(MAA-g-EG), poly(methacrylic acid-g-ethylene glycol); NPs, nanoparticles; chitosanTBAinsulin, chitosan4-thiobutylamidine insulin conjugate; BA, absolute bioavailability. PA of insulin systems was determined based on the extent of the hypoglycemic response relative to that achieved with subcutaneousa or intravenousb insulin injection.
2.1.2. Absorption enhancers Absorption enhancers improve the absorption of drugs by increasing their paracellular and transcellular transport. They involve several different mechanisms of action, including changes in membrane fluidity, decrease in mucus viscosity, the leakage of proteins through membranes, and the opening of tight junctions [4]. Common examples of non-specific permeation enhancers are bile salts, fatty acids, surfactants, salicylates, chelators, and zonula occludens toxin. Bile salts in mixed micellar systems increase the permeation of insulin by accessing a paracellular pathway [13]. A study of N-lauryl--D-maltopyranoside also suggested that this enhancer may open the tight junctions of the epithelium, thereby increasing the permeation of insulin via a paracellular pathway [14]. In another interesting study, water-in-oil-in-water multiple emulsions incorporating 2% docosahexaenoic acid or eicosapentaenoic acid had dose-related pharmacological effects on insulin and may potentially become the formulations for the enteral delivery of insulin [15]. Another report demonstrated the hypoglycemic effects of enteric-coated capsules containing insulin formulated in Witepsol W35 with sodium salicylate, which significantly
decreased plasma glucose levels and increased hypoglycemia relative to the effects of a subcutaneous injection of regular soluble insulin [16]. Morishita et al. evaluated the administration of insulin solution to the various colonic and rectal loops of fasted rats in situ, with or without sodium caprate, Na2EDTA, or sodium glycocholate as an absorption enhancer, and with or without protease inhibitors such as aprotinin [17]. Their results suggested that absorption enhancers increase insulin efficacy more effectively in the colon than in the small intestine. An innovative strategy involving the modulation of tight junctions to improve the transport of paracellular drugs and proteins normally not absorbed through the intestine is a very attractive solution [18]. In diabetic rats, the bioavailability of oral insulin coadministered with zonula occludens toxin was sufficient to lower serum glucose concentrations to levels similar to those achieved after the parenteral injection of insulin [19]. However, the use of absorption enhancers is limited by the fact that once cell membranes are permeabilized or tight junctions opened, transport is enhanced not only for peptide and protein drugs but also for undesirable molecules present in the GIT [9].
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2.1.3. Enzyme inhibitors Recent studies have evaluated the use of enzyme inhibitors to slow the rate of insulin degradation. The coadministration of enzyme inhibitors provides a viable means to circumvent the enzymatic barrier to the delivery of peptide and protein drugs. Insulin is strongly degraded by trypsin, -chymotrypsin, and elastase, and to a lesser extent, by brush-border membrane-bound enzymes [20]. In an interesting study, Yamamoto et al. evaluated the effects of five different enzyme inhibitorssodium glycocholate, camostat mesilate, bacitracin, soybean trypsin inhibitor, and aprotininon the intestinal metabolism of insulin in rats [21]. Among these enzyme inhibitors, sodium glycocholate, camostat mesilate, and bacitracin were effective in improving the physiological availability of insulin in the large intestine. However, none of these enzyme inhibitors was effective in the small intestine, possibly because of the numerous enzymes secreted there. Liu et al. also evaluated the potential utility of various enzyme inhibitors in improving the intestinal absorption of insulin and investigated their efficacy in different intestinal regions [22]. Recently, chicken and duck ovomucoids have been identified as a new class of enzyme inhibitors [23,24]. Ovomucoids derived from the egg whites of avian species were tested for their efficacy in preventing insulin degradation in the presence of trypsin and -chymotrypsin. A formulation containing insulin and chicken ovomucoid (CkOVM) or duck ovomucoid (DkOVM) was evaluated for its dissolution stability in the presence of trypsin and -chymotrypsin [25]. The results suggested that the inhibitory effect of DkOVM was due to the inactivation of the enzyme -chymotrypsin, which is mainly responsible for the breakdown of insulin. Polymerinhibitor conjugates have been shown to offer in vitro protection against trypsin, -chymotrypsin, and elastase [20]. A drugcarrier matrix has been developed that protects embedded insulin from in vitro degradation by the luminally secreted serine proteases trypsin (EC 3.4.21.4), chymotrypsin (EC 3.4.21.1), and elastase (EC 3.4.21.36). Increasing amounts of the BowmanBirk inhibitor (BBI) and elastatinal were covalently bound to the mucoadhesive polymer sodium carboxymethylcellulose (Na-CMC). All polymerBBI conjugates showed strong inhibitory activity toward trypsin and chymotrypsin, whereas this was markedly lower toward elastase. The polymerelastatinal conjugates displayed higher inhibitory activity toward elastase. Even after 4 h of incubation, 33.6% 3.2% of the therapeutic agent remained stable against enzymatic attack. These conjugates, when combined with polycarbophilcysteine, induced a 20%40% reduction in basal glucose levels for more than 80 h [26]. Recent evidence has elegantly demonstrated that the mucus and glycocalyx layers, extracellular domains directly attached to the intestinal epithelium, function significantly as absorption and/or proteolytic impedimental compartments for insulin [27,28]. However, the use of enzyme inhibitors may also affect the absorption of other peptides or proteins that would normally be degraded. A major drawback of these inhibitors is their high toxicity, especially during chronic drug therapy. Furthermore, the
non-site-specific intestinal application of such compounds may change the metabolic pattern in the GIT, because of the reduced digestion of food proteins. 2.1.4. Mucoadhesive polymeric systems The term mucoadhesion refers to the adhesion between polymeric carriers and the mucosa and is exhibited by certain polymers, which become adhesive upon hydration [29,30]. Thus, the goals of mucoadhesive drug delivery systems are to extend the residence time at the site of drug absorption, to intensify contact with the mucus to increase the drug concentration gradient, to ensure immediate absorption without dilution or degradation in the luminal fluid, and to localize the drug delivery system to a certain site [31,32]. Delivery systems containing mucoadhesive polymers provide intimate contact with the mucosa, thereby reducing drug degradation between the delivery system and the absorbing membrane. They are controlled release systems that provide the simultaneous release of both drug and inhibitor, and allow the immobilization of enzyme inhibitors in the delivery systems [33]. Novel polymers have shown excellent inhibitory activity against proteolytic enzymes and reasonable mucoadhesivity, and might therefore be a useful tool in overcoming the enzymatic barrier to oral peptide therapeutics. The binding of hydrophilic polymers, such as polyacrylates, cellulose derivatives, and chitosan derivatives, to biological surfaces is based on hydrogen bonding and ionic interactions. In the last few years, a large number of mucoadhesive systems have been developed, including superporous hydrogel-composite-based systems [34], lipid-based nanocarriers [35], thiolated polymers [36], and chitosan-based carriers [37,38]. Some mucoadhesive polymers have also been shown to act as absorption enhancers or inhibitors of proteolytic enzymes [39]. Several research groups have attempted to integrate pH sensitivity into mucoadhesive polymeric carriers [4042]. The aim of these is to protect the sensitive drug from proteolytic degradation in the stomach and the upper part of the small intestine. The feasibility of systemic insulin delivery by an oral route using graft copolymer networks of poly(methacrylic acid-gethylene glycol) [P(MAA-g-EG)] has been studied, and Morishita et al. found the polymer system to be a very promising candidate for oral drug delivery [43,44]. The smaller-sized microparticular insulin-loaded polymer showed a rapid burst-type insulin release and higher insulin absorption compared with that achieved with larger microparticles, resulting in a greater hypoglycemic effect without detectable mucosal damage [44]. The combined effects of these approaches have been demonstrated in the development of multifunctional P(MAA-g-EG) hydrogels, a smart polymer that has sharp pH-dependent release, Ca2+-deprivation ability, and mucoadhesive characteristics [45,46]. This system shows very high (10%) pharmacological availability of insulin after oral administration [47]. In another reported study, lectin-conjugated alginate microparticles enhanced the intestinal absorption of insulin to facilitate a drop in glucose levels in the blood [48]. In a similar study, mucoadhesive polysaccharide (chitosan) nanoparticles seemed to enhance the intestinal absorption of many peptides and proteins [49].
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In recent years, thiolated polymers, designated thiomers, which are mucoadhesive-based polymers with thiol-bearing side chains, have appeared as a promising alternative in the arena of non-invasive peptide delivery [50]. So far, the cationic thiomers chitosancysteine [51], chitosanthiobutylamidine [52,53], and chitosanthioglycolic acid [54,55], and the anionic thiomers poly (acrylic acid)cysteine [56], poly(acrylic acid)cysteamine [57], carboxymethylcellulosecysteine [58], and alginatecysteine [59] have been generated. Because inter- and intramolecular disulfide bonds form within the thiomer itself, dosage forms such as tablets and microparticles display strong cohesive properties, resulting in higher stability, prolonged disintegration times, and a more controlled release of the embedded peptide drug [60]. After the oral administration of insulin tablets based on thiolated polymer to non-diabetic conscious rats, their blood glucose levels decreased significantly for 24 h relative to the decrease achieved with subcutaneous injection [61]. As described above, numerous mucoadhesive polymeric delivery systems have been proposed. These delivery systems are thought to be effective in enhancing the intestinal absorption of biological molecules vulnerable to proteolytic enzymes [62,63]. However, their toxicity over a long period is still unclear, and human data are required to regulate their potential use for clinical applications. 2.1.5. Particulate carrier delivery systems Most oral delivery strategies for insulin based on particulate carriers have been developed to circumvent the barriers to oral peptide delivery. They efficiently protect protein and peptide drugs against enzymatic degradation in the harsh environment of the GIT, provide high transfer of drugs across the epithelial mucosa, control the release rate, and target drug delivery to specific intestinal sites [64]. Pathogens and microparticles smaller than 10 m enter the gut-associated lymphoid tissues (GALT), which include Peyer's patches, the appendix, and small solitary lymphoid nodules. Peyer's patches are follicles of lymphoid tissue covered with a specialized epithelium containing M cells [65]. The potential modes of entry of submicron particles from the intestine include via M cells and enterocytes, and by paracellular routes. Histological evaluation of tissue sections has demonstrated that 100 nm particles diffuse throughout the submucosal layers, whereas larger particles (10 m) are predominantly localized in the epithelial lining of the tissue. Similar particle size-dependent uptake was also confirmed in an experiment with Caco-2 cells [66]. Lysosomal degradation is normally associated with the endocytotic uptake of microparticles, but because this can interfere with the antigen-sampling role of the M cells, Peyer's patches are deficient in lysosomes. These favorable characteristics of the GALT have stimulated research into targeting Peyer's patches for peptide and protein delivery [67]. Colloidal carrier systems that have already been studied to improve peptide delivery include microemulsions [68], liposomes [69], polymeric nano- and microparticles [70], and polymeric micelles [71]. A novel oral dosage formulation of dry insulin emulsion responded to changes in the external environment, simulating gastrointestinal conditions, suggesting that this new enteric-coated dry emulsion formulation is potentially applicable to the oral
delivery of peptide and protein drugs [72]. In another related study, a new solid-in-oil-in-water emulsion for the oral administration of insulin has been developed using surfactant-coated insulin [73]. A microemulsion of recombinant human (rh)-insulin has also demonstrated an improved efficacy of orally administered insulin [74,75]. Liposomes are also a potential alternative carrier for the oral delivery of proteins. In one particular study, double liposomes containing insulin were examined in combination with aprotinin [76]. In a similar approach, Zelihagl et al. investigated the penetration properties of various liposome formulations containing insulin through a Caco-2 cell monolayer. They found that the oral administration of insulin- and sodium-taurocholate-incorporated liposomes significantly decreased blood glucose levels. Furthermore, a high in vitro/in vivo correlation was observed using the Caco-2 cell monolayer model [77]. In one specific study, fusogenic liposomes were shown to be unique delivery vehicles capable of introducing their contents directly into the cytoplasm with the aid of the envelope glycoproteins of Sendai virus [78]. The results indicated that fusogenic liposomes are useful carriers with which to improve the absorption of insulin via the intestinal tract. Recently, a layer-by-layer self-assembly technique has been applied to chitosan and sodium alginate microencapsulation [79]. Alginatechitosan microcapsules provide a simple method for controlling the loading and release of protein molecules within these polysaccharide microcapsules. Nanocapsules based on poly (ethyl 2-cyanoacrylate) containing insulin to form biocompatible microemulsions represent a convenient method for the entrapment of bioactive peptides [80]. Research in this area has also shed new light on the potential use of chitosan microspheres in orally administered and other mucosally administered protein and peptide drugs, because they show excellent mucoadhesive and permeation-enhancing effects across biological surfaces [81]. Control of the size and size distribution of chitosan microspheres is necessary to improve their reproducibility, bioavailability, and repeatable release behavior. Polyacrylic acid, a pH-dependent material, has revived some hope of achieving an oral insulin formulation. Eudragit S100 microspheres have the potential to act as an oral carrier for peptide drugs like insulin [82]. In a similar approach, novel pH-sensitive polymethacrylic acidchitosanpolyethylene glycol nanoparticles were prepared under mild aqueous conditions by polyelectrolyte complexation [83]. A preliminary investigation indicated that these particles are a good candidate for oral peptide delivery. In this context, biodegradable nanoparticles loaded with an insulinphospholipid complex were prepared by a novel reverse micellesolvent evaporation method, in which soybean phosphatidylcholine was used to improve the liposolubility of insulin, with biodegradable polymers used as the carrier material to control drug release [84]. Serum insulin levels following the intragastric administration of insulinsoybean phosphatidylcholine (Ins SPC) nanoparticles are illustrated in Fig. 1. However, difficulties have been encountered that must be overcome to achieve success in carrier delivery systems: the low incorporation efficiency of hydrophilic drugs; the precise control of drug release; the avoidance of particle aggregation; and the
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possible accumulation of non-degradable particles in tissues. Even with degradable particles, the use of unreasonably high quantities of carrier can lead to harmful carrier toxicity [85]. 2.1.6. Targeted delivery systems The desire to deliver protein and peptide biopharmaceuticals conveniently and effectively has led to the intense investigation of targeted delivery systems. Despite various challenges, progress toward the convenient non-invasive delivery of proteins and peptides has been made through specific routes of administration. The delivery of proteins and peptides to specific sites of action has been used to lower the total dose delivered and to concentrate the therapeutic dose at specific sites of pharmacological action [86]. Absorption is not uniform throughout the GIT, and site-specific absorption occurs because of differences in the composition and thickness of the mucus layer, pH, surface area, and enzyme activity [87]. Drug delivery to the colon, for instance, has several attractive features, including a prolonged residence time, reduced enzymatic activity, increased tissue responsiveness to absorption enhancers, and natural absorptive characteristics [88]. Oral administration offers a potential portal to the superficial layers of the GIT (local delivery) and to the blood and lymphatic systems (systemic delivery). However, the harsh hydrolytic environment of the GIT and the epithelial barriers to absorption pose major challenges to the success of this mode of drug delivery for peptide and protein drugs. Insulin administration in a colon-targeted delivery system has been developed extensively over the past few years [89]. The colon-targeted delivery of insulin with sodium glycocholate was more effective in increasing hypoglycemic effects after oral administration. The combination of sodium glycocholate and poly (ethylene oxide) tended to prolong the absorption of insulin after oral administration using the colon-targeted delivery system [90]. Tozaki et al. also reported that novel azopolymer-coated pellets may be useful carriers for the colon-targeted delivery of peptides, including insulin and (Asu1,7)eelcalcitonin [91].
The release of a peptide in a specific region of the GIT, where uptake into the lymph system is maximized or where enzyme activity is low, has been used to increase the absorption of drugs after oral administration [92]. Surface charge and particle size are the main factors that control the uptake of particulates by Peyer's patches [93]. Proteins such as lectins and transferrin have also been suggested as transport carriers in the gastrointestinal absorption of polypeptides. The covalent attachment of tomato lectin molecules to polystyrene particles significantly enhanced their uptake by Peyer's patches and normal intestinal tissues [94]. The total percentage of the administered dose taken up through the lymphoid tissue was statistically much greater than that absorbed through non-lymphoid tissue. It was estimated that 60% of the uptake in the small intestine occurred through the Peyer's patches, even though the patches comprise a small percentage of the total surface area of the small intestinal tissue. A significant amount of total uptake was also shown to occur in the large intestine, particularly in the lymphoid sections of this tissue. These results were confirmed by fluorescence microscopy. Joseph et al. used poly (lactide-co-glycolide) (PLGA) microspheres for the delivery of oral peptides in diabetic mice [95]. The microsphere formulation lowered the glycemic response to oral glucose challenge in the mice. The microspheres used in this study were 1 m in size and were supposedly absorbed through the Peyer's patches. The transferrin-receptor-mediated transcytosis of an insulintransferring (InTf) conjugate has been demonstrated in Caco-2 cell monolayers [96]. The results indicated that transepithelial transport by Tf-receptor-mediated transcytosis is a feasible approach to the development of an oral delivery system for insulin, as well as other peptide drugs. Tyrphostin-8, as an enhancer of Tf-receptor-mediate transcytosis, enhanced hypoglycemic effects of In-Tf conjugate in diabetic rats, especially at 7 h after oral administration [97]. Although there have been promising results with agents that increase targeted delivery or specific-receptor-mediated transcytosis, insufficient quantities of drug-loaded particles were absorbed through the intestinal epithelium. Whether the physicochemical properties of polymers or ligand conjugates favor the non-specific uptake by enterocytes or M cells remains controversial. Furthermore, toxicity problems might arise as the result of the continued absorption of particles by M cells into Peyer's patches, which could induce an immune response. 2.2. Buccal administration In the various transmucosal routes of insulin delivery, many strategies have been used by scientists, and they are compiled in Table 2. The buccal mucosa has excellent accessibility, an expanse of smooth muscle, and a relatively immobile mucosa, and is hence suitable for the administration of retentive dosage forms. Direct access to the systemic circulation through the internal jugular vein allows drugs to bypass the hepatic first-pass metabolism, leading to high bioavailability. Other advantages include low enzymatic activity, suitability for drug excipients that mildly and reversibly damage or irritate the mucosa, painless administration, easy drug withdrawal, facility to include a permeation enhancer/enzyme
Fig. 1. Plasma glucose levels after oral administration of InsSPC nanoparticles to diabetic rats: NPs 20 IU/kg (), Ins solution control 20 IU/kg (), Ins solution 1 IU/kg s.c. (). The serum insulin levels after oral administration of InsSPC nanoparticles in diabetic rats: NPs 20 IU/kg (), Ins solution control 20 IU/kg (), Ins solution 1 IU/kg s.c. (). Data represent means SD (n = 6) [84].
E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546 Table 2 Transmucosal routes of insulin delivery systems Administration route Buccal Insulin solution/lysalbinic acid Deformable lipid vesicles Nasal Nasal powder formulation Insulin solution/SDC + CDs Insulin solution/Alkylglucosides Insulinchitosan powder ChitosanTBAinsulin microparticles AGMS Pulmonary Insulin microcrystals/Zn2+ Insulin/DPPC physical mixture Insulin/TDM or DMCD Insulin liposomes InsulinCAPPEG particles Insulin PLGA nanospheres Insulinpolybutylcyanoacrylate NPs Ocular Insulin solution/SGC, SDC, STC or POELE Insulin solution/Alkylglucosides Insulin solution/sucrose cocoate Gelfoam ocular device Rectal Insulin suppositories/Witepsol W35, SDC, SC, STDC Dogs or STC Insulin suppositories/Witepsol W35, NaSal and POELE Dogs Insulin glycerolgelatin suppositories/snail mucin Rats PAa was 50% Rabbits Rats Rats Rabbits BAa was 3.6%8.2% Significantly stimulated systemic insulin absorption BA was 5.2% 60% reduction in blood glucose levels over 8 h Rats Rats Rats Mice Rats Guinea pigs Rats 17% reduction in blood glucose levels Significant reduction in blood glucose levels BRa was 0.19%0.84% Significant reduction in blood glucose levels BRa was increased 1.8-fold Long-lasting hypoglycemic response BRa was 57.2% Rabbits Rats Rats Sheep Rats Rats BA was 11.1%22.4% 48%72% reduction in blood glucose levels Significantly enhanced insulin absorption BRa was 17% BA was 7.24% PAb was 8.6% Hamster cheek pouch model Significantly increased insulin permeability Rabbits BRa was 19.78% System Model Results
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Refs.
[101] [103]
[113] [114] [116] [126] [128] [130]
[137] [144] [146] [147] [148] [152] [159]
[174] [176] [178] [184]
[187]
PAa was 49%55% [188] 44% reduction in blood glucose levels within 2 h [190]
Abbreviations: BR, relative bioavailability; BA, absolute bioavailability; SDC, sodium deoxycholate; CDs, cyclodextrins; chitosanTBAinsulin, chitosan4thiobutylamidine insulin conjugate; AGMS, aminated gelatin microspheres; PA, pharmacological availability; DPPC, 1,2-dipalmitoylphosphatidylcholine; TDM, tetradecyl--maltoside; DMCD, dimethyl--cyclodextrin; insulinCAPPEG, insulincalcium phosphate polyethylene glycol; PLGA, poly(lactide-co-glycolide); NPs, nanoparticles; SGC, sodium glycocholate; STC, sodium taurocholate; POELE, polyoxyethylene-9-lauryl ether; SC, sodium cholate; STDC, sodium taurodeoxycholate; NaSal, sodium salicylate. PA and BR of insulin systems were determined based on the extent of the hypoglycemic response relative to that achieved with subcutaneousa or intravenousb insulin injection.
inhibitor or pH modifier in the formulation, and versatility in the design of multidirectional or unidirectional release systems for local or systemic action. The mucosa lining the oral cavity represents a potentially important topical route for the delivery of proteins and therapeutic peptides [98]. It has been shown that the buccal administration of proteins, such as insulin, interferons, and interleukins, has some advantages and reduces many related side effects. For example, the buccal route provides a constant, predictable drug concentration to the blood. Veuillez et al. have shown that peptide transport across the buccal mucosa occurs via passive diffusion and is often accompanied by varying degrees of metabolism [99]. Various approaches have been taken to improve the buccal absorption of peptides, including the use of absorption enhancers to increase membrane permeability and/or the addition of enzyme inhibitors to increase drug stability. From this point of view, the role of absorption enhancers in the buccal transport of proteins is crucial. Many substances can function as absorption enhancers,
the most popular being detergents such as bile acid salts, sodium lauryl sulfate, etc. However, many absorption enhancers have some side effects, often causing irritation of the buccal mucosa. An additional problem is the taste of buccal compositions. The most efficient absorption enhancers, bile acids salts, have a strong bitter taste, so the regular use of compounds containing bile acids is hardly acceptable for long-term administration. Pluronic F-127 (PF-127) gel containing insulin and unsaturated fatty acids, such as oleic acid (18:1), eicosapentaenoic acid (20:5), or docosahexaenoic acid (22:6), showed a continuous hypoglycemic effect following its buccal administration in normal rats [100]. PF-127 gels containing oleic acid showed the highest pharmacological availability (15.9% 7.9%). Comparative analyses indicated that 20% PF-127 gels containing unsaturated fatty acids are potential formulations for the buccal delivery of insulin. In particular, a good candidate for an effective absorption enhancer seems to be lysalbinic acid [101]. Lysalbinic acid, a product of the alkaline hydrolysis of egg albumin and a mild detergent, meets
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those requirements. The experimental data suggest that, using this method, it is possible to determine quickly and qualitatively the composition of the formulation to be used for the buccal delivery of large medicinal molecules like -interferon and insulin. Thus, lysalbinic acid has been shown to increase significantly the paracellular permeability of the hamster oral mucosa to peptide compounds of low to medium molecular weights. The molecular mechanism by which lysalbinic acid increases transmucosal transport is not yet completely clear. However, it may be similar to that of other detergent enhancers (sodium dodecyl sulfate, bile salts, etc.), based on intercellular lipid solubilization. Histological investigation of the rat mucosa has shown that lysalbinic acid has no irritating or sensibilizing effects during buccal use [102]. In recent years, a novel type of highly deformable lipid vesicle (transferosome), composed of soybean phosphotidylcholine, cholesterol, and sodium deoxycholate, has been developed to enhance insulin bioavailability [103]. Compared with the subcutaneous administration of insulin solution, the relative pharmacological bioavailability and the relative bioavailability in the experimental group treated with insulin-deformable vesicles were 15.59% and 19.78%, respectively, which were higher than those of rabbits treated with conventional insulin vesicles (P b 0.05), blank deformable vesicles, or insulin mixture (P b 0.05). Deformable vesicles may be a better carrier than conventional vesicles for buccal insulin delivery. It is anticipated that the effects of salivary scavenging and accidental swallowing of the delivery system, in addition to the barrier properties of the buccal mucosa, will remain major limitations in the development of buccal drug delivery systems. Therefore, various buccal mucoadhesive delivery systems have been used in many different dosage forms, in an attempt to achieve the delivery of drugs through the buccal mucosa and to overcome the side effects of absorption enhancers. By creating an adhesive interaction between the delivery system and the oral mucosa, the residence time of the drug at the absorption site is extended, which allows therapeutic drug levels to be maintained for the desired length of time [104]. Nagai was among the first to pioneer the mucoadhesive drug delivery system in the early 1980s by administering insulin across the buccal mucosa in beagle dogs [105]. Pelleted mucoadhesive polymeric nanoparticles for the buccal delivery of insulin were an attempt to develop an alternative buccal delivery system for insulin [106]. A significant hypoglycemic response was observed after 7 h, without any detectable fluctuation in the blood glucose profile or risk of hypoglycemia. In another related work, insulin was formulated into mucoadhesive buccal tablets using Carbopol 934, hydroxypropyl cellulose, or hydroxypropylmethyl cellulose and different absorption promoters [107]. Furthermore, Insulin Buccal Spray (IBS), a formulation with soybean lecithin and propanediol combined as an absorption enhancer, improved the hypoglycemic effect of insulin in diabetic rabbits and rats [108]. The hypoglycemic effect lasted over 5 h and 4 h in diabetic rabbits and rats, respectively, and blood glucose levels decreased significantly in both species compared with those of the control groups. Pharmacodynamic and pharmacokinetic results showed that IBS is a promising buccal delivery system for clinical trials and future clinical applications.
In the many buccal delivery systems for numerous peptide/ protein drugs, the exciting challenge remains to increase the bioavailability of the therapeutic drugs across the oral buccal mucosa. So far, efficacy studies have only been presented as abstracts, and safety reports of buccal insulin are scare. The majority of the above mentioned clinical studies did not assess the side effects of treatments. 2.3. Nasal administration Nasal insulin delivery has been widely investigated as an alternative to subcutaneous injection for the treatment of diabetes and is considered to be a promising technique for the following reasons: the nose has a large surface area available for drug absorption because the epithelial surface is covered with numerous microvilli; the subepithelial layer is highly vascularized, and the venous blood from the nose passes directly into the systemic circulation, thereby avoiding the loss of drug by first-pass metabolism in the liver; it allows lower doses, more rapid attainment of therapeutic blood levels, quicker onset of pharmacological activity, fewer side effects, high total blood flow per cm3, and a porous endothelial basement membrane; it is easily accessible; and the drug is delivered directly to the brain along the olfactory nerves [109,110]. The pharmacokinetic profile of intranasal insulin is similar to that achieved with intravenous injection and, in contrast to subcutaneous insulin delivery, bears a close resemblance to the pulsatile pattern of endogenous insulin secretion during meal times [111]. To date, attempts to implement this approach have indicated that intranasal insulin therapy has considerable potential for the control of postprandial hyperglycemia, especially in the treatment of patients with insulin-dependent diabetes mellitus [112]. Despite the potential of the nasal route, a number of factors limit the intranasal absorption of drugs, especially peptide and protein drugs. Mucociliary clearance, enzymatic activity, and the epithelium combined with the mucus layer constitute barriers to the nasal absorption of high-molecular-weight and hydrophilic peptides. Therefore, the use of absorption enhancers and proteolytic enzyme inhibitors, and the design of suitable dosage formulations, such as mucoadhesive and dry powder delivery systems, have been investigated to enhance the nasal bioavailability of these drugs [113]. The effects of sodium deoxycholate (SDC) in combination with cyclodextrins (CD) as enhancers of the nasal absorption of insulin have been determined by measuring blood glucose levels [114]. Combining SDC with beta-CD lowered the serious nasal ciliotoxicity of SDC and had a marked absorption-promoting effect, which was due not to the low concentration of SDC but to the inhibition of leucine aminopeptidase activity. The effects of a soybean-derived sterol mixture and of a steryl glucoside mixture as enhancers of the nasal absorption of insulin in rabbits have been investigated [115]. A series of new glycosides with extended alkyl side chains (C1316) linked to maltose or sucrose were synthesized and used effectively to enhance nasal insulin absorption in anesthetized rats [116]. Cross comparisons of alkylmaltoses and alkanoylsucroses showed that the alkyl chain length had a greater effect than the glycoside moiety in determining the potency of
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potential insulin absorption-enhancing agents. When tetradecylmaltoside was applied to the nasal mucosa 15 min before insulin was applied, enhanced insulin absorption was observed. Another study reported that lipid-emulsion-based formulations were devised to enhance insulin absorption through the nasal cavity, although at lower insulin doses, but showed no statistically significant enhancement [117]. Unfortunately, many absorption enhancers cause significant damage to the nasal mucosa or other side effects when used at very effective concentrations, particularly with long-term exposure. Most of the traditional absorption enhancers, such as surfactants and bile salts, have limited clinical use because of the irreversible damage to the nasal mucosa that accompanies their absorptionenhancing effects [118120]. In another approach, the mucociliary clearance rate can be reduced with the use of mucoadhesive systems. These drug delivery systems can control the rate of drug clearance from the nasal cavity and protect the drug from enzymatic degradation by nasal secretions. Increasing the residence time of the drug formulation in the nasal cavity, and hence prolonging the period of contact with the nasal mucosa, may improve drug absorption [121,122]. Approaches that increase the residence times of drug formulations in the nasal cavity usually involve the use of microspheres, liposomes, or gels that have mucoadhesive properties. These nasal drug delivery systems absorb water, swell, and form a gel-like layer in contact with the nasal mucosa, which is cleared slowly from the nasal cavity. Therefore, absorption occurs rapidly, often with high bioavailability. Mucoadhesive polymers exert a direct effect on the mucosa by absorbing water from the mucus and swelling. The epithelial cells are dehydrated, causing the tight junctions to separate, increasing the absorption of drugs that are transported via the paracellular pathway [123]. The physicochemical properties of the drugs are also important factors affecting nasal drug absorption. A number of lipophilic drugs are completely or almost completely absorbed from the nasal mucosa. The mechanisms and effectiveness of these drug delivery systems are described to guide the development of specific and effective therapies for the future development of preparations of peptides and other drugs that would otherwise be administered parenterally. The insulin gel formulation produced a significant hypoglycemic response in rabbits, and insulin bioavailability from the nasal gel formulation was 20.6% of that achieved with intravenous injection. These results suggest that the carbopol nasal gel can be considered as a preferred platform in macromolecular nasal administration [124]. Recently, Varshosaz et al. studied the development of a chitosan bioadhesive gel for the nasal delivery of insulin [125]. A 2% medium-molecular-weight chitosan gel with EDTA caused an increase in insulin absorption and a reduction in glucose levels of as much as 46% relative to those achieved via the intravenous route. Therefore, insulinchitosan nanoparticles are widely accepted as a nasal drug delivery system [126]. Other results showed that 400 mg of chitosan and 70 mg of ascorbyl palmitate used as a cross-linker in insulinchitosan microspheres, caused a 67% reduction in blood glucose compared with that achieved with delivery via the intravenous route, and the absolute bioavaliability of insulin was 44% [127]. Furthermore, chitosan4-thiobutyla-
midine (chitosanTBA) microparticles showed the controlled release of insulin over 6 h, with an absolute bioavailability of 7.24% 0.76% in conscious rats [128]. These data indicated that the potential of chitosanTBA microparticles in nasal insulin administration is substantially higher than that of unmodified chitosan [129]. Aminated gelatin microspheres (AGMS) were recently investigated as a nasal drug delivery system for peptide drugs [130]. AGMS significantly increased the nasal absorption of insulin in rats when administered as a dry powder formulation, but no significant hypoglycemic effect was observed when given in suspension. One of the proposed mechanisms for the increased insulin absorption involved the hydrogel nature of the microspheres, which can absorb water from the nasal mucosa, thus resulting in the temporary dehydration of the epithelial membrane and the opening its tight junctions. The electrostatic interactions between model drugs and the microspheres were also considered to be major factors controlling release behavior. Therefore, the positive charge on the AGMS also evidently contributes to their absorption-enhancing effect. Therefore, AGMS might be a new candidate carrier for the nasal delivery of peptide drugs. Many preclinical and clinical studies of the intranasal delivery of proteins, peptides, and DNA have been completed, and they indicate that efficacious delivery can be achieved systematically. Despite the promising results, the development of nasal insulin biotherapeutics is beset with problems that require an integrated and rational approach. To date, relatively limited clinical experience with intranasal insulin indicates a need for high and repeated doses to achieve glycemic control. The occurrence of nasal irritation in up to 25% of patients and the potential for damage to the nasal mucosa and nasal-ciliary function are causes for concern, especially when viewed in the context of the requirement for long-term exposure. Another problem of the nasal mode of insulin application is the considerable intra- and interindividual variability in bioavailability. The amount of insulin that can be applied at one time is also limited, because high-frequency nasal insulin applications reduce the bioavailability of the applied insulin. 2.4. Pulmonary administration 2.4.1. Background The lungs offer a large surface area for drug absorption, of approximately 140 m2. The alveolar epithelium is very thin (approximately 0.10.5 mm thick), thereby permitting rapid drug absorption. The alveoli can be effectively targeted for drug absorption by delivering the drug as an aerosol, with a mass median aerodynamic diameter of less than 5 m. Furthermore, the first-pass metabolism of the GIT is avoided. Although metabolic enzymes are found in the lungs, the metabolic activities and pathways may differ from those observed in the GIT, and this makes the pulmonary administration of many peptides and proteins very promising [131]. Inhaled insulin is a novel approach to delivering insulin noninvasively and is emerging as a viable alternative to injectable insulin. Intensive insulin therapy has been shown to have significant benefits in patients with type 1 or type 2 diabetes [132]. The reality of pulmonary insulin becoming a viable alternative to
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injections is, in large measure, due to the inherent anatomical advantages that make it an ideal route for the administration of insulin. The availability of inhaled insulin will open new possibilities in treating patients with diabetes. Patients who are reluctant to accept insulin injections can now be offered a real alternative. This should facilitate the earlier initiation of insulin therapy where appropriate and the intensification of existing regimens. Inhaled insulin will provide an alternative even for those patients who may not be resistant to the idea of injections. The pulmonary route of administration was targeted to increase the compliance and life quality of patients with diabetes, who may otherwise have to endure multiple daily subcutaneous injections of insulin. Increased compliance is important in decreasing the severe and debilitating long-term effects of poorly controlled diabetes [133]. As a consequence, the permeability of insulin as a model peptide was examined to characterize the tracheal epithelial barrier in in vitro experiments using excised rabbit tracheae [134]. Insulin showed slight degradation during the 150 min duration of tracheal permeation, and the apparent permeability coefficient for insulin was 7 10 9 cm/s. The tracheal permeability to insulin was significantly increased by 10 mM glycocholate, 1 mM bestatin (aminopeptidase B and leucine aminopeptidase inhibitor), and 10,000 kIU/mL aprotinin (inhibitor of trypsin and chymotrypsin). The peptidase activity of the rabbit tracheal epithelium was as follows: di-peptidyl-aminopeptidase IVN leucine aminopeptidase N cathepsin B N trypsin. These activities were significantly lower than those of jejunal mucosal tissues. These results suggest that the tracheal absorption of peptide drugs through the respiratory tract may contribute to the systemic delivery of these drugs following pulmonary administration by intratracheal insufflation or instillation. 2.4.2. Dry powder inhalation Insulin was used as a model protein to demonstrate the feasibility of using protein crystals for the pulmonary delivery of a sustained-release protein drug formulation [135]. The hypoglycemic effects of the microcrystal suspension were prolonged over 7 h. These results could be attributed to the sustained release of insulin from the microcrystals, which were deposited widely throughout the entire lung. Insulin dry powder, made of insulin and other appropriate materials, was also insufflated into rat lungs from an incision in the throat [136]. The area above the curve (AAC) for insulin (5 U/kg) administered by pulmonary delivery was very close to that of insulin given by subcutaneous administration at the same dose. Thus, the pulmonary delivery of insulin acts effectively and rapidly. The feasibility of insulin microcrystals as a long-acting formulation for pulmonary delivery was examined [137]. In an in vivo experiment with rats, zinc enhanced the hypoglycemic effects of insulin microcrystals, with minimum reductions in blood glucose of 17%. To investigate the enhancement effect of lanthanide ions (Ln3+) on the absorption of larger molecules from the pulmonary pathway, insulin (mol. wt. = 5730) was chosen as the model peptide [138]. Lanthanum is an inhibitor of calcium flux and inhibits the insulin secretion induced by glucose and acetylcholine to basal levels but does not alter the stimulatory effects of insulin
[139]. The temporal changes in the gadolinium (Gd3+) content of serum were also investigated because Gd3+ prevents the lipopolysaccharide-induced decrease in the expression of hepatic insulin-like growth factor-I (IGF) and IGF-binding protein-3 [140]. The effect of Ln3+ in promoting the bioavailability of insulin is closely related to its species, concentration, and order of delivery. The anionic form of gadolinium seems to be more effective than its cationic form. The coadministration of Gd3+ with insulin was most effective in increasing insulin absorption in the lung. Hyaluronic acid (HA) and recombinant human insulin were cospray-dried to form a dry powder suitable for inhalation [141]. Several properties of HA support its unique utility and consequent selection for the pulmonary route of insulin administration. Some studies have investigated the inhibition by HA of phagocytosis by macrophages [142]. This phenomenon, combined with the mucoadhesive activity of HA, may prolong the time that HAbased microparticles remain close to the main absorption site in the deep lung [143]. Systemic insulin levels and the corresponding glucose levels were monitored following the administration of these microparticles to the lungs of male beagle dogs. The addition of Zn2+ or hydroxypropyl cellulose improved the mean residence time, AUC/dose, and Tmax, compared with those of pure spraydried insulin. 2.4.3. Absorption enhancers Several approaches have been used to increase the bioavailability of inhaled insulin, including the coadministration of absorption enhancers or delivery agents and the encapsulation of insulin in proprietary particles. Mitra et al. investigated the enhancement of insulin absorption in the presence of phospholipids and lung lavage fluid in vivo and in vitro [144]. A significantly greater reduction in blood glucose was observed with a physical mixture of 1,2-dipalmitoyl phosphatidylcholineinsulin compared with that observed with liposomes, suggesting a possible effect of the physical state of the phospholipid chain on insulin absorption in vivo. In another study, several dry powder formulations of insulin were prepared using a spray-drying technique to examine the effects of additives on insulin absorption [145]. The absolute bioavailability of insulin solution and dry powder containing bacitracin or Span 85 was almost 100% and 20% of that of the insulin solution, respectively. Citric acid was more effective in increasing the hypoglycemic effect of the dry powder than that of the solution. When dry insulin powder containing 0.036 mg/dose of citric acid was administered, lactate dehydrogenase activity, a sensitive indicator of acute toxicity in lung cells, in the bronchoalveolar lavage was as low as that observed after saline administration. Thus, citric acid appears to be a safe and potent absorption enhancer for insulin in a dry powder form. Cyclodextrin (CD) derivatives, such as tetradecyl--maltoside (TDM) and dimethyl--cyclodextrin (DMCD), enhance the pulmonary absorption of insulin and have a reversible action on the respiratory epithelium through complexation [146]. CDs enhance the transmucosal absorption of insulin, by forming an inclusion complex with insulin or by direct action on the membrane. When insulin formulated with increasing concentrations
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(0.06%0.25%) of TDM or DMCD was administered to anesthetized rats, there was a concentration-dependent decrease in plasma glucose and an increase in plasma insulin concentrations. The relative bioavailability of insulin formulations containing TDM was higher (0.34%0.84%) than that of formulations containing DMCD (0.19%0.48%). This study also implied that TDM enhances absorption, perhaps by solubilizing membrane components or loosening cellcell tight junctions. 2.4.4. Particulate carrier systems The pulmonary delivery of peptides and proteins is complicated by the complexity of the anatomical structure of the human respiratory system and the effects on the disposition of the drug caused by the respiration process. A novel nebulizer-compatible liposomal carrier for the aerosol pulmonary delivery of insulin was developed and characterized [147]. Experimental results showed that insulin could be efficiently encapsulated in liposomes using a method involving preformed vesicles and detergent dialysis. The optimal encapsulation efficiency was achieved when 40% ethanol was used. The particle size of the liposomal aerosols expressed from an ultrasonic nebulizer approximated 1 m. Animal studies showed that plasma glucose levels were effectively reduced when liposomal insulin was delivered by the inhalation route using aerosolized insulin-encapsulated liposomes, as shown in Fig. 2. By including a fluorescent probe (phosphatidylethanolamine rhodamine) into the liposome, researchers found that the liposomal carriers were effectively and homogeneously distributed in the lung aveoli. Liposome-mediated pulmonary drug delivery promotes an increase in the drug retention time in the lungs, and more importantly, a reduction in extrapulmonary side effects, which invariably results in enhanced therapeutic efficacy. The influence of calcium phosphate (CAP) and polyethylene glycol (PEG) particles on the systemic delivery of insulin administered by the pulmonary route appears to be a crucial factor [148]. InsulinCAPPEG particles in suspension (1.2 U/kg, 110 140 L) were administered to the lungs of fasted rats by intratracheal instillation (INCAPEG) or spray instillation (SINCAPEG). Pharmacokinetic and pharmacodynamic analyses showed that the presence of CAPPEG particles positively influenced the disposition of the insulin administered to the lungs of rats.
Fig. 2. Result of blood glucose level reduction in diabetic mice (n = 9) [147].
Poly(lactide-co-glycolide) (PLGA) and polylactide particles have already been used for drug delivery to the lungs. In cases of lung infections, such as tuberculosis, particles with a mean diameter of 13 m have been produced to target the resident alveolar macrophages [149,150]. In contrast, large porous particles of PLGA have been shown to escape macrophage uptake because of their large size, and they therefore permit the efficient delivery of inhaled insulin into the systemic circulation over long periods [151]. To produce insulin-loaded particles, PLGA nanospheres with a mean diameter of 400 nm were prepared by a modified emulsion solvent diffusion method in water [152]. After the administration of 3.9 IU/kg of insulin with the PLGA nanospheres, blood glucose levels were reduced significantly and hypoglycemia was prolonged for over 48 h, compared with the effects of a nebulized aqueous solution of insulin used as a reference (6 h). This result could be attributed to the sustained release of insulin from nanospheres deposited widely throughout the whole lung. Conversely, the use of CD in PLGA microparticles for the controlled release of proteins has primarily been considered as a way to stabilize the encapsulated macromolecule, improving its therapeutic efficacy [153155], and in some cases, to modulate the release features of the particles [156,157]. For this purpose, hydroxypropyl-cyclodextrin was used to produce the large porous particles of PLGA intended for the pulmonary delivery of insulin [158]. The system developed appears to have great potential for the combined delivery of the protein and an adsorption promoter to the respiratory tract. In another related investigation, insulin-loaded polybutylcyanoacrylate nanoparticles were prepared by the emulsion polymerization of various doses of insulin-loaded nanoparticles and given intratracheally to normal rats [159]. A significant decrease in glucose levels of from 5 IU/kg to 20 IU/kg was achieved in each dose group. The relative pharmacological bioavailability of insulin-loaded nanoparticles given by pulmonary administration was 57.2% greater than that achieved with the same formulation administered subcutaneously. Spray-drying is a valuable technique for producing dry powders suited to the pulmonary delivery of drugs. Chitosan tripolyphosphate nanoparticles promote peptide absorption across mucosal surfaces [160]. The microencapsulation of protein-loaded chitosan nanoparticles using typical aerosol excipients, such as mannitol and lactose, produces microspheres as carriers of protein-loaded nanoparticles to the lung. Protein-loaded nanoparticles can also be successfully incorporated into microspheres to reach the deep lung. After contact with their aqueous environment, they are expected to release the nanoparticles and thus the therapeutic macromolecules. The great challenge for researchers remains the full optimization of the delivery system, which is the culmination of all those particle properties required for therapeutic applications: good encapsulation efficiency, the prevention of protein degradation, and the predictable release of the drug. This breakthrough in the availability of inhaled insulin is certain to have exceptions. It must be recognized that inhaled insulin may not be ideally suited to all patients. Enthusiasm for novelty must not override clinical priorities, and a number of issues remain to be resolved. Patients
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receiving inhaled insulin had more episodes of hypoglycemia and gained more weight than did patients treated with oral agents [161,162]. Mild to moderate cough was also reported in up to 25% of patients receiving inhaled insulin [163,164]. Uncontrollable factors also affect pulmonary absorption, and smokers need lower [165] and asthmatics higher doses [166]. The pulmonary insulin dose required for a similar glycemic effect is approximately 20 times that required for a subcutaneous injection [167], and insulindirected antibodies are an issue [168]. However, as a substitute for short-acting insulin, inhaled insulin appears to be safe, efficient, and satisfactory for clinical use and acceptable to patients at this early stage in its development [169]. 2.5. Ocular administration Numerous research groups have reported early exploratory work on systemic drug absorption via the ocular route. This efficient systemic absorption can be utilized as a non-invasive means of delivering drugs systemically. It also offers the advantages that it is much easier to administer than is an injection; the rate of systemic absorption through the ocular route is as fast as via an injection; eye tissues are much less sensitive to the development of immunological reactions than are other tissues; it bypasses first-pass gastrointestinal and liver effects, which are responsible for the low oral bioavailability of peptides and other drugs; and no tolerance and ocular side effects have been detected after long-term (3 months) daily administration of insulin eyedrops [170]. The eye presents unique opportunities and challenges when it comes to the delivery of pharmaceuticals, and it is very accessible to the application of topical medications. The potential route for insulin delivery to the anterior segment of the eye has been the conjunctival sac [171]. More recent investigations have shown that the conjunctival route of entry plays an important role in the penetration of drugs into the anterior segment. Furthermore, topically applied drugs have been shown to have access to the sclera from the conjunctiva. Therefore, it is conceivable that such drugs could find their way to the posterior segment. It has been shown that even a highmolecular-weight peptide like insulin can accumulate in the retina and optic nerve after topical application, supporting the contention that topically applied drugs can both reach the posterior segment and be therapeutic. Finally, topically applied insulin also accumulates in both the contralateral eye and the central nervous system [172]. After the pioneering work of Christie and Hanzal (1931), numerous investigations of the systemic delivery of insulin via the ocular route were undertaken. Bartlett et al. investigated the feasibility of using insulin eyedrops in humans by studying the local toxicity and efficacy of insulin administered without surfactant to the eyes of healthy volunteers [173]. The results of this study suggest that single-dose insulin at concentrations of up to 100 U/mL, formulated in saline, has no detectable clinical toxicity on the anterior structures of the human eye. Not surprisingly, this therapy was abandoned in humans because of its low bioavailability. Since then, the development of ophthalmic drug delivery systems has always been hindered by local irritation, rapid loss in drainage, blinking, and tearing.
The results of previous studies suggest that the use of absorption enhancers should be introduced. A wide variety of absorption enhancers have been evaluated in the delivery of insulin via the ocular route. Yamamoto et al. determined the extent, pathways, and effects of absorption enhancers on the systemic absorption of insulin after the instillation of a topical solution to albino rabbit eyes [174]. The absorption enhancers used were polyoxyethylene-9-lauryl ether (POELE), sodium glycocholate, sodium taurocholate, and sodium deoxycholate, all at a concentration of 1%. The nasal mucosa contributed about four times more than the conjunctival mucosa to the systemic absorption of ocularly applied insulin. However, the conjunctival mucosa was more discriminating in its sensitivity to the nature of the bile salts used than was the nasal mucosa. Collectively, these findings indicate that it is feasible to achieve hypoglycemia with ocularly administered insulin. Consequently, eyedrops of 0.25% insulin plus 0.5% POELE or polyoxyethylene-20-stearyl ether (Brij-78) were instilled into rabbit eyes twice a day for 3 months [175]. The efficacy of the insulin in lowering the blood glucose concentration and the uptake of insulin into the systemic circulation remained the same throughout the experimental period. No allergic responses or local side effects were detected, indicating that both insulin and the absorption enhancers (POELE and Brij78) are safe for instillation into the eyes over long periods. A series of alkylglycosides with various alkyl chain lengths and carbohydrate moieties were tested for their ability to enhance the systemic absorption of insulin after topical ocular delivery in anesthetized rats [176]. All the reagents were effective only when used at concentrations above their critical micelle concentrations, and the most hydrophobic alkylglycoside reagents were the most efficacious in promoting systemic insulin absorption. Regular porcine insulin was administered as eyedrops, either alone or in combination with several different absorption enhancers, to eight healthy euglycemic dogs [177]. No ocular symptoms occurred with the administration of insulin alone or together with 0.5% solutions of Brij-78, fusidic acid, POELE, dodecylmaltoside, or tetradecylmaltoside. This study demonstrated that short-acting insulin is systemically absorbed in dogs via the ocular route when applied with certain emulsants. Sucrose cocoate (SL-40) is an emulsifier used in emollients and skin-moisturizing cosmetic formulations that contains a mixture of sucrose esters of coconut fatty acids in an aqueous ethanol solution. Sucrose cocoate was examined to determine its potential usefulness and enhancing effects in nasal and ocular drug delivery [178]. When insulin was administered ocularly in the presence of 0.5% sucrose cocoate, significant increases in plasma insulin levels and a decrease in blood glucose levels were observed. To prolong the retention time of the formulation in the precorneal area, a positively charged insulin-containing liposome was prepared [179,180]. This formulation reduced the blood glucose concentrations of rabbits to 65%70% of the initial levels for up to 5 h. Commercially available Gelfoam, an absorbable gelatin sponge, is used in the fabrication of an ocular insert in the form of a matrix system. Both in vitro flow-through and in vivo methods of device removal were examined to determine the dissolution rate of insulin from a Gelfoam-based eye device [181]. Two eyedrop formulations and 13 eye device formulations
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were evaluated [182]. The in vivo results for devices containing 0.5 or 1.0 mg of insulin with 20 g of Brij-78 showed substantial improvement in insulin activity and a significantly prolonged systemic delivery of insulin within the desired therapeutic levels, with no risk of hypoglycemia. The prolonged activity of the insulin was due to its gradual release from the device, which slowed tear production. Furthermore, the mean blood glucose concentration returned to a nearly normal level within 60 min of the removal of the device. Although it is known that enhancers can promote the systemic absorption of insulin via the ocular route, little is known about the long-term toxicity of these enhancers. For this practical reason, sodium insulin and zinc insulin Gelfoam ocular devices have been developed as insulin carriers for the systemic delivery of insulin, and they do not contain any surfactant or absorption enhancer [183,184]. Lee and Yalkowsky investigated the role of acid in the enhancer-free absorption of insulin from Gelfoam ocular devices [185]. A Gelfoam device containing 0.2 mg of insulin is sufficient to control blood glucose levels in a uniform manner (60% of the initial concentration) for over 8 h. These results suggest that a change in the Gelfoam when treated with acid is responsible for the efficient systemic absorption of insulin from these enhancer-free devices. Whereas all ocular preparations must be compatible with the iris, corneal, and conjunctival tissues, these factors are especially important for ocular devices. Because the device must remain in one place for several hours, irritation of the local tissue can be more problematic with an eye device than with an eyedrop, which is eliminated within seconds. A device must also be comfortable and designed so that it does not fall out during sleep. Most importantly, the device must release the drug in a constant and reproducible manner. Ultimately, all the preclinical studies suggest the feasibility of delivering insulin systemically via the ocular route. No toxic effects were observed in several preliminary human studies. However, the application of this approach still requires further investigation to be clinically useful. 2.6. Rectal administration During the past few years, considerable interest has arisen in the rectal route for insulin administration. This route is regarded as a more physiological route for the application of insulin. Rectal insulin delivery offers several advantages over some of the other enteral routes. First, the rectal route is independent of intestinal motility, gastric-emptying time, and diet. It is most likely that the presence of degrading enzymes in the gut wall decreases from the proximal end to the distal end of the small intestine and rectum. The most important advantage suggested for the rectal administration of insulin is the possibility of avoiding, to some extent, the hepatic first-pass metabolism. Hosny [186] found that insulin suppositories containing 50 U of insulin incorporated with 50 mg of deoxycholic acid, sodium taurocholate, or both, placed in the rectum of alloxan-induced hyperglycemic rabbits, caused a large decrease in plasma glucose concentrations, and the relative hypoglycemia was calculated to be 38.0%, 34.9%, and 44.4%, respectively, compared with that observed for insulin (40 U) injected subcutaneously. The most pronounced effect was observed with the addition of polycarbo-
phil to a suppository formulation containing a combination of deoxycholic acid and sodium taurocholate, which produced 56% relative hypoglycemia compared with that achieved with a subcutaneous injection. These suppository formulations are very promising alternatives to current insulin injections, because they are roughly half as efficacious as subcutaneous injections. Insulin suppositories were formulated using Witepsol W35 as the base, to investigate the effects of various bile salts/acids on the plasma glucose concentrations of diabetic beagle dogs [187]. A relative hypoglycemia of about 50% was achieved using insulin suppositories containing Witepsol W35 as the base and sodium deoxycholate (100 mg) plus sodium cholate (50 mg), sodium taurodeoxycholate (100 mg), or sodium taurocholate (100 mg) as enhancers of the rectal absorption of insulin, as shown in Fig. 3. A desirable hypoglycemia, expressed as Cmax, and/or AUC, can be achieved by adjusting the insulin dose in the formulation according to the degree of initial hyperglycemia. Investigation of the effects of insulin suppositories on the plasma glucose concentrations of diabetic beagle dogs showed that a relative hypoglycemic effect of about 50%55% can be achieved using insulin suppositories containing Witepsol W35 as the base, insulin (5 U/kg), and sodium salicylate (50 mg) or POELE (1%) as rectal absorption enhancers [188]. Studies have recently shown that the formation of an adhesive interaction between the delivery system and the rectal mucosa can be harnessed as an absorption modifier because it increases the contact time of the coadministered drug and possibly acts as a sustained-release polymer. A thermoreversible liquid insulin suppository, which undergoes a phase transition to a bioadhesive gel at body temperature, enhances the bioavailability of insulin [189]. The thermoreversible liquid insulin suppository (containing 100 IU/g insulin, 15% poloxamer P407, 20% poloxamer P188, 0.2% polycarbophil, and 10% sodium salicylate) could potentially be developed as a more convenient, safe, and effective rectal delivery system for insulin. Adikwu [190] evaluated snail mucin motifs as rectal absorption enhancers for insulin. The mucins were
Fig. 3. Effect of sodium taurodeoxycholate (NaTDC; 100 mg) or sodium taurocholate (NaTC; 100 mg) alone or in combination with sodium cholate (NaC; 50 mg) on the mean plasma glucose levels (% of initial values) in hyperglycemic beagle dogs after rectal administration of Witepsol W35 suppositories containing human insulin (5 U/kg) compared with the effects of subcutaneously injected insulin (Ins s.c., 4 U/kg) [188].
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extracted from the giant African snail Archachatina marginata by differential precipitation with acetone. Mucin administered exogenously formed disulphide linkages between its cysteine domain and those of endogenous mucin, increasing the gel network and hence the viscosity of the mucus, probably conferring sustained- or prolonged-release properties to the dosage form. A batch with 7% mucin reduced the basal glucose level to 44% within 2 h of administration of the glycero-gelatin loaded mucin suppository. The efficacy and bioavailability of rectally delivered peptide remained low compared with those of peptide delivered by intravenous or subcutaneous injection. These delivery systems appeared to significantly increase the uptake of high-molecularweight polar drugs, such as insulin, before surfactant and other absorption enhancers were introduced. This is a concern in longterm therapy, because of the absorption of unwanted toxic molecules present in the GIT and disturbance to the permeability of the mucosal membrane. Patient compliance and the pain that accompanies rectal administration are both challenges for its widespread use as a therapeutic dosage form. Its irreproducible bioavailability and the special storage conditions required are also great obstacles to the rectal delivery of insulin. 2.7. Transdermal administration 2.7.1. Background Because the skin is the largest organ of the human body, transdermal drug delivery is an appealing alternative to subcutaneous delivery. It offers good patient compliance and the possibility of controlled release over time, while avoiding possible drug degradation resulting from GIT or first-pass liver effects. The skin also provides a painless interface for systemic drug delivery [191,192]. Despite these advantages, the human skin is an extremely effective barrier that protects against and is impermeable to foreign molecules, especially large hydrophilic molecules. The low permeability of the skin is caused mainly by the stratum corneum, the skin's outermost layer [193]. The development of a sophisticated new approach to overcome the skin permeability obstacle has challenged the pharmaceutical community to develop new delivery methods. Attempts to overcome this skin barrier to allow the transfer of large drugs have included techniques that
weaken the barrier with skin absorption enhancers [194], iontophoresis [195], ultrasound [196], or microneedles [197]. These are reviewed in Table 3. 2.7.2. Absorption enhancers In the last 50 years, a large number of chemical absorption enhancers (CAEs) belonging to several different classes, such as surfactants, fatty acids, fatty esters, and azone-like compounds, have allowed limited skin absorption enhancement [198]. CAEs have two major limitations: skin irritation and an inability to deliver large molecules. CAEs are generally unable to deliver therapeutic levels of relatively large drugs (molecular mass, 4500 Da) through intact skin to the systemic circulation [199]. Recent progress in high-throughput screening to identify enhancer combinations [200] and in the application of CAE design principles [201] may help to overcome these two limitations, but the transdermal delivery of large hydrophilic proteins remains a formidable task. The short synthetic cyclic peptide, TD-1, identified by in vivo phage display, facilitates efficient transdermal protein drug delivery through intact skin [202]. The coadministration of the peptide and insulin to the abdominal skin of diabetic rats resulted in elevated systemic levels of insulin and suppressed serum glucose levels for at least 11 h. The transdermal-enhancing activity of the peptide was sequence specific and dose dependent, did not involve direct interaction with insulin, and allowed the penetration of insulin into hair follicles beyond a depth of 600 m. Time-lapse studies have suggested that the peptide creates a transient opening in the skin barrier that allows macromolecular drugs to reach the systemic circulation. 2.7.3. Transdermal drug delivery systems Transdermal drug delivery systems can be generally divided into physical, biochemical, and chemical methods. Further strategies have been investigated for the carriage of insulin using the enhancing effects of flexible lecithin vesicles containing insulin, designed for the transdermal delivery of hydrophilic proteins [203]. The entrapment efficiencies of conventional and flexible vesicles were 35% and 81%, respectively. When flexible vesicles were non-occlusively applied to the abdominal skin of mice at a dose of 0.90 IU/cm2, an in vivo hypoglycemic study
Table 3 Transdermal formulation technologies of insulin delivery systems Formulation/technology Synthetic peptides Flexible lecithin vesicles Nanoinsulin Iontophoresis Iontophoresis/penetration enhancer Iontophoresis/LA, OA, LOA or LLA Iontophoresis/Poloxamer P407 gel Sonophoresis Sonophoresis Microneedles Application STZ-induced diabetic rats Mice Mice STZ-induced diabetic rats Rabbits Excised rat skin STZ-induced diabetic rats Hairless rats Rabbits STZ-induced diabetic hairless rats Outcome Sustained suppression of blood glucose levels for 11 h More than 50% reduction in blood glucose levels in 18 h Significant reduction in blood glucose levels Significant reduction in blood glucose levels Significant reduction in stratum corneum barrier Significant insulin flux enhancement 36%40% reduction in blood glucose levels Significant reduction in blood glucose levels for 60 min Significant hypoglycemic response 0.57.4 ng/mL plasma insulin levels and 80% reduction in blood glucose levels Refs. [202] [203] [204] [211] [215] [217] [219] [252] [253] [267]
Abbreviations: STZ, streptozotocin; LA, lauric acid; OA, oleic acid; LOA, linoleic acid; LLA, linolenic acid.
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showed a percentage decrease in blood glucose of 21.42% 10.19% at 1 h, which reached 61.48% 8.97% at 5 h and was still greater than 50% at 18 h. An advanced study evaluated the pharmacokinetic and pharmacodynamic effects of transdermally delivered insulin using novel CaCO3 nanoparticles in normal mice and those with diabetes [204]. CaCO3 nanoparticles encapsulating insulin (nanoinsulin) were transdermally applied to the back skin of normal ddY mice and to dB/dB and kkAy mice with diabetes after fasting for 1 h. Maximum serum insulin was 67.1 25.9 IU/mL at 4 h in ddY mice administered 200 g of transdermal nanoinsulin, whereas it was 462 20.9 IU/mL 20 min after the subcutaneous injection of 3 g of monomer insulin. Transdermal nanoinsulin reduced glucose levels in a dose-dependent manner. In ddY mice, insulin bioavailability was 0.9% with transdermal nanoinsulin for 6 h, based on serum insulin levels, and 2.0% based on pharmacodynamic blood glucose-lowering effects. This CaCO3 nanoparticle system successfully delivered insulin transdermally, as demonstrated by significant sustained decreases in blood glucose in both normal and diabetic mice. These results support the feasibility of developing transdermal nanoinsulin for human applications. 2.7.4. Iontophoresis More recently, one of the most advanced technologies that have been developed in the 20th century to overcome low skin permeability to insulin is iontophoresis [205]. Iontophoresis is a technique used to enhance the transdermal delivery of compounds through the skin by the application of a small electric current. Using the processes of electromigration and electro-osmosis, iontophoresis increases the permeation of charged and neutral compounds. It offers the option of a programmed drug delivery technique that physically facilitates the transport of permeates across the skin [206]. Transdermal iontophoresis is one such technique that shows promise and is believed to be a future option in the controlled and enhanced delivery of peptides and proteins [207]. It allows non-invasive, continuous, pulsatile delivery, as well as preprogrammed complex dosing regimens. Combinations of iontophoresis with absorption enhancers, electroporation, and sonophoresis have been tested to increase transdermal drug permeation and decrease possible side effects further. At present, research is focused on resolving skin toxicity issues and other problems, to make the technology a commercial reality [208]. Mao et al. [209] reported that in the transdermal delivery of insulin by pulse-current iontophoresis, the pulse permeation rate correlates positively with the reservoir insulin concentration and with skin penetration by insulin. In another iontophoretic delivery study, Zakzewski et al. [210] reported experimental evidence indicating a substantial increase in the penetration by insulin with the same-day application of a depilatory lotion, in conjunction with iontophoretic enhancement. Kanikkannan et al. [211] studied the delivery of bovine insulin to streptozotocin-induced diabetic rats by iontophoresis. The iontophoresis of a monomeric human insulin analogue (B9 Asp, B27 Glu) through intact skin produced a significant decrease in plasma glucose levels in the diabetic rats. Insulin was used as the model for large peptides, to understand better the effect of peptide concentration, NaCl concentration, and
buffer type and concentration on the transport efficiency of iontophoresis [212]. Overall, the findings revealed that the transport efficiency of large peptides like insulin might be improved by the optimization of the competing ions in solution. Pillai et al. [213] investigated the role of electronic parameters in the iontophoretic transport of large peptides using insulin as the model peptide. Ex vivo permeation experiments were conducted using excised rat skin and the influence of varying current strengths, durations, on/off ratios, and switching on iontophoretic insulin permeation were studied. Insulin permeation was found to increase as a function of current strength and the duration of current application, and switching iontophoresis reduced the pH shift, thereby improving the electrochemical stability of insulin at pH 3.6 and pH 7.4. Significant permeation of large peptides like insulin has been achieved using combination strategies involving absorption enhancers and transdermal iontophoresis [214]. Recently, Choi et al. demonstrated the effectiveness and mechanism of a transdermal drug delivery system using iontophoresis plus an absorption enhancer [215]. A combination of absorption enhancer pretreatment and iontophoresis delivered drugs more effectively than iontophoresis alone. The proposed theory is that iontophoretic drug delivery may be easiest through the dilated intercellular spaces of the stratum corneum, which have lowered electrical impedance following absorption enhancer pretreatment. The effects of pretreatment with commonly used vehicles, such as ethanol, propylene glycol, water, and their binary combinations, dimethyl acetamide, 10% dimethyl acetamide in water, ethyl acetate, and isopropyl myristate on insulin iontophoresis have been investigated. Another study compared the effects of a terpeneethanol combination with ethanol and neat terpene on transdermal iontophoretic permeation by insulin [216]. Terpene ethanol synergistically enhanced insulin permeation when combined with iontophoresis and was influenced by the type and concentration of terpene. The combination of fatty acids with iontophoresis was predicted to result in greater enhancement than that achieved with either of them alone [217]. The saturated fatty acid lauric acid (LA), and the cis-unsaturated fatty acids oleic acid (OA), linoleic acid (LOA), and linolenic acid (LLA), were studied in combination with iontophoresis using excised rat skin. Unsaturated fatty acids showed greater enhancement than LA, and the flux enhancement of unsaturated fatty acids was increased with the number of double bonds in the following (decreasing) order: LOA N OA N LLA. Conversely, in the presence of iontophoresis, LAethanol showed the greatest enhancement. Transdermal transport data for insulin under anodal iontophoresis (electro-osmosis) following electroporation in the presence of 1,2 dimyristoylphophatidylserine (DMPS) have been reported [218]. When electro-osmosis was applied across the epidermis following electroporation with DMPS, the enhancement of insulin transport was 18-fold higher than that achieved with electroporation alone. It was suggested that DMPS increased the lifetime of the electropores in the epidermis, resulting in the enhanced transport of permeates. Gels are considered the most suitable delivery vehicle for iontophoresis, because they can easily be amalgamated with the iontophoretic delivery system and match the contours of the skin
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[219]. The poloxamer P407 gel formulation of insulin was evaluated by ex vivo and in vivo skin permeation studies in rats, with absorption enhancer and/or iontophoresis. Iontophoresis either alone or in combination with linoleic acid produced a reduction in blood glucose levels of 36%40%. The major challenges in this area are the development of portable, cost-effective devices and suitable semi-solid formulations that are compatible with both the device and the skin, because the combination of absorption enhancers and iontophoresis causes greater skin irritation than is caused when either is used alone. 2.7.5. Sonophoresis (ultrasound) For the past two decades, sonophoresis (ultrasound) has been used to enhance the delivery and activity of drugs [220]. Ultrasound has an ever-increasing role in the delivery of therapeutic agents, including genetic material, proteins, and chemotherapeutic agents. There is a tremendous corpus of literature on the use of ultrasound to enhance the permeability of the skin for transdermal drug delivery [221228]. Therapeutic levels of ultrasound (13 MHz, 13 W/cm2) have been used for years to drive small hydrophobic molecules, like steroids, into or through the skin [229232]. Absorption enhancers have sometimes been used to increase skin permeability further [233245]. However, no significant transport of protein was achieved until 10 years ago, when Mitrogotri et al. showed that low-frequency ultrasound was much more effective than higher frequencies, and provided evidence of the mechanism involved [233245]. Skin permeability increased with decreasing frequency, and with increasing time of exposure and intensity (beyond a certain threshold), thus identifying collapse cavitation as a causative mechanism [236 238,241,242,246]. The current theory is that cavitation events open reversible channels in the lipid layers of the stratum corneum and provide less tortuous paths of transport for proteins such as insulin [221,236238,241]. Electron microscopy of skin exposed to low-frequency ultrasound revealed the removal of surface cells and the formation of pores and pockets large enough (20 m) to accommodate the transport of proteins and other large molecules [247250]. Tezel and Mitrogotri have formulated a model of shock-wave and microject cavitation events and their impact upon skin permeability [251]. Although their model can be fitted to their data, there are many assumptions and parameters in the model, and more direct evidence is needed to identify conclusively the mechanisms of ultrasound-enhanced transdermal protein delivery. Boucaud et al. investigated the dependence of ultrasoundinduced transdermal delivery of insulin on ultrasound parameters [252]. Insulin was delivered in vivo to hairless rats using 20 kHz ultrasound applied over a range of ultrasound intensities, application times, and pulse lengths. The most significant effect in lowering glycemia was achieved with the application of less than 15 min ultrasound and was similar to that achieved with a subcutaneous injection of 0.5 U of insulin. Pretreatment of hairless rat skin with ultrasound followed by the application of insulin resulted in no significant modification in blood glucose levels, indicating that the transdermal transport of insulin occurred mainly during sonication. Therefore, sonophoresis may potentially be used for the non-invasive and painless delivery of insulin
in the treatment of insulin-dependent diabetes. A recent study demonstrated the ultrasonic transdermal delivery of insulin in vivo in rabbits with a novel, low-profile two-by-two ultrasound array based on the cymbal transducer [253]. Glucose levels decreased by 132.6 35.7 mg/dL from the initial baseline for 60 min. Even after the array and insulin reservoir were removed, the blood glucose levels of the ultrasoundinsulin group continued to decrease by 208.1 29 mg/dL from the initial baseline. Although the future of ultrasound-enhanced transdermal protein delivery is brimming with potential, it has not yet appeared in the clinic. Because large pores and channels are opened through natural skin barriers, many hormones and proteins are candidates for transdermal delivery [236,237,254259]. However, the effect of ultrasound on protein conformation and/or activity needs to be addressed in more detail. 2.7.6. Microneedles A novel approach that increases transdermal transport involves the use of microneedles that pierce the skin and create micrometerscale openings. Although still extremely small on a clinical level, channels of micrometer dimensions are much larger than macromolecules and therefore should dramatically increase skin permeability to large drug molecules. Microneedles of micrometer dimensions can create transport pathways large enough for small drugs, macromolecules, nanoparticles, and fluid flow, but small enough to avoid pain and facilitate highly localized and even intracellular targeting. The microelectronic revolution has provided tools for highly precise, reproducible, and scalable methods to fabricate structures of micrometer dimensions. This lithography-based approach can produce large arrays of microneedles that can be inserted into cells, skin, or other tissues. Arrays of micrometer-scale needles could be used to deliver drugs, proteins, and particles across skin in a minimally invasive manner. The increased importance of macromolecular therapeutics, combined with the newly acquired power of microfabrication, has recently prompted interest in fabricating [260263] and testing [264,265] microneedles for drug delivery. Practical microfabrication techniques have been developed to yield microneedle arrays of silicon, metal, and biodegradable polymers of micrometer dimensions in various geometries [266]. Microneedle arrays having solid or hollow bores with tapered or beveled tips may provide a minimally invasive method to increase skin permeability for diffusion-based transport of large molecules such as proteins. Hollow microneedles have permitted the flow of microliter quantities into the skin in vivo, including the microinjection of insulin to reduce blood glucose levels in diabetic rats. These results suggest that microneedles are a useful approach to transdermal drug delivery. Building on microneedle transdermal studies, Martanto et al. [267] designed and fabricated arrays of solid microneedles to be inserted into the skin of diabetic hairless rats for the transdermal delivery of insulin to lower blood glucose levels. Fig. 4 shows that the microneedles increased the permeability of the skin to insulin, which rapidly and steadily reduced blood glucose levels to an extent similar to that achieved with 0.050.5 U of insulin injected subcutaneously. Plasma insulin concentrations were measured directly as 0.57.4 ng/mL. Solid metal microneedles are capable of increasing transdermal insulin
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Fig. 4. Changes in blood glucose levels in diabetic hairless rats after insulin delivery using microneedles (), subcutaneous hypodermic injection of 0.05 U (), 0.5 U (), or 1.5 U () of insulin, or passive delivery across untreated skin (). Microneedles were inserted into the skin for 10 min and then removed. Insulin solution was applied to the skin immediately after microneedle insertion and left on the skin for 4 h (as shown by arrow). Data are expressed as mean values (n 3) with average standard deviations associated with each data point of 14% [267].
delivery and lowering blood glucose levels by as much as 80% in diabetic hairless rats in vivo. Hypodermic needles have provided the gold standard for drug delivery for over a century, but advances in biotechnology make their limitations increasingly apparent. It seems that a transdermal delivery system for insulin is an attractive option. Although progress in the transdermal delivery of insulin and other peptides seems encouraging, it is still doubtful whether this delivery route provides a general approach to the noninvasive delivery of insulin. Because of the poor permeation capacity and large molecular size of insulin, the poor bioavailability of insulin during transdermal delivery compared with that achieved with subcutaneous injection, and the high susceptibility of the skin to adverse immunological reactions, more studies, including clinical studies, are required to assess the potential impact of these factors on novel transdermal insulin delivery techniques. 3. Recent marketed and developed formulations for non-invasive insulin delivery Significant progress has been reported in the recent past in the delivery of insulin using buccal and pulmonary routes, as has been achieved for many other hormonal drugs, such as calcitonin and vasopressin, which are available in intranasal sprays. The field of insulin delivery took a tremendous step forward with the approval of Exubera from Pfizer and Nektar Therapeutics. Insulin has long been a target of drug delivery companies because of the number of patients using it and the difficulties and issues surrounding the reliance on injections. Pharmaceutical companies are confident that ease of use and the elimination of the needle will be enough to counter the added costs of alternative insulin delivery systems, and Exubera is expected to reinforce this notion. The approval of this drug has legitimized alternative forms of drug delivery, providing patients with increased hope of eliminating or
reducing their dependence on injections and instilling confidence in numerous drug delivery companies that alternative forms of insulin delivery systems can win the approval of federal authorities. Marketed developed insulin formulations and technologies for non-invasive routes are summarized in Table 4. Researchers working in academic institutions and drug delivery companies have begun collaborative work on several novel delivery technologies to introduce a viable and feasible oral insulin dosage form that can potentially replace painful insulin therapy. The overwhelming attractiveness of oral administration is prompting numerous companies to develop technologies to overcome the challenges of oral peptide delivery. As a result, there is a high degree of innovation and competition, with multiple products already in clinical trials. One of the more unusual alternatives is from Emisphere Technology, Inc. Emisphere Technology has very recently made public that it is undertaking clinical phase II trials in type 2 diabetic patients in order to file an investigational new drug (IND) application with the U.S. Food and Drug Administration (FDA). This will be the first attempt by Emisphere Technology to test the Eligen oral drug delivery strategy that delivers insulin with the Emisphere delivery agent or carrier in a capsule. Their proprietary Eligen technology platform is based upon the use of synthetic non-acylated amino acids as carriers, which allow the peptide to enter the bloodstream through the body's natural passive transcellular transport processes in the GIT. Non-acylated amino acids, when used as carriers, do not alter the conformation of the delivered drug but do alter the physical properties at the point of transport, while not affecting the efficacy of the drug [268,269]. The interim results of a U.S. phase II trial of AI-401, an oral tolerance product of AutoImmune, Inc. developed for the treatment of diabetes, were presented at a poster session at the American Diabetes Association meeting in Chicago, in June 1998. The trial evaluated the feasibility of oral insulin therapy, delaying -cell destruction in the pancreas, and thus preserving endogenous insulin secretion in newly diagnosed type 1 diabetic patients. This study is one of four trials undertaken using AI-401, an oral formulation of recombinant human insulin. The Eli Lilly Company is AutoImmune's worldwide partner in autoimmune (type 1) diabetes [272]. The final data from the oral insulin arm of the NIHsponsored Diabetes Prevention Trial-Type 1 (DPT-1) showed a statistically significant benefit for patients with type 1 diabetes [273]. The Generex Biotechnology Corporation, a small Canadian drug delivery firm, recently stole the march on the pharmaceutical giants by launching the oral insulin, Oral-lyn, in the form of an oral spray for the treatment of patients with type 1 and type 2 diabetes, in Ecuador last December [274,275]. Generex has developed a proprietary platform technology for the delivery of drugs into the human body through the oral cavity (with no deposit in the lungs). The company's proprietary liquid formulations allow drugs typically administered by injection to be absorbed into the body through the lining of the inner mouth using the company's proprietary RapidMist device. The process involves the creation of a stable mixed micellar solution containing the pharmaceutical agent, absorption enhancers, and other excipients.
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Table 4 Recent marketed and developed formulations for non-invasive insulin delivery Route of administration Oral Eligen Macrulin AI-401 Emisphere Technology, Inc. Cortecs International/Provalis PLC AutoImmune, Inc./Eli Lilly Oral capsule using non-acylated amino acids as carriers Macrosol W/O microemulsion technology Oral formulation of recombinant human insulin Phase II Phase II Phase II [268,269] [270,271] [272,273] Trade name/insulin product Company/Developer & Researcher Technology Status Refs.
Buccal Oral-lyn Generex Biotechnology Corp. Mixed micellar solution Market available [274,275]
Nasal Nasulin QDose ChiSys Pulmonary Exubera AERxiDMS HIIP Technosphere Aerodose Spiros Insulin inhaler MicroDose DPI ProMaxx Nectar Therapeutics, Inc./Pfizer/ SanofiAventis SA Aradigm Corp./Novo Nordisk A/S Alkermes, Inc./Eli Lilly PDC/MannKind Corp. AeroGen, Inc./Nektar Therapeutics, Inc. Dura Pharmaceuticals, Inc./Elan Corp. Kos Pharmaceuticals, Inc./Abbott Laboratories MicroDose Technologies, Inc./Novartis Epic Therapeutics, Inc./ Baxter Healthcare Corp. Human insulin (rDNA origin) inhalation powder Liquid aerosol AIR technology Encapsulated microsphere Liquid aerosol Dry powder Crystalline insulin Dry powder Insulin microsphere Market available Phase III Phase III Phase III Phase IIa Phase II Phase IIa Phase I Phase I [279286] [287297] [298300] [301] [302,303] [304] [305] [306] [307] Bentley Pharmaceutical, Inc. Vectura, Ltd./MicroDose Technologies Inc. West Pharmaceutical Services New physiological absorption enhancer Dry powder Chitosan-based system Phase II Phase I Phase I [276] [277] [278]
Transdermal PassPort Transfersulin U-Strip Macroflux Altea Therapeutics IDEA AG Encapsulation System, Inc. Alza Corp. Microporation technique Transferosome Iontophoresis/sonophoresis Passive transdermal/ electrotransport systems Phase I Phase I Phase II Market available [308] [309311] [312] [313]
When the solution is introduced to the buccal mucosa, it results in the increased bioavailability of the active drug and more rapid onset of its action. RapidMist is a small, lightweight, hand-held, easy-to-use aerosol applicator containing an oral formulation, which is aerosolized with a pharmaceutical-grade chemical propellant. To promote Oral-lyn in USA and Europe, Generex is currently commencing clinical trials involving thousands of patients around the world. West Pharmaceutical Services' ChiSys formulation technology, a chitosan-based nasal delivery system, enhances formulations for nasal insulin delivery and acts as a bioadhesive to help drugs adhere to the nasal mucosa. Phase I trials for nasal insulin were completed in 2001 [278]. Entering the era of systemic pulmonary delivery, the healthcare community is awaiting a revolution in many insulin delivery technologies. Several pharmaceutical companies are developing pulmonary insulin delivery systems. These products fall into two main groups: solution and drug powder formulations, which are delivered through different patented inhaler systems.
The approval of Exubera, a human insulin (rDNA origin) inhalation powder, by the U.S. FDA has opened up a whole world of possibilities for the deep lung delivery of drugs [279,280]. An important milestone in the treatment of systemic diseases with pulmonary delivery, it is set to revolutionize the drug delivery market. Exubera is the first new inhaled form of insulin and the first insulin option in the European Union and USA in more than 80 years that does not need to be administered by injection. In developing Exubera, Pfizer and SanofiAventis have collaborated with Nektar Therapeutics (formerly Inhale Therapeutics), a company that specializes in finding delivery solutions for oral, injectable, and pulmonary drug administration, to create an inhaler that will support the manufacture (including powder processing) of Exubera insulin and of Inhance (Exubera pulmonary delivery inhaler). Inhance weighs about 115 g and, when closed, is about the size of an eyeglass case. Inhance produces a cloud of insulin powder in a clear chamber visible to the patient. This insulin powder is designed to pass rapidly into the bloodstream to regulate the body's blood sugar levels [281].
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Exubera, a rapid-acting insulin in powder form that is inhaled before each meal, has been studied extensively in patients with type 1 and type 2 diabetes mellitus [282285]. The powder preparation is packed into blisters of different dosages (1 mg and 3 mg blisters). Inhance generates a pulse of compressed air, thus deagglomerating the dry powdered insulin into a cloud and delivering it from the blister into a reservoir, from which it is inhaled. The standing cloud of aerosol eliminates the highvelocity impact of the insulin on the throat and upper airway. The bioavailability of this product is approximately 10%, compared with that of regular human insulin administered by subcutaneous injection [286]. Aradigm Corporation reports that Novo Nordisk A/S is pursing additional clinical phase III trials of AERx insulin Diabetes Management System (AERx iDMS), which delivers a liquid form of human insulin [287]. The AERx Essence microprocessor-controlled inhaler offers a high level of performance (efficiency and reproducibility) in a smaller and less expensive package. In AERx Strip technology, the singleuse nozzle contained in each disposable AERx Strip makes dosage adjustment possible to the nearest unit, as is possible with insulin injections. The system has been studied in patients with type 1 and type 2 diabetes mellitus, and the bioavailability of insulin following the use of AERx iDMS was 13%17% [288297]. Alkermes, Inc. and its partner Eli Lilly are also utilizing proprietary technology to create large porous particles of low mass that consist of a biodegradable polymer of a phospholipid matrix that contains fast-acting human insulin. Future developments might involve the production of a sustained-release formulation [298,299]. Their partnership is built upon the AIR (Advanced Inhalation Research) technology platform that creates small (5 m) particles to be delivered through a small, easy-to-use inhaler as capsules containing human inhalable insulin powder (HIIP) as a dry powder in two dose strengths, 0.9 mg or 2.6 mg, equivalent to 2 or 6 units of subcutaneous insulin, respectively [300]. This platform has produced inhalable insulin that is undergoing phase III testing as a substitute for meal-time insulin injections in patients with type 1 or type 2 diabetes. MannKind Corporation announced the results of its phase III clinical study of inhaled insulin in patients with type 2 diabetes in September 2006 at the 42nd Annual Meeting of the European Association for the Study of Diabetes in Copenhagen [301]. This study was designed to evaluate whether the MannKind Technosphere Insulin System shows safety and efficacy similar to those observed in treatments with insulin aspart (NovoLog), an injected rapid-acting insulin analogue. Technosphere insulin, which was developed by the Pharmaceutical Discovery Corporation (PDC), is an ordered lattice array of spherical microparticles at low pH, with 18% insulin trapped as a dry crystalline powder, which uses a diketopiperazine derivative that dissolves at the neutral pH of the alveolar surface, rapidly releasing the insulin. The bioavailability of Technosphere insulin is 15%26%. The formulation is designed for use with the MedTone Dry Powder Inhaler, a capsule-based highimpedance inhaler that uses a passive powder deagglomeration mechanism.
AeroGen, Inc. (acquired by Nektar Therapeutics in August 2005) developed the pocket-sized Aerodose insulin inhaler, designed to deliver a proprietary liquid insulin formulation. It is breath activated and incorporates a titratable cartridge that allows patients to adjust their dose based on their insulin requirements [302]. The development of this product was placed on hold in early 2003, after the completion of phase IIa trials. Nektar Therapeutics is now continuing to evaluate partnering opportunities, which may permit further development and commercialization of this product. The product has been studied in a small group of patients with type 2 diabetes mellitus [303]. Clinical studies showed that the relative bioavailability of inhaled Aerodose insulin was approximately 21%, yet its development has been halted. Altea Therapeutics has announced that it has commenced phase I clinical trials in USA of PassPort, the company's daily insulin skin patch designed to provide continuous basal levels of insulin for patients with diabetes [308]. 4. Conclusion There has been a long history of research directed toward the development of novel routes of insulin delivery since recombinant DNA technology made insulin available at a reasonable cost in an injectable dosage form. Needle phobia and stress have encouraged scientists to investigate and exploit all promising routes of insulin delivery, ranging from oral to rectal, with a wide variety of devices and delivery systems. Many approaches have been used to study various strategies to overcome the inherent barriers to insulin uptake across the GIT and by transmucosal and transdermal routes. Each of the various routes of insulin administration has its own set of favorable and unfavorable properties. Most of the approaches described above represent long-term possibilities for insulin delivery, but difficulties in achieving adequate blood insulin concentrations are yet to be overcome. Over the last several decades, these formidable tasks have focused on oral insulin delivery. Our final achievement will be a clinically therapeutic bioavailable oral insulin that bypasses the obstacles of the GIT and overcomes the challenges inherent in the physicochemical properties of the insulin molecule. In recent years, the development of innovative oral insulin delivery carriers that improve oral insulin absorption has thrown some promising light on the new horizon of oral insulin therapy. Although extensive human clinical studies are still required, especially of long-term clinical applications, researchers in academic institutions and several drug delivery pharmaceutical companies are actively involved in the development of an oral insulin delivery system. Significant progress has been reported in recent years in the delivery of insulin using pulmonary and buccal routes, which have led to market approval for Exubera and Oral-lyn, suggesting that this breakthrough in oral insulin delivery marketing will soon become a larger reality. Some of the delivery systems discussed in this review are likely to reach patients in the next few years. The new millennium promises a revolutionary change in the delivery of insulin for billions of sufferers who are currently reliant on subcutaneous administration.
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Current Challenges in Non-Invasive Insulin Delivery Systems A Comparative Review

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Current Challenges in Non-Invasive Insulin Delivery Systems A Comparative Review

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Available online at www.sciencedirect.

Advanced Drug Delivery Reviews 59 (2007) 1521 1546 www.elsevier.com/locate/addr

Current challenges in non-invasive insulin delivery systems: A comparative review

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

1534 1534 1534 1535 1536 1536 1537 1539 1540

Refs. [13] [14] [15] [16] [17]

[20] [21] [22] [25] [27]

In vivo/rats In vivo/rats In vivo/rats In vivo/rats

[47] [48] [49] [61]

In vivo/rats In vivo/rats In situ/rat intestine In vivo/rabbits In vivo/rats

[74] [76] [78] [82] [84]

In vivo/dogs In vivo/rats In vivo/rats

[90] [91] [96]

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

[113] [114] [116] [126] [128] [130]

[137] [144] [146] [147] [148] [152] [159]

[174] [176] [178] [184]

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

Fig. 2. Result of blood glucose level reduction in diabetic mice (n = 9) [147].

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

E.-S. Khafagy et al. / Advanced Drug Delivery Reviews 59 (2007) 15211546

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