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The objective of the present investigation was to formulate and characterize the human insulin entrapped Eudragit S100 microspheres containing protease inhibitors and to develop an optimized formulation with desirable features. A w/o/w multiple emulsion solvent evaporation technique was employed to produce microspheres of human insulin using Eudragit S-100 as coating material and polyvinyl alcohol as a stabilizer. The resultant microspheres were evaluated for drug-excipient compatibility, encapsulation efficiency, particle size, surface morphology, micromeritic properties, enteric nature, and in vitro drug release studies. Micromeritic properties indicated good flow properties and compressibility. In present investigation formulation F6 with drug/polymer ratio (1:100) was found to be optimal in terms of evaluated parameters where it showed a significantly higher percentage of encapsulation efficiency (76.84%) with minimal drug release (3.25%) in an acidic environment. The optimized formulation (F6) also possessed good spherical shape and particle size (57.42 µm) required to achieve the desired in vitro drug release profile at pH 7.4. The results confirmed that human insulin-loaded Eudragit S-100 microspheres containing protease inhibitor possessed good encapsulation efficiency, pH dependant controlled release carrying encapsulated insulin to its optimum site of absorption. This ultimately resulted in enhanced insulin absorption and biological response. Graphical Abstract: [ABSTRACT FROM AUTHOR]

The only effective treatment for type 1 and advanced insulin-dependent type 2 diabetes mellitus is frequent subcutaneous insulin injections, which are physiologically different from endogenous insulin secretion and can result in hyperinsulinemia, pain, infection and patients' low compliance. Thus, efforts were devoted to changing the management of insulin-dependent diabetes through oral insulin delivery. Although the oral route is the most convenient way of drug delivery, insulin is vulnerable to rapid degradation in the stomach. Polymeric nanocarriers have recently attracted considerable attention as oral delivery vehicles that can be used to protect insulin from degradation and facilitate insulin absorption. This study aims to fabricate cationic β-cyclodextrin (CβCD)-insulin-loaded alginate nanoparticles and evaluate their potential as an oral insulin delivery system. CβCD were prepared from β-cyclodextrin (β-CD) through a onestep polycondensation using choline chloride (CC) to provide an ammonium group and epichlorohydrin (EP) to form polymeric chains. Insulin was complexed with CβCD to enhance the release profile, then encapsulated into calcium alginate nanoparticles via the ionic gelation method. The size, zeta potential, encapsulation efficiency (EE), surface morphology and cumulative drug release of the nanoparticles were recorded. In-vitro cytotoxicity of the nanoparticles against HT-29 cells was evaluated by MTT assay. CβCDinsulin-loaded alginate nanoparticles were characterized by reduced particle size, improved encapsulation efficiency and controlled insulin release in the simulated gastric fluid (SGF). The optimised nanoparticles exhibited a suitable particle size, with high encapsulation efficiency >80% and a controlled cumulative insulin release profile in simulated gastric fluid. MTT assay revealed that all formulations were non-toxic. The present study advocates that CβCD-insulin-loaded alginate nanoparticles is a promising system for enhancing oral insulin delivery. [ABSTRACT FROM AUTHOR]

The advancements in nanoscience have brought attention to the potential of utilizing nanoparticles as carriers for oral insulin administration. This study aims to investigate the effectiveness of synthesized polymeric mesoporous silica nanoparticles (MSN) as carriers for oral insulin and their interactions with insulin and IR through in-silico docking. Diabetic rats were treated with various MSN samples, including pure MSN, Amin-grafted MSN/PEG/Insulin (AMPI), Al-grafted MSN/PEG/Insulin (AlMPI), Zinc-grafted MSN/PEG/Insulin (ZNPI), and Co-grafted MSN/PEG/Insulin (CMPI). The nanocomposites were synthesized using a hybrid organic-inorganic method involving MSNs, graphene oxide, and insulin. Characterization of the nanocomposites was conducted using X-ray diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM). In vivo tests included the examination of blood glucose levels and histopathological parameters of the liver and pancreas in type 1 diabetic rats. The MSN family demonstrated a significant reduction in blood glucose levels compared to the diabetic control group (p < 0.001). The synthesized nanocomposites exhibited safety, non-toxicity, fast operation, self-repairing pancreas, cost-effectiveness, and high efficiency in the oral insulin delivery system. In the in-silico study, Zn-grafted MSN, Co-grafted MSN, and Al-grafted MSN were selected. Docking results revealed strong interactions between MSN compounds and insulin and IR, characterized by the formation of hydrogen bonds and high binding energy. Notably, Co-grafted MSN showed the highest docking scores of -308.171 kcal/mol and -337.608 kcal/mol to insulin and IR, respectively. These findings demonstrate the potential of polymeric MSN as effective carriers for oral insulin, offering promising prospects for diabetes treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Virus-capsid mimicking mucus-permeable nanoparticles are promising oral insulin carriers which surmount intestinal mucus barrier. However, the impact of different virus-capsid mimicking structure remains unexplored. In this study, utilizing biotin grafted chitosan as the main skeleton, virus-mimicking nanoparticles endowed with biologic-shell (streptavidin coverage) and polymeric-shell (hyaluronic acid/alginate coating) were designed with insulin as a model drug by self-assembly processes. It was demonstrated that biologic-shell mimicking nanoparticles exhibited a higher intestinal trans-mucus (>80%, 10 min) and transmucosal penetration efficiency (1.6-2.2-fold improvement) than polymeric-shell counterparts. Uptake mechanism studies revealed caveolae-mediated endocytosis was responsible for the absorption of biologic-shell mimicking nanoparticles whereas polymeric-shell mimicking nanoparticles were characterized by clathrin-mediated pathway with anticipated lysosomal insulin digestion. Further, in vivo hypoglycemic study indicated that the improved effect of regulating blood sugar levels was virus-capsid structure dependent out of which biologic-shell mimicking nanoparticles presented the best performance (5.1%). Although the findings of this study are encouraging, much more work is required to meet the standards of clinical translation. Taken together, we highlight the external structural dependence of virus-capsid mimicking nanoparticles on the muco-penetrating and uptake mechanism of enterocytes that in turn affecting their in vivo absorption, which should be pondered when engineering virus-mimicking nanoparticles for oral insulin delivery., Competing Interests: The authors declare no conflict of interest., (© 2023 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Aims: To verify whether the oral insulin N11005 is administered as a prandial insulin by assessing the pharmacokinetics (PK), pharmacodynamics (PD), and safety profiles of N11005 with a short-acting biosynthetic human insulin (Novolin R) as reference., Methods: This was a randomized, open-label, single-dose, crossover hyperinsulinemic-euglycemic clamp study in healthy Chinese male subjects. A total of 12 subjects were enrolled in the test (T) group (N11005, 300 IU, p.o.) and the reference (R) group (Novolin R, 0.1 IU/Kg, i.h.) with a washout period of 14 days. All subjects were administered on the same day of the clamp study. Glucose Infusion Rates (GIR), serum insulin, and C-peptide concentration were determined during every 8-hour clamp cycle. Trial registration: Clinicaltrials.gov identifier NCT04975022., Results: After administration, the ratios of mean serum C-peptide concentration to baseline concentration in both T and R groups were lower than 50%, which confirmed the stability of the clamp platform. T group (N11005) showed a more rapid onset of action (tGIR 10%max ≈11 min) and a comparable duration of action to the R group, which was basically in line with the characteristics of prandial insulins. No adverse events (AEs) occurred throughout the study, which demonstrated that N11005 and Novolin R are safe and well-tolerated., Conclusions: The PD profiles of the single-dose N11005 in the human body are similar to those of prandial insulins, with an excellent safety profile., Clinical Trial Registration: Clinicaltrials.gov, identifier NCT04975022., Competing Interests: Authors WL, XC, YLZ, QZ, YH, YJZ, LL, ZW, WW, and JH were employed by the company Sunshine Lake Pharma Co., Ltd. Authors W-HH and Y-TY were employed by the company INNOPHARMAX, INC. The authors declare that this study received funding from Sunshine Lake Pharma Co., Ltd. The funder had the following involvement in the study: experiment development, data research, statistical support, and animal studies. W.H., and Y.Y. from INNOPHARMAX, INC. also contributed to animal studies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pan, Wang, Li, Chen, Zhuang, Zhou, Huang, Zhou, Lan, Wang, Wang, Hong, Hao, Yang and Guo.)

The oral form of insulin is more convenient and has better patient compliance than subcutaneous or intravenous insulin. Current oral insulin preparations, however, cannot overcome the enzyme barrier, chemical barrier, and epithelial barrier of the gastrointestinal tract completely. In this study, a microalgae-based oral insulin delivery strategy (CV@INS@ALG) was developed using Chlorella vulgaris (CV)-based insulin delivery system cross-linking with sodium alginate (ALG). CV@INS@ALG could overcome the gastrointestinal barrier, protect insulin from harsh gastric conditions, and achieve a pH-responsive drug release in the intestine. CV@INS@ALG might contribute to two mechanisms of insulin absorption, including direct insulin release from the delivery system and endocytosis by M cells and macrophages. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, CV@INS@ALG showed a more effective and long-lasting hypoglycemic effect than direct insulin injection and did not cause any damage to the intestinal tract. Additionally, the long-term oral administration of the carrier CV@ALG effectively ameliorated gut microbiota disorder, and significantly increased the abundance of probiotic A kkermansia in db / db type 2 diabetic mice, thereby enhancing the insulin sensitivity of mice. Microalgal insulin delivery systems could be degraded and metabolized in the intestinal tract after oral administration, showing good biodegradability and biosafety. This insulin delivery strategy based on microalgal biomaterials provides a natural, efficient, and multifunctional solution for oral insulin delivery.

[Display omitted] • Oral administration of insulin mimics the endogenous insulin secretion. • Strategies for PLGA nanoparticles to overcome different barriers for oral insulin delivery are discussed. • Challenges and future perspectives of PLGA nanoparticles for oral insulin delivery are also put forward. Currently, the only practical way to treat type 1 and advanced insulin-dependent type 2 diabetes mellitus (T1/2DM) is the frequent subcutaneous injection of insulin, which is significantly different physiologically from endogenous insulin secretion from pancreatic islets and can lead to hyperinsulinemia, pain, and infection in patients with poor compliance. Hence, oral insulin delivery has been actively pursued to revolutionize the treatment of insulin-dependent diabetes. In this review, we provide an overview of recent progress in developing poly(lactic co-glycolic acid) (PLGA) nanoparticles (NPs) for oral insulin delivery. Different strategies for insulin-loaded PLGA NPs to achieve normoglycemic effects are discussed. Finally, challenges and future perspectives of PLGA NPs for oral insulin delivery are put forward. [ABSTRACT FROM AUTHOR]

Studies for different ways of insulin delivery have started since the first discovery of insulin. However, desired biological effect of non-parenteral routes has not been achieved, yet. Unfortunately the use of insulin has been limited to parenteral routes due to enzymatic degradation process by mucosal peptidase, mucosal barrier resulting in insufficient absorption and poor permeability throughout the intestinal mucosa. The parenteral route of insulin has been used in different ways including intramuscular, subcutaneous, intravenous and intraperitoneal ways. However, the parenteral route has side effects involving patient's incompliance due to fear of injection, local discomfort including bleeding at injection site, injection pain, lipohypertrophy as well as some disadvantages such as glycemic fluctuation. Alternative routes of non-invasive insulin delivery including oral, nasal, buccal, ophtalmic, rectal, vaginal and transdermal systems have been performed eventhough successful results have not been achived due to the abovementioned barriers. Additionally, recently approved tecnology of insulin delivery through pulmoner route has also been one of the methods aimed at replacing parenteral route. However, recent pulmonary technology of insulin delivery requires higher doses and frequent applications. Furthermore, inhaler insulin is not applicable to smokers and is not used in patients with pulmonary diseases or infections. Today, desired clinical efficacy and safety on the use of non-invasive routes of insulin have not yet been achieved and studies are continuing with newly developed technologies. [ABSTRACT FROM AUTHOR]

Many patients with advanced type 2 diabetes mellitus (T2DM) and all patients with T1DM require insulin to keep blood glucose levels in the target range. The most common route of insulin administration is subcutaneous insulin injections. There are many ways to deliver insulin subcutaneously such as vials and syringes, insulin pens, and insulin pumps. Though subcutaneous insulin delivery is the standard route of insulin administration, it is associated with injection pain, needle phobia, lipodystrophy, noncompliance and peripheral hyperinsulinemia. Therefore, the need exists for delivering insulin in a minimally invasive or noninvasive and in most physiological way. Inhaled insulin was the first approved noninvasive and alternative way to deliver insulin, but it has been withdrawn from the market. Technologies are being explored to make the noninvasive delivery of insulin possible. Some of the routes of insulin administration that are under investigation are oral, buccal, nasal, peritoneal and transdermal. This review article focuses on the past, present and future of various insulin delivery techniques. This article has focused on different possible routes of insulin administration with its advantages and limitation and possible scope for the new drug development. [ABSTRACT FROM AUTHOR]

The use of intelligent insulin delivery systems has become more important for treating diabetes. In this study, a dual-responsive oral insulin delivery nanocarrier that responds to glucose and pH has been developed. First, the oleic acid hydrophobic modified guar gum (GG) was synthesized by the esterification reaction, and the γ-polyglutamic acid (γ-PGA) was coupled with GG by the amidation reaction. The obtained pH-responsive copolymer (γ-PGA-GG) was cross-linked by concanavalin A to obtain pH/glucose dual-responsive nanocarriers, and insulin was effectively loaded into the dual-responsive nanocarriers. The insulin-loaded nanoparticles can achieve effective pH and glucose responses, releasing insulin on demand. In vitro and in vivo studies demonstrated the dual-responsive nanoparticles can protect insulin against the pH changes in the digestive tract and deliver insulin into the body to exert a hypoglycemic effect. Moreover, the dual-responsive nanoparticles have significant potential to be employed for oral insulin delivery. [Display omitted] • γ-PGA-GG copolymer was used as a oral insulin carrier material. • Concanavalin A was used as functional molecule, assisted nanoparticles achieving blood glucose response. • Nanoparticles could significantly improve the delivery efficiency of oral insulin. • Nanoparticle provided long-term glycemic control in T1D mice without any toxicity. [ABSTRACT FROM AUTHOR]

Introduction: Despite therapeutic advances in the field of diabetes management since the discovery of insulin 100 years ago, there are still unmet clinical needs for people with type 1 diabetes mellitus (T1DM)., Areas Covered: Genetic testing and islet autoantibodies testing allow researchers to design prevention studies. This review discusses the emerging therapy for prevention of T1DM, disease modification therapy in early course of T1DM, and therapies and technologies for established T1DM. We focus on phase 2 clinical trials with promising results, thus avoiding the exhausted list of every new therapy for T1DM., Expert Opinion: Teplizumab has demonstrated potential as a preventative agent for individuals at risk prior to the onset of overt dysglycemia. However, these agents are not without side effects, and there are uncertainties on long-term safety. Technological advances have led a substantial influence on quality of life of people suffering from T1DM. There remains variation in uptake of new technologies across the globe. Novel insulins (ultra-long acting), oral insulin, and inhaled insulin attempt to narrow the gap of unmet needs. Islet cell transplant is another exciting field, and stem cell therapy might have potential to provide unlimited supply of islet cells.

Background: Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin., Research Design and Methods: In this open-label, active-controlled trial, patients with T2D, HbA 1c ≥7%-≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, n = 30; 45 mg, n = 31) and IAsp, n = 30. Primary outcome was change from baseline (CFB) in HbA 1c at week 24. Secondary outcomes included PPG excursion (PPGE) and PPG assessed from standardized test meal (STM) and 9-point self-monitored blood glucose., Results: The observed mean HbA 1c did not improve at week 24 in Tregopil groups (30 mg [0.15%], 45 mg [0.22%] vs. a reduction in IAsp group [-0.77%]). Combined Tregopil group showed better 1-h PPGE control versus IAsp following STM (CFB, estimated treatment difference, 95% CI, -45.33 mg/dL [-71.91, -18.75], p = 0.001) and 1-h PPG trended toward better control. Tregopil showed lower PPGE at 15 min versus IAsp. Clinically significant hypoglycemia was lower with Tregopil versus. IAsp (rate ratio: 0.69)., Conclusions: Tregopil demonstrated an ultrafast, short-duration prandial profile with good safety. While Tregopil's early postprandial effects were comparable to IAsp, its late postprandial effects were inferior., Trial Registration: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03430856).

The delivery of macromolecular drugs via the gastrointestinal (GI) tract is challenging as these drugs display low stability as well as poor absorption across the intestinal epithelium. While permeation-enhancing drug delivery methods can increase the bioavailability of low molecular weight drugs, the effective delivery of high molecular weight drugs across the tight epithelial cell junctions remains a formidable challenge. Here, we describe autonomous microinjectors that are deployed in the GI tract, then efficiently penetrate the GI mucosa to deliver a macromolecular drug, insulin, to the systemic circulation. We performed in vitro studies to characterize insulin release and assess the penetration capability of microinjectors and we measured the in vivo release of insulin in live rats. We found that the microinjectors administered within the luminal GI tract could deliver insulin transmucosally to the systemic circulation at levels similar to those with intravenously administered insulin. Due to their small size, tunability in sizing and dosing, wafer-scale fabrication, and parallel, autonomous operation, we anticipate that these microinjectors will significantly advance drug delivery across the GI tract mucosa to the systemic circulation in a safe manner.

This investigation describes the synthesis and in vitro evaluation of cationic hydrogel sub-microparticles based on polydimethylaminoethylmethacrylate for oral insulin delivery. Polymerization of dimethylaminoethylmethacrylate was carried out in aqueous medium with potassium persulfate as the initiator. Quaternization of the resulting hydrogel was carried out to introduce cationic surface groups and the derivatization was confirmed by zeta potential measurements, nuclear magnetic resonance and infrared spectroscopies. Swelling behavior of these particles was evaluated for dependence of pH. Insulin-loaded particles were subjected to in vitro release experiments at gastric and intestinal pH. Moreover, cytotoxicity evaluation showed that both polydimethylaminoethylmethacrylate and its quaternized derivative were non-toxic to Caco-2 and L929 cell lines. The presence of quaternary ammonium groups improved the cationic charge and enhanced the mucoadhesive properties of the hydrogel. Confocal microscopic observations showed that these sub-microparticles were capable of opening tight junctions between the Caco-2 cells and thus increased the paracellular permeability. The above studies suggest that cationic hydrogel sub-microparticles can act as a good candidate for oral insulin delivery. [ABSTRACT FROM PUBLISHER]

Abstract: Nanothickness encapsulation using a layer-by-layer technique has applications in several areas of diabetes research, including improved glucose sensors, islet cell transplantation and oral insulin delivery. We have fabricated microvesicles containing a fluorescence lifetime-based glucose sensing system, with bacterial glucose-binding protein as the glucose receptor. Such sensors are suitable for impregnation in the dermis as a ‘smart tattoo’ type of non-invasive glucose monitoring technology. Nanoencapsulation of islet cells is intended to alleviate the immediate blood-mediated inflammatory reaction which is responsible for early islet loss post-transplant. In an allogeneic diabetic mouse model, nanoencapsulated islets with phosporylcholine-modified polysaccharide coating, significantly extended survival of transplanted islets. In early studies aimed at formulating an effective oral insulin preparation, insulin-chitosan colloids coated with nanolayers of chitosan and heparin had enhanced acid stability and effectively lowered blood glucose in an animal model. [Copyright &y& Elsevier]

Abstract: Nanosized calcium phosphates studied as drug delivery systems are highly compatible with the various drugs like insulin, antibiotics etc. Zinc is an essential trace element that plays a crucial role in the synthesis, storage and release of insulin in a human body. Therefore, an attempt has been made to develop zinc modified calcium phosphate nanoparticles (less than 100nm) as carriers for intestinal delivery of insulin. The insulin loaded nanoparticles were coated with pH sensitive alginate. These pH sensitive nanoparticles released insulin in the intestinal medium, and the conformation of released insulin was stable. The blood glucose level of diabetic rats came to normal on administration of the formulation. With the beneficial effect of zinc reported on diabetic patients, the present system seems to be an excellent carrier for intestinal delivery of insulin. [Copyright &y& Elsevier]

Purpose: We have recently reported that oral insulin (OI) stimulates intestinal adaptation after bowel resection and that OI enhances enterocyte turnover in correlation with insulin receptor expression along the villus-crypt axis. The purpose of the present study was to evaluate the effect of OI on intestinal epithelial cell proliferation and apoptosis in a rat model of short bowel syndrome (SBS) and in a cell culture model. Methods: Caco-2 cells were incubated with increasing concentrations of insulin. Cell proliferation and apoptosis were determined by FACS cytometry. Cell viability was investigated using the Alamar Blue technique. Male rats were divided into three groups: Sham rats underwent bowel transection, SBS rats underwent a 75% bowel resection, and SBS-OI rats underwent bowel resection and were treated with OI given in drinking water (1 U/ml) from the third postoperative day. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined on day 15. Real time PCR was used to determine the level of bax and bcl-2 mRNA and western blotting was used to determine bax, bcl-2, p-ERK and AKT protein levels. Statistical analysis was performed using the one-way ANOVA test, with P < 0.05 considered statistically significant. Results: Treatment of Caco-2 cells with insulin resulted in a significant increase in cell proliferation (twofold increase after 24 h and 37% increase after 48 h) and cell viability (in a dose-dependent manner), but did not change cell apoptosis. In a rat model of SBS, treatment with OI resulted in a significant increase in all parameters of intestinal adaptation. Elevated cell proliferation rate in insulin treated rats was accompanied by elevated AKT and p-ERK protein levels. Decreased cell apoptosis in SBS-INS rats corresponded with a decreased bax/bcl-2 ratio. Conclusions: Oral insulin stimulates intestinal epithelial cell turnover after massive small bowel resection in a rat model of SBS and a cell culture model. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) results from defects in insulin secretion (type 1) or insulin resistance (type 2). Insulin is used to manage type 1 DM, and oral hypoglycemic agents are used to manage type 2 DM. These therapies are inconsistent in maintaining glycemic control and cause some severe adverse effects such as undue weight gain and hypoglycemia. New and appropriate therapies are needed to overcome these problems. Drugs that are in the pipeline include oral insulins for type 1 DM and incretin mimetics, incretin enhancers, gastric inhibitory peptides, amylin analogues, peroxisome proliferator-activated receptor-α/γ ligands, sodium-dependent glucose transporter inhibitors, and fructose 1,6-bisphosphatase inhibitors for type 2 DM. This article describes the mechanisms of action and relative advantages and disadvantages of the promising therapies [ABSTRACT FROM PUBLISHER]

Abstract: The present investigation explores an oral insulin delivery system based on the modification of chitosan, N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan (HTCC). Synthesis of HTCC was carried out by coupling glycidyl trimethylammonium chloride (GTAC) to chitosan in aqueous medium. Quaternization was confirmed by TNBS assay, FTIR, NMR, SEM studies and zeta potential analysis. Cytotoxicity studies of the derivative were carried out by MTT assay and release profile of insulin from HTCC matrix was monitored under in vitro experimental conditions. Further biological activity and conformational stability of released insulin were confirmed using ELISA and circular dichroism studies. Adhesion studies on mucin and freshly excised rat intestinal sections were carried out to evaluate the mucoadhesive nature of the matrix. Confocal microscopy observations showed that these microparticles were capable of opening tight junctions. By exploiting the mucoadhesive and controlled drug releasing capabilities, HTCC particles seems to be a promising candidate for oral insulin delivery. [ABSTRACT FROM AUTHOR]

Abstract: An oral insulin delivery system based on methyl-β-cyclodextrin (MCD) complexed insulin encapsulated polymethacrylic acid (PMAA) hydrogel microparticles was evaluated in this investigation. Poly(methacrylic acid)-chitosan-polyethylene glycol (PCP) microparticles were prepared by ionic gelation method. The insulin–MCD (IC) complex prepared was characterized by fluorescence spectroscopic and isothermal titration micro-calorimeteric (ITC) methods. MCD complexed insulin was encapsulated onto PCP microparticles by diffusion filling method. Loading and release properties of the complexed insulin from microparticles were evaluated under in vitro conditions. The effect of MCD complexation on the permeability of insulin was studied using Caco 2 cell monolayers and excised intestinal tissue with an Ussing chamber set-up. In vivo experiments were carried on streptozotocin induced diabetic rats to evaluate the efficacy of MCD complexed insulin encapsulated PCP microparticles to deliver insulin by the oral route. IC complex formation was established by fluorescence and ITC investigations. Insulin loading and release properties from the hydrogel matrix was rather unaffected by the MCD complexation. However MCD complexation was effective in enhancing insulin transport across Caco 2 cell monolayers, when applied in combination with the PMAA hydrogel system. Both insulin and MCD complexed insulin encapsulated PCP microparticles were effective in reducing blood glucose level in diabetic animal models. Cyclodextrin complexed insulin encapsulated hydrogel microparticles appear to be an interesting candidate for oral delivery of insulin. [Copyright &y& Elsevier]

Abstract: In this study, we report the biodistribution of aspart-insulin, a rapid-acting insulin analogue, following oral or subcutaneous (SC) administration to rats using the single-photon emission computed tomography (SPECT)/computed tomography (CT). Oral delivery of aspart-insulin was achieved using a pH-responsive nanoparticle (NP) system composed of chitosan (CS) and poly(γ-glutamic acid). The results obtained in the SPECT/CT study indicate that the orally administered aspart-insulin was absorbed into the systemic circulation, while the drug carrier (CS) was mainly retained in the gastrointestinal tract.Via the SC route, the peak aspart-insulin concentration in the peripheral tissue/plasma was observed at 20 min after injection. Within 3 h, half of the initial dose (ID) of aspart-insulin was degraded and excreted into the urinary bladder. In contrast, via oral delivery, there was constantly circulating aspart-insulin in the peripheral tissue/plasma during the course of the study, while 20% of the ID of aspart-insulin was metabolized and excreted into the urinary bladder. In the pharmacodynamic (PD) and pharmacokinetic (PK) evaluation in a diabetic rat model, the orally administered aspart-insulin loaded NPs produced a slower hypoglycemic response for a prolonged period of time, whereas the SC injection of aspart-insulin produced a more pronounced hypoglycemic effect for a relatively shorter duration. Finally, comparison of the PD/PK profiles of the orally administered aspart-insulin with those of the SC injection of NPH-insulin, an intermediate-acting insulin preparation, suggests the suitability of our NP system to be used as a non-invasive alternative for the basal insulin therapy. [Copyright &y& Elsevier]

Aim: The objective of the study was to establish the dose response of IN-105 tablets and explore a possible therapeutic window in type 2 diabetes subjects poorly controlled on metformin. Methods: The primary objective was to examine the effect of sequential single ascending doses of IN-105 on the plasma glucose concentration under fed conditions. All subjects received, sequentially, matching placebo, 10, 15, 20 and 30 mg IN-105 tablets in five consecutive periods. Tablets were administered 20 min prior to meal in all the periods. Plasma levels of immunoreactive insulin, C-peptide and glucose were measured up to 180 min from the time of dosing. The changes in postprandial glucose levels at 120 min in response to IN-105 administration were also compared against those of placebo. Results: Changes in glucose from baseline (mean ± s.d.) at 140 min (2 h postprandial) were 94.84 ± 22.3, 79.45 ± 43.00, 70.68 ± 35.71, 63.47 ± 42.75 and 53.06 ± 47.27 mg/dL, respectively, and exhibited linear dose–response. The insulin Cmax values were found to be 50.8 ± 26.0 mU/L for placebo, 100.3 ± 66.7 with 10 mg IN-105, 177.69 ± 150.3 with 15 mg IN-105, 246.2 ± 245.2 with 20 mg IN-105 and 352.5 ± 279.3 mU/L with 30 mg of IN-105. Conclusions: IN-105 absorption is proportional to the dose administered. The 2-h postprandial glucose excursion was reduced in a dose proportional manner. Circulating C-peptide levels were found to be suppressed in proportion to the IN-105 exposure. IN-105 reduces glucose excursion despite lower endogenous insulin secretion. IN-105 seems to have a wide therapeutic window as no clinical hypoglycaemia was observed at any of the doses studied. [ABSTRACT FROM AUTHOR]

Abstract: In the present study thiol functionalized polymethacrylic acid–polyethylene glycol–chitosan (PCP)-based hydrogel microparticles were utilized to develop an oral insulin delivery system. Thiol modification was achieved by grafting cysteine to the activated surface carboxyl groups of PCP hydrogels (Cys-PCP). Swelling and insulin loading/release experiments were conducted on these particles. The ability of these particles to inhibit protease enzymes was evaluated under in vitro experimental conditions. Insulin transport experiments were performed on Caco-2 cell monolayers and excised intestinal tissue with an Ussing chamber set-up. Finally, the efficacy of insulin-loaded particles in reducing the blood glucose level in streptozotocin-induced diabetic rats was investigated. Thiolated hydrogel microparticles showed less swelling and had a lower insulin encapsulation efficiency as compared with unmodified PCP particles. PCP and Cys-PCP microparticles were able to inhibit protease enzymes under in vitro conditions. Thiolation was an effective strategy to improve insulin absorption across Caco-2 cell monolayers, however, the effect was reduced in the experiments using excised rat intestinal tissue. Nevertheless, functionalized microparticles were more effective in eliciting a pharmacological response in diabetic animal, as compared with unmodified PCP microparticles. From these studies thiolation of hydrogel microparticles seems to be a promising approach to improve oral delivery of proteins/peptides. [Copyright &y& Elsevier]

Many challenges are associated with the oral delivery of insulin, relating to the physical and chemical stability of the hormone, and its absorption and metabolism in the human body. The present study aims to demonstrate the oral delivery of insulin in both normal and steptozotocin (STZ)–induced diabetic rats with the help of the aqueous extract of Desmodium gangeticum (DG) root. Human insulin was mixed with the aqueous extract of DG root (0.1 mg⁄ml) with human insulin (40 IU⁄ml) in ratio 1:1(v⁄v), to prepare oral insulin drug. Decreased plasma glucose level and increased plasma insulin in normal and STZ–induced diabetic rat suggested the probable absorption of insulin through GI tract when insulin was administered by mixing with DG extract. Indeed, insulin mixed DG potentially stimulates the release of insulin in STZ–induced diabetic rat rather than in normal animal. In vivo insulin secretaguage action of oral insulin drug was determined by isolated rat heart model and the results showed a significant cardio protection in STZ rat. The finding of this study suggests that insulin mixed with DG extract can be a promising vehicle for oral delivery of insulin. However, further studies are required to explore the exact compound(s) responsible for the protective delivery of insulin orally. Increased plasma insulin level by insulin mixed DG extract administration in STZ–treated diabetic rat indicates not only insulin secretaguage action of the mixture but also a probable altered insulin release mechanism in diabetic condition. [ABSTRACT FROM AUTHOR]

Oral insulin is one of the most exciting areas of development in the treatment of diabetes because of its potential benefit in patient convenience, rapid insulinization of liver, adequate insulin delivery avoiding peripheral hyperinsulinaemia while potentially avoiding adverse effects of weight gain and hypoglycaemia. Growing evidence that earlier initiation of intensive insulin therapy produces sustained tight glycaemic control resulting in substantial delay in complications makes an effective oral insulin product even more vital for the management of patients with diabetes. Despite knowledge of this unmet medical need, oral delivery of insulin has been unsuccessful because of several barriers. For several decades, researchers have tried to develop oral insulin using various technologies without much clinical or commercial success. This review summarizes the development status of oral insulins which are publicly reported to be undergoing clinical studies. Currently, two oral insulin products are in an advanced stage of clinical development and first data from long-term therapy are expected to be available in the second half of 2010. [ABSTRACT FROM AUTHOR]

Nanoparticles prepared with a blend of a biodegradable polyester (poly(ℇ-caprolactone)) and a polycationic nonbiodegradable acrylic polymer (Eudragit® RS) have been used as a drug carrier for oral administration of a short-acting insulin analogue, aspart-insulin. Insulin-loaded nanoparticles, about 700 nm in diameter, encapsulated 97.5% of insulin and were able to release about 70% of their content in vitro in a neutral medium over 24 h. When administered orally to diabetic rats, insulin-loaded nanoparticles (50 IU/kg) decreased fasted glycemia for a prolonged period of time and improved the glycemic response to glucose in a time-dependent manner, with a maximal effect between 12 and 24 h after their administration. In parallel, plasma insulin levels increased. However, higher (100 IU/kg) and lower (25 IU/kg) doses of insulin did not exert any biological effect. It is concluded that polymeric nanoparticles composed of poly(ℇ-caprolactone)/Eudragit® RS are able to preserve the biological activity of the insulin analogue aspart-insulin; however, the postprandial peak suppression was prolonged more than 24 h by comparison with regular insulin working only 6–8 h. This effect may be explained by the monomeric configuration of aspart-insulin, which is probably better taken up by the intestinal mucosa than regular insulin. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:879–889, 2010 [ABSTRACT FROM AUTHOR]

Aim: Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). Methods: Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m2, haemoglobin A1c (HbA1c) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. Results: Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280–330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC0–6 h (910 ± 270 vs. 472 ± 245 pmol h/L; 950 ± 446 vs. 433 ± 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA1c, weight and triglycerides were observed. Conclusions: Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations. [ABSTRACT FROM AUTHOR]

For many decades, rigorous efforts have been made worldwide to develop a successful oral insulin-delivery system, which still remains an elusive goal. However, over the past few years, tremendous understanding has evolved in the development of biocompatible and biodegradable polymers, synthesis of nanopeptide delivery systems, bicompatibility and its cellular uptake mechanisms. With these advancements, efforts are being directed toward nanoparticle-based oral peptide-delivery systems. It is established that nanoparticles enhance oral bioavailability by facilitating insulin uptake via a transcellular or paracellular pathway. In this process, the particle also reaches the systemic circulation. Hence, biocompatibility and the half-life of the particles in the systemic circulation is an important aspect that needs to be looked into. In this review, the various approaches adopted for nanoparticle-based oral insulin delivery, uptake mechanisms, biocompatibility and bioavailability of the nanoparticle are discussed. INSETS: Examples of organic/inorganic materials used in …;Key issues. [ABSTRACT FROM AUTHOR]

[Display omitted] Polyelectrolyte nanocomplex (PEC) is a promising carrier for insulin encapsulation. However, tenacious enzymatic degradation and insufficient penetration in mucus and enterocyte are the dominating obstacles for their oral insulin delivery. Besides, the rate of insulin release should be tuned to achieve desired therapeutic effect and meanwhile with scale-up potential. Thus, PEC embedded microparticles were fabricated in this study to solve the above dilemma. First of all, insulin loaded PEC with sodium dodecyl sulfate (SDS) coating was prepared by self-assembly method and then spray-dried using different ratio chitosan (CS)/ polyvinyl alcohol (PVA) as the matrix to obtain the microparticles. Influence of the CS/PVA ratio on the in vitro and in vivo properties of the redispersed PEC was investigated systemically. It was demonstrated that when CS 50 kDa was used in the matrix, all the PEC could be well redispersed with particle size less than 250 nm, and good stability in the gastrointestinal tract, further improved enzymatic stability was achieved by nanoparticles-in-microparticles design, with CS/PVA 1:1 and 4:1 groups showing better and comparable protection. Insulin release from the microparticles decreased with the increase of CS ratio in the CS/PVA matrix. Spray-dried microparticles had less influence on the mucus penetration of the in situ redispersed PEC, with enhanced insulin permeation observed in different intestinal segments in a CS/PVA ratio dependent manner. And the CS/PVA 1:1 group, which presented good enzymatic stability, enhanced mucus penetration and moderate insulin release rate, exhibited the highest relative pharmacological availability of 6.80%. In conclusion, PEC in microparticles design using CS/PVA as the composite matrix is a potential platform for enhanced oral insulin delivery. [ABSTRACT FROM AUTHOR]

The inconvenience of subcutaneous insulin delivery leads to low patient compliance with the dosage regimens. The most desirable form of administration seems to be through the oral route. This work investigates the utility of PEGylated calcium phosphate nanoparticles as oral carriers for insulin. Calcium phosphate nanoparticles (CaP) with an average particle size of 47.9 nm (D50) were synthesized and surface modified by conjugating it with poly(ethylene glycol) (PEG). These modified nanoparticles were having a near zero zeta potential. Protection of insulin from the gastric environment has been achieved by coating the nanoparticles with a pH sensitive polymer that will dissolve in the mildly alkaline pH environment of the intestine. The release profiles of coated nanoparticles exhibited negligible release in acidic (gastric) pH, i.e., only 2% for CaP and 6.5% for PEGylated CaP. However, a sustained release of insulin was observed at neutral (intestinal) pH for over 8 h. The conformation of the released insulin, studied using circular dichroism, was unaltered when compared with native insulin. The released insulin was also stable as it was studied using dynamic light scattering. Radioimmunoassay was performed and the immunoreactivity of the released insulin was found to be intact. These results suggest PEGylated calcium phosphate nanoparticles as an excellent carrier system for insulin toward the development of an oral insulin delivery system. © 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2009 [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The aim of this study was to develop and evaluate a novel three-layered oral delivery system for insulin in vivo. Methods: The patch system consisted of a mucoadhesive layer, a water insoluble backing layer made of ethylcellulose and an enteric coating made of Eudragit®. Drug release studies were performed in media mimicking stomach and intestinal fluids. For in vivo studies patch systems were administered orally to conscious non-diabetic rats. Orally administered insulin in aqueous solution was used as control. After the oral administration of the patch systems a decrease of glucose and increase of insulin blood levels were measured. Results: The mucoadhesive layer, exhibiting a diameter of 2.5mm and a weight of 5mg, comprised polycarbophil-cysteine conjugate (49%), bovine insulin (26%), gluthatione (5%) and mannitol (20%). 74.8±4.8% of insulin was released from the delivery system over 6h. Six hours after administration of the patch system mean maximum decrease of blood glucose level of 31.6% of the initial value could be observed. Maximum insulin concentration in blood was 11.3±6.2ng/ml and was reached 6h after administration. The relative bioavailability of orally administered patch system versus subcutaneous injection was 2.2%. Conclusion: The results indicate that the patch system provides enhancement of intestinal absorption and thereby offers a promising strategy for peroral peptide delivery. [Copyright &y& Elsevier]

Abstract: Oral delivery of insulin is convenient and physiologically desirable in the treatment of diabetes. However, this route of administration has presented substantial challenges as insulin is degraded enzymatically in the gut, resulting in low bioavailability. We have developed a conjugated insulin product (IN-105) that has high bioavailability and is currently undergoing clinical trials for the treatment of diabetes. A process for the manufacture of IN-105 was developed. Initially, recombinant human insulin was conjugated covalently with a monodisperse, short-chain methoxypolyethylene glycol derivative. The desired product, IN-105, was purified from its closely related species using RP-HPLC and cation exchange chromatography to a purity of 98.5%. The elution pool from cation exchange chromatography was crystallized and lyophilized into the dry active pharmaceutical ingredient. [Copyright &y& Elsevier]

The present study describes the fabrication of insulin loaded chitosan succinate microspheres to improve the efficacy of orally administered insulin. Chitosan succinate polymer was synthesized and its microspheres were prepared by emulsion phase separation technique. The microspheres were characterized by FT-IR spectroscopy, scanning electron microscopy, particle size, X-ray diffraction, and swelling index. Insulin was loaded into the microspheres by passive absorption technique. The ability of microspheres to protect insulin from gastric enzymatic degradation was investigated. Stability of insulin in the microspheres was determined by gel electrophoresis and circular dichroism (CD). In vitro release studies were performed under simulated gastric and intestinal pH conditions (pH 2.0 and pH 7.4). The pharmacokinetic parameters were monitored after oral administration of insulin loaded chitosan succinate microspheres, chitosan succinate–insulin solution, as well as after subcutaneous injection of insulin to diabetic rats. The degree of succinate substitution in the synthesized polymer was 16%. The prepared microspheres were spherical with an average diameter of 49 ± 2 µm. The insulin-loading capacity was 62%. Chitosan succinate microspheres were found to protect the degradation of insulin from gastric enzymes. The encapsulated insulin was quickly released in simulated intestinal fluid (SIF, pH 7.4), whereas a small fraction of insulin was released in simulated gastric fluid (pH 2.0). The relative pharmacological efficacy for chitosan succinate microspheres (16 ± 4%) was almost fourfold higher than the efficacy of the chitosan succinate–insulin solution administration (4 ± 1.5%). The results suggest that chitosan succinate microspheres could be used as a potential carrier for oral insulin delivery. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 3010–3023, 2007 [ABSTRACT FROM AUTHOR]

Although most protein pharmaceuticals are usually formulated as a solution or suspension and delivered by invasive routes such as subcutaneous injections, major efforts in both academic and industrial laboratories have been directed towards developing effective oral formulations and increasing the oral absorption of intact protein through the use of formulations that protect the macromolecule and/or enhance it's uptake into the intestinal mucosa. However, in spite of these major attempts, relatively little progress has been made. For the efficient delivery of peptides and proteins by non-parenteral route, in particular via the gastrointestinal tract, novel concepts are needed to overcome significant enzymatic and diffusion barriers. The properties of protein and peptides, which are of major interest in oral delivery, are highlighted in the article. This article reviews the various problems associated and novel approaches for formulation and development of oral protein and peptide drug delivery systems. [ABSTRACT FROM AUTHOR]

Abstract: The potential utility of vitamin B12 carrier system for the oral delivery of conjugated peptides/proteins and enhancement of nanoparticles (NPs) transport has been demonstrated. The present study aims to optimize the effectiveness of VB12–NPs conjugates using different levels of cross-linking, linked with different VB12-coatings and evaluates in animal models to investigate an efficient insulin carrier. Amino alkyl VB12 derivatives suitable for oral delivery were synthesized at 5′hydoxy ribose and e-propionamide sites via carbamate and ester/amide linkages, and were coupled to succinic acid modified dextran NPs of varied cross-linking. VB12 binding was confirmed by XPS analysis, and was quantified by HPLC (4.0 to 5.7% w/w of NPs). These polydisperse NPs conjugates showed higher size, high insulin entrapment and faster insulin release with low levels of cross-linking. These VB12–NPs conjugates (150–300 nm) showed profound (70–75% blood glucose reductions) and prolonged (54 h) anti-diabetic effects with biphasic behaviour in STZ diabetic rats. NPs with the low levels of cross-linking were found to be superior carriers, and were more effective with VB12 derivatives of carbamate linkage. The pharmacological availability relative to SC insulin was found to be 29.4%, which was superior compared to NPs conjugate of ester linked VB12 (1.5 fold) and relatively higher cross-linked particles (1.1 fold). Further, the NPs carrier demonstrated a similar oral insulin efficacy in congenital diabetic mice (60% reduction at 20 h). Significant quantities of plasma insulin were found in both animal models (231 and 197 μIU/ml). At two investigated doses, the carrier system shows dose response. Pre-dosing with a large excess of free VB12 minimized the observed activity, indicating predominance of VB12 mediated uptake. It is concluded that VB12–dextran NPs conjugate is a viable carrier for peroral insulin delivery to treat diabetics. [Copyright &y& Elsevier]

Our aim was to evaluate insulin autoantibody (IAA) levels over time in the Diabetes Prevention Trial Type 1 (DPT-1) oral insulin study to determine the effect of oral insulin compared with placebo on IAA levels. The DPT-1 trial randomised 372 relatives of subjects with type 1 diabetes, positive for IAA and with normal IVGTTs and OGTTs, to oral insulin 7.5 mg daily or placebo. Subjects were followed with IVGTTs, OGTTs and serial IAA measurements. The change in IAA level over time was modelled statistically using mixed model longitudinal data analysis with spatial exponential law for unevenly spaced data. In a separate analysis, subjects were divided into four groups by treatment and diabetes status at the end of the study. IAA levels were compared amongst the groups at randomisation, last sampling and at the maximum level. Longitudinal data analysis showed that treatment did not affect levels of IAA over time. After controlling for age, the IAA levels at randomisation and the last visit and the maximum values were different in the four groups. Significantly higher levels were noted in groups that developed diabetes compared with those that did not, with no significant difference by treatment group. This suggests that IAA levels over time were not influenced by oral insulin in subjects already positive for IAA at the start of treatment. ClinicalTrials.gov ID no.: NCT00004984. [ABSTRACT FROM AUTHOR]

One main barrier for the peroral administration of therapeutic peptides and proteins is the enzymatic barrier, that is mediated by luminally secreted and membrane bound proteolytic enzymes. It was the aim of the study to synthesise, characterise and evaluate a novel polymer-inhibitor conjugate in order to improve the bioavailability of orally-administered peptides and proteins. The trypsin/chymotrypsin inhibitor aprotinin was covalently bound to chitosan. The percentage of the inhibitor in the polymer-inhibitor conjugate (m/m) was determined to be between 1.11 ± 0.36 and 1.92 ± 0.05%. In vitro enzyme assays clearly demonstrated the potential of the novel conjugate to inhibit trypsin and chymotrypsin. Moreover, studies in rats were performed to evaluate the efficacy of the conjugate in vivo. Eight hours after oral administration of tablets containing insulin and the novel chitosan-aprotinin conjugate, the mean blood glucose level decreased to 84 ± 6%. In contrast, the mean blood glucose level in the control group increased to 121 ± 8% of the initial measured blood glucose level. In conclusion it was demonstrated that chitosan-aprotinin conjugate represents a novel and promising tool for the oral administration of therapeutic peptides and proteins susceptible to enzymatic degradation caused by trypsin and chymotrypsin. [ABSTRACT FROM AUTHOR]

Chitosan phthalate polymer was synthesized and its microspheres were prepared by emulsion phase separation technique. The characterization of microspheres was determined by means of FTIR spectroscopy, electron microscopy, particle size, and zeta potential. The insulin was loaded to the microspheres by passive absorption technique. The peptic and tryptic enzymes degradation of insulin in microspheres was investigated. The in vitro release behavior of the microspheres was investigated under different pH conditions (pH 2.0 and pH 7.4). The degree of phthalate substitution in the synthesized polymer was 20%. The prepared microspheres were spherical with an average diameter 46.34 μ m. The insulin-loading capacity was 62%. Chitosan phthalate microspheres protect the insulin from gastric enzymes degradation that may enhance the oral stability of insulin. The encapsulated insulin was quickly released in a phosphate buffer saline (pH 7.4), whereas a small amount of insulin was released under acidic condition (0.1N HCl; pH 2.0) because under acidic conditions, carboxylic groups present in the system exist in nonionized form and are poorly hydrophilic. However, in alkaline conditions, it exists in ionized form and is considerably hydrophilic. The results suggest that chitosan phthalate microspheres may be used as a potential carrier for oral insulin delivery. [ABSTRACT FROM AUTHOR]

Abstract: Background:: Several advances in insulin delivery systems and devices have been made in recent years. Objective:: This article summarizes study findings on recent advances and emerging insulin delivery systems in various stages of development. Methods:: Materials used for this article were identified through a search of MEDLINE from 1993 to 2006. English-language articles were chosen using the search terms transdermal delivery system, inhaled insulin, and oral insulin. Results:: These developments are intended to enhance patient compliance with insulin therapy to achieve tighter glycemic control and thereby prevent or delay the onset of diabetes mellitus (DM)-related complications. Recently, the US Food and Drug Administration provided regulatory approval for recombinant human insulin for inhalation; availability of this first inhaled insulin is expected in the near future. Several other inhaled insulin products are now in clinical trials. Also available are the insulin pump and insulin pen, which can facilitate self-administration for some patients. Research is under way to develop an insulin tablet that is coated so it resists breakdown in the digestive tract. Intranasal and transdermal delivery systems are also being investigated. Conclusion:: Progress has been made in the development of alternative delivery routes for insulin therapy. Clinicians who provide DM care can look forward to the availability of more options in insulin delivery systems to help their patients meet the challenges of DM management. [Copyright &y& Elsevier]

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Abstract: Cell-penetrating peptide (CPP) was linked to insulin to form insulin–CPP hybrids. The intestinal absorption efficiency of CPP hybridized insulin was 6–8 times increased compared to normal insulin as tested on Caco-2 cell monolayer, a widely used in vitro model for intestinal absorption. Insulin–CPP hybrid transportation seemed to be through an active and transcytosis-like mechanism. Importantly, insulin in hybrids kept intact after they passed through the Caco-2 cell monolayer. This study provides a new clue for oral insulin development. [Copyright &y& Elsevier]

In normal humans, blood glucose and insulin are maintained within a narrow range despite wide variations in physical activity and dietary intake. At present, reproducing this pattern is an impossible task in type 1 diabetes and extremely difficult in type 2 DM. New approaches using novel insulin analogs and routes of administration, attempting to replicate physiological insulin secretion in diabetic patients, are improving the profiles of glucose levels and, thus, the quality of life. Ultra-short-acting insulin analogues and ultra-long-acting analogues are being used for prandial and basal effects with better results, lower prevalence of hypoglycemia, and, hopefully, fewer chronic complications. Non-invasive routes of administration are being developed. The most promising appears to be inhaled insulin according to studies demonstrating excellent control, apparently without significant side effects, although in relatively short-term trials. Longer-term studies to assure the safety are still necessary before recommending its extended use. This is an extensive, up-to-date review of recent advances in insulin therapy. [Copyright &y& Elsevier]

Abstract: Dispersions of insulin poly(isobutylcyanoacrylate) nanoparticles were obtained by anionic in situ polymerization using aqueous pluronic acid solution. Results showed a decrease in particle size diameter by increasing the pluronic acid concentration. Nanoparticles prepared in the presence of 2.5% pluronic acid resulted in particles of 85nm average diameter and 59% intra-particular insulin load without the use of the oily core [Damge, C., Michel, M., Aprahamian, M., Couveur, P., 1988. New approach for oral administration with polycyanoacrylate nanocapsules as drug carrier. Diabetes 37, 246–251]. In vivo testing was performed on streptozocin induced diabetic rats. The subcutaneous injection of insulin nanoparticles was able to prolong its duration of hypoglycemic effect from 6 to 72h. Effective oral absorption of the entrapped insulin was significantly better (p &#60;0.01) when compared with non-encapsulated insulin or the control experiments. [Copyright &y& Elsevier]