Exploiting Apical Sodium-Dependent Bile Acid Transporter (ASBT)-Mediated Endocytosis with Multi-Functional Deoxycholic Acid Grafted Alginate Amide Nanoparticles as an Oral Insulin Delivery System.

OBJECTIVE: Oral administration of insulin is a potential candidate for managing diabetes. However, it is obstructed by the gastrointestinal tract barriers resulting in negligible oral bioavailability. METHODS: This investigation presents a novel nanocarrier platform designed to address these challenges. In this regard, the process involved amination of sodium alginate by ethylene diamine, followed by its conjugation with deoxycholic acid. RESULTS: The resulting DCA@Alg@INS nanocarrier revealed a significantly high insulin loading content of 63.6 ± 1.03% and encapsulation efficiency of 87.6 ± 3.84%, with a particle size of 206 nm and zeta potentials of -3 mV. In vitro studies showed sustained and pH-dependent release profiles of insulin from nanoparticles. In vitro cellular studies, confocal laser scanning microscopy and flow cytometry analysis confirmed the successful attachment and internalization of DCA@Alg@INS nanoparticles in Caco-2 cells. Furthermore, the DCA@Alg@INS demonstrated a superior capacity for cellular uptake and permeability coefficient relative to the insulin solution, exhibiting sixfold and 4.94-fold enhancement, respectively. According to the uptake mechanism studies, the results indicated that DCA@Alg@INS was mostly transported through an energy-dependent active pathway since the uptake of DCA@Alg@INS by cells was significantly reduced in the presence of NaN3 by ~ 92% and at a low temperature of 4°C by ~ 94%. CONCLUSIONS: Given the significance of administering insulin through oral route, deoxycholic acid-modified alginate nanoparticles present a viable option to surmount various obstacles presented by the gastrointestinal.

Emerging drugs for the treatment of type 1 diabetes mellitus: a review of phase 2 clinical trials.

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.

Multi-functional self-assembly nanoparticles originating from small molecule natural product for oral insulin delivery through modulating tight junctions.

BACKGROUND: Oral administration of insulin (INS) could be absorbed into systemic circulation only if the carrier protected it from the hostile gastrointestinal conditions. However, traditional macromolecular carriers have not totally overcome challenges in addressing these biological barriers. RESULT: In this study, inspired by small molecule natural products (SMNPs), we demonstrate the multi-functional self-assembly nanoparticles (BA-Al NPs) originating from baicalin (BA) and AlCl3 through coordination bonds and hydrogen bonds. As a novel carrier for oral insulin delivery (INS@BA-Al NPs), it displayed effective capacity in pH stimuli-responsive insulin release, intestinal mucoadhesion and transepithelial absorption enhance. Meanwhile, BA improved the paracellular permeability for insulin absorption, because of its downregulation at both mRNA and protein level on internal tight junction proteins. In vivo experiments exhibited remarkable bioavailability of INS and an ideal glucose homeostasis in the type I diabetic rat model. CONCLUSION: This study offers a novel frontier of multi-functional carriers based on SMNPs with self-assembly character and bioactivity, which could be a promising strategy for diabetes therapy.

Novel strategies to oral delivery of insulin: Current progress of nanocarriers for diabetes management.

Diabetes mellitus is one of the most serious public health problems in the world. Repeated daily injections of subcutaneous insulin is the standard treatment for patients with type 1 diabetes mellitus; however, subcutaneous insulin injections can potentially cause local discomfort, patient noncompliance, hypoglycemia, failure to regulate glucose homeostasis, infections, and fat deposits at the injection sites. In recent years, numerous attempts have been made to produce safe and efficient nanoparticles for oral insulin delivery. Oral administration is considered the most effective alternative route to insulin injection, but it is accompanied by several challenges related to enzymatic proteolysis, digestive breakdown, and absorption barriers. A number of natural and synthetic polymeric, lipid-based, and inorganic nanoparticles have been investigated for use. Although improvements have recently been made in potential oral insulin delivery systems, these require further investigation before clinical trials are conducted. In this review, new approaches to oral insulin delivery for diabetes treatment are discussed, including polymeric, lipid-based, and inorganic nanoparticles, as well as the clinical trials performed for this purpose.

Versatile Oral Insulin Delivery Nanosystems: From Materials to Nanostructures.

Diabetes is a chronic metabolic disease characterized by lack of insulin in the body leading to failure of blood glucose regulation. Diabetes patients usually need frequent insulin injections to maintain normal blood glucose levels, which is a painful administration manner. Long-term drug injection brings great physical and psychological burden to diabetic patients. In order to improve the adaptability of patients to use insulin and reduce the pain caused by injection, the development of oral insulin formulations is currently a hot and difficult topic in the field of medicine and pharmacy. Thus, oral insulin delivery is a promising and convenient administration method to relieve the patients. However, insulin as a peptide drug is prone to be degraded by digestive enzymes. In addition, insulin has strong hydrophilicity and large molecular weight and extremely low oral bioavailability. To solve these problems in clinical practice, the oral insulin delivery nanosystems were designed and constructed by rational combination of various nanomaterials and nanotechnology. Such oral nanosystems have the advantages of strong adaptability, small size, convenient processing, long-lasting pharmaceutical activity, and drug controlled-release, so it can effectively improve the oral bioavailability and efficacy of insulin. This review summarizes the basic principles and recent progress in oral delivery nanosystems for insulin, including physiological absorption barrier of oral insulin and the development of materials to nanostructures for oral insulin delivery nanosystems.

Efficacy and safety of 28-day treatment with oral insulin (ORMD-0801) in patients with type 2 diabetes: A randomized, placebo-controlled trial.

AIM: To assess the safety and efficacy of oral insulin (ORMD-0801) in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: After a 2-week washout of other medications, adult metformin-treated patients with T2D were randomized to receive placebo or 16 or 24 mg ORMD-0801, once daily, at bedtime, for 28 days. The mean change from baseline weighted mean night-time glucose levels was determined from 2 nights of continuous glucose monitoring (CGM) recordings during the placebo run-in and last week of treatment. RESULTS: In total, 188 patients (HbA1c: 7.82% ± 0.88% [placebo] and 8.08% ± 1.11% [pooled ORMD-0801 group]) were enrolled. In the placebo group, mean night-time CGM increased from baseline by 13.7 ± 26.1 mg/dL, whereas the increase was significantly smaller in the pooled ORMD-0801 group (1.7 ± 23.5 mg/dL, P = .0120). Glycaemic control variables (24-hour, fasting and daytime CGM glucose) also displayed smaller increases with ORMD-0801 versus placebo. Change from baseline HbA1c was -0.01% in the pooled ORMD-0801 group versus +0.20% in the placebo group (P = .0149). ORMD-0801 was well tolerated, with similar adverse event and hypoglycaemia rates as placebo. CONCLUSIONS: In patients with T2D, bedtime ORMD-0801 curbed increases in night-time glycaemia, 24-hour glycaemia and HbA1c, without increasing the risk of hypoglycaemia or safety events compared with the control arm.

Ionic liquids for oral insulin delivery.

With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3-10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

Comparative efficacy of oral insulin sensitizers metformin, thiazolidinediones, inositol, and berberine in improving endocrine and metabolic profiles in women with PCOS: a network meta-analysis.

BACKGROUND: Multiple oral insulin-sensitizing agents, such as metformin, thiazolidinediones, inositols, and berberine, have been proven safe and efficacious in improving the endocrine, metabolic, and reproductive abnormalities seen in polycystic ovary syndrome (PCOS), providing more options for healthcare providers and patients. These oral insulin sensitizers are more convenient, practical, and economic than agents that need to be injected. A comparison of the clinical effectiveness of the four different classes of oral insulin sensitizers in PCOS has not been explored, leading to clinical uncertainty about the optimal treatment pathway. The present study aims to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with PCOS. METHODS: We identified randomized controlled trials for PCOS from a variety of databases, published from January 2005 to October 2020. Outcomes included changes in menstrual frequency, improvements in hyperandrogenism and glucolipid metabolism and adverse side effects. A random-effects network meta-analysis was performed. RESULTS: Twenty-two trials comprising 1079 patients with PCOS were included in this study. Compared with metformin, treatment with myo-inositol + D-chiro-inositol was associated with a greater improvement in menstrual frequency (odds ratio 14.70 [95% confidence interval (CI) 2.31-93.58]). Myo-inositol + D-chiro-inositol and metformin + thiazolidinediones combination therapies were superior to respective monotherapies in reducing total testosterone levels. Thiazolidinediones, metformin + thiazolidinediones, and myo-inositol + D-chiro-inositol were associated with a lower insulin resistance index (HOMA-IR) compared with that in metformin alone (mean differences: - 0.72 [95% CI (- 1.11)-(- 0.34)] to - 0.89 [95% CI (- 1.460)-(- 0.32)]). Metformin + thiazolidinediones treatment was associated with lower triglyceride levels compared with that in metformin and thiazolidinediones monotherapy, while thiazolidinediones was superior to metformin in increasing high-density lipoprotein cholesterol and decreasing fasting plasma glucose, triglycerides, low-density lipoprotein cholesterol, and gastrointestinal adverse events. CONCLUSIONS: Ours is the first study to report that for women with PCOS, myo-inositol combined with D-chiro-inositol and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone. Myo-inositol combined with D-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than metformin alone. Trial registration PROSPERO CRD42020211524.

This study aimed to compare the effects of oral insulin sensitizers on endocrine and metabolic profiles in women with polycystic ovary syndrome (PCOS). A random-effects network meta-analysis including 22 trials was conducted. For women with PCOS, myo-inositol combined with D-chiro-inositol and metformin combined with thiazolidinediones appear superior to metformin alone in improving insulin resistance and decreasing total testosterone level. Myo-inositol combined with D-chiro-inositol is particularly efficacious in menstrual recovery. Thiazolidinediones and metformin combined with thiazolidinediones improve lipid metabolism better than metformin alone.

pH-sensitive chitosan-deoxycholic acid/alginate nanoparticles for oral insulin delivery.

Oral absorption of peptides/proteins is usually compromised by various gastrointestinal tract barriers. To improve delivery efficiency, chitosan-conjugated deoxycholic acid (CS-DCA) coupled with sodium alginate (ALG) was prepared to load insulin into pH-sensitive nanoparticles. The insulin-loaded chitosan-deoxycholic acid/alginate nanoparticles (CDA NPs) were characterized by size (143.3 ± 10.8 nm), zeta potential (19.5 ± 1.6 mV), entrapment efficiency (61.14 ± 1.67%), and insulin drug loading (3.36 ± 0.09%). The CDA NPs exhibited pH-triggered release characteristics in vitro and protected the wrapped insulin from gastric degradation. Stability of the CDA NPs in enzyme-containing simulated gastrointestinal fluids suggested that the NPs could partially protect the wrapped insulin from enzymatic degradation. Additionally, CS-DCA-modified NPs promoted the permeability of Caco-2 cells and enhanced intracellular absorption of FITC-labeled insulin by 9.4 and 1.2-folds, when compared to insulin solution and unmodified NPs, respectively. The positively charged NPs increased intestinal villi adhesion and enhanced insulin absorption in the intestines of diabetic rat models. Furthermore, the hypoglycemic test showed that CDA NPs prolonged insulin release in vivo and exerted a remarkable hypoglycemic effect on diabetic rats with an oral bioavailability of 15%. In conclusion, CDA NPs is a potential oral insulin delivery system.

In vitro and in vivo evaluations on nanoparticle and phospholipid hybrid nanoparticles with absorption enhancers for oral insulin delivery.

Oral delivery of peptide and proteins is challenging due to their poor physical and chemical stability which usually results in inadequate therapeutic efficacy. Nanoparticles encapsulating insulin was developed by the ionic gelation technique using sulfobutyl ether-ß-cyclodextrin as an anionic linker. Phospholipid hybrid nanoparticles were formulated by utilizing ionic gelation and thin-film hydration methods using D-α-Tocopheryl polyethylene glycol 1000 succinate, sodium deoxycholate separately and in combination to take the advantage of liposomes and nanoparticles also various absorption enhancement mechanisms. All formulations were characterized and tested for in vitro gastrointestinal stability, in vitro drug release, and cytotoxicity. On the other hand, in vivo effects of developed formulations on reducing blood glucose levels were monitored for 8 hours. Phospholipid hybrid nanoparticles including D-α-Tocopheryl polyethylene glycol 1000 succinate and sodium deoxycholate in combination with 548.7 nm particle size, 0.332 polydispersity index, 22.0 mV zeta potential, and 61.9% encapsulation efficiency, exhibited desired gastrointestinal stability and insulin release in vitro. In addition, the formulation proved its safety with cytotoxicity studies on L929 cells. The subjected phospholipid hybrid nanoparticle formulation was found to be the most effective formulation by reducing and maintaining blood glucose levels with avoiding fluctuations.

Glucose-Responsive Polyelectrolyte Complexes Based on Dendritic Mesoporous Silica for Oral Insulin Delivery.

The postprandial glycemic regulation is essential for diabetic patients to reduce the risk of long-term microvascular and macrovascular complications. Herein, we designed a glucose-responsive oral insulin delivery system based on polyelectrolyte complexes (PECs) for controlling the increasing postprandial glucose concentrations. Briefly, alginate-g-3-aminophenylboronic acid (ALG-g-APBA) and chitosan-g-3-fluoro-4-carboxyphenylboronic acid (CS-g-FPBA) were wrapped on mesoporous silica (MSN) to form the negative charged ALG-g-APBA@MSN and the positive charged CS-g-FPBA@MSN nanoparticles, with an optimum insulin loading capacity of 124 mg/g and 295 mg/g, respectively. ALG-g-APBA@MSN was further cross-linked with CS-g-FPBA@MSN to form PECs through electrostatic interaction and borate esters. The dense polyelectrolyte network wrapped on MSN was capable of preventing insulin from diffusion and regulating its release. The in vitro insulin release of PECs demonstrated an obvious glucose response profile in different glucose concentrations (0 mg/mL, 2 mg/mL, 5 mg/mL) and presented a switch "on" and "off" release regulation at hyperglycemic or normal state. The CCK-8 assay showed that none of the MSN, ALG-g-APBA@MSN, CS-g-FPBA@MSN, and PECs possessed cytotoxicity to Caco-2 cells. For in vivo tests, the oral PECs exhibited a significant hypoglycemic effect and maintained in the euglycemic levels up to approximately 12 h on diabetic rats. Overall, the PECs directly triggered by postprandial glucose in the intestine have a good potential to be applied in intelligent insulin delivery by the oral route.

Smart Protein-Based Formulation of Dendritic Mesoporous Silica Nanoparticles: Toward Oral Delivery of Insulin.

Oral insulin administration still represents a paramount quest that almost a century of continuous research attempts did not suffice to fulfill. Before pre-clinical development, oral insulin products have first to be optimized in terms of encapsulation efficiency, protection against proteolysis, and intestinal permeation ability. With the use of dendritic mesoporous silica nanoparticles (DMSNs) as an insulin host and together with a protein-based excipient, succinylated ß-lactoglobulin (BL), pH-responsive tablets permitted the shielding of insulin from early release/degradation in the stomach and mediated insulin permeation across the intestinal cellular membrane. Following an original in vitro cellular assay based on insulin starvation, direct cellular fluorescent visualization has evidenced how DMSNs could ensure the intestinal cellular transport of insulin.

Oral delivery of insulin with intelligent glucose-responsive switch for blood glucose regulation.

BACKGROUND: The traditional treatment for diabetes usually requires frequent insulin injections to maintain normoglycemia, which is painful and difficult to achieve blood glucose control. RESULTS: To solve these problems, a non-invasive and painless oral delivery nanoparticle system with bioadhesive ability was developed by amphipathic 2-nitroimidazole-L-cysteine-alginate (NI-CYS-ALG) conjugates. Moreover, in order to enhance blood glucose regulation, an intelligent glucose-responsive switch in this nanoparticle system was achieved by loading with insulin and glucose oxidase (GOx) which could supply a stimulus-sensitive turnover strategy. In vitro tests illustrated that the insulin release behavior was switched "ON" in response to hyperglycemic state by GOx catalysis and "OFF" by normal glucose levels. Moreover, in vivo tests on type I diabetic rats, this system displayed a significant hypoglycemic effect, avoiding hyperglycemia and maintaining a normal range for up to 14 h after oral administration. CONCLUSION: The stimulus-sensitive turnover strategy with bioadhesive oral delivery mode indicates a potential for the development of synthetic GR-NPs for diabetes therapy, which may provide a rational design of proteins, low molecular drugs, as well as nucleic acids, for intelligent releasing via the oral route.

Enterically delivered insulin tregopil exhibits rapid absorption characteristics and a pharmacodynamic effect similar to human insulin in conscious dogs.

AIMS: Current therapy fails to emulate rapid (first-phase) insulin release in relation to a meal, a key defect in types 1 and 2 diabetes. We aimed to quantify the pharmacokinetic (PK) and pharmacodynamic (PD) profile of insulin tregopil, an enterically-absorbed insulin analog that restores the normal distribution of insulin between the hepatic portal and peripheral circulations. MATERIALS AND METHODS: The PK and PD profiles of insulin tregopil were studied in overnight-fasted, catheterized, conscious canines using four approaches: (1) equimolar intraportal infusions of tregopil vs human insulin; (2) escalating doses of oral tregopil; (3) identical, consecutive enteric doses of tregopil; and (4) comparison of oral tregopil to inhaled and subcutaneous human insulin administration. RESULTS: Equimolar intraportal infusions of tregopil and human insulin resulted in very similar PK profiles and PD profiles were nearly identical. Enteric delivery of tregopil brought about rapid absorption with tmax = 20 minutes in most cases. Median tmax was 20 minutes for oral tregopil and inhaled insulin and 88 minutes for subcutaneous human insulin. The time required for arterial plasma insulin levels to return to baseline was approximately 90, 210 and 360 minutes for oral tregopil, inhaled insulin and subcutaneous insulin, respectively. CONCLUSIONS: Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.

Immense Insulin Intestinal Uptake and Lymphatic Transport Using Bile Acid Conjugated Partially Uncapped Liposome.

We provide immense insulin absorption from the gastrointestinal tract, combining apical sodium-dependent bile acid transporter-mediated intestinal uptake and the lymphatic transport pathway. This strategy has proven to employ chondroitin sulfate- g-taurocholic acid coated, insulin-loaded partially uncapped liposome (IPUL-CST) for type 1 diabetes mellitus (T1DM) treatment. The loading efficiency of insulin in IPUL-CST increased significantly from 33% to 75% via the partially uncapped liposome preparation method. Moreover, the IPUL-CST revealed an improved insulin protection efficacy in GIT simulated pH and digestive enzyme conditions. The high dose of IPUL-CST in the small intestine was detected 4 h post-oral administration using ex vivo optical imaging and fluorescence intensity. The IPUL-CST exhibited significantly enhanced intestinal absorption (oral bioavailability, 34%; Tmax, 9 h) and reduced blood glucose levels for 16 h in T1DM. The results demonstrated that the new investigated IPUL-CST is a promising carrier for oral insulin delivery.

Efficacy and safety of oral insulin compared to subcutaneous insulin: a systematic review and meta-analysis.

INTRODUCTION: A systematic review and meta-analysis of interventional studies was conducted to compare the efficacy and safety of oral insulin versus subcutaneous (SC) insulin in diabetic patients. METHODS: Medline, Scopus, ISI Web of Knowledge and Cochrane Central Register of Controlled Trials were searched. Two independent reviewers evaluated studies for eligibility and quality and extracted the data. The primary outcomes were fasting blood glucose (FBG), 1h and 2h postprandial blood glucose, HbA1c, AUC of insulin, C max and T max of insulin, and T max of glucose infusion rate. Secondary outcomes were adverse events. RESULTS: Eleven studies (n = 373) met the inclusion criteria. Meta-analyses showed that there is no significant difference between oral and SC insulin in controlling HbA1c, FBG, 1 and 2 h postprandial blood glucose and producing C max of insulin (P > 0.05); however oral insulin had faster action as indicated by the shorter T max, compared to SC insulin (P < 0.05). The most included studies were varied in their methodological quality. CONCLUSION: This systematic review and meta-analysis showed that oral insulin is comparable to SC insulin with regard to glycemic efficacy and safety. However, is necessary to conduct additional studies in which oral insulin administered to large number of patients for long enough periods of time.

Anti-inflammatory Fucoidan-ConA oral insulin nanosystems for smart blood glucose regulation.

The smart oral administration Insulin device has the potential to improve glycemic management. It can reduce the risk of hypoglycemia associated with exogenous Insulin (INS) therapy while also avoiding many of the disadvantages associated with subcutaneous injections. Furthermore, diabetes mellitus (DM) is an endocrine illness characterized by inflammation, and it is critical to minimize the amount of inflammatory markers in diabetic patients while maintaining average blood glucose. In this study, a responsive nanosystem vitamin B12-Fucoidan-Concanavalin A (VB12-FU-ConA NPs) with anti-inflammatory action was developed for smart oral delivery of Insulin. Con A has high sensitivity and strong specificity as a glucose-responsive material. Fucoidan has anti-inflammatory, immunomodulatory, and hypoglycemic functions, and it can bind to Con A to form a reversible complex. Under high glucose conditions, free glucose competitively binds to Con A, which swells the nanocarrier and promotes Insulin release. Furthermore, in the low pH environment of the gastrointestinal tract, positively charged VB12 and anionic fucoidan bind tightly to protect the Insulin wrapped in the carrier, and VB12 can also bind to intestinal epithelial factors to improve transit rate, thereby promoting INS absorption. In vitro tests showed that the release of nanoparticles in hyperglycemic solutions was significantly higher than the drug release in normoglycemic conditions. Oral delivery of the nanosystems dramatically lowered blood glucose levels in type I diabetic mice (T1DM) during in vivo pharmacodynamics, minimizing the risk of hypoglycemia. Blood glucose levels reached a minimum of 8.1 ± 0.4 mmol/L after 8 h. Administering the nanosystem orally notably decreased the serum levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in diabetic mice. The nano delivery system can be degraded and metabolized in the intestinal tract after being taken orally, demonstrating good biodegradability and biosafety. In conclusion, the present study showed that VB12-FU-ConA nanocarriers are expected to be a novel system for rationalizing blood glucose.

Design and optimization of chitosan-coated solid lipid nanoparticles containing insulin for improved intestinal permeability using piperine.

The objective of this research was to optimize the composition and performance of chitosan-coated solid lipid nanoparticles carrying insulin (Ch-In-SLNs) and to assess the potential of piperine in enhancing the intestinal permeability of insulin from these SLNs in vitro. The SLNs were formulated from glyceryl behenate (GB), soya lecithin, and poloxamer® 407, and then coated with a combination of chitosan and piperine to facilitate insulin penetration across the gastrointestinal (GI) mucosa. A Box-Behnken Design (BBD) was utilized to optimize the Ch-In-SLNs formulations, with PDI, particle size, zeta potential, and association efficiency (AE) serving as the response variables. The resulting Ch-In-SLNs exhibited excellent monodispersity (PDI = 0.4), optimal particle size (654.43 nm), positive zeta potential (+36.87 mV), and low AE values. The Ch-In-SLNs demonstrated sustained release of insulin for 12 h in simulated gastric fluid (SGF) and intestinal fluid (SIF), with increased release in the latter. After incubation in SGF and SIF for 12 h, the insulin SLNs retained 54 and 41 % of their initial insulin load, respectively, indicating effective protection from gastric enzymes. Permeation studies using goat intestine and Caco-2 cell lines indicated improved insulin permeation in the presence of piperine. Additionally, cell uptake studies confirmed the role of piperine in enhancing insulin permeation.

A review on oral novel delivery systems of insulin through the novel delivery system formulations: A review.

Parenteral administration of insulin remains the most common route of administration, causing local hypertrophy at the injection sites because of multiple daily injections. Because of this, there is an interest and effort in oral insulin administration that is convenient and mimics the physiology of endogenous insulin secreted in the liver. However, oral insulin encountered different challenges due to abundant enzyme degradation, the presence of a mucus layer, and the underlying intestinal epithelial membrane barrier in the gastrointestinal tract. This narrative review reviewed the literature dealing with novel oral insulin delivery approaches. Various pieces of literature were searched, filtered, and reviewed from different sources, and the information obtained was organized, formulated, and finalized. Oral insulin has been formulated and extensively studied in various novel delivery approaches, such as nanoparticles, microspheres, mucoadhesive patches, encapsulations, hydrogels, ionic liquids, liposomes, and complexation. The efficiency of these formulations demonstrated improved efficiency and potency compared to free oral insulin delivery, but none of them have greater or equivalent potency to subcutaneous insulin. Future studies regarding dose-dependent therapeutic efficacy and the development of new novel formulations to produce comparable oral insulin to subcutaneous insulin are warranted to further support the suitability of the current platform for oral insulin delivery.

Fabrication of Ca-alginate microspheres by diffusion-induced gelation in double emulsion droplets for oral insulin.

Sodium alginate has good biocompatibility and is widely used in the study of drug carriers. In this paper, a method to prepare calcium alginate microspheres with high sphericity based on double emulsion droplets was proposed, in which sodium alginate is used as the innermost phase. By adjusting the density of the system, the double-emulsion droplets could be suspended in the collecting solution, leading to the homogeneous reaction between the sodium alginate droplets and the calcium ions. By changing the flow rate, the size of the droplets could be changed, and by changing the concentration of calcium ions in the collecting solution, the sphericity of the calcium alginate microspheres could be changed. Then the swelling properties and drug release properties of calcium alginate microspheres were determined. The drug delivery study revealed that the insulin-loaded Ca-Alginate microspheres were able to decrease blood glucose by 41.4 % after oral administration to mice. Thus, the Ca-Alginate microsphere is a suitable candidate for controlled pH-sensitive drug delivery.