Oral Insulin Formulation Research Articles

Pioneering Oral Insulin Formulations and Delivery Techniques: A Review

The development of oral insulin presents significant promise for diabetes treatment, mitigating peripheral hyperinsulinemia, weight gain, and hypoglycemia while enhancing patient convenience and facilitating rapid insulinization of the liver. Effective oral insulin products are crucial for early intensive insulin therapy, which ensures tight glycaemic control and delays diabetes complications. However, despite the need, oral insulin has faced many challenges, and past technologies have had limited success. Repeated insulin injections can result in local hypertrophy over time generating attention to user-friendly oral insulin delivery systems that are not invasive to the body and copy the natural pathway. This review article examines New methods for oral insulin delivery that have shown promise, using techniques like complexation, hydrogels, and nanoparticles to boost effectiveness, though they still trail injectable insulin. Further studies will help determine how well oral insulin works at various doses and inform the development of competing formulations.

Muco-Adhesive and Muco-Penetrative Formulations for the Oral Delivery of Insulin.

Insulin, a pivotal anabolic hormone, regulates glucose homeostasis by facilitating the conversion of blood glucose to energy or storage. Dysfunction in insulin activity, often associated with pancreatic β cells impairment, leads to hyperglycemia, a hallmark of diabetes. Type 1 diabetes (T1D) results from autoimmune destruction of β cells, while type 2 diabetes (T2D) stems from genetic, environmental, and lifestyle factors causing β cell dysfunction and insulin resistance. Currently, insulin therapy is used for most of the cases of T1D, while it is used only in a few persistent cases of T2D, often supplemented with dietary and lifestyle changes. The key challenge in oral insulin delivery lies in overcoming gastrointestinal (GI) barriers, including enzymatic degradation, low permeability, food interactions, low bioavailability, and long-term safety concerns. The muco-adhesive (MA) and muco-penetrative (MP) formulations aim to enhance oral insulin delivery by addressing these challenges. The mucus layer, a hydrogel matrix covering epithelial cells in the GI tract, poses significant barriers to oral insulin absorption. Its structure, composition, and turnover rate influence interactions with insulin and other drug carriers. Some of the few factors that influence mucoadhesion and mucopenetration are particle size, surface charge distribution, and surface modifications. This review discusses the challenges associated with oral insulin delivery, explores the properties of mucus, and evaluates the strategies for achieving excellent MA and MP formulations, focusing on nanotechnology-based approaches. The development of effective oral insulin formulations holds the potential to revolutionize diabetes management, providing patients with a more convenient and patient-friendly alternative to traditional insulin administration methods.

Novel Black Seed Polysaccharide Extract-g-Poly (Acrylate) pH-Responsive Hydrogel Nanocomposites for Safe Oral Insulin Delivery: Development, In Vitro, In Vivo and Toxicological Evaluation.

Oral delivery of insulin has always been a challenging task due to harsh gut environment involving variable pH and peptidase actions. Currently, no Food and Drug Administration (FDA) approved oral insulin formulation is commercially available, only intravenous (IV) or subcutaneous (SC) routes. Therefore, it is really cumbersome for diabetic patients to go through invasive approaches for insulin delivery on daily basis. In the present study, a novel pH-responsive hydrogel nanocomposite (NC) system was developed and optimized for safe oral delivery of insulin. Black seed polysaccharide extract-based hydrogel (BA hydrogel) was formulated by free radical polymerization and loaded with insulin. Blank BA hydrogel was also incorporated with insulin-loaded montmorillonite nanoclay (Ins-Mmt) to form an Ins-Mmt-BA hydrogel NC and compared with the insulin-loaded hydrogel. Swelling, sol-gel analysis and in vitro release studies proved that Ins-Mmt-BA6 hydrogel NC has the best formulation, with 96.17% maximum insulin released in 24 h. Kinetic modeling applied on insulin release data showed the Korsemeyer-Peppas model (R2 = 0.9637) as the best fit model with a super case II transport mechanism for insulin transport (n > 0.89). Energy Dispersive X-ray (EDX) Spectroscopy, Fourier Transformed Infrared (FTIR) spectroscopy and Powdered X-ray diffraction (PXRD) analysis results also confirmed successful development of a hydrogel NC with no significant denaturation of insulin. Toxicity results confirmed the safety profile and biocompatibility of the developed NC. In vivo studies showed a maximum decrease in blood glucose levels of 52.61% and percentage relative bioavailability (% RBA) of 26.3% for an Ins-Mmt-BA hydrogel NC as compared to BA hydrogels and insulin administered through the SC route.

Counteractive Effects of Choline Geranate (CAGE) ILs and Ethanol on Insulin’s Stability—A Leap Forward towards Oral Insulin Formulation

Choline geranate (CAGE) ionic liquids (ILs) stabilize insulin, thereby aiding its oral delivery, whereas ethanol (EtOH) affects its stability by disrupting the hydrophobic interactions. In this study, cognizance of the stabilization mechanism of insulin dimer in the presence of both CAGE ILs and EtOH mixtures is achieved through biased and unbiased molecular dynamics (MD) simulations. Here, two order parameters are employed to study the insulin dimer dissociation using well-tempered metadynamics (WT-MetaD). The stability of insulin is found to be strongly maintained until a 0.20 mole fraction of EtOH. Besides, higher concentrations of EtOH marginally affect the insulin stability. Moreover, geranate anions form a higher number of H-bonding interactions with water molecules, which aids insulin stabilization. Conversely, the addition of EtOH minimizes the water-mediated H-bonding interactions of geranate. Additionally, geranate traps the EtOH molecules, thereby preventing the interactions between insulin and EtOH. Furthermore, the free energy landscape (FEL) reveals the absence of dimer dissociation along with noticeable deviations in the distances R and the number of contacts Q. The dimerization free energy of insulin was calculated to be −16.1 kcal/mol at a 0.20 mole fraction of EtOH. Moreover, increments in mole fractions of EtOH effectuate a decrease in the insulin stability. Thus, the present study represents CAGE ILs as efficient insulin dimer stabilizes at low concentrations of EtOH.

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.

Strategies to Improve Insulin Delivery through Oral Route: A Review.

Diabetes mellitus is found to be among the most suffered and lethal diseases for mankind. Diabetes mellitus type-1 is caused by the demolition of pancreatic islets responsible for the secretion of insulin. Insulin is the peptide hormone (anabolic) that regulates the metabolism of carbohydrates, fats, and proteins. Upon the breakdown of the natural process of metabolism, the condition leads to hyperglycemia (increased blood glucose levels). Hyperglycemia demands outsourcing of insulin. The subcutaneous route was found to be the most stable route of insulin administration but faces patient compliance problems. Oral Insulin delivery systems are the patient-centered and innovative novel drug delivery system, eliminating the pain caused by the subcutaneous route of administration. Insulin comes in contact across various barriers in the gastrointestinal tract, which has been discussed in detail in this review. The review describes about the different bioengineered formulations, including microcarriers, nanocarriers, Self-Microemulsifying Drug Delivery Systems (SMEDDs), Self-Nanoemulsifying drug delivery systems (SNEDDs), polymeric micelles, cochleates, etc. Surface modification of the carriers is also possible by developing ligand anchored bioconjugates. A study on evaluation has shown that the carrier systems facilitate drug encapsulation without tampering the properties of insulin. Carrier-mediated transport by the use of natural, semi-synthetic, and synthetic polymers have shown efficient results in drug delivery by protecting insulin from harmful environment. This makes the formulation readily acceptable for a variety of populations. The present review focuses on the properties, barriers present in the GI tract, overcome the barriers, strategies to formulate oral insulin formulation by enhancing the stability and bioavailability of insulin.

Oral Insulin Delivery by Chitosan Coated Solid Lipid Nanoparticles: Ex vivo and in vivo Studies

<p style="text-align: justify;"><strong>Objectives: </strong>The objective of this investigation was to formulate chitosan coated, insulin-loaded solid lipid nanoparticles (SLN) for oral administration and investigate their potential as an effective alternative to the subcutaneous injection. <strong>Methods: </strong>The SLN were prepared from glyceryl monostearate and coated with the mucoadhesive polymer, chitosan and were investigated for physical properties, <em>ex vivo</em> permeation through Caco-2-cell monolayer and goat intestinal mucosa. The<em> in vivo</em> efficacy of the optimized formulation in controlling blood glucose levels was studied in streptozotocin induced diabetic rats.<strong> Results: </strong>Coating in the presence of Poloxamer 407 resulted in significantly smaller nanoparticles than those with Tween 80. Scanning electron microscopy and transmission electron microscopy revealed spherical particles of uniform size distribution. The insulin association efficiency and loading efficiency of SLN prepared with Poloxamer were much greater than those with Tween 80. <em>Ex vivo p</em>ermeability studies in Caco-2 cell monolayer revealed a 4 fold increase in insulin permeation from chitosan coated SLN (<em>P</em>&lt; 0.005) as compared to uncoated SLN at the end of 6 h. The percentage permeation through excised sheep intestinal mucosa from coated SLN was twice that from uncoated SLN and nearly 20 times from insulin solution. The oral administration of chitosan-coated insulin SLN to streptozotocin-induced diabetic rats resulted in a significant hypoglycemic effect (<em>P</em>&lt;0.05) when compared to the groups that received uncoated insulin-loaded SLN or the oral insulin solution and was comparable to that of subcutaneous insulin at the end of an 8 h study. <strong>Conclusion:</strong> Chitosan coated SLN can be considered promising as an effective oral insulin formulation. <p style="text-align: justify;"><strong>Key words:</strong> Chitosan, Diabetes, Glyceryl monostearate, Insulin, Nanoparticles, Permeation.

The molecular mechanism behind the stabilization of insulin by choline and geranate (CAGE) ionic liquids - computational insights into oral insulin drug formulation.

Insulin is a principal hormone that is involved in the regulation of glucose levels in the blood. Oral insulin formulation is a recent development in drug delivery systems. Biocompatible choline-based ionic liquids (ILs) show promising antibacterial activity and are useful for oral and transdermal drug delivery applications. Choline and geranate (CAGE) ILs enhance the stability and oral efficacy of insulin delivery. The molecular mechanism behind insulin formulation in the oral form is at issue. In the present work, the molecular-level understanding of CAGE ILs in insulin is scrutinized by employing atomistic molecular dynamics (MD) simulations. To identify the stability of insulin in an IL medium, we have studied a series of concentration (mole fraction 0.05-1.00) of CAGE ILs with an insulin dimer. It can be well evidenced from the experimental reports that in an aqueous medium, there is a refashioning of CAGE nanostructures at 0.50 mole fraction. It is found from our calculations that the first solvation shell of insulin is readily occupied by choline and geranate ions in the presence of water. Moreover, the geranate ions strongly interacted with the water molecules and thereby, eliminating the intermolecular hydrogen bonding (H-bonding) interactions towards the insulin at 0.30-0.50 mole fraction of CAGE ILs. The most desirable 0.30-0.50 mole fraction of CAGE invigorates water-mediated H-bonding interactions with geranate ions, which also enhances the electrostatic behavior around the vicinity of the insulin dimer. These important findings can help in the development of oral insulin drug delivery and related applications.

Recent Progress of Chitosan and Chitosan Derivatives-Based Nanoparticles: Pharmaceutical Perspectives of Oral Insulin Delivery.

Diabetes mellitus is a chronic endocrine disease, affecting more than 400 million people around the world. Patients with poorly controlled blood glucose levels are liable to suffer from life-threatening complications, such as cardiovascular, neuropathy, retinopathy and even premature death. Today, subcutaneous parenteral is still the most common route for insulin therapy. Oral insulin administration is favourable and convenient to the patients. In contrast to injection route, oral insulin delivery mimics the physiological pathway of endogenous insulin secretion. However, oral insulin has poor bioavailability (less than 2%) due to the harsh physiological environment through the gastrointestinal tract (GIT). Over the last few decades, many attempts have been made to achieve an effective oral insulin formulation with high bioavailability using insulin encapsulation into nanoparticles as advanced technology. Various natural polymers have been employed to fabricate nanoparticles as a delivery vehicle for insulin oral administration. Chitosan, a natural polymer, is extensively studied due to the attractive properties, such as biodegradability, biocompatibility, bioactivity, nontoxicity and polycationic nature. Numerous studies were conducted to evaluate chitosan and chitosan derivatives-based nanoparticles capabilities for oral insulin delivery. This review highlights strategies that have been applied in the recent five years to fabricate chitosan/chitosan derivatives-based nanoparticles for oral insulin delivery. A summary of the barriers hurdle insulin absorption rendering its low bioavailability such as physical, chemical and enzymatic barriers are highlighted with an emphasis on the most common methods of chitosan nanoparticles preparation. Nanocarriers are able to improve the absorption of insulin through GIT, deliver insulin to the blood circulation and lower blood glucose levels. In spite of some drawbacks encountered in this technology, chitosan and chitosan derivatives-based nanoparticles are greatly promising entities for oral insulin delivery.

Oral Insulin Delivery Platforms: Strategies To Address the Biological Barriers.

Diabetes mellitus is a lifelong metabolic disease that requires frequent subcutaneous injections of insulin. However, this method of administration can be associated with patient discomfort and local tissue infection. Oral delivery of insulin has been pursued as a more convenient method for diabetes treatment, given its likely superior patient compliance and convenience as well as cost-effectiveness. However, various biological barriers hinder the clinical translation of oral insulin. The rapid development of nanotechnology over the last decade offers great promise in improving the bioavailability of oral insulin. This Minireview provides an overview of biological barriers to oral insulin delivery, summarizes significant technological advances, and outlines future perspectives in oral insulin formulations as well as their hypoglycaemic effects.

Zwitterionic micelles efficiently deliver oral insulin without opening tight junctions.

Oral delivery of protein drugs is considered a life-changing solution for patients who require regular needle injections. However, clinical translation of oral protein formulations has been hampered by inefficient penetration of drugs through the intestinal mucus and epithelial cell layer, leading to low absorption and bioavailability, and safety concerns owing to tight junction openings. Here we report a zwitterionic micelle platform featuring a virus-mimetic zwitterionic surface, a betaine side chain and an ultralow critical micelle concentration, enabling drug penetration through the mucus and efficient transporter-mediated epithelial absorption without the need for tight junction opening. This micelle platform was used to fabricate a prototype oral insulin formulation by encapsulating a freeze-dried powder of zwitterionic micelle insulin into an enteric-coated capsule. The biocompatible oral insulin formulation shows a high oral bioavailability of >40%, offers the possibility to fine tune insulin acting profiles and provides long-term safety, enabling the oral delivery of protein drugs.

1004-P: Oral Insulin (ORMD-0801) Effects on Glucose Parameters in Uncontrolled T2DM on OADs

ORMD-0801 is a novel oral human insulin formulation which can potentially improve acceptance and adherence, as well as glycemic control by increasing hepatic insulin exposure, without increasing hypoglycemia risk. This randomized, placebo-controlled, multi-center, phase 2b 12-week study, in 273 T2DM subjects, on metformin ±1-2 oral antidiabetic drugs (OADs), including sulfonylurea, compared placebo vs. 32 mg ORMD-0801 capsules administered once daily (QD) at bedtime, or two (BID) or three (TID) times daily at bedtime, and 30-40 min before breakfast/lunch. Blinded continuous glucose monitoring (CGM) was performed during a two-week run-in period and over the last two weeks of treatment. HbA1c levels improved from baseline for all active treatment regimens (Table). Glucose AUC improved from baseline following QD and BID treatment. Hypoglycemia rates were low and relatively similar to the placebo arm, and body weight was unchanged in all treatment arms. Frequency of drug-related adverse events was similar across treatment groups. In conclusion, ORMD-0801 elicited clinically significant HbA1c reductions among T2DM patients inadequately controlled on standard therapies, without increasing hypoglycemia rates, or inducing severe or serious adverse effects or significant weight gain. Disclosure R. Eldor: Advisory Panel; Self; Oramed. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Medtronic, Merck Sharp &amp; Dohme Corp., Novo Nordisk Inc., Sanofi. Stock/Shareholder; Self; Oramed. G. Fleming: Consultant; Self; ADOCIA, Biocon, Caladrius Biosciences, Inc., Dance Biopharm Holdings, Inc., Diasome Pharmaceuticals, Inc., Intarcia Therapeutics, MannKind Corporation, NuSirt Biopharma, Inc., Oramed Pharmaceuticals, Sanofi, Tolerion, Inc. J. Neutel: None. K.E. Homer: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals. Stock/Shareholder; Self; Oramed Pharmaceuticals. J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc., REMD Biotherapeutics. Other Relationship; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi.

115-LB: Oral Insulin–Induced Reduction in Liver Fat Content in T2DM Patients with Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) and subsequent nonalcoholic steatohepatitis are leading causes of chronic liver disease, with disease progression directly associated with insulin resistance and T2DM. In light of the common risk factors, pathogenesis and complications with T2DM, direct insulin intervention has been suggested for T2DM patients with NAFLD. Recently, salient metabolic effects of oral insulin have been suggested, owing to first pass metabolism and local insulin availability and concentration in liver fat cells. This pilot study assessed the safety, tolerability and early effects on liver fat content of an oral insulin formulation (ORMD-0801), preprandially administered once-daily (2x8 mg capsules) for 12 consecutive weeks, to 8 T2DM patients with NASH. The 12-week ORMD-0801 treatment proved safe and tolerable in all patients, with no serious or severe adverse events recorded throughout the study period. The 12-week treatment induced a mean -6.9±6.8% reduction in liver fat content (sign test p value: 0.035), as measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). In parallel, concentrations of gamma-glutamyltransferase (GGTP), a key marker of chronic hepatitis, were significantly lower after 12 weeks of treatment as compared to baseline (-14.6±13.1 U/L; sign test p value: 0.008), as were fasting insulin levels (-96.5±206.0 pmol/L; sign test p value: 0.035). Taken together, these preliminary observations suggest a palliative effect of oral insulin on NASH in T2DM patients, as shown by reductions in liver fat content and chronic hepatitis. These encouraging findings will require further validation in large-scale, randomized clinical trials. Disclosure M. Kidron: Employee; Self; Oramed Pharmaceuticals. Stock/Shareholder; Self; Oramed Pharmaceuticals. S. Perles: Employee; Spouse/Partner; Haddassah Medical Center. Employee; Self; Oramed Pharmaceuticals. R. Kaloti: None. R. Ghantous: None. S.F. Sandouka: None. Y. Malaabi: None. R. Safadi: None.

Assessment of Hypoglycemic Effect of an Oral Insulin Formulation in Chickens as an Experimental Animal Model

The study aims to design and evaluate oral insulin for the purpose of achieving the following criteria: effectiveness in controlling blood sugar when taking insulin orally, palatability of the oral dose characteristics in terms of shape, color, smell and taste to be acceptable, especially for children. Stability of oral insulin against intestinal metabolism achieves constant bioavailability as well as oral doses are eligible to all diabetic patients. The oral nano polymer insulin (NPI) was assessed by GC mass, FTIR, electrophoresis, melting point, fluorescence labeling, microscopy, calorimetric, albumin binding assay and hydrophobicity test. The overall in vivo findings showed that NPI had onset of action 35+15 min and 5+1.5 hr duration of action with oral efficacy of 34+4% of that for intraperitoneal (IP) route. The pharmaceutical properties were convenient for oral use.

OR14-1 Pharmacodynamics, Safety, Tolerability, and Efficacy of Oral Insulin Formulation (Oshadi Icp) among Young Adults with Type 1 Diabetes: A Summary of Clinical Studies Phases I, Ib, and Ii

Background Replacement of subcutaneous (SC) insulin by oral insulin for Type I diabetes (T1D) could promote patient compliance and minimize hyperinsulinemia. Oshadi Drug Administration Ltd. has developed an oral carrier for proteins delivery, composed of known ingredients, including polysaccharides and nano-silica , and based on quantum theory of biochemical reactions. Objectives To assess the pharmacodynamics of Oshadi oral insulin formulation (Oshadi-I) and the safety, tolerability and glucose-lowering effect of Oshadi oral insulin, proinsulin and c-peptide formulation (Oshadi-Icp) in young patients with T1D. Methods Phase I: a single blinded crossover between Oshadi-I and placebo. Glucose concentration was followed over 13 hours post a single dose. Phase Ib: a crossover open label comparison between 2 sessions of 3 days of Oshadi-Icp or placebo. During both sessions patients stayed at the research unit, provided with identical low carbs diet and minimal doses of SC insulin. Phase II:a prospective 4 weeks open-label follow-up of patients using an insulin pump combined with Oshadi-Icp at home. During Phases Ib and II iinterstitial glucose (IG) was monitored by CGMS, and capillary glucose by finger pricks (CG). Mean IG, mean CG, their area under the curve (AUC), weight adjusted total daily dose (TDD) of SC insulin, BMI, HbA1c, fructosamine, and safety parameters were compared. Results Eight patients, mean age 27.7±4.8 years, 5 males, were included in Phase I study, 10 patients mean age 26.2±4.7 years, 7 males, were included in Phase Ib study, and 16 patients mean age 23.5± 4.6 years, 12 males, were included in Phase II study. Oshadi-Icp was well tolerated, with no adverse events nor clinically relevant changes in vital signs, electrocardiograms, and standard safety laboratory parameters during all study phases. Phase I demonstrated a significantly lower plasma glucose AUC within 7 hours post Oshadi-I compared with placebo: 1116.1mg/dl±107.0 vs. 1345.7mg/dl ±82.0, p <0.01. Phase Ib study demonstrated significantly lower mean post meals GC, AUC-GC and mean insulin TDD at the third day during Oshadi-Icp session compared to placebo: 207.5mg/dl± 6.0 vs. 265.4mg/dl±3.9, p<0.001, 3107.57mg/dl±20.5 vs. 4031.58mg/dl±26.76, p<0.001, 0.14 ±0.04 IU/kg/day vs. 0.18 ±0.06 IU/kg/day, p≤0.01. Four episodes of GC ≤70mg/dL were detected during the Oshadi Icp session and 1 episode of mild DKA was detected during the placebo session. Phase II study demonstrated the ratio of SC insulin dose to carbohydrate intake was significantly lower during Oshasi-Icp month 78-80% for each week compared to baseline 100%. Fructosamine was stable throughout the study, with no episodes of severe hypoglycemia and DKA. Conclusions A substantial safety and glucose lowering effect of Oshadi-Icp formulation were demonstrated. Its clinical potential and beneficial effect for patients with T1D should be further studied.

Oral Insulin: Myth or Reality.

Diabetes Mellitus (DM) is a disorder of glucose metabolism marked by hyperglycemia, glycosuria, hyperlipidemia, negative nitrogen balance and ketonaemia. DM is a major healthcare problems today and its treatment costs billions of dollars worldwide annually. The cases of diabetes have increased rapidly in recent years throughout the world. Currently, for the management of Type-1 Diabetes Mellitus (TIDM), Multiple Daily Insulin (MDI) injections is the most popular treatment. Oral administration of insulin is the most suitable and attractive as compared to subcutaneous route but unfortunately cannot be utilized for the administration of peptides and proteins due to poor epithelial permeability and enzymatic degradation within the gastrointestinal tract. Since many years, extensive research has been carried out to explore the potential ways of insulin administration based on novel methods such as liposome, microsphere, nanoparticle, mouth dissolving strips, sprays exploiting oral and pulmonary route. These next generation efficient therapies for T1DM may help to improve the quality of life of diabetic patients especially in Insulin Dependent Diabetes Mellitus (IDDM). This review emphasizes on the most recent progress made in the development of oral insulin delivery formulations, and focuses on key lessons and implications from studies undertaken till date with the oral insulin formulations. Further, this review analyzes effectiveness of the advancements, applications and limitations of the technologies in delivering insulin to the targeted site through oral administration.

Oral insulin delivery by carboxymethyl-β-cyclodextrin-grafted chitosan nanoparticles for improving diabetic treatment

In this paper, a new oral insulin formulation, insulin-loaded carboxymethyl-β-cyclodextrin-grafted chitosan nanoparticles (insulin/CMCD-g-CS NPs), was fabricated by ionic crosslinking technique. The therapeutic efficacy of new formulation was investigated in detail. Firstly, the CMCD-g-CS was synthesized by EDC-mediated esterification reaction. The prepared CMCD-g-CS exhibited favourable loading capacity and encapsulation efficiency of drug. The release experiment in vitro showed that the nanocarrier could efficiently protect encapsulated insulin at simulated gastric environment and release drug in the simulated colonic fluid. The insulin/CMCD-g-CS NPs effectively promoted drug internalization into Caco-2 cells and could reversibly open the tight junction between cells. The oral administration of insulin/CMCD-g-CS NPs could lastingly decrease blood sugar level in diabetic mice. The liver function study verified that the insulin/CMCD-g-CS NPs had not obvious toxicity to experimental mice. Therefore, the CMCD-g-CS could be an effective and safe oral insulin delivery carrier for future clinical application.A new biocompatible polysaccharide nanoparticle was fabricated as oral insulin delivery carrier for improving diabetic treatment.

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.

Recombinant Protease Inhibitor Enhances Oral Insulin Pharmacodynamics in Pigs

Oral insulin delivery is projected to provide both physiologic and technical benefits, and has been the focus of rigorous research efforts in recent years. The ORMD-0801 oral insulin formulation relies on the activities of both protease inhibitors and an absorption enhancer to ensure insulin integrity and bioavailability. In efforts to further improve its efficacy, a recombinant protease inhibitor (rPI), identical in sequence to its naturally sourced (nsPI) counterpart, was cloned and expressed in Pichia pastoris. The enzymatic activity of the isolated and purified protein was then tested in vitro. In addition, the glucose-lowering effect of ORMD-0801 formulated with various doses of rPI was assessed in 8 healthy, fasting pigs administered the preparation directly to the duodenum. rPI effectively inhibited its standard substrate in a dose-dependent manner and demonstrated &amp;gt;2.5-fold higher activity as compared to nsPI. When integrated in the ORMD-0801 formulation, pigs treated with the formulation containing 25 mg rPI experienced a 20% greater change from baseline serum glucose concentrations as compared to those treated with the PI-free formulation (AUC: -6369 mg/dL vs. -2201 mg/dL, respectively). In parallel, the duration of its effect (140±33 minutes) was 75% longer than the duration of the effect of the PI-free formulation (80±37 minutes). Further calibrations of the rPI-supplemented ORMD-0801 formulation promise to enhance oral insulin bioavailability and its salutary effects, subsequently improving its clinical potential and value. Disclosure R. Nagaraju: None. S. Madan: None. K. Arora: None. N.M. Arora: None. P.K. Kundu: None. Y. Greenberg-Shushlav: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc. A. Hershko: Advisory Panel; Self; Oramed Pharmaceuticals, Inc..

Future Prospects for Clinical Development of Oral GLP-1 and Insulin Formulations

Future Prospects for Clinical Development of Oral GLP-1 and Insulin Formulations