An Israeli company created the world’s first oral insulin


An Israeli company has started final-stage tests of its oral insulin, bidding to become the first to make the product available on the international market.

The product started phase three trials under the US Food and Drug Administration in California on Monday, after 14 years of development.

If all goes well, Oramed Pharmaceuticals says it expects type 2 diabetics to start taking its pills in just over three years, followed by type 1 diabetics after further testing.

“This has the potential to improve lives of hundreds of millions of diabetics worldwide,” Oramed CEO Nadav Kidron told The Times of Israel.

“And by improving treatment it can reduce complications and, in turn, reduce the cost of treating diabetics.”

He said that the dosing tech that is being used for insulin has “very significant” potential for the creation of oral versions of other medical injections.

An Indian company, Biocon, is also working on oral insulin, but unlike Oramed it has not started advanced trials with the FDA, which is seen as the main path to the international market.

Insulin pills produced by Oramed (courtesy of Oramed Pharmaceuticals)

Oramed has big money behind its innovation: In 2015 it signed a $50 million licensing and investment deal with China’s Hefei Life Science & Technology Park Investments and Development Co. (HLST), a subsidiary of Chinese pharma giant Sinopharm, for the rights to its oral insulin capsule in China.

Kidron said his product transports insulin to where the body can make the best use of it — the liver, rather than the bloodstream, where it is currently delivered.

“One benefit of oral insulin is that we overcome the fear of the needle, but, more importantly, the insulin is being delivered directly to the liver.

“By taking it to the liver we are stopping the excessive production of glucose in the place where the production actually happens. Usually, injections go into the bloodstream and deal with glucose there instead of stopping production in the liver, its source.”

Pills will become a major source of insulin, he predicted, but they won’t replace injections entirely, as type 1 diabetics will still need to inject some of their doses.

He said that as well as helping insulin-dependent diabetics, it will allow doctors who are hesitant to start injections to prescribe occasional insulin via pills.

The direct delivery minimizes side effects, especially weight gain which is the bane of many diabetics’ lives, Kidron said.

“So far in the phases of trials conducted to date, we [have] not seen the weight gain that is associated with injected insulin,” he commented.

In Phase 2b trials, the oral insulin showed a statistically significant lowering of hemoglobin A1c levels, a key marker of diabetes, without serious adverse events or weight gain.

The initial technology was developed at Hadassah Medical Center in Jerusalem – by Kidron’s mother, biochemist Miriam Kidron, today Oramed’s chief scientific officer. The Israel Prize-winning biochemist Avram Hershko is one of the company’s scientific advisers.

The big obstacle to oral insulin has been that the gut would harm it before it reaches the liver. Oramed’s tech overcomes this with a specially-coated pill that stays whole and releases the insulin as it gets to the liver.

“The fact we’re able to get the pill to the liver, which is exactly where the insulin is needed, is a major achievement,” said Kidron. “For nearly 100 years the world has looked for ways to be able to give insulin orally. This technology could be a real game-changer in how we treat diabetes.”

Drug delivery via the oral route is preferred over other strategies, owing to high patient compliance and the ease of home-based drug ingestion [1, 2]. However, because of the low permeability and poor enzymatic stability of large molecules in the gastrointestinal (GI) tract, the oral route is usually not appropriate when proteins/peptides are directly delivered in a free form.

The effective oral administration of protein-based drugs remains a challenge [3]. Insulin, the first protein-based drug synthesized for human use, has been used for the treatment of diabetes since 1921. Insulin is a 51-polypeptide hormone comprising an A chain (21 amino acids) and B chain (30 amino acids) linked by two disulfide bonds [4].

Its large size and hydrophilic nature hinder its permeation through absorption barriers. To date, most major commercial formulations of insulin are administered by subcutaneous injection. This conventional route of protein delivery may lead to poor patient compliance because of inconvenience and pain.

To improve patient compliance, the oral route is considered a better alternative. In addition, the oral delivery of insulin is advantageous because it closely imitates the physiological behavior of endogenous insulin [2, 5]. Around 80% of oral/pancreatic insulin is cleared in the liver, while the rest reaches systemic circulation.

Oral administration can thus avoid subcutaneous injection-related hyperinsulinemia. Several approaches have been adopted in recent decades to improve the oral bioavailability of insulin and other proteins/peptides [2, 6, 7]. Nevertheless, the development of a commercial oral formulation for insulin remains a challenge because no strategies have been able to successfully overcome both physicochemical drawbacks (molecular size, stability, and high hydrophilicity) and biological barriers (proteolysis in the stomach, poor permeation, and membrane efflux) [8, 9].

Recently, several products have completed or are currently undergoing phase II or phase III clinical trials, including oral insulin capsules (NIDDK; NIH, Bethesda, MD, USA), rH-insulin crystals (Technische Universität München, Munich, Germany), oral ORMD-0801 (Oramed, Jerusalem, Israel), Oshadi Icp (Oshadi Drug Administration, Rehovot, Israel), IN-105 (Biocon, Bangalore, India), insulin 338 (GIPET1), insulin glargine (Novo Nordisk, Bagsværd, Denmark), and an oral formulation of insulin (Nutrinia, Ramat Gan, Israel) [3, 10, 11].

Most approaches for oral insulin administration have focused on structural modifications, absorption and penetration enhancers, complicated carriers (nanoparticles, polymer micelles, liposomes), or enzyme inhibitors. Although these products have marginally improved the oral bioavailability of insulin, they require complicated formulations and excessive bioactive additives, which result in undesirable effects, increased manufacturing costs, and a high risk of drug development. Notably, Banerjee et al. [2] developed an ionic liquid (IL)-based oral formulation of insulin (insulin-CAGE).

They reported an unprecedented improvement in the oral bioavailability of insulin. The oral bioavailability of 5 U/kg IJ insulin-CAGE was found to be 51% higher than that of 2 U/kg subcutaneous injection. Nonetheless, IL preparations have their own drawbacks, such as potential long-term toxicity, negative effects on the GI tract, and low biocompatibility. Hence, there has been increasing interest in drug delivery research to develop oral carriers of insulin showing both high efficacy and safety.

Our recent study reported a technique to encapsulate and “dissolve” water-soluble chemotherapeutic agents into vegetable oil by forming “oil-soluble” reversed lipid nanoparticles (ORLN) [12, 13]. This carrier can either decrease the intestinal hydrolytic degradation of topotecan (TPT) via protection by both a phospholipid (PC) shell and oil medium, or improve the oral absorption of TPT by enhancing the intestinal lymphatic transport.

In the present study, we designed an oral insulin formulation based on the ORLN system, in which amphipathic PC molecules could self-assemble to construct an internal polar pool for insulin molecules, with non-polar tails radiating to the outer oil phase to form ORLN. ORLN-insulin dispersed in medium-chain triglyceride (MCT) was prepared as an oral formulation to evaluate its efficacy and stability both in vitro and in vivo.

Materials and methods

Peptide recombinant human insulin (PHI) was kindly provided as a gift from the Department of Drug synthesis, Beijing Institute of Pharmacology and Toxicology (China). MCT was supplied by Gattefossé (Lyon, France). Soya phosphatidyl choline (LIPOID E80) was purchased from Lipoid GmbH (Ludwigshafen, Germany).

High-performance liquid chromatography (HPLC)-grade acetonitrile and methanol were purchased from Thermo Fisher Scientific (Waltham, MA, USA). Human insulin enzyme-linked immunosorbent assay (ELISA) quantitative kit was purchased from Boster Biological Technology (Pleasanton, CA, USA). Simulated Intestinal Fluid Powder (SIF, pH 6.5) was purchased from Biorelevant (London, UK).

Preparation of ORLN conjugated with insulin

The oral formulations of insulin-conjugated ORLN (ORLN-PHI) were prepared through a two-step method (Fig. 1). First, small empty unilamellar liposomes were obtained by probe sonication as follows: 0.01–0.05 g lipoid S100 was dissolved in 15 mL chloroform, the solvent was evaporated by a rotary evaporator, and the dispersion was obtained by adding 10 mL pure water and shaking vigorously.

The dispersion was sonicated using a probe-type sonicator at 200 W for 20 min and filtered through a 0.2-μm membrane (Millipore, Billerica, MA, USA). The PHI solution was prepared by dissolving 1.0 mg PHI in 10 mL acidic water. Then, a 2-mL mixture of the two solutions described above was added to a 7-mL vial at a ratio of 1:1 (v/v) and lyophilized in a freeze drier for 48 h (FD-1; Beijing SiHuan Technology Company, Beijing, China) to remove all water.

Lyophilization was performed under the following conditions: freezing at − 50 °C for 4 h, primary at − 45 °C to − 10 °C for 20 h, secondary at − 10 °C to 20 °C for 15 h, and maintaining at 20 °C for 9 h. Finally, oral formulations of ORLN-PHI with different PC contents were obtained by dissolving the lyophilized dry cake in 0.5 mL MCT. The resulting formulation contained PHI at a concentration of 0.2 mg/mL.

An external file that holds a picture, illustration, etc.
Object name is 12951_2020_657_Fig1_HTML.jpg
Fig. 1
Preparation and structure of “oil-soluble” reversed lipid nanoparticle (ORLN)-insulin system


Oral administration of insulin must be able to overcome challenges such as the low pH of the GI tract, enzymatic degradation, and barriers including mucus layers and the intestinal epithelium [16]. The requirements for an effective drug carrier include preventing drug release in the stomach, reduced protease degradation, increased infiltration through the mucus layer, and successful permeation across the epithelium.

Various approaches have been applied to design and prepare carriers for the oral delivery of insulin, including polymeric nanoparticles and hydrogels or other functional nanoparticles [17–20]. Most of these strategies have shown advantages in terms of the carriers themselves or been successful in animal experiments. Some nanoparticles are highly stable and prevent the release of drugs in an acidic environment through the modification of pH-sensitive polymers [21].

Other nanoparticles have been designed to target intestinal cells such as goblet cells to directly transport insulin [22]. However, the complexity of the synthesis of polymeric nanoparticles increases the manufacturing costs and restricts their applications in a clinical setting. Furthermore, these nanocarrier-related formulations show poor oral bioavailability.

In this study, the development of oral insulin using ORLN technology represents a significant advancement in insulin administration strategies. In contrast to conventional nanocarriers, liquid oil was used as a dispersing medium in this system and phospholipids were used as the shell material for the nanoparticles.

Amphipathic phospholipid molecules can self-assemble into a regularly arranged internal polar region for hydrophilic molecules, while the non-polar tails radiate to the solvent. As a result, water-soluble proteins were encapsulated and formed a core–shell lipid nanoparticle in oil. The ORLN system combines the advantages of liposomes and lipid nanoparticles and avoids drawbacks such as poor stability and complicated drug-encapsulating processes.

Unlike subcutaneously administered insulin, the effectiveness of ORLN-insulin was shown to be sustained until the end of the study at 17 h, demonstrating its potential for development as a long-acting oral insulin formulation.

The absorption-enhancing effect of ORLN on PHI was probably related to the decrease in enzymatic degradation of PHI in the intestinal tract, as well as the increase in drug transcytosis across the intestinal epithelia. The enhancement of insulin absorption by ORLN was attributed to the formulation of the PC shell and oil medium.

Phospholipids played a dual role in absorption in the ORLN-PHI system, acting as both “helper” and “protector” for transcytosis under enzymatic conditions. Thus, a higher PC content led to increased hypoglycemic efficacy. When PHI was released from the oil phase into the aqueous medium, the molecules likely interacted with several external PC layers and to form vesicle-like structures in the intestinal fluid. This process may have decreased enzymatic degradation and increased the lipophilicity of PHI, thereby promoting absorption through the intestinal tract.

An oil medium, such as MCT, can also work as a “helper” and “protector” for protein absorption because oil barriers can protect insulin from degradation by preventing direct contact with gastric acid or protease. Furthermore, the digestive products of oils, such as fatty acids, can promote oral absorption.

The PC layer increased the hydrophilicity of the When ORLN oil solution mixed with an aqueous medium such as intestinal fluid, the movement of water molecules into the hydrophilic core of ORLN, which is dependent on the PC concentration in the system, can result in the reorganization of the reversed lipid nanoparticles and the formation of vesicles.

Many nanoscale vesicles are known to aggregate to form larger micrometer-scale particles. These larger vesicles will enter the aqueous medium, driven by gravity and gastrointestinal motility, until they reach the surface of the intestinal epithelium. Finally, PC can interact weakly and non-covalently with insulin, increasing its lipophilicity and thereby its ability to cross the epithelium via a transcellular route (Fig. 8).

PC acts as a water-absorbing agent and film material for the vesicles in this process. We investigated the mechanism of ORLN-PHI on the enhancement of oral insulin delivery. Our results showed that the enhancement was related to two effects of ORLN: a protective effect and transcellular enhancement.

The oil barrier prevents the release of insulin into the stomach due to the absence of bile salts, thus avoiding chemical degradation in the acidic stomach environment. The formation of vesicles can decrease the contact between insulin molecules and intestinal fluid, thereby inhibiting enzymatic hydrolysis by proteases. Because PC served as a layer material to construct vesicles, the protective effects of ORLN on insulin were PC concentration-dependent.

An external file that holds a picture, illustration, etc.
Object name is 12951_2020_657_Fig8_HTML.jpg
Fig. 8
Mechanism of ORLN system in improving the intestinal absorption of insulin

The enhancement mechanism of PC was likely due to its weak and non-covalent interactions with insulin, which increased its lipophilicity and consequently its ability to cross the Caco-2 monolayers. PC layers also play a role in cell-membrane fusion with the intestinal epithelium, which is the driving force for transcellular insulin absorption. Moreover, the unchanged TEER value of the cell monolayers throughout the treatment indicated that insulin was transported transcellularly without any detectable alterations in the tight junctions between adjacent cells. The transcellular pathway of oral insulin implies that insulin can be safely transported without disturbing the integrity of the epithelium [23]. PC in ORLN played an important role in the absorption of insulin as a transcytosis “helper.” Thus, a higher PC content led to stronger hypoglycemic efficacy and higher oral bioavailability of the ORLN-insulin formulation. The enhancement mechanism of MCT is likely related to its digestive products, such as fatty acids. This amphipathic substance can play a similar role to that of PC in protein absorption.


  • 1. Kirby CJ. Oil-based formulations for oral delivery of therapeutic peptides. J Liposome Res. 2000;10:391–407. doi: 10.3109/08982100009031106. [CrossRef] [Google Scholar]
  • 2. Banerjee A, Ibsen K, Brown T, Chen R, Agatemor C, Mitragotri S. Ionic liquids for oral insulin delivery. Proc Natl Acad Sci USA. 2018;115:7296–7301. doi: 10.1073/pnas.1722338115. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • 3. Aguirre TAS, Teijeiro-Osorio D, Rosa M, Coulter IS, Alonso MJ, Brayden DJ. Current status of selected oral peptide technologies in advanced preclinical development and in clinical trials. Adv Drug Deliv Rev. 2016;106:223–241. doi: 10.1016/j.addr.2016.02.004. [PubMed] [CrossRef] [Google Scholar]
  • 4. Norbert S, Hans-Dieter J. Peptides: chemistry and biology. New york: Wiley; 2002. p. 101. [Google Scholar]
  • 5. Arbit E, Kidron M. Oral insulin delivery in a physiologic context: review. J Diabetes Sci Technol. 2017;11:825–832. doi: 10.1177/1932296817691303. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • 6. Fonte P, Araújo F, Reis S, Sarmento B. Oral insulin delivery: how far are we? J Diabetes Sci Technol. 2013;7:520–531. doi: 10.1177/193229681300700228. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • 7. Kapitza C, Zijlstra E, Heinemann L, Castelli MC, Riley G, Heise T. Oral insulin: a comparison with subcutaneous regular human insulin in patients with type 2 diabetes. Diabetes Care. 2010;33:1288–1290. doi: 10.2337/dc09-1807. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • 8. Renukuntla J, Vadlapudi AD, Patel A, Boddu SH, Mitra AK. Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm. 2013;447:75–93. doi: 10.1016/j.ijpharm.2013.02.030. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • 9. Rekha MR, Sharma CP. Oral delivery of therapeutic protein/peptide for diabetes–future perspectives. Int J Pharm. 2013;440:48–62. doi: 10.1016/j.ijpharm.2012.03.056. [PubMed] [CrossRef] [Google Scholar]
  • 10. The search results for oral insulin. US National Library of Medicine.
  • 11. Zijlstra E, Heinemann L, Plum-Mörschel L. Oral insulin reloaded: a structured approach. J Diabetes Sci Technol. 2014;8:458–465. doi: 10.1177/1932296814529988. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • 12. Wang T, Shen L, Zhang Z, Li H, Huang R, Zhang Y, et al. A novel core-shell lipid nanoparticle for improving oral administration of water soluble chemotherapeutic agents: inhibited intestinal hydrolysis and enhanced lymphatic absorption. Drug Deliv. 2017;24:1565–1573. doi: 10.1080/10717544.2017.1386730. [PubMed] [CrossRef] [Google Scholar]
  • 13. Shen L, Zhang Z, Wang T, Yang X, Huang R, Quan D. Reversed lipid-based nanoparticles dispersed in oil for malignant tumor treatment via intratumoral injection. Drug Deliv. 2017;24:857–866. doi: 10.1080/10717544.2017.1330373. [PubMed] [CrossRef] [Google Scholar]
  • 14. Gupta V, Doshi N, Mitragotri S. Permeation of insulin, calcitonin and exenatide across Caco-2 monolayers: measurement using a rapid, 3-day system. PLoS ONE. 2013;8:e57136. doi: 10.1371/journal.pone.0057136. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  • 15. Tian Li, Ya-lou Zhang, et al. Study of type 1 diabetes model induced by streptozotocin in the C57 mouse. Progress Modern Biomed. 2014;14:5031–5033. [Google Scholar]
  • 16. Chen MC, Sonaje K, Chen KJ, Sung HW. A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery. Biomaterials. 2011;32:9826–9838. doi: 10.1016/j.biomaterials.2011.08.087. [PubMed] [CrossRef] [Google Scholar]
  • 17. Damgé C, Maincent P, Ubrich N. Oral delivery of insulin associated to polymeric nanoparticles in diabetic rats. J Control Release. 2007;117:163–170. doi: 10.1016/j.jconrel.2006.10.023. [PubMed] [CrossRef] [Google Scholar]
  • 18. Yin L, Ding J, He C, Cui L, Tang C, Yin C. Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. Biomaterials. 2009;30:5691–5700. doi: 10.1016/j.biomaterials.2009.06.055. [PubMed] [CrossRef] [Google Scholar]
  • 19. Chaturvedi K, Ganguly K, Nadagouda MN, Aminabhavi TM. Polymeric hydrogels for oral insulin delivery. J Control Release. 2013;165:129–138. doi: 10.1016/j.jconrel.2012.11.005. [PubMed] [CrossRef] [Google Scholar]
  • 20. Su FY, Lin KJ, Sonaje K, Wey SP, Yen TC, Ho YC, et al. Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery. Biomaterials. 2012;33:2801–2811. doi: 10.1016/j.biomaterials.2011.12.038. [PubMed] [CrossRef] [Google Scholar]
  • 21. Makhlof A, Tozuka Y, Takeuchi H. Design and evaluation of novel pH-sensitive chitosan nanoparticles for oral insulin delivery. Eur J Pharm Sci. 2011;42:445–451. doi: 10.1016/j.ejps.2010.12.007. [PubMed] [CrossRef] [Google Scholar]
  • 22. Jin Y, Song Y, Zhu X, Zhou D, Chen C, Zhang Z, et al. Goblet cell-targeting nanoparticles for oral insulin delivery and the influence of mucus on insulin transport. Biomaterials. 2012;33(1):573–582. [PubMed] [Google Scholar]
  • 23. Malkov D, Angelo R, Wang HZ, Flanders E, Tang H, Gomez-Orellana I. Oral delivery of insulin with the eligen(®) technology: mechanistic studies. Curr Drug Deliv. 2005;2:191–197. doi: 10.2174/1567201053586001. [PubMed] [CrossRef] [Google Scholar]


Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.