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This is a white paper on the evolution of needle free insulin administration and its current state of research and patenting activities.

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  2. 2. Table of Contents 1. Diabetes –Complexity of the Disorder.............................................................. 1 2. Traditional Insulin Delivery Procedures ........................................................... 2 3. Non-Invasive Techniques for Insulin Delivery ................................................. 3 4. Oral Delivery ....................................................................................................... 4 5. Pulmonary Delivery............................................................................................ 6 6. Patenting Trend in Non-Invasive Technologies............................................... 7 7. Overall Market Trend in Insulin Delivery Systems........................................... 8 8. Key Players in the Industry................................................................................ 9 9. Conclusion........................................................................................................ 11
  3. 3. Page # 1 1. Diabetes –Complexity of the Disorder With the changing life style, diabetes has become a common health disorder among people of all ages, which was a predominantly elderly disease. Onset of diabetes results in various complications that cause excess morbidity/mortality, resulting in loss of independence and deteriorated quality of life. Diabetes can turn out acute if not treated properly on time. If left unattended, it can cause serious complications to virtually every system of the body. Diabetes is a key risk factor for coronary artery diseases, cerebral vascular diseases, peripheral vascular diseases and heart failure. It can also lead to other critical complications such as blindness (due to diabetic retinopathy), end-stage renal disease (due to diabetic nephropathy), lower extremity amputations (resulting from diabetic neuropathy), decreased ability to fight infection and impotence or sexual dysfunction. There are various types of diabetes suffered by people across the world; a large percentage is affected by diabetes mellitus, of which 5-10% suffers from Type-1 diabetes while 90% are affected with Type-2 diabetes. As per the estimates of World Health Organization (WHO), 135 million people worldwide were diabetics in 1995, and the number increased to 171 million in 2000, which is equivalent to 2.8% of world’s population. Further, WHO expects the number of people with diabetes disorder to increase to around 366 million by 2030. In countries such as Jordan, UAE and Saudi Arabia, diabetes is widespread with over 9% of the total population suffering from diabetics. As per a survey on dependency of insulin administration, there were about 12.8 million of Type-1 diabetic patients with greater dependency on insulin intake in 2000. In addition, 11.1 million patients also require the administration of insulin for regularizing blood sugar level, thereby making the insulin dependents to 23.9 million.
  4. 4. Page # 2 2. Traditional Insulin Delivery Procedures Since its discovery in 1921, insulin has become a key remedy for diabetes, with its ability to improve users’ metabolism and several other body systems, and thus has become indispensable in the management of diabetes mellitus. Traditionally (over 80 years), insulin was administered via subcutaneous injections. It is used as a first-line agent in Type-1 diabetes and in Type-2 diabetes if appropriate metabolic control could not be achieved through oral anti-hyperglycemic agents along with ideal diet and physical exercise. People with diabetes may have to take more than 60,000 insulin injections during their lifetime. For proper glycemic control in Type-1 diabetes, more than two insulin injections per day are required, while this method is painful. But, non-compliance would mandate the patient to be on multiple dose injections of four times a day. However, patients with hypoglycemic episodes, who should be on multi-dose injections of insulin, avoid the use injections due to pain and associated issues. In a recent survey of insulin-treated patients affected with Type-1 or Type-2 diabetes, 13% of respondents avoided injections due to anxiety, and 42% refused to increase their number of injections. Approximately 45% of patients with hypoglycemic episodes avoided injections and were extremely troubled by the idea of giving themselves multiple injections. Such invasive, intensive technique urges alternative, pain-free methods for administering insulin. It is predicted that when non-invasive insulin delivery technology becomes available, 2.5% of the total diabetic population will use it, with projected rapid increase by time. With this demand increasing, the ultimate goal of future research would focus on to eliminate the delivery of insulin exogenously and revive the ability of patients to produce and use their own insulin. As the major drawback of these forms of the insulin therapy is the invasive nature, this report focuses on painless non- invasive or non-injectable modes of insulin delivery that are being explored to make the medication pain- free in the future.
  5. 5. Page # 3 3. Non-Invasive Techniques for Insulin Delivery Several new approaches for administering insulin have been adopted to decrease the suffering of the diabetic patients, including the use of supersonic injector, infusion pump, sharp needles and pens. While some of them could ease the pain encountered by the diabetic patients, they could not offer complete convenience. Even though the researches are aimed at eliminating the need to deliver insulin exogenously and regaining patients’ ability to produce and use own insulin, new concepts are currently explored to deliver insulin using non-invasive administration routes, including oral, pulmonary, nasal, ocular, rectal, vaginal and transdermal routes. Among these non-invasive delivery routes, oral and pulmonary routes are considered to be the most convenient and preferred by patients affected with Type- 1 or Type-2 diabetes mellitus. Analysis of insulin pipeline by drug delivery technology 3 2 1 1 1 1 Oral Pulmonary Subcutanoues injection Delivery technolgy No.Ofproductsin development Phase II Phase III Registration
  6. 6. Page # 4 4. Oral Delivery On practical grounds, oral insulin administration, where uptake occurs either in the gastrointestinal tract or the buccal mucosa, is a very desirable approach as it offers specific advantages in terms convenience and thus, has the potential to greatly improve patient compliance. However, administration of insulin via the gastrointestinal tract has numerous barriers to overcome before it becomes a clinical reality. Oral insulin provides low bioavailability (i.e. ≤0.5%), as insulin molecules tend to be too large yet hydrophilic, hence can easily cross mucosa. Insulin molecules may undergo extensive enzymatic and chemical degradation within the enzymatic barrier of the gastrointestinal tract mucosa. In an effort to overcome these anatomical and physiological barriers, the use of protease inhibitors (to limit degradation) and absorption enhancers has been evaluated. The process of enclosing insulin within microspheres, thereby protecting it against hydrolization or enzymatic degradation, has also been proposed. Various formulations investigated for oral-buccal routes are Pluronic F-127 gel, transferosomes, pelleted nanoparticles, tablets, sponges, pills, and sprays. Advantages of Insulin Delivery through Oral-Buccal Route:  Oral insulin via the gastrointestinal tract would more closely mirror the enterohepatic transport of endogenous insulin  Avoids presystemic metabolism of insulin  Avoids exposure of acid labile insulin to the destructive environment of stomach  Offers low enzymatic activity  Provides improved patient compliance due to elimination of pain incurred while using injections The most promising oral insulin to date is hexyl-insulin-monoconjugate-2 (HIM2) by Nobex Corporation, native recombinant insulin with a small polyethylene glycol 7-hexyl group attached to the position B29 amino acid lysine. Novo Nordisk had initiated its first phase 1 trial with oral insulin analogue (NN1952) on December 7, 2009. Furthermore, it uses the GIPET ® formulation technology from Merrion Pharmaceuticals to facilitate insulin absorption from the gut. In November 2008, Merrion entered into a development and license agreement to develop and commercialise oral formulations of Novo Nordisk's proprietary insulin analogues.
  7. 7. Page # 5 Biodel Inc., a Connecticut-based biopharmaceutical company, has developed VIAtab, an oral formulation of insulin designed to be administered sublingually. This therapy uses a tablet that dissolves in minutes when placed under the tongue. In Phase I study, VIAtab delivered insulin to the blood stream quickly and resembled the first-phase insulin release spike found in healthy individuals. The company claims that oral therapy would be more convenient than currently available injectable therapies, and they expect the convenience to result in increased insulin usage among the currently underserved early-stage patients with Type-2 diabetes, thus helping to create better long-term outcomes for that patient population.
  8. 8. Page # 6 5. Pulmonary Delivery Unlike the other non-invasive routes, the physiological and anatomical barriers do not hinder the feasibility of pulmonary delivery of insulin, given the favourable anatomy of the lung. Specifically, the lung is characterized by millions of highly vascularised alveoli where drug absorption takes place and has an extensive surface area (approximately 80 m 2 ) that enables rapid drug absorption. Further absorption of insulin is aided by the thin-walled alveoli with intercellular gaps that make the alveoli more permeable to large proteins, compared to other mucosal beds. Inhaled insulin was first commercially launched in 2005 in the United Kingdom. In 2006, the U.S. Food and Drug Administration approved the use of Exubera, the first commercial-marketed inhalable insulin. Exubera was developed by Pfizer and Aventis, in collaboration with Nektar Therapeutics (formerly Inhale Therapeutics), a company specializing in finding optimal delivery solutions for oral, injectable and pulmonary drug administration. Exubera is a rapid-acting, fine dry-powder insulin developed using Nektar Therapeutics’ proprietary inhalation technology. Several other insulin inhalers are under research to improve their compatibility and to ramp their usage in the global market. Functional Merits in Delivering Insulin via Pulmonary Route  Quicker insulin uptake across the pulmonary mucosa, even without absorption enhancers  Better predictability of the blood glucose response, even though the bioavailability in pulmonary delivery is relatively low (between 20 and 25%) compared to subcutaneous insulin  Rapid onset of action of inhaled insulin and maximal metabolic response  In addition to needless administration, rapid entry of the medication into the bloodstream than the traditional method  Time for reaching maximum insulin concentration and glucose-lowering effect is similar to that of subcutaneous short-acting insulin analogues. Thus, inhaled insulin is potentially suitable for delivering meal-related insulin requirements. The possibility has been tested in several recently published, randomized clinical studies. Further studies, both in vitro and clinical trials, are necessary for a deeper understanding of the cause for the low bioavailability of inhaled insulin and accordingly guide the development of pharmaceutical formulations.
  9. 9. Page # 7 6. Patenting Trend in Non-Invasive Technologies An IP analysis on the patenting trend since 2003 to present has shown 15 patent applications claiming the technology of ‘insulin delivery with a use of pharmaceutical formulation via oral route’. Of the total, Emisphere Technologies INC and Biocon Limited have filed 5 and 2 patents, respectively, pertaining to the technology. Interestingly, three patent applications have been published in the same technology in India between 2004 and 2005. Novo Nordisk AS, a key player in the stream, has filed a single patent application claiming the intake of insulin through pharmaceutical formulation that can be delivered via oral or pulmonary route. Over the last decade, a total of 23 patent applications have been recorded pertaining to ‘insulin delivery through pulmonary route of administration’. Of the total, nine patent grants claim the use of pharmaceutical formulation for insulin delivery via pulmonary route, and the remaining 14 patent applications have been granted for ‘device for inhaling insulin composition via pulmonary route’. Oriel Therapeutics INC, Novo Nordisk AS, Roche Diagnostics GMBH, Mannkind Corporation, Aradigm Corporation and Baxter Healthcare are the key players with their patenting activities concerning this new non-invasive technique for insulin delivery. In terms of patenting trend on this technology across the geographies, the U.S.A. has recorded the maximum number of patent applications. Geography-wise patenting trend in the non-invasive insulin therapy Technology Trend Across Geographies 2222 16 9 16 9 1 11 1 2 2 1 3 3 2 1 2 1 1 1 Pharmacuetical formulation Inhaler Device Pulmonary Oral Buccal DeliveryMechanismAdministrationRoute WO US KR JP IN EP CN
  10. 10. Page # 8 7. Overall Market Trend in Insulin Delivery Systems Insulin delivery systems are growing in the market, primarily due to changing consumer preferences towards convenient and painless blood glucose testing methodologies. A research report entitled "Insulin Delivery Systems Market Forecast to 2014" by RNCOS has revealed that a huge global diabetic population and their rising demands are driving growth in the overall insulin delivery systems market. Countries across the world have very high rates of diabetes, and the number has been found to be ever increasing. China has the highest number of people affected with diabetes, with around 90 million diabetic patients in 2011, and the figure is expected to reach around 129.7 million by 2030. India has the second highest number of people affected with diabetes; in 2011, around 61 million Indians had diabetes, and an enormous increase in the number is expected by 2030. Apart from traditional methods of delivering insulin through syringes, pens, pumps and jet injectors, the global market has witnessed rapid displacement towards alternate non-invasive insulin delivery systems such as insulin tablets, insulin pills, sponges, insulin inhalers, insulin sprays and insulin patches. Amongst these, insulin delivery through oral and pulmonary routes, with highly promising developments, form the fastest growing segment in the insulin delivery devices market. Currently, modern insulin accounts for more than 76% of the global insulin market. According to Global Data’s new report, ‘Insulin delivery devices - global pipeline analysis, opportunity assessment and market forecasts to 2016’, the global insulin delivery devices market is expected to grow at a compound annual growth rate (CAGR) of 6.8% between 2009 and 2016, reaching $10.8 billion in 2016. 2009 2016 0 2 4 6 8 10 12 Revenue($billions) Global Insulin Delivery Devices Market, Revenue ($ billions), 2009-2016 CAGR 6.8 %
  11. 11. Page # 9 8. Key Players in the Industry The global insulin delivery devices market is dominated by Novo Nordisk with 18% of total market share, followed by Eli Lilly and Company and Medtronic with 16 and 13% market share, respectively. The top three players collectively accounted for 47% of the total market value in 2009. Novo Nordisk is the market leader in the insulin pens market, with Flexpen and Novopen as their major products. For Eli Lilly and Company, the Humalog pen and Humulin pen are their major revenue generators. Medtronic, with a 13% share, has a significant presence in the overall insulin delivery devices market and is the leader in the insulin pumps market, with MiniMed Paradigm as its best-selling product. The other significant players in the market include Becton, Dickinson and Company (11%), sanofi-aventis (10%) and Roche (6%). Global insulin delivery devices market, Key players Shares (%) Novo Nordisk, 18% Eli Lilly and Company, 16% Medtronic, 13% Becton, Dickinson and Company, 11% Sanofi-Aventis, 10% Others, 26% F.Hoffmann-Le Roche, 6% Anticipating the future growth, the pharmaceutical giants are investing in active R&D on improving the compatibility of non-invasive insulin delivery systems to increase their market share.
  12. 12. Page # 10 Recently developed and marketed formulations for non-invasive insulin delivery Route of Administration Trade name / insulin Product Company/Developer & Researcher Technology Status Oral Eligen™ Emisphere Technology, Inc. Oral capsule using non- acylated Amino acids as carriers Phase II Macrulin™ Cortecs International / Provalis PLC Macrosol RM W/O Microemulsion technology Phase II AI-401 AutoImmune, Inc. / Eli Lilly Oral formulation of recombinant human insulin Phase II Buccal Oral-lyn™ Generex Biotechnology Corp. Mixed micellar solution Market Available Nasal Nasulin™ Bentley Pharmaceutical, Inc. New Physiological absorption enhancer Phase II QDose™ Vectura, Ltd. / MicroDose Technologies Inc. Dry powder Phase I ChiSys™ West Pharmaceutical Services Chitosan-based system Phase I Pulmonary Exubera® Nectar Therapeutics, Inc. / Pfizer / Sanofi- aventis SA Human insulin (rDNA origin) inhalation powder Market Available AERx® iDMS Aradigm Corp. / Novo Nordisk A/S A Liquid aerosol Phase III HIIP® Alkermes Inc. / Eli Lilly AIR ® technology Phase III Technosphere® PDC / MannKind Corp. Encapsulated microsphere Phase III Acrodose® AeroGen, Inc. / Nektar Therapeutics, Inc. Liquid aerosol Phase IIa Spiros® Dura Pharmaceuticals,Inc. / Elan Corp. Dry powder Phase II Insulin inhaler Kos Pharmaceuticals, Inc. / Abbott Lab. Crystalline insulin Phase IIa MicroDose DPI® MicroDose technologies, Inc. / Novartis Dry powder Phase I ProMaxx® Epic therapeutics, Inc. / Baxter Healthcare Corp. Insulin microsphere Phase I Transdermal Passport™ Altea Therapeutics Microporation technique Phase I Transfers ulin® IDEA AG Transferosome Phase I U- Strip™ Encapsulation System, Inc. Iontophoresis / sonophoresis Phase II Macroflux® Alza Corp Passive transdermal / electrontransport systems Market Available
  13. 13. Page # 11 9. Conclusion An increasingly large number of people worldwide are being reported with clinical and preclinical diabetes mellitus. Since the evolution of the non-invasive technology for delivery of insulin, it has poised to change the statue for treatment of both Type-1 and Type-2 diabetes mellitus with a lot of progress being made in the techniques. Various researches have been done to find an alternative insulin delivery via novel formulations and innovative devices. Of the various delivery routes, insulin administration via pulmonary route has received much clinical significance due to the availability of novel devices. The transdermal and oral routes are also becoming common, and considerable researches have been done to augment the formulations and techniques on the whole. The other delivery routes are also claiming their share of attention from researchers as they too promise to be an alternate to the traditional methods. However, the alternative delivery systems have their own set of merits and demerits, which need to be circumvented to make the alternative insulin delivery system a reality. Given the increased focus, the new millennium promises a revolutionary change in the delivery of insulin with improved efficacy, giving the much-awaited relief to those billions of sufferers who are reliant on subcutaneous administration.
  14. 14. Page # 12 Referred URLs: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792528/ http://www.rsc.org/chemistryworld/2012/11/hydrogel-deliver-insulin-through-nose http://www.worldpublicunion.org/2013-03-27-NEWS-Study-shows-insulin-injections-doubles- risk-of-death-in-Type-II-diabetics.html http://www.diabetes.co.uk/insulin/Diabetes-and-insulin-delivery-devices.html http://blog.jdrf.org.au/2012/12/07/promising-study-tests-revolutionary-new-way-to-take-insulin/ http://www.ncbi.nlm.nih.gov/pubmed/7587918 http://www.ncbi.nlm.nih.gov/pubmed/17373639 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792528/ - CIT19