DIABETES TECHNOLOGY & THERAPEUTICS Volume 17, Supplement 1, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/dia.2015.1506
ORIGINAL ARTICLE
Insulin Pens and New Ways of Insulin Delivery Lutz Heinemann
Introduction
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earching for clinical studies in which new ways of insulin delivery were studied is frustrating; as a matter of fact, no (!) clinical study with, for example, inhaled insulin or oral insulin was published in the time frame searched (middle of 2013 to middle of 2014). It appears as if alternative routes of insulin administration (ARIA) are also not a hot topic in preclinical research (practically no relevant publications about dermal insulin, nasal insulin, or buccal insulin). Complaining about the gray present, we have hope for a rosy future. Recently, the FDA approved Afrezza, an inhaled insulin developed by MannKind, after several years of development time with several ups and downs. Most probably, the global cooperation with Sanofi is a crucial step to achieve a wider market access. If this pulmonary insulin will become a market success, this might give this whole area of research the push that is desperately needed. Insulin Pens In view of their huge market relevance, it is not a surprise that at least a number of clinical studies with insulin pens were published in the last year. In addition, also some interesting publications about novel needles have been published. In a commentary about insulin pens (1), the barriers contributing to delays in initiating insulin therapy in patients with type 2 diabetes were discussed. Compared with the vial and syringe, insulin pens are more accurate, associated with greater adherence, and preferred by patients because of their convenience and ease of use. These advantages explain why in Europe the vast majority of patients use pens. Most probably due to the higher costs of insulin pens versus vials and syringes, the use of insulin pens within the United States lags far behind that in Europe and Japan. However, recent data indicate that patients in the United States also prefer pens over vial-and-syringe (2). When it comes to microneedles/needle-free insulin delivery systems, no data from clinical studies were published, but some reviews and reports about building up manufacturing capacities for such systems (see www.transdermalspecialties.com). However, some good reviews were published,
indicating what might come to clinical studies soon (3,4). Not much was published about intradermal insulin application with short conventional needles in the last year. Dose accuracy and injection force of different insulin glargine pens Friedrichs A 1, Bohnet J 2, Korger V 3, Adler S 1, Schubert-Zsilavecz M 2,4, Abdel-Tawab M 2 1
LWS Risk Management Consult, Brannenburg, Germany; Central Laboratory of German Pharmacists, Eschborn, Germany; 3Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany; and 4Institute of Pharmaceutical Chemistry, J.W. Goethe University, Frankfurt, Germany 2
J Diabetes Sci Technol 2013; 7: 1346–53
Background Key parameters of insulin pens like dose accuracy and injection force were determined for three pens delivering copies of insulin glargine: Pen Royale (WR) and DispoPen (WD) for Glaritus (Wockhardt) and GanLee Pen (GL) for Basalin (Gan & Lee), compared with pens of the originator, ClikSTAR (CS) and SoloSTAR (SS) for Lantus (Sanofi). Methods Dose accuracy was evaluated based on nonrandomized delivery of low (5 U), mid (30 U), and high (60 U) dosage levels, using the weighing procedure recommended by DIN EN ISO 11608-1:2000. Injection force was measured by dispensing the maximum dose of insulin (60 U for the GL, WR, and WD; 80 U for the SS and CS) at dose speeds of 6 and 10 U/s. Results All pens studied delivered comparable average doses within the limits given by the ISO standards at all dosage levels. One pen (GL) revealed a higher coefficient of variation (CV) at 5 U; two others (WR and WD) had higher CVs at all dosage levels compared with the pen of the originator (CS
Science & Co., Du¨sseldorf, Germany.
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and SS). Injection force was higher for the WR, WD, and GL compared with the CS and SS at both dose speeds. In contrast to the CS and SS with an end-of-content feature, doses exceeding the remaining insulin could be dialed with the WR, GL, and WD and, apparently, dispensed with the WD.
Methods
Conclusions
Results
It is of interest to note that all pens studied fulfilled the dose accuracy requirements defined by ISO standards at all three dosage levels; however, the pens manufactured by Wockhardt/Gan & Lee showed higher dosage variability and injection force compared with those manufactured by Sanofi. Thus, the pens that deliver insulin glargine copies show different performance characteristics compared with the originator.
Both pens revealed excellent dosing accuracy, delivering all doses within the limits set by ISO standards. The average relative deviation of the actual dose from the target dose was + 6.86% and + 3.87% at the minimum, - 0.72% and - 1.01% at the mid, and - 0.68% and - 1.06% at the maximum dose for the SS and FT, respectively. The difference at maximum dose was significant ( p = 0.006) in favor of the SS. The FT showed a maximum flow rate of 15.6 U/s, with 81% of the total dose delivered at an injection speed exceeding 10 U/s.
Comment It is clear that in the next years a number of copies of insulin formulations will come to market also in regulated markets in Europe and the United States. Such ‘‘biosimilar insulins’’ will show similar pharmacokinetic and pharmacodynamic properties to the existing insulins; however, they might differ to a given extent, and we will have to see if such differences are of clinical relevance or not. In addition, such insulins might differ in their immunogenic properties; that is, they might stimulate generations of (neutralizing) insulin antibodies. Another hot topic is the devices that are used to apply such biosimilar insulins. As shown in this interesting study, practically relevant differences exist between the pens manufactured by companies that are working on biosimilar insulin in comparison to the originator pens. Another question is, who is liable in case cartridges with a biosimilar insulin are used in a pen manufactured by the originator (assuming that the cartridges fit into this pen)? One can foresee a number of tricky questions coming along with the market introduction of, for example, a number of ‘‘different’’ insulin glargines in the next years.
Thirty new pens from one batch of each pen type were used to test dosing accuracy at minimum (1 U), mid (40 U), and maximum dose (80 U). Insulin flow was determined with 20 FT pens ejecting 80 U three times per pen using a mass flow meter.
Conclusions Both pens showed excellent dosing accuracy at all tested dosage levels. The maximum injection speed of the FT was higher than the usual range of 6–10 U/s assumed for a smooth and painless injection. Comment As already mentioned in previous years, evaluations of pens (and other devices) performed by an institute that is paid by a manufacturer of one of the pens tested have a high risk of bias. Ideally, such studies would be performed by an independent institute. In view of the amount of money spent by the healthcare insurances on such devices, it is somewhat surprising that they do not invest more into such evaluations. It would be truly of interest to know if a lower or higher flow rate is associated with a different ‘‘perception’’ of the insulin injection (see below). This required adequately designed and performed blinded studies. It is of interest to read the analysis publication for this article, putting some of the data reported by Bohnet et al. in a different perspective (5). Which accuracy, or better, which differences in the accuracy with which a given insulin dose is delivered are of clinical relevance? Most probably, this question can only be answered with having the needs of different patient groups in mind; for example, for children that apply only 3 or 4 U the dosing accuracy if of higher relevance than injection 100 or 150 U in an insulin-resistant subject. They also address interpen variability; it would be of interest to know more about this; for example, which range of accuracy has to be expected.
Dosing accuracy and insulin flow rate characteristics of a new disposable insulin pen, FlexTouch, compared with SoloSTAR Bohnet J 1, Schmitz M 2, Kamlot S 2, Abdel-Tawab M 1 1
Central Laboratory of German Pharmacists, Eschborn, Germany; and 2Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany J Diabetes Sci Technol 2013; 7: 1021–26
Background The introduction of a prefilled insulin pen with a springloaded mechanism (FlexTouch; FT; Novo Nordisk; insulin aspart) has created more insulin pen options. In this study the dosing accuracy of the FT was compared with that of the manually operated SoloSTAR (SS; Sanofi; insulin glulisine). The flow rate of insulin delivery with the FT was also evaluated.
Impact of injection speed and volume on perceived pain during subcutaneous injections into the abdomen and thigh: a single-center, randomized controlled trial Heise T1, Nosek L1, Dellweg S1, Zijlstra E 1, Præstmark KA 2, Kildegaard J 2, Nielsen G 3, Sparre T 3 Profil, Neuss, Germany; 2Novo Nordisk A/S, Ma˚løv, Denmark; and 3Novo Nordisk A/S, Søborg, Denmark
1
Diabetes Obesity Metab 2014; 16: 971–6
INSULIN PENS AND NEW WAYS OF INSULIN DELIVERY Background Aim of this study was to assess pain associated with s.c. injection into the abdomen and thigh of various combinations of injection speeds and volumes. Methods Eighty-two adults with type 1 or type 2 diabetes participated in this single-center, one-visit, double-blinded, randomized controlled trial. Participants received 17 subcutaneous injections (12 in abdomen, 5 in thigh) of saline at different injection speeds (150, 300, and 450 lL/s), with different volumes (400, 800, 1200, and 1600 lL), and two needle insertions without any injection. Pain was evaluated on a 100 mm visual analog scale (VAS). Results Injection speed had no impact on injection pain ( p = 0.833). Injection of larger volumes caused significantly more pain (VAS least square mean differences 1600 vs. 400 lL, p < 0.0001; 1600 vs. 800 lL, p < 0.0001; 1200 vs. 400 lL, p = 0.025; 1200 vs. 800 lL, p = 0.027). Significantly more pain occurred in cases of injections in the thigh versus the abdomen ( p < 0.0001). Conclusions Injection speed had no effect on injection pain, whereas higher injection volumes caused more pain. These findings have implications for the development of new pens. Comment Evaluation of medical devices should be performed in an adequate manner to be able to draw sound conclusions. This double-blind study is a good example of how a clinical–experimental study can provide clinically relevant information. Interestingly, some participants in this study reported pain (including unacceptable pain) for needle insertions alone ( = no fluid was injected), indicating that needle insertions per se can cause pain. It is of note that the injected volume is of higher importance for the pain noted than the injection speed of the fluid, and this clearly votes for usage of higher concentrated insulins. Insulin pen needles: effects of extra-thin wall needle technology on preference, confidence, and other patient ratings Aronson R 1, Gibney MA 2, Oza K 2, Be´rube´ J 2, Kassler-Taub K 2, Hirsch L 2 1
LMC Diabetes & Endocrinology, Toronto, Ontario, Canada; and 2BD (Becton, Dickinson and Company), Franklin Lakes, NJ Clin Ther 2013; 35: 923–33
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preference and a number of related parameters. Patients with diabetes injected insulin with three different pens, the KwikPenTM (Eli Lilly and Company, Indianapolis, IN), SoloSTAR (Sanofi, Bridgewater, NJ), and FlexPen (Novo Nordisk A/S, Bagsvaerd, Denmark). Methods Quantitative tests of XTW and comparable PNs with the three insulin pens were performed for: thumb force, flow rate, and time to deliver medication. An RCT was then conducted in patients aged 35–80 years with type 1 or type 2 diabetes who injected insulin by pen for ‡ 2 months, with at least 1 daily dose ‡ 10 U. Patients who used 4–8-mm-long PNs were randomly assigned to use their current PN or an XTW PN at home for *1 week and the other PN the second week. They completed visual analog scales and direct questions at the end of period 2. Results XTW PNs had significantly better performance for each studied PN characteristic (thumb force, flow, and time to deliver medication) for all pens combined and each individual pen brand (all, p £ 0.05). Of 216 patients randomized to study groups (80, SoloSTAR; 77, FlexPen; 59, KwikPen), 209 completed both periods; 198 were evaluable. Nearly 99% used a single PN: 8 mm, 49.5%; 5 mm, 24.1%; 6 mm, 14.4%; and 4 mm, 12.0%. Patients rated the XTW PNs (mean [95% CI]) as preferable by a mean of 31.9 mm (27.2–36.6) on the visual analog scale, p < 0.001. XTW PNs required less thumb force and less time to inject the dose, and were rated as providing greater confidence in full-dose delivery by 28.4 mm (23.7–33.2), 21.7 mm (17.0–26.4), and 24.4 mm (19.7–29.1), respectively; all, p < 0.001. Skin leakage and insulin dripping from the needle tip were rated as less frequent with the XTW PNs ( p < 0.05). Conclusions Needles with thinner walls were preferred overall, rated as requiring less time and less thumb force to inject, and providing greater confidence in completing a full dose compared with usual PNs. Comment It is impressive to learn how much technology is required to be able to manufacture needles with a thin wall without running into the risk of having needles that kink easily. Such needles enable application of sufficient amounts of volume in an acceptable time without having the need for too much pressure and injection speed of the fluid (see above). The data presented in this study clearly document that the development of needles has come a long way. We have seen a considerable evolution of needles of the last decades, resulting in massively reduced pain of the insulin injection.
Background Needles are essential for insulin injections using pens. The characteristics of pen needles (PNs) affect patients’ injection perception. The aim of this study was to evaluate the impact of an extra-thin-wall (XTW) PN versus usual PNs on patient
Biological contamination of insulin pens in a hospital setting Herdman ML1, Larck C 2, Schliesser SH 3, Jelic TM 4
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Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, University of Charleston, Charleston, WV; 2Edwards Comprehensive Cancer Center, Huntington, WV; 3School of Pharmacy, University of Charleston, and Charleston Area Medical Center (CAMC), Charleston, WV; and 4Department of Pathology and Laboratory, Charleston Area Medical Center (CAMC), Charleston, WV Am J Health Syst Pharm 2013; 70: 1244–48
Background In a hospital setting, it was studied if biological contamination of insulin pens takes place. Methods In a prospective study, conducted at two hospitals within a multihospital system, examined 125 insulin pens that had been returned to the inpatient pharmacies after patient discharge and were refrigerated for up to 48 hours before laboratory testing. Insulin was removed from the pens and examined microscopically for the presence of nucleated cells and red blood cells (RBCs). Positive samples were examined by a pathologist to determine the cell types present. Results Seven (5.6%) of the 125 pens tested positive for cells or hemoglobin. Microscopic examination revealed six positive samples containing a total of nine cells, including macrophages, squamous cells, and an RBC. The sample containing the RBC was not the same sample that tested positive for hemoglobin. Based on findings of intact cells and hemoglobin, the potential exists for transmission of infectious agents from patient to patient if a single pen cartridge is used to administer insulin to multiple patients, even if a new needle is used for each individual. Conclusion Examination of 125 insulin pens used in hospitals revealed hemoglobin in 1 pen and at least 1 cell in another 6 pens. Comment I have to confess that I have no clue about how often the same pen is used with hopefully new needles in hospitals in different countries. So, is this a relevant risk or not? Another question is if the detection of hemoglobin in 1 of 125 pens represents a high or a small number. In view of other reports hinting in the same direction, it appears as if sharing insulin pens is associated with a certain risk (6). Inhaled Insulin The waiting game is over and inhaled insulin has won! I’m pretty sure that the FDA itself had a more negative view on this pulmonary insulin and that the positive vote of the Advisory Committee was a surprise for them. The prescribing information (35 pages) contain a number of statements about the decline in lung function observed with this inhaled insulin, the risk of lung cancer, that smokers should not use it, and so on, that reflect concerns of the regulatory body. The
HEINEMANN need to assess pulmonary function at baseline, after the first 6 months of therapy and annually thereafter might have an impact on the patient’s interest in using pulmonary insulin, especially when this is associated with additional costs. Having Afrezza as the second inhaled insulin on the market (after the approval and withdrawal of Exubera) is an important step. We have to congratulate Al Mann for his sturdiness and willingness to invest a lot of his own money in this development. We will have to see how smart MannKind and Sanofi will promote this inhaled insulin and how the market success will be, which will also depend on the price of the product. I believe that they can learn a lot from the mistakes Pfizer made with their market approach. It will be crucial to convince diabetologists/practitioners and patients to test this insulin and to evaluate if their individual prandial insulin requirements can be covered more appropriately with this ultra-fast acting insulin. They will also have to address safety concerns dating back to Exubera adequately. I believe that it is important that MannKind will have to institute a risk mitigation plan to ensure patient safety in the long run. One clear advantage of Afrezza is the small size of their inhaler in comparison to that of Exubera. In view of my own history with this development, we performed and published a number of clinical–experimental studies with Technosphere insulin some 10 years ago (7). It is worth noting that the patent of Afrezza dates back to 1992. I have to say that I’m happy to see that at least one inhaled insulin product will be on the market in the future. The high insulin absorption rates of Afrezza, which clearly differentiate this inhaled insulin from Exubera and others, support patients with diabetes to optimize their prandial insulin therapy (8). This is why I regard Afrezza as a good extension of our armamentarium for diabetes therapy. I also believe that certain patient groups like obese subjects might benefit a lot from a more rapid insulin absorption before a meal; however, the number of respective studies is small. The availability of an inhaled insulin might also be of help to overcome the ‘‘psychological insulin resistance,’’ which is an obstacle to initiate insulin treatment in patients with type 2 diabetes (9). No data from a clinical study with Afrezza were published in the last year; however, the FDA is requiring the following postmarketing studies:
a clinical trial in pediatric patients; a clinical trial to evaluate the potential risk of pulmonary malignancy (also assessing cardiovascular risk and long-term pulmonary function); and two glucose-clamp trials, one to characterize dose–response and one to characterize within-subject variability. The clamp studies will also be of help to see how rapid the absorption and action of the marketed inhaled insulin formulation (along with the inhaler) is in comparison to subcutaneously injected rapid-acting insulin analogs and how consistent the data are with prior studies. It appears as if the FDA does not perceive Afrezza as an ‘‘ultra-rapid-acting’’ insulin that is faster than current rapid-acting analogs; this is why this term did not make it into the label. It will be of interest to see how the payers perceive the advantages of Afrezza; currently, it is not clear when and if Afrezza will come to the European market. Having Sanofi as a strong commercial partner will be a big help for MannKind on the different markets.
INSULIN PENS AND NEW WAYS OF INSULIN DELIVERY It is worth noting that in the last year the results of a clinical study were announced with a novel inhaled insulin that is in clinical development by Dance Pharma (www.dancebiopharm.com). They regard ‘‘Adagio’’ as a second-generation inhaled insulin product that could resolve problems inherent in the first-generation inhaled insulin products. The liquid formulation of human insulin is dispensed through a small, silent, handheld electronic aerosol device intended to deliver the patient’s individualized dose of insulin in one to three breaths at mealtime. The liquid insulin formulation—instead of a dry powder—shall have advantages when it comes to manufacturing costs, cough, and ease of use. Oral Insulin It appears as if none of all the attempts made to develop an oral insulin (OI) have led to a major breakthrough; that is, the obstacles remain the same, such as low permeability of large molecules, lack of lipophilicity, and inactivation or rapid enzymatic degradation in the gastrointestinal tract (10). All OIs developed that far showed an extremely low bioavailability; that is, large amounts of insulin have to be applied to induce a blood glucose lowering effect. Also this year, a number of publications about OI were published in pharmaceutical journals, demonstrating how nicely the given development works in rats. The last sentence is always: ‘‘XYZ is a promising candidate for oral insulin delivery.’’ However, it appears as if practically none of these (also none of the numerous articles published in previous years) made it into clinical development. We recently published a critical overview about the known OI developments (11). It is somewhat disappointing to see how small the number of OI developments is that have made in into later phases of clinical development. It appears as if Novo Nordisk is the only one large insulin manufacturing company that is intensively working on the development of an OI. Interestingly enough, they switched their interest from a prandial OI formulation to a long-acting OI one. However, Novo is not reporting much about their activities. We will have to see how much progress will be made in the next year. Miscellaneous Each year some studies are published that do not fit into one of the above categories but that are clearly interesting for insulin treatment in general, even if no data from clinical studies have been published that far. For example, it was interesting to learn from a press release that glucoseresponsive insulin development by Merck is moving into phase 1. L-490 is an insulin–oligosaccharide conjugate (an insulin molecule attached to a small chain of carbohydrates). The oligosaccharide component binds to the lectin receptor (a carbohydrate-binding protein), preventing L-490’s insulin portion from binding with the insulin receptor to lower glucose levels. When glycemia is high, the glucose blocks the lectin receptor so that L-490 cannot bind to it and its insulin side instead binds to the insulin receptor, lowering glucose levels. In a steady-state study in dogs, the glucose infusion rate (GIR) required to keep blood glucose levels in range (90– 120 mg/dL) following the injection of L-490 was lower than that for Lilly’s Humulin, so long as the baseline glucose level was in range. This indicates that when the dogs were euglycemic, L-490 did not work to lower their blood glucose
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level as much as Humulin. Clearly, each of these attempts to develop a ‘‘smart’’ insulin generates a long list of questions and we will have to see if and when one of these will get market approval in regulated markets. Participatory surveillance of diabetes device safety: a social media-based complement to traditional FDA reporting Mandl KD 1–3, McNabb M 4, Marks N 5, Weitzman ER 1,3,6, Kelemen S1, Eggleston EM 7,8, Quinn M 3,9 1
Children’s Hospital Informatics Program at Harvard-MIT Health Sciences and Technology, and 2Division of Emergency Medicine, Boston Children’s Hospital, Boston, MA; 3 Department of Pediatrics, Center for Biomedical Informatics, Harvard Medical School, Boston, MA; 4Department of International Health, Boston University School of Public Health, Boston, MA; 5U.S. Food and Drug Administration, Silver Spring, MD; 6Division of Adolescent Medicine, Boston Children’s Hospital, Boston, MA; 7Department of Population Medicine, Harvard Pilgrim HealthCare Institute, Harvard Medical School, Boston, MA; 8Division of Endocrinology, Brigham and Women’s Hospital, Boston, MA; and 9Division of Endocrinology, Boston Children’s Hospital, Boston, MA J Am Med Inform Assoc 2014; 21: 687–91
Background Malfunctions or poor usability of medical products measuring blood glucose or delivering insulin are reportable to the FDA. The majority (99.9%) of such reports are submitted by the manufacturers. Online social networks might act as a complementary source to FDA reporting of device-related adverse events (AE). Methods Participatory surveillance of members of a nonprofit online social network, TuDiabetes.org, from October 2011 to September 2012. Subjects were volunteers from a group within TuDiabetes, actively engaged online in participatory surveillance. They used the free TuAnalyze app to report clinical information. Network members were polled about blood glucose monitors, CGM systems, and insulin pumps and insulin pens. Results Seventy-five of 549 participants reported device-related AE, nearly half (48%) requiring intervention from another person to manage the event. Only three (4%) of these AE were reported by participants to the FDA. All TuAnalyze reports contained outcome information compared with 22% of reports to the FDA. Hypoglycemia and hyperglycemia were experienced by 48% and 49% of participants, respectively. Conclusions Members of an online community readily engaged in participatory surveillance. Engagement of distributed communities in social networks is a viable complementary approach to traditional public health surveillance to report AE related to medical devices.
S-52 Comment This article shed some light on an important topic: How good are our reporting systems with which we believe we can detect issues of medical devices? Probably such a complementary approach to current FDA reporting systems for detecting AE should be implemented to make sure that we detect issues more rapidly and completely. To involve the patients, consumers, and caregivers more directly might be crucial to improve healthcare product quality and patient-centered factors at an early stage.
HEINEMANN
3. 4. 5.
Author Disclosure Statement
6.
L.H. is a consultant for a number of diagnostic and pharmaceutic companies developing novel options for diabetes therapy. He is also a member of a number of advisory boards for different companies. He is a partner of Profil Institut fu¨r Stoffwechselforschung, Neuss, Germany and Profil Institut for Clinical Research, San Diego, CA, USA.
7. 8. 9.
References 1. Cuddihy RM, Borgman SK. Considerations for diabetes: treatment with insulin pen devices. Am J Ther 2013; 20: 694–702. 2. Ahmann A, et al. Comparing patient preferences and healthcare provider recommendations with the pen versus
10. 11.
vial-and-syringe insulin delivery in patients with type 2 diabetes. Diab Tech Ther 2014; 16: 76–83. Tuan-Mahmood TM, et al. Micro needles for intradermal and transdermal drug delivery. Eur J Pharm Sci 2013; 50: 623–37. Hultstro¨m M, et al. Intradermal Insulin Delivery: A Promising Future for Diabetes Management. JDST 2014; 8: 453–57. Yeager HK, Ignaut DA. Analysis and perspective of dosing accuracy and insulin flow rate characteristics of a new disposable insulin pen, FlexTouch, compared with SoloSTAR. J Diabetes Sci Technol 2013; 7: 1027–29. Schaefer MK, et al. Sharing insulin pens: are you putting patients at risk? Diabetes Care 2013; 36: e188–89. Steiner S, et al. Technosphere/Insulin—proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endo Diab 2002; 110: 17–21. Heinemann L, Heise T. Current status of the development of inhaled insulin. Brit J Diab Vasc Dis 2004; 4: 295–301. Petrak F, et al. Psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin. Diab Tech Ther 2013; 15: 702–10. Navgire SD, et al. Recent patents on oral insulin delivery. Recent Pat Drug Deliv Formul 2014. [Epub ahead of print] Zijlstra E, et al. Oral Insulin Reloaded: A Structured Approach. JDST 2014; 8: 458–65.
ORIGINAL ARTICLE
Insulin Pens and New Ways of Insulin Delivery Lutz Heinemann
Introduction
S
earching for clinical studies in which new ways of insulin delivery were studied is frustrating; as a matter of fact, no (!) clinical study with, for example, inhaled insulin or oral insulin was published in the time frame searched (middle of 2013 to middle of 2014). It appears as if alternative routes of insulin administration (ARIA) are also not a hot topic in preclinical research (practically no relevant publications about dermal insulin, nasal insulin, or buccal insulin). Complaining about the gray present, we have hope for a rosy future. Recently, the FDA approved Afrezza, an inhaled insulin developed by MannKind, after several years of development time with several ups and downs. Most probably, the global cooperation with Sanofi is a crucial step to achieve a wider market access. If this pulmonary insulin will become a market success, this might give this whole area of research the push that is desperately needed. Insulin Pens In view of their huge market relevance, it is not a surprise that at least a number of clinical studies with insulin pens were published in the last year. In addition, also some interesting publications about novel needles have been published. In a commentary about insulin pens (1), the barriers contributing to delays in initiating insulin therapy in patients with type 2 diabetes were discussed. Compared with the vial and syringe, insulin pens are more accurate, associated with greater adherence, and preferred by patients because of their convenience and ease of use. These advantages explain why in Europe the vast majority of patients use pens. Most probably due to the higher costs of insulin pens versus vials and syringes, the use of insulin pens within the United States lags far behind that in Europe and Japan. However, recent data indicate that patients in the United States also prefer pens over vial-and-syringe (2). When it comes to microneedles/needle-free insulin delivery systems, no data from clinical studies were published, but some reviews and reports about building up manufacturing capacities for such systems (see www.transdermalspecialties.com). However, some good reviews were published,
indicating what might come to clinical studies soon (3,4). Not much was published about intradermal insulin application with short conventional needles in the last year. Dose accuracy and injection force of different insulin glargine pens Friedrichs A 1, Bohnet J 2, Korger V 3, Adler S 1, Schubert-Zsilavecz M 2,4, Abdel-Tawab M 2 1
LWS Risk Management Consult, Brannenburg, Germany; Central Laboratory of German Pharmacists, Eschborn, Germany; 3Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany; and 4Institute of Pharmaceutical Chemistry, J.W. Goethe University, Frankfurt, Germany 2
J Diabetes Sci Technol 2013; 7: 1346–53
Background Key parameters of insulin pens like dose accuracy and injection force were determined for three pens delivering copies of insulin glargine: Pen Royale (WR) and DispoPen (WD) for Glaritus (Wockhardt) and GanLee Pen (GL) for Basalin (Gan & Lee), compared with pens of the originator, ClikSTAR (CS) and SoloSTAR (SS) for Lantus (Sanofi). Methods Dose accuracy was evaluated based on nonrandomized delivery of low (5 U), mid (30 U), and high (60 U) dosage levels, using the weighing procedure recommended by DIN EN ISO 11608-1:2000. Injection force was measured by dispensing the maximum dose of insulin (60 U for the GL, WR, and WD; 80 U for the SS and CS) at dose speeds of 6 and 10 U/s. Results All pens studied delivered comparable average doses within the limits given by the ISO standards at all dosage levels. One pen (GL) revealed a higher coefficient of variation (CV) at 5 U; two others (WR and WD) had higher CVs at all dosage levels compared with the pen of the originator (CS
Science & Co., Du¨sseldorf, Germany.
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and SS). Injection force was higher for the WR, WD, and GL compared with the CS and SS at both dose speeds. In contrast to the CS and SS with an end-of-content feature, doses exceeding the remaining insulin could be dialed with the WR, GL, and WD and, apparently, dispensed with the WD.
Methods
Conclusions
Results
It is of interest to note that all pens studied fulfilled the dose accuracy requirements defined by ISO standards at all three dosage levels; however, the pens manufactured by Wockhardt/Gan & Lee showed higher dosage variability and injection force compared with those manufactured by Sanofi. Thus, the pens that deliver insulin glargine copies show different performance characteristics compared with the originator.
Both pens revealed excellent dosing accuracy, delivering all doses within the limits set by ISO standards. The average relative deviation of the actual dose from the target dose was + 6.86% and + 3.87% at the minimum, - 0.72% and - 1.01% at the mid, and - 0.68% and - 1.06% at the maximum dose for the SS and FT, respectively. The difference at maximum dose was significant ( p = 0.006) in favor of the SS. The FT showed a maximum flow rate of 15.6 U/s, with 81% of the total dose delivered at an injection speed exceeding 10 U/s.
Comment It is clear that in the next years a number of copies of insulin formulations will come to market also in regulated markets in Europe and the United States. Such ‘‘biosimilar insulins’’ will show similar pharmacokinetic and pharmacodynamic properties to the existing insulins; however, they might differ to a given extent, and we will have to see if such differences are of clinical relevance or not. In addition, such insulins might differ in their immunogenic properties; that is, they might stimulate generations of (neutralizing) insulin antibodies. Another hot topic is the devices that are used to apply such biosimilar insulins. As shown in this interesting study, practically relevant differences exist between the pens manufactured by companies that are working on biosimilar insulin in comparison to the originator pens. Another question is, who is liable in case cartridges with a biosimilar insulin are used in a pen manufactured by the originator (assuming that the cartridges fit into this pen)? One can foresee a number of tricky questions coming along with the market introduction of, for example, a number of ‘‘different’’ insulin glargines in the next years.
Thirty new pens from one batch of each pen type were used to test dosing accuracy at minimum (1 U), mid (40 U), and maximum dose (80 U). Insulin flow was determined with 20 FT pens ejecting 80 U three times per pen using a mass flow meter.
Conclusions Both pens showed excellent dosing accuracy at all tested dosage levels. The maximum injection speed of the FT was higher than the usual range of 6–10 U/s assumed for a smooth and painless injection. Comment As already mentioned in previous years, evaluations of pens (and other devices) performed by an institute that is paid by a manufacturer of one of the pens tested have a high risk of bias. Ideally, such studies would be performed by an independent institute. In view of the amount of money spent by the healthcare insurances on such devices, it is somewhat surprising that they do not invest more into such evaluations. It would be truly of interest to know if a lower or higher flow rate is associated with a different ‘‘perception’’ of the insulin injection (see below). This required adequately designed and performed blinded studies. It is of interest to read the analysis publication for this article, putting some of the data reported by Bohnet et al. in a different perspective (5). Which accuracy, or better, which differences in the accuracy with which a given insulin dose is delivered are of clinical relevance? Most probably, this question can only be answered with having the needs of different patient groups in mind; for example, for children that apply only 3 or 4 U the dosing accuracy if of higher relevance than injection 100 or 150 U in an insulin-resistant subject. They also address interpen variability; it would be of interest to know more about this; for example, which range of accuracy has to be expected.
Dosing accuracy and insulin flow rate characteristics of a new disposable insulin pen, FlexTouch, compared with SoloSTAR Bohnet J 1, Schmitz M 2, Kamlot S 2, Abdel-Tawab M 1 1
Central Laboratory of German Pharmacists, Eschborn, Germany; and 2Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany J Diabetes Sci Technol 2013; 7: 1021–26
Background The introduction of a prefilled insulin pen with a springloaded mechanism (FlexTouch; FT; Novo Nordisk; insulin aspart) has created more insulin pen options. In this study the dosing accuracy of the FT was compared with that of the manually operated SoloSTAR (SS; Sanofi; insulin glulisine). The flow rate of insulin delivery with the FT was also evaluated.
Impact of injection speed and volume on perceived pain during subcutaneous injections into the abdomen and thigh: a single-center, randomized controlled trial Heise T1, Nosek L1, Dellweg S1, Zijlstra E 1, Præstmark KA 2, Kildegaard J 2, Nielsen G 3, Sparre T 3 Profil, Neuss, Germany; 2Novo Nordisk A/S, Ma˚løv, Denmark; and 3Novo Nordisk A/S, Søborg, Denmark
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Diabetes Obesity Metab 2014; 16: 971–6
INSULIN PENS AND NEW WAYS OF INSULIN DELIVERY Background Aim of this study was to assess pain associated with s.c. injection into the abdomen and thigh of various combinations of injection speeds and volumes. Methods Eighty-two adults with type 1 or type 2 diabetes participated in this single-center, one-visit, double-blinded, randomized controlled trial. Participants received 17 subcutaneous injections (12 in abdomen, 5 in thigh) of saline at different injection speeds (150, 300, and 450 lL/s), with different volumes (400, 800, 1200, and 1600 lL), and two needle insertions without any injection. Pain was evaluated on a 100 mm visual analog scale (VAS). Results Injection speed had no impact on injection pain ( p = 0.833). Injection of larger volumes caused significantly more pain (VAS least square mean differences 1600 vs. 400 lL, p < 0.0001; 1600 vs. 800 lL, p < 0.0001; 1200 vs. 400 lL, p = 0.025; 1200 vs. 800 lL, p = 0.027). Significantly more pain occurred in cases of injections in the thigh versus the abdomen ( p < 0.0001). Conclusions Injection speed had no effect on injection pain, whereas higher injection volumes caused more pain. These findings have implications for the development of new pens. Comment Evaluation of medical devices should be performed in an adequate manner to be able to draw sound conclusions. This double-blind study is a good example of how a clinical–experimental study can provide clinically relevant information. Interestingly, some participants in this study reported pain (including unacceptable pain) for needle insertions alone ( = no fluid was injected), indicating that needle insertions per se can cause pain. It is of note that the injected volume is of higher importance for the pain noted than the injection speed of the fluid, and this clearly votes for usage of higher concentrated insulins. Insulin pen needles: effects of extra-thin wall needle technology on preference, confidence, and other patient ratings Aronson R 1, Gibney MA 2, Oza K 2, Be´rube´ J 2, Kassler-Taub K 2, Hirsch L 2 1
LMC Diabetes & Endocrinology, Toronto, Ontario, Canada; and 2BD (Becton, Dickinson and Company), Franklin Lakes, NJ Clin Ther 2013; 35: 923–33
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preference and a number of related parameters. Patients with diabetes injected insulin with three different pens, the KwikPenTM (Eli Lilly and Company, Indianapolis, IN), SoloSTAR (Sanofi, Bridgewater, NJ), and FlexPen (Novo Nordisk A/S, Bagsvaerd, Denmark). Methods Quantitative tests of XTW and comparable PNs with the three insulin pens were performed for: thumb force, flow rate, and time to deliver medication. An RCT was then conducted in patients aged 35–80 years with type 1 or type 2 diabetes who injected insulin by pen for ‡ 2 months, with at least 1 daily dose ‡ 10 U. Patients who used 4–8-mm-long PNs were randomly assigned to use their current PN or an XTW PN at home for *1 week and the other PN the second week. They completed visual analog scales and direct questions at the end of period 2. Results XTW PNs had significantly better performance for each studied PN characteristic (thumb force, flow, and time to deliver medication) for all pens combined and each individual pen brand (all, p £ 0.05). Of 216 patients randomized to study groups (80, SoloSTAR; 77, FlexPen; 59, KwikPen), 209 completed both periods; 198 were evaluable. Nearly 99% used a single PN: 8 mm, 49.5%; 5 mm, 24.1%; 6 mm, 14.4%; and 4 mm, 12.0%. Patients rated the XTW PNs (mean [95% CI]) as preferable by a mean of 31.9 mm (27.2–36.6) on the visual analog scale, p < 0.001. XTW PNs required less thumb force and less time to inject the dose, and were rated as providing greater confidence in full-dose delivery by 28.4 mm (23.7–33.2), 21.7 mm (17.0–26.4), and 24.4 mm (19.7–29.1), respectively; all, p < 0.001. Skin leakage and insulin dripping from the needle tip were rated as less frequent with the XTW PNs ( p < 0.05). Conclusions Needles with thinner walls were preferred overall, rated as requiring less time and less thumb force to inject, and providing greater confidence in completing a full dose compared with usual PNs. Comment It is impressive to learn how much technology is required to be able to manufacture needles with a thin wall without running into the risk of having needles that kink easily. Such needles enable application of sufficient amounts of volume in an acceptable time without having the need for too much pressure and injection speed of the fluid (see above). The data presented in this study clearly document that the development of needles has come a long way. We have seen a considerable evolution of needles of the last decades, resulting in massively reduced pain of the insulin injection.
Background Needles are essential for insulin injections using pens. The characteristics of pen needles (PNs) affect patients’ injection perception. The aim of this study was to evaluate the impact of an extra-thin-wall (XTW) PN versus usual PNs on patient
Biological contamination of insulin pens in a hospital setting Herdman ML1, Larck C 2, Schliesser SH 3, Jelic TM 4
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Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, University of Charleston, Charleston, WV; 2Edwards Comprehensive Cancer Center, Huntington, WV; 3School of Pharmacy, University of Charleston, and Charleston Area Medical Center (CAMC), Charleston, WV; and 4Department of Pathology and Laboratory, Charleston Area Medical Center (CAMC), Charleston, WV Am J Health Syst Pharm 2013; 70: 1244–48
Background In a hospital setting, it was studied if biological contamination of insulin pens takes place. Methods In a prospective study, conducted at two hospitals within a multihospital system, examined 125 insulin pens that had been returned to the inpatient pharmacies after patient discharge and were refrigerated for up to 48 hours before laboratory testing. Insulin was removed from the pens and examined microscopically for the presence of nucleated cells and red blood cells (RBCs). Positive samples were examined by a pathologist to determine the cell types present. Results Seven (5.6%) of the 125 pens tested positive for cells or hemoglobin. Microscopic examination revealed six positive samples containing a total of nine cells, including macrophages, squamous cells, and an RBC. The sample containing the RBC was not the same sample that tested positive for hemoglobin. Based on findings of intact cells and hemoglobin, the potential exists for transmission of infectious agents from patient to patient if a single pen cartridge is used to administer insulin to multiple patients, even if a new needle is used for each individual. Conclusion Examination of 125 insulin pens used in hospitals revealed hemoglobin in 1 pen and at least 1 cell in another 6 pens. Comment I have to confess that I have no clue about how often the same pen is used with hopefully new needles in hospitals in different countries. So, is this a relevant risk or not? Another question is if the detection of hemoglobin in 1 of 125 pens represents a high or a small number. In view of other reports hinting in the same direction, it appears as if sharing insulin pens is associated with a certain risk (6). Inhaled Insulin The waiting game is over and inhaled insulin has won! I’m pretty sure that the FDA itself had a more negative view on this pulmonary insulin and that the positive vote of the Advisory Committee was a surprise for them. The prescribing information (35 pages) contain a number of statements about the decline in lung function observed with this inhaled insulin, the risk of lung cancer, that smokers should not use it, and so on, that reflect concerns of the regulatory body. The
HEINEMANN need to assess pulmonary function at baseline, after the first 6 months of therapy and annually thereafter might have an impact on the patient’s interest in using pulmonary insulin, especially when this is associated with additional costs. Having Afrezza as the second inhaled insulin on the market (after the approval and withdrawal of Exubera) is an important step. We have to congratulate Al Mann for his sturdiness and willingness to invest a lot of his own money in this development. We will have to see how smart MannKind and Sanofi will promote this inhaled insulin and how the market success will be, which will also depend on the price of the product. I believe that they can learn a lot from the mistakes Pfizer made with their market approach. It will be crucial to convince diabetologists/practitioners and patients to test this insulin and to evaluate if their individual prandial insulin requirements can be covered more appropriately with this ultra-fast acting insulin. They will also have to address safety concerns dating back to Exubera adequately. I believe that it is important that MannKind will have to institute a risk mitigation plan to ensure patient safety in the long run. One clear advantage of Afrezza is the small size of their inhaler in comparison to that of Exubera. In view of my own history with this development, we performed and published a number of clinical–experimental studies with Technosphere insulin some 10 years ago (7). It is worth noting that the patent of Afrezza dates back to 1992. I have to say that I’m happy to see that at least one inhaled insulin product will be on the market in the future. The high insulin absorption rates of Afrezza, which clearly differentiate this inhaled insulin from Exubera and others, support patients with diabetes to optimize their prandial insulin therapy (8). This is why I regard Afrezza as a good extension of our armamentarium for diabetes therapy. I also believe that certain patient groups like obese subjects might benefit a lot from a more rapid insulin absorption before a meal; however, the number of respective studies is small. The availability of an inhaled insulin might also be of help to overcome the ‘‘psychological insulin resistance,’’ which is an obstacle to initiate insulin treatment in patients with type 2 diabetes (9). No data from a clinical study with Afrezza were published in the last year; however, the FDA is requiring the following postmarketing studies:
a clinical trial in pediatric patients; a clinical trial to evaluate the potential risk of pulmonary malignancy (also assessing cardiovascular risk and long-term pulmonary function); and two glucose-clamp trials, one to characterize dose–response and one to characterize within-subject variability. The clamp studies will also be of help to see how rapid the absorption and action of the marketed inhaled insulin formulation (along with the inhaler) is in comparison to subcutaneously injected rapid-acting insulin analogs and how consistent the data are with prior studies. It appears as if the FDA does not perceive Afrezza as an ‘‘ultra-rapid-acting’’ insulin that is faster than current rapid-acting analogs; this is why this term did not make it into the label. It will be of interest to see how the payers perceive the advantages of Afrezza; currently, it is not clear when and if Afrezza will come to the European market. Having Sanofi as a strong commercial partner will be a big help for MannKind on the different markets.
INSULIN PENS AND NEW WAYS OF INSULIN DELIVERY It is worth noting that in the last year the results of a clinical study were announced with a novel inhaled insulin that is in clinical development by Dance Pharma (www.dancebiopharm.com). They regard ‘‘Adagio’’ as a second-generation inhaled insulin product that could resolve problems inherent in the first-generation inhaled insulin products. The liquid formulation of human insulin is dispensed through a small, silent, handheld electronic aerosol device intended to deliver the patient’s individualized dose of insulin in one to three breaths at mealtime. The liquid insulin formulation—instead of a dry powder—shall have advantages when it comes to manufacturing costs, cough, and ease of use. Oral Insulin It appears as if none of all the attempts made to develop an oral insulin (OI) have led to a major breakthrough; that is, the obstacles remain the same, such as low permeability of large molecules, lack of lipophilicity, and inactivation or rapid enzymatic degradation in the gastrointestinal tract (10). All OIs developed that far showed an extremely low bioavailability; that is, large amounts of insulin have to be applied to induce a blood glucose lowering effect. Also this year, a number of publications about OI were published in pharmaceutical journals, demonstrating how nicely the given development works in rats. The last sentence is always: ‘‘XYZ is a promising candidate for oral insulin delivery.’’ However, it appears as if practically none of these (also none of the numerous articles published in previous years) made it into clinical development. We recently published a critical overview about the known OI developments (11). It is somewhat disappointing to see how small the number of OI developments is that have made in into later phases of clinical development. It appears as if Novo Nordisk is the only one large insulin manufacturing company that is intensively working on the development of an OI. Interestingly enough, they switched their interest from a prandial OI formulation to a long-acting OI one. However, Novo is not reporting much about their activities. We will have to see how much progress will be made in the next year. Miscellaneous Each year some studies are published that do not fit into one of the above categories but that are clearly interesting for insulin treatment in general, even if no data from clinical studies have been published that far. For example, it was interesting to learn from a press release that glucoseresponsive insulin development by Merck is moving into phase 1. L-490 is an insulin–oligosaccharide conjugate (an insulin molecule attached to a small chain of carbohydrates). The oligosaccharide component binds to the lectin receptor (a carbohydrate-binding protein), preventing L-490’s insulin portion from binding with the insulin receptor to lower glucose levels. When glycemia is high, the glucose blocks the lectin receptor so that L-490 cannot bind to it and its insulin side instead binds to the insulin receptor, lowering glucose levels. In a steady-state study in dogs, the glucose infusion rate (GIR) required to keep blood glucose levels in range (90– 120 mg/dL) following the injection of L-490 was lower than that for Lilly’s Humulin, so long as the baseline glucose level was in range. This indicates that when the dogs were euglycemic, L-490 did not work to lower their blood glucose
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level as much as Humulin. Clearly, each of these attempts to develop a ‘‘smart’’ insulin generates a long list of questions and we will have to see if and when one of these will get market approval in regulated markets. Participatory surveillance of diabetes device safety: a social media-based complement to traditional FDA reporting Mandl KD 1–3, McNabb M 4, Marks N 5, Weitzman ER 1,3,6, Kelemen S1, Eggleston EM 7,8, Quinn M 3,9 1
Children’s Hospital Informatics Program at Harvard-MIT Health Sciences and Technology, and 2Division of Emergency Medicine, Boston Children’s Hospital, Boston, MA; 3 Department of Pediatrics, Center for Biomedical Informatics, Harvard Medical School, Boston, MA; 4Department of International Health, Boston University School of Public Health, Boston, MA; 5U.S. Food and Drug Administration, Silver Spring, MD; 6Division of Adolescent Medicine, Boston Children’s Hospital, Boston, MA; 7Department of Population Medicine, Harvard Pilgrim HealthCare Institute, Harvard Medical School, Boston, MA; 8Division of Endocrinology, Brigham and Women’s Hospital, Boston, MA; and 9Division of Endocrinology, Boston Children’s Hospital, Boston, MA J Am Med Inform Assoc 2014; 21: 687–91
Background Malfunctions or poor usability of medical products measuring blood glucose or delivering insulin are reportable to the FDA. The majority (99.9%) of such reports are submitted by the manufacturers. Online social networks might act as a complementary source to FDA reporting of device-related adverse events (AE). Methods Participatory surveillance of members of a nonprofit online social network, TuDiabetes.org, from October 2011 to September 2012. Subjects were volunteers from a group within TuDiabetes, actively engaged online in participatory surveillance. They used the free TuAnalyze app to report clinical information. Network members were polled about blood glucose monitors, CGM systems, and insulin pumps and insulin pens. Results Seventy-five of 549 participants reported device-related AE, nearly half (48%) requiring intervention from another person to manage the event. Only three (4%) of these AE were reported by participants to the FDA. All TuAnalyze reports contained outcome information compared with 22% of reports to the FDA. Hypoglycemia and hyperglycemia were experienced by 48% and 49% of participants, respectively. Conclusions Members of an online community readily engaged in participatory surveillance. Engagement of distributed communities in social networks is a viable complementary approach to traditional public health surveillance to report AE related to medical devices.
S-52 Comment This article shed some light on an important topic: How good are our reporting systems with which we believe we can detect issues of medical devices? Probably such a complementary approach to current FDA reporting systems for detecting AE should be implemented to make sure that we detect issues more rapidly and completely. To involve the patients, consumers, and caregivers more directly might be crucial to improve healthcare product quality and patient-centered factors at an early stage.
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3. 4. 5.
Author Disclosure Statement
6.
L.H. is a consultant for a number of diagnostic and pharmaceutic companies developing novel options for diabetes therapy. He is also a member of a number of advisory boards for different companies. He is a partner of Profil Institut fu¨r Stoffwechselforschung, Neuss, Germany and Profil Institut for Clinical Research, San Diego, CA, USA.
7. 8. 9.
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vial-and-syringe insulin delivery in patients with type 2 diabetes. Diab Tech Ther 2014; 16: 76–83. Tuan-Mahmood TM, et al. Micro needles for intradermal and transdermal drug delivery. Eur J Pharm Sci 2013; 50: 623–37. Hultstro¨m M, et al. Intradermal Insulin Delivery: A Promising Future for Diabetes Management. JDST 2014; 8: 453–57. Yeager HK, Ignaut DA. Analysis and perspective of dosing accuracy and insulin flow rate characteristics of a new disposable insulin pen, FlexTouch, compared with SoloSTAR. J Diabetes Sci Technol 2013; 7: 1027–29. Schaefer MK, et al. Sharing insulin pens: are you putting patients at risk? Diabetes Care 2013; 36: e188–89. Steiner S, et al. Technosphere/Insulin—proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endo Diab 2002; 110: 17–21. Heinemann L, Heise T. Current status of the development of inhaled insulin. Brit J Diab Vasc Dis 2004; 4: 295–301. Petrak F, et al. Psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin. Diab Tech Ther 2013; 15: 702–10. Navgire SD, et al. Recent patents on oral insulin delivery. Recent Pat Drug Deliv Formul 2014. [Epub ahead of print] Zijlstra E, et al. Oral Insulin Reloaded: A Structured Approach. JDST 2014; 8: 458–65.
