Toshinari Asakura

A comparison of the handling and accuracy of syringe and vial versus prefilled insulin pen (FlexPen).

BACKGROUND To determine the preferable method for self-injecting insulin, we compared the handling, safety, and dose accuracy of a conventional disposable syringe and vial with FlexPen (Novo Nordisk A/S, Bagsvaerd, Denmark), a prefilled pen. METHODS Insulin therapy-naive healthcare professionals (HCPs) (n = 30), unfamiliar with insulin delivery, injected 10 U of insulin into a sponge pad using either a syringe and vial or the FlexPen, both with 30-gauge 8-mm needles, on day 1. The following day, they used the alternative method. They evaluated the handling of the two methods on device-specific questionnaires and compared overall preference on a third questionnaire. To evaluate dose accuracy, 30 insulin therapy-experienced HCPs and 20 insulin therapy-naive HCPs were asked to deliver 10 U of insulin using each method, and the amount discharged was weighed. RESULTS FlexPen was rated easier to use and overall more preferable than the syringe and vial by insulin therapy-naive HCPs (P < 0.001). The pen device was more accurate than the syringe and vial when used by experienced HCPs (mean +/- SD dose delivered, 9.91 +/- 0.11 U vs. 9.82 +/- 0.25 U, respectively; P < 0.001) and by insulin therapy-naive HCPs (9.91 +/- 0.12 U vs. 9.74 +/- 0.85 U; P < 0.001). CONCLUSIONS Insulin therapy-naive HCPs found FlexPen easier to handle and preferable to use compared to a conventional syringe and vial. Both insulin therapy-experienced and -naive HCPs were able to deliver insulin significantly more accurately with the FlexPen than with a syringe and vial (P < 0.001).

Dosing accuracy of two insulin pre-filled pens.

ABSTRACT Objective: This study was designed to determine the dose accuracy of two commonly available insulin pre-filled pens for use in diabetes – FlexPen*, † (Novo Nordisk A/S, Bagsværd, Denmark) (FP) and SoloStar† (Sanofi-Aventis, Paris, France) (SS). Research design and methods: Dosing accuracy was tested at 5 U, 10 U and 30 U doses – three previously unused pens of both pre-filled pens were used for each dose. At the 5 U dose each pen was tested 42 times, at the 10 U dose each pen was tested 25 times and at the 30 U dose each pen was tested 9 times. The pre-filled pens were used strictly according to manufacturers’ instructions and measurements were made on a sensitive balance and corrected for the specific density of the insulin formulations used. Specified limits were based on ISO standards (±1 U for the 5 U and 10 U doses and ±1.5 U for the 30 U dose). Results: FP was more accurate for injecting 5 U, 10 U and 30 U doses (absolute mean 4.95 ± 0.19 U, 9.61 ± 0.27 U and 29.70 ± 0.34 U, respectively) than SS (absolute mean 4.86 ± 0.39 U, 9.27 ± 0.52 U and 28.73 ± 0.47 U, respectively). No doses were outside specified limits for 5 U and 30 U with FP and 1.3% of doses were outside these limits at the 10 U dose. For SS; 1.6%, 29.3% and 33.3% of doses were below the pre-specified threshold for the 5 U, 10 U and 30 U doses, respectively. Conclusions: This non-blinded comparison indicates that FP is a more accurate insulin pre-filled pen than SS at three different insulin doses. In this single-user study, FP delivered consistent and accurate doses of insulin but SS had a high frequency of under dosing. No assessment was made of user variability in this study.

Comparison of Intuitiveness, Ease of Use, and Preference in Two Insulin Pens

Background: The intuitiveness, instruction time, and handling of the Levemir® (insulin detemir) FlexPen® and the Lantus® OptiClik® pen (with insulin glargine) were investigated. Methods: This randomized open-label crossover study involved two groups of insulin-device-naive Japanese patients with type 2 diabetes [mean (SD) age 61.9 ± 12.3 years, 57% male]. Patients were evaluated on the ease-of-use of each insulin pen without instruction [intuitiveness group (n = 32)], or with instruction [instruction time group (n = 29)]. Patient preferences for the respective devices were assessed by questionnaire. Results and Discussion: FlexPen required significantly less instruction time (p < .001) and was objectively more intuitive to use (p < .001) than OptiClik. Nevertheless, few patients in the intuitiveness group felt confident injecting either pen prior to instruction (FlexPen, 31%; OptiClik, 16%). No patients in the instruction time group found FlexPen difficult to learn, whereas 45% of patients found OptiClik difficult or very difficult to learn. FlexPen was rated simpler to use (77% versus 12%; p < .001), easier to inject (67% versus 13%; p < .001), and more convenient (71% versus 12%; p < .001) compared with OptiClik. More patients would trust FlexPen to deliver insulin injections (p < .01) and would prefer to use FlexPen compared with OptiClik (82% versus 13%; p < .001). Conclusions: FlexPen was faster to teach, simpler to use, and more trusted by patients compared with OptiClik. Mean injection time was significantly shorter for FlexPen than OptiClik, with or without instruction. This study highlights not only how easy it is for patients to learn to use FlexPen, but also how easily health care providers can teach patients to use it.

Evaluation of injection force of three insulin delivery pens

Objective: Reduced injection force is among the modifications to the Next Generation FlexPen® (NGFP). This force was compared with two other prefilled pens: SoloStar® (SS) and KwikPen® (KP). Research design/methods: The injection force of the pens was measured, with either a BD Micro-Fine™ 31G thin-wall needle, or a NovoFine® 32G Tip extra thin wall needle attached. Pens of each type were tested with both needles, during injection of 20 U insulin, at speeds 3.3, 5 and 8.3 mm/s. Results: NGFP had a significantly (p < 0.05) lower mean injection force than SS or KP, at all injection speeds, with both needles. Injection forces (mean ± s.d.) with NGFP and the BD Micro-Fine™ 31G thin-wall needle were: 8.1 ± 0.7, 10.7 ± 1.4 and 15.6 ± 0.9 N at the three speeds, respectively. For SS, the corresponding values were: 9.2 ± 0.5, 13.3 ± 0.8 and 20.7 ± 2.4 N. For KP they were: 12.5 ± 1.6, 16.9 ± 1.2 and 24.5 ± 2.6 N. Attached to the NovoFine® 32G Tip extra thin wall needle, the NGFP injection forces were: 5.7 ± 0.4, 8.2 ± 0.7 and 12.7 ± 0.5 N; with SS were: 6.7 ± 0.3, 10.4 ± 2.1 and 16.3 ± 1.1 N; and with KP were: 9.1 ± 1.3, 13.1 ± 0.8 and 21.6 ± 2.0 N. The injection force with NGFP was 12 – 25% lower compared with SS and 35 – 41% lower compared with KP. Conclusions: This study shows that NGFP has a significantly lower injection force than SS or KP.

Patient Acceptance and Issues of Education of Two Durable Insulin Pen Devices

BACKGROUND Insulin pen devices offer patients a more convenient, accurate, and discreet mode of insulin delivery than traditional syringes and vials. This open-label, randomized, comparative crossover study assessed patient preference for two reusable pens: NovoPen 4 (Novo Nordisk A/S, Copenhagen, Denmark) and OptiClik (Sanofi-Aventis, Bridgewater NJ). METHODS Thirty-five diabetes patients with no previous experience of pen devices (mean age 56.7 years; range 17-80 years; 57% male) used both pens to deliver a 10 unit saline dose into an injection cushion. Half received guidance according to official instruction manuals, and half were given no instructions. Learning times were also measured. Participants completed a detailed questionnaire to determine their preferences. RESULTS Overall, 32 of 35 participants preferred NovoPen 4 compared with two of 35 for OptiClik (91.4% vs. 5.7% respectively, P<0.001), and one had no preference. NovoPen 4 was significantly favored over OptiClik in almost all questionnaire criteria, including safety (P<0.001), size of pen (P<0.001), appearance (P<0.001), and ease of use (P<0.001). The majority of patients were able to use NovoPen 4 without guidance (94.4%) compared with just over half for for OptiClik (55.6%, P<0.01). Learning time was also significantly faster for NovoPen 4 (62.6 s) than for OptiClik (95.8 s) (P<0.05). CONCLUSIONS Patients learned how to use both pens quickly (under 2 min), but NovoPen 4 was preferred by participants over OptiClik. Patient acceptance of a pen device may support insulin initiation, particularly in type 2 diabetes.

Characterization of Novel Insulin Fibrils That Show Strong Cytotoxicity Under Physiological pH

Amyloid fibrils are β-sheet-rich protein aggregates that are associated with more than 20 diseases. Insulin is known to form amyloid fibrils under a variety of conditions in vitro. Insulin fibrillations have been generally performed under acidic conditions, which are conducive to the formation of fibrils. As insulin is found almost exclusively as a monomer in acidic solutions, insulin fibrillation under acidic conditions is proposed to occur via its monomer. However, insulin fibrils, which cause injection-localized amyloidosis, form under neutral pH conditions in vivo, because both subcutaneous tissue and almost all insulin formulations maintain a neutral pH. In this study, we induced fibrillation under conditions more closely resembling physiological conditions than those used in previous studies with the aim of better understanding the nature of injection-localized amyloidosis in vivo. The results of transmission electron microscopy, structural analyses, and MTT assay show that the fibrils formed under conditions more closely resembling physiological conditions have different properties from the fibrils described to date. The results of this study indicate that fibrils formed under conditions more closely resembling physiological conditions have different properties from insulin fibrils induced under the conditions reported in previous studies.

Comparative Usability Study of the Dulaglutide Single-use Pen versus the Insulin Degludec FlexTouch® among Self-injection-naïve Patients with Type 2 Diabetes Mellitus in Japan

Abstract Objective: This study assessed training time with the dulaglutide single-use pen (SUP) and the insulin degludec disposable prefilled pen (FlexTouch®) in self-injection–naïve patients with type 2 diabetes mellitus (T2DM) in Japan. Methods: This multi-center, open-label, comparative, crossover study measured training time with the dulaglutide SUP vs FlexTouch®. Participants learned how to use both devices in a randomly assigned order. Healthcare providers (HCP) conducted the training. The primary end-point was the time required to train self-injection-naïve T2DM participants to self-inject correctly using each device. Secondary end-points included performance measures, such as success and error rates, patient perceptions related to ease-of-use, and factors associated with training time and performance. Results: Overall, 48 participants were randomized and completed the study. The mean training time to achieve correct administration was significantly shorter with the dulaglutide SUP vs FlexTouch® (7.4 min vs 19.7 min, p < .001). The proportions of participants who successfully completed the mock injection without error were similar for both devices. Ninety-two percent (44/48) of participants reported that the dulaglutide SUP was easier to use than FlexTouch®. Conclusions: In this study, participants required a shorter training time to achieve correct administration with the dulaglutide SUP, and had a higher preference for the dulaglutide SUP, when compared to FlexTouch®. These data suggest that the dulaglutide SUP is easy-to-use, which may decrease the burden on HCPs to train diabetic patients how to administer injection therapy and reduce patient injection hurdles, such as needle fear.

Effects of the calcineurin inhibitors cyclosporine and tacrolimus on bone metabolism in rats

Immunosuppressive therapy is considered as one of the factors inducing to the onset of osteoporosis after organ transplantation. Chronic immunosuppressive therapy after transplantation is required for organ transplant patients, and it is important to prevent the occurrence of osteoporotic fractures to maintain the quality of life in patients. In this study, we examined the effects of cyclosporine and tacrolimus on bone metabolism in rats. Five-week-old male Wistar rats were treated orally with 15 mg/kg cyclosporine or 1.5 mg/kg tacrolimus daily for 4 weeks. Each of cyclosporine and tacrolimus significantly reduced the bone strength of the femoral mid-diaphysis and bone mineral density of the tibia and femur. Bone histomorphometry showed that the administration of both drugs resulted in a decrease in bone volume, number and thickness of trabeculae, and an increase in trabecular separation. Bone formation parameters such as osteoid volume, osteoblast surface, mineralizing surface, mineral apposition rate, and bone formation rate significantly increased in the cyclosporine-treated group. Bone resorption parameters such as eroded surface, osteoclast surface, and osteoclast number significantly increased in both the cyclosporine- and the tacrolimus- treated groups. These results showed that cyclosporine increases both bone formation and bone resorption, leading to a high-turnover bone loss, and that tacrolimus increases bone resorption without affecting bone formation, leading to bone loss.

Comment and reply on: Dosing accuracy of two insulin pre-filled pens

The recent publication by Asakura et al. reports a smallscale laboratory experiment comparing the dosing accuracy of two insulin injection devices (FlexPen [FP], and SoloSTAR* [SS]), suggesting that FP is more accurate than SS. However, there are numerous elements that should be taken into consideration when interpreting the results and the authors’ conclusion. As part of the approval process for introducing an insulin injection device to the market, accurate dose delivery must be demonstrated. This is commonly achieved through studies that show that the device meets the requirements of a technical laboratory standard developed by the International Organization for Standardization (namely DIN EN ISO 11608-1 for pre-filled/disposable insulin pen devices). SS met the ISO requirements for dose accuracy at each dose tested under all conditions. The compliance of sanofi-aventis data with the ISO requirements is documented by the data submitted, reviewed and approved by the relevant regulatory authorities. The publication by Asakura et al., however, makes reference to the respective ISO standard by referring to the tolerance limits (i.e. 1 unit for doses dialled of 0–20 units or 5% for doses of 20 units or more), but neither the design of this laboratory study nor the evaluation of the results completely follow ISO 11608-1. Firstly, ISO 11608-1 requires a minimum of 15 pen devices to be tested in a laboratory setting repeatedly across three specified doses, for 60 single doses at each dose level. In contrast, Asakura et al. used only three pen devices at each dose level. Each pen was tested only for dispensing one specific dose instead of the whole range of doses. Furthermore, Asakura et al. did not reach the required number of 60 single doses for the highest dose chosen by the authors. With the inconsistency in the number of doses, 126 at 5 units, 75 at 10 units and 27 at 30 units, comparing the percentages of inaccurate doses is misleading. No clear rationale was provided for why additional pen devices were not tested, particularly at the 30-unit dose, to ensure equal numbers of doses tested. Secondly, each pen device should be tested repeatedly across the range of doses, to deliver doses at the minimum, middle and maximum. For SS, this translates to doses of 1, 40 and 80 units and for FP, 1, 30 and 60 units. However, in the study by Asakura et al., the accuracy of both pen devices was determined at 5, 10 and 30 units, neglecting the higher doses. Finally, when evaluating the data, all single values were measured by Asakura et al. against the defined limits for dose accuracy individually, whereas ISO 11608-1 does not evaluate the individual measurements, but rather the mean value and the standard deviation. ISO 11608-1 is a standard for design verification purposes and acknowledges the fact that, given the limited number of data points, the accuracy can only be stated with a certain confidence level. Consequently, ISO 11608-1 claims that a defined proportion has to be within the tolerance limits (97.5%) and thereby recognises that individual values may be outside the limits without affecting the overall accuracy of the device. Asakura et al. applied the limits defined in the standard, but did not follow the respective statistical process. The authors refer to a study by Bell et al. to support the suggestion that ‘dose accuracy is better at the higher doses and poorer at the lower insulin doses’. However, in that study, the authors compared the dose accuracy of split-mix versus premixed insulin delivered via vial and syringe by diabetes or healthcare professionals.