Insulin Capsules Research Articles

Fabrication and characterization of AlN-based flexible piezoelectric pressure sensor integrated into an implantable artificial pancreas

This study reports on the fabrication and characterization of an event detection subsystem composed of a flexible piezoelectric pressure sensor and the electronic interface to be integrated into an implantable artificial pancreas (IAP) for diabetic patients. The developed sensor is made of an AlN layer, sandwiched between two Ti electrodes, sputtered on Kapton substrate, with a preferential orientation along c-axis which guarantees the best piezoelectric response. The IAP is made of an intestinal wall-interfaced refilling module, able to dock an ingestible insulin capsule. A linearly actuated needle punches the duodenum tissue and then the PDMS capsule to transfer the insulin to an implanted reservoir. The device is located at the connection of the needle with the linear actuator to reliably detect the occurred punching of the insulin-filled capsule. Finite Element Analysis (FEA) simulations were performed to evaluate the piezoelectric charge generated for increasing loads in the range of interest, applied on both the sensor full-area and footprint area of the Hamilton needle used for the capsule punching. The sensor-interface circuit was simulated to estimate the output voltage that can be obtained in real operating conditions. The characterization results confirmed a high device sensitivity during the punching, in the low forces (0–4 N) and low actuator speed (2–3 mm/s) ranges of interest, meeting the requirement of the research objective. The choice of a piezoelectric pressure sensor is particularly strategic in the medical field due to the request of self-powered implantable devices which do not need any external power source to output a signal and harvest energy from natural sources around the patient.

Multiple Oral Insulin (ORMD-0801) Doses Elicit a Cumulative Effect on Glucose Control in T2DM Patients

Efforts to overcome the narrow therapeutic index of subcutaneously delivered insulin, have propelled the development of orally delivered alternatives. The enteric-coated ORMD-0801 oral insulin capsule has been shown to provide effective glucose control in both type 1 and type 2 diabetes patients. In this single-center, randomized, double-blind, placebo-controlled, three-way crossover study, 31 adult T2DM patients were treated with a placebo capsule during the first three days of three 1-week treatment periods, followed by five days of treatment with an oral placebo (n=31) or a 460 IU insulin capsule, delivered one (qd; n=20), two (bid; n=21) or three (tid; n=20) time per day. Run-in (Days 1-3) vs. treatment (Days 4-8) period continuous glucose monitoring (CGM) data were compared, as were pre- vs. post-treatment insulin and c-peptide levels. Patients were of a mean age of 57.5±7.8, and most were male (61.3%) and Caucasian (80.6%). Mean placebo-adjusted change from baseline in 24-hour glucose (all run-in days vs. all treatment days) ranged from -7.65 mg/dL for qd to -9.91 mg/dL for tid, with a more dramatic change observed in subjects with higher glucose (>190 mg/dL; n=17) at baseline (-12.44 mg/dL (qd) and -18.43 (tid)). Pre- vs. posttreatment and placebo vs. active treatment c-peptide and insulin ratios were similar across all regimens. ORMD-0801 was well tolerated and did not elicit any serious adverse effects. The vast majority of hyperglycemic events were recorded during placebo treatment (n=27), while hypoglycemic events were evenly distributed across treatment groups (≤5/group). Thus, multiple-dose ORMD-0801 regimens safely provide for improved glucose control, which is expected to be enhanced with more extended treatment. Its impact may be of particular benefit to patients uncontrolled by current drug regimens. Disclosure R. Eldor: Consultant; Self; Oramed Pharmaceuticals, Inc.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Medtronic. J. Neutel: None. K.E. Homer: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc..

Glucose-Reducing Effect of the ORMD-0801 Oral Insulin Preparation in Patients with Uncontrolled Type 1 Diabetes: A Pilot Study

The unpredictable behavior of uncontrolled type 1 diabetes often involves frequent swings in blood glucose levels that impact maintenance of a daily routine. An intensified insulin regimen is often unsuccessful, while other therapeutic options, such as amylin analog injections, use of continuous glucose sensors, and islet or pancreas transplantation are of limited clinical use. In efforts to provide patients with a more compliable treatment method, Oramed Pharmaceuticals tested the capacity of its oral insulin capsule (ORMD-0801, 8 mg insulin) in addressing this resistant clinical state. Eight Type I diabetes patients with uncontrolled diabetes (HbA1c: 7.5–10%) were monitored throughout the 15-day study period by means of a blind continuous glucose monitoring device. Baseline patient blood glucose behavior was monitored and recorded over a five-day pretreatment screening period. During the ensuing ten-day treatment phase, patients were asked to conduct themselves as usual and to self-administer an oral insulin capsule three times daily, just prior to meal intake. CGM data sufficient for pharmacodynamics analyses were obtained from 6 of the 8 subjects. Treatment with ORMD-0801 was associated with a significant 24.4% reduction in the frequencies of glucose readings >200 mg/dL (60.1±7.9% pretreatment vs. 45.4±4.9% during ORMD-0801 treatment; p = 0.023) and a significant mean 16.6% decrease in glucose area under the curve (AUC) (66055±5547 mg/dL/24 hours vs. 55060±3068 mg/dL/24 hours, p = 0.023), with a greater decrease during the early evening hours. In conclusion, ORMD-0801 oral insulin capsules in conjunction with subcutaneous insulin injections, well tolerated and effectively reduced glycemia throughout the day.Trial RegistrationClinicaltrials.gov NCT00867594.

Time–Action Profile of an Oral Enteric Insulin Formulation in Healthy Chinese Volunteers

BackgroundInsulin is an essential treatment for both type 1 and 2 diabetes. Among the available routes of insulin administration, oral delivery is the most appealing option. ObjectiveThe purpose of this study was to evaluate the pharmacodynamic and pharmacokinetic profiles of orally administered enteric insulin and compare the time–action of these oral insulin capsules with neutral protamine Hagedorn (NPH) insulin. MethodsThis was a single-center, randomized, 4-period, crossover study. Twelve healthy volunteers (3 per group) received 1 of 3 doses of oral enteric insulin (50, 100, or 200 U) or 1 subcutaneous injection of NPH insulin (6 U) on 4 separate days. After administration, glucose infusion rates and serum insulin concentrations were monitored for 10 hours. ResultsGlucose infusion rates increased after administration of either NPH or oral enteric insulin. The mean times for maximal metabolic effects for 50, 100, and 200 U of oral enteric insulin were 250 (118), 170 (58), and 236 (132) minutes, respectively, compared with 243 (79) minutes for NPH insulin. The onset of action was slower for oral enteric insulin at 50 U (38 [10] minutes), 100 U (41 [18] minutes), and 200 U (65 [58] minutes) compared with NPH insulin (35 [8] minutes). The maximum glucose infusion rates for oral enteric insulin treatment (1.66 [0.50], 1.61 [1.00], and 1.80 [0.60] mg/kg/min for 50, 100, and 200 U, respectively) were lower compared with NPH insulin (2.06 [0.82] mg/kg/min), although these differences were not statistically significant. ConclusionsOral enteric insulin capsules induced significant glucodynamic effects and exhibited a time–action profile similar to that of NPH insulin in these healthy volunteers. No detectable increases in serum insulin concentration were observed in any treatment group. Trial registry number: ChiCTR-TRC-12001872.

AIR Insulin Capsules of Different Dose Strengths May Be Combined to Yield Equivalent Pharmacokinetics and Glucodynamics

In order to assess pharmacokinetic (PK) and glucodynamic (GD) attributes relevant to the end user of an inhaled insulin, this study examined the exposure and GD effect of doses of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) by combining capsules of different strengths in healthy subjects. Fifty-nine healthy, nonsmoking, male or female subjects with normal pulmonary function were enrolled in an open-label, randomized, crossover study. Subjects underwent up to five euglycemic glucose clamp procedures, separated by 5-18 days. The five AIR insulin treatments tested included one 6 unit-equivalent (U-eq) capsule containing 2.6 mg of insulin, three 2 U-eq (0.9 mg) capsules (2.7 mg total), one 10 U-eq (3.9 mg) capsule, one 6 U-eq capsule plus two 2 U-eq capsules (4.4 mg total), and two 10 U-eq capsules (7.8 mg total). Samples for PK and GD assessments were taken up to 10 h post-dose. Based on both PK (area under the curve from time 0 to time of return to baseline and maximum concentration) and GD (total amount of glucose infused and maximum glucose infusion rate) responses, administration of a 6 U-eq capsule was equivalent to three 2 U-eq capsules; 90% confidence intervals for the ratios were contained within the interval (0.8, 1.25). Similarly, both overall exposure and glucodynamic response after administration of a 10 U-eq capsule were comparable to the 6 U-eq plus two 2 U-eq capsule combination. AIR insulin exhibited PK dose proportionality and dose-dependent increases in GD responses over the 2.6-7.8 mg dose range. AIR insulin exhibited dose strength interchangeability and dose proportionality after single-dose administration in healthy subjects.

Rx Report

Rx Report

Effect of Bioadhesive Polymers, Sodium Salicylate, Polyoxyethylene-9-lauryl Ether, and Method of Preparation on the Relative Hypoglycemia Produced by Insulin Enteric-Coated Capsules in Diabetic Beagle Dogs

ABSTRACTThe hypoglycemic effect of oral insulin capsules coated with pH-dependent Eudragit® S100 and containing various absorption promoters was studied in hyperglycemic beagle dogs. The absorption enhancers used were bioadhesive polymers, sodium salicylate, and non-ionic surfactants. A comparative study of the bioadhesive polymers, polycarbophil (PC), hydroxypropyl methylcellulose (HPMC), and carbopol 934 in insulin-coated capsules revealed no significant difference between the insulin capsules containing these polymers, giving relative hypoglycemia (RH) values ranging from 4.3±2.3% to 6.5±5.1%. It was also found that the method of preparation of the mixture of the bioadhesive polymer with insulin either by physical mixing or freeze-drying did not affect the RH values obtained. Sodium salicylate, when used in insulin enteric-coated capsules (50 mg) mixed with insulin as a physical mixture, or prepared by wet granulation using 10% polyvinyl pyrollidone (PVP), or by freeze-drying, produced RH values ranging from 7.3±2.9% to 9.4±3.7%. When sodium salicylate (100 mg) was used with insulin in freeze-dried granules an RH value of 10±2.6% was produced. As the dose of insulin increased from 6 to 9 U/kg, the area under curve (AUC) of the enteric-coated capsules containing 50 mg sodium salicylate increased from 73.2±27.8% to 121.4±102.7% reduction, but the RH did not change significantly. Insulin capsules containing polyoxyethylene-9-lauryl ether (POELE) used in its optimum concentration (2%), found in these experiments, produced RH of 9.5±6.8% when prepared as granules by wetting with a few drops of absolute alcohol in the presence of PC (50 mg). Insulin capsules containing lower (1%) or higher (3%) concentrations of POELE and prepared with PC, 50 mg by wet granulation produced lower RH of about 6%. The enteric-coated oral insulin capsules containing insulin (6 or 9 U/kg) and sodium salicylate (50 mg) as an absorption promoter, together with the bioadhesive polymer polycarbophil (50 mg), and prepared either by wet granulation using ethanol or by freeze-drying, are the best formulations to be used. They achieved a reduction in plasma glucose levels of about 25–30% and RH of about 10%. Also insulin (9 U/kg) capsules containing 2% POELE produced a 28% reduction in plasma glucose levels and RH of 9.6±6.8%.

Promotion of oral insulin absorption in diabetic rabbits using pH-dependent coated capsules containing sodium cholate

The hypoglycemic effect of oral insulin (40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing various doses of sodium cholate (20, 50, 100 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). Sodium cholate (20 and 50 mg/capsule) produced a dose-related enhancement of an insulin-induced decrease in the blood glucose level. Insulin capsules containing sodium cholate (50 mg/capsule) produced a steady reduction of the blood glucose level reaching 69% of the initial values (P < 0.01) by 3 h and 48% (P < 0.001) by 5 h after administration. This capsule produced an AUC0–5h of 125 ± 14.8 mg · hdl with relative hypoglycemia (R.H.) of 25.8% compared with insulin s.c. The capsules containing sodium cholate (100 mg), however, did not significantly (P > 0.05) improve the hypoglycemic effect of insulin more than the smaller dose (50 mg/capsule) producing an AUC and R.H. of 135 ± 12.3 mg · hdl and 27.9%, respectively. The capsule coated with Eudragit S100 and containing insulin mixed with sodium cholate seems to be a promising formulation to overcome the unavailability of oral insulin.

Effective Intestinal Absorption of Insulin in Diabetic Rats Using Enteric Coated Capsules Containing Sodium Salicylate

AbstractThe absorption of insulin manifested as percent reduction of blood glucose was evaluated after placement of capsules containing 4.6 units of the drug and 20 mg of Sodium salicylate as an absorption promoter in the rate stomach. The capsules were coated with either Eudragit L100 or Eudragit 9100 to deliver insulin in different regions of small intestine of the rats as they are pH dependent. The data obtained after administration of the capsules were compared with that after intraperitoneal injection of 1 U of insulin and ALSO after administration of coated capsules containing insulin alone. The administration of insulin capsules containing sodium salicylate result in a significant (p<0.01) increase of the hypoglycemic effect over the 5 h period of the experiments. They produced the same hypoglycemia effect as I.P. injection at 5 h point. The areas under the % blood glucose reduction curves produced were 363.5, 221.7 and 236.5% h for I.P. injection and capsules coated with Eudragit L100 and Eudragit...