Insulin precipitation in artificial infusion devices

Summary Precipitation of insulin is a problem with mechanical insulin infusion devices. Therefore conditions affecting insulin precipitation have been studied in a recirculating system using a peristaltic pump. Acetate buffer favoured precipitation and a pH of 2, 3 or 8 resulted in no less (and often more) precipitation than a pH of 7 using either acetate or phosphate buffer. However, no precipitation occurred in a phosphate buffered neutral preparation after ten days of pumping through tubing pretreated with EDTA. In comparison at pH 7, using acetate buffer with untreated tubing, more than 95% of insulin was precipitated in ten days. A heavy metal-insulin association appears to be a major factor in the precipitation. However, some formation of insulin fibrils is probable as the precipitate is autocatalytic and partially acid insoluble. Phosphate buffered highly purified porcine insulin is suitable for relatively prolonged infusion if metal ion contamination of the delivery system is minimised.     

Insulin aggregation in artificial delivery systems

Conclusions Abrupt changes in flow path, motion, elevated temperatures, metal ion contamination, impure insulin formulations, CO₂ diffusion, pH drop, dissimilar metal pump components, salt concentration, inappropriate diluents, elevated temperatures, refrigeration temperatures, processing, insulin heterogeneity, and buffering systems have been implicated to a greater or lesser extent in the plugging of insulin delivery devices. Before the rate at which insulin loses its biological activity in delivery systems can be assessed it is obvious that anti-aggregating diluents must be developed and subjected to long-term testing both in vitro and in vivo. Until such stable homogenous formulations are available the knowledge presented in this article will serve to decrease, but not eliminate, the problem of insulin aggregation in delivery systems. Further experiments are in progress and preliminary results [41] provide evidence that the problems cited are not without resolution. In this regard serum apparently contains factor(s) that promote the dissolution of insulin and prevent the formation of peptide aggregates in dilute solutions [41]. Many laboratories are now working to resolve the problem of insulin aggregation in artificial delivery devices.     

Resource guide 2004. Insulin delivery

Syringes...pumps...jet infectors...pens...infusers...they all do the same basic thing--deliver insulin. These items carry insulin through the outermost layer of skin and into fatty tissue so it can be used by the body. This section will also cover injection aids, products designed to make infecting easier.     

Insulin antibodies with pulmonary delivery of insulin

BACKGROUND AND METHODS: Delivery of insulin to the deep lung presents unique challenges to the body's mucosal defense system. Pulmonary mucosal defense has the ability to discriminate between self and non-self antigens and has the potential for induction of immunologic tolerance. Published data concerning the immunogenicity of inhaled human insulin in drug trials will be reviewed, and data regarding the possible adverse effects of anti-insulin antibody development will be presented. Examination of the immunologic safety of inhaled human insulin will include discussion of comparator studies, factors affecting immunogenicity, the effects of insulin immunity on glycemic control and pulmonary function, and the relationship of insulin antibodies to dose requirements, pharmacodynamics, and hypoglycemia. CONCLUSIONS: Inhaled human insulin, whether formulated as a powder or liquid, has been shown to be more immunogenic than comparator insulins given by subcutaneous routes; however, adverse effects of antibody formation have not been demonstrated.     

Drug delivery devices: issues in drug development

New techniques for delivery of drugs by inhalation are discussed in this article. Devices that promise to improve the efficiency of lung delivery are described along with some of the regulatory challenges faced by their development scientists. Although high delivery efficiencies are possible, such devices are expensive to develop and may only be feasible in the event that they are partnered with drugs whose therapeutic and economic value is truly enhanced by the effort invested in the process. Appropriate devices must also be selected after paying careful attention to the physicochemical and dosing demands associated with the drug substance to be inhaled. Even newly launched commercial products display large variations in dose delivery to the lung, in spite of increased global efforts to regulate and ensure the uniformity of delivered doses and their aerosol size distributions; this because of variations in the inspiratory maneuvers used by patients and the lack of control exercised over these maneuvers by most new inhalers. Sophisticated electromechanical techniques are discussed as possible ways of overcoming some of the common difficulties associated with ensuring reproducibility of dose and drug delivery to the lung.     

Inaccurate oxygen delivery in some portable liquid oxygen devices

After documenting that the measured flow from a portable liquid oxygen device was different from the set flow and that this difference caused hypoxemia in a patient with chronic obstructive pulmonary disease, we compared the measured and set flows from 23 portable devices supplied by 2 different providers. Nine of 13 devices (69%) from Provider A gave measured flows that differed from the set flows at 14 of 65 (21%) settings (13 devices times 5 flow settings). Three of 10 devices (30%) supplied by Provider B gave measured flows that differed from the set flow in only 5 of 50 (10%) possible settings (10 units times 5 flow settings). Oxygen delivery may be inaccurate from portable liquid systems serviced by some suppliers. This problem may cause patients to become hypoxemic despite using the devices in the prescribed fashion.     

American Diabetes Association. Resource guide 2005. Insulin delivery

Syringes...pumps...jet injectors...pens...infusers...they all do the same basic thing--deliver insulin. These items carry insulin through the outermost layer of skin and into fatty tissue so it can be used by the body. This section will also cover injection aids, products design to make injecting easier.     

Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism

Summary Insulin delivery rates were estimated from the peripheral serum insulin response to a single bolus injection of glucose or arginine in eight normal subjects and eight patients with hyperthyroidism. The mean rate constant for insulin disappearance was 0.2380±0.0052 per min in the control subjects, which was not significantly different from that observed in the patients with hyperthyroidism (0.2147±0.0111 per min). There were also no significant differences in the insulin response to glucose infusion (1.7±0.3 U during the first phase (0–10 min) and 5.6±1.6 U during the second phase (11–60 min) in normal subjects compared with 1.2±0.5 and 3.7±1.1 U respectively in the hyperthyroid patients). The delivered insulin in response to glucose infusion was similar in the two groups. The kg-value in the patients with hyperthyroidism was lower than that in the control subjects (1.24±0.11 versus 2.11±0.22;p < 0.005). In hyperthyroidism, the low kg-value was not a result of the diminished insulin delivery to the general circulation. Insulin delivery showed a monophasic pattern following arginine infusion in both patients and control subjects. For the control subjects, the amount of insulin delivered was estimated to be 0.53±0.12 U during the first 10 min and 0.37±0.14 U during 11–30 min. In hyperthyroidism, the amount of insulin delivered was significantly lower than in the control subjects (0.21±0.06 U during the first 10 min and 0.07±0.03 U during 11–30 min). In the control subjects, the plasma glucose level was raised transiently following arginine infusion, but in hyperthyroidism, there was no change in plasma glucose levels. In hyperthyroidism, therefore, glucose intolerance appears to be primarily related to an antagonism of the hepatic effect of insulin by thyroxine rather than an inhibitory effect of thyroxine on insulin secretion. However, since delivery rate represents the measurement of peripheral serum insulin concentrations, these results cannot exclude an abnormality of hepatic insulin metabolism in hyperthyroidism.     

Methods and devices for local drug delivery in coronary and peripheral arteries

New developments in catheter design, molecular biology, and polymer chemistry have made it possible to deliver pharmaceutical agents and genetic material directly into the arterial wall to modulate the response to injury. Several local drug delivery catheters of various designs in addition to biodegradable and coated stents are currently being evaluated as devices to facilitate local delivery of agents into the arterial wall. Approaches to locally sustained delivery include the controlled release of medications, the affinity-based delivery of medications administered systemically but accumulated locally, and gene therapy.     

妊娠糖尿病患者分娩后胰岛素抵抗和胰岛B细胞功能研究

目的研究妊娠糖尿病患者分娩后胰岛素抵抗、胰岛B细胞功能状态,探讨其在分娩后糖耐量异常发生发展中的作用。方法对2008-09-01—2009-07-10中国医科大学附属盛京医院内分泌科根据口服糖耐量试验筛选出8例有妊娠糖尿病史的妇女妊娠后糖耐量正常(NGT)者,另选取8例有妊娠糖尿病病史的妇女妊娠后糖耐量异常(IGT)者与之匹配。应用高胰岛素-正葡萄糖钳夹技术和静脉葡萄糖耐量试验评估胰岛素抵抗和胰岛B细胞功能。结果 NGT组和IGT组体重指数(BMI)及三酰甘油比较差异无统计学意义(P<0.05);IGT组葡萄糖输注速率(GIR)明显低于NGT组(5.70±1.14对7.79±1.75,P<0.05);NGT组胰岛素一时相分泌量高于IGT组(5.32±0.37对4.35±0.46,P<0.05);两组间胰岛素第二时相分泌量(4.35±0.31对4.38±0.56,P>0.05)比较差异无统计学意义。结论妊娠糖尿病患者分娩后糖耐量异常者较糖耐量正常者存在更为明显的胰岛素抵抗及胰岛B细胞功能缺陷。     

Access routes,devices and guidance methods for intrapericardial delivery in cardiac conditions

Drug deposition into the intrapericardial space is favourable for achieving localised effects and targeted cardiac delivery owing to its proximity to the myocardium as well as facilitating optimised pharmacokinetic profiles and a reduction in systemic side effects. Access to the pericardium requires invasive procedures but the risks associated with this have been reduced with technological advances, such as combining transatrial and subxiphoid access with different guidance methods. A variety of introducer devices, ranging from needles to loop-catheters, have also been developed and validated in pre-clinical studies investigating intrapericardial delivery of therapeutic agents. Access techniques are generally well-tolerated, self-limiting and safe, although some rare complications associated with certain approaches have been reported. This review covers these access techniques and how they have been applied to the delivery of drugs, cells, and biologicals, demonstrating the potential of intrapericardial delivery for treatments in cardiac arrhythmia, vascular damage, and myocardial infarction.     

Comparison of two demand oxygen delivery devices for administration of oxygen in COPD

AIM: Demand oxygen delivery systems (DODSs) were developed to secure the mobility of patients requiring oxygen therapy. The aim of the present study was to compare the efficacy of two currently available DODS with continuous oxygen administration (CONT). PATIENTS: Thirteen patients with COPD (mean [+/- SD] FEV1, 28 +/- 5.2% predicted; mean P(O2), 56.4 +/- 8.1 mm Hg [breathing room air]). INTERVENTION: Treatment for 30 min with CONT at a flow rate of 2 L/min, with the DODSs Oxytron 3 (Weinmann; Hamburg, Germany) or DeVilbiss EX 3000 (Somerset, PA) in random sequence. Arterialized blood samples were obtained from a hyperaemized ear lobe after 15 and 30 min. RESULTS: After 15 min, no significant differences in P(O2) or arterial oxygen saturation (Sa(O2)) were observed. In comparison with CONT (mean P(O2), 70.5 +/- 10.4 mm Hg; mean Sa(O2), 94.8 +/- 2.13%), oxygenation with the Oxytron 3 (mean P(O2), 66.3 +/- 10.3 mm Hg; mean Sa(O2), 93.5 +/- 2.6%) was significantly less after 30 min when measured independently by blood gas analysis and pulse oximetry. The DeVilbiss EX 3000 (mean P(O2), 69.1 +/- 12.0 mm Hg; mean Sa(O2), 94.5 +/- 3.2%) and CONT showed no differences. CONCLUSIONS: P(O2) did not reach equilibrium after 15 min of treatment with the DODSs. The titration of a patient to a DODS is recommended, since simply accepting the manufacturer's information on oxygen equivalent does not guarantee an adequate supply of oxygen.