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Ward W.K.,Legacy Health and Legacy Research Institute | Ward W.K.,Oregon Health And Science University | Castle J.R.,Oregon Health And Science University | Branigan D.L.,Legacy Health and Legacy Research Institute | And 2 more authors.
Clinical Drug Investigation | Year: 2012

Background and Objective: There is a paucity of data regarding tolerability of alkaline drugs administered subcutaneously. The aim of this study was to assess the tolerability of alkaline preparations of human albumin delivered subcutaneously to healthy humans. Methods: We compared the tolerability of neutral versus alkaline (pH 10) formulations of human albumin in ten volunteers. With an intent to minimize the time required to reach physiological pH after injection, the alkaline formulation was buffered with a low concentration of glycine (20 mmol/L). Each formulation was given at two rates: over 5 seconds and over 60 seconds.A sixpoint scale was used to assess discomfort. Results: For slow injections, there was a significant difference between pH 7.4 and pH 10 injections (0.4 ± 0.2 vs 1.1 ± 0.2, mean ± SEM; p = 0.025), though the degree of discomfort at pH 10 injections was only 'mild or slight'. For fast injections, the difference between neutral and alkaline formulations was of borderline significance. Inflammation and oedema, as judged by a physician, were very minimal for all injections, irrespective of pH. Conclusion: For subcutaneous drug administration (especially when delivered slowly), there was more discomfort associated with alkaline versus neutral formulations of albumin, though the discomfort was mild. This study suggests that there is little discomfort and inflammation resulting from subcutaneous administration of protein drugs formulated with weak buffers at alkaline pH. © 2012 Springer International Publishing AG. All rights reserved.


Bakhtiani P.A.,Oregon Health And Science University | Zhao L.M.,Legacy Health and Legacy Research Institute | El Youssef J.,Oregon Health And Science University | Castle J.R.,Oregon Health And Science University | And 2 more authors.
Diabetes, Obesity and Metabolism | Year: 2013

Since the discovery of insulin, great progress has been made to improve the accuracy and safety of automated insulin delivery systems to help patients with type 1 diabetes achieve their treatment goals without causing hypoglycaemia. In recent years, bioengineering technology has greatly advanced diabetes management, with the development of blood glucose meters, continuous glucose monitors, insulin pumps and control systems for automatic delivery of one or more hormones. New insulin analogues have improved subcutaneous absorption characteristics, but do not completely eliminate the risk of hypoglycaemia. Insulin effect is counteracted by glucagon in non-diabetic individuals, while glucagon secretion in those with type 1 diabetes is impaired. The use of glucagon in the artificial pancreas is therefore a logical and feasible option for preventing and treating hypoglycaemia. However, commercially available glucagon is not stable in aqueous solution for long periods, forming potentially cytotoxic fibrils that aggregate quickly. Therefore, a more stable formulation of glucagon is needed for long-term use and storage in a bi-hormonal pump. In addition, a model of glucagon action in type 1 diabetes is lacking, further limiting the inclusion of glucagon into systems employing model-assisted control. As a result, although several investigators have been working to help develop bi-hormonal systems for patients with type 1 diabetes, most continue to utilize single hormone systems employing only insulin. This article seeks to focus on the attributes of glucagon and its use in bi-hormonal systems. © 2013 John Wiley & Sons Ltd.


PubMed | Legacy Health and Legacy Research Institute
Type: Comparative Study | Journal: Clinical drug investigation | Year: 2012

There is a paucity of data regarding tolerability of alkaline drugs administered subcutaneously. The aim of this study was to assess the tolerability of alkaline preparations of human albumin delivered subcutaneously to healthy humans.We compared the tolerability of neutral versus alkaline (pH 10) formulations of human albumin in ten volunteers. With an intent to minimize the time required to reach physiological pH after injection, the alkaline formulation was buffered with a low concentration of glycine (20 mmol/L). Each formulation was given at two rates: over 5 seconds and over 60 seconds. A six-point scale was used to assess discomfort.For slow injections, there was a significant difference between pH 7.4 and pH 10 injections (0.4 0.2 vs 1.1 0.2, mean SEM; p = 0.025), though the degree of discomfort at pH 10 injections was only mild or slight. For fast injections, the difference between neutral and alkaline formulations was of borderline significance. Inflammation and oedema, as judged by a physician, were very minimal for all injections, irrespective of pH.For subcutaneous drug administration (especially when delivered slowly), there was more discomfort associated with alkaline versus neutral formulations of albumin, though the discomfort was mild. This study suggests that there is little discomfort and inflammation resulting from subcutaneous administration of protein drugs formulated with weak buffers at alkaline pH.

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