Insulin formulations

Systemic absorption of pulmonary-deUvered peptides and proteins has been the objective of many investigations [2]. The most successful work in this field is the development of insulin formulations for inhalation.These dosage forms might, in the near future, become a suitable alternative for the current subcutaneous injection of insulin that is used to obtain meal-time glucose control [3]. In spite of the strict requirements regarding dose variability for insulin, the pulmonary products under development seem to be as safe as the subcutaneous injections. 

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

Martindale, H., Marsh, J., Hallett, F.R., Albisser, A.M. (1982). Examination of insulin formulations using quasi-elastic light scattering. Diabetes, 31, 364—366. 

Steiner, S., Pfutzner, A., Wilson, B.R., Harzer, O., Heinemann, L., and Rave, K. (2002). Technosphere (TM)/Insulin - proof of concept study with a new insulin formulation for pulmonary delivery. Exp. Clin. Endocrinol. Diabetes, 110, 17-21. 

A skin reaction to latex in rubber associated with an insulin formulation has been reported (181). 

Both powdered insulin formulations and liquid inhaled insulin formulations are being developed. There have been no direct comparisons of these formulations, and it is therefore difficult to make definitive statements about whether one is superior to the other (274). 

Kidron M, Dinh S, Menachem Y, Abbas R, Variano B, Goldberg M, Arbit E, Bar-On H. A novel per-oral insulin formulation proof of concept study in non-diabetic subjects. Diabetic Med 2004 21 354-7. 

Touitou, E., and M. Donbrow. 1983. Promoted rectal absorption of insulin Formulative parameters involved in the absorption from hydrophilic bases. Int J Pharm 15 13. 

Another type of absorption enhancer, which has been shown to have a better safety profile, is cyclodextrin (CD) [39]. CDs have been shown to form inclusion complexes with lipophilic drugs, thereby improving their aqueous solubility and stability. A powdered insulin formulation containing dimethyl-(3-cyclodextrin improved the absolute bioavailability of insulin by 13% in rabbits compared to a control liquid formulation (1%) of insulin with dimethyl-(3-cyclodextrin [40]. Recently, hydroxypropyl (3-cyclodextrin has been shown to be more effective for enhancing the nasal absorption of acyclovir than a range of other absorption enhancers in vivo [41]. 

Commercial insulin preparations differ in a number of ways, including differences in the recombinant DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and duration of their biologic action. In 2003, seventeen insulin formulations were available in the USA. 

AERx was developed by Aradigm Corporation in collaboration with Novo Nor-disk A/S. It is a liquid insulin formulation which can create aerosols of 1-3 pm particle diameter [62]. In a study involving 23 healthy volunteers, AERx was used to deliver aqueous insulin aerosols to the lungs at two concentrations (250 U/mL and 500 U/mL), and was compared with a SC injection of insulin solution. The results showed the absorption of insulin to be more rapid after pulmonary dosing... 

E. Schrader and E. P. Pfeiffer, The influence of motion and temperature upon the aggregational behavior of soluble insulin formulations investigated by high performance liquid chromatography, J. Liquid Chromatogr., 5 1139 (1985). 

Data obtained in the HPLC analysis of insulin formulations, utilizing a 25-cm column and a 4-cm (3-um particle) column, are summarized in Table VII. The data clearly show the equivalent performance of both columns. 

Table VII. Comparison of a 25-cm Column and a 4-cm (3-um) Column in the Analysis of Insulin Formulations(a)...

Insulin formulated with 0.06 or 0.125% hexadecylmaltoside produced a pronounced and rapid dose-dependent decrease in blood glucose levels after nasal administration. The effects of seven different alkylmaltosides were studied, and all the reagents (Figure 6) showed a similar maximal enhancement of insulin uptake when a concentration of 0.125% was employed. The figure demonstrates that TDM showed the greatest effect when concentrations of 0.03 and 0.06% were used. 

Similar experiments were carried out using sucrose esters in nasal insulin formulations (Figure 7). It was observed that tetradecanoylsucrose and tridecanoylsucrose were more effective in stimulating insulin absorption as compared with decanoyl-sucrose and dodecanoylsucrose. But—compared with TDM at concentrations of 0.03%—the sucrose esters were less effective in promoting nasal absorption [66], Sucrose cocoate (SL-40) is produced by the chemical esterification of coconut oil with sucrose it has frequently been used in cosmetic and dental preparations as an excipient. When this excipient was formulated with insulin at 0.125,0.25, and 0.5% concentrations, the associated plasma levels of insulin increased rapidly whereas there was no enhancement of insulin plasma levels when insulin in saline was admin-... 

FIGURE 6 Changes in area under the curve (AUC0 i2o) for blood glucose values in rats that received 2U insulin in presence of alkylmaltosides. Data represent mean change in AUC0120 in arbitrary units (AU) + standard error of the mean (SEM) compared with rats that received insulin formulated without alkylmaltoside (n = 3,4). (Reproduced from ref. 66 with permission of John Wiley Sons.)... 

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