Insulin formulations soluble insulins

In order to prolong the duration of insulin action, soluble insulin may be formulated to generate insulin suspensions. This is generally achieved in one of two ways ... 

Soluble insulin = regular insulin = unmodified insulin any insulin solution from any source which is not formulated/changed in any way in order to prolong its duration of action... 

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. 

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). 

The second example (Section 2.3) describes the formulation of a model that explains an observed initial slow absorption of soluble insulin [11], The model resembles to some extent a typical PK model, except that instead of determining all parameters simultaneously, the parameters are deduced one by one from different features of the absorption curve. More importantly, however, when the model was first formulated, it served to examine different hypotheses about the processes that took place in the tissue. The model also involves simulation of the diffusion of insulin in subcutis. Finally, it is worth mentioning that, in contrast to typical PK models, our model allows slower parts of the absorption process to play out before the more rapid parts. 

The second example considered the absorption of soluble insulin from subcutus. The problem here was to establish a set of consistent hypotheses that could explain the observed volume and concentration effects. At the time when the model was formulated there was no notion of the possible role of polymerization in the absorption process for insulin. Most experiments were performed at normal pharmacological concentrations (40 IU/ml) and injection volumes (0.3 ml), and the work was oriented towards elucidating the importance of exercise and skin temperature at the absorption site. Such experiments are obviously important, since variations in skin temperature may pose a problem in the control of labile type I diabetes. Analyses of a single set of data, obtained partly at micro-dose levels, allowed us to identify processes in the skin that were not amenable to direct experimentation. 

Mixing drugs formulated for injection in a syringe may cause interaction, e.g. protamine zinc insulin contains excess of protamine which binds with added soluble insulin and reduces the immediate effect of the dose. 

Soluble and neutral insulin are the same the British National Formulary favours the former term, but neutral is the INN (internationally approved) name, dating back to when there were acid and neutral pH formulations of soluble insulin. Human, porcine and beef are available. 

Soluble insulin is neutral, adjusted to pH 7.0. Acid formulations of soluble insulin are no longer available. 

Insulin is a classic example of what can be achieved by manipulation of the properties of the dmg and its formulation. Modification of the crystallinity of the insulin allows control over solubility and duration of activity. An acid-soluble formulation of insulin was introduced for clinical use in 1923. It had a short... 

The seoondary and tertiary struoture is substantially the same for all insulins despite differences in the primary structure from various speoies. The A ohain has two a-helices and the B-chain an a-helix and a p-turn, with the B21 to B30 region as a p-strand. This oonformation buries a number of hydrophobic A-chain residues in the interior of the peptide, which improves water solubility and stability. The presence of phenol and cresol that often are used as preservatives in insulin formulations results in substantial ohanges in the insulin conformation. Phenol, in the presenoe of zinc ions, causes the formation of a B1-B8 helix, which involves movement of more than 25 A in the B1 residue (33). 

Figure 2. Isocratic reversed-phase separation of insulin mixtures in four different systems. Conditions Panel A Column, 10 X 0.5 cm SAS—Hypersil (Cl, 5 /tm). Mobile phase, 1% w/v cetrimide in 0.1 M Tris—HCI 10 mM EDTA pH 7.5 methanol, 27 73 (28) temperature, ambient sample, upper trace, bovine insulin soluble formulation lower, porcine insulin neutral formulation following accelerated degradation. Panel B 15 X 0.46 cm ODS Hypersil. Mobile phase, 5 mM tartaric acid—0.1 M ammonium sulphate pH 3 acetonitrile, 73 27 (29) temperature, ambient sample, international reference preparation of insulin for bioassay (established 1956). Panel C 15 X 0.46 cm ODS Hypersil. Mobile phase, 5 mM tartaric acid—0.1 M ammonium sulphate pH 3 acetonitrile 75 25 containing 14 /iM cetrimide (30) temperature, ambient sample, artificial mixture of bovine and porcine insulins and monodesamido insulins. Panel D 25 x 0.46 cm Ultrasphere ODS. Mobile phase, 0.1 M dihydrogen phosphate/phosphoiic acid pH 2 acetonitrile 70 30 temperature, 45°C (30) sample, artificial mixture. Peak identities a, bovine native b, porcine native c bovine A monodesamido d. porcine A monodesamido e. human native f human A monodesamido p, preservative.

Sadeghi, A.M.M., Dorkoosh, F.A., Avadi, M.R., Bayat, A., Delie, F., Gurny, R., Rafieeh-Tehrani, M. and Junginger, H.E. (2008a) Permeation enhancer effect of chit-osan and chitosan derivatives comparison of formulations as soluble polymers and nanoparticulate systems on insulin absorption in Caco-2 cells. Eur. J. Pharm. Bio-pharm. 70 270-278. 

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