Formulation of Insulin

During the first decade of the insulin era, only an acid solution of an impure form of the hormone was available for therapy. When it became possible to crystallize insulin, the purity, and hence the biological potency, of the hormone improved substantially (Table I). These improvements were mainly achieved by introduction of Ztf+-crystallization (Scott, 1934) and recrystallization methods, the latter based on the observation that insulin recrystallized several times was better tolerated by patients suffering from allergic reactions (Jorpes, 1949). Until the late 1960s, recrystallized insulin was considered to be an essentially pure substance, but the introduction of new analytical methods made it possible to detect the presence of significant amounts of protein impurities by disc electrophoresis (Mirsky and 

International standard Purification method Desamido insulins Promsulin + Diderivatives and polymers of insulin lU/mg 

Whereas extensive purification has resulted in a very pure and homogeneous insulin product, the protamine used for retardation in NPH type preparations (see Section 2.2.1) is highly inhomogeneous as it contains four major components, which are present in approximately equal amounts. AU four components show close structural homology with one another, and consequently they generate nearly identical protamine-insulin complexes (Hoffinaneta/., 1990). 

As a result of derivatization of insulin during isolation and purification steps, and during storage of the pharmaceutical preparations, therapeutic insulin contains smaller amounts of desamido insulins, covalent insulin dimers, and other insulin derivatives. Physical and chemical stability of insulin in formulations for injection therapy has recently been reviewed in a previous volume of this series (Brange and Langkjser, 1993) and in a monograph (Brange, 1994). 

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More subtle effects of preservatives on injectable formulations are possible. Formulation of insulin is an illustrative case study. Insulin is usually formulated as a multiple-dose vial, since individual dosage varies among patients. Preservation of zinc insulin with phenol causes physical instability of the suspension, whereas methyl-paraben does not. However, the presence of phenol is required for obtaining protamine insulin crystals [9]. 

Protein-based drugs have been formulated mainly as stable liquids or in cases where liquid stability is limiting as lyophilized dosage forms to be reconstituted with a suitable diluent prior to injection. This is because their delivery has been limited primarily to the parenteral routes of intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. There are a few drugs that have been developed for pulmonary delivery, such as rhDNase (Pulmozyme ) and an inhalable formulation of insulin (e.g., Exubra ). However, even such drugs have been formulated as either liquid or lyophilized or spray-dried powders. This chapter will focus only on excipients that are applicable to liquid and lyophilized protein formulations. 

Rave K, Heinemann L, Puhl L, Gudat U, Woodworth JR, Weyer C, Heise T. Premixed formulations of insulin lispro. Activity profiles in type 1 diabetic patients. Diabetes Care 1999 22(5) 865—6. 

Chitosan is a cationic polysaccharide produced from the deacetylation of chitin, a component of crab and shrimp shells [7,57,58], Chitin is composed of units of 2-deoxy-2-(acetylamino) glucose joined by glycosidic bonds that form a linear polymer. Ilium et al. [7,57,58] demonstrated the ability of chitosan to increase the bioavailability of insulin and other small peptides and polar macromolecules in different animal models. In both the sheep and rat models, the addition of chitosan at concentrations of 0.2%-0.5% to nasal formulations of insulin resulted in significant increases in plasma insulin and reductions in blood glucose. Reversibility studies indicated that the effect of chitosan on the nasal absorption of insulin... 

Insulin preparations that are commercially available differ in their relative onset of action, maximal activity, and duration of action. Conjugation of the insulin molecule with either zinc or protamine, or both, will convert the normally rapidly absorbed parenterally administered insulin to a preparation with a more prolonged duration of action. The various formulations of insulin are usually classified as short acting (0.5 to 14 h), intermediate acting (1 to 28 h), and long acting (4 to 36 h). The duration of action can vary, however, depending on injection volume, injection site, and blood flow at the site of administration. 

Fernandez-Urrusuno R, Romani D, Calvo P, Vila-Jato JL, Alonso MJ (1999) Development of a freeze-dried formulation of insulin-loaded chitosan nanoparticles intended for nasal administration. S.T.P. Pharma Sci 9 429-436... 

In contrast, different formulations of insulin and growth hormone containing the same active ingredient exhibit significant differences in bioavailability [20]. Additionally, the inability to adequately predict immunogenic responses from in vitro data or animal studies remains a concern. 

The formulation of insulin differs in various countries. A strength of 100 U/ml (UlOO) is increasingly used in many countries, but in other countries strengths of 20, 40, or 80 U/ml (U20, U40, and U80) are still in use. The increased frequency of travelling and tourism has increased the importance of the problem. In some... 

Oleyl alcohol is mainly used in topical pharmaceutical formulations and has been used in transdermal delivery formulations. It has been utilized in the development of biodegradable injectable thermoplastic oligomers, and in aerosol formulations of insulin and albuterol. ... 

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 most common pancreatic disease requiring pharmacologic therapy is diabetes meliitus, a deficiency of insulin production or effect. Diabetes is treated with several formulations of insulin (all administered parentertdly at present) eind with four types of oral antidiabetic agents (Figure 41-1). 

Intranasal Insulin. Insulin administered nasally has considerable potential for the treatment of both type 1 and type 2 diabetes. Using enhancers or novel delivery systems such as adequate bioadhesive microspheres, it is believed that the low bioavailability of simple formulations of insulin can be greatly improved [33]. 

Directly from the beginning of the therapeutic use of proteins and peptides, parenteral formulations were of utmost importance, like sc formulations of insulin, for example. This was mainly triggered by special aspects from three different areas ... 

TakenagaM, Yamaguchi Y, Kitagawa A, Ogawa Y, Mizushima Y, Igarashi R. A novel sustained-release formulation of insulin with dramatic reduction in initial rapid release. J Contr Rel 2002 79 81-91. 

Iontophoresis. An aqueous formulation of insulin is placed on the skin, and delivery through the skin to the epidermal vasculature is accomplished using a weak electric field. Variable delivery is accomplished by adjusting the current. 

Infiision pump. An aqueous formulation of insulin is placed in a pump connected to a catheter placed either in subcutaneous tissue or in a vein. Variable delivery of insulin is accomplished by adjusting the pumping rate. 

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