Insulin administration limitations

Schurr et al.43 reported the amino acid concentrations in various tissues of the rat. Using these data to calculate tissue-to-plasma ratios, it becomes apparent that the relative availability of plasma tryptophan to tissues is much less than that of other amino acids. The finding, described elsewhere, that tryptophan in serum or plasma can be present as free and bound (to plasma albumin) is unique among amino acids,44 and this further limits or controls the availability of tryptophan from the blood to organs or tissues, especially the brain. Tryptophan differs from other amino acids in that its concentration in plasma of rats increases (30 to 40%) after fasting, after insulin administration, or after consuming a carbohydrate meal.45... 

F. Role in therapy Limited evidence suggests that better control of postprandial glucose may lead to long-term benefits. Both insulin lispro and insulin aspart, because of their rapid absorption after subcutaneous administration, are effective in this regard, but they have not been compared. 

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. 

Many authors used mice instead of rats (Gross et al. 1994, Bailey et al. 1997, Ahren et al. 2000). However, parallel insulin measurements are much more limited in mice than in rats. Also oGTT in insulin resistant animal disease models in mice (e.g. genetic ob/ob, db/db, Ay) are described to assess peripheral insulin resistance (Xiao et al. 2001, Arakawa et al. 2001, Nagakura et al. 2003, Thorkildsen et al. 2003, Minoura et al. 2004). Other routes for glucose administration (e.g. intraperitoneal) are also reported (Xie et al. 2004). 

Although routine oral delivery of proteins has not been realized, some protein formulations have been developed for pulmonary delivery. Pulmonary delivery can result in either parenteral or local administration of the drug and, like oral delivery, is considered non-invasive. As with other routes of delivery, the size of the protein may limit its ability to be delivered systemi-cally via the pulmonary route of administration. Pulmozyme , a DNase-based formulation approved for the treatment of cystic fibrosis (CF), is delivered to the lungs by a nebulizer to clear blockage of the airways in the CF patient.Formulations for insulin to be administered by inhalation for systemic delivery of... 

With the exception of a few approved products for nasal administration of peptides and the very recent regulatory approvals of delivery systems for both pulmonary and buccal delivery of insulin, there is relatively little precedence with the worldwide regulatory approval process for non-invasive delivery systems incorporating protein or peptide pharmaceuticals. Consequently, there is limited specific information... 

In some cases, cell surface expression of certain species can be induced for example, interleukin-1 has been shown to induce the biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells [197]. Such materials may also be exploitable as candidates for bioadhesion studies. Millions of lives of patients with diabetes have been saved since the introduction of insulin therapy. However, several daily injections of insulin are required to maximize glucose control in diabetic patients. Insulin is administered by subcutaneous injection, but this route of administration has a slow onset and subsequent prolonged duration of action. These limitations show up more when higher doses of insulin are injected, which results in a long duration of action and forces the patients to consume additional amounts of food to limit the risk of hypoglycemia [198]. 

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