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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Patients suffer from many diseases as a result of deficiency in the endogenous proteins. Protein hormones such as insulin and human growth hormone belong to this category of endogenous proteins. Insulin deficiency causes type I diabetes. Hence, Insulin is given exogenously to the patients suffering from diabetes. Insulin is the first human recombinant protein therapeutic that is also known as Humulin®. It was prepared by Eh Lilly at Genentech and was approved by the US FDA in 1982 (Goeddel et al., 1979). Humulin® was used to replace the natural insulin which is absent in diabetic patients. With advancements in proteins engineering, several of insulin analogs have been designed that are classified into two categories, namely (1) fast-acting analog formulations for bolus injection before meals, and (2) basal analog formulations intended for once-a-day injections (Berenson et al., 2011). Insulin lispro, insulin aspart, and insulin glulisine are the fast-acting insulin analogs that are safe and effective in multi-injection regimens. Insulin lispro was engineered in which the C-terminal lysine and proline residues of insulin B-chain were swapped. This mutation completely knocked out the insulin hexamer formation without affecting its receptor binding efficiency, thus allowing the presence of higher concentration of insulin monomers in postprandial injections. Insulin lispro was first approved in the United States in 1996 (Thrasher et al., 2015b). Insulin aspart is the fast-acting insulin analog that gets absorbed quickly in the blood. It starts its action in several minutes and hence can be taken by the patients just before the meal (Muchmore, 2018). Insulin glulisine, marketed as Apidra, is a rapidly acting insulin analogue in which the amino acid aspargine at third position in the B-chain was swapped with lysine and the lysine residue at 29th position in B-chain was replaced by glutamic acid. Its receptor binding properties are same as the human insulin but it appears faster in the blood. Insulin glulisine also follows flexible administration, that is, it can be administered immediately before or after the meal (Garnock-Jones and Plosker, 2009). Insulin glargine is marketed as Lantus, is most widely used as long-acting insulin analogue. It contains two basic arginine residues at the end of the B-chain that shifts the isoelectric point to neutrality, hence resulting in precipitation when injected subcutaneously in an unbuffered pH-4 formulation form. The precipitation results in its prolonged actions (Goykhman et al., 2009). Insulin detemir sold by Novo-Nordisk as Levemir, contains a prosthetic fatty acyl group on Lys 29 of B-chain, which causes its binding to serum albumin and results in circulating depot. This analog also exhibits more stable hexameric structure in comparison to natural insulin (Vigneri et al., 2010). Levemir is administered twice a day, as its actions are not as prolonged as that of Lantus.
The influence of spatial distribution on add-on therapy of designed Ca-Alg/CS MEMs system
Published in Journal of Biomaterials Science, Polymer Edition, 2018
Qinglei Dai, Xia Zhou, Kejing Wu, Ruimin Long, Shibin Wang, Haiwang Huang, Yanhua Xia, Yuangang Liu
Diabetes is a metabolic disease in which there are high blood sugar levels over a prolonged period. The patients may suffer greatly from increased urine output, excessive thirst, weight loss, hunger, fatigue, skin problems, etc. [1]. Based on recent studies, metformin monotherapy [2] as first-line therapy were initially recommended in type 2 diabetes mellitus (T2DM), eventually the patients will require insulin therapy to maintain adequate glycemic control [3,4]. Currently, add-on combination therapy with two antidiabetic drugs is beneficial in the treatment of type 2 diabetes mellitus, such as empagliflozin/linagliptin combined with metformin [5], insulin glargine plus metformin [6], or metformin in combination with insulin analogues [7]. To reduce the side effects of the direct-use drugs, multiple functional drug delivery systems have been used for combined medication which possesses important advantages regarding biological compatibility, sustained drug release and drug targeting [8,9].