Pharmaceuticals Polypeptides

In spite of the obstacles to oral delivery, substantial evidence suggests that pharmaceutical polypeptides are absorbed through the intestinal mucosa, although in minute amounts.10 Small amounts of polypeptide drugs can be absorbed by the action of specific peptide transporters in the intestinal mucosa cells.11 This suggests that properly formulated proteins or peptide drugs may be administered by the oral route with retention of sufficient biological activity for their therapeutic use. 

The relevance of such a diastereomer discrimination to the transport of chiral molecules, such as pharmaceuticals or biochemicals, through hydrophobic barriers, such as cell membranes, is obvious. Furthermore, since poly(DL-lysine) followed the same general pattern of behavior displayed by the other three samples, the observed surface-pressure changes probably were not due to helicalization of the polypeptide. Whereas poly(L-lysine) and poly(D-lysine) form helices with opposite screw sense, the random copolymer poly(DL-lysine) is to a large extent prevented from forming helices. 

DKPs are simple and easy to obtain and are quite common by-products of synthetic, spontaneous, and biological formation pathways. DKP formation has been well documented as side reactions of solid-phase and solution-phase peptide synthesis. In addition, DKPs have been shown to be decomposition products of various peptides, proteins, and other commercial pharmaceuticals. Cyclic dipeptides were found to be present in solutions of human growth hormone, bradykinin, histerlin, and solutions of agents within the classes of penicillins and cephalosporins. " DKPs are also enzymatically synthesized in several protists and in members of the plant kingdom. Hydrolysates of proteins and polypeptides often contain these compounds and they are commonly isolated from yeasts, lichens, and fungi. ... 

A wide range of pharmaceutical substances are derived from animal sources (Table 1.10). Many are protein-based and detailed description of products such as insulin and other polypeptide hormones, antibody preparations, vaccines, enzymes, etc., have been deferred to subsequent chapters. (Many of the therapeutic proteins are now also produced by recombinant DNA technology. Considerable overlap would have been generated had a product obtained by direct extraction from native sources been discussed here, with further discussion of a version of the same product produced by recombinant DNA technology at a later stage.) Non-proteinaceous pharmaceuticals originally derived from animal sources include steroid (sex) hormones, corticosteroids and prostaglandins. A limited discussion of these substances is presented below, as they will not be discussed in subsequent chapters. Most of these substances are now prepared synthetically. 

G. Fong and B. T. Kho, Improved HPLC of cyclic polypeptide antibiotics-polymixins B- and its application to assays of pharmaceutical formulations, J. Liquid Chromatogr., 2 957 (1979). 

Bernkop-Schnurch A. and Fragner R. (1996) Investigations into the diffusion behavior of polypeptides in native intestinal mucus with regard to their peroral administration. Pharmaceutical Sci 2, 361-363... 

CD spectroscopy is not limited to the study of small molecules, and has become extremely important in the characterization of biomolecules. The secondary structure of proteins can be characterized through studies of the CD associated with the amide chromophores. Using a combination of models and calibration spectra, it is possible to deduce the relative contributions to the overall secondary structure made by a-helix, antiparallel B-sheet, B-turn, and random coil portions of the polypeptide [11]. With the increasing use being made of such agents in the pharmaceutical industry, it... 

Brayden, D.J. and O Mahony, D.J. (1998) Novel oral drug delivery gateways for biotechnology products polypeptides and vaccines. Pharmaceutical Science and Technology Today, 1 291-299. 

Such methods have been widely used for a number of years as multidimensional techniques in the HPLC separation of polypeptides and proteins as well as many lower molecular weight compounds within the pharmaceutical industry. Integral to these HPLC approaches has been the application of... 

---