Protein pharmaceuticals drugs

As pharmaceutical scientists gain experience and tackle the primary challenges of developing stable parenteral formulations of proteins, the horizons continue to expand and novel delivery systems and alternative routes of administration are being sought. The interest in protein drug delivery is reflected by the wealth of literature that covers this topic [150-154]. Typically, protein therapeutics are prepared as sterile products for parenteral administration, but in the past several years, there has been increased interest in pulmonary, oral, transdermal, and controlled-release injectable formulations and many advances have been made. Some of the more promising recent developments are summarized in this section. 

The PAB undertakes drug dossier evaluations, a process that normally takes 18 months. The approval requirements/process for pharmaceuticals (including biopharmaceuticals) are, in broad terms, quite similar to the USA. The PAB have issued specific requirements (Notification 243) for submission of recombinant protein drugs. 

Unlike the small molecule drugs (pharmaceuticals) described in Chapter 3, large molecule drugs (biopharmaceuticals) are mainly protein based. Another distinction is that these protein-based drugs are, in the main, similar to natural biological compounds found in the human body or they are fragments that mimic the active part of natural compounds. 

Protein drugs have been formulated with excipients intended to stabilize the protein in the milieu of the pharmaceutical product. It has long been known that a variety of low molecular weight compounds have the effect of preserving the activity of proteins and enzymes in solution. These include simple salts, buffer salts and polyhydroxylated compounds such as glycerol, mannitol, sucrose and polyethylene glycols. Certain biocompatible polymers have also been applied for this purpose such as polysaccharides and synthetic polymers such as polyvinyl pyrrolidone and even nonionic surfactants. 

Because most proteins are susceptible to protease degradation and denaturation in biologic fluids, most biopharmaceuticals must be administered by intravenous, intramuscular, or subcutaneous injection (see Table 5.5). High concentrations of proteases are found in the gastrointestinal tract, nasal mucosa, bronchioles, and alveoli, which severely limit the bioavailability of protein pharmaceuticals after oral, intranasal, and inhalation administration. Diffusional barriers to the passage of relatively large macromolecules preclude transdermal and mucosal administration of protein pharmaceuticals. Research is under way to develop methods that will protect protein drugs from proteolysis and improve transmembrane diffusion. 

Some of the dosage formulations available for protein pharmaceuticals are listed in Table 5.7. An examination of Table 5.7 reveals that no protein drug up until this time has been formulated for oral administration. Most protein drugs are administered by means of injection (parenteral administration). Parenteral administration includes intravenous, intra-arterial, intracardiac, intraspinal or intrathecal, intramuscular, intrasynovial, intracuta-neous or intradermal, subcutaneous injections, and injection directly into a dermal lesion (e.g., a wart). The parenteral route of administration requires a much higher standard of purity and sterility than oral administration. It also may require trained... 

A biopolymer-based drug carrier designed for protein delivery must meet the following requirements. In addition to controlling the release of drug, (1) the carrier must be biocompatible and degraded products must be nontoxic, (2) the carrier must incorporate the protein in a sufficiently gentle manner to retain bioactive conformation, and (3) the carrier must be able to incorporate the protein in pharmaceutical scale [12]. 

Toxic Decomposition Products In situations where the content of the API in a drug product is well above 90% as indicated above, the formation of toxic degradation products within the shelf life (which may cause untoward effects to the patients) may warrant the reassignment of a different expiration date or recall of the drug product in question. Consequently, the pharmaceutical industry is often concerned with both the amount as well as the nature of the degradation products. The formation of toxic products is particularly problematic with protein drugs which may maintain therapeutic activity after deliberate modification or pertubation of molecular structure in a domain removed from that associated with therapeutic activity... 

Peptide and Protein Drug Analysis, edited by Ronald E. Reid Transport Processes in Pharmaceutical Systems, edited by Gordon L. Amidon, Ping I. Lee, and Elizabeth M. Topp... 

Several pharmaceutical and physiological barriers must be overcome for the successful pulmonary delivery of peptide and protein drugs [3], For example, many of these macromolecular drugs have relatively low permeability when they are administered without any absorption enhancers [4], Furthermore, the clinical toxicology of peptides/proteins in the lung, especially for chronic disease, should be of some concern [6], Therefore, cost-benefit ratios should be evaluated in the... 

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