Peptides & Therapeutic Proteins: Characteristics, Stability & Administration
Characteristics
Peptides and therapeutic proteins, classified as biopharmaceuticals, have emerged as useful and promising drugs in the treatment of various diseases such as diabetes, cancer or autoimmune diseases.[11] These have gained, in the last decade, an increasing share of the global pharmaceutical market.[12] This is due to the development of molecular biology that allowed the understanding of the role of proteins in pathophysiological processes as well as the growing development of biotechnology, bioengineering and recombinant DNA technology, which allowed large-scale production. The first biotechnologically derived drug product approved for market was recombinant human insulin in 1982.[13] There is a tendency to classify the proteins as new therapeutic agents; however, insulin was produced at industrial level for the first time in 1923 by the company Eli Lilly (Indianapolis, IN, USA).[14]
Owing to their selectivity and ability to foster a strong and effective action, therapeutic proteins have a high potential for cure.[15]
Despite all the therapeutic potential associated with proteins, they have physicochemical characteristics that limit their therapeutic applications. Because of their high molecular weight and general hydrophilicity, proteins have limited ability to cross biological membranes and consequently have reduced bioavailability.[16]
Stability & Formulation Challenges
Owing to their complex structure, peptides and therapeutic proteins have a limited chemical stability in vivo, undergo degradation and proteolytic cleavage and are removed from the bloodstream, thus having reduced systemic half-life. Besides the above characteristics, which determine their pharmacokinetics and pharmacodynamics, they present in vitro barriers to their stability during the pharmaceutical development. This is due to the reactivity of some amino acids, resulting in degradation reactions such as racemization, oxidation or hydrolysis that are dependent on conditions during production or storage such as pH, temperature, agitation, ionic strength and the presence of metal ions or surfactants. When unstable, they tend to undergo aggregation with possible precipitation, adsorption and denaturation, which will limit their concentration in vivo and thus will prevent them from reaching therapeutic levels after administration.[14,16,17]
The problems of in vitro and in vivo instability of proteins can be resolved with the addition of excipients that act as stabilizers by different mechanisms. Examples are sugars and salts that increase the thermal stability of proteins, the nonionic surfactants that reduce their aggregation, metal chelators and enzyme inhibitors that reduce the ability of various proteolytic enzymes or polymers such as polyethylene glycol (PEG) to decrease the immunogenicity of proteins and increase their resistance to proteolysis by conformational restriction in vivo.[16]
Administration
Parenteral administration can overcome the problem of reduced bioavailability of proteins through biological membranes, thus this is the usual route of administration for such drugs. However, it does not eliminate the problem of instability in the bloodstream.[16] Moreover, this is an invasive route, which can lead to a reduced acceptance by patients and, consequently, increased costs of therapy, especially when it requires prolonged or chronic treatment. Besides, there is a need for sterilization and cold storage (2–8°C) of various formulations of proteins, as well as the need for specialized personnel for its administration.[2,3]
In order to overcome the problems associated with parenteral administration, the pharmaceutical industry has been channeling efforts on developing systems for the administration of biopharmaceuticals without resorting to injections. Among the different noninvasive routes of administration are the oral, buccal, pulmonary, transdermal, ocular, rectal and vaginal routes.[16]
Oral administration is considered the more attractive route for drug administration because of its convenience of administration and high acceptance by patients. However, the bioavailability of proteins and peptides after oral administration is very low due to their instability in the gastrointestinal tract (acidic pH and proteolytic degradation) and low permeability through the intestinal mucosa.[4,5] In fact, several studies are focused on oral administration of proteins, many of them using nanotechnology to increase their bioavailability.
Parallel to the oral route, inhalation is seen the most effective to deliver proteins and appears as an alternative route to parenteral administration, as demonstrated by the several experimental and clinical assays proposed so far.
Nanomedicine. 2011;6(1):123-141. © 2011
Future Medicine Ltd.
Cite this: Nanocarriers for Pulmonary Administration of Peptides and Therapeutic Proteins - Medscape - Jan 01, 2011.
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