Protein and peptide drug delivery

Protein and peptide drug delivery

Introduction

The use of therapeutic proteins to replace or supplement endogenous protein molecules has been a long established treatment for diseases such as diabetes, growth hormone deficiency, and hemophilia. The use of proteins and peptides as pharmaceutical products has increased significantly in recent years with the commercialization of monoclonal antibody (mAb)-based therapeutics such as immune-oncology agents Opdivo® and Yervoy®, and the antibody– drug conjugates (ADCs) such as Kadcyla® and Adcentris®.

Protein and peptide drugs are either natural in origin or synthetically produced using recombinant DNA technology or from transgenic animals. Recombinant DNA technology has allowed the large-scale production and biological characterization of several therapeutic proteins, including gran-ulocyte macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), interleukins, insulin-like growth factor-1 (IGF-1), human factors VIII and IX (involved in blood coagulation and useful for hemophilia), mAbs, and tissue plasminogen activator (t-PA). Table 25.1 lists some of the FDA-approved marketed products of therapeutic proteins.

Table 25.1 List of some commercial products of therapeutic proteins

The physical and chemical instabilities of proteins and peptides, arising from their large molecular weight and complex structure, pose many chal-lenges for pharmaceutical formulation development. Clinical applications of protein drugs are limited by their inadequate concentration in blood, poor oral bioavailability, high manufacturing cost, chemical or biologi-cal instability, and/or rapid hepatic metabolism. In addition, most protein drugs do not efficiently pass through biological membranes and enter their target cells. These limitations lead to their high dose and/or need for fre-quent administration, which can cause undesirable side effects. Also, pro-teins can elicit host immune response following repeated use due to the development of neutralizing antibodies or hypersensitivity reactions.

Proteins and peptides are rapidly degraded in the gastrointestinal tract due to the harsh pH and enzymatic environment, resulting in poor oral bioavail-ability. Therefore, proteins are primarily administered parenterally by intrave-nous (IV), subcutaneous (SC), and/or intramuscular (IM) injection. Thus, the development of a protein formulation is primarily focused on a sterile solu-tion or a sterile, lyophilized powder for reconstitution prior to administration.