Elsevier

Advanced Drug Delivery Reviews

Volume 93, 1 October 2015, Pages 95-108
Advanced Drug Delivery Reviews

Stabilization Challenges and Formulation Strategies Associated with Oral Biologic Drug Delivery Systems

https://doi.org/10.1016/j.addr.2015.08.001Get rights and content

Abstract

Delivery of proteins to mucosal tissues of GI tract typically utilize formulations which protect against proteolysis and target the mucosal tissues. Using case studies from literature and the authors' own work, the in-process stability and solid state storage stability of biopharmaceuticals formulated in delivery systems designed for oral delivery to the GI tract will be reviewed. Among the range of delivery systems, biodegradable polymer systems for protection and controlled release of proteins have been the most studied; hence these systems will be covered in greater depth. These delivery systems include polymeric biodegradable microspheres or nanospheres that contain proteins or vaccines, which are designed to reduce the number of administrations/inoculations and the total protein dose required to achieve the desired biological effect. Specifically, this review will include a landscape survey of the systems that have been studied, the manufacturing processes involved, stability through the manufacturing process, key pharmaceutical formulation parameters that impact stability of the encased proteins, and storage stability of the encapsulated proteins in these delivery systems.

Section snippets

Introduction and challenges with oral delivery route

Due to the rapid progress in biotechnology, the industry has produced a large number of therapeutic peptides and proteins on commercial scale. Over 130 biotechnologically derived drug products are approved by the US Food and Drug Administration (FDA) [1]. Most biopharmaceutical drug products (proteins, peptides, and vaccines) are administered parenterally because of their poor bioavailability from different alternate routes of administration, including the oral route. Poor intestinal absorption

Methods employed in preparation of biopharmaceutical oral solid dosage forms

Proteolysis (e.g. enzymatic, pH-driven, etc.) is a common problem throughout the gastro-intestinal (GI) tract, especially in the stomach and upper GI tract, thus affecting subsequent oral bioavailability of proteins and peptides. Overcoming the potential proteolysis, and thereby enhancing absorption through the GI epithelium and improving oral bioavailability, has been achieved mainly via protein and peptide encapsulation. For example, polymeric microspheres of poly(methacrylic-g-ethylene

Stresses encountered during manufacture of oral solid dosage forms and ways to improve in-process stability

During the manufacture of oral solid dosage forms proteins can be subjected to certain stresses that threaten their stability, such as extremes in heat, shear or pH, in addition to exposure to aggressive process steps from freezing and drying. This section will review the range of stresses involved. There are already excellent reviews elsewhere in this special focus edition and in other articles and books on the general topic of the stresses associated with freezing and drying, commonly used in

Formulation and stability aspects in oral solid dosage forms for biomacromolecules

A drug product for oral delivery of a biomacromolecule may have a more complex formulation compared to its parenteral counterpart. Formulations for oral protein and peptide delivery will usually contain the well-known ingredients in parenteral formulations that include the active ingredient, a suitable buffer (e.g. phosphate, citrate, histidine, succinate, etc.), a surfactant (e.g. polysorbates, pluronics) and a stabilizer (e.g. sucrose, trehalose). Theories proposed for explaining

Storage stability

Following manufacture, the drug delivery systems is typically stored for some time period prior to administration. While the storage stability of proteins in liquid or lyophilized formulations have been extensively described in the literature, significantly less information is available on the storage stability of proteins within biodegradable drug delivery systems, especially oral delivery systems.

In the authors’ own development of oral thin film (OTF) delivery systems, the storage stability

Summary and future prospects and trends

In spite of the major hurdles in oral delivery of proteins and peptides (in both liquid and solid dosage forms), oral delivery remains the major route of interest (and the holy grail of macromolecule delivery) in developing biologicals after parenterals. Because much of these preparations have not established potential oral bioavailability, work has been halted after animal testing. Some work has shown promising results with a few molecules, most notably with insulin. However, there are many

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    This review is part of the Advanced Drug Delivery Reviews theme issue on "Protein stability in drug delivery applications".

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