For many years, pharmaceutical and academic scientists have sought ways to deliver protein and peptide therapeutics by the oral route. Many encouraging results from animal experiments have been published and offer insights into the prospects of translating these discoveries to delivery systems suitable for human use. To date, the only accepted delivery systems for macromolecules in man are parenteral or pump. There are, however, a wide variety of techniques and formulations that have been applied to overcoming this challenge and paving the way for oral delivery of macromolecules.

The vast therapeutic potential of proteins and peptides has prompted biomedical scientists to greatly expand research into producing active macromolecules for treating human diseases. As a result of this research, there are over 350 peptide and protein drugs in various stages of clinical development. Many other candidates will likely be identified as genomic studies successfully translate genetic data into knowledge about proteins and their functions.

The broad availability of therapeutically potent macromolecules has not been matched by a diverse array of dosage forms for clinical development, mostly because of the poor delivery properties of peptide- and protein-based products. The most common means for administering protein drugs is intravenous, intramuscular, or subcutaneous administration. Delivering therapeutically active proteins and peptides by any route has been a challenge and a goal for many decades. Among the alternate routes that have been tried with varying degrees of success are the oral, buccal, intranasal, pulmonary, transdermal, ocular, and rectal approaches. Oral delivery stands out from among these alternatives due to the high levels of patient acceptance and long-term compliance, avoidance of pain and discomfort associated with injections and greater convenience.

The oral route of administration is among the most problematic of delivery regimens for several reasons. Delivery via the gastrointestinal (GI) tract requires that therapeutic proteins be exposed to the same digestive processes that are designed to degrade them. The GI tract has innumerable ways to digest nutrients and dietary materials into small molecules and to prevent the indiscriminate passage of macromolecules into the systemic circulation.

In spite of these obstacles, there is substantial evidence that pharmaceutical polypeptides can be absorbed through the GI tract and that properly formulated proteins or peptide drugs may be delivered by the oral route. This does require a multitude of strategies. , The dosage form and packaging must protect the drug from environmental effects. The formulation must then protect the protein from pepsin and the high acidity of the stomach. Once the protein drug reaches the intestine, there must be some means of protecting the drug from enzymatic digestion. Then the formulation must facilitate both aqueous solubility and lipid layer penetration in order for the protein to cross the intestinal membrane for entry into the bloodstream.

The general approaches that have been used to successfully achieve the formulation development goals for oral delivery include: minimizing enzymatic degradation, enhancing intestinal absorption, and facilitating aqueous solubility and dissolution. Nearly every oral dosage form used for delivery of conventional small molecule drugs has been used to explore oral delivery of polypeptides. There have been a few human clinical trials where adequate bioavailability and pharmacokinetics have suggested that the successful oral delivery of proteins can be achieved, but so far nothing commercially viable has emerged.

A number of researchers have evaluated protease inhibitors to reduce the degradation of protein therapeutics the GI tract. Their belief was that slowing degradation will allow more of the protein drug to survive and be available for absorption. Two of the main intestinal enzymes are trypsin and chymotrypsin. Some inhibitors of these enzymes include pancreatic inhibitor, soybean trypsin inhibitor, FK-448, camostat mesylate and aprotinin. Another formulation development approach to enzyme inhibition is to manipulate the pH to inactivate local digestive enzymes. A sufficient amount of a pH-lowering buffer that lowers local intestinal pH to values below 4.5 can deactivate trypsin, chymotrypsin and elastase.

Using permeation enhancers is another tactic to improve the absorption of protein drugs. These can operate by increasing either paracellular or transcellular transport systems. An increase in paracellular transport can be achieved by opening the tight junctions of the cells; an increase in transcellular transport can be achieved by increasing the fluidity of the cell membrane. Paracellular permeation enhancers include calcium chelators, bile salts and fatty acids. Transcellular permeation enhancers used in formulation development include surfactants, medium chain fatty acids, non-ionic surfactants sodium cholate and other bile salts.

Nanoparticles can be used as particulate carriers to deliver protein drugs orally. Some investigators have shown that particles in the nanosize range are absorbed intact by the intestinal epithelium, especially, Peyer’s patches. The proteins encapsulated in these nanoparticles are less sensitive to enzyme degradations because they are isolated from the intestinal fluids by their polymer coating. Other researchers demonstrated that proteins in nanoparticle formulation development have better absorption through the GI track compared to their native counterpart. The factors affecting the uptake include; particle size, surface charge,, influence of surface ligands and the dynamic nature of particle interactions in the gut. Considering the generally low encapsulation efficiency of the protein in nanoparticles and the variable nature of nanoparticle absorption, this technique will need more study to make a commercially viable delivery system.

Liquid emulsions are another formulation development approach for the oral delivery of proteins and peptides. These are formulations whereby oil and water are mixed in a way that small uniformly shaped oil droplets are dispersed in the water phase (oil in water) or water droplets are dispersed in a continuous oil phase (water in oil). An emulsion appears as a cloudy suspension. When an oil in water emulsion has oil droplets so small as to produce a clear solution, the formulation is called a microemulsion. The oil phase of the emulsion can provide protection for lipophillic proteins from enzymatic digestion while the product is in the intestinal tract. Water in oil microemulsion formulations have been developed for oral insulin delivery. Human clinical investigations have been conducted with a chemically modified insulin formulated as an emulsion. These studies showed control of postprandial glucose levels after oral administration thus indicating that a significant amount of protein was delivered through the GI tract and there is potential for an orally delivered therapeutic protein treatment.

Because there is a hydrophobic component to all emulsions, they can protect the drug from chemical and enzymatic breakdown in the intestinal lumen by limiting the drugs’ aqueous exposure. There are several examples of water-in-oil microemulsions that have enhanced oral bioavailability of proteins and peptides. Micelle systems are another form of emulsions; these can be either water based or oil based. Recent experience with self-emulsifying or mixed micelles based lipid formulations products, such as Sandimmun Neoral (cyclosporin), Norvir (ritonavir) and Fortovase (saquinavir), has caused an increase in interest in the application of lipid based micelle formulation to improve oral delivery of protein and peptide drugs.

Liposomes have been studied as a way to deliver peptides and proteins orally as well. However, liposomes are prone to degradation from the acidic pH of the stomach, from bile salts and from pancreatic lipase. Where liposomes have demonstrated increased bioavailability, it was not clear if the liposome was absorbed intact, or if the lipid has increased permeation at the site of absorption. This technique has not garnered as much promise as other formulation alternatives.

Delivering therapeutic proteins and peptides orally is very challenging. The digestive system is designed to break down these macromolecules into amino acids prior to absorption. Therefore techniques and formulations have to protect against the acidity of the stomach and the natural enzymatic processes of digestion. Once that protection is provided, the formulation or delivery system must enhance the absorption across the epithelial layer. These challenges are likely to be overcome only by using multiple formulation development approaches simultaneously.

Richard Soltero, Ph.D., President of PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We design and direct IND enabling programs for biotech and pharma.

Richard Soltero, Ph.D., President of http://www.PharmaDirections.com, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We design and direct IND enabling programs for biotech and pharma companies.

Author Bio: Richard Soltero, Ph.D., President of PharmaDirections, a pharmaceutical consulting and project management company specializing in preclinical development, formulation development and regulatory affairs. We design and direct IND enabling programs for biotech and pharma.

Category: Medical Business
Keywords: Pharmaceutical Consulting, Project Management, Formulation Development, Preclinical, CMC