From Needle to Pill: Reformulating Injectable Drugs for Oral Delivery

This article is part of PharmTech's supplement "Injectable Drug Delivery."

Most biologicals and some small-molecule drugs are best administered through injections. Although this delivery route has its advantages, economic considerations, side effects, and practical concerns could dissuade some patients from maintaining full compliance with a parenteral-drug regime. Technological advances now make it possible to reformulate some injectable drugs for administration through other delivery routes.

One company pursuing this goal is formulation specialist Merrion Pharmaceuticals (Dublin), which develops improved tablet and capsule dosage forms of drugs with poor bioavailability, including injectable and intravenous forms. Merrion uses an oral drug-delivery technique called Gastrointestinal Permeation Enhancement Technology (GIPET) to produce oral formulations (i.e., tablets or capsules) of drugs that are now only given parenterally. The company acquired GIPET from drug developer and manufacturer Élan (Dublin) in 2003, when the latter company refocused its activities. The technology can be applied to a wide range of compounds with various physiochemical properties and molecular weights, including traditional small molecules and biopharmaceutical peptides and proteins.

The GIPET method uses a mixture of the therapeutic drug and various small- and large-molecule enhancers to improve absorption and bioavailability. The enhancers activate the formation of micelles, which become a passive transport system for the drug, helping to carry it efficiently within the body. With GIPET, Merrion has achieved increases in bioavailability from five- to 200-fold, and this increase is achieved consistently from patient to patient.

Unlike other reformulation techniques, the GIPET technology does not chemically modify the drug. The therapy's previously established safety profile therefore remains unchanged. GIPET consequently eliminates the need for further toxicity studies and greatly reduces development time for the new formulation.

Figure 1: Demonstration of how the GIPET technology works. (FIGURE IS COURTESY OF MERRION)

To choose which enhancers to use to reformulate a parenteral drug, Merrion's scientists perform simple preclinical studies. Rapid experiments are carried out with liquid formulations that mimic what happens in the body after a tablet releases its drug load. The experiments' model allows scientists to screen various formulations that increase bioavailability and seek formulations that will release the drug quickly. After results are obtained, scientists can decide which formulation shows the most promise and begin the proper formulation-development process for a tablet.

Formulators ensure that the drug and enhancers are mixed into a uniform blend and compressed evenly. Enteric coatings that protect the formulation from stomach acid are added as appropriate. For example, these coatings are important for formulations that incorporate fragile peptides.

The GIPET technology uses ingredients that are generally recognized as safe by the US Food and Drug Administration. Because the reformulated drugs have already received the necessary regulatory approvals, their time to market is swift compared with that for drugs developed from scratch. Drug manufacturers can use abbreviated regulatory pathways that rely on the known efficacy and safety properties of the established drug.

GIPET has helped Merrion to develop its own products, including Orazol (MER 101), an oral bisphosphonate traditionally administered intravenously as an oncology treatment. Biophosphonates are a class of drugs that are poorly bioavailable, and their presence in the intestinal tract is associated with side effects. In addition, infusions of zoledronic acid or Novartis's (Basel) Zometa are associated with reduced kidney function and flulike symptoms.

GIPET technology has helped Merrion overcome these hurdles, which had hindered the development of a tablet form of the drug. The technology increases the drug's bioavailability by at least fivefold, and this increase results in a consistent, improved absorption. It also reduces the amount of drug that could remain in the intestinal tract and potentially cause side effects. Orazol is also well tolerated and has not been associated with flulike symptoms.

The product, which has completed Phase II development, can be given weekly, instead of monthly infusions. The tablets therefore have a different absorption profile and do not require the kidney to process as much drug at a time. Orazol is intended to produce therapeutic results equivalent to those of infusions and offer a better experience for the patient than infusions, in terms of quality of life, side effects, and safety.

During the first half of 2009, the final results of a multicenter Phase IIb cancer-patient study showed that weekly therapy with 20-mg Orazol tablets was as therapeutically effective as monthly treatment with Zometa.

Merrion also used GIPET to develop MER 102 (fondaparinux), which the company intends to introduce as the first oral product in the class of low molecular-weight heparin drugs. These drugs are primarily used to prevent deep-vein thrombosis and are given prophylactically through daily subcutaneous injections after surgery to prevent the formation of blood clots. MER 102 is an anticoagulant designed to replace daily injections and is now in preclinical testing.

Merrion has used GIPET in its collaborations with pharmaceutical companies such as Novo Nordisk (Bagsværd, Denmark). The companies signed a development and license agreement for the oral formulation of insulin analogues with GIPET in November 2008. In January 2009, the firms signed a second agreement for the development and commercialization of Novo Nordisk's GLP-1 receptor agonist using GIPET technology.

Merrion is also collaborating on drug-delivery research with Ferring Pharmaceuticals (Saint-Prex, Switzerland). The companies are studying the ability of GIPET technology to provide a significant increase in an undisclosed compound's bioavailability.

Erik Greb contributed to the reporting of this article.

Anna Nolan is a freelance business, science, and technology journalist based in Cratloe, County Clare, Ireland, anolan@iol.ie