Meeting the Challenges of Poorly Soluble Drug Compounds

“These approaches have enabled Eurand to develop products comprising one or more controlled release bead populations of weakly basic actives for absorption throughout the GI tract”
-Dr. Stephen Perrett, VP Portfolio Development, Eurand

Advances in science have allowed for better characterization of biochemical targets for drug development, leading to the proliferation of compounds with great potential to act on these targets – but in their natural state, nearly half of these are poorly suited to delivery in the body as needed due to low water solubility. Despite their challenges, the potential efficacy of these insoluble compounds is too compelling to ignore.

Instead of simply discounting drug candidates that present difficulties in terms of solubility, such as in cases where compounds have no solubility or the dose is high relative to solubility, Eurand has developed several approaches that overcome the limits of aqueous media.

Amorphous Drug Forms
The best known technique for addressing insolubility is the creation of what are called "solid solutions" containing non-crystalline, or amorphous, drug. In such a formulation, the drug is taken into solution with another material – generally a polymer – either through melting and/or through the use of a solvent. The mixture is then cooled or the solvent evaporated. The presence of the polymer prevents the drug from crystallizing and holds it in a molecularly dispersed state, analogous to it being in solution.

There are some limitations associated with this technique: (1) the drug still needs to exit the bulk of the formulation while being prevented from agglomerating or re-crystallizing; (2) the technique requires the use of heat and/or solvent; and (3) there is an inherent physical instability in such an amorphous form.

In theory, these are significant challenges; however, there have been some commercialized successes using this technology, including Prograf® (tacrolimus) and Sporanox® (itraconazole) capsules.

Biorise® Technology
Biorise®, a technology developed by Eurand, involves the use of a specific type and configuration of high energy mechanical mill, along with a specific type of stabilizing agent – generally a polymer (Figure 1) – to create drug forms from insoluble compounds. The milling process does not generate appreciable heat and no solvent is used. The polymers used are standard GRAS (generally recognized as safe) tablet excipients. The conditions used and energy input can be adjusted so that product can progress from microcrystalline, to nano-crystalline, to amorphous drug. The polymer is effective in preventing the processed drug, which is generated by the high energy input, from either agglomerating (in the case of nano-crystal formation) or reverting back to the crystalline form (in the case of amorphous drug production).

Figure 1

The polymer used is generally highly cross-linked and undergoes a reversible deformation of its network during the milling process, providing a system that is able to accommodate the drug on a molecular basis. The amorphous drug form is effectively stabilized within this polymer network, which physically interacts, constrains and limits the movement of the drug material to prevent re-crystallization. The introduction of the dry powder to an aqueous environment results in a swelling of the polymer network and, through this agency, the drug is able to exit its support. This presents the drug in the form that has the best chance of crossing an absorptive surface, in a manner analagous to a true solution.

In the case of nano-crystalline drug, the polymer is also effective at stabilization, through an interaction with the crystal surface on a macro scale that keeps the drug particles from coming together.

This technology can also be expanded upon by incorporating other approaches to create soluble drug forms, such as complexation of the drug with cyclodextrin in an essentially non-aqueous process, or by using some solvent or solvent vapor.

Figures 2 and 3 illustrate different aspects of the Biorise® technology and the attainment of different desired clinical endpoints - demonstrating the effectiveness and versatility of the technology, and the degree to which it is possible to adjust the pharmacokinetic profile of the drug. In Figure 2, for example, the milling process and a cross-linked polymer were used, increasing the speed of onset and the overall bioavailability of the drug. In Figure 3 solvent was used, greatly increasing the bioavailability but with a much less pronounced effect on the speed of onset.

Diffucaps® Technology
Certain drugs have aqueous solubility under only some of the conditions of pH encountered physiologically. Carvedilol and dipyridamole, for example, are soluble in the acidic conditions of the stomach, but are effectively insoluble in the neutral/slightly alkaline conditions found in the intestine.

The Diffucaps® technology involves the application of one or more sequential coats of functional polymers to drug-containing core particles – such as beads, pellets, or micro- or mini-tablets provided with an inert seal-coat – to modify the release of the drug (Figure 4). In this way, the formulation can be easily devised to sustain release of drug over several hours after a predetermined lag-time following oral administration. The finished product could be a modified-release capsule, a conventional tablet or an orally disintegrating tablet consisting of one or more coated spherical bead populations to allow for a once- or twice-daily dosing regimen.

Figure 4

The most difficult candidates to work with are weakly basic pharmaceutically active ingredients comprising N-containing moieties with a pKa of less than 14, which are practically insoluble (less than 50 ųg/ml) at a pH>5 and have a daily dosing requirement of over 10mg. However, many of these drugs are fairly soluble under acidic conditions.

The proprietary technology developed for these weakly basic drugs involves the incorporation of a pharmaceutically acceptable organic acid or a crystallization-inhibiting polymer onto inert cores, and coating the drug-layered beads with proprietary functional polymers. These approaches have enabled Eurand to develop products comprising one or more controlled release bead populations of weakly basic drugs for absorption throughout the GI tract, which are currently in the clinic.

Eurand's proprietary technology reliably overcomes the issues associated with pH-dependent insolubility. Combined with its controlled release technologies, long-acting formulations of challenging immediate-release products can be developed, resulting in more convenient dosing schedules, better control of drug levels in the plasma, and ultimately, better compliance and fewer side effects.

Stephen Perrett
Stephen Perrett is the Vice President, Portfolio Development at Eurand. He is responsible for the internal pipeline at Eurand through re-formulation, in-licensing and drug polymer conjugation. Dr. Perrett has over 18 years experience in the specialty pharmaceutical and the drug delivery Industry and has worked in the U.K, France, Italy and the USA. He obtained his Ph.D. from Kings College London and his MBA from the Ecole de Management de Lyon and Carnegie Mellon University, Pittsburgh, PA.

Gopi Venkatesh
Gopi Venkatesh is currently R&D Director, Eurand USA. He has over 20 years of pharmaceutical industry experience in the fields of drug delivery, development of novel controlled-release dosage forms and physics of compaction of pharmaceutical materials. He has worked in the solids formulations group in the Pharmaceutical Technology Department at SB Pharmaceuticals, King of Prussia, PA. His responsibilities include the development and application of novel technologies to in-house pipeline and client-sponsored active compounds. Dr. Venkatesh earned his PhD degree from Indian Institute of Science, Bangalore (India).

About Eurand (NASDAQ: EURX)
Eurand is a global specialty pharmaceutical company that develops, manufactures and commercializes enhanced pharmaceutical and biopharmaceutical products based on its proprietary drug formulation technologies. Eurand has had five partnered products approved by the FDA since 2001 and has a pipeline of product candidates in development for itself and collaboration partners.

Eurand has a strong track record of developing products using its innovative drug formulation technologies. With integrated manufacturing and R&D facilities in the U.S. and Europe, the Company has four primary technology platforms:

• Customized Drug Release
• Bioavailability Enhancement
• Taste Masking / Orally Disintegrating Tablets (ODTs)
• Drug Conjugation

These platforms include nine distinct technologies and are covered by more than 300 patents. Eurand uses these technologies to develop and expand the Company's own internal pipeline and to partner with pharmaceutical and biopharmaceutical companies to develop their products. For more information, feel free to visit our website at www.eurand.com.