Controlled Release Moves Beyond Patent Extension

Prized for benefits that include reduced toxicity, controlled release — and the “manufacturability” issues it raises — is being considered much earlier in drug development process.

By Angelo De Palma, Ph.D., Contributing Editor

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Next to discovery of new chemical entities, drug delivery has become the method of choice for differentiating pharmaceutical products within a therapeutic or molecular class. Applicable to oral, injectible, topical and implantable delivery, controlled release (CR) provides a straightforward route to new products with reduced toxicity and side effects, more desirable pharmacokinetics and better patient compliance.

Until recently, CR was viewed primarily as a lifecycle management tool, which some observers unjustly criticized as mere “gaming” of the patent and regulatory system. Specialized drug-delivery technology was the nearly exclusive domain of boutique delivery companies, which maintained tight reins on their intellectual property. Large pharmaceutical companies maintained in-house formulation development, but only as a backup.

Controlled Release article: man in isolation chamber at OctoPlus
A technician in the OctoPlus pilot plant, which produces microspheres on a preclinical and clinical scale. Courtesy of OctoPlus.

Today, drug developers consider CR technologies early as an integral part of drug development, and even discovery. They also consider manufacturability (see Think Manufacturing, below) sooner than ever, and some may even tinker with esoteric delivery systems through their own formulation groups.

CR strategies are becoming more common as drug developers struggle to replace pipeline compounds with new products. CR formulations offer companies breathing room through new products that maximize usage, patentability and return on investment for existing portfolio products or generics.

CR also offers entrée into combined products, according to Jack Cardinal, a consultant who has worked in drug delivery and development at several top pharmaceutical companies. Cardinal’s last project, at Andrx (Plantation, Fla.), combined a CR form of the diabetes drug metformin with another insulin sensitizer, piaglitazone.

Cardinal sees combination products as the logical continuation of CR technology, provided that either the combination or the introduction of one or two CR formulations adds clinical benefit — sometimes the combined efficacy is not enough. “Added value often comes from the controlled release, which, by decreasing peak plasma levels of the drug, decreases side effects,” he says.

CR’s status as an advanced delivery technology has led to heavy patenting in this area, and more than the usual amount of contract manufacturing, outsourced development and in-licensing. Although this model still dominates, the leverage held by CR patent-holders has been lessened by fierce competition.

Consider osmotic delivery, in which tablets absorb gastric fluids and swell, forcing the active ingredient out through a microscopic hole. Alza Corp. (Mountain View, Calif.) once had a lock on osmotic CR delivery, but specialty companies like Andrx, Shire (Hampshire, U.K.) and Osmotica (Boca Raton, Fla.) soon developed osmotic delivery systems of their own.

Osmotica has since moved on to apply its know-how to develop a combination anti-allergy drug that contains both pseudoephedrine and fexophenadine, while Andrx applies its osmotic technology to its Fortamet CR metformin and a once-daily lovastatin product for cholesterol lowering.

Manufacturability is always a concern with advanced delivery technologies, which is why so much of this work has typically been outsourced. Since formulations must behave physically and mechanically as well as pharmacologically, drug companies may become even more concerned than usual about quality control. “All these products have fairly narrow regulatory specifications,” Cardinal adds.

Biopharma the next frontier

Although most of the excitement surrouncing CR has, so far, been restricted to small molecules, biopharma delivery is the future, says Vitthal Kulkarni, Ph.D., principal research scientist at the contract manufacturer and formulator DPT Laboratories (San Antonio, Texas). DPT develops custom formulations based on its own patented, multi-vesicular emulsion system, for topical delivery. The company can also manufacture drugs using in-house or licensed CR technology. “Our clients typically have a good idea of what the final dosage form will look like,” Kulkarni says.

A new formulation project at DPT begins with preformulation studies that provide data on drug solubility and compatibility with anticipated excipients. This exercise leads to prototype formulations, which development scientists characterize and monitor for stability, and subsequently bring to pilot scale.

CR presents a separate level of manufacturing complexity, which is why many innovator companies outsource development and small-scale production. CR formulations demand extra precautions and precise monitoring to assure product integrity down to the particle level. Many CR-specific ingredients are sensitive to heat, pH, mechanical disruption and the co-mingling of aqueous or non-aqueous excipients. Natural product raw materials such as starches must be rigorously sourced and monitored for consistency, Kulkarni says.

Biodegradable polymers have been the workhorses for CR formulations for many years. GRAS (generally recognized as safe) polymers provide a range of release profiles, from simple mechanical protection (delayed release, as in enteric-coated aspirin) to semipermeable materials that release drug as the dose moves through the digestive tract. Fabricated into microspheres, tablets or capsules, polymers offer relatively straightforward manufacturing and predictable kinetics. “But just when you think they’re simple, something happens,” says Linda Felton, Ph.D., associate professor of pharmacy at the University of New Mexico (Albuquerque).

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