Controlled Release Moves Beyond Patent Extension

April 7, 2006
Prized for benefits that include reduced toxicity, controlled release — and the “manufacturability” issues it raises — is being considered much earlier in drug development process.

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.

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).

Polymeric micelles sequester active ingredient, helping to maintain solubility. Courtesy of Labopharm.

Felton has made a career of studying the interactions between the active material plus excipients (which she calls the “substrate”) and polymer coatings. Pharmaceutical-grade polymers, which are water-soluble, are sprayed onto the substrate using aqueous atomization, which initiates some dissolution and interaction between the medicine and coating material. Formulators would do well to take note of drug-coating interfaces, Felton says. “Sometimes we don’t observe the kinetics we expect due to coating-substrate interactions.”

The potential for these adverse interfacial events is multiplied in newer CR formulations consisting of multiple coatings, or those where drug is encapsulated into microbeads, then compressed into tablets. Depending on the solubility of the active analgesic ingredient and the thickness of the coating, a significant portion of drug can migrate into the polymer, which may then release the active ingredient before the dose reaches its target.

Newer technologies are eliminating the potential for unfavorable formulation chemistries. Melt extrusion, for example, uses a waxy excipient, melted intimately with the active. The combination is then extruded to create the dose. Another work-around is dry powder coating of active ingredients, which uses no water but requires a curing step. Still another is electrostatic deposition, which creates opposite static charges in polymer powder and active, driving the two materials together. This technology also requires a cure step.

Covering all bases

Covering all bases — soluble, insoluble, small-molecule, peptide-protein — is becoming a strategic advantage for technology-based drug delivery companies. OctoPlus (Leiden, the Netherlands) offers OctoDEX, a dextran-based microsphere for proteins, PolyActive, a biodegradable polymer for CR of proteins and lipophilic small molecules, and SynBiosys, a biodegradable polymeric drug-delivery system for the controlled release of peptides and small molecules.

The company is also working on an encephalitis vaccine delivery system based on its CR technology. The CR format reduces the need for two shots to one, according to CEO Joost Holthuis, while boosting the vaccine’s normal immune response. OctoPlus is planning a Phase II trial in Europe using a PolyActive version of alpha interferon which the company claims could work for six weeks or more. Highly active, low-dose, high-cost, frequently-administered interferons, interleukins and growth factors are all good candidates for the PolyActive formulation, says Holthuis.

Similarly, Labopharm’s (Laval, Quebec) Contramid Oral and Polymeric Nano-Delivery CR technologies cover the gamut of small, relatively insoluble drugs to large peptides and proteins. Based on a cross-linked high-amylose starch (classified as an excipient) and targeted for oral solid-dosage forms, Contramid releases active ingredients over a precisely adjustable period. Once ingested, it forms a semipermeable, three-dimensional matrix that releases poorly-soluble or pH-sensitive drugs at a constant rate for up to 24 hours. Contramid accommodates dosages of up to 700 mg.

Labopharm’s lead product, once-daily tramadol for moderate to severe pain, is based on the Contramid delivery system and reduces dosing from five to six tablets per day to just one. CR tramadol has been approved in Europe and is close to regulatory review in the U.S. Combined, those two markets present Labopharm with a potential yearly market worth $1.3 billion. The company is also working on once-daily versions of oxybutin (pain), betahistine (vertigo), trazodone (anxiety), and gabapentin (seizures, pain).

Dealing with insolubility

Labopharm developed Polymeric Nano-Delivery (PND) for drugs that are poorly water soluble and therefore cannot be administered safely or effectively either by infusion or injection. Many cancer drugs fall into this category. PND employs GRAS polymers which, when mixed with the target drug, self-assemble into nano-scale micelles that sequester the active ingredient and maintain its solubility. According to CEO James Howard-Tripp, Labopharm has determined that PND will work with peptides, genes and proteins, for both injectible and oral formulations.

Labopharm continues to perform contract dosage form and delivery research, but is slowly morphing into a technology-based pharmaceutical developer in its own right. The company is testing whether PND can help convert an intravenous oncology drug, paclitaxel, to oral form. “Paclitaxel is a good test case because so much data exists on it,” says Howard-Tripp.

Reaction vessels such as that shown here in Nektar Therapeutics’ Huntsville, Ala. facility are used in the manufacture of multi-kilogram batches of PEG reagents. Courtesy of Nektar.

Paclitaxel suffers from a double-whammy. The drug itself is toxic and almost insoluble. Intravenous formulations therefore utilize cremophor, a nonionic solubilizer and emulsifier manufactured by combining castor oil and ethylene oxide. Cremophor does a reasonably good job of solubilizing the drug, but it has been associated with nasty side effects of its own, such as pancreatitis and other life-threatening hypersensitivity reactions. A good deal of paclitaxel’s opportunity value is therefore lost through poor pharmacokinetics and toxicity.

The PND format is completely non-toxic, and can increase the solubilized paclitaxel dose by as much as fivefold. “Suddenly, paclitaxel is a much more attractive drug,” comments Howard-Tripp. “We can now get more of it into patients with less toxicity.”

Mechanical prolongation of drug release, although thus far dominating CR markets, is not the only strategy. Conjugation with polyethylene glycol (PEG; “PEGylation”) has created immense value for developers of protein drugs. When attached to proteins or peptides, highly water-soluble PEG polymer chains sustain bioavailability by protecting drug molecules from immune responses, proteolysis and other clearance mechanisms. The result is sustained availability that cuts dosing by factors of up to four. Think of PEG as a “molecularly endogenous” controlled release technology.

Nektar Therapeutics’ (Huntsville, Ala.) PEGylation, launched in the 1970s, has been so successful that new twists are emerging. Neose (Horsham, Pa.) is working on glycoPEGylation, which uses enzymes to attach PEG polymers through the glycans (sugars) added to proteins during their expression in mammalian cells. In glycoPEGylated proteins, the PEG moiety sits farther from the active site than in some PEG preparations, and therefore has less opportunity to interfere with protein activity. Researchers are also working on lipid PEGylation, which uses PEGylated lipids to form liposomes — microscopic vesicles with hydrophilic surfaces and hydrophobic interiors that can carry insoluble pharmaceuticals. PR Pharmaceuticals (Fort Collins, Colo.) combines PEGylation with more traditional CR microencapsulation to achieve sustained release plus controlled bioavailability. The company’s InsuLAR injected CR insulin product provides basal insulin for one week.

Early use of PEGylation strategy could keep more protein therapeutic companies from traveling down blind development alleys, says Tacey Viegas, Ph.D., Nektar’s senior R&D director. “Biotech companies should think about PEG during the discovery cycle, not the development cycle,” he says. Proteins often fail in early clinical trials due to immunogenicity or poor pharmacokinetics. Because of their size (up to hundreds of thousands of Daltons) and shapes (long chain, branched, star-shaped), PEG thwarts immune system cells while providing predictable circulating half-life and availability.

Through various tissue models and in vitro models, developers can get a pretty good idea of how their PEGylated proteins will behave in animals and humans. During development of Macugen, early studies in eyeballs found that the drug cleared too quickly. By testing various PEG molecular weights and morphologies, researchers optimized pharmacokinetics “ex vivo,” eventually settling on a branched, 40-kD polymer that gave the best pharmacokinetics.

PEGylation is not a panacea, as conjugation involves some protein loss. Reagents can attach PEG at cysteine (through a sulfhydryl group) or lysine (through nitrogen). Yields can be quite high through a shotgun approach that PEGylates every site, but that strategy may lead to diminished activity — too much of a good thing, so to speak. PEGylation targeted to either lysine or cysteine may produce a better drug, but is trickier to execute since both sites are reactive. Cysteine PEGylation yields range up to about 70%, while lysine conjugation is somewhat lower. Removing unPEGylated product can reduce the yield to 40%. Developers must balance loss of protein with possible loss of activity on one hand, and improved plasma half-life on the other.

Think Manufacturing

Manufacturers considering a CR formulation would do well to pay special attention to manufacturability, says Steve Howard, Ph.D., who chaired the January 2006 AAPS Arden Conference on oral controlled-release technology. Whether the formulated product is manufactured in-house or at a contractor’s facility depends on the complexity of the formulation. Early-stage materials are likely to be outsourced, however, if producing them involves significant capital expenses. “When we knew were doing something in a big-time way, we brought in pilot equipment and learned how to operate it from the equipment vendors,” says Howard of his days at Purdue Pharma and Johnson & Johnson.

When equipment must be added, vendors can be an invaluable resource for process know-how. For one project involving sustained release beads, ColorCon (West Point, Pa.) sold Howard’s company the production equipment and trained him in its use. For fluid-bed coating projects, Niro (Columbia, Md.) and Glatt (Ramsey, N.J.) were equally accommodating. Vendors of polymeric coatings freely provide materials-processing expertise as well. “An equipment purchase may be a one-shot deal, but if your NDA is approved you’ll be buying hundreds of kilograms of their materials over many years,” Howard notes. “These vendors are more than happy to demonstrate how their coatings work and will even find processors who can manufacture the final product.”

Contract formulators and specialty drug-delivery firms can provide a good deal of production expertise, which is most useful if they perform early-stage manufacturing or the sponsor is willing to take on this task. Otherwise, moving into preclinical or Phase I testing will necessarily involve a technology transfer step. “Contract labs that develop the formulation but can’t manufacture the drug might not be the best choice,” Howard notes. “You have to think a few steps ahead with respect to manufacturing.”

Often, drug sponsors with strong formulation expertise will try to design formulations around the equipment and expertise already on hand. But when in-house technology falls short, drug developers should budget for formulation early and generously. A high-tech drug delivery project can involve acquisition of new plant, equipment, expertise, or some combination of the three. Balancing the risk of this investment against the likelihood of a product succeeding is essential, says Howard. “I’ve seen companies construct new buildings just for formulation and the project subsequently failed.”

Finally, a development plan for a CR formulation must account, in some reasonable way, for the formulation’s manufacturability. For exotic CR oral and topical formulations, this means not only manufacturing millions of doses per month, but the ability to prove in regulatory filings that the components or ingredients are safe and available, and that the doses will be stable and consistent as formulated. Several speakers at the Arden House conference mentioned CR technologies that were scientifically awe-inspiring but could not be produced reliably to industry standards.

About the Author

Angelo De Palma | Ph.D.