Pharmaceutical Commerce - April 2010 - (Page 23)

Packaging & Drug Delivery Drug-Delivery Technologies for Controlled Release Score With Manufacturers The types of delivery mechanisms that vary the uptake of a drug are multiplying By Nicholas Basta The picture for drug-delivery technologies that alter an oral solid’s pharmacokinetics—primarily controlled- (or -extended) release technologies, but including fast-dissolve, taste-masking, enteric coatings and “abuse/misuse deterrent”—is looking fairly bright these days. One of the drivers has been the longstanding search for ways to convert injected drugs into pills or tablets. Controlled release (CR) has traditionally been a desirable option for brand owners looking to extend the patent life of their products, and while that still occurs, the trickle of drugs that have used these delivery enhancements for other reasons is turning into a steady flow. In the past year, FDA has approved a number of these drugs, across diverse therapeutic classes: Last month, Acorda Therapeutics (Hawthorne, NY) announced availability of Ampyra (dalfampridine), a potassium channel blocker indicated for improving the walking ability of multiple sclerosis patients. The drug, an extended-release tablet, uses the MXDAS technology of Elan Drug Technologies (King of Prussia, PA), and consists of a hydrophilic matrix that controls the uptake of the drug in the gastrointestinal tract. While this is the first commercially approved application of MXDAS, Elan has been involved in the commercialization of a dozen other products featuring its family of drug-delivery technologies since 2000. In February, Labopharm Inc. (Laval, QC) won FDA approval for Olpetro (trazodone hydrochloride), an antidepressant formulated with the company’s Contramid CR technology. Contramid also figures in Labopharm’s previous FDA approval, for the analgesic Ryzolt (tramadol), marketed in partnership with Purdue Pharma. Last August, Eurand (Amsterdam, Netherlands; US HQ in Philadelphia) won approval for Zenpep (pancrelipase), a delayedrelease enzyme indicated for cystic fibrosis and pancreatic conditions (Pharmaceutical Commerce, Jan/Feb, p. 9). It is the first proprietary product from Eurand, which offers several types of CR technology, including the Minitabs formulation used in Zenpep. Last October, Unigene Laboratories (Boonton, NJ) licensed its Phase III development product, oral calcitonin, to a newly formed venture, Tarsa Therapeutics, in which it will retain partial ownership. Calcitonin, indicated for treating osteoporosis, is a peptide normally administered by injection or intranasally; Unigene has a formulation with an enteric coating to get the drug past the stomach, and an “absorption enhancer” to facilitate uptake. Emisphere Technologies (Cedar Knolls, NJ) is about to launch Eligen B12, an oral form of vitamin B12, which is normally provided to anemic patients via injection. Emisphere’s drug-delivery technology, Eligen, comprises a library of “delivery agents” that facilitate the transfer of complex biomolecules across the gastrointestinal lining. This product will be FDA-regulated as a “medical food” rather than a prescribed drug, but requiring medical supervision to be administered. Emisphere is working on delivery of peptides, hormones and proteins. Arguably the biggest recent announcement—but one with a mixed message for CR advantages—is Purdue Pharma’s approval of reformulated Oxycontin (hydrocodone) this month. Purdue has said very little about the CR technology applied; one publication, Bioworld Today, called it simply “a drug coated in a plastic-like polymer.” In announcing the approval, Purdue said that the reformulated product is bioequivalent to existing Oxycontin dosages, and that while the reformulation is intended to lower the misuse of this much-abused drug, “there is no evidence that the reformulation of OxyContin is less subject to misuse, abuse, diversion, overdose or addiction.” The concentration of a drug in the bloodstream is a key determinant both in efficacy and toxicity for many drugs, notes Patrick Crowley, head of Callum Consultancy (, former VP of pharma development at GSK, and who will be delivering a keynote address at this summer’s Controlled Release Society annual meeting. “Determining the appropriate concentration of a drug in the body remains a diffi- cult research problem in drug development, holding back the application of many CR technologies,” he says. New science in biomarkers could open up the field, which in turn could bring more drugs through commercialization. Datamonitor (London) estimates that oral medications accounted for 58.8% of prescription pharmaceutical revenues in 2009, making them the dominant revenue-generating drug-delivery type. Worldwide, oral drugs enjoyed sales of $460 billion in 2008, based on a consensus market figure (from several market studies) for worldwide pharmaceutical sales of $780 billion. Datamonitor predicts that the market share for oral formulations will decline by 2014 to 53.2% due to approvals of injectable drugs, mostly biologics, which are forecast to grow from 28.7% of the market in 2009 to 34.2%. Annual sales figures, however, misrepresent the extent of oral-solids usage, and of the potential for CR and related technologies, primarily because generics manufacturers (who are the beneficiaries of the patent cliff that branded pharma companies are facing) are latching onto CR technologies to differentiate themselves from each other, and to align with the CR formulations that many pharma manufacturers have applied to their products near the end of their life cycle. Mylan Pharma (Pittsburgh), for example, has announced in the past few months approved ANDAs for a delayed-release version of didanosine, an AIDS treatment that is the generic version of Bristol Myers Squibb’s Videx; for buprion hydrochloride extendedrelease tablets, the generic of GSK’s Wellbutrin SR; and a licensing agreement with Pfizer for venlafaxine HCl extended-release capsules, the generic version of what had been originally Wyeth’s Effexor, a treatment for major depressive disorder (and a $2.9-billion product during a recent 12-month period, according to IMS Health). In the latter case, Mylan will be in a position to launch in mid-2011. According to The Freedonia Group (Cleveland, OH) controlled/sustained release, with about 80%, was the predominant valueadded oral formulation technology in 2007, followed by chewable (9.3%), disintegrating (4.2%), nanoparticulate (4.1%), and transmucosal (1.8%). Freedonia expects demand for these technologies to double between 2007 and 2017. Aside from the pharmacology, CR and related formulations must navigate sticky payer and physician obstacles. Creating a new drug that, say, carries a nonsoluble biomolecule into the intestine via an innovative drug delivery mechanism is a clear benefit. But adapting CR technology to convert a twice-aday pill to a once-a-day depends on the cost of the reformulation and how strong the patient benefit is. “Now, you have price points to deal with. Payers’ position today is, ‘If you want your super-duper once-daily dose that’s up to you, but if there’s no therapeutic benefit we will not pay more than for the generic,’” says Angus Forster, principal consultant at PA Consulting Group (London). CREDIT: EURAND Technology options multiply Pharmaceutical formulators have worked with combinations of excipients, especially starches and cellulosics, for years to adjust the bioavailability of the active ingredient. The drug delivery technology vendors have taken those excipients (and other compounds) and have devised methods to agglomerate or otherwise tailor the excipients so that the active ingredient is delivered in a measured fashion. Examples include: • Elan’s family of oral controlledrelease technologies (Spheroidal Oral Drug Absorption System, SODAS; Matrix Drug Absorption System, MXDAS, Intestinal Protective Drug Absorption System, IPDAS; and others). The company is also enjoying success with NanoCrystal Technology, a method to produce ultra-finely-divided particles combined with CR techniques to improve the bioavailability of poorly water-soluble drugs. The first product using the technology was Wyeth’s Rapamune in 2001; the latest is J&J’s Invega Sustenna (paliperidone palmitate), approved last July, a treatment for schizophrenia whose long-acting formulation continued on page 24 > Fig. 1. Labopharm’s Contramid technology used crosslinked starch to create a matrix out of which active ingredient gradually is gradually released. APRIL 2010 23

Table of Contents for the Digital Edition of Pharmaceutical Commerce - April 2010

Pharmaceutical Commerce - April 2010
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Pharmaceutical Commerce - April 2010