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 delayed-release 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 (callumconsultancy.com), 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 difficult 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 extended-release 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 value-added 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-a-day 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).
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 controlled-release 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 allows for one injection monthly.
• Eurand’s Minitabs, used in its just-approved Zenpep product, involves a functional membrane that coats small (2-mm-dia.) tablets, which are in turn contained in a capsule. Other technologies (Diffucaps, Diffitab, Orbexa) involve a combination of shaping drug particles, then coating them with polymers. Similar techniques are used with its oral-dissolving technologies, Advatab, Liquitard and Microcaps, to provide taste-masking and controlled bioavailability. Advatab is used in GSK’s Lamictal (lamotrigine), introduced in mid-2009 for bipolar disorders.
• Labopharm’s Contramid technology involves a “crosslinked, high-amylose starch” that creates a matrix within which the active ingredient is held. The matrix controls the release of the drug; Labopharm says that it can also release multiple drugs with different release rates from the same matrix. The company is also commercializing the Polymeric Nano-Delivery System, which involves creating micelles (roughly speaking, a soap bubble) that can carry an insoluble molecule into the bloodstream. Most recently, it entered the misuse/abuse arena for opiods with Intellitab technology, a method said to maintain the opioid’s CR properties even if a tablet is crushed.
Opioids (hydrocodone, oxycodone, morphine) are being reformulated by several companies besides Purdue Pharma to counter the abuse potential. Last year, FDA cleared King Pharmaceutical’s (Bristol, TN) application for Embeda (morphine), which combines the opioid with an “antagonist”—naltrexone—that counters the effects of the opioid. In principle, crushing the drug or dissolving it in alcohol to defeat the extended-release feature will also release the antagonist.
However, King has struck out, for now, with another reformulation, Acurox, of short-acting oxycodone combined with niacin, a deterrent technology in which King partnered with Acura Pharmaceuticals (Palatine, IL). In late April, an FDA committee voted that it did not have enough evidence to support the approval of the drug (incidentally causing Acura’s stock value to drop by half in one day). King is also struggling with another misuse/abuse opioid project, Remoxy, in which oxycodone is formulated with a tar-like hard liquid, again, to prevent the drug’s immediate release by crushing or dissolving. FDA rejected the application, calling for more data. King has continued with data collection on Remoxy, but no decision has been announced yet for Acurox.
Peptides and proteins
Oral drugs must be at least partially water-soluble or they will not enter the bloodstream. But overcoming poor solubility by no means suffices for making a successful pill or tablet. Peptides and proteins are highly soluble yet have poor oral bioavailability because the stomach digests them as it does food. And many small-molecule drugs, whether soluble by nature or as a result of formulative legerdemain, may still not absorb in the right place along the digestive tract.
Still others may have a therapeutic index (roughly, the quantity of a drug that helps compared with the dose that harms) so narrow that oral delivery is simply not worth pursuing. Insulin in tablet form is a long shot because the vagaries of the digestive tract are incompatible with precise dosing. Other proteins, like monoclonal antibodies, are given in such high doses anyway that pill forms – if the drugs could be made orally bioavailable at all – would raise serious cost-of-goods issues.
While oral delivery of peptides and proteins has improved considerably, success depends on the interplay between bioavailability, cost of goods, therapeutic index, and the need for precision dosing. That is why Warren Levy, PhD, CEO of peptide specialty firm Unigene Laboratories (Boonton, NJ), believes the industry will likely never see a successful insulin pill. “Peptides are difficult to manufacture and their stability is always an issue. They’re not user-friendly, either for the patient or the supply chain.” The key to success for peptide pills, Levy tells Pharmaceutical Commerce, is selecting economically-produced molecules that do not require precision dosing.
Besides the calcitonin product licensed to Tarsa Therapeutics, Unigene has licensed its calcitonin manufacturing technology to Novartis, but in that case Novartis plans to use Emisphere Technologies’ Eligen delivery technology. Both products are in Phase III and whichever one succeeds, Unigene wins. The company also has a phase I program for oral parathyroid hormone, another osteoporosis peptide, with GlaxoSmithKline.
In commenting on Eligen’s applicability, Emisphere CEO Michael Novinski says that it works best with with highly soluble drugs. “Lipophilicity is definitely limiting,” says CEO Michael Novinski. “Smaller peptides are the best, but Elligen can accommodate larger ones as well.” The company announced in March that Alchemia (Brisbane, Australia) will jointly develop a pill form of the injected anti-coagulant drug fondaparinux. The medication, better known as Arixtra (GlaxoSmithKline), went off-patent in 2002 but because it is so difficult to manufacture no generic has emerged. Alchemia has devised a highly efficient synthesis for fondaparinux that significantly improves prospects for a pill form.
One wonders, for mega-markets like diabetes drugs – Datamonitor estimates $20 billion in 2008, $37 billion by 2018) – about how significantly custom thwarts or delays innovation. Pfizer’s spectacular write-off of its Exubera inhaled insulin in 2007 immediately comes to mind, while in March, 2010 FDA rejected Mannkind’s inhaled insulin product, Afrezza, citing issues with the delivery device.
As dead as inhaled insulin appears, the quest for an insulin pill continues. In December, 2009, Merrion Pharmaceuticals (Dublin, Ireland) announced that Novo Nordisk had initiated a phase I study for an oral insulin pill formulated with Merrion’s GIPET delivery technology. GIPET combines excipients that enhance GI absorption. Unlike most such formulations, GIPET works with a broad range of chemical structures, improving bioavailability by up to two hundred-fold for some compounds, according to the company. While bioavailability is certainly an issue for oral peptide drugs, the critical issue for insulin is the ability to absorb – and not just deliver – precise doses.
One of Merrion’s pipeline products, Orazol, is a tablet form of the intravenous cancer drug zoledronic acid. The company expects Orazol to enter phase III testing this year. “Orazol provides tremendous benefit to patients,” says CEO John Lynch, who estimates the administration costs alone for zoledronic acid at $370 per monthly infusion. Whether the economics translate to actual cost savings is anyone’s guess.
Given today’s reimbursement climate, premium pricing for such products is by no means guaranteed unless developers can demonstrate concrete therapeutic advantages. No longer will insurers pony up for marginal quality of life improvements, or blatant me-too products. “In today’s marketplace, you need a really innovative, beneficial product to get payers to pay,” says John Lynch of Merrion. PC