Peggy Wright, Contributing Editor

Fig. 1. Extended-release formulation is rated as one of the most effective methods of extending the life cycle of a drug. Credit: Best Practices LLC

		The FDA clarified the regulatory thicket surrounding the 505(b)(2) approval pathway for drug formulations just over a decade ago. In the intervening years, this pathway has become an increasingly popular way for drug makers to commercialize products. The 505(b)(2) pathway allows companies to make modest changes to an already approved drug and get continued market exclusivity for from three to as many as seven years. And among those changes, one of the more popular is to develop a controlled-release, long-acting, extended-release, or XR version of the drug, all of which constitute a modified-release approach.

		Some drugs, from their first launch, are formulated to provide a relatively steady dose to the patient over an extended period of time, either to provide more effective therapy or better patient acceptance. Transdermal patches or medical devices like infusion pumps can serve a similar purpose. Most often XR formulations show up because a company is attempting to extend the exclusivity of its proprietary product, a form of life-cycle management for the drug as it nears patent expiration (expiry).

		The choice is not without some controversy. Over the years drug makers have been accused of artificially extending patent life with this stratagem, presumably because only a sketchy justification exists for the XR form. In the case of opioid pain products, XR forms of drugs have been subverted by drug abusers seeking an instant high. Most XR opioid products 

now operate under Risk Evaluation and Mitigation Strategies [REMS]

		Officials making drug-abuse policy are anxiously watching the introduction of Zohydro, an extended-release hydrocodone that the FDA approved last fall, by Zogenix (San Diego). Meanwhile, Purdue Pharma (Stamford, CT) is entering Phase-III trials of its version of XR hydrocodone. Officials fear a repeat of the drug abuse that occurred when Oxycontin, an extended-release oxycodone, was introduced in the mid-1990s.

		However, many valuable justifications for the XR form—including formulations for pediatric or geriatric patients&mdash;exist. “FDA approvals under 505(b)(2) have risen every year since 2003 because it offers a faster and less costly process that permits developers to minimize risk and still receive marketing exclusivity,” said Ken Phelps in a statement commemorating the 10-year anniversary of his Cincinnati firm, Camargo Pharmaceutical Services, which specializes in those regulatory approvals. “Today, more drugs are approved through 505(b)(2) than through traditional development.”

Fig. 2. Rated on the basis of difficulty of implementing, extended-release formulation is considerably easier to deploy than obtaining new indications or new dosage forms, and about as easy as setting up a marketing program in emerging markets. It is harder to implement, though, compared to commercial practices like generating new publications on use, revised pricing or contracting with large-volume purchasers (not shown).

		A just-published study, surveying the experiences of 25 pharma companies and their approaches to life cycle management (LCM), gives a context to XR decisionmaking. The study’s authors, Best Practices, LLC (Chapel Hill, NC), benchmarked respondents’ experiences with and results from a variety of LCM strategies. These approaches range from fairly straightforward ones, such as adjusting pricing of the product as expiry approaches, to fairly complex ones, such as researching a new indication for the drug, which can require nearly the same effort as for initial approval.*

		Among top-rated choices (Fig. 1), the extended-release reformulation was rated as the second-most effective—just nosed out by repricing the drug&mdash;and having the highest “highly effective” rating. The companies preferred this strategy despite the fact that respondents noted in other polling that the strategy is expensive&mdash;$10 million or more according to two-thirds of respondents&mdash;and that it was one of the strategies that took longest to apply, upwards of three years to implement. By comparison, repricing the product takes less than a year to execute.

		Another benchmarking comparison, of barriers to use (Fig. 2), demonstrates that XR reformulating is one of the more expensive approaches but not as expensive as developing a new indication. Lower-cost options are not shown in the chart. Best Practices rated XR formulation as about as difficult as setting up the drug’s marketing in an emerging market.

		The grand-total benchmark, as it were, compares the cost and difficulty of the LCM techniques to the value obtained. Here, Best Practices found that XR reformulation has one of the highest ROIs, 84%, which is on par with development of an authorized generic.

		Some pharma companies have in-house expertise in modified-release techniques; alternatively, a wide variety of formulation and drug-delivery providers in-license the technology and/or provide manufacturing expertise. These companies include:

Catalent Pharma Solutions (Somerset, NJ).

 This contract development and manufacturing organization (CDMO) offers its OSCrC (one-step dry coating) OptiDose tableting technology, in partnership with Sanwa Kagaku Kenkyusho Co., Ltd., together with a variety of particle-coating and spray-processing techniques. In January, the company announced an agreement with Adamas Pharmaceuticals for Phase III trials of extended-release amantadine HCl, a treatment for side effects of Parkinson’s disease.

 This CDMO was acquired by Capsugel late last year and offers particle-coating and microsphere techniques, including an “osmotic swellable core” technique, and can provide scale-up production services.

 This specialty pharmaceutical company has in-house technology for immediate-release and extended-release products of its own and out-licenses its Acuform XR technology. Mallinckrodt Pharma, J&J Janssen, and Ironwood Pharma have products in Phase I-III stages.

 The company, a contract research organization (CRO) provides formulation and drug-delivery services, with an emphasis on difficult modes of delivery, such as intraocular and intranasal.

 Now owned by Australia’s Mayne Pharma, the CDMO provides a variety of modified, delayed, sustained, and pulsed drug delivery, and Cleantaste technology for taste-masking and controlled release.

 The company, another CDMO, provides a wide range of milling, extrusion, encapsulation, and coating technologies. It also develops elution techniques for implantable drugs or devices.

 This CDMO provides services primarily for solid and sterile dosage forms as well as offers specialized capabilities in high potency, controlled or sustained release and sterile manufacturing, including aseptic filling and lyophilization.

The Controlled Release Society (St. Paul, MN)

 is an international, individual-member society for advancing modified-release technology, both within and outside of life sciences (www.controlledreleasesociety.org).

		Provided a pharmaceutical company has established a pharmacokinetic rationale, a strategic path to an improved version of the original drug, experts recommend starting the development of the XR form for LCM as early as is possible. Companies often initiate such programs even before the regulatory agency has approved the original, immediate-release version of the product.

		Bend Research often uses a combination of bioavailability-enhancing technologies with sustained-release technologies for LCM. W. Brett Caldwell, director of formulation science, says “Recently, our clients have brought us more problem statements earlier in development that require modified-release formulations, combined with bioavailability enhancement, to help progress efficacious drugs that might not be viable as immediate-release candidates. Modified release can help a drug stay in the therapeutic window. Companies are much more savvy about optimizing the therapeutic window and are optimizing earlier in development.”

		Caldwell indicates that the modification of a crystalline, immediate-release formulation into a sustained-release formulation is the most commonly considered method for LCM. He also sees increasing interest from clients in creating combination drugs, improving bioavailability, enabling new indications, and/or targeting specific populations through XR technologies. For example, moving from a tablet formulation to multiparticulates can help a pediatric or geriatric population by improving the ease of swallowing and avoiding the risk of dose dumping in the stomach. Developers can also design capsules that open and deliver the dose in milk or other foods.

Articles

Both pharmacological and economic factors drive the decision to use these technologies

Modified release formulations give new life to drugs

NuPathe’s Zecuity ionotophoretic patch (left) and a Theraject application (right). Credit: NuPathe, Theraject

		The skin, the largest organ, effectively prevents passage of many foreign substances into the body. Passive transdermal products, such as patches and gels, creams, and sprays are able to pass some drugs through the skin at therapeutic rates to deliver drugs systemically. Drugs that are lipophilic, with low molecular weights and low dosages, can pass through the skin most easily. Not all small-molecule drugs, however, can do so; e.g., charged molecules. To enable delivery, products often use various passive technologies, including:

			Particulate systems, such as liposomes, transfersomes (synthetic vesicles), microemulsions, or solid lipid nanoparticles

			Chemical penetration enhancers, such as glycols and terpenes

		The skin provides an effective barrier as well to large-molecule drugs, such as proteins and peptides, and this obstacle has led to efforts to develop physical or active methods of overcoming the skin barrier, including:

			Microneedles—sharp microprojections, frequently in patch form

			Iontophoresis—a weak, continuous electrical current

			Electroporation—short, high-voltage pulses

		Passive patches still dominate the transdermal market. Despite years of effort, the movement of active technologies into the market has been slow, and few have reached the market or been successful. In May 2011, FDA approved Sanofi Pasteur’s microneedle-based product, an influenza-virus vaccine called Fluzone Intradermal. In January, FDA approved Zecuity (sumatriptan), a single-use, battery-powered, iontophoretic patch for treatment of migraine in adults, developed by NuPathe Inc. (Conshohocken, PA). These achievements may open the way for development of more drugs using active technologies.

Fig. 1. Transdermal drug and technology market, 2010—2017. Credit: Kalorama Information

			Historically, many transdermal products have delivered drugs that provide treatment for hormonal deficiencies, help with smoking cessation, or manage pain. In addition to Sanofi and NuPathe, two other pharmaceutical companies have recently developed new products that treat other types of medical conditions. In January 2009, FDA approved Watson Pharmaceuticals’ Gelnique (oxybutynin), a gel for the treatment of overactive bladder. Last April, FDA approved UCB’s Neupro (rotigotine), a transdermal patch, for treatment of Parkinson’s disease and restless legs syndrome.

		In a market study published in September, Kalorama Information (New York) puts the current market for transdermal and transmucosal products at about $8.4 billion, with around $700 million being spent on the delivery technology. By 2017, the product value will be just over $10 billion, with delivery technology at $900 million (Fig. 1).

		Pharmaceutical companies initially became interested in transdermal technology for systemic drug delivery because it: 1) avoids problems related to gastrointestinal passage and hepatic first-pass metabolism in which absorption in the liver and the gut wall reduces the amount of drug available for systemic delivery; i.e., its bioavailability; 2) offers a controlled, continuous delivery of drugs; 3) provides the option of delivery once or twice weekly; and 4) facilitates easy termination of the drug.

		In addition to those benefits, companies have used the introduction of transdermal products as a method of extending the life cycle of products originally introduced in another form, such as capsules. Prior to entry of generic competitors into the market, a company can move the revenue base for its product from the original form to a transdermal solution. If patient acceptance is high, a barrier is created for generic products stuck with the original form of delivery.

		Transdermal technologies not only provide benefits for systemic drug delivery but also for local delivery of dermatological and cosmeceutical products, the latter not being subject to FDA’s stringent requirements regarding therapeutic effects. Transdermal delivery includes topical products such as gels that deliver drugs systemically, and many topical products are available for dermatological and cosmeceutical purposes. The skin is the common thread that unites systemic transdermal and local dermatological and cosmeceutical development, and many technology companies have sought partnerships with companies in all three fields. The cosmeceutical industry actually developed some of the technologies, and pharmaceutical companies later adopted them.

		Given the benefits of passive and active technologies for local and systemic delivery, companies will continue to develop pharmaceutical, dermatological, and cosmeceutical products, and both passive and active technologies provide opportunities for development of marketable transdermal drugs.

		Nanotechnologies seem to hold some hope of expanding the transdermal market. In 2010, NewGen BioPharma (Titusville, NJ) bought a transdermal platform, Micellar Nanoparticulates (MNP), from Novavax. That company had developed one transdermal product using MNP, Estrasorb (estradiol), which is currently on the market for treatment of symptoms of menopause. The platform improves the solubility and bioavailability of topically delivered products. Providing an increased residence time for an active pharmaceutical ingredient (API), the technology can reduce the dosage or the number of applications per day.

		MNP offers a solution for delivery not only of systemic transdermal products but also of topical local, oral, injectable, and ophthalmic products. Navdeep Jaikaria, NewGen’s CEO, indicates that MNP gives NewGen the ability to reformulate 60% of all small-molecule drugs. The company also has a platform for delivery of inhaled products and is developing a technology for large-molecule peptides. These peptides must have a stable conformation that withstands the high pressure under which formulations are produced; Jaikaria adds that only GRAS-listed (Generally Recognized As Safe) additives are used.

		Jaikaria has indicated that NewGen’s MNP platform holds promise for transdermal technology because it may improve patient acceptance of transdermal products. While common and well accepted in Asia, transdermal products such as patches can cause irritation and itching, and US consumers have not been as tolerant. NewGen’s nanoformulated, medicated lotions are nonirritating and are moisturizing rather than dehydrating, unlike patches in the first instance and gels in the second.

		NewGen is developing its own pipeline of drugs, currently 20 APIs that it has reformulated using the MNP platform. This year NewGen plans to launch an ophthalmic and a topical drug in India as well as a reformulation of Estrasorb that keeps estrogen in the skin longer. NewGen has used its technology to develop cosmeceutical products as well, one for hair regrowth and an anti-aging cream.

		The company will work with partners as a contract service provider, developing drugs using the platform. Jaikaria indicates that hormonal (steroidal) conditions, pain, urinary incontinence, erectile dysfunction, and smoking cessation are examples of the types of conditions that drugs using the platform can treat. The technology primarily permits delivery of small-molecule drugs, but Jaikaria says that it also will function with small peptides as long as conformation is not an issue. He says that any drug listed as BCS Class 2 (a measure of drug absorption), or that is poorly water-soluble, is a possibility for delivery.

		Like NewGen, Particle Sciences, a Bethlehem, PA, contract development and manufacturing organization, sees nanoparticles as a standard drug-delivery option. The company can incorporate APIs into particles using its proprietary technologies, with the possibilities ranging from an emulsion droplet to a nanoparticle of the API itself, from tens of microns down to several nanometers. Particle Sciences also uses an in-licensed technology, LyoCell, which combines a lipid-based approach with nanoparticles, with the particles having unique solubilization properties.

Microneedles and 'active' patches extend the reach of transdermal applications