DRUG DELIVERY 2

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Transdermal Tweaking Enhances Drug Delivery

Novel drug delivery vehicles manage life cycle and create value

Transdermal drug delivery and topical dosage forms have traditionally received less attention than oral or parenteral drug delivery. This is because very few drugs are potent enough to be considered candidates for transdermal delivery into systemic circulation. There is also the fact that relatively few medical conditions can be treated efficiently with topical dosage forms.

Recognition of the clinical benefits of transdermal delivery for certain drugs, however, has brought this approach to the forefront. Today, specialty and innovator companies view novel delivery mechanisms as a strategic asset in pharmaceutical life cycle management. Controlled release transdermal formulations provide increased patient convenience and compliance for several drug classes, including analgesics and hormone and nicotine replacement products. For certain lipophilic drug compounds, the skin can serve as a depot, of sorts, to facilitate sustained drug release.

Because the skin'S stratum corneum (SC) functions as a protective barrier against toxins and pathogens, the goal of transdermal delivery is to overcome those obstacles. Transdermal drug delivery depends on a drug'S inherent ability to partition into the skin-or on vehicles that overcome the skin'S natural protective function-while sparing the patient from adverse or permanent effects.

Optimally formulated topical drugs can affect controlled release into the bloodstream through intact skin while avoiding first-pass metabolism. Manufacturers of products that employ transdermal patches have long recognized the elimination of gastrointestinal side effects and digestive system degradation as major benefits.

Skin penetration enhancement depends to a considerable degree on the formulation carrying the drug. Researchers have used various physical and chemical methods to enhance transdermal penetration of pharmaceuticals. Many compounds have been tried-sulfoxides (e.g., dimethylsulfoxide), pyrrolidones, alcohols, glycols, surfactants, and terpenes-but few have been successfully commercialized.

An active topical formulation is critical for successful transdermal penetration. Significant factors include a high concentration gradient of the active ingredient, appropriate vehicle viscosity, and potency of the penetration enhancer. Skin conditions such as thickness, hydration, temperature, and vascular perfusion also affect penetration.

Create New Value

Topical, enhanced-penetration drug delivery provides innovative companies with the opportunity to differentiate their products both during and after patent expiration. The strategy also offers the ability to more effectively manage the life cycle for certain types of drugs. And it affords specialty pharma companies the opportunity to innovate by creating new value from existing, off-patent drugs. Products must differentiate themselves at a more sophisticated level by, for example, providing greater efficacy or significantly fewer adverse reactions. Simultaneously, such products must demonstrate cost-effectiveness, as insurers closely scrutinize new medications for value.

Soft enhancement of percutaneous absorption (SEPA) is a molecule with demonstrated potency in transdermal penetration enhancement. MacroChem Corporation (Wellesley Hills, Mass.) holds numerous composition-of-matter patents on SEPA formulations. SEPA is synthesized by the condensation of ethylene glycol and decyl aldehyde; several members of this chemical class are currently used as flavoring agents for human use.

SEPA'S amphiphilic structure, containing both polar and hydrophobic ends, transiently disrupts the skin'S lipid bilayer as it traverses the tightly packed membrane structure. SEPA was designed not to contain nitrogen because of potential toxicology problems with such metabolites. Physicochemical studies show that SEPA changes the packing in the lipid matrix of the SC, raising the entropy (or disorder) in the normally highly structured bilayers. This packing order prevents most compounds from entering the skin; by disrupting this order, SEPA creates temporary pathways that allow drugs or other substances to pass.

SEPA has undergone testing as extensive as that required for a new chemical entity and has been determined to be pharmacologically inert. SEPA has been tested alone or with several active drugs in more than 4,000 human subjects without any evidence of systemic toxi-city. Topically applied formulations containing up to 10% SEPA, while clearly absorbed into systemic circulation, produce no systemic toxicities in humans.

Recently, MacroChem filed for patent protection on a second-generation absorption enhancer, DermaPass. This novel group of penetration enhancers operates in a manner similar to SEPA, but the DermaPass molecules can be custom-designed to enhance transdermal delivery of highly polar, water-soluble molecules, in addition to a good number of hydrophobic drugs.

An active topical formulation is critical for successful transdermal penetration. Significant factors include a high concentration gradient of the active ingredient, appropriate vehicle viscosity, and potency of the penetration enhancer.

MacroChem is also developing a series of biodegradable polymers as part of their set of penetration inhibitor products. Laboratory testing has shown that these polymers can modulate delivery in a dose-response fashion. Development efforts for MacroDerm are focused in the areas of cosmetics, personal care products, and selected pharmaceuticals. As an example, MacroDerm significantly reduced transdermal absorption of insect repellents or sunscreen ingredients while maintaining those products in an active state on the skin surface. MacroDerm is not a barrier-that is, it does not form an occlusive film on the skin. Rather, it can be synthesized to change partitioning of certain molecule types between a topical formulation and the skin. Patents for MacroDerm extend to the year 2020.

Transdermal Applications

There is a great need for topically delivered antifungals that are as effective as oral medications. For example, onychomycosis-a fungal infection of the nail-is estimated to affect approximately 30 to 35 million Americans. Of the total number of potential patients, only about 20% are treated with currently available drugs, and only a small percentage of those are eventually cured. Current onychomycosis therapy in the United States consists of orally administered antifungal drugs and a lacquer-based product. Patients do not generally undergo systemic antifungal therapy due to frequent liver toxicity, and the existing lacquer product has a low cure rate of about 7%. The incidence of onychomycosis rises with age, as do liver problems associated with systemic anti-fungal treatment.

The $750 million U.S. onychomycosis market is dominated by two products. Lamasil (terbinafine; Novartis; East Hanover, N.J.) tablets control 30% to 40% of the market; Sporanox (itraconazole; Ortho-McNeil; Raritan, N.J.) capsules control about 20%. Both drugs act systemically. Lamisil has demonstrated efficacy in the 40% range, while Sporanox'S demonstrated efficacy is about 15%. Additionally, both drugs share a common liability of adversely affecting liver function, making patient liver function monitoring a necessity during therapy. Penlac (ciclopirox; Dermik; Berwyn, Pa.), a topical lacquer, is also available, but its cure rate is about 10%. Despite the fact that it is not particularly effective, Penlac sales are about $100 million annually. The high level of interest in new topical treatments for onychomycosis is underscored by a deal that was arranged early in 2007. ScheringPlough Corp. (Kenilworth, N.J.) and Anacor Pharmaceuticals (Palo Alto, Calif.) agreed to team up to develop and commercialize Anacor'S AN2690, a Phase II topical nail fungus product.

EcoNail is a SEPA-based nail lacquer containing econazole, a well-documented antifungal compound. SEPA softens the lacquer'S delivery matrix to allow econazole to diffuse out of the lacquer film into the nail-lacquer interface, creating a high concentration gradient locally. Such a concentration gradient serves to drive econazole into and through the human nail. Laboratory studies on human nails show that EcoNail provides an occlusive environment over the nail, resulting in the delivery of high concentrations of drug into the ventral nail plate and nail bed. Econazole concentrations reach approximately 14,000 times the minimum inhibitory concentration for the commonly encountered dermatophytes, which is several times higher than has been achieved through systemic administration.

Transdermal approaches also have applications for hypogonadism, a condition in which the testes produce insufficient amounts of testosterone. According to the Endocrine Society, this disorder affects an estimated four to five million men in the United States. The incidence of hypogonadal testosterone levels in U.S. males increases from approximately 20% in men older than 60 to approximately 50% in men older than 80. Fewer than 5% of the men affected by hypogonadism are treated with hormone replacement therapy.

For hormone replacement to be effective, testosterone must be delivered into the circulatory system to act systemically. Administration by injection is far from optimal, however. Ideally, testosterone replacement should mimic the body'S testosterone production, which is approximately 4 to 7 mg per day, peaking in the morning. No current testosterone replacement therapy approaches these levels.

Drugs that act in or near the skin, those with toxicology that is less than ideal for systemic delivery, or those that would benefit from controlled release are all excellent candidates for transdermal approaches.

Oral testosterone replacement is associated with elevated liver function and abnormalities detected in liver scans and biopsies. When testosterone is injected, initial serum concentrations are high, causing wild fluctuations in libido and mood; they fall to approximately normal doses after two weeks. Patients must receive injections every month in a clinical setting.

Several transdermal testosterone formulations are on the market. Testosterone patches require large depot doses of the hormone and often cause local irritation, forcing patients to change the area of administration repeatedly. Topical gels overcome some of these concerns, but systemic absorption can be variable. Also, administration is often inconvenient, because the gels that are currently available require application over a relatively large body surface area.

Testosterone is a drug ideally suited to transdermal delivery. Opterone, for example, is a SEPA-enhanced 1% topical testosterone cream formulation developed to treat hypogonadism. Preclinical and early-stage human studies demonstrate that SEPA enhances absorption of testosterone through the skin. In vitro studies suggest a SEPA-testosterone gel formulation delivered up to 400% more testosterone per gram of applied dose over a 24-hour period compared with commercialized testosterone gel formulations. An early pharmacokinetics study using a first-generation testosterone/SEPA gel demonstrated that 2.5 grams of the product produced systemic testosterone levels comparable to five grams of the gel. Opterone cream, a second-generation product, delivers similar levels of drug systemically but does so using a more sustained delivery mechanism. Opterone is ready to enter Phase II clinical testing.

The need for alternatives to solid-dosage oral delivery or parenteral injections has never been greater. Issues of compliance, safety, efficacy, and convenience have caused many approved drugs in traditional dosage forms to lose popularity among prescribers. Due to these factors, novel drug delivery has become a strategic asset for patent holders, developers, and marketers of innovative follow-on products. Drugs that act in or near the skin, those with toxicology that is less than ideal for systemic delivery, or those that would benefit from controlled release are all excellent candidates for transdermal approaches. Elderly and pediatric patients-in particular, those who suffer from serious gastrointestinal side effects-and surgical patients represent an expanding marketplace for novel delivery technologies. �

DeLuccia is president and CEO of MacroChem Corp. Reach him at (781) 489-7310 or rdeluccia@macrochem.com.