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.

DRUG DELIVERY

Lipogelosome and niogelosome drug formulations can offer controlled/sustained release and site-specific delivery.

ALL IMAGES COURTESY OF BY YEKTA OZER, PHD

Liposomes, Niosomes Could Improve Drug Delivery

They can prolong the time a drug spends at the target site

L iposomes and niosomes, which deliver drugs for the diagnosis or treatment of diseases, have been a popular scientific area in recent years. Phospholipids and nonionic surfactants are the main ingredients of liposomes and niosomes, respectively. The combination of liposomes or niosomes with gel-form lipogelosome or niogelosome complexes has generated a great deal of interest in the scientific community over the last decade.

The main obstacle to using liposomes is that they are rapidly cleared by macrophage cells in the circulatory system. Although there are several alternatives-such as steric stabilization or targeting to the tissue or organs to increase the residence time of liposomes in the circulatory system-this is still a problem.

Furthermore, the release of a drug might be more effective when it is applied locally than when it takes the systemic route. Researchers have shown by using a chemotherapeutic agent that release time can be longer when the agent is injected into the tumor after entrapment in gel.

In several studies, liposomes and polymeric materials have been combined in order to prolong the residence time of a drug at the target site. In this type of system, liposomes have been dispersed in the gel. The function of the polymer is to provide a matrix for the entrapment of liposomes, while the function of the liposome is to provide a reservoir for the controlled release of the drug.

Due to their phospholipids and surfactants, liposomes and niogelosomes contain lipidic ingredients. They are prepared with the dispersion of this lipidic phase in the polymer. For the formulation of lipogelosome and niogelosome combinations, several matrix materials-chitosan, collagen, alginate, alginate-polylysine, carboxy vinyl acid copolymers, poloxamer 407, and gelatin-were used. Reportedly, the type and the concentration of gel-forming agents have the most effect on the rheological properties and physical stability of the formulation.

Research has shown that liposomes are compatible with high molecular weight polymers like carbopols, which form during the cross-linking of methyl cellulose and acrylic acid with polyalkenyl ether. Carbopols are often preferred due to their ability to increase the residence time of the formulation at the application site, as well as for their bio-adhesive and viscosity enhancement properties. When carbopols come into contact with water, they have the ability to swell and form dispersions if they are in free acidic forms. When they react with bases, they form high viscosity gels at low concentrations. The rheological properties depend on the type and amount of the organic or inorganic bases reacted. It has been reported that the maximum viscosity can be obtained around the neutral pHs.

The compound's effect on the carboxylic group's ionization or the hydration stages of macromolecules (like electrolytes, alcohols, and polyalcohols) has been reported to play an important role in the viscosity of gels.

Still Some Difficulties

Although the entrapment of liposomes in gel and the evaluation of lipogelosome release profiles seem simple, there are still some difficulties that arise in promoting the liposome-gel combination. The most important of these is the tendency of polymers to interact with the liposomal surface. In order to prevent this interaction, specific functional groups can be added to the liposomal surface or the gel. For example, liposomes coated with polyethylene glycol (PEG) have been used to decrease the liposome/matrix polymer interaction. According to reports, the availability of PEG chains on the liposomal surface stabilizes the membrane by creating a polymeric barrier, blocking the interaction between the matrix polymer and the lipid.

Liposome-gel complexes (lipogelosomes) are, reportedly, the most preferable systems for prevention of bacterial adhesion to catheters, prolongation of antigen release for the enhancement of immunization, hormone transport, drug delivery system development for topical use, and prolongation of drug delivery to cell cultures.

The first lipogelosome drug delivery system was designed in our department and involved buccal application of dexamethasone sodium phosphate (DSP) lipogelosomes for the treatment of aphtous stomatitis in rats and human volunteers. DSP lipogelosomes successfully treated recurrent aphtous stomatitis when compared histopathologically to the commercial DSP ointment.

Because of problems in ocular drug delivery, researchers have developed new drug delivery systems that have depot effect and provide slow release. Previously, many studies have shown liposomes to be promising systems for ocular drug delivery. It has been shown, for example, that the pre-corneal residence time of ophthalmic solutions can be increased by viscosity enhancers. Given these results, researchers thought that an increase in the pre-corneal residence times might be valid for the vesicular systems; they dispersed tropicamide liposomes in polycarbofil gels and applied them topically to rabbits. When tropicamide lipogelosomes were compared with neutral liposomes, the residence time and effect of the drug substance were found to be considerably higher due to increased viscosity.

Lipogelosome and niogelosome formulations are promising drug delivery systems. The advantages for patients are easy application, controlled/sustained release, and site-specific delivery for drug substances.

Other researchers prepared lipogelosome formulations by dispersing liposomes in poloxamer 407 copolymer. After characterization studies, these preparations were found to have temperature sensitive and controlled release properties and are, therefore, very promising for ocular drug delivery.

In another study, topical lipogelo-some complexes were prepared with diclofenac sodium liposomes in Carbopol 934 gels. Lipogelosomes, lotion, and a commercial product (Voltaren Emulgel, Novartis) were compared; the former was found to be the most convenient for topical application.

Effect on NSAIDs

The chemical structure of ibuprofen. Lipogelosome formulation increased the epidural absorption of ibuprofen in vitro.

When non-steroidal anti-inflammatory drugs (NSAIDs) are applied topically in inflammatory arthritis, drug concentration in synovial liquid increases in comparison to the plasma drug concentration. According to researchers, if the drug is entrapped in a niosome drug delivery system, the active drug released from topically applied niosomes prevents the systemic effect to a great extent. This occurs because the drug directly penetrates the joint. In this research, an NSAID-nimesulide-was dispersed in Carbopol 940 gel; this niogelosome complex was topically applied to rats and compared with control gel formulation. According to the results, niogelosome complexes maintained the anti-inflammatory effect, increased the therapeutic index, and increased the concentration of the drug at the site of action, thus decreasing the side effects.

Other researchers have studied lipogelosomes and niogelosomes containing diclofenac sodium (DFNa) for the treatment of rheumatoid arthritis in rabbits. Depending on the scinti-graphic images, lipogelosomes were found to be the optimum formulation when compared with the commercial product. By applying this optimum lipogelosome formulation in lower doses intra-articularly, researchers found they could administer lower doses less frequently and still decrease rheumatoid arthritis inflammation.

The use of liposomal systems in the treatment of dermatological diseases has led researchers to believe they are good candidates for vaginal applications. The main problem with topical or vaginal liposomes is their liquidity and flowability. When researchers employed polyacrilate gels in order to facilitate liposomal stability, they observed an increase in vaginal drug delivery.

In addition, these systems have exhibited controlled or sustained release properties. Methyl nicotine (MN) absorption by the skin was investigated when applied MN liposomes were dispersed in Carbopol 934 P gel as lipogelosomes. The results led researchers to conclude that MN permeability is in proportion to the phospholipid's concentration, but not with the liposomal vesicle size and viscosity. In this research, MN change is not an important factor for dermal absorption.

For the treatment of aches and pains, ibuprofen lipogelosomes have been used via an epidural route. Because it is less toxic and has weak immunogenicity, poloxamer 407 was employed. Lipogelosome formulation increased the epidural absorption of ibuprofen in vitro.

Lipogelosome and niogelosome formulations are promising drug delivery systems. The advantages for patients are easy application, controlled/sustained release, and site-specific delivery for drug substances.