FORMULATION: Drug Delivery
Delivery is Only Skin Deep
Transdermal Drug Delivery: Today and Tomorrow
The skin of an average adult human weighing 65 kg has a surface area of roughly 18,000 cm2 and weighs 6 to 7 kg (roughly 10 percent of the body weight). By comparison, the liver weighs roughly 2 kg. As a result, drug delivery via the transdermal route appears to offer great potential. The greatest resistance to transdermal drug penetration comes from the stratum corneum-which accounts for 10 to 15 percent of the epidermis, which makes up less than 6 percent of the total skin thickness. Therefore, the keys for successful transdermal drug delivery remain in clever formulations and the use of external devices to enhance the penetration of the drugs.
The advantages of transdermal drug delivery include its ease of use, patient compliance, sustained drug delivery, local application and safety. Oral medications must pass through the gastrointestinal tract, into the liver-where drugs are broken down, possibly lowering their effectiveness. With the transdermal patch, drugs enter directly into the bloodstream, reducing the risk of gastrointestinal side effects and bypassing breakdown by the liver.
Parenteral medications also bypass the digestive system, but patient non-compliance poses a threat. Often the oral medications need to be taken 2 to 3 times a day, which also increases the chances of noncompliance. Drug patches are more convenient because they usually only need to be applied once a day, or every few days. In addition, orally administered medications show an initial "burst" of active ingredients in the bloodstream soon after taking a dose; this activity decreases with time. With the transdermal patch there is a constant, slow release of medication into the bloodstream.
Since the first approved transdermal patch of scopolamine in 1979, there have been several financially successful passive transdermal drug delivery patches-including those of nicotine, nitroglycerin, estradiol and fentanyl. This commercial success has generated further interest to expand the range of therapeutics for the transdermal route.
Most of the current transdermal patches have "small molecules" as drug actives 1. It is generally thought that the molecular weight of a drug is negatively correlated with its ability to pass through the intercellular regions of stratum corneum. A recent report indicates that chemicals and drugs with a molecular weight less than or equal to 500 Dalton can passively penetrate the skin. This "500 Dalton" rule precludes biopharmaceutical actives, proteins and peptides for passive transdermal delivery 2.
Consequently, the use of penetration enhancers (such as hydrocarbons, fatty acids, fatty esters, surfactants, and alcohols) to temporarily alter the barrier properties of the stratum corneum can increase the permeability to the drug molecules. These chemical penetration enhancers, however, may not be effective in promoting the penetration of therapeutic macromolecules to a pharmacologically effective extent. The outcome of this is that skin penetration enhancement by chemical excipients has reached its limitation, and the focus has switched to enhancement by external devices.
A possible explanation for increased skin permeability by the acoustic waves is due to the formation and oscillation of gas bubbles in the intercellular bilayer regions of the stratum corneum forming microchannels, thereby allowing the passage of the drug molecules.
Recent advancements in the electronics, polymers, chemical engineering and micro-mechanics fields have been successfully applied to skin penetration3. These new "active" skin penetration techniques can be classified into three main categories, as shown in Table I.
Electrical Delivery Platforms
The technique of iontophoresis dates back more than 100 years and involves the application of a small electric current (0.5 mA/cm2) to a drug reservoir on the surface of the skin. A study by Anderson et al 4 suggests that comparable iontophoretic doses delivered at low currents over several hours are more effective than those delivered by high currents overa short duration. The study also suggests that the drug penetrates the stratum corneum at a rate proportional to the magnitude of the applied current, and that iontophoresis may facilitate the penetration of drugs such as dexamethasone/ dexamethasone phosphate up to 8 to 10 mm into the local tissue at pharmacologically effective concentrations 4. There have also been numerous publications on studies using iontophoresis to deliver a number of therapeutic proteins and peptides-including inulin, insulin, gonadotropin releasing hormone, and delta sleep-inducing peptide 2.
Arrays of silicone needles (roughly 150 mm long and 80 mm diameter at the base) are fabricated on to a 3x3 mm patch (roughly 400 needles). When the patch is mounted on the skin, the needles penetrate the epidermis forming channels that allow passage of the drug.
Another method, electroporation, involves the application of high voltage (30 to 100V) pulses (10ms to 100 ms) to the skin, and is hypothesized to induce the formation of transient pores that subsequently allow the passage of macromolecules into the intercellular space. The transport of the therapeutic macromolecules takes place via a combination of possible processes including diffusion, local electrophoresis, and electro-osmosis 2.
Ultrasound, or devices using sonophoresis produce low frequency energy in the 20KHz region that has the capability of producing a physical increase in the air pressure above the site of application. A possible explanation for increased skin permeability by the acoustic waves is due to the formation and oscillation of gas bubbles in the intercellular bilayer regions of the stratum corneum forming microchannels, thereby allowing the passage of the drug molecules 2. Portable ultrasonic devices for transdermal drug delivery have already appeared on the market 5, 6.
Magnetophoresis, which is still in the research phase, enhances skin permeability by applying a magnetic field. The research data on animal models suggests that skin penetration can be enhanced by applying a magnetic field to therapeutic molecules that are diamagnetic or paramagnetic in nature 7.
Lasers, Micro-needles and Jet Propulsion
Photomechanical waves and laser ablation are also known as laser generated stress waves. Photomechanical waves use a laser pulse (at 694.3 nm) of 208J for 20 to 30ns. In the laser ablation technique, the stratum corneum is ablated using a mild laser (0.91 to 1.17J/cm2, using an erbium: yttrium-aluminum-garnet (YAG) laser at 2940nm) 2. Although animal models have shown that insulin can be successfully delivered transdermally using photomechanical waves, the mechanism of enhanced skin permeability is not well understood. It is theorized, however, that photomechanical waves induce the expansion of the lacunar spaces within the stratum corneum leading to the formation of transient channels 8. Both of these laser techniques are currently being studied in animal models.
Microneedles was developed in the last five to 10 years as a result of advancements in micro-fabrication technology. Arrays of silicone needles (roughly 150 mm long and 80 mm diameter at the base) are fabricated on to a 3x3 mm patch (roughly 400 needles). When the patch is mounted on the skin, the needles penetrate the epidermis forming channels that allow passage of the drug. One possible use for this method of transdermal drug delivery would be in the field of intracutaneous immunization 2, 9.
While the human body temperature varies from 24oC to 37oC depending on the site 10, temperatures modulation has also been established that skin permeability increases with temperature. Skin patches that can locally heat the skin are patented for transdermal drug delivery 11.
...Combining electrical or mechanical device-induced skin penetration methods with improved formulations (comprised of chemical penetration enhancers or nano-drug delivery systems) is likely to produce the ideal transdermal drug delivery devices.
Jet-propelled particles, or needleless injection, uses high velocity jets (>100m/s) of compressed helium gas to propel liquid or powdered drug particles into the skin. The speed of the gas jet and the particle size of the drug determine the extent of penetration into the skin. Patents have been filed for transdermal delivery using this technique 12.
In summary, this review shows that new and alternative drug delivery systems are currently the focus of many research activities. Efficacy, safety and convenience of use are important factors that need to be considered when developing alternate
drug delivery systems. In recent years, the transdermal route of drug delivery has evolved considerably and it now competes with oral treatment. Most of the device-induced transdermal drug delivery techniques are still in the early stages of commercialization. All device-induced transdermal delivery techniques have a common concern regarding the safety of use, and skin reactions arising due to perturbing the stratum corneum-even though it is only temporary. However, combining electrical or mechanical device-induced skin penetration methods with improved formulations (comprised of chemical penetration enhancers or nano-drug delivery systems) is likely to produce the ideal transdermal drug delivery devices. Although pain management and hormone replacement therapy (HRT) dominate the current transdermal products, the trends indicate that many more new products comprised of therapeutic proteins and peptides for transdermal delivery will be seen in the near future. The market value for transdermal delivery was $12.7 billion in 2005, and is expected to increase to $21.5 billion in the year 2010 and $31.5 billion in the year 2015-suggesting a significant growth potential over the next 10 years 13. �
Langer R. Transdermal drug delivery: past progress, current status, and future prospects. Adv Drug Delv Rev. 2004;56:557-558.
Cross SE, Roberts MS. Physical enhancement of transdermal drug application: Is delivery technology keeping up with pharmaceutical development? Current Drug Delv. 2004;1:81-92.
Meidan VM, Michniak BB. Emerging technologies in transdermal therapeutics. Am J Therapeut. 2004;11(4):312-316.
Anderson CR, Morris RL, Boeh SD, Panus PC, Sembrowich WL. Effects of iontophoresis current magnitude and duration on dexamethasone deposition and localized drug retention. Phy Therap. 2003;83:161-170.
Maione E, Shung KK, Meyer Jr RJ, Hughes JW, Newnham RE, Smith NB. Transducer design for a portable ultrasound enhanced transdermal drug-delivery system. IEEE transactions on ultrasonics, ferroelectrics, and frequency control. 2002;49(10):1430-1436.
Murthy SN. Magnetophoresis: an approach to enhance transdermal drug diffusion. Die Pharmazie. 1999;54(5):377-379.
Menon GK, Kollias N, and Doukas AG. Ultra-structural evidence of stratum corneum permeabilization induced by photomechanical waves. J Invest Dermatol. 2003;121(1):104-109.
Prausnitz MR. Microneedles for transdermal drug delivery. Adv Drug Delv Rev. 2004;56:581-587.
Sun Y. Skin absorption enhancement by physical means: Heat, ultrasound, and electricity. Transdermal and Topical Drug Delivery Systems. Eds. Ghosh TK, Pfister WR. Interpharm Press, Buffalo Grove, IL. 1997, pp.327-355.
Stanley T, Hull W, Rigby L. Transdermal patch comprising controlled heating device. International Patent WO 01/64150 A1 (2001).
Roser BJ, Kampinga J, Colaco C, Blair J. Solid dose delivery vehicle and methods of making same. U.S. patent 6,811,792 (2004).