Break the Stratum Corneum Barrier

By Maybelle Cowan-Lincoln

Enhance transdermal drug delivery through physical means

The market for products that use transdermal drug delivery (TDD) is exploding. In 2009, sales grew to $5.6 billion, and this growth is expected to continue for the foreseeable future.^1-2
This attractive technology already exists for a wide range of disease areas, including postmenopausal osteoporosis, angina, pain, Parkinson’s, and dementia. But products are in development for the treatment of a host of other disorders such as glaucoma, hypertension, attention deficit hyperactivity disorder, and central nervous system disorders, to name just a few.³
The growth of TDD systems is easy to understand given the advantages they offer over other delivery systems:

• Painless application;⁴
• Ease of use;
• Increased patient compliance;
• Avoidance of first-pass metabolism;
• Controlled release of drug; and
• Ability to maintain steadier plasma levels, often decreasing side effects by reducing peak plasma levels.

Despite these many advantages, TDD systems have significant limitations. The tough barrier of the stratum corneum precludes the use of this technology for certain compounds. Drugs that are either hydrophilic or have high molecular weight cannot penetrate the skin easily, nor can drugs with insufficient potency. Another drawback is the possibility of an adverse reaction. TDD products can cause marked irritation at the application site.
These challenges notwithstanding, TDD systems offer the opportunity for highly effective drug delivery. Transdermally delivered drugs cross the epidermis via one of three pathways: through the hair follicles and their sebaceous glands, through the sweat ducts, or across the stratum corneum.⁵ Once the barrier of the stratum corneum has been breached, the drug can enter the layer just below it—the dermis. This skin layer houses capillaries that transport approximately one-third of the blood supply throughout the body. When a drug reaches this system of capillaries, it can be absorbed into the bloodstream through passive diffusion.

The Problem with Peptides

Transdermal penetration is difficult for certain compounds, such as drugs with high molecular weight. Peptides, macromolecular drugs responsible for major biological reactions and processes, are too cumbersome for most existing TDD systems. More and more peptides are on the market to treat cardiovascular conditions, immunity, diabetes, and viral infections.⁶
Delivering these cutting-edge drugs presents a significant challenge. The oral route is unacceptable. Peptides are degraded by the gastrointestinal enzymes and may display poor bioavailability because the intestinal mucosa is impermeable to their high molecular weight and hydrophilicity. The parenteral route is the current delivery system of choice, but there are drawbacks for this method: invasiveness, patient inconvenience, and systemic side effects. Given the challenges presented by the oral and parenteral routes, an effective TDD system for peptide drug delivery is certainly desirable.
Chemical penetration enhancers (CPEs) have been extensively researched as possible solutions to the peptide penetration challenge. These additives decrease the barrier function of the skin through stratum corneum lipid fluidization. Although some success has been demonstrated in the lab, the usefulness of CPEs is limited by the irritation they often cause; the more potent the CPE, the greater the irritation.⁷
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Case study

Intradermal Injection in the Developing World

eedle-free injection devices may well be the holy grail of TDD enhancement systems for vaccination delivery. The high presence of dendritic cells in the epidermis can help elicit a heightened immune response, significantly higher than that obtained after intramuscular injection.^1-2
This increased efficiency offers the potential to make vaccinations in developing countries substantially more affordable, more available, and safer. For some vaccines, intradermal (ID) delivery can fully immunize a person against a disease while using up to 80% less vaccine. The reduced dosage can cut costs and increase availability, allowing more children to be vaccinated.³
But accurate ID delivery is hard to guarantee. Needle-free technologies are a boon to the developing world, offering the advantages of targeted delivery while reducing the risks of needle reuse and needlestick injuries.
Several recent clinical trials have supported the benefits of needle-free injections. In a 2007 study in Oman approved by the World Health Organization (WHO), 373 infants received either a full dose intramuscular polio vaccine at 2, 4, and 6 months, or a fractional dose of the vaccine intradermally using the Biojector 2000 (Bioject Medical Technologies, Ore.) on the same schedule. Thirty days after completing the three-dose protocol, the rates of seroconversion were tested. The rates of seroconversion in the fractional, intradermally delivered group were similar to those in the full dose, intramuscularly delivered group.⁴
Fractional dose polio vaccines could transform health care in developing countries by controlling costs and stretching the vaccine supply. The savings are significant: The cost of the fractional dose polio vaccine would be about $3 per infant versus $9 per infant for the full dose.
Research continues to evaluate the safety and efficacy of similar needle-free vaccine delivery devices. A study completed in May 2010 in the Dominican Republic assessed the rates of seroconversion one month after trivalent inactivated influenza vaccination using the Biojector 2000. Results of the study, sponsored by the Centers for Disease Control and Prevention in collaboration with WHO, the Pan American Health Organization, and the Program for Appropriate Technology in Health, have not been published.⁵
Additional means to further enhance the efficacy of ID injections are being studied, including coating DNA nanoparticles in the vaccine to enhance the immune response. The success of these trials encourages further investigation into the benefits of this technology.

References

1. Cui Z, Baizer L, Mumper RJ. Intradermal immunization with novel plasmid-DNA-coated nanoparticles via a needle-free injection device. J Biotechnol. 2003;102(2):105-115.
2. Cui Z, Mumper RJ. Topical immunization using nanoengineered genetic vaccines. J Control Release. 2002;81(1-2):173-184.
3. Medical Technology Business Europe. Bioject to provide needle-free injector for Global Polio Eradication Initiative study. MTB Europe website. February 22, 2011. Available at: http://www.mtbeurope.info/news/2011/1102056.htm. Accessed June 5, 2011.
4. Mohammed AJ, AlAwaidy S, Bawikar S, et al. Fractional doses of inactivated poliovirus vaccine in Oman. N Engl J Med. 2010;362(25):2351-2359.
5. U.S. National Institutes of Health. Needle-free jet injection of reduced-dose, intradermal, influenza vaccine in >=6 to <24-month-old children. ClinicalTrials.gov website. Available at: www.clinicaltrials.gov/ct2/show/NCT00386542. Accessed June 5, 2011.

Microneedles

Because CPEs are not the ideal solution, physical methods to increase transdermal delivery of peptides and higher molecular weight drugs are being developed. One option is the microneedle. These sharp projections pierce the skin, extending down for less than 1 mm, the level at which blood vessels and nerves typically reside. Because of the shallowness of their penetration, microneedles do not cause bleeding or pain.
There are four models of microneedles:

1. Piercing array of microneedles followed by the application of a drug patch to the site;
2. Microneedles coated with the drug;
3. Biodegradable polymeric needles that encapsulate a drug and release it in a controlled dose over time; and
4. Hollow microneedles.

Each of these models offers advantages. For example, coated microneedles are useful for bolus drug delivery, and storing the medicament as a solid coating may improve stability over time. Hollow microneedles can deliver a larger dose of drug in a single application or can be used for prolonged infusion.
A primary concern with microneedles is the possibility that they may break off in the skin. The evidence suggests that this is unlikely. Since the introduction of the technology, minimal breakage has been recorded with correctly inserted silicon microneedles.

Metal microneedles

are even stronger. A safe alternative to both these materials is microneedles made from biodegradable polymers. Because microneedles provide enhanced delivery in a painless and convenient format, it is likely this system will appear in future TDD products.

An array of biodegradable polyethylene glycol-based microneedles with antimicrobial properties.

Encapsulation

Encapsulation is a process by which peptide drugs are entrapped in a particle-delivery system such as liposomes. These phospholipid-based vesicles deliver compounds to superficial skin layers. Extensive research has also demonstrated that they can achieve higher tissue concentrations of drugs like γ-interferon.
Liposomes have their limitations, however. They are most effective for local skin delivery. Liposomes create a drug reservoir in the upper layer of the stratum corneum. If a compound needs to enter systemic circulation, ethosomes are more effective.⁸
Ethosomes are soft, phospholipid-based vesicles formulated with a high concentration of ethanol. The ethanol makes the ethosome a uniquely efficient transdermal drug transporter. Ethanol affects both the skin and the structure of the vesicle. In the skin, it increases permeability by disrupting the lipid bilayer of the stratum corneum. Concurrently, the ethanol concentration causes the lipid membrane to be more malleable than conventional vesicles but just as stable. This increased flexibility allows the ethosome to squeeze through smaller openings in the stratum corneum, namely the ones created when the skin came into contact with the ethanol in the ethosome. This efficient transport system has been demonstrated to be effective with macromolecules such as peptides, making ethosomes a promising candidate for future TDD products.

Electricity

Another exciting approach to TDD is the use of physical energy. Iontophoresis uses small voltage constant current to actively transport a charged medication within an electric field. This method works on several levels. Electrodes are placed on the skin in an area coated with a solute containing drug molecules with the same charge. The like charge repels the drug molecules into the skin. Simultaneously, the applied current promotes electroosmosis, the convective flow of water molecules. Also, the current itself may temporarily increase skin permeability.⁹

Coated microneedles are useful for bolus drug delivery. Hollow microneedles can deliver a larger dose of drug in a single application or can be used for prolonged infusion.

The quantity of a drug delivered by iontophoresis can be affected by a number of factors. For instance, adjusting the duration and intensity of the current, as well as the surface area of the skin in contact with the electrodes, alters the efficiency of the transport.
Another variable that influences transdermal delivery is the chemical properties of the drug itself. At present, the most successful transdermal delivery has occurred with lipophilic, positively charged drugs with low molecular weight. However, research has demonstrated that iontophoresis can effectively deliver a number of peptides, including luteinizing hormone-releasing hormone, cyclosporin, calcitonin, and insulin. To date, iontophoresis has not achieved the delivery of therapeutic levels of these compounds in humans.
In general, iontophoresis has been shown to be well tolerated by the skin. Adverse reactions were minor and included mild sensations from the current flow and erythema in the skin in contact with the electrodes, which was generally resolved within 24 hours.
Electroporation involves a different use of electricity. Unlike iontophoresis, electroporation uses short pulses of high voltage to increase skin permeability. These short bursts cause small, short-lived aqueous pores to appear in the stratum corneum lipid bilayers. During electrical pulses, the drug is driven into the skin. The increased permeability of the stratum corneum persists for several hours after treatment, allowing for continued transdermal delivery. This method has been shown to enhance peptide penetration substantially more than iontophoresis.¹⁰
To increase drug delivery during electroporation, a number of variables can be adjusted. Electrical charge, lipophilicity, and molecular weight affect transport. Increasing the charge of the permeant can enhance delivery. Also, the lower the molecular weight of the drug, the higher its transport. In addition, although it is less efficient, electroporation can be used for macromolecule delivery as well as for small and moderate molecular weight compounds, making it an attractive technology to pursue for future TDD systems.

Electroporation uses short pulses of high voltage to increase skin permeability. These short bursts cause small, short-lived aqueous pores to appear in the stratum corneum lipid bilayers. During electrical pulses, the drug is driven into the skin.

Additional Methods

A number of other TDD systems are being researched to facilitate medication delivery, particularly technologies that can be used with macromolecules.

• Ultrasound is an effective physical TDD enhancement technique, proved efficient for the enhanced delivery of several peptides and proteins, including insulin, erythropoietin, and heparin. Interestingly, low frequency ultrasound (20 KHZ – 100 KHZ) has been shown to increase skin permeability more than high frequency ultrasound (1 MHZ – 16 MHZ). The mechanism by which this occurs is not fully understood, but it is hypothesized that the ultrasound waves disrupt lipids in the stratum corneum. This disruption allows the drug, housed in a coupling agent like gel, cream, or ointment, to pass through the skin.
• Several needle-free injection technologies use velocity to cross the stratum corneum. These jet-propelled devices can deliver a variety of medications, from human growth hormone to insulin in liquid and particle form, and achieve a bioavailability equivalent to conventional injections. But a particularly exciting use of needle-free injections is vaccine delivery. Compressed helium delivers vaccinations in the form of particles at velocities of up to 800 m/s. The benefit of this form of vaccine is that in the epidermis, particles can stimulate higher immune response than intradermal or intramuscular injection.
• Heat can enhance skin penetrability by increasing microcirculation and blood vessel permeability. One new TDD technology that employs heat is the controlled heat-aided drug delivery (CHADD) system. A small heating unit powered by oxidation upon exposure to air is placed over a medication patch to facilitate more effective delivery.
• Physically removing or disrupting the stratum corneum can increase transdermal penetration. Microscissuining abrades the skin by creating microchannels in the outer layer using microscopic metal granules. Laser ablation has been demonstrated to enhance the delivery of both lipophilic and hydrophilic compounds, but long-term safety and reversibility need to be assessed, particularly at the intensities necessary for higher molecular weight drugs.

References

1. Salisonline. Advances in the transdermal drug delivery market: market size, leading players, therapeutic focus and innovative technologies. March 11, 2011. Available at: www.salisonline.org/market-research/ advances-in-the-transdermal-drug-delivery-market-market-size-leading-players-therapeutic-focus-and-innovative-technologies. Accessed June 6, 2011.
2. Kumar R, Philip A. Modified transdermal technologies: breaking the barriers of drug permeation via the skin. Trop J Pharm Res. 2007;6(1):633-644.
3. Mathias NR, Hussain MA. Non-invasive systemic drug delivery: developability considerations for alternate routes of administration. J Pharm Sci. 2010;99(1):1-20.
4. Gill HS, Prausnitz MR. Coated microneedles for transdermal delivery. J Control Release. 2007;117(2):227-237.
5. Benson HA, Namjoshi S. Proteins and peptides: strategies for delivery to and across the skin. J Pharm Sci. 2008;97(9):3591-3610.
6. Mao S, Cun D, Kawashima Y. Novel non-injectible formulation approaches of peptides and proteins. In: Jorgensen L, Nielsen HM, eds. Delivery Technologies for Biopharmaceuticals: Peptides, Proteins, Nucleic Acids and Vaccines. West Sussex, U.K.: John Wiley & Sons, Ltd.; 2009:29-67.
7. Karande P, Jain A, Ergun K, et al. Design principles of chemical penetration enhancers for transdermal drug delivery. Proc Natl Acad Sci U S A. 2005;102(13): 4688-4693.
8. Anitha P, Ramkanth S, Sankari KU, et al. Ethosomes: a noninvasive vesicular carrier for transdermal drug delivery. Int J Rev Life Sci. 2011;1(1):17-24.
9. Power I. Fentanyl HCl iontophoretic transdermal system (ITS): clinical application of iontophoric technology in the management of acute postoperative pain. Br J Anaesth. 2007;98(1):4-11.
10. Denet AR, Vanbever R, Préat V. Skin electroporation for transdermal and topical delivery. Adv Drug Deliv Rev. 2004;56(5):659-674.