Recent Progress in Active Transdermal Drug Delivery Technologies

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Parul B. Patel
Parul B. Patel

When one hears the words transdermal drug delivery, what comes to mind? More than likely one thinks about a simple patch that one stick onto skin like an adhesive bandage such as nicotine patch.

Transdermal drug delivery system was first introduced more than 20 years ago. The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s. By the mid to late 1990s, the trend of transdermal drug delivery system companies merging into larger organizations. Transdermal drug deliveries in the text of research articles grow continuously in the transdermal drug delivery 1980s, and has remained constant throughout the past decade.

Innovations in technologies continue to occur at a positive rate, making the technology a fertile and vibrant are a of innovation, research and product development. In the present study, various new development in the field of TDDS are included to improve the release rate and other parameters on need base system and most suitable to the patient.

Key Words:

TDDS, active delivery, iontophoresis, electrophoresis, microneedle, needle-less injection, ultrasound, magnetophoresis, radio frequency, lasers.

Introduction

Novel drug delivery is geared towards developing friendly dosage forms of various formulations with the ultimate aim of increasing their dosing convenience to the patient. The NDDS may involve a new dosage form e.g., from thrice a day dosage to once a day dosage form or developing a patch form in place of injections. Today, about 74% of drugs are taken orally and are found not to be as effective as desired. Thus, various forms of NDDS such as transdermal delivery systems, controlled release systems; transmucosal delivery systems etc. emerged. When one hears the words transdermal drug delivery, what comes to mind? More than likely one thinks about a simple patch that one stick onto skin like an adhesive bandage such as nicotine patch. Throughout the past 2 decades, the transdermal patch has become a proven technology that offers a variety of significant clinical benefits over other dosage forms. Because transdermal drug delivery offers controlled release of the drug into the patient, it enables a steady blood-level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms1. In addition, because transdermal patches are user-friendly, convenient, painless, and offer multi-day dosing, it is generally accepted that they offer improved patient compliance2.

Since the first transdermal patch was approved in 1981 to prevent the nausea and vomiting associated with motion sickness, the FDA has approved, throughout the past 22 years, more than 35 transdermal patch products, spanning 13 molecules3. Transdermal drug delivery system was first introduced more than 20 years ago. The technology generated tremendous excitement and interest amongst major pharmaceutical companies in the 1980s and 90s. By the mid to late 1990s, the trend of transdermal drug delivery system companies merging into larger organizations. Transdermal drug deliveries in the text of research articles grow continuously in the 1980s, and has remained constant throughout the past decade. Innovations in transdermal drug delivery technologies continue to occur at a positive rate, making the technology a fertile and vibrant area of innovation, research and product development.

According to one survey throughout past 10 years or so there have been more than 7000 transdermal related presentations and poster presentation at the annual meetings of the Controlled Release Society (CRS) and American Association of Pharmaceutical Scientists. Even though scientists and engineers with high interest continue to this day to publish transdermal related scientific papers in great numbers, it is intriguing to find such continued interest while only 10 or so new drugs utilizing transdermal technology have been introduced during these past 20 years4. One striking element of Table 1 is the number of new compounds in development.

Transdermal Current Status and New Market Opportunities

Interest in transdermal has increased on several fronts over the past several years technology companies have generated additional clinical data demonstrating the potential advanced transdermal technology, pharmaceutical companies there become more aggressive in exploring alternate formulations to extend patent life.

Innovation in Transdermal Technology

The conventional passive means of applying drugs to skin include the use of vehicles such as ointments, creams, gels and patch technology. More recently, such dosage forms have been developed and/or modified in order to enhance the driving force of drug diffusion (thermodynamic activity) and/or increase the permeability of the skin. These approaches include the use of penetration enhancers5, supersaturated systems6, hyaluronic acid7, prodrugs8,9, liposomes and other vesicles10-13.

However, the amount of drug that can be delivered using these methods is still limited since the barrier properties of the skin are not fundamentally changed and as such, with the exception of patches, the majority are used to treat localized skin diseases where systemic absorption is not required. Thus, while new passive technologies typically offer an improvement in dose control, patient acceptance and compliance compared to more traditional semisolid formulations, they do not have the potential to widen the applicability of transdermal drug delivery unlike active transdermal drug delivery technologies. Table 2 shows a summary of the various physicochemical properties of the molecules for various tansdermal technologies.

Active Methods

A rich area of research over the past 10 to 15 years has been focused on developing transdermal technologies that utilize mechanical energy to increase the drug flux across the skin by either altering the skin barrier (primarily the stratum corneum) or increasing the energy of the drug molecules. Recent progress in active transdermal drug delivery technologies has occurred as a result of advances in precision engineering (bioengineering), computing, chemical engineering and material sciences, which have all helped to achieve the creation of miniature, powerful devices that can facilitate the generation of a required clinical response.

These so-called “active” transdermal technologies include iontophoresis, electroporation, microneedles, abrasion, needle-less injection, suction, stretching, ultrasound, magnetophoresis, radio frequency, lasers, photomechanical waves, and temperature manipulation. Some most commonly employed techniques include the following14(PF).

Iontophoresis:

This method involves the application of a low level electric current either directly to the skin or indirectly via the dosage form in order to enhance permeation of a topically applied therapeutic agent15-18. Products have already reached the US market using iontophoresis e.g., recently , FDA approved a pre-filled, pre-programmed iontophoric device for sale in the United States. This product, called LidositeTM , delivers lidocaine  and epinephrine to intact skin to provide local anesthesia for superficial dermatological procedures.

Increased drug permeation as a result of this methodology can be attributed to either one or a combination of the following mechanisms: Electro-repulsion (for charged solutes), electro-osmosis (for uncharged solutes) and electro-pertubation (for both charged and uncharged). Several iontophoretic systems are currently under commercial development including the Phoresor device developed by Iomed Inc. and the Vyteris and E-TRANS devices developed by Alza Corp.19,20.

Electroporation:

This method involves the application of high voltage pulses to the skin which has been suggested to induce the formation of transient pores. High voltages (Ž100 V) and short treatment durations (milliseconds) are most frequently employed. Other electrical parameters that affect delivery include pulse properties such as waveform, rate and number17. The technology has been successfully used to enhance the skin permeability of molecules with differing lipophilicity and size (i.e. small molecules, proteins, peptides and oligonucleotides) including biopharmaceuticals with molecular weights greater that 7kDA.

As electroporation improves the diffusion of such a wide range of compounds, it is thought that the pores created in the superficial layers of the skin are directly responsible for the increase in skin permeability21. Genetronics, Inc. has developed a prototype electroporation transdermal device, which has been tested with various compounds with a view to achieving gene delivery, improving drug delivery and aiding the application of cosmetics22.

Microneedle-based Devices:

A new area of intense transdermal research and development is the development of devices that create micropores in the stratum corneum, the topmost layer of the skin that serves as the greatest barrier to drug diffusion. Such devices include microstructured arrays , sometimes called microneedles, that, when applied to the skin, painlessly create micropores in the stratum corneum without causing bleeding. These micropores offer lower resistance to drug diffusion than normal skin without micropores23. The very first microneedle systems, described in 1976, consisted of a drug reservoir and a plurality of projections (microneedles 50 to 100 mm long) extending from the reservoir, which penetrated the stratum corneum and epidermis to deliver the drug24. More recently, as a result of the rapid advancement in microfabrication technology in the last 10 years, numerous cost-effective methods of producing microneedle devices have been developed25-27 . The ALZA Corp. has recently commercialized a microneedle technology named Macroflux which can either be used in combination with a drug reservoir28 or by dry coating the drug on the microprojection array29; the latter being better for intracutaneous immunization.

Skin Abrasion:

The abrasion technique involves the direct removal or disruption of the upper layers of the skin to facilitate the permeation of topically applied medicaments. Some of these devices are based on techniques employed by dermatologists for superficial skin resurfacing (e.g. microdermabrasion) which are used in the treatment of acne, scars, hyperpigmentaion and other skin blemishes.

Microscissuining is a process which creates microchannels in the skin by eroding the impermeable outer layers with sharp microscopic metal granules. Carlisle Scientific is currently in the process of developing a pen-like handheld device called the microscissioner.

In addition, MedPharm Ltd. has recently developed a novel dermal abrasion device (D3S) for the delivery of difficult to formulate therapeutics ranging from hydrophilic low molecular weight compounds to biopharmaceuticals. In vitro data has shown that the application of the device can increase the penetration of angiotensin into the skin 100-fold compared to untreated human skin. This device is non-invasive and histological studies on human skin show that the effects on the stratum corneum are reversible and non-irritating.

Needle-less Injection:

This is reported to involve a pain-free method of administering drugs to the skin. Over the years, there have been numerous examples of both liquid (Ped-O-Jet, Iject, Biojector2000, Medi-jector and Intraject) and powder (PMED device formerly known as Powderject injector) systems. The latter device has been reported to successfully deliver testosterone, lidocaine hydrochloride and macromolecules such as calcitonin and insulin30-32.

This method of administering drugs circumvents issues of safety, fear and pain associated with the use of hypodermic needles. Transdermal delivery is achieved by firing the liquid or solid particles at supersonic speeds through the outer layers of the skin using a suitable energy source. The PMED device consists of a helium gas cylinder, drug powder sealed in a cassette made of plastic membrane, a specially designed convergent-divergent supersonic nozzle and a silencer to reduce the noise associated with the rupturing of the membrane when particles are fired.

The mechanism involves forcing compressed gas (helium) through the nozzle, with the resultant drug particles entrained within the jet flow reportedly traveling at sufficient velocity for skin penetration. An essential difference between administration of a DNA vaccine by needle injection or by PMED is the efficiency with which the administered DNA generates the encoded protein for presentation on the surface of antigen-presenting cells (APCs). Using PMED, it is possible to deliver the DNA directly to the intracellular compartment of cells within the epidermis, and because the epidermis is rich in APCs, significant numbers can potentially be targeted with each administration. This is supported by non-clinical studies in pigs that have included histological examination of PMED administration sites.

Ultrasound (sonophoresis and phonophoresis): This technique involves the use of ultrasonic energy to enhance the transdermal delivery of solutes either simultaneously or via pre-treatment and is frequently referred to as sonophoresis or phonophoresis. The SonoPrep device (Sontra Medical Corp.) uses low frequency ultrasound (55 kHz) for an average duration of 15 seconds to enhance skin permeability. This battery-operated, handheld device consists of a control unit, ultrasonic horn with control panel, a disposable coupling medium cartridge, and a return electrode.

Laser Radiation:

This method involves direct and controlled exposure of a laser to the skin which results in the ablation of the stratum corneum without significantly damaging the underlying epidermis. Removal of the stratum corneum using this method has been shown to enhance the delivery of lipophilic and hydrophilic drugs34-36. A handheld portable laser device has been developed by Norwood Abbey Ltd. (Victoria, Australia), which, in a study involving human volunteers, was found to reduce the onset of action of lidocaine to 3 to 5 minutes, while 60 minutes was required to attain a similar effect in the control group. The Norwood Abbey system has been approved by the U.S. and Australian regulatory bodies for the administration of a topically-applied anaesthetic. Laser systems are also being developed to ablate the stratum corneum from the epidermal layer37. As with microneedles, the ablated regions offer lower resistance to drug diffusion than non-ablated skin. One company has recently received FDA approval to market this device with a lidocaine cream38.

Dispenser for Transdermal Patches

3M core pop-up dispensing technology is being used to develop compact transdermal patch dispensers. The patented dispenser is designed to dispense patches in a manner that makes the patches convenient to apply. The dispenser appearance, size, shape and quantity of patches stored can be customized to meet patients needs39.

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 40,41.

Future Prospects

Subjective and objective analysis of the next generation of transdermal devices is required to make sure that scientific, regulatory and consumer needs are met. Many of the devices currently in development are more costly and complicated compared to conventional therapies. As such they may contain electrical and mechanical components which could increase the potential safety risks to patients due to poor operator techniques or device malfunction.

Conclusion

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.

References

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8.Tsai, J.C., Guy, R.H., Thornfeldt, C.R., Gao, W.N., Feingold, K.R. and Elias, P.M., “Metabolic Approaches to Enhance Transdermal Drug Delivery. 1. Effect of lipid synthesis inhibitors,” J. Pharm. Sci., 1998, 85, 643-648.

9.Elias, P.M., “Epidermal Lipids, Barrier Function and Desquamation”, J. Invest. Dermatol., 1983, 80, 44-49.

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11.Cevc, G., “Transferosomes, liposomes and other lipid suspensions on the skin: permeation enhancement, vesicle penetration and transdermal drug delivery”, Crit. Rev. Ther. Drug Carrier Syst., 1996, 13, 257-388.

12.Cevc, G., “Transferosomes: Innovative Transdermal Drug Carriers”, In: Rathbone, M.J., Hadgraft, J. and Roberts, M.S., eds., Modified Release Drug Delivery Technology, Marcel Dekker, 2003, 533-560.

13.Godin, B. and Touitou, E., “Ethosomes: New prospects in transdermal delivery,” Crit. Rev. Ther. Drug. Carrier, 2003, 20, 63-102.

14.Jones, S. A.  and Brown , M. B., Evolution of Transdermal Drug Delivery: Recent progress in active transdermal drug delivery technologies has helped miniature, powerful devices to generate required clinical responses, Drug Delivery, Formulation, 2005, www.pharmaquality.com

15.Wang, Y., Allen, L.V., Li, C. and Tu, Y., “Iontophoresis of Hydrocortisone across Hairless Mouse Skin: Investigation of Skin Alteration,” J. Pharm. Sci., 1993, 82, 1140-1144.

16.Turner, N.G., Kalia, Y.N. and Guy, R.H.7) “The Effect of Current on Skin Barrier Function In Vivo: Recovery Kinetics Post Iontophoresis,” Pharm Res., 1997, 14, 1252-1255.

17.Banga, A.K., Bose, S. and Ghosh, T.K., “Iontophoresis and Electroporation: Comparisons and Contrasts”, Int. J. Pharm., 1999, 179, 1-19.

18.Guy, R.H., Kalia, Y.N., Delgado-Charro, M.B., Merino, V., López, A. and Marro, D., “Iontophoresis: Electrorepulsion and Electroosmosis,” J. Control. Rel., 2000, 64, 129-132.

19.Gupta, S.K., Sathyan, G., Phipps, B., Klausner, M. and Southam, M., “Reproducible Fentanyl Doses Delivered Intermittently at Different Time Intervals from an Electrotransport system,” J. Pharm. Sci., 1999, 88, 835-841.

20.Gupta, S.K., Southam, M., Sathyan, G. and Klausner, M., “Effect of Current Density on Pharmacokinetics following Continuous or Intermittent Input from a Fentanyl Electrotransport system,” J. Pharm. Sci., 1998, 87, 976-981.

21.Weaver, J.C., Vaughan, T.E. and Chizmadzhev, Y.A., “Theory of Electrical Creation of Aqueous Pathways across Skin Transport Barriers,” Adv. Drug. Del. Rev., 1999, 35, 21-39.

22.Genetronics Web site, Retrieved January 31, 2005

23.Sebastien, H., McAllister, D.V., Allen, M.G., Prausnitz, M.R., Microfabricated Microneedles: A Novel Approach to Transdermal Drug Delivery, J. Pharm. Sci., 1998, 87(8), 922-925.

24.Gerstel, M.S. and Place, V.A. “Drug Delivery Device,” US Patent No., US3, 964, 482, 1976.

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29.Matriano, J.A., Cormier, M., Johnson, J., Young, W.A., Buttery, M., Nyam, K. and Daddona, P., “Macroflux Technology; A new and Efficient Approach for Intracutaneous Immunization,” Pharm. Res., 2002, 19; 63-70.

30. Muddle, A.G., Longridge, D.J., Sweeney, P.A., Burkoth, T.L. and Bellhouse, B.J., “Transdermal Delivery of Testosterone to Conscious Rabbits using Powderject (R): A Supersonic Powder Delivery System,” Proc. Int Symp. Control. Rel. Bioact. Mat., 1997, 24, 713.

31. Longbridge, D.J., Sweeney, P.A., Burkoth, T.L. and Bellhouse, B.J., “Effects of Particle Size and Cylinder Pressure on Dermal Powderject® Delivery of Testosterone to Conscious Rabbits,” Proc. Int. Symp. Control. Rel Bioact. Mat., 1998, 25, 964.

32. Burkoth, T.L., Bellhouse, B.J., Hewson, G., Longridge, D.J., Muddle, A.J. and Sarphie, D.J., “Transdermal and Transmucosal Powdered Delivery,” Crit. Rev Ther. Drug Carrier. Syst., 1999, 16, 331-384.

33. Kost, J., Katz, N., Shapiro, D., Herrmann, T., Kellog, S., Warner, N. and Custer, L., “Ultrasound Skin Permeation Pre-Treatment to Accelerate the Onset of Topical Anaesthesia,” Proc. Inter. Symp. Bioact. Mater., 2003.

34. Jacques, S.L., McAuliffe, D.J., Blank, I.H. and Parrish, J.A., “Controlled Removal of Human Stratum Corneum by Pulsed Laser to Enhance Percutaneous Transport,” US Patent No., US 4, 775, 361, 1988.

35. Lee, S., Kollias, N., McAuliffe, D.J., Flotte, T.J. and Doukas, A.G., “Topical Drug Delivery in Humans with A Single Photomechanical Wave,” Pharm. Res., 1999, 16, 514-518.

36. Lee, S., McAuliffe, D.J., Flotte, T.J., Kollias, N. and Doukas, A.G., Photomechanical Transcutaneous Delivery of Macromolecules,” J. Invest. Dermatol., 1998, 111, 925-929.

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TABLE 1: Transdermal Products that are in Clinical Development in the United States
Compound TDD Technology Development Stage
Alprostadil Gel Preclinical
Buprinorphine Patch Phase III
Dexamethasone Iontophoresis Phase III
Dextroamphetamine Patch Preclinical
Diclofenac Patch Preclinical
Dihydrotestosteron Gel Phase III
Estradiol Gel Phase III
Androgen/ Estradiol Patch Phase II
Estradiol/ Progestin Patch Submitted NDA
Testosterone/ Estradiol Patch Phase III
Fentanyl Patch, Iontophoresis Preclinical to Phase III
Flurbiprofen Patch Preclinical
Lidocaine Iontophoresis Phase III
Glucagons-like peptide-1 Microneedle Preclinical
Methylphenidate Patch Submitted NDA
Parathyroid hormone Microneedle Preclinical
Rotigotin Patch Phase III
Testosterone Gel Preclinical to Submitted NDA
Vaccines (various) Patch Preclinical
Various (macromolecules, etc.) Sonophoresis Preclinical
TABLE 2: Transdermal Technologies Grid Showing the Preferred Compound Physiochemical and Clinical Properties for each Transdermal Technology

Technology

Polarity

Molecular

Weight

(g/mole)

log P

Melting

Point ( °C)

Daily Dose

(mg /day)

Passive DIA

Neutral

< 500

Near 2

< 150

< 10

Gel

Neutral

< 500

Near 2

< 150

< 20

Thermal

Neutral

< 500

Near 2

< 150

< 15

Iontophoresis

Ionic

No limit

< 1

No limit

< 20

Sonophoresis

Neutral

No limit

No limit

No limit

< 20

Microporation

All

No limit

No limit

No limit

< 30

About Authors    

Parul B. Patel*, Amit Chaudhary, and Dr. G. D. Gupta

Parul B. Patel
*Lecturer, M. Pharm. (Pharmaceutics), L.B. Rao institute of Pharmaceutical Education and Research, Khambhat- 388 620 (Gujarat), E mail address: patel_p29@ yahoo.co.in, Mobile No.: 09879861263
*Address for correspondence

Mr. Amit Chaudhary, Lecturer, M. Pharm (Pharmaceutics), SBS(PG)I, Balawala, Dehradun-248161

Dr. G. D. Gupta, M. Pharm (Ph. D.), Principal, Sagar Institute of Pharmaceutical Sciences, Sagar-470 008 (M. P.)

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