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Iontophoretic (Transdermal) Delivery of Drugs: Overview of Historical Development
JOURNAL OF PHARMACEUTICAL SCIENCES
May 1989 Volumne 78, Number 5
A publication of the American Pharmaceutical Association
SYMPOSIUM ARTlCL ES Papers presented at the symposium “lontophoretic Delivery of Drugs”, International Conference on Pharmaceutical Sciences and Clinical Pharmacology, May 31, 1988, Jerusalem, Israel
lontophoretic (Transdermal) Delivery of Drugs: Overview of Hisltorical Development YIE
\N.CHIEN’
AND
AJAY K. BANGA
Received September 6, 1988, from Confrolled Drug-Delivery Research Center, College of Pharmacy, Rutgers-The Sfate University, Piscafaway, NJ Ot1855-0789. Accepted for publication November 30, 1988. The potential of biomedical applications of electricity was explored even before its discovery! When the Greek physician Btius prescribed the shocks of Torpedo, a n electric fish, for the treatment of gout, he probably had little idea of the potential of the physical force he was dealing with. William Gilbert, a physician to Queen Elizabeth I, published a book on “De Magneto” as early as 1600; this volume stimulated further interest in the use of electricity for treatment. Alessandro Volta, in the spring of 1800, proved that current flow occurs between two dissimilar metals when they are placed in contact, and he attributed the twitching of frog leg muscles, observed by Galvani in 1780, to this phenomenon. He made a pile of metal discs of zinc and copper with moist cloth between them, the basis for the invention of the electric cell or battery.’ The idea of applying electric current to increase the penetration of electrically charged drugs into surface tissues was probably originated by Veratti in 1747.2 In the latter part of the 1.9th century, Morton was interested in the electrical transport of drugs through the skin and wrote a book in 1898 on cataphoresis of ions into the tissues.3 He conducted an experiment on himself in which finely powdered graphite was driven into his arm under positive electrode, producing small black spots which persisted for several weeks. The first well-documented experiments were done at the beginning of the i!Oth century by Leduc.495 Placing two rabbits in series with a direct-current generator, Leduc demonstrated the introduction of strychnine and cyanide ions into the rabbits when the correct polarity was applied. The results were rather dramatic: the first rabbit was seized by tetanic convulsions, due 1.0 the introduction of strychnine ion, while the second rabbit died with symptoms of cyanide poisoning. Similar expel-iments were also carried out by Inchley in 1921.6 In one of the experiments, a zinc-silver couple was applied to an anesthetized cat’s tongue in which the lint sandwiched be0022-3549/89/0800-0353$0 l.OO/O @ 7 9139, American Pharmaceutical Association
tween the tongue and the zinc plate was presoaked in a solution of atropine sulfate. Complete paralysis of the cranial autonomic nerves occurred in 5 to 10 min. Good news for patients with sweaty palms came in 1936 when Ichihashi7 noted that sweating could be reduced by ion transfer of certain applied solutions by electrophoretic techniques. This was the origin of the application of iontophoresis t o the treatment of hyperhidrosis, a condition characterized by excessive sweating, which can be socially and occupationally distressing. To date, there have been a t least 18 other publications on this topic: a listing of these publications can be found in a recent review by Banga and Chiens on the principles and biomedical applications of iontophoretic delivery of drugs. Many of these studies involved a subjective recording of sweat output, but recent studies have used scientific measurements. For example, Akins et al.9 measured sweat output by a perspirant paper, quantitated the data by a n image analysis computer, and then evaluated the results for statistical significance. Today, the treatment of hyperhidrosis is the most successful and popular application of iontophoresis in dermatologic medication.10 While these investigators were busy trying to reduce sweating, Gibson and Cooke in 195911 had an altogether different problem. They wanted to increase sweating in order to get enough sweat for diagnosis of cystic fibrosis, as it was known that cystic fibrosis patients have a high concentration of sodium and chloride in their sweat. The simplest method available to increase sweating and avoid a painful intraderma1 injection of a cholinergic drug was to place the patient in a plastic bag. The procedure was obviously uncomfortable and required a long period of time. Besides, some infants became hyperpyrexic within 30 min. Some clinicians even tried t o place some bottles containing hot water into the bag with the patient to expedite sweating. Apparently, the idea was not a good one; it led to a fatal heat stroke.12 Alternatively, Gibson Journal of Pharmaceufical Sciences i 353 Vol. 78, No. 5,May 1989
and Cooke used iontophoretic application of pilocarpine to induce sweating, The procedure was found painless and required only 5 min; rapid sweating was induced and continued for 30 min. Following this discovery, additional studies were conducted8 and iontophoresis of pilocarpine has been approved by the FDA and is now widely used by pediatricians for the diagnosis of cystic fibrosis.1° In 1967,Harris wrote a review on iontophoresis which is fairly comprehensive in terms of the biomedical applications of iontophoresis developed by that time.13 A decade earlier, in 1957, Harris himself had used iontophoresis to deliver local anesthetics for the painful and “trigger areas” of trigeminal neuralgia.14 Several other studies have also been done on the iontophoretic delivery of local anesthetics, metallic and nonmetallic ions, vasodilators, and steroids. An updated listing of these applications can be found in a recent review by Banga and Chien.8 In 1978, Gangarosa’“ did conductivity studies to determine which drugs would be the best candidates for iontophoretic delivery. The hydrochloride salts of local anesthetics and vasoconstrictors, which had been delivered iontophoretically in earlier studies, were found t o be highly conductive. Investigation of iontophoresis as a means for systemic delivery of drugs has a relatively recent origin. Some of the drugs investigated in the 1980s for feasibility of iontophoretic systemic delivery include propranolol,l6 metoprolol,17 oxycodone,ls thyrotropin-releasing hormone,’g insulin,20 verapamil,21 and vasopressin.22 Active research is also underway to investigate the mechanisms of iontophoretic drug delivery.1s-24 The efforts of several researchers in academia and industry are beginning to unravel the intricacies and complexities involved, as reflected by several very recent publications .2%27 Some major limitations for transdermal drug delivery, such as the requirements of low molecular weight, low dose, and ‘balanced’ water-oil partition coefficient can be easily overcome by iontophoretic delivery. The fact that so many researcherszOz2a1 are investigating the transdermal delivery of insulin, a macromolecule with a molecular weight of 6000, speaks for the potential of iontophoresis in achieving the systemic delivery of peptide and protein drugs. Such possibilities open the doors to noninvasive transdermal delivery of peptide-based pharmaceuticals, which, thanks to the advances in recombinant DNA technology, are the wonder drugs of tomorrow. Monkhouse and Huq32 predict that in the future, patients may be seen wearing transdermal systems in the form of disposable, battery-operated wrist watches that will be operated and controlled by microchips to deliver the drug at the desired rate. To realize such objectives, however, extensive research is still required to elucidate more thoroughly the mechanisms of iontophoretic drug delivery and the reversibility of skin permeability.21 Also, it must be ensured that the skin is not burned or irreversibly altered in any way by iontophoresis application.
354 I Journal of Pharmaceutical Sciences Vol. 78, No. 5,May 1989
References and Notes 1. Watkins, A. L. A Manual of Electrotherapy, 3rd ed.; Lea and Febiger: Philadelphia, 1968. 2. Turnell, W. J. Proc. Royal SOC.Med. 1921, 14, 41-52. 3. Morton, W. J. Cata horesis or Electric Medicamental Surgery; American Technicaf Book New York, 1898. 4. Leduc, S. A n n d‘electrobwl. 1900,3, 545-560. 5. Leduc, S. Electric Ions and Their Uses in Medicine; Rebman: London, 1908. 6. Inchley, 0. J . Pharmacol. Exp. Ther. 1921,18, 241-256. 7. Ichihashi, T. J . Orient. Med. 1936,25, 101. 8. Banga, A. K.; Chien, Y. W. J . Controlled Release 1988, 7, 1-24. 9. Akins, D. L.; Meisenheimer, J. L.; Dobson, R. L. J . A m . Acad. Dermatol. 1987,16, 82-32. 10. Sloan. J. B.: Soltani. K. J . A m . Acad. Dermatol. 1986., 15., 671684. 11. Gibson, L. E.; Cooke, R. E. Pediatrics 1959,23, 54S549. 12. Misch, K. A.; Holden, H. M. Arch. Dis. Childhood 1958,33,179. 13. Harris, R. In Therapeutic Electricity and Ultraviolet Radiation; Licht, S., Ed.; Waverly: Baltimore, MD, 1967, pp 156178. 14. Harris, R. Lancet, 1957,1,378. 15. Gan arosa, L. P ;Park, N. H.; Fong, B. C.; Scott, D. F.; Hill, J. M. J . Pfarm. Sci. 1978, 67, 1439-1443. 16. Padmanabhan, R. V.; Phipps, J. B.; Lattin, G. A. Proceedings of the 13th International Symposium; Controlled Release Society: Lincolnshire, IL, 1986; p 198. 17. Okabe, K.; Yamaguchi, H.; Kawai, Y. J . ControlledRelease 1986, 4. 79-85. 18. Kuo, P. C . ; Liu, J. C.; Chang, S. F.; Chien, Y. W. Pharm. Res. 1987, 4, S-61-S-62. 19. Burnette, R. R.; Marrero, D. J . Pharm. Sci. 1986, 75, 738-743. 20. Chien, Y. W.; Siddiqui, 0.; Sun, Y.; Shi, W. M.; Liu, J . C. Ann. N.Y. Acad. Sci. 1988, 507, 32-51. 21. Wearley, L.; Liu, J. C.; Chien, Y. W. 3rd National Meeting of American Association of Pharmaceutical Scientists, Orlando, FL, October, 1988. 22. Lelawongs, P.; Liu, J. C.; Chien, Y. W. 8th Annual Meeting of Graduate Research Association of Students in Pharmaceutics, June 1988, Hartford, CT. 23. Keister, J. C.; Kasting, G. B. J . Membr. Sci. 1986,29, 155-167. 24. Burnette, R. R.; Ongpipattanakul, B. J . Pharm. Sci. 1987, 76, 765-773. 25. Kasting, G. B.; Merritt, E. W.; Keister, J. C. J . Membr. Sci.1988, 35,137-159. 26. Burnette, R. R.;Ongipattanakul, 3.J . Pharm. Sci. 1988,77,132137. 27. Burnette, R. R.; Bagniefski, T. M. J . Pharm. Sci. 1988, 77, 492497. 28. Stephen, R. L.; Petelenz, T. J.; Jocobsen, S. C. Biomed. Biochim. Acta 1984,43, 553-558. 29. Kari, B. Diabetes 1986.35, 217-221. 30. Siddiqui, 0.;Sun, Y.;Liu,J. C.; Chien, Y. W. J .Pharm. Sci. 1987, 76,341-345. 31. Liu, J. C.; Sun, Y.; Siddiqui, 0.;Chien, Y. W. Int. J . Pharm. 1988, 44,197-204. 32. Monkhouse, D. C.; Huq, A. S. Drug. Deu. Ind. Phurm. 1988,14, 183-209.
Acknowledgments This paper is based on a presentation made by Y. W. Chien at the International Conference on Pharmaceutical Sciences and Clinical Pharmacology, Jerusalem, Israel, May 2 9 J u n e 3, 1988.
May 1989 Volumne 78, Number 5
A publication of the American Pharmaceutical Association
SYMPOSIUM ARTlCL ES Papers presented at the symposium “lontophoretic Delivery of Drugs”, International Conference on Pharmaceutical Sciences and Clinical Pharmacology, May 31, 1988, Jerusalem, Israel
lontophoretic (Transdermal) Delivery of Drugs: Overview of Hisltorical Development YIE
\N.CHIEN’
AND
AJAY K. BANGA
Received September 6, 1988, from Confrolled Drug-Delivery Research Center, College of Pharmacy, Rutgers-The Sfate University, Piscafaway, NJ Ot1855-0789. Accepted for publication November 30, 1988. The potential of biomedical applications of electricity was explored even before its discovery! When the Greek physician Btius prescribed the shocks of Torpedo, a n electric fish, for the treatment of gout, he probably had little idea of the potential of the physical force he was dealing with. William Gilbert, a physician to Queen Elizabeth I, published a book on “De Magneto” as early as 1600; this volume stimulated further interest in the use of electricity for treatment. Alessandro Volta, in the spring of 1800, proved that current flow occurs between two dissimilar metals when they are placed in contact, and he attributed the twitching of frog leg muscles, observed by Galvani in 1780, to this phenomenon. He made a pile of metal discs of zinc and copper with moist cloth between them, the basis for the invention of the electric cell or battery.’ The idea of applying electric current to increase the penetration of electrically charged drugs into surface tissues was probably originated by Veratti in 1747.2 In the latter part of the 1.9th century, Morton was interested in the electrical transport of drugs through the skin and wrote a book in 1898 on cataphoresis of ions into the tissues.3 He conducted an experiment on himself in which finely powdered graphite was driven into his arm under positive electrode, producing small black spots which persisted for several weeks. The first well-documented experiments were done at the beginning of the i!Oth century by Leduc.495 Placing two rabbits in series with a direct-current generator, Leduc demonstrated the introduction of strychnine and cyanide ions into the rabbits when the correct polarity was applied. The results were rather dramatic: the first rabbit was seized by tetanic convulsions, due 1.0 the introduction of strychnine ion, while the second rabbit died with symptoms of cyanide poisoning. Similar expel-iments were also carried out by Inchley in 1921.6 In one of the experiments, a zinc-silver couple was applied to an anesthetized cat’s tongue in which the lint sandwiched be0022-3549/89/0800-0353$0 l.OO/O @ 7 9139, American Pharmaceutical Association
tween the tongue and the zinc plate was presoaked in a solution of atropine sulfate. Complete paralysis of the cranial autonomic nerves occurred in 5 to 10 min. Good news for patients with sweaty palms came in 1936 when Ichihashi7 noted that sweating could be reduced by ion transfer of certain applied solutions by electrophoretic techniques. This was the origin of the application of iontophoresis t o the treatment of hyperhidrosis, a condition characterized by excessive sweating, which can be socially and occupationally distressing. To date, there have been a t least 18 other publications on this topic: a listing of these publications can be found in a recent review by Banga and Chiens on the principles and biomedical applications of iontophoretic delivery of drugs. Many of these studies involved a subjective recording of sweat output, but recent studies have used scientific measurements. For example, Akins et al.9 measured sweat output by a perspirant paper, quantitated the data by a n image analysis computer, and then evaluated the results for statistical significance. Today, the treatment of hyperhidrosis is the most successful and popular application of iontophoresis in dermatologic medication.10 While these investigators were busy trying to reduce sweating, Gibson and Cooke in 195911 had an altogether different problem. They wanted to increase sweating in order to get enough sweat for diagnosis of cystic fibrosis, as it was known that cystic fibrosis patients have a high concentration of sodium and chloride in their sweat. The simplest method available to increase sweating and avoid a painful intraderma1 injection of a cholinergic drug was to place the patient in a plastic bag. The procedure was obviously uncomfortable and required a long period of time. Besides, some infants became hyperpyrexic within 30 min. Some clinicians even tried t o place some bottles containing hot water into the bag with the patient to expedite sweating. Apparently, the idea was not a good one; it led to a fatal heat stroke.12 Alternatively, Gibson Journal of Pharmaceufical Sciences i 353 Vol. 78, No. 5,May 1989
and Cooke used iontophoretic application of pilocarpine to induce sweating, The procedure was found painless and required only 5 min; rapid sweating was induced and continued for 30 min. Following this discovery, additional studies were conducted8 and iontophoresis of pilocarpine has been approved by the FDA and is now widely used by pediatricians for the diagnosis of cystic fibrosis.1° In 1967,Harris wrote a review on iontophoresis which is fairly comprehensive in terms of the biomedical applications of iontophoresis developed by that time.13 A decade earlier, in 1957, Harris himself had used iontophoresis to deliver local anesthetics for the painful and “trigger areas” of trigeminal neuralgia.14 Several other studies have also been done on the iontophoretic delivery of local anesthetics, metallic and nonmetallic ions, vasodilators, and steroids. An updated listing of these applications can be found in a recent review by Banga and Chien.8 In 1978, Gangarosa’“ did conductivity studies to determine which drugs would be the best candidates for iontophoretic delivery. The hydrochloride salts of local anesthetics and vasoconstrictors, which had been delivered iontophoretically in earlier studies, were found t o be highly conductive. Investigation of iontophoresis as a means for systemic delivery of drugs has a relatively recent origin. Some of the drugs investigated in the 1980s for feasibility of iontophoretic systemic delivery include propranolol,l6 metoprolol,17 oxycodone,ls thyrotropin-releasing hormone,’g insulin,20 verapamil,21 and vasopressin.22 Active research is also underway to investigate the mechanisms of iontophoretic drug delivery.1s-24 The efforts of several researchers in academia and industry are beginning to unravel the intricacies and complexities involved, as reflected by several very recent publications .2%27 Some major limitations for transdermal drug delivery, such as the requirements of low molecular weight, low dose, and ‘balanced’ water-oil partition coefficient can be easily overcome by iontophoretic delivery. The fact that so many researcherszOz2a1 are investigating the transdermal delivery of insulin, a macromolecule with a molecular weight of 6000, speaks for the potential of iontophoresis in achieving the systemic delivery of peptide and protein drugs. Such possibilities open the doors to noninvasive transdermal delivery of peptide-based pharmaceuticals, which, thanks to the advances in recombinant DNA technology, are the wonder drugs of tomorrow. Monkhouse and Huq32 predict that in the future, patients may be seen wearing transdermal systems in the form of disposable, battery-operated wrist watches that will be operated and controlled by microchips to deliver the drug at the desired rate. To realize such objectives, however, extensive research is still required to elucidate more thoroughly the mechanisms of iontophoretic drug delivery and the reversibility of skin permeability.21 Also, it must be ensured that the skin is not burned or irreversibly altered in any way by iontophoresis application.
354 I Journal of Pharmaceutical Sciences Vol. 78, No. 5,May 1989
References and Notes 1. Watkins, A. L. A Manual of Electrotherapy, 3rd ed.; Lea and Febiger: Philadelphia, 1968. 2. Turnell, W. J. Proc. Royal SOC.Med. 1921, 14, 41-52. 3. Morton, W. J. Cata horesis or Electric Medicamental Surgery; American Technicaf Book New York, 1898. 4. Leduc, S. A n n d‘electrobwl. 1900,3, 545-560. 5. Leduc, S. Electric Ions and Their Uses in Medicine; Rebman: London, 1908. 6. Inchley, 0. J . Pharmacol. Exp. Ther. 1921,18, 241-256. 7. Ichihashi, T. J . Orient. Med. 1936,25, 101. 8. Banga, A. K.; Chien, Y. W. J . Controlled Release 1988, 7, 1-24. 9. Akins, D. L.; Meisenheimer, J. L.; Dobson, R. L. J . A m . Acad. Dermatol. 1987,16, 82-32. 10. Sloan. J. B.: Soltani. K. J . A m . Acad. Dermatol. 1986., 15., 671684. 11. Gibson, L. E.; Cooke, R. E. Pediatrics 1959,23, 54S549. 12. Misch, K. A.; Holden, H. M. Arch. Dis. Childhood 1958,33,179. 13. Harris, R. In Therapeutic Electricity and Ultraviolet Radiation; Licht, S., Ed.; Waverly: Baltimore, MD, 1967, pp 156178. 14. Harris, R. Lancet, 1957,1,378. 15. Gan arosa, L. P ;Park, N. H.; Fong, B. C.; Scott, D. F.; Hill, J. M. J . Pfarm. Sci. 1978, 67, 1439-1443. 16. Padmanabhan, R. V.; Phipps, J. B.; Lattin, G. A. Proceedings of the 13th International Symposium; Controlled Release Society: Lincolnshire, IL, 1986; p 198. 17. Okabe, K.; Yamaguchi, H.; Kawai, Y. J . ControlledRelease 1986, 4. 79-85. 18. Kuo, P. C . ; Liu, J. C.; Chang, S. F.; Chien, Y. W. Pharm. Res. 1987, 4, S-61-S-62. 19. Burnette, R. R.; Marrero, D. J . Pharm. Sci. 1986, 75, 738-743. 20. Chien, Y. W.; Siddiqui, 0.; Sun, Y.; Shi, W. M.; Liu, J . C. Ann. N.Y. Acad. Sci. 1988, 507, 32-51. 21. Wearley, L.; Liu, J. C.; Chien, Y. W. 3rd National Meeting of American Association of Pharmaceutical Scientists, Orlando, FL, October, 1988. 22. Lelawongs, P.; Liu, J. C.; Chien, Y. W. 8th Annual Meeting of Graduate Research Association of Students in Pharmaceutics, June 1988, Hartford, CT. 23. Keister, J. C.; Kasting, G. B. J . Membr. Sci. 1986,29, 155-167. 24. Burnette, R. R.; Ongpipattanakul, B. J . Pharm. Sci. 1987, 76, 765-773. 25. Kasting, G. B.; Merritt, E. W.; Keister, J. C. J . Membr. Sci.1988, 35,137-159. 26. Burnette, R. R.;Ongipattanakul, 3.J . Pharm. Sci. 1988,77,132137. 27. Burnette, R. R.; Bagniefski, T. M. J . Pharm. Sci. 1988, 77, 492497. 28. Stephen, R. L.; Petelenz, T. J.; Jocobsen, S. C. Biomed. Biochim. Acta 1984,43, 553-558. 29. Kari, B. Diabetes 1986.35, 217-221. 30. Siddiqui, 0.;Sun, Y.;Liu,J. C.; Chien, Y. W. J .Pharm. Sci. 1987, 76,341-345. 31. Liu, J. C.; Sun, Y.; Siddiqui, 0.;Chien, Y. W. Int. J . Pharm. 1988, 44,197-204. 32. Monkhouse, D. C.; Huq, A. S. Drug. Deu. Ind. Phurm. 1988,14, 183-209.
Acknowledgments This paper is based on a presentation made by Y. W. Chien at the International Conference on Pharmaceutical Sciences and Clinical Pharmacology, Jerusalem, Israel, May 2 9 J u n e 3, 1988.