Iontophoretic Drug Delivery: Effects of Physicochemical Factors on the Skin Uptake of Nonpeptide Drugs

lontophoretic Drug Delivery: Effects of Physicochem Factors on the Skin Uptake of NonpeptideDrugs CHARANR. BEHL*,', SARANKUMAR*,A. WASEEMMALICK*,SABINODELTERZO*, WILLIAMI. HIGUCHI*, AND R. A. N A S H ~ Received September 6, 1988, from 'Pharmaceutical Research and Development, Hoffmann-La Roche, lnc., Nutley, NJ 071 10, the *Department of Pharmaceutics, University of Utah, Salt Lake City, UT 841 12, and the §Collegeof Pharmacy, Sf. John's University, Jamaica, NY 11439. Accepted for publication November 30, 1988.

Iontophoresis has been known for a long time to influence drug transport into and across biological membranes and tissues; it has been defined by different investigators in a number of different ways.'-10 Using the most common elements of these definitions, iontophoresis can be described as the permeation of ionized imolecules across biological membranes under the influence of electrical current. This definition is incomplete in two ways: it does not refer to the influence of iontophoresis on drug retention in the biological membranes or the permeation and retention of nonionized molecules. There is some evidence that the uptake of nonionized molecules is also affected by electrical current. Over the past 60 or more years, the principles of iontophoresis have been applied for drug delivery to the muscle and joints,8JlJ2 tympanic cavity,1%18dental area,19>20cervix (cervical hypersensitivity),21eyes,22-26and skin.27-29 Some of the specifc indications where iontophoresis has been demons t r a t ed t o be effective a r e local anesthesia,30.31 hyperhidrosis,32,33 edema formation,34 calcium deposits,"5 pain and inflammatory conditions,8.l',l2.36-39 h aY fever.28,29,4o341and herpes simplex.42,43 Almost all of these efforts were tailored towards delivering drug molecules in a membrane or tissue for a local therapeutic effect. Little or no attempt was made to simultaneously study the net transport acros;j the membranes. Furthermore, the beneficial effects of iontophoresis were assessed via pharmacological or therapeutic oblservations as opposedl to determining drug concentrations in the membranes. Therefore, from these studies, it is difficult to precisely define the basic principles of iontophoretic (drugdelivery and factors which affect it. Recently, there has been a great emphasis on delivering drugs through the transdeimal route. Since the skin rightfully is impermeable to most chemicals, researchers have been looking for ways to enhance skin permeability. Iontophoresis is being explored for those drugs whose delivery is not benefited by chemical enhancers.9.44 This is especially true lfor ionized drugs, and this approach is believed to be promising for peptides and proteins.44.45

Experimental Considerations Aniimal Models-It i s most desirable to carry out skin uptak.e research in the ultimate model-human in vivo. Of course, this is not a practical approach. The next choice is the use of cadaver skin. Even that model poses difficulties, especially in terms of the availability of suitable skin samples. l'urther complicating factors are that it is not possible to control the gender, age, race, site, and skin quality of the donor. Therefore, for the bulk of research in this area, one needs to depend on animal models. A large number of animal models have been explored in passive skin uptake studies, yet the search for the most suitable model continues. Some of the animal models studied are hairless mouse,46 furry mouse,47 0022-:3549/89/0800-0355$0 l.OO/O 0 1989, American Pharmaceutil:al Association

rat,48 hairless rat,49 nude rat,so fuzzy rat,51 hairless guinea ~ i g , rhesus ~2 monkey,53and mini pig.54 It has been found that hairless animals are far better models for human skin (hairy regions excluded)than are furry animals.@It should be noted that the hairless animals have skin which is not devoid ofhair follicles. They have some residual follicles in the skin and perhaps it is this feature which makes the skin a good uptake model for the human. The most suitable animal for passive skin uptake studies is believed to be hairless guinea pig.52 In contrast to passive skin uptake, much less is known about suitable animal models for iontophoretic skin uptake studies. Various models used so far are hairless mouse,45.5558 nude rat,59 furry rat,60and hairless guinea pig. As can be seen, both furry as well as hairless animals have been used. Unlike the passive skin uptake case, no one has yet shown a mechanistic difference between the two skin types. However, by extrapolating knowledge and experience gained in the passive skin uptake studies, and based on the histological similarity and dissimilarity to human skin, we believe that even for the iontophoretic studies the hairless animal skin provides a better model for human skin. The ongoing studies in various laboratories are expected to add to the data base and knowledge in this area. It is important that a suitable animal be identified and that all those involved in research on iontophoresis recognize that model. Apparatus-It can be readily realized from the literature on passive skin uptake studies that a large number of different types of apparatus have been designed and utilized, and that different investigators have preferences for certain types of apparatus. It should be well understood that using a certain type of uptake apparatus is only a means of answering the unknown: it should really not make a difference and should not have any influence on the results. However, consistency and uniformity in the choice of apparatus and experimental conditions is always helpful in avoiding experimental artifacts and confusion. Since iontophoresis is still in its begining stages, only a few different types of in vitro apparatus have been reported in the literature.3,45,55,56,61-63 The tendency has been to try to modify the simple two-compartment diffusion cell for iontophoretic experiments. A good example of such modification can be found in the studies of Bellantone and co-workers.55 Most of the in vitro apparatuses utilize a system of two electrodes, one in each compartment of the apparatus. In this case, a voltage or current measurement is made between the two electrode locations across the skin. Recently, a more sophisticated version of this simple design, which utilizes four electrodes,45 was developed. This four-electrode system is advantageous in that it measures the voltage drop across the skin surface and thus provides a more precise determination of the voltage. The mechanistic and skin uptake enhancement aspects of these two different types of apparatuses should, Journal of Pharmaceutical Sciences I 355 Vol. 78, No. 5, 1989

however, be similar to each other. A side-by-sidecomparison of the two apparatuses, which will provide information on the extent of error made in the measurement of voltage using the two-electrode system, should be made. Continuous and Pulsatile Current-Most of the iontophoretic skin uptake studies have been carried out using continuous current. The application of continuous current to the skin has a serious disadvantage as it builds up charge in the skin and can cause irritation and burn. A prolonged iontophoretic delivery, therefore, cannot be used. These limitations can be overcome by using “depolarizing” or pulsatile current.64 In this case, the current is turned on and off in short intervals, thus preventing build up of charge in the skin. By using pulsatile current, iontophoresis can be used continuously and the skin can tolerate much higher voltage and current conditions. The marketed iontophoretic device, Phoresor (Iomed, Salt Lake City, UT), is based on continuous current. This device is for use in clinics and for only short periods of time not exceeding 20 min. For such a treatment, the use of continuous current is acceptable. The present and future iontophoretic research should, however, utilize pulsatile current.

Factors Affecting Skin Permeability Skin uptake of drugs using the passive absorption process has received a great deal of interest during the past decade. This is primarily because of the recent developments in the transdermal and topical drug delivery areas. Various factors affecting this mode of drug uptake have been identified and extensively studied (Table I), and knowledge is still being gained through skin uptake studies using new compounds, vehicles, and enhancer systems.52 Iontophoresis, however, has not received a great deal of attention in terms of identifylng and understanding the factors. While the factors listed in Table I for passive skin uptake are also relevant, some additional factors which may affect iontophoretic skin uptake of drugs are also listed in Table I. A mechanistic understanding of these factors is essential to optimizing skin uptake enhancement by iontophoresis. A review of the skin uptake literature reveals that rather extensive research has been carried out to understand the mechanisms of uptake and topical formulation development, including vehicle effects and means of enhancing the skin uptake of poorly absorbed drugs. Most of the information Table I-Factors Which Affect the Skin Uptake of Drugs

Drug Uptake

Passive

Factor Drug lipophilicity and molecular weight Drug solubility and concentration Drug binding, metabolism, and degradation

Vehicleldosage form effects Diseasedhormal skin; occlusion Frequency of application Enhancer (permeation or retention) Site, age, sex, race Prodrugs Drug complexation lontophoretic Skin Permeation

Current density Skin impedance (site,age, sex, race) Ion mobility and conductivity;ion valence Ionic strength State of ionization Duration of iontophoresis Effect of iontophoresis on drug binding, metabolism and degradation in the skin Dual enhancement Dosage form limitations

356 I Journal of Pharmaceutical Sciences Vol. 78,No. 5, 1989

gained was acquired in pieces and isolated segments. The physicochemical factors can be evaluated in the following manner. Test compounds, individual compounds, or homologous series of solutes can be used in a systematic fashion, and parameters of interest can be varied in an organized manner. Solutes from different classes of compounds can be used to vary a certain physicochemical parameter. Any available information on any type of compound can be compiled in order to draw correlations or lack of them. When specific studies designed to evaluate the factors are not available, this remains the only source of information. The most desirable way of evaluating the variables affecting skin uptake is the use of test compounds, particularly homologous series of simple solutes. The test compounds chosen should have the following characteristics: They should be simple chemical entities that are stable chemically and metabolically under normal experimental conditions; they should provide wide ranges of physicochemical parameters, such as partition coefficients and solubilities; they should be readily available at reasonable costs; and, for peptide or protein drugs, the test compounds should cover a wide range of molecular weights and isoelectric points. The most notable compounds with the above properties are the homologous series of alkanols and alkanoic acids. Alkanols have been studied in detail to elucidate the effects of several factors on passive skin permeation. Some examples of these studies are effect of hydration,65 species and skin sectioning related to hydration effe~ts,~7@ effects of age,66 effects of skin sectioning,67 vehicle effects,6&70 enhancer e~aluation,71,7~ effect of skin storage in freezer,50 and correlations between in vitro and in vivo experiments.73~74These studies have provided a great deal of useful information. Recently, test compounds have also been used to study iontophoretic skin permeation. For example, Bellantone and co-workersused benzoic acid,55 Masada et al. used tetraethylammonium bromide,45 salicylic acid,fi3 nicotine,63 benzoic acid,63 and thyrotropin releasing hormone.56 More recently, DelTerzo and co-workers used n-alkanols and n-alkanoic acids and studied the effects of the following parameters99 solute lipophilicity, permeant ionization, pH, permeant concentration, current, competitive ions, skin appendages, and skin sectioning. While notable work has been done in iontophoretic drug delivery, it provides only a limited level of understanding of the factors which affect this mode of drug delivery. In the following text, some of the most common and most relevant factors will be discussed. Drug Concentration-In the case of passive skin permeation, the flux is directly proportional to the drug concentration, thus allowing the calculation of a permeability coefficient parameter (P value). For benzoic acid55 and butyric acid59 the flux increased linearly with the permeant concentration (Figures 1A and 1B); however, this increase was proportional to the concentration only in the case of butyric acid. The experimental conditions in the two studies were different. The concentration of the co-salts was much higher in the case of benzoic acid and seemingly contributed to a disproportional increase in the flux. This is an important parameter because drug concentration provides an easy way to control the rate of drug delivery. It is, therefore, desirable to establish the flux versus concentration relationship in the beginning of a study as a part of the experimental conditions. Current and Voltage-Several criteria should be considered in selecting current and voltage conditions. These are as follows: the current and voltage should be sufficientlyhigh to provide a desired delivery rate; they should not produce any

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harmful effects on the skin, including a permanent alteration in the skin permeability; there should be a quantitative relatitonship between the flux and the applied current and voltage; there should be constancy of the current and voltage during the experimental period; and there should be electrochemical stability of the drug, DelTerzo et al.59 noted a change in the measured voltage with time for the applied currents higher than 0.1 mA in the in vitro system utilizing nude rat skin (Figure 2). These investigators chose 0.1 mA current for the alkanol and alkanoic acid studies becawe the voltage remained invariant during the course of the experiment. The permeant flux is shown to increase linearly with the applied current for benzoic acid55 and butyric a ~ i d . As 5 ~can be seen in Figures 3A and 3B, the lines pass through the origin. An in vivo confirmation of such a relationship can be seen in studies reported by Sanderson et a1.'75on the drug KM-13 (Figure 3C). All these studies are based on the use of a constant current system where the voltage varies according to the resistance offered by the skin. Studies utilizing a constant voltage approach have also been reported.45 A linear relationship was shown to exist between flux enhancement and the applied voltage for tetraethylammonium bromide using hairless mousc skin (linear up to 1.0 V) and cellulose acetate membrane in a four-electrode system (Figure 4A). However, a curvilinear relationship was reported when the flux enhancement was plotted as a function of the measured current (Figure 4B). Additional studies are required to establish such data and to understand the mechanistic basis for the trends observed. Salt Concentration-If the ionic concentration provided by the drug itself is insuffkient to optimally conduct electrical current, one may have to use additional salts. In that case, it is imlportant to demonstraite the effects of the type and concentration of the salts used on the delivery rate. As shown in Figures 5A and 5B, the delivery rate declined almost exponentially with the salt concentration for butyric acid59 and benzoic acid,55 respectively. Note that data are plotted as a function of square root of salt concentration for butyric acid. This clearly demonstrates tlhe negative impact of other salts present and, therefore, all efforts must be made to minimize their presence to optimize drug delivery. Hair Follicles-Several investigators have raised the possibility that the primary patlhway of iontophoretic permeation

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is via the hair follicular ro~te.45~56-58.76 To get some preliminary insight into this mechanistic aspect, DelTerzo and co-workers compared the iontophoretic permeation enhancement of acetic acid, pentanoic acid, and octanoic acid between the nude rat and furry rat skins.59 The furry rat provided a higher enhancement than the nude rat although the effect was moderate. It was further noted that the advantage of the furry rat declined as the permeants became more lipophilic (e.g., in going from acetic acid to octanoic acid the ratio of furrv rat enhancement t o nude rat .--_ .-.enhancempnt dprrpnnprl from 1.61 to 1.12). In a different study, the insulin delivery through hairless rat skin (in vivo) under iontophoresis was found to be comparable to that through the furry rat skin.60 At this time, with the limited data available, it is premature to unequivocally attribute the primary iontophoretic pathway to the follicular route. Skin Sectioning-The iontophoretic skin enhancement of acetic acid, pentanoic acid, and octanoic acid decreased by a factor of -3 to 4 when the stratum corneum was stripped off nude rat skin.59 This observation has practical implications. If the stratum corneum is a n important layer for iontophoretic transport, care will have to be taken in examining the intactness of the skin where the iontonhoretic device tn . .._. _ _ ..-is ..-he -_ used. Very limited data are available in this area and the specific roles of the epidermis and the dermis in iontophoretic drug delivery are yet to be defined. Effect of Permeant Lboahilicitv (Alkvl Chain LenFth Effects)-While several factors affect passive skin pe&eation, the single most important factor is the permeant lipophilicity or oil-water partition coefficient. It is important to determine the effect of permeant lipophilicity on its iontophoretic permeation. The only systematically done study in this a r e a used alkanols and alkanoic acids a s test ~~~

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Journal of Pharmaceutical Sciences I 357 Vol. 78, No. 5, 1989

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Figure +Semilogarithmic plots of iontophoretic and passive perme. ability coefficientsof water and n-alkanolsas a function of the alkyl chain length. The plots show the effect of iontophoresis on the permeation of water and alkanols through nude rat skin (abstracted from ref 59).

compounds.59 F i g u r e 6 shows data reported o n the passive and iontophoretic transport of water, methanol, ethanol, butanol, hexanol, and octanol. As can be seen, the whole series o f alkanols i s affected by iontophoresis, w i t h a greater effect evident w i t h t h e polar alkanols. The enhancement ratios obtained f r o m these data are plotted as a function of t h e alkyl chain length in F i g u r e 7A. The ratios decline almost l i n e a r l y

as the permeant becomes more lipophilic. Ratios o f <1 were obtained for octanol and decanol (data for decanol are not shown in these figures), indicating a negative effect of iontophoresis o n the highly nonpolar permeants. A similar observation was made for t h e alkanoic acids at a pH of 10, where the permeants were completely ionized (Figure 7B), and at a pH o f 1.5, where the permeants were fully un-ionized (Figure 7 0 . These data have unequivocally shown that iontophoretic

358 I Journal of Pharmaceutical Sciences Vol. 78,No. 5, 1989

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passive permeability coefficients of n-alkanols in nude rat skin experiments as a function of the alkyl chain length (abstractedfrom ref 59).(6) Plot of ratios of iontophoretic permeability coefficients to passive permeabi;litycoefficients of n-alkanoic acids at a pH of 10 (fully ionized) in nude rat skin experiments as a function of the alkyl chain length (abstracted from ref 59). (C) Plot of ratios of iontophoretic permeability coefficients to passive permeability coefficients of n-alkanoic acids at a pH of 1.5 (fully un-ionized) in nude rat skin experiments as a function of the allryl chain length (abstracted from ref 59). permeation enhancement is more significant for polar compounds. Iontophoresis may therefore be detrimental to highly lipophilic drugs. A similar observation was made by Chantraine et a1.62 who studied the iontophoretic transport of corticosteroids. The results on alkanols mentioned above need additional elaboration.59 Alkanols are neutral molecules and, under the experimental conditions used, they were present as unionized species. In that state how and why was an iontophoretic enhancement observed? It is important to note here that there are at least three publications which report similar findings. Gangarosa et al. in 197742 found that the skin permeation of 5-iodo-2’-deoxyuridine was enhanced even in the un-ionized form. B.urnette and Marrero56 reported higher transport rates of thgrotropin releasing hormone at pH 8 (un-ionized) than a t pH 4 (ionized). Gangarosa and co-workers in 1!38076 provided a detailed explanation of the enhanced permeation of un-ioniz,edsolutes. They proposed a hypothesis of ellactroosmosis and attributed the increased permeation of nonelectrolytes to increased water movement. Of course it is widely known that iontophoresis can reduce sweating, especially in the plantar and palmar areas. While there seems t o be a rational explanation for the iontophoretic enhancement of un-ionized solutes, it is our belief that more work needs to be done and a better understanding of the underlying mechanisms needs to be achieved before precise prediction of the effect of iontophoresis on un-ionized permeants is possible.

Coinclusions It appears that the present drug delivery research utilizing iontophoresis is focused on systemic drug delivery. The use of iontophoresis to optimize local d r u g delivery is not fully explored. Also, the potential of iontophoresis to enhance the skin permeation of neutral molecules needs to be further researched and understood. A mechanistic understanding of iont’ophoretic enhancement should lead to broader applicatiom of this concept to drug delivery systems. As research progresses, it should be possible to devise sophisticated drug delivery systems in whichL the drug delivery can actually be programmed (Figure 8).

References and Notes 1. ‘Turnell,W. J. Proc. Royal SOC. Med. 1921, 14, 41.

2. Harpuder, K. Arch. Phys. Ther. X-Ray Radium 1937,18, 221. 3. Molitor, H. In The Merck Report; January, 1943; pp 22-29. 4. O’Molley, E. P.; Oester, Y. T. Arch. Phys. Med. Rehab. 1955,36, 310. 5. Stephen, R. L.; Petelenz, T. J.; Jacobsen, S. C. Biomed. Biochim. Acta 1984, 5, 553. 6. Gan arosa, L. P.; Park, N. H.; Fong, B. C.; Scott, D. F.; Hill, J. M. J . Pfarm. Sci. 1978, 67, 1439. 7. Grimnes. S. Acta Dermatol. Venerol. (Stockholm). 1984, 64, 93. 8. Pratzel, HI;Dittrich, P.; Kukovetz, W. J . Rheumutol. 1986, 13, 1122. 9. Sloan, J. B.; Soltanik, K. J . Am. Acad. Dermatol. 1986,15, 671. 10. Tyle, P. Pharm. Res. 1986,3, 318. 11. Delacerda, F. G. J . Orth. SportsPhys. Ther. 1982, 4, 51. 12. Bertolucci, L. E. J . Orth. SportsPhys. Ther. 1982, 4,103. 13. Stecker, R. H.; Cody, D. T. R. Arch. Otolaryngol. 1966, 83, 213. 14. Ramsden, R. T.; Gibson, W. P. R.; Moffat, D. A. J . Laryngol. Otol. 1977, 91, 779. 15. Comeau, M.; Brummett, R. The Laryngoscope 1978,88, 277. 16. Rahm, W. E.; Strother, W. F.; Crump, J. F.; Parker, D. E. Ann. Otol. Rhinol. Laryngol. 1962, 71, 116. 17. Comeau, M.; Brummett, R.; Vernon, J . Arch. Otolaryngol. 1973, 98, 114. 18. Schleuning, A.; Comeau, M.; Brummett, R. Trans. A m . Acad. Ophthalmol. Otolaryngol. 1974, 78, 453. 19. Murthy, K. S.; Talim, S. T.; Singh, I. Oral Surg. Oral Med. Oral Pathol. 1973, 36, 448. 20. Gangarosa, L. P. JADA 1974, 88, 125. 21. Schaeffer, M. L.; Bixler, D.; Yu. P. J . Periodontal 1971.42. 695. 22. Shimomuro, Y.; Gan arosa, L. P.; Kataoka, M.; Hill, J . M. Znuest. Ophthalmol Visual 8ci. 1983,24, 1588. 23. Kwon, B. S.; Gangarosa, L. P.; Park, N. H.; Hull, D. S.; Fineberg, E.; Wiggins, C.; Hill, J. M. Invest. Ophthalmol. Visual Sci.1979, 18, 984. 24. Fellner, R.; Glawogger, F. Klm. Mbl. Augenheilk 1972,160,300. 25. Hill, J . M.; Shimomuro, Y.; Dudley, J. B.; Berman, E.; Haruta, Y.; Kwon, B. S.; Maguire, L. J. J . Invest. Ophthalmol. Visual Sci. 1987,28, 585. 26. Rootman, D. S.; Hobden, J. A.; Jantzen, J. A,; Gonzaler, J . R.; O’Callaghan, R. J.;Hill, J . M. Arch. Ophthalrnol. 1988,106,262. 27. Jenkinson, D. M.; McLean, J. A. The Veterinary Record; January 5, 1974; PP 8--12. 28. Shelley; W. B.; Conaby, J . C.; Hesbacher, E. N. J . Invest. Dermatol. 1950, 15, 343. 29. Abramson, H. A. J . Allergy 1941, 12, 169. 30. Glass, J. M.; Stephen, R. L.; Jacobson, S. 0. Znt. J . Dermatol. 1980. 19. 519. 31. Peteienz: T.; ~ x e n t iI., A.; Petelenz, T.J.; Iwinski, J.; Dubel, S. Znt. J . Clin.Pharmacol. Ther. Tor. 1984>22, 152. 32, Levit, F, ~ ~~ ~ h~1968, . 98,~ 505, ~ ~ ~ 33. White, j.w.Mayo Clin. Proc. 1986, 61, 951. 34. Secher-Hansen, E.; Langgard, H.; Jansen, J . Acta Pharmacol. Toxicol. 1967, 25, 258. 35. Kahn, J. PhYS. Ther. 19773 57,658. 36. Garzione, J. E. phys. Ther. 19789 58, 570. 37. Csillik, B.; Knyihar-Csillik, E.; Szues, A. Neurosci. Letters 1982, 31, 87. 38. Martin, L.; Eaton, G. 0.Arch. Phys. Ther. X-Ray Radium 1937, 18, 226. 39. Kling, D. H.; Sashin, D. Arch. Phys. Ther. X-Ray Radium 1937, 18, 333. 40. Shilkret, H. H. J . Invest. Dermatol. 1942, 5, 11. 41. Rasmussen, K. A. Acta Dermatol. Venereol. 1949, 29, 564. 42. Gangarosa, L. P.; Park, N. H.; Hill, J. M. Proc. SOC.Exptl. Biol. ~

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Acknowledgments This paper is based on a presentation made by C. R. Behl at the International Conference on Pharmaceutical Sciences and Clinical Pharmacology, Jerusalem, Israel, May 2 9 J u n e 3, 1988.