The Potential of Metabolic Interventions to Enhance Transdermal Drug Delivery
2002; Elsevier BV; Volume: 7; Issue: 1 Linguagem: Inglês
10.1046/j.1523-1747.2002.19632.x
ISSN1529-1774
AutoresPeter M. Elias, Walter M. Holleran, Kenneth R. Feingold, Janice Tsai, Gopinathan K. Menon,
Tópico(s)Bee Products Chemical Analysis
ResumoThe stratum corneum is a complex tissue that is metabolically active, and undergoes dynamic structural modifications due to the presence of several self-regulating enzymatic systems. A large number of defensive (protective) functions are embodied in this tissue, each with its own structural and biochemical basis. Moreover, the stratum corneum is responsive to external perturbations to the permeability barrier, upregulating a variety of metabolic processes aimed at restoring normal barrier function. Traditional drug delivery methods, which are of limited effectiveness, view the stratum corneum as a static, but semipermeable membrane. In contrast, newer metabolically based methods, which can be deployed alone, or in conjunction with standard methods, have been shown to expand the spectrum of drugs that can be delivered transdermally in hairless mouse epidermis. Yet, while these new approaches hold great promise, if equally effective in human skin, they pose new questions about the risks of a highly permeabilized stratum corneum. The stratum corneum is a complex tissue that is metabolically active, and undergoes dynamic structural modifications due to the presence of several self-regulating enzymatic systems. A large number of defensive (protective) functions are embodied in this tissue, each with its own structural and biochemical basis. Moreover, the stratum corneum is responsive to external perturbations to the permeability barrier, upregulating a variety of metabolic processes aimed at restoring normal barrier function. Traditional drug delivery methods, which are of limited effectiveness, view the stratum corneum as a static, but semipermeable membrane. In contrast, newer metabolically based methods, which can be deployed alone, or in conjunction with standard methods, have been shown to expand the spectrum of drugs that can be delivered transdermally in hairless mouse epidermis. Yet, while these new approaches hold great promise, if equally effective in human skin, they pose new questions about the risks of a highly permeabilized stratum corneum. acetyl coenzyme A carboxylase acidic sphingomyelinase β-glucocerebrosidase ceramides cholesterol cholesterol sulfate extracellular processing free fatty acids Gaucher disease hydroxymethylglutaryl Coenzyme A reductase lamellar bodies recessive x-linked ichthyosis stratum corneum stratum granulosum secretory phospholipase serine palmitoyl transferase transepidermal water loss The paper-thin SC is a composite material made of proteins and lipids that are crucial for life in a terrestrial environment. In the traditional view, the SC is regarded as impermeable, but inert and highly resilient, analogous to a sheet of plastic wrap. According to this model, transdermal permeation is governed solely by the physical-chemical properties of this supposedly homogenous tissue (Scheuplein and Blank, 1971Scheuplein R.J. Blank I.H. Permeability of the skin.Physiol Rev. 1971; 51: 702-747Crossref PubMed Scopus (1121) Google Scholar), and barrier properties can be assessed readily in vitro, in either devitalized or fresh epidermal sheets. Site-related variations in the number of SC cell layers, which govern the diffusion path length, again can be integrated into kinetics predicted by the plastic-wrap model. The first development to cast doubt upon both the plastic-wrap model and its suppositions, was the discovery of the unique structural heterogeneity of the SC; i.e., its "bricks and mortar" organization (Elias, 1983Elias P.M. Epidermal lipids, barrier function, and desquamation.J Invest Dermatol. 1983; 80: 44s-49sAbstract Full Text PDF PubMed Google Scholar). Rather than being uniformly dispersed, the lipids in normal SC are sequestered within the extracellular spaces, where they are organized into lamellar bilayers that surround the corneocytes (Elias, 1983Elias P.M. Epidermal lipids, barrier function, and desquamation.J Invest Dermatol. 1983; 80: 44s-49sAbstract Full Text PDF PubMed Google Scholar;Elias and Menon, 1991Elias P.M. Menon G.K. Structural and lipid biochemical correlates of the epidermal permeability barrier.Adv Lipid Res. 1991; 24: 1-26Crossref PubMed Google Scholar). Hence, instead of thickness of the SC "membrane", variations in lamellar membrane structure and in total lipid content provide the structural and biochemical basis for site-related variations in permeability (Lampe et al., 1983Lampe M.A. Burlingame A.L. Whitney J. Williams M.L. Brown B.E. Roitman E. Elias P.M. Human stratum corneum lipids. Characterization and regional variations.J Lipid Res. 1983; 24: 120-130Abstract Full Text PDF PubMed Google Scholar). It follows, then, that the extracellular, lipid-enriched matrix of the SC comprises not only the structure that limits transdermal delivery of hydrophilic drugs, but also the so-called SC "reservoir" (Nemanic and Elias, 1980Nemanic M.K. Elias P.M. In situ precipitation. A novel cytochemical technique for visualization of permeability pathways in mammalian stratum corneum.J Histochem Cytochem. 1980; 28: 573-578Crossref PubMed Scopus (107) Google Scholar). Human SC typically comprises about 20 corneocyte cell layers, which differ in their thickness, packing of keratin filaments, filaggrin content, and number of corneodesmosomes, depending on body site. Corneocytes are surrounded by a highly cross-linked, resilient sheath, the cornified envelope (CE), whereas the cell interior is packed with keratin filaments surrounded by a matrix composed mainly of filaggrin and its breakdown products. Individual corneocytes, in turn, are surrounded by a lipid-enriched extracellular matrix, organized largely into lamellar bilayers, which derive from secreted lamellar body (LB) precursor lipids. Following secretion, LB contents fuse end-to-end, forming progressively elongated membrane bilayers (Elias and Menon, 1991Elias P.M. Menon G.K. Structural and lipid biochemical correlates of the epidermal permeability barrier.Adv Lipid Res. 1991; 24: 1-26Crossref PubMed Google Scholar), a sequence mediated by a battery of lipolytic "processing" enzymes (see below). Yet, despite the clear importance of corneocytes both as spacers and as a scaffold for the extracellular matrix, transdermal drug development has focused primarily on manipulations of the extracellular lipid milieu (Flynn et al., 1989Flynn G.L. Mechanism of percutaneous absorption from physicochemical evidence.in: Bronaugh R.L. Maibach H.I. Percutaneous Absorption. New York, Dekker1989: 27-51Google Scholar;Schaefer and Redelmeier, 1996Schaefer H. Redelmeier T.E. Skin Barrier. Principles of Percutaneous Absorption. Basel, Karger1996: 310Google Scholar). The existence of aqueous pores (Menon and Elias, 1997Menon G.K. Elias P.M. Morphologic basis for a pore-pathway in mammalian stratum corneum.Skin Pharmacol. 1997; 10: 235-246Crossref PubMed Scopus (116) Google Scholar) not only adds further complexity to the extracellular pathway, but also additional opportunities for novel delivery strategies. The exceptionally low permeability of normal SC to water-soluble drugs is the consequence of several characteristics of the lipid-enriched, extracellular matrix (Table I), including the highly convoluted and tortuous extracellular pathway created by corneocyte "spacers" (Potts and Francoeur, 1991Potts R.O. Francoeur M.L. The influence of stratum corneum morphology on water permeability.J Invest Dermatol. 1991; 96: 495-499Abstract Full Text PDF PubMed Google Scholar). Moreover, not only the bilayered arrangement of extracellular lipids, but also their extreme hydrophobicity, and their occurence in a critical (1:1:1) molar ratio of the three key species, ceramides (Cer), cholesterol (Chol), and free fatty acids (FFA) (Man et al, 1993), are further characteristics that provide for barrier function.Table IHow stratum corneum lipids mediate barrier function1.Extracellular localization (only intercellular lipids play role)2.Amount of lipid (lipid wt %)3.Elongated, tortuous pathway (increases diffusion path length)4.Organization into lamellar membrane structures5.Hydrophobic composition (absence of polar lipids and presence of very long chain, saturated fatty acids)6.Correct molar ratio (approximately 1:1:1 of three key lipids: ceramides, cholesterol, and free fatty acids)7.Unique molecular structures (e.g., acylceramides) Open table in a new tab Ceramides account for about 50% of total SC lipid mass (Schurer et al., 1991Schurer N. Elias P.M. The biochemistry and function of stratum corneum lipids.in: PM Elias Advances in Lipid Research. London, Academic Press1991: 27-56Crossref Google Scholar;Wertz and Downing, 1991Wertz P.H. Downing D.L. Epidermal lipids.in: Goldsmith L.A. Physiology, Biochemistry and Molecular Biology of the Skin. New York, Oxford University Press1991: 205-236Google Scholar), and are crucial for the lamellar organization of the SC barrier (Bouwstra et al., 1996Bouwstra J.A. Gooris G.S. Chang K. Weerheim A. Bras W. Ponec M. Phase behaviour of isolated skin lipids.J Lipid Res. 1996; 37: 999-1011PubMed Google Scholar). Of the seven Cer classes, acylceramides or Cer 1, which contains ω-hydroxy-linked, essential fatty acids in an amide linkage, are believed to be uniquely important for the barrier (Wertz and Downing, 1983Wertz P.N. Downing D.L. Ceramides of pig epidermis: structure determination.J Lipid Res. 1983; 24: 759-765Abstract Full Text PDF PubMed Google Scholar). Chol, the second most abundant lipid by weight in the SC, promotes the intermixing of different lipid species, and regulates its "phase" behavoir (Norlen et al., 1999Norlen L. Nicander I. Rozell B.L. Ollmar S. Forslind B. Inter- and intra-individual differences in human stratum corneum lipid content related to physical parameters of skin barrier function in vivo.J Invest Dermatol. 1999; 112: 72-77Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). FFA, which account for 10%–15% of SC lipids, consist predominantly of very long-chain, saturated species with > 20 carbon atoms (Wertz and Downing, 1991Wertz P.H. Downing D.L. Epidermal lipids.in: Goldsmith L.A. Physiology, Biochemistry and Molecular Biology of the Skin. New York, Oxford University Press1991: 205-236Google Scholar). A decrease in the concentrations of any of these critical lipid species compromises barrier integrity, by altering the molar ratio required for normal barrier function (Man et al., 1995Man M-Q Brown B.E. Wu-Pong S. Feingold K.R. Elias P.M. Exogenous nonphysiologic vs. physiologic lipids. Divergent mechanisms for correction of permeability barrier dysfunction.Arch Dermatol. 1995; 131: 809-816Crossref PubMed Google Scholar). The "domain-mosaic model" advocates a meandering, polar (pore) pathway for water transport through grain boundaries within the lipid mosaic (Forslind, 1994Forslind B. A domain mosaic model of the skin barrier.Acta Derm Venereol. 1994; 74: 1-6PubMed Google Scholar), adding potential complexity to the already tortuous, extracellular pathway. The morphologic basis of the aqueous pore pathway (Flynn et al., 1989Flynn G.L. Mechanism of percutaneous absorption from physicochemical evidence.in: Bronaugh R.L. Maibach H.I. Percutaneous Absorption. New York, Dekker1989: 27-51Google Scholar), however, instead appears to be lacunar domains embedded within the lipid bilayers (Menon and Elias, 1997Menon G.K. Elias P.M. Morphologic basis for a pore-pathway in mammalian stratum corneum.Skin Pharmacol. 1997; 10: 235-246Crossref PubMed Scopus (116) Google Scholar). These lacunae correspond to sites of subjacent corneodesmosome degradation (Haftek et al., 1998Haftek M. Teillon M.H. Schmitt D. Stratum corneum, corneodesmosomes and ex vivo percutaneous penetration.Microsc Res Tech. 1998; 43: 242-249Crossref PubMed Scopus (62) Google Scholar). Whereas these lacunae are scattered and discontinuous under basal conditions, following certain types of permeabilization (e.g., occlusion, prolonged hydration, sonophoresis, iontophoresis), they expand until they interconnect, forming a continuous "pore pathway". The pore pathway reverts back to its original, discontinuous state once the permeabilizing stimulus disappears. Such a lacunar system, then, does not correspond to the grain boundaries of the "domain mosaic model", but instead it forms an "extended macrodomain mosaic" within the SC interstices (Menon et al., 1998Menon G.K. Lee S.H. Roberts M.S. Ultrastructural effects of some solvents and vehicles on the stratum corneum and other skin components: evidence for an "extended mosaic – partitioning model of the skin barrier".in: Roberts M.S. Walters K.A. Dermal Absorption and Toxicity Assessment. New York, Marcel Dekker1998: 727-751Google Scholar). Epidermal differentiation is a vectorial process that is accompanied by dramatic changes in lipid composition, including loss of phospholipids with the emergence of Cer, Chol, and FFA in the SC (Schurer et al., 1991Schurer N. Elias P.M. The biochemistry and function of stratum corneum lipids.in: PM Elias Advances in Lipid Research. London, Academic Press1991: 27-56Crossref Google Scholar;Wertz and Downing, 1991Wertz P.H. Downing D.L. Epidermal lipids.in: Goldsmith L.A. Physiology, Biochemistry and Molecular Biology of the Skin. New York, Oxford University Press1991: 205-236Google Scholar). Although epidermal lipid synthesis is both highly active and largely autonomous from systemic influences, it can be modified by external influences; i.e., changes in permeability barrier status (Feingold, 1991Feingold K.R. The regulation and role of epidermal lipid synthesis.Adv Lipid Res. 1991; 24: 57-82Crossref PubMed Google Scholar). Acute perturbations of the permeability barrier in mice stimulate a characteristic recovery sequence that leads to restoration of normal function over about 72 h in young skin (the cutaneous stress test). This sequence includes an increase in Chol, FA, and Cer synthesis that is restricted to the underlying epidermis, and attributable to a prior increase in mRNA and enzyme activity/mass for each of the key synthetic enzymes. Furthermore, synthesis of each of the three key lipids is required for normal barrier homeostasis; i.e., topically applied inhibitors of the key enzymes in each pathway produce abnormalities in permeability barrier homeostasis (cited inFeingold, 1991Feingold K.R. The regulation and role of epidermal lipid synthesis.Adv Lipid Res. 1991; 24: 57-82Crossref PubMed Google Scholar). These experiments provided the seminal observations, as well as the model ("stress test") that led to development of a biochemical strategy to enhance transdermal drug delivery (see below). The unique two-compartment organization of the SC is attributable to the secretion of LB-derived lipids and colocalized hydrolases at the stratum granulosum (SG)–SC interface (Elias and Menon, 1991Elias P.M. Menon G.K. Structural and lipid biochemical correlates of the epidermal permeability barrier.Adv Lipid Res. 1991; 24: 1-26Crossref PubMed Google Scholar). Under basal conditions, LB secretion is slow, but sufficient to provide for barrier integrity. Following acute barrier disruption, calcium is lost from the outer epidermis, and much of the preformed pool of LB in the outermost SG cell is quickly secreted (Menon et al., 1992aMenon G.K. Feingold K.R. Elias P.M. The lamellar body secretory response to barrier disruption.J Invest Dermatol. 1992; 98: 279-289Crossref PubMed Scopus (234) Google Scholar,Menon et al., 1994Menon G.K. Elias P.M. Feingold K.R. Integrity of the permeability barrier is crucial for maintenance of the epidermal calcium gradient.Br J Dermatol. 1994; 130: 139-147Crossref PubMed Scopus (97) Google Scholar). Calcium (Ca++) is an important regulator of LB secretion, with the high levels of Ca++ in the SG restricting LB secretion to low, maintenance levels (Lee et al., 1992Lee S.H. Elias P.M. Proksch E. Menon G.K. Mao-Qiang M. Feingold K.R. Calcium and potassium are important regulators of barrier homeostasis in murine epidermis.J Clin Invest. 1992; 89: 530-538Crossref PubMed Scopus (177) Google Scholar). Although exposure to high Ca++ (and K+) delays barrier recovery following acute perturbations, this delay is reversible by coapplications of L-type Ca++ channel or calmodulin inhibitors (Lee et al., 1992Lee S.H. Elias P.M. Proksch E. Menon G.K. Mao-Qiang M. Feingold K.R. Calcium and potassium are important regulators of barrier homeostasis in murine epidermis.J Clin Invest. 1992; 89: 530-538Crossref PubMed Scopus (177) Google Scholar). Finally, barrier homeostasis and LB secretion are regulated not only by changes in Ca++ concentrations, but also by agents that block organellogenesis and secretion; e.g., monensin and brefeldin A (Man et al., 1995Man M-Q Brown B.E. Wu-Pong S. Feingold K.R. Elias P.M. Exogenous nonphysiologic vs. physiologic lipids. Divergent mechanisms for correction of permeability barrier dysfunction.Arch Dermatol. 1995; 131: 809-816Crossref PubMed Google Scholar) (see also below). These experiments provide further potential, biochemical approaches to enhance drug delivery. Extrusion of LB contents at the SG/SC interface is followed by processing into mature, lamellar membrane unit structures (Elias and Menon, 1991Elias P.M. Menon G.K. Structural and lipid biochemical correlates of the epidermal permeability barrier.Adv Lipid Res. 1991; 24: 1-26Crossref PubMed Google Scholar). As noted above, marked alterations in lipid composition occur, including depletion of glucosylCer and phospholipids, and cholesterol sulfate with accumulation of Cer, FFA, and Chol in the SC. This sequence, called extracellular processing (ECP), is attributable to the secretion of hydrolytic enzymes that convert cosecreted LB-derived lipid precursors into the nonpolar species that form the membrane bilayer system (Elias and Menon, 1991Elias P.M. Menon G.K. Structural and lipid biochemical correlates of the epidermal permeability barrier.Adv Lipid Res. 1991; 24: 1-26Crossref PubMed Google Scholar). Direct evidence for the central role of ECP in barrier homeostasis came first from studies on glucosylCer-to-Cer processing. For example, applications of specific, conduritol-type inhibitors of β-glucocerebrosidase (β-GlcCer'ase) both delayed barrier recovery after acute perturbations, and produced a progressive abnormality in barrier function when applied to intact skin (Holleran et al., 1993Holleran W.M. Takagi Y. Feingold K.R. Menon G.K. Legler G. Elias P.M. Processing of epidermal glucosylceramides is required for optimal mammalian permeability barrier function.J Clin Invest. 1993; 91: 1656-1664Crossref PubMed Scopus (226) Google Scholar). Moreover, both in a transgenic murine model of Gaucher disease (GD), produced by targeted disruption of the β-GlcCer'ase gene (Holleran et al., 1994Holleran W.M. Sidransky E. Menon G.K. Fartasch M. Grundmann J-U Ginns E.I. Elias P.M. Consequences of β-glucocerebrosidase deficiency in epidermis: Ultrastructure and permeability barrier alterations in Gaucher disease.J Clin Invest. 1994; 93: 1756-1764Crossref PubMed Scopus (242) Google Scholar), and in the severe, type 2 neuronopathic form of GD, infants present with a barrier abnormality (Sidransky et al., 1996Sidransky E. Fartasch M. Lee R.E. et al.Epidermal abnormalities may distinguish Type 2 from Type 1 and Type 3 of Gaucher disease.Pediatr Res. 1996; 39: 134-141Crossref PubMed Scopus (76) Google Scholar). The functional deficit in all three models (inhibitor, transgenic murine, type 2 GD) was attributable to accumulation of glucosylCer, depletion of Cer, and persistence of immature LB-derived membrane structures within the SC interstices. Phospholipid hydrolysis, catalyzed by one or more 14 kDa secretory phospholipases (sPLA2), generates a family of nonessential FFA, which are required for barrier homeostasis (Mao-Qiang et al., 1995Mao-Qiang M. Feingold K.R. Jain M. Elias P.M. Extracellular processing of phospholipids is required for permeability barrier homeostasis.J Lipid Res. 1995; 36: 1925-1935PubMed Google Scholar;Mao-Qiang et al., 1996Mao-Qiang M. Jain M. Feingold K.R. Elias P.M. Secretory phospholipase A2 activity is required for permeability barrier homeostasis.J Invest Dermatol. 1996; 106: 57-63Crossref PubMed Scopus (96) Google Scholar). As applications of either bromphenacylbromide (BPB) or MJ33 (chemically unrelated sPLA2 inhibitors) modulate barrier function in intact murine skin, sPLA2 appears to play a critical role in barrier homeostasis (Mao-Qiang et al., 1995Mao-Qiang M. Feingold K.R. Jain M. Elias P.M. Extracellular processing of phospholipids is required for permeability barrier homeostasis.J Lipid Res. 1995; 36: 1925-1935PubMed Google Scholar;Mao-Qiang et al., 1996Mao-Qiang M. Jain M. Feingold K.R. Elias P.M. Secretory phospholipase A2 activity is required for permeability barrier homeostasis.J Invest Dermatol. 1996; 106: 57-63Crossref PubMed Scopus (96) Google Scholar). Moreover, applications of either inhibitor to perturbed skin sites delays barrier recovery. Sphingomyelin hydrolysis by acidic sphingomyelinase (aSMase) generates two of the seven members of the Cer family required for normal barrier homeostasis. Moreover, patients with mutations in the gene encoding aSMase (Tay-Sachs, Type A) that lead to low enzyme activity, display an ichthyosiform dermatosis, and transgenic mice with an absence of aSMase demonstrate a barrier abnormality. Finally, applications of nonspecific inhibitors of aSMase to perturbed murine skin sites lead to a delay in barrier recovery (Schmuth et al., 2000Schmuth M. Man M-Q Weber F. et al.Permeability barrier disorders in Niemann-Pick disease: Sphingomyelin-ceramide processing is required for normal barrier homeostasis.J Invest Dermatol. 2000; 115: 459-466Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Hence, aSMase represents another key ECP enzyme that in theory, could be manipulated to enhance drug delivery. Just as with glucosylCer and sphingomyelin, Chol SO4 content increases during epidermal differentiation, and then decreases progressively as Chol SO4 is desulfated during passage from the inner to the outer SC (Elias et al., 1984Elias P.M. Williams M.L. Maloney M.E. Bonifas J.A. Brown B.E. Grayson S. Epstein Jr, E.H. Stratum corneum lipids in disorders of cornification: Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis.J Clin Invest. 1984; 74: 1414-1421Crossref PubMed Scopus (162) Google Scholar). Both Chol sulfate and its processing enzyme, steroid sulfatase, are concentrated in SC membrane domains, and the content of Chol sulfate in these sites increases by approximately 10-fold (Elias et al., 1984Elias P.M. Williams M.L. Maloney M.E. Bonifas J.A. Brown B.E. Grayson S. Epstein Jr, E.H. Stratum corneum lipids in disorders of cornification: Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis.J Clin Invest. 1984; 74: 1414-1421Crossref PubMed Scopus (162) Google Scholar) in recessive X-linked ichthyosis (RXLI). Not only is RXLI characterized by a barrier defect (Zettersten et al., 1998Zettersten E. Mao-Quiang M. Sato J. et al.Recessive x-linked ichthyosis. Role of cholesterol-sulfate accumulation in the barrier abnormality.J Invest Dermatol. 1998; 111: 784-790Crossref PubMed Scopus (85) Google Scholar), but also repeated applications of Chol SO4 to intact murine skin produce a barrier abnormality (Maloney et al., 1984Maloney M.E. Williams M.L. Epstein Jr, E.H. Law M.Y.L. Fritsch P.O. Elias P.M. Lipids in the pathogenesis of ichthyosis: Topical cholesterol sulfate-induced scaling in hairless mice.J Invest Dermatol. 1984; 83: 253-256Abstract Full Text PDF Scopus (43) Google Scholar). In both cases, the barrier abnormality is attributable to Chol SO4-induced phase separation in lamellar membrane domains (Zettersten et al., 1998Zettersten E. Mao-Quiang M. Sato J. et al.Recessive x-linked ichthyosis. Role of cholesterol-sulfate accumulation in the barrier abnormality.J Invest Dermatol. 1998; 111: 784-790Crossref PubMed Scopus (85) Google Scholar). But the barrier defect may also be, in part, attributed to the fact that Chol SO4 is a potent inhibitor of HMGCoA reductase (Williams et al, 1992). In summary, manipulation of a variety of ECP enzymes represents a cohort of potential biochemical methods that can be employed to manipulate drug delivery. That the SC displays an acidic external pH ("acid mantle") is well documented, but its origin is not known. Extra-epidermal mechanisms, including both surface-deposited eccrine and sebaceous gland-derived products, and metabolites of microbial metabolism, as well as endogenous catabolic processes, such as phospholipid-to-free FFA hydrolysis, and deimination of histidine to urocanic acid have been proposed to influence SC acidity. Protons can also be generated locally in the lower SC by sodium-proton antiporters inserted into the plasma membrane (BehneBehne MJ, Meyer J, Crumrine D, et al:The sodium/hydrogen antiporter, NHE1, regulates stratum corneum acidi¢cation. J Biol Chem, in pressGoogle Scholar). Moreover, if the limiting membrane of the LB contains energy-dependent proton pumps (Chapman and Walsh, 1989Chapman S.J. Walsh A. Membrane-coating granules are acidic organelles which possess proton pumps.J Invest Dermatol. 1989; 93: 466-470Abstract Full Text PDF PubMed Google Scholar), then active acidification of the extracellular space (ECS) could also accompany insertion of such pumps coincident with LB secretion. Thus, ongoing proton secretion at the SG/SC interface, coupled with one or more of the other mechanisms described above, could explain not only the pH gradient across the SC interstices, but also selective acidification of membrane microdomains. The concept that acidification is required for permeability barrier homeostasis is supported by the observation that barrier recovery is delayed when acutely perturbed skin sites are immersed in neutral pH buffers (Mauro et al., 1998Mauro T. Holleran W.M. Grayson S. et al.Barrier recovery is impeded at neutral pH independent of ionic effects: Implications for extracellular lipid processing.Arch Derm Res. 1998; 290: 215-222Crossref PubMed Scopus (221) Google Scholar), or when either the sodium-proton antiporter (NHE1) or sPLA2-mediated, phospholipid catabolism to FFA (Fluhr et al, 2001; Behne et al, in press) is blocked. Acidification appears to impact barrier homeostasis through regulation of ECP enzymes, such as β-GlcCer'ase and aSMase, which exhibit acidic pH optima. Whether altering pH alone could facilitate transdermal drug delivery, and serve as an independent or additive-enhancing method remains unknown (see below). Because of its theoretical advantages, enormous efforts have been expended on the development of new approaches to enhance transdermal drug delivery. Yet, despite these efforts, the current list of drugs that have been delivered transdermally for systemic applications is small (< 10), and limited to highly lipophilic compounds of both low molecular weight, and low total absorbed-dose (e.g., nitroglycerin, clonidine, sex steroids, scopolamine, and nicotinic acid). We will now provide a brief overview of current transdermal technology, before proceeding to a discussion of biochemical/metabolic approaches. The strategies that have been devised to enhance transdermal drug delivery can be classified as either physical, chemical, mechanical, or biochemical approaches. Combinations of these strategies can also be employed to increase efficacy (Johnson et al., 1996Johnson M.E. Mitragotri S. Patel A. Blankschtein D. Langer R. Synergistic effects of chemical enhancers and therapeutic ultrasound on transdermal drug delivery.J Pharm Sci. 1996; 85: 670-679Crossref PubMed Scopus (120) Google Scholar;Tsai et al., 1996Tsai J.C. Guy R.H. Thornfeldt C.R. Gao W.N. Feinbold K.R. Elias P.M. Metabolic approaches to enhance transdermal dug delivery. 1. Effect of lipid synthesis inhibitors.J Pharm Sci. 1996; 85: 643-648Crossref PubMed Scopus (83) Google Scholar;Choi et al., 1999Choi E.H. Lee S.H. Ahn S.K. Hwang S.M. The pretreatment effect of chemical skin penetration enhancers in transdermal drug delivery using iontophoresis.Skin Pharmacol Appl Skin Physiol. 1999; 12: 326-335Crossref PubMed Scopus (66) Google Scholar), or for extending the time available for transdermal delivery (see below). Physical techniques vary from straightforward approaches, such as occlusion and tape stripping, to highly sophisticated instrumentation and miniaturization (e.g., iontophoresis, electroporation). The most straightforward of physical methods is prolonged occlusion, which alters the barrier properties of SC (Van Den Merwe and Ackermann, 1987Van Den Merwe E. Ackermann C. Physical changes in hydrated skin.Int Nat J Cosmet Sci. 1987; 9: 237-247Crossref PubMed Scopus (19) Google Scholar;Mikulowska, 1992Mikulowska A. Reactive changes in human epidermis following simple occlusion with water.Contact Dermatitis. 1992; 26: 224-227Crossref PubMed Scopus (24) Google Scholar). Following 24–48 h of occlusion with resultant hydration, corneocytes swell, the intercellular spaces become distended, and the lacunar network becomes dilated. Distention of lacunae eventually leads to connections within an otherwise discontinuous system, creating "pores" in the SC interstices through which polar and nonpolar substances can penetrate more readily. Another straightforward physical method to abrogate the barrier is removal of portions of the SC by stripping with either adhesive tapes or cyanoacrylate glue. Sequential stripping increases transepidermal water loss (TEWL), an indicator of a barrier defect, which correlates well with enhanced transdermal drug deliver
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