A review of the effect of occlusive dressings on lamellar bodies in the stratum corneum and relevance to transdermal absorption
Published Web Locationhttps://doi.org/10.5070/D36z32h7hm
A review of the effect of occlusive dressings on lamellar bodies in the stratum corneum and relevance to transdermal absorption
1. Cornell University, Ithaca and NY, NY. firstname.lastname@example.org. Purdue Pharma, Stamford, CT
Lauren Kennish1 and Bruce Reidenberg1, 2
Dermatology Online Journal 11 (3): 7
Transdermal drug delivery is becoming a widely used tool in the pharmaceutical industry. Many factors can influence the transdermal flux of medication from a transdermal drug delivery system. The recently described skin physiology of lamellar bodies and skin responses to occlusive dressings provide new insights into transdermal drug delivery. This paper reviews the literature on occlusive dressings and lamellar bodies as it relates to transdermal drug delivery. An understanding of the physiology of lamellar bodies is important to understand and improve transdermal drug delivery.
Transdermal drug delivery is becoming a widely used tool in the pharmaceutical industry as an alternative to more commonly used routes of drug administration. The benefits of transdermal delivery include a) prolonged continuous and consistent release of drug to the systemic circulation, b) ability to bypass the digestive system for patients with digestive diseases, and c) ability to avoid "first pass" gastrointestinal and hepatic metabolism to minimize any adverse effects of drug metabolism. Transdermal drug delivery systems (TDS) for nicotine, estrogen, testosterone, scopolamine, physostigmine, and fentanyl are available in the United States. TDS are under development for buprenorphine, buspirone, estradiol, estradiol and progesterone, insulin, fentanyl, galanthamine, and selegiline [1-8]. This technology depends on the skin, not as a barrier to protect and maintain physical and chemical integrity of the individual, but as a delivery membrane. This is the aspect of the skin that must be carefully understood to develop the best methods of transdermal drug delivery. This brief review examines the effects of occlusive dressings as they pertain to transdermal absorption of medicines.
Transdermal drug delivery systems can be constructed with varying degrees of occlusivity. Reservoir designs require a water-impermeable membrane to contain the reservoir of drug. Therefore, the skin beneath the reservoir is subjected to complete occlusion. In contrast, matrix designs depend on the adhesive to contain the drug and the adhesive can be designed with varying degrees of permeability to water. To understand the impact of occlusion, the skin physiology of water barrier response to occlusion will be reviewed.
Stratum corneum structure and biochemistry
The stratum corneum (SC) plays the most active and important role in maintaining water balance and preventing entrance of foreign bodies into the deeper layers of the skin . Therefore, this layer is the first defense against the environment, and a critical layer in understanding transdermal drug absorption. The SC is a biphasic layer made up of orderly stacks of protein-filled corneocytes with lipid bilayer membranes spaced in between. This results in a lipid-protein separation, or a hydrophobic-hydrophilic partition that plays a key role in determining drug permeation.
However, this is a simplification of the SC, because in these lipid bilayers one also finds proteins and enzymes [10, 11]. The thickness of the SC is approximately 5-50 µm depending on the area of the body .
Deep to the SC is the stratum granulosum (SG). Within the SG are keratohyaline granules that contain the protein profilaggrin, which then gives rise to filaggrin as the cell becomes cornified. The function of filaggrin is to assemble the keratin filaments within the corneocytes [9, 10]. The keratin filaments are a possible site for nonspecific drug binding and an explanation of the often observed skin depot. The lamellar bodies, containing disc-shaped polar lipids such as glycosphingolipids and phospholipids, free sterols, and hydrolytic enzymes that are involved in the formation of the intercellular lipid bilayers . In the SG, these lamellar bodies grow in number, eventually fuse with the cell membrane, and release their contents into the intercellular spaces forming lipid bilayers that constitute the permeability barrier of the skin . The importance of both the protein keratin and the lipid lamellar bodies in drug permeability is discussed in more detail below.
In the granular layer at the SG-SC interface, the plasma membranes of the differentiating cells become thickened by a deposit of protein, called the marginal band [9, 10]. This insoluble layer at the SG-SC interface is thought to contribute to the barrier function of the SC as it provides resistance to chemicals and enzymes. The primary lipids making up the corneocyte envelope surrounding the cells are hydroxyceramides [13, 14]. Most of these lipids have only single bonds in their fatty acid chains and are amphipathic—possessing both polar and nonpolar ends. The consequence of this is closely packed molecules that are highly structured, making the lipid membrane relatively impermeable to most compounds.
The other lipid component of the SC is the lipid bilayer located between cells. Originating in the lamellar granules, as described above, the lipids forming these bilayer sheets include mainly ceramides, cholesterol, free fatty acids, and cholesterol esters. Thus there is a shift in the originally released polar lipids (phospholipids and glycolipids) from the lamellar granules to the more nonpolar and neutral lipids that make up the bilayers (ceramides and free fatty acids). It has been suggested by Elias and Feingold that this change is a result of the proteases found in the lamellar bodies altering the type of lipids in the intercellular space. It has also been proposed in the same study that certain new lipids found uniquely in the SC are a result of synthesis in the viable upper layers of the epidermis, the SG, and that lipid synthesis is not just localized to the basal layer, as previously thought .
Therefore, there is a shift in the lipid components from polar lipids in the lower layers of the epidermis (basal layer to SG) to nonpolar and neutral lipids in the SC. The SC layer is left with a mix of primarily nonpolar, hydrophobic lipid bilayers that give the skin the first line of defense in preventing water loss and thus upholding the barrier function.
It is widely accepted that all of the cell layers of the SC are equally involved in upholding the barrier function of the skin [15, 16]. Its high lipid content as described above allows for its selective permeability and its primary responsibility to maintain water balance.
There has been no correlation found between the permeability of the SC and the thickness or number of cell layers, suggesting that these factors do not per se control permeation of drugs. This leaves the lipid content to play that part of upholding the barrier . The barrier is initially established at the SG-SC interface where the lamellar bodies first secrete their lipids, but the barrier extends to the entire SC as lipids fill the extracellular spaces of this region .
Pathway of molecules through the skin
The combination of these lipophilic areas along with the hydrophilic protein-filled corneocytes allows for the regulation of nonpolar molecules into the skin as well. Therefore, it is the biphasic composition of the outer SC, hydrophilic and lipophilic, that is the primary determinant of permeability and is the aspect of the skin that must be overcome to effectively introduce medicines via the transdermal pathway. Transdermal drug delivery depends upon passage of drugs between cells ("intercellular route"), which has been found to be the principle pathway for both polar and nonpolar substances . The molecules that have been studied are reviewed in Nemanic and Elias and Bodde et al. . Despite the fact that this route has been observed, a question still remains regarding the details of this movement. Do the molecules pass between the hydrophobic or hydrophilic areas of the bilayers, or is it through another intercellular space altogether? Menon and Elias have examined this question. Certain polar molecules (ferratin, HRP, lanthanum, sucrose and dextran) and nonpolar molecules (nonyl-PABA and n-butanol) were traced within the SC to see where they localized to under basal conditions and with enhancing methods.
Under basal conditions, the polar molecules (ferratin, HRP, and lanthanum) localized to discrete spaces within the SC intercellular bilayers. These spaces are called lacunar domains. With enhancing methods such as sonophoresis, iontophoresis and chemical permeability enhancers, these originally isolated lacunar domains expanded to form continuous networks in which the molecules were found to travel. With occlusion, the increased hydration that resulted also expanded the domains to provide the substances with a path to move through. Therefore, the authors propose that the passage of both polar and nonpolar drugs through the SC consist of travel through lacunar domains, which become networks with enhancing methods and increase the permeability of the drug. These critical observations are valuable in understanding the functioning of currently available TDS and in designing new TDS.
Effect of occlusion on skin permeability
With a vapor-permeable dressing, following occlusion for 8 days, it was found that trans-epidermal water loss (TEWL) increased significantly within the first 3 days, but then dropped significantly until the eithth day . Measuring TEWL after 5 days with the same dressing increase in TEWL . After a 4 day study using a more impermeable membrane, the TEWL increased on day two and then reached a plateau . Aly proposed that the change in TEWL observed is a result of the increased hydration and thus permeability of the skin under the dressing.
Occlusion and hydration have also been shown to increase the permeability of most molecules into the skin. When an occlusive patch is left on the skin, it prevents the loss of water from the surface of the skin (TEWL) and therefore increases the hydration level of the skin. The SC water levels, estimated using measurements from the devices explained above (see TEWL), have been shown to increase by up to 50 percent (Blank and Scheuplein, 1964 as stated in Bucks et al.  ). When nitroglycerin was placed occlusively onto the skin, an increase in absorption was found along with an increase in hydration. The mechanism was suggested to be a concurrent increase in SC water level leading to the fluidization of the lipid bilayers and therefore increasing the permeability . However, occlusion does not always increase the permeability of a drug. For example, hydrocortisone absorption was not increased with occlusive conditions and neither were certain phenols .
The effects of occlusion are also summarized in Zhai and Maibach, using other molecules, who described that the hydration effects of occlusion increased absorption for the more lipophilic molecules, such as citropten and progesterone, but had a smaller effect on the more hydrophilic compounds, for example hydrocortisone. Zhai and Maibach concluded that other physiochemical factors of the molecule need to be simultaneously evaluated absorption rates. Bucks et al. also had similar observations. To account for these counterintuitive results, Bucks et al. proposed that the mechanism behind this is as follows. As a result of the increased hydration due to occlusion, the SC and SG layers become more similar with respect to hydrophilicity and this makes the partition-coefficient of the molecule passing through the SC-SG interface lower. Due to this lowering of the partition coefficient, the passage of the molecule out of the SC would then be faster.
Mathematical modeling of permeability
In many fields of science, mathematical modeling has provided a unifying theory to help understand and predict observations. Mathematical models have been developed to estimate the permeability of molecules through the skin. Among them is Fick's first law of diffusion which states that J = (D/h)(c1-c2), where J is the flux, D is the diffusion coefficient, h is the thickness and c1-c2 is the concentration gradient . This model has been used as an approximation for permeability, however, it applies to a homogenous state and the SC, as discussed above, is certainly not homogenous. The permeating molecule's characteristics, such as partition coefficient and size, are also used to estimate their permeability. Partition coefficient is the ratio of solubility of a substance in organic solvent to an aqueous one. Due to the hydrophobic and hydrophilic nature of the SC, an optimum condition would be to have a drug whose partition coefficient indicates a solubility in both aqueous and organic solvents .
Many articles refer to these variables and equations; however, they are a simplification of the complex environment of the skin. Unfortunately, none of these models have been validated by prospective studies. More importantly, other factors affecting permeability must be analyzed.
Skin stripping, occlusion and hydration, temperature, patient age, and enhancers (iontophoresis, chemical enhancers and vehicles) are all elements that influence the permeability of the skin. At present, no validated mathematical model of skin penetration exists.
Relation between blood flow and transdermal absorption
Since capillaries are only present in the dermis, any materials entering to the blood must passively diffuse through the entire epidermis first. The process of diffusion is difficult to overcome as a result of the relative impermeability of the epidermis; diffusion is the rate-limiting factor in drug uptake. Therefore, it has been proposed that capillary uptake does not restrict absorption rate in most circumstances [9, 27]. The blood flow to a chest-skin area is 60-120 times greater than the permeability constant for fentanyl, for example . Therefore, the permeability of the drug through the skin is the limiting factor in the drug absorption process, and the uptake into the blood stream should not have a large effect on the rate of drug absorption.
On the other hand, it has also been found that the rate of drug absorption can be affected by blood flow rate for certain drugs. An instance where drug absorption may be affected by the vascular flow is if the drug is highly lipophilic or the normal skin diffusion barrier is severely damaged. In these cases, the first step of diffusion through the epidermis would occur faster than the next step of vascular uptake and therefore this second step would be the rate-limiting process. In a study of topical salicylic acid by Benfeldt , stripped skin was compared to normal skin with respect to circulating salicylic acid concentrations and the amount of salicylic acid not taken up by the capillaries. There was a greater accumulation of salicylic acid in the dermis of stripped skin than in normal skin. This was because the rate of blood circulation was not fast enough to remove the excess salicylic acid that built up in the dermis as a result of the high epidermal diffusion rate of the tape-stripped skin.
Effect of occlusion on skin repair
As discussed above, diffusion of molecules through skin is the critical pathway for transdermal drug delivery. Occlusion of the skin facilitates this process. Occlusion can also affect the regeneration path and regeneration rate of damaged skin and "occlusion" affects the permeability barrier, thus increasing the penetration of a drug. Occlusive dressings were found to decrease the rate of mitotic activity in response to skin stripping as compared to the normal response with no occlusion [26, 30]. The thickness of the epidermis, however, was still shown to increase under occlusion, as it does without occlusion. This is because there is still an increase in mitotic rate following skin stripping, even though that rate may be lower with the dressing.
The recovery rate of the permeability barrier with respect to lipid composition and occlusion was measured in subsequent studies.
When an impermeable membrane where the water flux is kept to a minimum, was applied following acetone damage to the SC, the restoration of the barrier and return of the lipids was delayed. However, with an application of a vapor-permeable membrane, and therefore an increased water flux, barrier function recovered at the normal rate, and lipid return followed the normal path . Possibly the transepidermal water flux is responsible for the regulation of lipid synthesis and therefore the rate of return of normal barrier function.
The abnormal return of lipids under occlusion following barrier disruption may be due to a disruption in lamellar body secretion. Since lipids secreted by these lamellar bodies are the primary components constituting the permeability barrier , it is reasonable to speculate if there is an effect of occlusion on their role. In rat studies [12, 23], it was noted that after acetone treatment and following impermeable occlusion, there were decreased numbers of lamellar bodies and abnormal lamellar body contents. In addition, decreased lamellar secretion and decreased bilayer formation succeeding secretion were identified. This did not occur when a vapor-permeable occlusive devise was used. Lamellar bodies were generated, released and formed into bilayers in the normal manner. The effects of occlusion after skin stripping were also examined and a follow-up study concentrating more on this provided the same results , therefore pertaining more appropriately to transdermal drug delivery. So, occlusion has been shown to disrupt normal barrier reformation by blocking the normal lipid repair and content.
Relevance and proposal
When an artificial vapor-impermeable barrier is placed on top of the skin, the normal recovery mitotic rate is decreased and the recovery of the lipid gradient is delayed due to abnormal lamellar body functioning. Thus the process of lamellar body formation in the stratum corneum is a critical process to fully understand transdermal drug delivery. We propose that this information should lead to efforts to prepare transdermal drug delivery systems that are non-occlusive and allow water flux from the skin under the device for more lipid soluble medicines. Optimal occlusive properties could be determined by relating water flux through the formulation to absorption of the molecule in test formulations of known varying occlusivity. For transdermal flux of more water soluble medicines, a more occlusive transdermal drug delivery system would be proposed. This reasoning also leads to an interest in developing excipients to alter lamellar body secretion to improve the efficiency of transdermal drug delivery. Further research leading to a better understanding of lamellar body functioning has the potential to improve the science of transdermal drug delivery.
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