This section reviews the most recent research advances in technology being mar- keted or being developed to deliver acne treatment medications to the target lesions. Two types of technologies are discussed. One is a recent technological approach based on lipid melts and particulates that target drugs to the PSU. Second is controlled release technology that delivers the drug into the PSU more slowly over time, and thereby provides milder topical treatment systems. These are based on the fundamental research findings reviewed in the last section and have been applied specifically to the delivery of antiacne drugs to the target site.
Advances in Use of Lipid Melts to Deliver Anti-acne Drugs to the Pilosebaceous Unit
The present authors, Rhein et al. (64), have investigated further the use of lipid melts to deliver SA to the PSU. It is hypothesized that vehicles that are miscible with sebum or a part of it will be effective in preferentially delivering drugs to the sebaceous glands. In a previous chapter, we have characterized model sebum based on its thermal behavior (Chapter 15) and identified four melting transitions by differential scanning calorime- try corresponding to four different species: Mp-1 and Mp-2 are transitions at 2158C and 2208C for the unsaturated triglycerides/fatty acids (overlapped) and the wax esters and Mp-3 and Mp-4 at þ408C and þ558C are for saturated triglycerides/fatty acids (overlapped) and wax esters, respectively. We refer to that chapter for detailing this information. In that chapter, we have also identified vehicles that are miscible with sebum because they lower the melting point of the solid components (saturated
triglycerides/fatty acids and wax esters, Mp-3 and Mp-4), and thereby enhance their dissolution by the liquid components in sebum. In this chapter, we have investigated the follicular delivery of SA using some of those vehicles; the hamster ear model dis- cussed earlier was used to quantify delivery of SA.
The strategy of using lipid melts to deliver drugs to the PSU can be achieved in two different ways. For hydrophobic drugs, lipid melts (combination of vehicle and sebum) can “soften” if not liquefy the solid components of sebum and the drug will essentially be solubilized in the sebum along with the vehicle; the drug is thus cotransported into the sebum along with the vehicle. For hydrophilic drugs, the vehicle serves a different function which is to facilitate partitioning of the drug from the vehicle into the sebum. We have therefore characterized two types of vehicles for effectiveness at delivering drugs, in particular SA into the PSU. These are fatty vehicles and polar vehicles, and are shown in Table 3 along with the percentage of delivery of SA from the vehicle into the sebaceous follicle and also the solubility of SA in the vehicle.
Comparing the solubility of SA in the vehicle and the delivery into the sebaceous glands, it was found that for fatty vehicles as the solubility of SA increased in the vehicles, more drug was delivered into the sebaceous glands (Table 3). For the polar vehicles, however, the trend was the opposite, that is, as solubility increased, delivery to the sebaceous gland went down (Table 3). This led to the conclusion that the mechanism of the drug delivery into the follicle was different for the two types of vehicles. It appears that the fatty vehicles are mis- cible with sebum and hence the increase in solubility leads to higher follicular deli- very, as SA is cotransported with the vehicle into the sebum. In the case of the polar vehicles, the decrease in follicular delivery with increase in solubility leads us to believe that it is a partitioning effect, that is, the more soluble in the polar vehicle the less likely SA is to partition into the sebum.
We then correlated the SA delivery with the results of DSC studies. The DSC of a model sebum showed four major transitions: Mp-1, Mp-2, Mp-3, and Mp-4. Of the four melting transitions in sebum described earlier, Mp-3 and Mp-4, transitions for the solid part of sebum occurred between 408C and 558C; these are the most meaning- ful transitions of the saturated and, therefore, solid species (saturated-fatty acid, trigly- cerides, and wax esters) that exist at the physiological temperature of skin. This solid part offers the challenge for drug delivery and dissolution of solid sebum in the follicle. The effect of the vehicles on Mp-3 and Mp-4 has been tabulated in Table 4. The delta values in the table are the difference between the transition of the model sebum and the model sebum plus vehicle. It was found that as the percent of drug delivered into the sebaceous glands increased as DMp-3 increased for fatty vehicles (Fig. 3). DMp-3 is the difference in the Mp-3 transition temperature of model sebum and the Mp-3 transition temperature of the model sebum treated with fatty vehicle. It is a measure of the effect of the vehicle on the Mp-3 fraction of model sebum and a higher number indicates higher miscibility of the vehicle with that fraction of sebum. This means that the higher the miscibility of the fatty vehicle with the Mp-3 fraction of sebum, the higher is the follicular deposition of SA using the vehicle.
Similarly for the polar vehicles as the effect on Mp-4 increases, the percent of drug delivered in the sebaceous glands decreases (Fig. 4). DMp-4 is referred to as the difference in the Mp-4 transition temperature of model sebum and the Mp-4 transition temperature of the model sebum and polar vehicle. DMp-4 is a measure of the effect of the vehicle on the Mp-4 fraction of model sebum and a higher number indicates higher miscibility of the vehicle with that fraction of sebum. These results can be explained by the fact that sebum is made up of nonpolar components. If a vehicle does not interact with sebum (as is observed from its none- ffect on Mp-4), it would mean that it is polar in nature and there would be a pro- nounced partitioning effect. The more soluble the drug is in the polar vehicle the less likely it is to penetrate into the sebaceous gland. Glycerine is a good
FIGURE 3 Correlation of the percent of salicylic acid in sebaceous glands to DMp-3 for fatty vehicles. Note: DMp-3 is designated Delta Mp-3. x-axis error bars indicate the standard error of the mean of three experiments and y-axis error bars indicate the standard error of the mean of six experiments. Abbreviations: IPM, isopropyl myristate; MSO, maleated soybean oil; OA, oleic acid. Source: From Ref. 64.
example; SA is delivered to sebaceous gland better compared to the other polar vehicles yet glycerine does not miscible with Mp-3 or Mp-4. SA therefore partitions better into the gland from glycerine. We would, however, anticipate that a more hydrophilic drug will present great difficulty partitioning from glycerine to the
FIGURE 4 Correlation of the percent of salicylic acid in sebaceous glands to DMp-4 for fatty vehicles. Note: DMp-4 is designated Delta Mp-4. x-axis error bars indicate the standard error of the mean of three experiments and y-axis error bars indicate the standard error of the mean of six experiments. Abbreviations: B, butanediol; DMI, dimethyl isosorbide; G, glycerin; MP, MP diol; SA, salicylic acid; T, transcutol. Source: From Ref. 64.
gland. These results further strengthen our theory of the miscibility of the fatty vehicles and the partitioning of the polar vehicles. Future research will investigate challenges of delivery of other drugs of varying hydrophilicity.
Delivery of Adapalene to the Pilosebaceous Unit
Using Polymeric Microspheres
A classic execution of a targeted delivery system for the anti-acne medication, adapalene, was done by Galderma Researchers (63,65 – 68). Adapalene is the chemi- cally stable form of naphthoic acid. It binds in skin to the RA receptor subtypes RAR gamma in the epidermis and RAR beta in the dermal fibroblasts activating differen- tiation specific genes and is a fast-acting anti-acne treatment. Researchers there have investigated the use of particulate microspheres to deliver this anti-acne medi- cations to the PSU. The drug is entrapped inside the microspheres. Shroot et al. (65) and Allec et al. (66) have discovered that delivery of the microspheres to the PSU depends on the size of the sphere. The composition of the microspheres is 50:50 poly(DL-lactic – coglycolic acid) and they are impregnated with adapalene using the solvent evaporation technique. Depending on the stir rate and emulsification technique, spheres of different diameter can be formulated, 1, 5, and 20 mm with corresponding doses of adapalene of 0.01%, 0.05%, and 0.1%.
The hairless mouse model along with full thickness human skin described earlier was used to assess site of penetration of the microspheres (63). The spheres were applied topically and the location of the spheres was determined using fluorescence microscopy and scanning electron microscopy. What was dis- covered was that spheres of 5 mm primarily were localized within the PSU and pen- etration depth was time-dependent. On the other hand, larger spheres, .10 mm, remained on the skin surface and smaller spheres, ,3 mm, penetrated both the PSU and the epidermis.
One could naively argue that smaller spheres would more effectively treat acne because they penetrate both the PSU and the epidermal surface since PSUs occupy only 0.1% of the epidermal surface. However, acne is a disease of the PSU and further studies showed that formulations of microspheres that target pen- etration to the PSU provide similar efficacy without irritation, a known side effect of other anti-acne medications such as tretinoin (68). This suggests that penetration through the epidermis rather than the PSU tends to deliver drugs into and through the living tissue and into the systemic circulation more readily, thus causing irritation. These results also suggest that the target site for optimal treat- ment of the disease is the PSU where acne develops. However, more research is needed to confirm these findings.
Controlled Release Systems
Various controlled release formulations are now on the market that are designed to deliver the acne medication into the skin more slowly to avoid an initial burst during the first few hours. Such an initial burst of drug and/or enhancers can lead to irritation that is frequently observed with acne medications and is the subject of numerous consumer complaints in the marketplace. However it is not known whether these technologies preferentially deliver the medicament to the PSU. Bertek and GlaxoSmithKline employ a polyurethane polymer technology— PP-2 that alters the activity of the free drug in the respective formulations. Bertek markets such a technology with RA and GlaxoSmithKline markets a similar
technology with SA. Rhein et al. (69) published studies showing the benefit of the controlled release PP-2 in controlling delivery of SA with regard to irritation reduction; however, they failed to demonstrate the benefit of this technology to the resolution of acne. Additionally, while studies were done to show targeted delivery to the cutaneous epidermis, no penetration experiments were done on the PSU versus epidermis.
Numerous methods have been reviewed that enable the researcher to study tar- geted delivery of acne medications and enhancers to the PSU. The current status of drug delivery to the PSU for the potential treatment of acne has been summar- ized in this chapter. Techniques to deliver anti-acne drugs have been summarized, along with methods to assess transfollicular delivery. What is eminently clear is that the biochemistry and physiology of the PSU is not well-understood fundamentally and the pathogenesis of acne as it progresses within the PSU is also not well- understood. It appears to be a chance occurrence that a delivery vehicle is formulated that targets delivery of anti-acne medications to the PSU with some fundamental learning emerging form it. The knowledge is thus very much in the rudimentary stages, given that the structure of sebum then manipulating the phase behavior by the appropriate chemical enhancers such as liposomes and fluidizing agents is feasible. It seems that by knowing the chemical structure of the active, that is, hydrophobic or hydrophilic in nature among other things, topical delivery vehicles can be developed that potentiate penetration into the PSU.
Future strategies will likely embrace new delivery devices to target the PSUs (71). Some of these are microneedle-based delivery systems, microfluid devices, sonophoresis, iontophoresis, and even magnetic modulation. The future of such techniques should yield interesting developments in the treatment of acne via the PSU. The continuing issue is the unavailability of an appropriate in vitro model. Directions of future developments have been review by Meiden et al. (72). A new in vitro skin sandwich model that mimics transfollicular penetration is discussed. Confocal laser scanning microscopy is the most focused direction as a noninvasive methodology for deriving high resolution images of the PSU the principal advan- tages is its capacity for in vivo application, good time-resolution and the ability to visualize at multiple depths parallel to the sample surface without the need for mechanical sectioning (73). The combination use with confocal Raman spec- troscopy is another promising tool for analyzing follicular drug delivery. New developments in innovative liposomes and microspheres continue to be on the fore- front (74,75). The porcine ear is emerging as an in vitro model that may better mimic human skin (76). Latest techniques being studied for follicular delivery is to remove the sebum plug and then apply treatment which greatly potentiates delivery to the PSU (74). The key decision of the researcher is whether they are targeting the PSU or is the intent transfollicular penetration. This will dictate the strategy to a large extent and the delivery systems required. The more formidable question is what is the appropriate pharmacology that identifies more effective actives targeting the appropriate site within the PSU? The delivery aspects will be tailored to that active depending on its chemical nature and the target site. Perhaps some of these questions are also answered in other chapters in this book.