Targeted Delivery of Actives from Topical Treatment Products to the Pilosebaceous Unit
Delivery of topical acne medications has focused on two challenges during the past decade. First, delivering the drug to the pilosebaceous unit (PSU) is required for treating diseases such as acne that have their origin in that unit. The other chal- lenge is delivering medications such as exfoliating agents via controlled release systems that keep the irritation caused by these drugs in abeyance. Follicular deliv- ery involves depositing drugs in the hair follicle, hair shaft, sebaceous glands, and all components of the PSU. It is hypothesized that vehicles, which are miscible with sebum, may help the active ingredient concentrate preferentially in the PSU. Such a preferential accumulation can be advantageous for increasing the transport of the drugs through the skin, as well as for targeting the drug to achieve therapeutic effi- cacy in the PSU itself. Knowledge of sebum lipid components helps us to consider how a penetrating vehicle will react upon entrance into the follicular canal. Additionally, these systems must release drugs into the follicle slowly over time, as well as target their delivery into the epidermis in the follicle via partitioning from slow release agents and mild vehicles so that the system is non-irritating. The major goals of this chapter are:
1. To review methods/models used to study penetration of and actions of ingre- dients within the PSU,
2. To review the fundamental research on technologies that target drugs to the PSU,
3. To review investigations of different vehicle effects on the thermal behavior of model sebum and their role in targeting delivery of acne medications to the PSU, and
4. To discuss recent advances in new drug delivery technologies in marketed or newly developed topical acne treatments.
The overall goal of this chapter is to summarize the state-of-the-art knowledge of targeting follicular delivery identifying strategies that could potentially provide effective topical anti-acne products.
SEBACEOUS GLANDS AND THE PILOSEBACEOUS UNIT
Sebaceous glands are generally found all over the body, except on the palms, soles, and dorsum of the feet. Most of the glands are associated with hair follicles and
hence are termed pilosebaceous glands. In humans, they are concentrated on the scalp, forehead, and face, where there may be as much as 320 glands/cm2 on the lateral regions of the face to as much as 1600 glands/cm2 on the alae nasi (1). Sebaceous follicles are particularly abundant in the face, ear canal, v-shaped parts of the face and chest, and on the sides of the upper arm. These skin areas are hence relatively greasy. They are also the regions where acne lesions seem to accumulate. There are a number of dermatological disorders involving the pilose- baceous structures, including acne, seborrhea, androgenic alopecia areata, and some skin cancers (2). Because the sebaceous gland is the primary source of the skin surface lipids covering large portions of the anatomy, understanding the anatomy and the properties of this skin appendage and its secretions becomes important to understanding the pathogenesis of acne, the subject of this book.
Sebaceous glands are multiacnar glands associated with hair follicles. They usually consist of a single lobule (acinus) or collection of lobules that open into a system of ducts, which in the case of pilosebaceous glands open into the piliary gland (Fig. 1).
FIGURE 1 (See color insert.) Schematic representation of the pilosebaceous unit and associated skin appendages. Source: From Ref. 70.
A sebaceous follicle consists of four parts (3):
1. The infundibulum, which is coated with keratinized epithelium
2. The large sebaceous gland acini (or lobes)
3. The small vellus hair structure
4. The sebaceous duct, via which the sebaceous gland lobes (sebaceous gland acini) open into the infundibulum.
The large, cauliflower – like, lobed acini produce the sebum, and its chemical composition and physical properties are also described in other chapters and by Thody and Shuster (4). The secretory duct, the infundibulum is a long duct lined by keratinocytes. After differentiating, the keratinocytes produce corneocytes, which are ejected outward; that is, into the lumen. The infundibulum consists of a distal part adjoining the epidermis, the acroinfundibulum. The infrainfundibu- lum is the lower part of the infundibulum and shows a keratinization differing from that of the epidermis. The corneocytes produced here are brittle and small. Human follicles can range in diameter from 10 to 70 mm (5).
There are two different types of sebaceous cells: the lipid-producing cells of the acinus and the stratified squamous epithelium of the duct, which is continuous with the wall of the piliary canal and the surface epidermis (4). Sebaceous glands are composed of undifferentiated, differentiated, and mature cells. The sebaceous glands are holocrine (self-destruct), and their secretion, sebum, is formed when the fully mature, lipid-rich cells die and disintegrate. This results because there is a large reserve of fully synthesized sebum contained in the follicular reservoir; that is, in the upper portions of the hair follicle and the orifice to the sebaceous gland. This source of sebum is not depleted, even by repeated solvent extractions. Thus, after careful cleansing of the skin, sebum contained in the follicular reservoir initially appears to flow out on to the skin surface at a constant rate over a several hour period, until the amount of sebum normally present on the skin surface is reached. After the normal level of sebum is reached, no further increase in the sebum concentration is observed (6). Once on the surface of the skin, the sebum has already been chemically modified by microorganisms in the PSU and becomes mixed with the lipids of epidermal origin (4). Hence, the term sebum is more precisely reserved to describe the lipid content of the sebaceous glands, and the term skin surface lipid is used to describe the lipid mixture on the skin surface. However, the composition of the sebum from the surface may not be the part that, is involved in acne.
While subsequent chapters cover the pathogenesis of acne in great detail, a brief overview will be provided here to set the stage for the discussion of delivery drug. Acne vulgaris, a multifactorial disease of the skin, is found in areas rich in sebaceous follicles. It is characterized by seborrhea, disturbed keratinization in the follicles with comedones, and subsequent inflammatory papules, pustules, and nodular abscesses and scars (3,7). In the absence of comedones, the large infun- dibulum channels are filled with white pasty material. It is the normal content of a sebaceous follicle, not of an acne lesion. Sometimes, the follicles are filled with a cocoon-type skeleton of corneocytes, with 20 to 40 cells surrounding the central fine hair, with a channel left free in which sebum, Propionibacterium acnes, and
staphylococci may be found (3). This is called a follicular filament or follicular cast. A comedo can arise from a follicular filament. It is believed that the lipid composition of the follicular casts may play a role in acnegenesis and in targeting therapies (6,7).
The primary event in acne is faulty keratinization and the production of microcomedones. The initial noninflammatory lesions of acne result from altera- tions in the follicular epithelium, as demonstrated both physiologically and by light and electron microscopic level (7). The proliferation and retention-type hyper- keratosis develops in the infundibulum, which expands like a balloon. Two path- ways define the subsequent development of the lesions of acne. In the noninflammatory pathway, the microcomedo proceeds to mature into closed and open comedones through distention of the follicle wall and lumen. Accumulation of corneocytes continues with the conversion of the follicle epithelium to the comedo epithelium. Open comedones arise from closed ones by continuous growth, sometimes directly from microcomedones without the intermediate stage. This plug consists of a very densely packed set of several hundred closely adhering corneocytes, together with sebum and P. acnes. Exfoliating drugs, such as salicylic acid (SA) and retinoic acid (RA), are often used to treat these types of lesions. In the inflammatory pathway, the extracellular products of P. acnes incite inflammation. P. acnes colonization occurs relatively early in acne, and the pro- duction of extracellular products by this organism provides multiple potential mechanisms for the development of inflammation. Among the earliest findings was that drugs that reduce free fatty acids (FFA), such as tetracycline, are beneficial in inflammatory acne (8). It must be noted that skin surface-derived lipids produce an inflammatory papule or nodule (9) and/or follicular hyperkeratosis and come- dones when they are injected into human skin or rabbit ears (10 – 12).
PRINCIPLES OF THERAPY AND TYPES OF DRUGS DELIVERED IN TOPICAL ACNE TREATMENTS
Four principles have been used to treat acne on an individualized basis, depending upon the clinical presentation (13).
1. Correcting the defect in keratinization, for example, SA, RA
2. Decreasing sebaceous gland activity, for example, antiandrogens
3. Reducing the population of P. acnes, for example, antibiotics, benzoyl peroxide
4. Producing an anti-inflammatory response, for example, benzoyl peroxide
In mild acne that consists mainly of comedones, it is important to correct the defect in keratinization using exfoliating agents. In inflammatory acne, it is import- ant to reduce the population of P. acnes in the follicle and the generation of extra- cellular products of the organism and reduce the inflammatory effects. In more severe, inflammatory acne that has proven to be resistant to therapy, it is important to consider adding a drug that decreases sebaceous gland activity. Since the comedo is the initial noticeable lesion even in inflammatory acne, it is important to correct the defect in keratinization in all cases of acne (13).
The follicular route is important for drug penetration as well as localized action to treat acne. Targeted delivery of active compounds to the PSU or its components can help treat a follicular disease, which for the purposes of this chapter is acne. Drug delivery through the follicular route has recently generated a growing interest. Appendages account for only 0.1% to 1% of the surface area of skin and only
0.01% to 0.1% of the skin volume. Thus, because of this, these appendages were not considered important routes for drug delivery (14). The maximum flux is low 26
because of this—0.5 – 1 10
cm/hr. In contrast, the flux across stratum
corneum (SC) is higher, 1023 cm/hr, due to the large surface area, but there is a lag time because of the slow diffusivity across the intercellular lipid. This is when the PSU becomes important (14). In order to influence the flux of compounds across skin significantly, the diffusion coefficient would have to be more than three orders of magnitude higher than across the intercellular lipid domains or the cor- neocytes of the SC. It is because of this that the shunt pathways that represent areas of discontinuities/areas of invagination in the SC will become important for the delivery of molecules that exhibit a slow rate of percutaneous penetration and they will be particularly important during the early stages immediately after topical application. Figure 2 is a hypothetical representation of this phenomenon showing greater penetration of the drug into the appendagial shunt at early time points. The nature of the drug and the vehicle, however, can greatly influence these differences. Increasingly, the PSU is gaining acknowledgment as a complex, dynamic structure that may contribute significantly to passive transport of compounds to the skin. There are several objectives of follicular delivery:
1. Reducing or bypassing the transepidermal route,
2. Increasing drug concentration in the PSU,
3. Increasing the therapeutic index of the drug,
4. Decreasing toxicity of the drug, and
5. Reducing the high dose of the applied drug and reducing the frequency of administration.
Arbitrary exposure time
FIGURE 2 Hypothetical comparison of penetration of a topical medication into the skin. Note that the appendagial shunt pathway is the favored pathway during early time points while the epidermis becomes important during the later time points (14). The extent of this difference depends on the nature of the drug and vehicle.