Targeted Delivery of Actives

15 May

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 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).


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.

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