RECENT ADVANCES IN THE DELIVERY OF TOPICAL ANTI-ACNE MEDICATIONS

15 May

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.

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