PHASE I CLINICAL TRIAL USING OCTADECENEDIOIC ACID

15 May

PHASE  I CLINICAL TRIAL USING OCTADECENEDIOIC  ACID, AZELAIC ACID, AND BENZOYL PEROXIDE
When  new  chemical   entities   are  tested   on  human skin,  it  is  advisable to  first conduct studies on healthy volunteers (so-called  Phase  I trials) prior  to conducting

TABLE 2    Skin Delivery of Octadecenedioic Acid or Azelaic Acid to the Superficial Layers  of the Stratum Corneum (Tapes), the Remainder of Skin (Skin), or the Receptor Fluid (Transdermal) Following Application of Three  Different Formulations on Dermatomed Pig Skin in In Vitro Bronaugh Flow-Through  Cells

FIGURE 4    (See  color  insert.)  Autoradiography  of  octadecenedioic  acid  and   azelaic  acid following  penetration  through   dermatomed  pig  skin  for  20  hours.   Images  show   transverse sections through  the upper  layers of skin treated with different formulations: untreated control (A and  B); Skinorenw containing  20% azelaic acid (C and  D); a gel containing  10% octadecenedioic acid  (E and  F); a gel containing  10%  azelaic acid  (G and  H). Stratum corneum, epidermis, and upper  dermis can  be  seen. Bright field (A, C, E, and  G) and  dark  field (B, D, F, and  H) images were  obtained using  a  Leitz  DMRB light microscope (Leica,  Milton Keynes, U.K.). The  bright reflectance in  each dark  field  picture  is  the  stratum corneum. The  scale bar  in  all  bright  field images represents 100 mm.

FIGURE 5    (See  color   insert.)   Examples  of  follicular  delivery  following  skin  penetration  of octadecenedioic acid from an  aqueous gel containing  10%  w/w octadecenedioic acid  (A and  B), azelaic  acid from an aqueous gel containing 10% azelaic  acid (C and  D), and  Skinorenw  containing

20% azelaic acid (E and  F). Images show  transverse sections through  the upper  layers of the skin. Bright  field (A, C, and  E) and  dark  field (B, D, and  F) images were  obtained using  a Leitz  DMRB light microscope (Leica, Milton Keynes, U.K.). The bright reflectance in each dark field picture  is the stratum corneum and  the  infundibulum.  Note  that  the  stratum corneum in (A) and  (B) has been predominantly lost from this section. The scale bar in all bright field images represents 100 mm.

studies on the intended product-user population. However, this has consequences for the type  of measurements that  one can undertake. The objective  of this Phase  I trial  was  to compare the  in vivo  antimicrobial activity  of topically applied DCA with  that  of AZA  and  BPO. Because  acne  lesions  cannot  be measured on healthy

volunteers, the basis of this trial was to measure changes in the skin surface  micro- flora count  (Micrococcaceae and  Propionibacteria) and  skin-surface free fatty  acid (FFA) levels  on  the  faces  of healthy volunteers as an  indicator of potential anti- acne activity.  The trial was  performed as a double-blind study.

A group of 59 volunteers (37 male, 22 female) aged 16 to 35 were recruited into the  study. All  volunteers were  medically screened to  ensure their  suitability to undertake the  study. Their  willingness to  participate was  documented through the completion of an informed consent form in the presence of medical staff.

Baseline  levels  of viable  propionibacteria on  the  surface  of the  skin  on  the right cheek of each volunteer were determined seven  days  prior  to commencement of the trial. The volunteers were  assigned to one of five groups, as determined by previsit numbers  of  skin  surface   propionibacteria,  so  that   each  group had   a similar statistical distribution of numbers of viable  propionibacteria:

1.    The first group (n ¼ 12) received the  aqueous gel containing 10% w/w DCA, which  was  also investigated for skin delivery.

2.    The second group (n ¼ 12) received the same aqueous gel formulation without the DCA (placebo).

3.    The formulation of the third group (n ¼ 12) was  the same  aqueous gel again, but this time with  10% w/w AZA.

4.    The  fourth group (n ¼ 12)  received “Panoxyl Aquagel  5,”  a  commercially available product  containing 5% BPO (Stiefel  Laboratories, High  Wycombe, Bucks, U.K.).

5.    The fifth group (n ¼ 11), finally, received Skinorenw, the commercially available product from Schering  containing 20% AZA.

All volunteers were provided with a non-antimicrobial soap and instructed to wash the whole  face twice  daily  prior  to application of treatment products. Each volun- teer applied one of the products to the test site (right-hand side of the face including forehead, just beyond the midline, cheek, and  chin, avoiding the eyes, nostrils, and mouth) for the 21 days  of duration of the trial.

The  surface   microbial populations  (Micrococcaceae and   Propionibacteria) were  enumerated on the right  cheek  at baseline and  after  3, 7, 14, and  21 days  of treatment. Sebum  was  collected  from  each  volunteer at  baseline and  after  7, 14, and  21 days  of treatment, and  the  FFA content was  determined by  gas – liquid chromatography. Volunteers were  also  asked  to maintain a daily  diary  and  note any  positive or negative effects of the treatment. Data  were  analyzed using  para- metric  and  nonparametric statistical tests.

The main  findings of the study were  as follows:

1.    Of the 59 volunteers recruited into the study, only six individuals failed to com- plete  the  study (10.2% drop-out rate).  The dropouts were  evenly  spread over the  treatment groups, and  there  was  no  evidence that  adverse reactions to any one treatment were  responsible for noncompletion. Only those  volunteers who completed the treatment were included in the subsequent statistical analysis of the results.

2.    All preparations containing dicarboxylic acids (both AZA and DCA) were well tolerated. In the BPO-treated group, 92% of volunteers reported adverse events (irritancy and  drying of the skin). However, the volunteers in this group were able   to  maintain  the   stipulated  treatment  regime  throughout  the   study, although some  were  advised to use a moisturizing lotion.

3.    None  of the treatment regimes had  any detectable effect on skin surface  FFAs.

FIGURE 6    Scatter plot of changes in Micrococcaceae count from baseline following treatment with a 10% w/w octadecenedioic acid gel (A), placebo gel (B), 10% w/w azelaic acid gel (C), 5% w/w benzoyl    peroxide  (Panoxylw    Aquagel   5)   (D),   or   20%   w/w   azelaic  acid   (Skinorenw)   (E). Abbreviations: AZA, azelaic acid; BPO, benzoyl  peroxide;  DCA, octadecenedioic acid.

4.    All the treatments, apart from  the placebo,  produced significant reductions in

Micrococcaceae after one week  of treatment (Fig. 6).

5.    Only  BPO  and  DCA  significantly reduced  the  propionibacteria population (Fig. 7). Both  compounds achieved reductions in  propionibacteria counts in the majority of volunteers in their  respective user  groups.

FIGURE 7    Scatter plot of the changes in propionibacteria count from baseline following treatment with a 10% w/w octadecenedioic acid gel (A), placebo gel (B), 10% w/w azelaic acid gel (C), 5% w/w benzoyl peroxide (Panoxylw Aquagel 5) (D), or 20% w/w azelaic acid (Skinorenw) (E). Abbreviations: AZA, azelaic acid; BPO, benzoyl  peroxide; DCA, octadecenedioic acid.

The results of this phase  I trial suggested that  DCA combines activity  against pro- pionibacteria with  a good  safety  and  tolerance profile.  It outperformed Skinorenw in  this  trial.  However, DCA  did  not  produce the  in  vivo  antimicrobial efficacy that  would have  been  predicted from  the  in  vitro  data   listed  in  Table  1. This suggested  that   the   delivery  of  DCA   from   the   gel  formulation  was   not   yet optimal, which  was  indeed confirmed in Table 2 and  Figure  3.

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