Friday, October 23, 2009

Beauty Is Only "Skin" Deep

Posted by Mary Liu at Friday, October 23, 2009

The term "beauty is only skin deep" is taken literally here at Kythera Biopharmaceuticals, Inc. in Calabasas, California. Throughout my 4 weeks here, I delved into the fascinating (not exaggerating) world of dermatologic drug products. I learned very quickly that the rules and regulations that apply to dermatologic products are quite different than those that apply to other medications.

My main project was to develop a formulation model that would not only be commercially viable, but also enhance the intellectual property (IP) of this product. I initially performed multiple literature searches, digging through articles to uncover clues and formulate educated hypotheses on a drug candidate Kythera is studying in disorders of pigmentation.

Formulation of a novel topical drug candidate, however, is no easy feat. Once I investigated possible formulation options, I realized that there is an entire set of related issues I had to address: IP, competition, manufacturing, pharmaceutics, and toxicology.

Thus, my wild adventure into the world of dermatologic products began...

The key question every dermatologic drug candidate needs to resolve prior to formulation development is: Can this drug molecule get into the skin? To answer this, two issues must be addressed: (1) size and (2) lipophilicity.

(1) 500 Daltons tends to be the upper limit of the size of a molecule that can penetrate through the stratum corneum. (A Dalton is a measure of molecular weight or mass equal to the mass of one hydrogen atom.) But that does not stop molecules like Protopic (Tacrolimus), which is over 800 Daltons, from being made into an ointment and applied directly to the skin. Recently, an article was published on topically applied cosmeceutical creams containing growth factors and cytokines. Growth factors range anywhere from 20 to 150 kDa (Kilodaltons), so how were they penetrating the skin? The answer may lie in the hair follicle, which has been studied for years by such experts as University of Michigan College of Pharmacy Pharmaceutics Professors Emeritus, Drs. Norm Weiner and Gordon Flynn. Their research, and that of other experts, studied how large molecules could penetrate the skin, and they discovered that transfollicular delivery, along with sebaceous glands, appeared to be most likely the route.

(2) A non-lipophilic drug molecule is not likely to penetrate through the stratum corneum layer of skin. (Lipophilic refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Stratum corneum is the outermost layer of the epidermis.) During my research, I found that various penetration enhancers can be added to the drug vehicle as well as novel drug delivery systems to encapsulate or surround the drug, such as liposomal delivery and molecular umbrellas.

Getting the drug molecule into the skin is just the first hurdle. If we create a formulation that successfully penetrates the skin and reaches the target site of action, then we have to start considering the possibility and consequences of systemic absorption and active metabolites. Based on discussions with a toxicology consultant, preliminary ADME (absorption, penetration, metabolism, elimination) studies could answer these concerns as well as provide a clue to the length of our toxicology study program.

The current commercial landscape is also another issue that we have to consider. Who are our potential competitors? What competing products are already in the marketplace? And from these questions, IP questions will inevitably follow. If other products are already in the marketplace, how will ours be better? What can we do to obtain IP protection and exclusivity in the market?

The majority of my time at Kythera was devoted to piecing together the answers to these questions, as well as to develop potential formulation pathways based on my own research and discussions with various experts in the fields of toxicology, IP, formulation, and penetration/absorption.

I spent the balance of my time at Kythera speaking with various functional leaders of the company (in regulatory, marketing, operations, quality assurance, etc.) to obtain a better understanding of the daily and long term operations of a pharmaceutical company. One valuable concept that I learned was that all roles are interconnected. One decision cannot be made without affecting another department within the company. Kythera grasped this concept from the beginning, reflected in the interior design of their office: glass walls on which people jot ideas, as well as open doors, which welcome a free flow of communication between people.

And although beauty may be skin deep, there's nothing else about this industry that is. The dermatologic drug industry is an increasingly crowded and competitive field. I learned from Kythera, however, that if you are driven, business-savvy, highly knowledgeable about your field, and think outside-the-box, you have great potential to be successful in this industry. This rotation has certainly opened my eyes to the plethora of job opportunities for PharmDs in the pharmaceutical industry — and possibly, a career in drug development for me.

1 comment:

Norm Weiner said...

Your blog is right on target. Advances in this field will occur by understanding skin properties and formulation design. Keep at it.

Norm Weiner