• Patchless Transdermal Drug Delivery ... - Ecn5.com ecn5

6
MARCH 2011 • TransDermal
Excipients for TDD formulations should be nontoxic,
nonirritating, and nonsensitizing to skin, even upon
repeated application to the same site. The transdermal
composition may use different excipients
depending on the dosage form. Excipients may
include solvents for the drug, thickeners, preservatives,
anti-oxidants, chelating agents, fragrances, etc.
A key ingredient for a patchless TDD formulation is
the skin-permeation enhancer, which facilitates
delivery of a therapeutically required dosage of the
drug. Some of the common enhancers include oleic
acid, dimethyl isosorbide, lauryl lactate, dimethyl
sulfoxide, decyl methyl sulfoxide, ethoxydiglycol,
N-methyl 2-pyrrolidone, and isopropyl myristate. A
review by Danyi Quan, et al provides a detailed discussion
of enhancers for TDD [1, 2]. Many enhancers
cause skin irritation when used at higher concentrations.
Therefore, a balance between drug-permeation
enhancement and skin safety is important in optimizing
the formulation.
One of the key issues with patchless TDDs is retention
of the drug and enhancer at the site of application.
Lack of retention for the desired duration of
time is a common problem. Nature designed the
skin to shed materials adhering to it. Loss of an
applied dose also can occur by transfer to other
objects, such as articles of clothing, or other people.
The loss results in an inadequate therapeutic effect
and a shorter duration of pharmacological activity
for the drug. In addition, transfer of a drug, such as
testosterone, to others by touch is a particularly sensitive
issue pertaining to safety of the product.
An appropriate film-forming polymeric delivery system,
which can serve as a matrix for the drug and
enhancers, can address some of these issues; however,
the use of a polymer delivery system for TDD has its
own challenges. Skin is a living substrate; that is, it
breathes, perspires, stretches, and contracts. The
formed film must accommodate the various functions
of the skin during different activities and environmental
conditions, such as temperature and humidity.
It must be bioadherent and possess viscoelastic properties,
breathability, and moisture-vapor permeability
similar to skin. In the absence of such characteristics,
the film tends to feel uncomfortable or tight and peels
and flakes during use. The net result is inadequate
wear time and loss of efficacy.
Another consideration is possible crystallization of
the drug on the skin when the applied formulation
dries. Other critical issues that formulators need to
address in patchless TDD development include the
hydrolytic and oxidative stability of the drug in
aqueous or hydroalcoholic medium, pH effects, and
cosmetic acceptability.
Commercial Approaches to Patchless
TDD Products
Acrux, Vivus, Ther-Rx
Acrux (www.acrux.com.au) initially acquired its
technology — discovered by B Finnin, B Reid, and
T Morgan — from Monash University in Australia.
Sunscreens have used its ACROSS ® enhancer octisalate
for a long time at higher doses. It is a known,
safe, nonirritating formulation and allows the passage
of drugs across the barrier layer of the skin.
Acrux has placed the ACROSS enhancer in a
Metered Dose Transdermal System ® (MDTS), allowing
application of a pre-set dose of a drug. The system
also creates a patchless reservoir in the skin that
can deliver drugs for various indications for human
and veterinary use. Vivus (www.vivus.com) is the
licensee in the USA for Acrux’s testosterone spray
for women, trademarked as Luramist ® . Another
ACROSS product, Evamist ® , is a 1.7% estradiol topical
spray for systemic transdermal delivery of the
hormone (Ther-Rx, www.ther-rx.com).
Biosante, Antares Pharma, Azur Pharma
Biosante Pharmaceuticals (www.biosantepharma
.com) is a company specializing in products for
female sexual-health and oncology. The lead is
LibiGel ® , a transdermal testosterone gel for treatment
of female sexual dysfunction. Antares Pharma
(www.antarespharma.com), Biosante’s partner, is
developing it. It is in Phase 3 clinical development
under an FDA Special Protocol Assessment. Biosante
intends to submit the LibiGel NDA in 2011 for potential
approval by the FDA in 2012.
Azur Pharma (www.azurpharma.com) in Ireland is
a private pharmaceutical company focused on the
Central Nervous System (CNS) and the health of
women. Azur is marketing Elestrin ® , which they
acquired from Biosante, in the USA. It is an estradiol
gel for the treatment of menopausal vasomotor
symptoms.