confers liposomes amphipathic properties, enabling encapsulation
of hydrophilic and hydrophobic drugs.23 Liposomal carriers
increase drug stability, enhance their therapeutic effects, and
promote uptake of the drug into target tissues.23,24 Given the
instability of liposomes within aqueous solutions, Ning et al.
prepared clotrimazole-containing proliposomes for vaginal
application. These prolipisomes were found to be capable of
sustained release for 24 hours and efficacious against Candida
albicans as seen by a decrease in colony forming units by day 7.25
Multilamellar vesicles are even capable of depositing a high concentration
of finasteride in the follicular region for the treatment
of androgenic alopecia.26 Pornpattananangkul et al observed that
liposomal lauric acid was able to fuse with bacterial membranes,
effectively eradicating Proprionibacterium acnes infection in a
mouse model, with minimal toxicity to unaffected skin.27 Further
in vitro and in vivo studies evaluated the effect of fluconazoleloaded
liposomes; authors found a higher accumulation of drug
following liposomal gel application compared to control, with a
significantly higher retention within the stratum corneum.23 The
ability of liposomes to penetrate the epidermis may be explained
by their lipid composition, facilitating greater penetration compared
to other vehicle forms. It has also been proposed that the
lipid matrix is able to intercalate with skin lipids, enabling loosening
of the encapsulated drug and thus accelerating its release.22
However, despite their improved permeation, confocal microscopy
found that liposomes were confined to the stratum corneum
and unable to penetrate the granular layers of the epidermis.28
Microspheres
Microspheres are another technological approach to deliver
low-dose sustained release treatment to control a variety of skin
disease. Microsphere technology eliminates the rapid delivery
of highly concentrated drug to the application site, allowing for
the sustained release of active drug. Microsphere technology
effectively traps the active ingredient at the skin surface, enhancing
drug delivery at the application site while limiting systemic
distribtion.29 While retinoids and benzoyl peroxide are extremely
effective in controlling acne vulgaris, therapy-associated
irritation is a serious complaint that limits patient compliance.30
Eichenfield et al demonstrated a statistically significant reduction
in the number of noninflammatory acne lesions after
treatment with tretinoin microsphere 0.04% gel compared to
empty vehicle.31 In another study, there was no significant difference
in tolerability (ie, erythema, dryness, itching, stinging) of
the same microsphere drug when compared to tretinoin 0.025%
cream applied to healthy skin, despite the increased concentration
of tretinoin in the drug of interest.32 Furthermore, topical
microsphere-based fluorouracil, has proven effective in the
treatment of actinic keratoses (AK) with a significant reduction
in AK lesion counts and lesion clearance compared to vehicle
control.29 There are currently a variety of topical microsphere
formulations on the market, each with increased efficacy and
reduced irritability compared to traditional vehicles.
Nanoparticles
Nanoparticles are another innovative carrier being investigated
and used in skin disease to harness potent drugs, allow for
targeted drug delivery, and minimize systemic side effects.33
Given their high surface-to-volume ratio, small size and stability,
nanoparticles are able to surpass barriers, penetrate the
stratum corneum and accumulate at target sites.34,35 There
are multiple pre-clinical programs in dermatology evaluating
the utility of these carriers. Friedman et al encapsulated and
enhanced the efficacy of benzoyl peroxide, finding improved
antimicrobial efficacy against P. acnes at lower concentrations
compared to native benozyl peroxide with less toxicity
to eukaryotic cells.35 In an in vivo murine MRSA intramuscular
abscess study, which compared the efficacy of topical and intralesional
nitric oxide releasing nanoparticles (NO-np) with
systemic vancomycin, all treatment arms accelerated the rate
at which the abscesses improved clinically. However, topical
and intralesional NO-np significantly decreased bacterial survival
as determined by tissue cultures as well as by histology,
which demonstrated less inflammatory infiltrate and muscle
necrosis as compared to other groups.36 A spherical nucleic
acid carrying gold nanoparticle (SNA-NC), when mixed with a
commercial moisturizing cream (aquaphor), allowed for topical
delivery of gene-targeting therapeutics into deep layers of
the skin without barrier disruption.37 SNA-NC was capable of
freely penetrating into keratinocytes, mouse skin and human
epidermis in concentrations sufficient to induce morphological
change via EGFR gene knockdown, an important signaling
molecule in epidermal cell proliferation and frequently overexpressed
in malignancy.37 Lastly, nanotechnology is allowing
topical delivery of botulinum toxin, with reported similar effects
to its injected formulation.38 A purified 150kD botulinum
toxin combined with a peptidyl macromolecule transport system,
a combination permitting transepidermal flux of toxin
into the dermis, was applied to subjects with moderate-to-severe
lateral canthal lines, revealing significant improvement
in wrinkling compared to placebo at both rest and smile.39
Together, these investigations highlight nanoparticle systems
as a promising new approach for targeted drug delivery, one
which can hopefully combat difficult to treat dermatologic
conditions and improve drug efficacy and patient compliance.
Conclusion
While topical drug delivery is a pillar of dermatologic therapy,
the choice of vehicle is a crucial decision that can significantly
alter efficacy, outcomes and patient compliance. An effective
topical management program is dependent on the properties
of the vehicle—physical chemistry, ease of applicability and
penetration of drug. Topical treatment of skin disease allows
for local delivery and rapid absorption of a high concentration
of active drug; however, the skin’s intrinsic function, to
counteract the penetration of foreign substances by creating
a physical barrier from the external environment, makes drug
