Botox
has proven its success in combating dynamic wrinkles and has acquired a star
status among anti-aging treatments during the past 25 years. Originally
approved for the treatment of eye muscle disorders like blepharospasm and
strabismus, Botox over the years has become an increasingly popular cosmetic
procedure. According to the American Society of Plastic Surgeons (ASPS), botox (BoNTA)
injections were the single most popular minimally invasive cosmetic procedure
performed in the United States in 2015. The ASPS report found that 7.3 million
injections were given in 2015, showing 3% rise from the year prior.
The Not So Glam Side Of
Botox
Although
cosmetic BoNTA has demonstrated strong efficacy and good safety profile, but adverse
events do occur from time to tome. Misplaced injections, unique anatomy of
patients and novice doctors doing the treatment can lead to unwanted effects in
non-target areas. Looking at the literature reviews side effects like eyelid
and brow ptosis and partial lip ptosis have been reported after injection of
BoNTA into the upper face and periocular areas, respectively. Few reported
cases of injection into the pretarsal portion of the orbicularis oculi muscle have
resulted in dry eyes. There have also been reported complications involving
pupillary reactions and light sensitivity in some cases.
Additionally
limitations of using injections include pain, erythema, swelling, bruising,
tenderness, and potential infection from needle use.
The
patient’s medical regimen is in selected cases potentially affected by being
advised to avoid aspirin, nonsteroidal antiinflammatory drugs, and vitamin E
before injection to reduce the risk of bleeding and bruising. Bruising is of
particular concern in the lateral canthus and orbicularis oculi region, where
the blood vessels are superficial and the skin is thin.
Next Step In Evolution
Research
conducted among consumers has shown that many consumers are needle averse and
would prefer a more noninvasive alternative that would provide the same
benefits as BoNTA injections. The survey showed that in US alone 11 million people
are potential target demographic for BoNTA treatments, but less than 10 percent
have actually received treatment. Providing an alternative non-injectable
option to current injections holds the potential to expand the market
considerably.
The
target consumer market can be organized into the following three categories:
1)
Past users of BoNTA injections who would like a less painful, and cheaper
option
2)
Consumers with no past history of injections because of the expense and/or pain
associated with them and
3)
Consumers currently undergoing regular injections who would welcome a more
comfortable way to maintain each treatment
A
safe, targeted alternative in the form of topical BoNTA makes an attractive
option.
Nanoparticle Technology &
BoNTA Cream
Nanotechnology
allows the potential to deliver molecules into the skin, which ordinarily do
not penetrate the superficial corneal layer. This ability to enhance
penetration of active ingredients offers many benefits. In the last decade two
companies, Transdermal Corp., Birmingham, Michigan, and Revance Therapeutics,
Newark, California, have made good progress on topical delivery of BoNTA sharing
their clinical trials.
CosmeTox
Transdermal
Corp. was formed in August 2008, since then it has developed an FDA-approved
topical BoNTA cream based on commercially viable ionic nano-particle technology
(InParT™). This technology consists of micelles (surfactants and protein
solubilizers), coated with lipid molecules that entrap the active component
with no changes in chemical composition - the particles are one to ten
nanometers in size; smaller than skin pores.
This
transdermal noninvasive drug delivery technique preserves the bioactivity of
molecules without denaturing them. The cream (CosmeTox) contains BoNTA and is
intended for the softening of facial rhytides as well as reduction in
hyperhidrotic (excessive sweating) conditions. Active ingredients in the cream
allow for greater toxin stability at room temperature for extended periods of
time.
How Does It Work?
Topical
BoNTA allows for deeper delivery of the active molecules into the skin in order
to encourage the same effect of injected BoNTA — inhibiting the release of Acetylcholine
and blocking neuromuscular transmission. The stabilized toxin cream is applied
topically onto the skin and dosed by the quantity of cream applied. Using
nanospheres and absorption enhancers, the toxin is delivered into the skin
without any known skin damage or systemic toxicity. The cream also behaves in a
similar fashion as an injectable in that when it is applied, it stays local for
targeted delivery.
A study was
conducted in 2008 to test the efficacy of this topical BoNTA cream (CosmeTox)
on facial wrinkles. The study involved 4 to 7 weeks of treatment with 12 weeks
of follow-up evaluation. Within the first two weeks of treatment, the BoNTA
group reported subjective improvements in their appearance, including less
wrinkling, but also noticed a fading of dark circles under their eyes as well
as a hyperpigmentation reduction in treatment areas. The active ingredient
cream was compared to a placebo on 40 female subjects. The active ingredient
cream contained a concentration of 2U/mL BT and the vehicle control contained
no BT. They were assessed by Facial Line Outcomes and Self Perception of Age
questionnaires. The Facial Lines Outcome scores were improved and maintained
for the duration of the study period of almost three months. The Self
Perception of Age was also reduced in the majority of subjects. At Week 4, more
than 85 percent of the BoNTA cream group rated their wrinkles as improved by at
least 75 percent.
RT001
RT001
Botulinum Toxin Type A Topical Gel Revance Therapeutics, Inc., Newark, CA
contains an albumin-free 150-kDa BoNTA and a novel peptide that enables
transcutaneous delivery of the BoNTA. RT001 raised a lot of hopes with
successful Phase 2 trials.
Two
efficacy scales — the Global Assessment of Lateral Canthal Line Severity and
the Patient Severity Assessment — have been used in phase 2 research
to quantify the degree of muscle rest achieved (the primary end point). To be
categorized at the most stringent level of efficacy, it was necessary for
physicians and patients to record a crow’s feet severity reduction of at least
2 points in their respective rating systems.
Investigators
with a 90-patient study
enrolled participants at 3 sites, and randomized them to active treatment or
placebo for a single treatment of RT001. A reduction in severity of 1 point was
demonstrated in 89% of the RT001 group and 28% in the control group
(P < .0001). A reduction of at least 2 points was demonstrated in 44%
of the RT001 group and in 0% of the control group (P < .0001).
Phase
3 Trial – REALISE 1
The Phase 3 trial was a randomized, double-blind, parallel-group, placebo-controlled study to evaluate the safety and efficacy of DaxibotulinumtoxinA Topical Gel (RT001) for the treatment of moderate to severe lateral canthal lines. A total of 450 adult patients were enrolled at seven sites in the United States and were randomized 1:1 to a single treatment of either RT001 or placebo topical gel applied to lateral canthal lines on both sides of the face using Revance’s proprietary applicator.
The Phase 3 trial was a randomized, double-blind, parallel-group, placebo-controlled study to evaluate the safety and efficacy of DaxibotulinumtoxinA Topical Gel (RT001) for the treatment of moderate to severe lateral canthal lines. A total of 450 adult patients were enrolled at seven sites in the United States and were randomized 1:1 to a single treatment of either RT001 or placebo topical gel applied to lateral canthal lines on both sides of the face using Revance’s proprietary applicator.
In
a press release Dan
Browne, President and Chief Executive Officer at Revance announced that, “We
are disappointed with the results of the REALISE 1 trial. The data was unambiguous,
and we do not plan to continue development of RT001 topical for crow’s feet.
Based on these results, we have also decided not to pursue the current clinical
development plan for RT001 in axillary hyperhidrosis. We are grateful to
all the patients and investigators for their participation in the REALISE 1
trial.” As of today the development of tropical botox RT001 has been shelved by
Revance after non satisfactory Phase 3 trial and long acting
DaxibotulinumtoxinA for Injection (RT002) has entered phase 3 trials.”
The Future
Delivery Of Botox Using
Iontophoresis
Iontophoresis
is a drug delivery system that uses a small external electric current to
deliver water-soluble, charged drugs into the skin. A case report
published in the British Journal of Dermatology has shown that iontophoresis
might enhance botox uptake by the sweatglands while treating cases of palmer hyperhidrosis.
Delivery Of Topical Botox Enhanced
by Fractional CO2 Laser:
As
previous studies have demonstrated that topical surface application of BoNT A
has negligible cutaneous bioavailability and is not effective in treating
wrinkles. A new study
was designed to determine the effect of BoNT a solution applied topically on
the skin surface immediately after ablative fractional CO2 laser treatment. There
was a clinically significant greater degree of improvement in wrinkles after
treatment with CO2 laser, on the topically applied BoNT A side. Also, the
difference between the 2 treatment types (laser followed by topical BoNT A vs
laser followed by saline) at 1 week and at 1 month was statistically
significant.
Another
study evaluated
the synergistic efficacy and safety of combined topical application of
Botulinum Toxin Type A (BTX-A) with fractional CO2 laser for facial
rejuvenation. Twenty female subjects were included for this split-face
comparative study. One side of each subject's cheek was treated with fractional
CO2 plus saline solution, and the other side was treated with fractional CO2
laser plus topical application of BTX-A. Patients received one session of
treatment and evaluations were done at baseline, one, four, and twelve weeks
after treatment. BTX-A combined with fractional CO2 laser sides showed higher
physician's global assessment score, subject satisfaction score, roughness,
skin hydration, and skin elasticity compared to that of fractional CO2 plus
saline solution side at 12 weeks after treatment.
Considering
the non chemoimmobilization effects of botox and its role in anti scaring and rejuvenation
it will remain a potential area of research. The newer non-invasive
delivery modes of Botox will be explored further in the future.