The Journey Of Botox — From Injections To Creams

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.

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.