Topical neurotoxin

Published on 26/02/2015 by admin

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Last modified 26/02/2015

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10 Topical neurotoxin

Jacob M. Waugh, Richard G. Glogau

Summary and Key Features

• Injectable BoNT-A has been successfully used across a range of medical disorders including strabismus, blepharospasm, focal dystonia, migraine, spasticity associated with juvenile cerebral palsy and adult stroke as well as various cosmetic treatments such as to temporarily relax hyperfunctional rhytides.

• Alternative methods have been developed due to limitations and disadvantages of injections of BoNTA which includes iontophoresis device-based approaches and topical liposomes and CPP drug delivery systems.

• Topical botulinum toxin delivery through the skin may offer opportunities to treat anatomical areas that are either difficult to manage with injectables or where patients may prefer to avoid injectables, and there may also be useful roles for topical botulinum therapies as adjunctive or extender therapies for the injectable techniques now in use.

Background

Injectable botulinum toxin type A (BoNT-A) has been successfully used across a range of medical disorders including strabismus, blepharospasm, focal dystonias, migraine, spasticity associated with juvenile cerebral palsy and adult stroke, and various cosmetic treatments. Thus, the safety and effectiveness of BoNT-A for treating these conditions have been well established over the past 20 years.

While aesthetic medicine has been inundated with treatments for facial rhytides, BoNT-A is the only Food and Drug Administration (FDA)-approved treatment to temporarily relax hyperfunctional rhytides. Since 1992, botulinum toxin has been used to treat a variety of cosmetic conditions and medical indications. Following the first description of the treatment for glabellar rhytides (‘frown line’ wrinkles) by Carruthers & Carruthers in 1992, botulinum toxin has revolutionized the practice of aesthetic medicine. In 2002, the United States (US) FDA approved the use of Botox^® Cosmetic (botulinum toxin type A purified toxin complex; Allergan, Inc.) for the treatment of moderate-to-severe glabellar rhytides, associated with corrugator and / or procerus muscle activity in adult patients 65 years of age and younger. In 2004, Carruthers et al reported the consensus recommendations that BoNT-A is effective and safe, and patient satisfaction is high. By 2005, Botox^® cosmetic injections were the most common non-invasive physician-administered cosmetic procedure worldwide.

Need for transcutaneous delivery systems

Matarasso & Matarasso reported in 2001 that the paralytic effect of injected BoNT-A can span up to 3 cm from the site of injection and even further when dilute concentrations and large volumes of BoNT-A are used. Limitations of injections of BoNT-A include pain, erythema, swelling, potential infection from needle use, and potential for reduced normal expression in the treated area. The patient’s pre-treatment medical regimen is potentially impacted by being advised to avoid aspirin, non-steroidal anti-inflammatory drugs, and vitamin E prior to injection, to reduce the risk of bleeding and bruising. Bruising is of particular concern in the crow’s feet (also known as lateral canthal lines or LCL), where the blood vessels are superficial and the skin is thin. Because of the disadvantage of requiring injection as the route of administration, alternative methods of drug delivery have been developed that can address some of these concerns.

Conventional transepidermal drug delivery systems can deliver only small molecules. Some examples of smaller molecules that can be delivered through the skin topically include progesterone, scopalomine, certain antibiotics, and nicotine. These are readily delivered in traditional topical preparations, creams, ointments, adhesive patches, etc. These systems range from very inefficient to completely ineffective in delivering biologically active proteins and other macromolecules across the skin barrier. The stratum corneum and upper layers of the epidermis are lipid-rich barriers to entry for most of the larger molecules, which is, after all, the skin’s primary function – to exclude assaults on the inner host by biologically active macromolecules. The flux of most proteins across the skin barrier is essentially zero.

Potential approaches to transcutaneous delivery of BoNT-A

Attempts to increase penetration by manipulation of drug structure have been largely ineffective for most proteins. For example, conjugation of a drug to a carrier can compromise drug activity and permeation enhancers may disrupt biological activity of the protein. At present, delivery of most macromolecules across the skin barrier requires direct injection (e.g. insulin, antibodies, toxins, and growth hormone).

Device-based approaches such as iontophoresis have been explored as well. Iontophoresis utilizes a different mechanism for drug delivery into the skin, but lacks targeting and delivery specificity and remains time dependent. By utilizing a direct current of relatively low amplitude, an active electrode is placed on the drug formulation that is to be driven into the skin by the electrons streaming from the active electrode. The ionic charge imparted to the target molecule allows the molecule to be driven into the skin as the indifferent ions are pulled from the skin by the indifferent electrode to complete the circuit. This process has typically been used to drive small charged molecules across skin. Interestingly, iontophoresis was reported to be successful with botulinum toxin for treating palmar hyperhidrosis although the practice has not become widely adopted since the initial reports (see Kavanagh et al and Solomon). The disadvantages are that the technique is very time and concentration dependent, requires that the patient have the ability to tolerate the sensation of the direct current, and is less effective with delivery of lipophilic molecules.

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