WO2020010391A1

WO2020010391A1 - A method and apparatus for enhanced transdermal, intradermal or transappendageal delivery of retinoids

Info

Publication number: WO2020010391A1
Application number: PCT/AU2019/050718
Authority: WO
Inventors: Jeffrey D Edwards; Matthew MCILDOWIE
Original assignee: International Scientific Pty Ltd
Priority date: 2018-07-13
Filing date: 2019-07-09
Publication date: 2020-01-16

Abstract

A method and a device for enhanced transdermal, intradermal or transappendageal delivery of a retinoid, comprising applying a composition containing a retinoid to a target portion of skin and applying an electromagnetophoretic waveform signal produced by an electromagnetophoretic delivery device, wherein the electromagnetophoretic waveform signal is selected to provide enhanced retinoid delivery.

Description

A METHOD AND APPARATUS FOR ENHANCED TRANSDERMAL, INTRADERMAL OR TRANSAPPENDAGEAL DELIVERY OF RETINOIDS

Technical Field

[0001] The present invention relates to a method and apparatus for the transdermal, intradermal or transappendageal delivery of enhanced or controlled concentrations and/or amounts of a retinoid.

Background Art

[0002] The following discussion of the background art is intended to facilitate an understanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge of the person skilled in the art as at the priority date of the application.

[0003] Retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth. Retinoids have many important functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes.

[0004] Retinoids are used in the treatment of many diverse diseases and are effective in the treatment of a number of dermatological conditions such as inflammatory skin disorders, skin cancers, autoimmune disorders and disorders of increased cell turnover (e.g. psoriasis), photoaging, and skin wrinkles. Common skin conditions treated by retinoids include acne and psoriasis. Isotretinoin is not only considered the only known possible cure of acne in some patients, but was originally a chemotherapy treatment for certain cancers, such as leukemia. Human embryonic stem cells also more readily differentiate into cortical stem cells in the presence of retinoids. Retinoids are known to reduce the risk of head and neck cancers.

[0005] The basic structure of the hydrophobic retinoid molecule consists of a cyclic end group, a polyene side chain and a polar end group. The major source of retinoids from the diet are plant pigments such as carotenes and retinyl esters derived from animal sources. Retinyl esters are hydrolyzed in the intestinal lumen to yield free retinol and the corresponding fatty acid (i.e. palmitate or stearate). After hydrolysis, retinol is taken up by the enterocytes. Retinyl ester hydrolysis requires the presence of bile salts that serve to solubilize the retinyl esters in mixed micelles and to activate the hydrolyzing enzymes.

[0006] Topical delivery of retinoids into or through the skin is commonly employed to treat numerous conditions including inflammatory skin disorders, skin cancers, autoimmune disorders, psoriasis, dermatitis, photoaging, and skin wrinkles. [0007] The delivery of a retinoid into or across the skin must occur in sufficient amounts and/or at sufficient concentrations to allow the retinoid to achieve the intended purpose. Techniques and devices have been developed to assist in the transmission of active compositions or compounds through membranes, such as the skin. For example, International Patent Application No. PCT/AU2010/000782, filed by International Scientific Pty Ltd and entitled“An Apparatus and Method of Treatment Utilizing a Varying Electromagnetic Energisation Profile" (which is incorporated herein by reference) describes an apparatus which is designed to improve the delivery of active substances across a membrane by utilising a varying electromagnetic energisation profile.

[0008] However, the use of delivery systems that have general applicability may result in a sub-optimal efficacy when utilized with certain retinoid compositions on certain specific individuals, patients or subjects and in certain specific environments. Different types of skin, different types of medical and genetic conditions, the nature of the retinoid composition and the ambient environment all have an effect on the efficacy of the delivery system on a given individual, patient or subject. As such, systems which have general applicability across a broad population and environment are typically sub-optimal in their ability to deliver the most efficient and effective dose in specific circumstances.

[0009] When a retinoid or compositions containing them are applied on the skin surface, penetration into and/or through the skin can occur via various routes. They may penetrate either via the stratum corneum (transdermal or intradermal penetration) or via the appendages, which includes via the follicular ducts of the hair follicles and/or via sweat glands (transappendageal penetration).

[0010] A problem with many retinoid compositions is that they are subject to variable degrees of tolerance or effectiveness by a population of users or subjects. For example, certain retinoid compositions typically designed for general use within a broad population of varying skin types may cause a high degree of skin irritation in some members of that population while for others, they may be well tolerated but less effective in producing the desired results due to insufficient penetration into the dermal layer.

[001 1] Subjects in need of transdermal, intradermal or transappendageal delivery of retinoid ingredients also face the problem of varying degrees of effectiveness due to varying degrees of skin penetration, and in many instances there is also a need for the ability to optimise the intensity of delivery of retinoid ingredients. For example, a subject requiring transdermal delivery of a retinoid in order to achieve a desirable treatment benefit may require more intense delivery of the retinoid but with shorter duration of delivery, in order to avoid problems associated with irritation and/or inflammation associated with prolonged exposure of the outer dermal layer to the retinoid. [0012] It is an object of the present invention to at least partially address one or more of the above illustrated problems in the art, or at least to provide an alternative to existing commercial products.

[0013] It is against this background that embodiments of the present invention have been developed.

Summary of Invention

[0014] The inventors have recognised a need to facilitate enhanced delivery of certain retinoid ingredients within retinoid compositions, tailored to the retinoid composition, so that the rate or intensity of the desired effect produced by the retinoid composition is enhanced, thereby improving the efficacy of the retinoid composition and/or reducing or eliminating the skin irritation associated with the topical application of the retinoid composition and/or obviating the need for the user or subject to change to a different retinoid composition in order to achieve the desired outcome.

[0015] In one embodiment, the invention described herein provides a method for enhanced transdermal, intradermal or transappendageal delivery of a retinoid, comprising; a) applying a composition to a target portion of skin, wherein the composition comprises a retinoid and a dermatologically acceptable carrier, excipient or matrix and; b) exposing the composition on the target portion of skin to an electromagnetophoretic waveform signal produced by an electromagnetophoretic delivery device, wherein the electromagnetophoretic waveform signal is selected to provide enhanced retinoid delivery, relative to applying the composition without applying the electromagnetophoretic waveform signal; wherein the electromagnetophoretic waveform signal comprises a waveform pattern (W1 ) and a waveform pattern (W2), and the electromagnetophoretic waveform signal has a Wave Factor of between about 0.05 to about 5.0, about 0.06 to about 4.5, about 0.07 to about 4.0, about 0.08 to about 3.5, about 0.09 to about 3.0 or about 0.1 to about 2.9, preferably about 0.1 to about 2.7, wherein the Wave Factor is derived from the equation;

Wave Factor = (W1 factor) + (W2 factor), wherein;

W1 factor is between about 0.01 to about 3.0, about 0.02 to about 2.9, about 0.03 to about 2.8, about 0.04 to about 2.7, about 0.05 to about 2.6, about 0.06 to about 2.5, about 0.07 to about 2.4, about 0.08 to about 2.3, about 0.09 to about 2.2, about 0.09 to about 2.1 , or about 0.1 to about 2.0, preferably about 0.1 to about 1.9; W2 factor is between about 0.0 to about 2.0, about 0.01 to about 1 .5, about 0.02 to about 1 .4, about 0.03 to about 1 .3, about 0.04 to about 1 .2, about 0.05 to about 1 .1 , or about 0.05 to about 1 .0, preferably between about 0.05 to about 0.9; optionally wherein W2 factor is less than W1 factor.

[0016] In some embodiments of the method of the invention described herein, the retinoid delivery is enhanced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 74% relative to applying the composition without applying the electromagnetophoretic waveform signal.

[0017] In some embodiments of the method of the invention described herein, the retinoid delivery is reduced by at least -10%, -9%, -8%, -7%, -6%, -5%, -4%, -3%, -2% or -1 % relative to applying the composition without applying the electromagnetophoretic waveform signal.

[0018] In some embodiments of the method of the invention described herein, the enhancement of the delivery of the retinoid relative to applying the composition without applying the electromagnetophoretic waveform signal is measured by tape stripping analysis.

[0019] In some embodiments of the method of the invention described herein, the retinoid is present at an amount of about 0.01 % to about 10%, about 0.02% to about 9%, about 0.03% to about 8%, about 0.04% to about 7%, about 0.05% to about 6.5%, about 0.06% to about 6.4%, about 0.07% to about 6.3%, about 0.08% to about 6.2%, about 0.09% to about 6.1 %, about 0.1 % to about 6%, about 0.1 1 % to about 5.9%, about 0.12% to about 5.8%, about 0.13% to about 5.7%, about 0.14% to about 5.6%, about 0.15% to about 5.5%, about 0.16% to about 5.4%, about 0.17% to about 5.3%, about 0.18% to about 5.2%, about 0.19% to about 5.1 %, or about 0.2% to about 5%, preferably at an amount of about 0.1 % to about 5% by weight of the composition.

[0020] In some embodiments of the method of the invention described herein, the electromagnetophoretic waveform signal produces a magnetic flux density of between about 1 mT and about 50mT, about 1 .5 mT and about 48mT, about 2mT and about 46mT, about 2.5mT and about 44mT, about 3mT and about 42mT, about 3.5mT and about 40mT, about 4mT and about 38mT, about 4.2mT and about 36mT, about 4.4mT and about 34mT, about 4.6mT and about 32mT, about 4.8mT and about 31 mT, or about 5mT and about 30mT, preferably of between about 5mT and about 30mT.

[0021 ] In some embodiments of the method of the invention described herein, the waveform pattern W1 has a duty cycle which may vary between about 1 % to about 50%, about 1 .1 % to about 45%, about 1 .2% to about 40%, about 1 .3% to about 35%, about 1 .4% to about 30%, about 1 .5% to about 25%, about 1 .6% to about 20%, about 1 .7% to about 15%, about 1 .8% to about 14%, about 1 .9% to about 13%, about 2% to about 12%, about 2.1 % to about 1 1 .9%, about 2.2% to about 1 1 .88%, or about 2.25% to about 1 1 .88%, preferably between about 1 % to about 20%.

[0022] In some embodiments of the method of the invention described herein, W1 has a duration which may vary between about 1 ms to about 5000 ms, about 10 ms to about 4500 ms, about 20 ms to about 4000 ms, about 30 ms to about 3500 ms, about 40 ms to about 3000 ms, about 50 ms to about 2500 ms, about 60 ms to about 2000 ms, about 70 ms to about 1500 ms, about 80 ms to about 1000 ms, about 90 ms to about 900 ms, about 100 ms to about 850 ms, about 150 ms to about 800 ms, about 200 ms to about 750 ms, about 250 ms to about 650 ms, about 300 ms to about 640 ms, about 350 ms to about 630 ms, about 400 ms to about 620 ms, about 450 ms to about 615 ms, about 500 ms to about 612 ms, about 530 ms to about 609 ms, or about 534 ms to about 606 ms, preferably between about 100 ms to about 1000 ms.

[0023] In some embodiments of the method of the invention described herein, the number of pulses in W1 may vary between about 1 to about 5000, about 2 to about 4500, about 3 to about 4000, about 4 to about 3500, about 5 to about 3000, about 6 to about 2500, about 7 to about 2000, about 8 to about 1500, about 9 to about 1000, about 10 to about 500, about 12 to about 450, about 14 to about 400, about 16 to about 350, about 18 to about 300, about 20 to about 250, about 22 to about 200, about 24 to about 180, about 26 to about 160, about 28 to about 140, or about 30 to about 120, preferably between about 5 to about 500.

[0024] In some embodiments of the method of the invention described herein, the waveform pattern W2 has a duty cycle which may vary between about 1 % to about 50%, about 1 .01 % to about 45%, about 1 .02% to about 40%, about 1 .03% to about 35%, about 1 .04% to about 30%, about 1 .05% to about 25%, about 1 .06% to about 20%, about 1 .07% to about 15%, about 1 .08% to about 14%, about 1 .09% to about 13%, about 1 .09% to about 12%, about 1 .1 % to about 1 1 %, about 1 .2% to about 10%, 1 .22% to about 9%, 1 .24% to about 8%, 1 .26% to about 7%, 1 .28% to about 6.5%, 1 .3% to about 6%, 1 .32% to about 5.8%, 1 .33% to about 5.7%, 1 .34% to about 5.6%, 1 .35% to about 5.58%, 1 .36% to about 5.57%, 1 .365% to about 5.56%, or about 1 .37% to about 5.55%, preferably between about 1 % to about 20%.

[0025] In some embodiments of the method of the invention described herein, W2 has a duration which may vary between about 1 ms to about 5000 ms, about 100 ms to about 4500 ms, about 200 ms to about 4000 ms, about 300 ms to about 3500 ms, about 400 ms to about 3000 ms, about 500 ms to about 2900 ms, about 600 ms to about 2850 ms, about 700 ms to about 2800 ms, about 800 ms to about 2750 ms, about 900 ms to about 2700 ms, about 1000 ms to about 2650 ms, about 1 100 ms to about 2600 ms, about 1200 ms to about 2550 ms, about 1300 ms to about 2500 ms, about 1400 ms to about 2450 ms, about 1500 ms to about 2400 ms, about 1600 ms to about 2350 ms, about 1700 ms to about 2300 ms, about 1800 ms to about 2250 ms, about 1900 ms to about 2200 ms, about 1950 ms to about 2150 ms, about 2000 ms to about 2100 ms, or about 2102 ms to about 2074 ms, preferably between about 100 ms to about 5000 ms.

[0026] In some embodiments of the method of the invention described herein, the number of pulses in W2 may vary between about 1 to about 5000, about 2 to about 4500, about 4 to about 4000, about 6 to about 3500, about 8 to about 3000, about 10 to about 2500, about 15 to about 2000, about 20 to about 1500, about 25 to about 1000, about 30 to about 500, about 35 to about 450, about 40 to about 400, about 45 to about 350, about 50 to about 300, about 55 to about 295, about 60 to about 292, about 65 to about 290, about 70 to about 289, or about 72 to about 288, preferably between about 5 to about 500.

[0027] In some embodiments of the method of the invention described herein :

• the waveform pattern W1 has a duty cycle which may vary between about 1 % to about 50%, about 1 .1 % to about 45%, about 1 .2% to about 40%, about 1 .3% to about 35%, about 1 .4% to about 30%, about 1 .5% to about 25%, about 1 .6% to about 20%, about 1 .7% to about 15%, about 1 .8% to about 14%, about 1 .9% to about 13%, about 2% to about 12%, about 2.1 % to about 1 1.9%, about 2.2% to about 1 1 .88%, or about 2.25% to about 1 1 .88%, preferably between about 1% to about 20%; and/or

• the waveform pattern W1 has a duration which may vary between about 1 ms to about 5000 ms, about 10 ms to about 4500 ms, about 20 ms to about 4000 ms, about 30 ms to about 3500 ms, about 40 ms to about 3000 ms, about 50 ms to about 2500 ms, about 60 ms to about 2000 ms, about 70 ms to about 1500 ms, about 80 ms to about 1000 ms, about 90 ms to about 900 ms, about 100 ms to about 850 ms, about 150 ms to about 800 ms, about 200 ms to about 750 ms, about 250 ms to about 650 ms, about 300 ms to about 640 ms, about 350 ms to about 630 ms, about 400 ms to about 620 ms, about 450 ms to about 615 ms, about 500 ms to about 612 ms, about 530 ms to about 609 ms, or about 534 ms to about 606 ms, preferably between about 100 ms to about 1000 ms; and/or

• the number of pulses in W1 may vary between about 1 to about 5000, about 2 to about 4500, about 3 to about 4000, about 4 to about 3500, about 5 to about 3000, about 6 to about 2500, about 7 to about 2000, about 8 to about 1500, about 9 to about 1000, about 10 to about 500, about 12 to about 450, about 14 to about 400, about 16 to about 350, about 18 to about 300, about 20 to about 250, about 22 to about 200, about 24 to about 180, about 26 to about 160, about 28 to about 140, or about 30 to about 120, preferably between about 5 to about 500; and/or

• the waveform pattern W1 produces a magnetic flux density of between about 1 mT and about 50mT, about 2mT and about 45mT, about 3mT and about 40mT, or about 4mT and about 35mT, preferably of between about 5mT and about 30mT ; and/or • the waveform pattern W2 has a duty cycle which may vary between about 1 % to about 50%, about 1 .01 % to about 45%, about 1 .02% to about 40%, about 1 .03% to about 35%, about 1 .04% to about 30%, about 1 .05% to about 25%, about 1 .06% to about 20%, about 1 .07% to about 15%, about 1 .08% to about 14%, about 1 .09% to about 13%, about 1 .09% to about 12%, about 1 .1 % to about 1 1 %, about 1 .2% to about 10%, 1 .22% to about 9%, 1 .24% to about 8%, 1 .26% to about 7%, 1 .28% to about 6.5%, 1 .3% to about 6%, 1 .32% to about 5.8%, 1 .33% to about 5.7%, 1 .34% to about 5.6%, 1 .35% to about 5.58%, 1 .36% to about 5.57%, 1 .365% to about 5.56%, or about 1 .37% to about 5.55%, preferably between about 1 % to about 20%; and/or

• the waveform pattern W2 has a duration which may vary between about 1 ms to about 5000 ms, about 100 ms to about 4500 ms, about 200 ms to about 4000 ms, about 300 ms to about 3500 ms, about 400 ms to about 3000 ms, about 500 ms to about 2900 ms, about 600 ms to about 2850 ms, about 700 ms to about 2800 ms, about 800 ms to about 2750 ms, about 900 ms to about 2700 ms, about 1000 ms to about 2650 ms, about 1 100 ms to about 2600 ms, about 1200 ms to about 2550 ms, about 1300 ms to about 2500 ms, about 1400 ms to about 2450 ms, about 1500 ms to about 2400 ms, about 1600 ms to about 2350 ms, about 1700 ms to about 2300 ms, about 1800 ms to about 2250 ms, about 1900 ms to about 2200 ms, about 1950 ms to about 2150 ms, about 2000 ms to about 2100 ms, or about 2102 ms to about 2074 ms, preferably between about 100 ms to about 5000 ms; and/or

• the number of pulses in W2 may vary between about 1 to about 5000, about 2 to about 4500, about 4 to about 4000, about 6 to about 3500, about 8 to about 3000, about 10 to about 2500, about 15 to about 2000, about 20 to about 1500, about 25 to about 1000, about 30 to about 500, about 35 to about 450, about 40 to about 400, about 45 to about 350, about 50 to about 300, about 55 to about 295, about 60 to about 292, about 65 to about 290, about 70 to about 289, or about 72 to about 288, preferably between about 5 to about 500; and/or

• the waveform pattern W2 produces a magnetic flux density of between about 1 mT and about 50mT, about 2mT and about 45mT, about 3mT and about 40mT, or about 4mT and about 35mT, preferably of between about 5mT and about 30mT.

[0028] In one embodiment, the invention described herein provides an electromagnetophoretic delivery device adapted to perform the method of enhanced retinoid delivery of the invention, comprising a power supply, a microcontroller, and an electromagnetophoretic waveform signal generator, wherein the microcontroller causes voltage from the power supply to be applied, thereby sending a plurality of energisation signals to an electromagnetophoretic waveform generating component such that an electromagnetophoretic waveform signal is generated, wherein the electromagnetophoretic waveform signal is selected to provide the enhanced transdermal, intradermal or transappendageal delivery of a retinoid to a target portion of skin. [0029] In some embodiments, each energisation signal of the electromagnetophoretic delivery device of the invention generally defines a square wave.

[0030] In some embodiments, the plurality of energisation signals of the electromagnetophoretic delivery device of the invention have a frequency of between about 0.1 Hz to about 2000 Hz, about 0.1 Hz to about 1900 Hz, about 0.1 Hz to about 1800 Hz, about 0.1 Hz to about 1700 Hz, or about 0.1 Hz to about 1600 Hz, preferably a frequency of between about 0.1 Hz to about 1500 Hz.

[0031] In one embodiment, the invention described herein provides a composition for use in the method of enhanced retinoid delivery of the invention, comprising a retinoid, and one or more dermatologically acceptable carriers, excipients or matrices.

[0032] In some embodiments, the retinoid of the composition of the invention is selected from retinol, retinal, retinoic acid, beta-carotene, retinyl palmitate, retinyl propionate, retinyl acetate, retinyl linoleate, retinol aldehydes, retinyl esters, synthetic retinoids, retinoid derivatives, tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, adapalene, bexarotene, tazarotene, including salts isomers, diastereomers or enantiomers of any of the preceding, or a combination of any of these.

[0033] In some embodiments, the composition of the invention comprises an additional active ingredient.

[0034] In one embodiment, the invention described herein provides a kit comprising the electromagnetophoretic delivery device of the invention and the composition of the invention, for use in the method of enhanced retinoid delivery of the invention.

Brief Description of the Drawings

[0035] Further features of the present invention are more fully described in the following description of several non-limiting embodiments thereof. This description is included solely for the purposes of exemplifying the present invention. It should not be understood as a restriction on the broad summary, disclosure or description of the invention as set out above. The description will be made with reference to the accompanying drawings in which:

Figure 1 is a generalised diagram of the electromagnetophoretic waveform signal which enables the enhanced transdermal, intradermal or transappendageal delivery of a retinoid according to an embodiment of the invention. Base parameters of waveform pattern W1 and waveform pattern W2 and their sub variables of number of pulses, duration and duty cycles are used to calculate the Wave Factor Parameter utilised by the device and method of the invention.

Figure 2 is a plot of the relationship or correlation between the Wave Factor Parameter derived from a test spectrum of the applied electromagnetophoretic waveform signal and the enhancement of delivery of retinoid, from a standard cream formulation containing 0.1% Retinyl Propionate.

Figure 3 is a plot of the relationship or correlation between the W1 factor Parameter derived from a test spectrum of the applied electromagnetophoretic waveform signal and the enhancement of delivery of retinoid, from a standard cream formulation containing 0.1% Retinyl Propionate.

Figure 4 is a Functional Block Diagram of an STM Engine Microprocessor Implementation for the device and method of the invention.

Figure 5 is an Circuit Schematic of an Implementation for the device and method of the invention using an STM8S003F3P6 Integrated Circuit.

Description of Embodiments

General Overview

[0036] The present invention relates generally to a method and apparatus for the enhanced transdermal, intradermal or transappendageal delivery of a retinoid.

[0037] In more detail, one aspect of the embodiments described herein provides a method for enhanced delivery of the desired level of effect of a retinoid ingredient or composition, such as, for example; the desired level of depth, concentration or intensity of delivery of a retinoid ingredient or composition in general.

[0038] In general terms, in the absence of any other influences, retinoid ingredient molecules partition from a retinoid formulation or composition and diffuse into the skin and through the various layers and/or appendageal routes due to random Brownian motion and concentration gradients. Molecules in fluids (at room temperature) move at approximately 590m/s, colliding with each other and as a result of this motion, and the laws of probability and progress of time, randomly drift and collide until equalization of concentrations of ingredient molecules between the formulation and the stratum corneum of the skin occur.

[0039] All molecules are influenced to a greater or lesser extent by magnetic fields. Paramagnetic molecules with large numbers of unpaired electrons are attracted by magnetic fields and diamagnetic molecules are repelled by magnetic fields because the arrangement and number of paired electrons in such molecules induces a magnetic field within the molecules that is of the same polarity as the field to which they are exposed.

[0040] In general, retinoid ingredient molecules which are organic molecules, exhibit diamagnetic properties and as such they are repelled by a magnetic field. [0041] The retinoid compositions herein include a safe and effective amount of a retinoid. As used herein, "retinoid" includes all natural and/or synthetic analogues of Vitamin A or retinol-like compounds which possess the biological activity of Vitamin A in the skin, as well as the geometric isomers and stereoisomers of these compounds. For example, the retinoid may be a retinol ester (e.g., C2 - C22 alkyl esters of retinol, including retinyl palmitate, retinyl acetate, and retinyl propionate), retinol aldehydes, retinal, beta-carotene, and/or retinoic acid (including all- trans retinoic acid and/or 13-cis-retinoic acid). A particularly suitable example of a retinoid for use in the present composition is Retinyl Propionate (“RP”). These compounds are well known in the art and are commercially available from a number of sources, e.g., Sigma Chemical Company (St. Louis, MO), Boerhinger Mannheim (Indianapolis, IN), BASF (Mt. Olive, NJ), and Roche (Basel, Switzerland). Other suitable retinoids are tocopheryl-retinoate [tocopherol ester of retinoic acid (trans- or cis-), adapalene {6-[3-(1 -adamantyl)-4-methoxyphenyl]-2-naphthoic acid}, and tazarotene (ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]-nicotinate). The retinoid may be included as a pure or substantially pure material, or as an extract obtained by suitable physical and/or chemical isolation from natural (e.g., plant) sources.

[0042] The inventors of the present invention have discovered that delivery of a retinoid can be advantageously enhanced by a specifically tuned electromagnetophoretic waveform signal that is tuned to the particular retinoid to be delivered, and induces molecular activation of retinoid ingredient molecules at an atomic level. Even when such molecules are associated or bound by intermolecular interactions with matrix/excipient or other ingredients, they are susceptible to electromagnetic influences and may be influenced by diamagnetic repulsion forces rather than merely being subject to diffusion or Brownian motion.

[0043] Exposing such molecules to a magnetic field induces a tendency for organized alignment in the molecules, with the kinetic energy component of the molecular moment being converted into diamagnetic repulsion in a direction away from the magnetic field source. In a skin interface environment, this can either be used to direct the passage of substances into or through the dermal membrane or can be used to enhance transappendageal pathways through which substance molecules pass by altering their relationship with loosely or tightly bound water, or with matrix/excipient components of the retinoid composition in use.

[0044] The inventors of the present invention have discovered that by exposing a retinoid composition in-situ at the skin interface, to a specifically selected electromagnetophoretic waveform signal that is tuned to exert a diamagnetic force upon a retinoid ingredient within the retinoid composition, that the dosage, rate or intensity of treatment by the retinoid composition may be enhanced or increased.

[0045] The inventors of the present invention have also discovered that by exposing a retinoid composition in-situ at the skin interface, to a specifically selected electromagnetophoretic waveform signal that is tuned to exert a diamagnetic force upon an inactive excipient or matrix ingredient within the retinoid composition, the dosage, rate or intensity of treatment by the retinoid composition may be decreased or reduced.

[0046] The inventors of the present invention have also discovered that for a given retinoid composition there is a spectrum or continuum of electromagnetophoretic waveform signals that may be programmed into the electromagnetophoretic device of the invention, thereby enabling optimisation, control or modulation of the dosage, rate or intensity of treatment, and/or the ability to reduce or increase the dosage, rate or intensity of treatment by the retinoid composition, within a dynamic range.

[0047] Advantages associated with such enhanced retinoid ingredient delivery include, without limitation:

• The ability to achieve the optimal desired outcome from a retinoid ingredient or composition to suit the ethnicity, skin type, pore structure, geographic location, lifestyle, climate or appearance of the user or subject.

• The ability to achieve the optimal desired outcome from a retinoid ingredient or composition, such as, for example and without limitation; the desired level of depth, concentration or intensity of delivery of a retinoid ingredient or composition in general.

• The concomitant advantage of the user or subject having at their disposal a dynamic range of pre-programmed treatments from a retinoid ingredient or composition, thereby enabling the optional ability to speed up or intensify (or reduce or decrease) a particular retinoid treatment to suit the particular needs and circumstances of the user or subject at the time of treatment.

• The concomitant advantage of the user or subject having at their disposal the ability to avoid problems of skin irritation and/or inflammation via the ability to start initially with a low intensity retinoid treatment and gradually over a period of time (for example, over a period of days or of weeks) ramp up the intensity of the retinoid treatment as the user, or subject acclimatizes, adjusts, builds resistance to or becomes less sensitive to the particular retinoid treatment.

[0048] In the context of the broader invention described herein, the retinoid ingredient delivery device used as an illustrative example is a novel implementation of the transdermal delivery device described in more detail in International Patent Application PCT/AU2010/000782. It will be understood, however, that the broader invention described herein is applicable to and finds use with any type or form of electromagnetophoretic ingredient delivery device. [0049] An additional example of a powered means for driving an electromagnetophoretic retinoid ingredient delivery device, is a novel implementation of the electromagnetophoresis device of International Patent Application PCT/AU2004/001599 which also may be used for programming penetration of a retinoid into or through the skin. Other examples of such powered devices include US Patent Application 2002/0147424.

[0050] The electromagnetophoretic retinoid ingredient delivery device of the invention may include one or more actuators (i.e., switches, buttons, sensors, or the like), which enable a user or subject to activate or deactivate the retinoid ingredient delivery device and/or one or more features of the retinoid ingredient delivery device (e.g., turn the retinoid ingredient delivery device on or off and/or select a pre-programmed electromagnetophoretic waveform setting or software application).

[0051] When activated, the retinoid ingredient delivery device can generate an electromagnetophoretic waveform, for example, by sending an energisation signal to an electromagnetophoretic waveform generating component such as a coil or a resistor-inductor circuit or the like. The energisation signal may be in the form of a direct current (DC) signal, an alternating current (AC) signal, and/or a modified AC or DC signal. The duration, amplitude, number of electrical pulses, and/or frequency of the energisation signal may be controlled by control circuitry in electronic communication with the electromagnetophoretic waveform generating component.

[0052] The control circuitry may include a programmable microcontroller in electronic communication with a solid state switching device, which can control current flow to the electromagnetophoretic waveform generating device. The microcontroller, when present, may be programmed to change one or more characteristics of the electromagnetophoretic waveform, which can, in turn, alter the depth of penetration of a particular retinoid ingredient into a target portion of skin. In some instances, the microcontroller can be manually programmed by a user and/or practitioner and/or pre-programmed by a manufacturer to alter the depth of penetration of a particular retinoid ingredient over the course of a treatment period. In some instances, the electromagnetophoretic waveform can be configured to enhance delivery of one or more other compounds or ingredients according to a patient, subject or user’s requirements.

[0053] In one embodiment, the means for producing an electromagnetophoretic waveform signal includes a capacitively coupled plate or coil. The means for producing an electromagnetophoretic waveform signal may further include a solid state switching device which may be a transistor such as a bipolar transistor connected in series with the coil.

[0054] In some embodiments, the energisation signal is provided as a plurality of electrical signal pulses that generally define a rectangular pulse or square wave having a frequency of between about 0.1 Hz to about 2000 Hz, about 0.1 Hz to about 1900 Hz, about 0.1 Hz to about 1800 Hz, about 0.1 Hz to about 1700 Hz, about 0.1 Hz to about 1600 Hz, or about 0.1 Hz to about 1550 Hz, preferably a frequency of between about 0.1 Hz and about 1500 Hz. The rectangular pulse or square wave shape may be provided by cycling a DC power supply on and off and/or using a switch (e.g., a solid state switching device such as a transistor) to apply and remove voltage to the waveform generating device. The duration of each electrical pulse in the energisation signal is selected to provide a desired duty cycle for the resulting waveform. For example, in some embodiments, the electrical pulse duration may be between about 1 ps and about 100 ms, about 10 ps and about 50 ms, about 50 ps and about 10 ms, or even between about 100 ps and about 1 ms. The amplitude, duration, and/or frequency properties of the energisation signal can be varied individually or in combination to provide the desired electromagnetophoretic waveform. While this example describes the energisation signal in the form of a square wave, it is to be appreciated that other wave shapes may also be selected, as desired. For example, an AC or bipolar DC energisation signal could be used to provide pulses of sinusoidal configuration. It will also be appreciated by the skilled addressee that the exact shape of the wave may vary depending on the properties of the waveform generating device employed, such as inductor time constant or other physical limitations of the device.

[0055] In some instances, the electromagnetophoretic waveform includes two or more discrete waveform patterns, each comprising one or more energisation signal packets. Each energisation signal packet comprises active portions defined as“on time”, which correspond to the active portions of the electrical signal pulse used to generate the energisation signal packet (i.e., when voltage is applied to the electromagnetophoretic waveform generating device), and inactive portions defined as“off time”, which correspond to the inactive portions of the electrical signal pulse (i.e., when voltage is removed from the electromagnetophoretic waveform generating device). The discrete waveform patterns are configured to provide a retinoid ingredient delivery enhancement benefit, individually and/or cooperatively.

[0056] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises a discrete waveform pattern defined as“W1”.

[0057] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises a discrete waveform pattern defined as“W2”.

[0058] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises a waveform pattern W1 , and a waveform pattern W2.

[0059] In some embodiments of the invention, the electromagnetophoretic waveform pattern W1 represents a charging phase, wherein a target portion of skin is charged with the retinoid composition to be delivered. [0060] In some embodiments of the invention, the electromagnetophoretic waveform pattern W2 represents a maintenance phase, wherein a target portion of skin is maintained with the retinoid composition to be delivered.

[0061] In one embodiment, the electromagnetophoretic waveform signal of the invention produces a magnetic flux density of between about 1 mT and about 50mT, about 2mT and about 45mT, about 3mT and about 40mT, or about 4mT and about 35mT, preferably of between about 5mT and about 30mT.

[0062] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises waveform pattern W1 , wherein the magnetic flux density of waveform pattern W1 produces a magnetic flux density of between about 1 mT and about 50mT, about 2mT and about 45mT, about 3mT and about 40mT, or about 4mT and about 35mT, preferably of between about 5mT and about 30mT.

[0063] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises waveform pattern W2, wherein the magnetic flux density of waveform pattern W2 produces a magnetic flux density of between about 1 mT and about 50mT, about 2mT and about 45mT, about 3mT and about 40mT, or about 4mT and about 35mT, preferably of between about 5mT and about 30mT.

[0064] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises a waveform pattern W1 , and a waveform pattern W2, wherein the magnetic flux density of waveform pattern W1 is greater than the magnetic flux density of waveform pattern W2.

[0065] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises a waveform pattern W1 , and a waveform pattern W2, wherein the most of the magnetic flux density of the electromagnetophoretic waveform signal resides in waveform pattern W1.

[0066] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises a waveform pattern W1 , and a waveform pattern W2, wherein the magnetic flux density of waveform pattern W1 is of about the same magnitude as the magnetic flux density of waveform pattern W2.

[0067] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises a waveform pattern W1 , and a waveform pattern W2, wherein the magnetic flux density of waveform pattern W1 is less than the magnetic flux density of waveform pattern W2. [0068] In some embodiments of the invention, the electromagnetophoretic waveform signal of the invention comprises a waveform pattern W1 , and a waveform pattern W2, wherein the most of the magnetic flux density of the electromagnetophoretic waveform signal resides in waveform pattern W2.

[0069] In one embodiment, the apparatus includes a control means arranged to produce an energisation signal useable to control switching of the solid state switching device, the energisation signal including a repeating energisation signal packet, each energisation signal packet including a plurality of energisation signal pulses of generally rectangular or square wave configuration.

[0070] The control means may comprise a microcontroller which may be programmed with predetermined factory settings. The microcontroller may be programmed such that retinoid ingredient delivery is effected at one or more specific times, is increased for a specific period of time, and so on.

[0071] In one embodiment, the energisation of each electromagnetic pulse within the electromagnetophoretic waveform signal is at a frequency of between 0.1 Hz and 2000 Hz, 0.1 Hz and 1900 Hz, 0.1 Hz and 1800 Hz, 0.1 Hz and 1700 Hz, 0.1 Hz and 1600 Hz, 0.1 Hz and 1550 Hz, more particularly between 0.1 Hz and 1500 Hz.

[0072] In one embodiment, the retinoid ingredient or composition is disposed on a surface of the apparatus.

[0073] In the present invention, the application of selected electromagnetophoretic waveform signals to retinoids results in directions of movement of those retinoids independent of other ingredients in the compositions within which they reside, thereby enhancing the delivery of the retinoids.

[0074] In one embodiment, the selected electromagnetophoretic waveform signal is chosen to effect enhanced delivery of active components or ingredients of retinoid compositions, thereby increasing the intensity of the resultant retinoid treatment.

[0075] In one embodiment, the selected electromagnetophoretic waveform signal is chosen to effect enhanced delivery of optional or additional components or ingredients of retinoid compositions (such as matrix/excipient components or ingredients), thereby reducing the intensity of the resultant retinoid treatment.

[0076] Further features of the present invention are more fully described in the following non limiting Examples. This description is included solely for the purposes of exemplifying the present invention. It should not be understood as a restriction on the broad description of the invention as set out above. Non-limiting Examples of the Invention

[0077] With reference to Figure 1 ; the variable electromagnetophoretic waveform signal which enables the enhanced transdermal, intradermal or transappendageal delivery of a retinoid according to an embodiment of the invention comprises a waveform pattern (W1 ) and a waveform pattern (W2).

[0078] Each waveform pattern of the electromagnetophoretic waveform signal is defined by certain base parameters which are listed and defined below:

• W1 % duty = Duty cycle of waveform 1

= Sum of“on time” for W1 pulses / W1 Duration ^* 100

• W1 Duration = Duration of waveform pattern 1 in milliseconds

• W2 % duty = Duty cycle of waveform 2

= Sum of“on time” for W2 pulses / W2 Duration ^* 100

• W2 Duration = Duration of waveform pattern 2 in milliseconds

[0079] From the above base parameters, the following further parameters are derived, which are then used to calculate the Wave Factor Parameter:

• W1 pulse x duty = (No. of pulses in W1 ) x (W1 % duty)

• W2 pulse x duty = (No. of pulses in W2) x (W2 % duty)

• W1 factor = (W1 pulse x duty) / W1 Duration

• W2 factor = (W2 pulse x duty) / W2 Duration

• Wave Factor = (W1 factor) + (W2 factor)

[0080] The calculated Wave Factor Parameter is then plotted against skin penetration or delivery enhancement data to define the relationship or correlation between the applied electromagnetophoretic waveform signal and skin penetration or delivery enhancement of the retinoid ingredient being tested, as depicted for example in Figure 2.

[0081] It is also possible to plot the derived W1 factor parameter against skin penetration or delivery enhancement data to define the relationship or correlation between the applied electromagnetophoretic waveform signal and skin penetration or delivery enhancement of the retinoid ingredient being tested, as depicted for example in Figure 3.

[0082] Utilising this data, the delivery of a specific retinoid may be enhanced to provide a desired dosage, quality, rate, depth, intensity or concentration of the retinoid ingredient to the user or subject. This relationship or correlation is unique for each retinoid ingredient and may be obtained by following the general experimental principles described in this specification.

[0083] Delivery of selected electromagnetophoretic waveform signals according to the present invention may be achieved according to one non-limiting embodiment, by a device as depicted in functional block diagram form in Figure 4.

[0084] Referring to Figure 4, the device includes the following I/O ports:

• Coil (output),

• beeper (output),

• vibration motor(output)

• red led (output)

• 3x green led (output)

• switch (input)

• programming

[0085] The unit depicted in functional block diagram form in Figure 4 is powered by li-polymer battery that is charged via USB (mini USB plug).

[0086] A recharge circuit utilising a Microchip MCP73832T-2ATI/OT (RS 738-6626) ensures correct charging of the battery.

[0087] A surface mount side emitting LED is used to indicate battery charging status. The board may also have through-hole pads in parallel to allow a 3mm leaded LED to be fitted if required.

[0088] A side activated push button switch is used to start the device from halt/sleep mode. Since this unit may be used in various products/formats, it includes pads in parallel to the switch, to mount a top activated push button switch on the front of the board or on the back of the board.

[0089] Solder pads for battery, motor and coil are plated through hole. The pads for the battery are in the shape of a“+” and a to easily identify the pads. There is also another battery minus connection pad at the other end of the board, allowing for batteries that have leads that are at opposite ends or battery packs that have leads from only one end.

[0090] Four indicator LEDs are top emitting surface mount (3 green and 1 red). Optionally the pad that connects the LED to the port pin may also have a plated through hole pad to allow the use of flying leads if required. [0091] Delivery of selected electromagnetophoretic waveform signals according to the present invention may be achieved according to a further non-limiting embodiment, by a device depicted in schematic circuit diagram form in Figure 5, which represents an Implementation for the device and method of the invention using an STM8S003F3P6 Integrated Circuit.

[0092] Utilising such an electromagnetophoretic device a spectrum or continuum of varying electromagnetophoretic waveform signals may be applied to a test subject, in order to correlate the Wave Factor Parameter of the present invention to enhancement of delivery of particular a retinoid.

[0093] Various test points along the spectrum or continuum of potential electromagnetophoretic waveform signals capable of being produced using the electromagnetophoretic device of the invention were chosen for the purposes of providing a consistent test method for correlating the degree of delivery enhancement of a retinoid composition, as shown in Table 1 :

Table 1 - Test spectrum of applied electromagnetophoretic waveform signals and corresponding calculated Wave Factor Parameters (Sum of“on time” and Duration measured in milliseconds):

[0094] The skilled addressee will of course understand and appreciate that a test spectrum of applied electromagnetophoretic waveform signals and corresponding calculated Wave Factor Parameters differing from the one described above in Table 1 may be employed and applied to testing a particular composition, programmed within the practical limitations of the implementation of the particular electromagnetophoretic device being used.

[0095] Utilising the test spectrum of electromagnetophoretic waveform signals represented by the above selected test points from the spectrum of calculated Wave Factor Parameters in Table 1 , a retinoid composition was tested according to the standard test method described herein:

[0096] The subject's volar forearm or upper arm was delineated into rectangular regions (2.2 x 5 cm) which were designated“Passive” (control) or“Wavefactor X.” An aliquot of the retinoid composition was applied to the passive and treatment regions. The Wavefactor X treatment regions were rubbed into the skin whilst applying the appropriate treatment with the corresponding Wave Factor electromagnetophoretic waveform signal using the device of the invention. The passive application was rubbed in using a finger. In each instance, the“Passive” or control experiment represents an enhancement of 1 (Figures 2 & 3).

[0097] For measuring the degree of enhancement of Retinoid delivery (Figures 2 & 3) due to application of the electromagnetophoretic waveform signal using the device of an embodiment of the invention, after an application period of 30 seconds, tape stripping analysis was performed using the procedure of Lademann et al (J. Lademann, U. Jacobi, C. Surber, H.-J. Weigmann, J. W. Fluhr. The tape stripping procedure— evaluation of some critical parameters. European Journal of Pharmaceutics and Biopharmaceutics 72 (2009) 317-323), the contents of which are incorporated herein in their entirety.

Test composition:

Figures 2 & 3: 0.1 % Retinyl Propionate in standard matrix formulation.

Standard matrix formulation contained the following matrix or excipient ingredients;

Water 70-90%

Caprylic Capric triglyceride 3-5%

Glycerin 1 -5%

Cetearyl alcohol 1 -3%

Cetearyl glucoside 1 -3%

Phenostat 3 0.5-2%

Sodium polyacrylate starch 0.1 -1% Table 2 - Test results

[0098] The above results are plotted in Figures 2 & 3 and provide an effective dynamic range for the delivery of a retinoid that may be used to select for or pre-program a desired outcome via the device of the invention.

[0099] The results demonstrate that a variable degree of enhancement of delivery of a retinoid is enabled by varying the wave factor delivered by the device of the invention.

[00100] The results show the variation from a 10% reduction in retinyl propionate delivery (wave factor 2.62) to a 74% enhancement of retinyl propionate delivery (wave factor 1 .37), demonstrating the ability of the electromagnetophoretic device of the invention to exert a preferential diamagnetic repulsion force upon optional or additional matrix or excipient ingredients and thereby reduce the intensity of the treatment at certain wave factors.

[00101 ] This is a surprising and advantageous effect of the invention as it enables delivery of retinoids at low concentration or intensity initially, in order to avoid undue irritation or inflammation, and after one or more treatments and/or a period of time in which the user or subject acclimatises and adjusts to the composition being used, the delivery of retinoids may be ramped up in terms of the concentration or intensity of treatment by varying the wave factor applied across the dynamic range available.

[00102] It will be understood that the above described examples are non-limiting and that the general methods for testing particular retinoid compositions with an embodiment of the device of the invention to produce a correlation between Wave Factor Parameter and degree of delivery of a retinoid ingredient selected represent a principle of general application that may be applied to any retinoid ingredient or composition, in order to enable the user or subject to select a particular quality of treatment, and including focusing the electromagnetophoretic delivery enhancement on optional or additional matrix or excipient ingredients, in order to reduce the intensity dosage or concentration of treatment provided by a particular retinoid composition. Definitions

[00103] As used herein,“electromagnetophoretic” and variations thereof refer to movement of a material, compound or ingredient in response to an electromagnetic field.

[00104] As used herein, the term“enhanced” as it pertains to delivery of a retinoid does not mean the“best” or“most effective” delivery of that retinoid in the direct and literal sense, devoid of any further context. Rather,“enhanced” refers to improved or more effective delivery, taken in the context of the problems associated with the delivery of the retinoid being delivered. For example, certain retinoid ingredients associated with irritation, allergies or inflammation may benefit from one or more treatments involving decreased intensities, rates and/or concentrations of delivery to allow the subject, a period of acclimation before initiating further treatments of increased intensity of delivery of the retinoid. Considered in this context, a reduction in the delivery of such active ingredients falls within the scope of“enhanced” delivery as used herein.

[00105] “Enhanced delivery” refers to controlling the penetration of a retinoid or other skin care composition ingredient into skin using an electromagnetic waveform. Enhanced delivery can refer to increasing penetration of a retinoid into skin or inhibiting penetration of the retinoid.

[00106] As used herein,“Skin” means the outermost protective covering of mammals that is composed of cells such as keratinocytes, fibroblasts and melanocytes. Skin includes an outer epidermal layer and an underlying dermal layer. Skin may also include hair and nails as well as other types of cells commonly associated with skin, such as, for example, myocytes, Merkel cells, Langerhans cells, macrophages, stem cells, sebocytes, nerve cells and adipocytes. Skin includes mucosal surfaces. Skin includes the skin of the scalp.

[00107] As used herein an "active ingredient" is directed to an Active Pharmaceutical Ingredient (API), a nutraceutical, a cosmeceutical or any other substance desired to be applied to the skin for the purpose of obtaining a beneficial effect. The preferred active ingredient to be delivered is a retinoid. However, other active ingredients can also be delivered in the compositions of the present invention. For example, they may be ions, phytochemicals, enzymes, antioxidants, herbs, spices, natural or semi- natural or refined plant extracts, oils, essential oils, vitamins, nutrients, minerals, macromolecules, DNA fragments, genes, proteins, amino acid sequences or any other substances desired to be applied to the skin for the purpose of obtaining a beneficial effect. More preferably, the substance is a product that is well tried and tested for mildness, efficacy, biodegradability, low toxicity, cleansing ability, emulsification, moisturisation, sun or UV screening effectiveness, toning, colouring or whitening effectiveness, skin appearance and feel, smell (fragrance) or lubrication.

[00108] As used herein a “composition” is directed to a composition containing an active ingredient, such compositions including but not being limited to medicines, pharmaceuticals, nutraceuticals, cosmeceuticals, colouring agents including coloured cosmetics, foundations, primers, concealers, contouring agents, blemish balms, pigments, highlighting agents, bronzing agents, fillers, setting agents, fixing agents, boosting agents, staining agents, exfoliating agents, dermabrasives, whitening agents, tanning agents, plumping agents, anti-inflammatory agents, anti-cancer agents, anti-autoimmune agents, dermatological agents, anti-aging agents, anti wrinkle agents, moisturisers, emollients, rehydrating agents, skin nourish agents, humectants, sloughing agents, pore treatment agents, detergents, cleaners, cleansers, bleaches, dyes, perfumes, fragrances, conditioners or polishes, oils, creams, gels and serums; antiperspirants, deodorants, and agents that alter the skin’s topography; peptides; astringents; antioxidants; vitamins; nutrients; minerals; skin restorative agents, and the like.

[00109] “Composition” includes a composition comprising at least one active ingredient, such as, without limitation, a compound or combination of compounds that, when applied to skin, provides an acute and/or chronic benefit to skin or a type of cell commonly found therein. Active ingredients may regulate and/or improve skin or its associated cells (e.g., improve skin elasticity; improve skin hydration; improve skin condition; and improve cell metabolism), for example by improving skin appearance and/or feel by providing a smoother, more even appearance and/or feel; increasing the thickness of one or more layers of the skin; improving the elasticity or resiliency of the skin; improving the firmness of the skin; and reducing the oily, shiny, and/or dull appearance of skin, improving the hydration status or moisturization of the skin, improving the appearance of fine lines and/or wrinkles, crevices, bumps, and large pores, improving skin exfoliation or desquamation, plumping the skin, improving skin barrier properties, improve skin tone, reducing the appearance of redness or skin blotches, and/or improving the brightness, radiancy, or translucency of skin, thickening of keratinous tissue {e.g., building the epidermis and/or dermis and/or sub-dermal layers of the skin, and where applicable the keratinous layers of the nail and hair shaft, to reduce skin, hair, or nail atrophy); increasing the convolution of the dermal-epidermal border (also known as the rete ridges); preventing loss of skin or hair elasticity, for example, due to loss, damage and/or inactivation of functional skin elastin, resulting in such conditions as elastosis, sagging, loss of skin or hair recoil from deformation; reduction in cellulite; change in coloration to the skin, hair, or nails, for example, under-eye circles, blotchiness {e.g., uneven red coloration due to, for example, rosacea), sallowness, discoloration caused by hyperpigmentation, etc.

[001 10] Compositions or ingredients suitable for use in the invention may be in the form of liquids, solutions, suspensions, emulsions, solids, semi-solids, gels, foams, pastes, ointments, or triturates. They may also be mixed with a range of optional or additional ingredients and those referred to herein as dermatologically acceptable carriers, matrices or excipients including penetration enhancers, adhesives and solvents. Some non-limiting examples of non-active or additional and optional ingredients include vitamins, minerals, peptides and peptide derivatives, sugar amines, oil control agents, flavonoid compounds, anti-oxidants and/or anti-oxidant precursors, preservatives, phytosterols, protease inhibitors, tyrosinase inhibitors, anti inflammatory agents, moisturizing agents, emollients, humectants, exfoliating agents, skin lightening agents, sunscreens, sunless tanning agents, pigments, film formers, thickeners, pH adjusters, opacifying agents, colourings/colourants, particles, fragrances, essential oils, lubricants, anti-acne actives, anti-cellulite actives, chelating agents, anti-wrinkle actives, anti atrophy actives, phytosterols and/or plant hormones, N-acyl amino acid compounds, antimicrobials, antifungals, and combinations of these. Some particularly suitable examples of optional ingredients are vitamin B3 compounds such as niacinamide, vitamin C, vitamin E and its derivatives (e.g., tocopherol), pantothenic acid and its salts and derivatives (e.g., panthenol), undecylenoyl phenylalanine, caffeine, green tea extract, carob fruit extract, aloe, cucumber extract, palmitoyl pentapeptide-4, palmitoyl dipeptide-7, hexamidine, hexyldecanol, hyaluronic acid and its salts, olive oil extracts such as sodium PEG-7 olive oil carboxylate, tapioca powder, titanium dioxide, and combinations of these.

[001 1 1 ] The compositions of the present invention can comprise, consist essentially of, or consist of, the essential components as well as optional ingredients described herein.

[001 12] As used herein,“consisting essentially of” means that the composition or component may include additional ingredients, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed compositions or methods. Throughout this specification, unless the context requires otherwise, the word“comprise” or variations such as “comprises” or“comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[001 13] As used in the description and the appended claims, the singular forms“a,”“an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[001 14] All documents cited in the specification are incorporated herein by reference in their entirety; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same or corresponding term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall override all other meanings or definitions.

[001 15] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention includes all such variation and modifications. The invention also includes all of the steps, features, formulations and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

[001 16] Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.

[001 17] “About” when used in the context of a value, parameter, dimension or range means a value, parameter, dimension or range that is within ±20% of the stated value, parameter, dimension or range (e.g., within ±20%, ±15%, ±10%, ±5%, ±2% or ±1% of the stated value, parameter, dimension or range).

[001 18] The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension or value is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension or value disclosed as“50 Hz” is intended to mean“about 50 Hz”.

[001 19] All ingredient percentages are by weight of composition, unless specifically stated otherwise. All ingredient ratios are weight ratios, unless specifically stated otherwise. All ranges are inclusive and combinable. The number of significant digits conveys neither a limitation on the indicated amounts nor on the accuracy of the measurements. Unless otherwise indicated, all measurements are understood to be made at approximately 25°C and at ambient conditions, where“ambient conditions” means conditions under about 1 atmosphere of pressure and at about 50% relative humidity. All numeric ranges are inclusive of narrower ranges; delineated upper and lower range limits are interchangeable to create further ranges not explicitly delineated.

[00120] Although not required, the embodiments described with reference to the method, computer program, data signal and aspects of the system can be implemented via an application programming interface, an application development kit (ADK) or as a series of program libraries, for use by a developer, for the creation of software applications which are to be used on any one or more computing platforms or devices, such as a terminal or personal computer operating system or a portable computing device, such as a smartphone or a tablet computing system, or within a larger server structure, such as a‘data farm’ or within a larger transaction processing system.

[00121 ] Generally, as program modules include routines, programs, objects, components and data files that perform or assist in the performance of particular functions, it will be understood that the functionality of the software application may be distributed across a number of routines, programs, objects or components to achieve the same functionality as the embodiment and the broader invention claimed herein. Such variations and modifications are within the purview of those skilled in the art.

[00122] It will also be appreciated that where methods and systems of the present invention and/or embodiments are implemented by computing systems or partly implemented by computing systems then any appropriate computing system architecture may be utilised. This includes standalone computers, network computers and dedicated computing devices (such as field-programmable gate arrays).

[00123] Where the terms“computer”,“computing system” and“computing device” are used in the specification, these terms are intended to cover any appropriate arrangement of computer hardware for implementing the inventive concept and/or embodiments described herein.

[00124] Where reference is made to communication standards, methods and/or systems, devices may transmit and receive data via a variety of forms including but not limited to 3G, 4G (CDMA/GSM), Wi-Fi, Bluetooth, etc., and/or via any type of radio frequency, optical, acoustic, magnetic, or any other form of communication that may become available from time to time.

[00125] Reference within the specification to an “embodiment” or the like means that a particular material, feature, structure and/or characteristic described in connection with the embodiment is included in at least one embodiment, optionally a number of embodiments, but it does not mean that all embodiments incorporate the material, feature, structure, and/or characteristic described. Furthermore, materials, features, structures and/or characteristics may be combined in any suitable manner across different embodiments, and materials, features, structures and/or characteristics may be omitted or substituted from what is described. Thus, embodiments and aspects described herein may comprise or be combinable with elements or components of other embodiments and/or aspects despite not being expressly exemplified in combination, unless otherwise stated or an incompatibility is stated.

[00126] Whereas particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the spirit and scope of this invention.

Claims

CLAIMS:

1 . A method for enhanced transdermal, intradermal or transappendageal delivery of a retinoid, comprising; a) applying a composition to a target portion of skin, wherein the composition comprises a retinoid and a dermatologically acceptable carrier, excipient or matrix and; b) exposing the composition on the target portion of skin to an electromagnetophoretic waveform signal produced by an electromagnetophoretic delivery device, wherein the electromagnetophoretic waveform signal is selected to provide enhanced retinoid delivery, relative to applying the composition without applying the electromagnetophoretic waveform signal; wherein the electromagnetophoretic waveform signal comprises a waveform pattern (W1 ) and a waveform pattern (W2), and the electromagnetophoretic waveform signal has a Wave Factor of between about 0.05 to about 5.0, about 0.06 to about 4.5, about 0.07 to about 4.0, about 0.08 to about 3.5, about 0.09 to about 3.0 or about 0.1 to about 2.9, preferably of about 0.1 to about 2.7, wherein the Wave Factor is derived from the equation;

Wave Factor = (W1 factor) + (W2 factor) wherein

W1 factor is between about 0.01 to about 3.0, about 0.02 to about 2.9, about 0.03 to about 2.8, about 0.04 to about 2.7, about 0.05 to about 2.6, about 0.06 to about 2.5, about 0.07 to about 2.4, about 0.08 to about 2.3, about 0.09 to about 2.2, about 0.09 to about 2.1 , or about 0.1 to about 2.0, preferably about 0.1 to about 1 .9;

W2 factor is between about 0.0 to about 2.0, about 0.01 to about 1 .5, about 0.02 to about 1 .4, about 0.03 to about 1 .3, about 0.04 to about 1 .2, about 0.05 to about 1 .1 , or about 0.05 to about 1 .0, preferably between about 0.05 to about 0.9.

2. The method of claim 1 wherein W2 factor is less than W1 factor.

3. The method of claim 1 or claim 2 wherein the retinoid delivery is enhanced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 74% relative to applying the composition without applying the electromagnetophoretic waveform signal.

4. The method of any one of claims 1 to 3 wherein the enhancement of the delivery of the retinoid relative to applying the composition without applying the electromagnetophoretic waveform signal is measured by tape stripping analysis.

5. The method of any one of claims 1 to 4 wherein the retinoid is present at an amount of about 0.01 % to about 10%, about 0.02% to about 9%, about 0.03% to about 8%, about 0.04% to about 7%, about 0.05% to about 6.5%, about 0.06% to about 6.4%, about 0.07% to about 6.3%, about 0.08% to about 6.2%, about 0.09% to about 6.1 %, about 0.1 % to about 6%, about 0.1 1 % to about 5.9%, about 0.12% to about 5.8%, about 0.13% to about 5.7%, about 0.14% to about 5.6%, about 0.15% to about 5.5%, about 0.16% to about 5.4%, about 0.17% to about 5.3%, about 0.18% to about 5.2%, about 0.19% to about 5.1 %, or about 0.2% to about 5%, preferably at an amount of about 0.1 % to about 5% by weight of the composition.

6. The method of any one of claims 1 to 5 wherein the electromagnetophoretic waveform signal produces a magnetic flux density of between about 1 mT and about 50mT, about 1 .5 mT and about 48mT, about 2mT and about 46mT, about 2.5mT and about 44mT, about 3mT and about 42mT, about 3.5mT and about 40mT, about 4mT and about 38mT, about 4.2mT and about 36mT, about 4.4mT and about 34mT, about 4.6mT and about 32mT, about 4.8mT and about 31 mT, or about 5mT and about 30mT, preferably of between about 5mT and about 30mT.

7. The method of any one of claims 1 to 6, wherein the waveform pattern W1 has: a) a duty cycle of between between about 1 % to about 50%, about 1 .1 % to about 45%, about 1 .2% to about 40%, about 1 .3% to about 35%, about 1 .4% to about 30%, about

I .5% to about 25%, about 1 .6% to about 20%, about 1 .7% to about 15%, about 1 .8% to about 14%, about 1 .9% to about 13%, about 2% to about 12%, about 2.1 % to about

I I .9%, about 2.2% to about 1 1 .88%, or about 2.25% to about 1 1 .88%, preferably a duty cycle of between about 1 % to about 20%; and/or b) a duration of between about 1 ms to about 5000 ms, about 10 ms to about 4500 ms, about 20 ms to about 4000 ms, about 30 ms to about 3500 ms, about 40 ms to about 3000 ms, about 50 ms to about 2500 ms, about 60 ms to about 2000 ms, about 70 ms to about 1500 ms, about 80 ms to about 1000 ms, about 90 ms to about 900 ms, about 100 ms to about 850 ms, about 150 ms to about 800 ms, about 200 ms to about 750 ms, about 250 ms to about 650 ms, about 300 ms to about 640 ms, about 350 ms to about 630 ms, about 400 ms to about 620 ms, about 450 ms to about 615 ms, about

500 ms to about 612 ms, about 530 ms to about 609 ms, or about 534 ms to about 606 ms, preferably a duration of between about 100 ms to about 1000 ms; and/or c) wherein the number of pulses in W1 is between about 1 to about 5000, about 2 to about 4500, about 3 to about 4000, about 4 to about 3500, about 5 to about 3000, about 6 to about 2500, about 7 to about 2000, about 8 to about 1500, about 9 to about 1000, about 10 to about 500, about 12 to about 450, about 14 to about 400, about 16 to about 350, about 18 to about 300, about 20 to about 250, about 22 to about 200, about 24 to about 180, about 26 to about 160, about 28 to about 140, or about 30 to about 120, preferably between about 5 to about 500; and/or d) a magnetic flux density of between about 1 mT and about 50mT, about 2mT and about 45mT, about 3mT and about 40mT, or about 4mT and about 35mT, preferably of between about 5mT and about 30mT.

8. The method of any one of claims 1 to 7, wherein the waveform pattern W2 has: a) a duty cycle of between about 1 % to about 50%, about 1 .01 % to about 45%, about

1 .02% to about 40%, about 1 .03% to about 35%, about 1 .04% to about 30%, about

1 .05% to about 25%, about 1 .06% to about 20%, about 1 .07% to about 15%, about

1 .08% to about 14%, about 1 .09% to about 13%, about 1 .09% to about 12%, about

1 .1 % to about 1 1 %, about 1 .2% to about 10%, 1 .22% to about 9%, 1 .24% to about 8%, 1 .26% to about 7%, 1 .28% to about 6.5%, 1 .3% to about 6%, 1 .32% to about 5.8%, 1 .33% to about 5.7%, 1 .34% to about 5.6%, 1 .35% to about 5.58%, 1 .36% to about 5.57%, 1 .365% to about 5.56%, or about 1 .37% to about 5.55%, preferably a duty cycle of between about 1 % to about 20%; and/or b) a duration of between about 1 ms to about 5000 ms, about 100 ms to about 4500 ms, about 200 ms to about 4000 ms, about 300 ms to about 3500 ms, about 400 ms to about 3000 ms, about 500 ms to about 2900 ms, about 600 ms to about 2850 ms, about 700 ms to about 2800 ms, about 800 ms to about 2750 ms, about 900 ms to about 2700 ms, about 1000 ms to about 2650 ms, about 1 100 ms to about 2600 ms, about 1200 ms to about 2550 ms, about 1300 ms to about 2500 ms, about 1400 ms to about 2450 ms, about 1500 ms to about 2400 ms, about 1600 ms to about 2350 ms, about 1700 ms to about 2300 ms, about 1800 ms to about 2250 ms, about 1900 ms to about 2200 ms, about 1950 ms to about 2150 ms, about 2000 ms to about 2100 ms, or about 2102 ms to about 2074 ms, preferably a duration of between about 100 ms to about 5000 ms; and/or c) wherein the number of pulses in W2 is between about 1 to about 5000, about 2 to about 4500, about 4 to about 4000, about 6 to about 3500, about 8 to about 3000, about 10 to about 2500, about 15 to about 2000, about 20 to about 1500, about 25 to about 1000, about 30 to about 500, about 35 to about 450, about 40 to about 400, about 45 to about 350, about 50 to about 300, about 55 to about 295, about 60 to about 292, about 65 to about 290, about 70 to about 289, or about 72 to about 288, preferably between about 5 to about 500; and/or d) a magnetic flux density of between about 1 mT and about 50mT, about 2mT and about 45mT, about 3mT and about 40mT, or about 4mT and about 35mT, preferably of between about 5mT and about 30mT.

9. An electromagnetophoretic delivery device adapted to perform the method of at least one of claims 1 to 8, comprising a power supply, a microcontroller, and an electromagnetophoretic waveform signal generator, wherein the microcontroller causes voltage from the power supply to be applied, thereby sending a plurality of energisation signals to an electromagnetophoretic waveform generating component such that an electromagnetophoretic waveform signal is generated, wherein the electromagnetophoretic waveform signal is selected to provide the enhanced transdermal, intradermal or transappendageal delivery of a retinoid to a target portion of skin.

10. The device of claim 9, wherein each energisation signal generally defines a square wave.

1 1. The device of claim 9 or claim 10, wherein the plurality of energisation signals have a frequency of between 0.1 Hz to about 2000 Hz, about 0.1 Hz to about 1900 Hz, about 0.1 Hz to about 1800 Hz, about 0.1 Hz to about 1700 Hz, about 0.1 Hz to about 1600 Hz, or about 0.1 Hz to about 1550, preferably a frequency of between about 0.1 Hz to about 1500 Hz.

12. A composition for use in the method of at least one of claims 1 to 8, comprising a retinoid, and one or more dermatologically acceptable carriers, excipients or matrices.

13. The composition of claim 12, wherein the retinoid is selected from retinol, retinal, retinoic acid, beta-carotene, retinyl palmitate, retinyl propionate, retinyl acetate, retinyl linoleate, retinol aldehydes, retinyl esters, synthetic retinoids, retinoid derivatives, tretinoin, isotretinoin, alitretinoin, etretinate, acitretin, adapalene, bexarotene, tazarotene, including salts isomers, diastereomers or enantiomers of any of the preceding, or a combination of any of these.

14. The composition of claim 12 or claim 13, comprising an additional active ingredient.

15. A kit comprising the device of any one of claims 9 to 1 1 and the composition of any one of claims 12 to 14, for use in the method of at least one of claims 1 to 8.

16. The kit of claim 15, wherein the device of any one of claims 9 to 1 1 produces the electromagnetophoretic waveform signal defined in claim 1 , when used in the method of any one of claims 1 to 8.