Patent Application
20230226068
This invention relates to the treatment of onychomycosis, and in particular, it relates to a novel method, a handheld compact photo activation system, and a novel formulation for the photodynamic treatment of onychomycosis. The system, method and formulation are used to allow an effective photodynamic treatment of the infected toe nail utilizing photoactivation of the dye. Optimal treatment outcomes are driven by an effective penetration of the nail bed by the photoactive agent and a compact illumination device for ease of use. In an embodiment the photoactive formulation includes Urea which greatly enhances the transungual penetration. A beneficial formulation uses Methylene Blue (MB), Riboflavin-5-phosphate (FMH) or Riboflavin (RF) as a photoactive agent. In a beneficial embodiment the method and system contains of a battery driven compact handheld LED light source.
Onychomycosis, or toe nail fungus is an infectious disease of the nail. The patient population is huge as about 10% of global population is affected. Worldwide overall about 780 million patients are affected in 2020. There also is a huge shift in market dynamics from 92% of oral treatments in 2009 to now 55% topical treatments in 2019 with a clear trend toward more topical solutions.
Existing treatment options for oral treatments are driven by different drugs like Terbinafine, Itraconazole, Fluconazole. They have a high mycological cure rate of 50-70% and moderate total cure rate of 14-38% but come with a considerable severe side effect of liver enzyme abnormalities, headaches, as well as gastrointestinal problems or rashes. Especially the significant possible liver side effects drive the now high adoption towards the less efficacious topical treatment solutions.
Topical drugs include Efinaconazole, Tavaborole, Ciclopirox and Amorolfine which allow some treatment success of 29-50% mycological cure rate and 5-18% total cure rate. But at the same time the topical treatment options come with a significant favorable safety profile only limited to local skin irritations. The lower efficacy is compensated with an improved side effect profile.
Typically, topical treatment is indicated for nails with relatively low fungus infestation and a low Onychomycosis Severity Index (OSI) of less than 15, while deep nail infestation is treated with oral treatment options for OSI > 15 with close to full nail involvement.
Other treatment options have been clinically tested which include Intense Pulsed Light (IPL), thermal laser treatment, plasma treatment or Low-Level Light Therapy (LLT). Although these modalities show a treatment effect, the efficacy is low compared to the available topical and oral pharmacological solutions. The FDA even had to introduce a low-end clinical endpoint which only relates to a clearing of the nail appearance - a visual improvement - which does not represent a mycological cure or full cure which are associated with the pharmacological solutions.
Growth rates of the nails are relatively low with 3.5 mm/month for finger nails and 1.6 mm/month for toe nails. This means that for a full regrowth cycle of the finger nail takes about 3-4 months while toe nails typically need up to a full year to fully regrow. That’s also why all treatment regimens require daily treatments for a full year for topical treatments. For oral treatment the regimens prescribe oral medication every week for a year. The typical treatment cost for full treatment cycles can be significant, with multiple thousands of dollars spent just on treatment supplies and drugs. But this clearly also includes a significant treatment burden on the patient as daily compliance with a treatment regimen is highly unlikely to happen in real world scenarios.
Photodynamic therapy (PDT) has been fully approved for use in many different clinical applications. In dermatology it is approved for the treatment of actinic keratoses using aminolevulinic acid (ALA). In ophthalmology it’s approved for the treatment of choridal neovascularizations in wet Agerelated Macula Degeneration (wet AMD) using Verteporfin, a benzoporphyrin derivative. Also corneal crosslinking for the treatment of keratoconus using Riboflavin is fully approved and represents the current standard of care.
PDT for the treatment of onychomycosis has been clinically tested utilizing many different photoactive drugs. These include MB, RF, Toluidine Blue, ALA as well as methyl aminolevulinate (MAL). Although initial results are encouraging, the overall treatment success was limited by several different issues. For all photoactive drugs there is no diffusion of the drug into the nail itself. This achieves only a superficial treatment effect while the core problem of deep nail plate infections is maintained and not treated. Also, the availability of appropriate light sources is limited to large LED panels as used for the treatment of large skin diseases or expensive high powered diode laser. This also excludes the possible treatment of the patient at home and thus requires full attention and treatment of either the podiatrist or dermatologist in possession of these light sources.
What is needed are new methods, systems, formulations and kits to advance the standard of care and enable a new and efficient treatment of onychomycosis and other nail infections.
Accordingly, the present invention is directed to a method of treating infections of the nail using photodynamic therapy that substantially obviates one or more of the problems due to limitations and disadvantages of the related art.
One object of the present invention is to provide efficient photodynamic treatment of the nail due to enhanced diffusion of the photoactive dye into the nail bed, allowing treatment of spores and bacteria which are deeply embedded in the nail plate, nail bed or root of the nail. The enhanced dye diffusion comprises of a formulation which contains Urea to soften the nail during the staining process.
It is a further object of the current invention to provide a compact battery driven light emitting system that enables activation of said photoactive dye by emitting a spectrum of wavelengths which significantly overlaps the absorption spectrum of the dye. This system also provides sufficient brightness to enable efficient treatment. The system is configured to be used by the patient at home.
In one aspect, a method of treating a nail infection includes staining the nail plate with a photoactive dye in a formulation containing urea, allowing the dye to diffuse deep into the nail plate, illuminating the nail with a spectrally matched light source to activate the photoactive dye at light irradiance and exposure levels sufficient to treat the nail. The system utilized for the illumination contains a battery to power the system and includes a timer to have control means for the exposure duration.
In yet another aspect, a method of treating nail infection includes a treatment regimen that gets repeated multiple times. In some embodiments the treatment cycle is repeated a fixed number of times, while in other embodiments the number of treatment cycles depends on the evaluation of the treated nail. In yet another aspect a kit or other product is provided for treating a nail having an infection. The kit includes: a formulation containing urea and a photoactive dye to stain the nail; and a system for illuminating the stained nail, wherein the system includes: an illuminator for emitting light to the stained nail having the formulation applied thereto; drive and control electronics for driving and controlling the illuminator; an initiator for commencing illumination of the stained nail having the formulation applied thereto; and a power source for supplying power to the drive and control electronics and the illuminator.
In some embodiments, the formulation may be provided, for example, in a tube, in a jar, in a roll-on applicator, embedded in one or more applicator strips, or in a prefilled brush pen. These are but a few examples and are non-limiting. In some embodiments, the illuminator includes an array of light sources. In some embodiments, the light sources are light emitting diodes (LEDs). In some embodiments, the photoactive dye has an activation or absorption spectrum, and the emitted light of the illuminator is spectrally matched to the activation spectrum of the photoactive dye.
Additional features and advantages will be set forth in the description that follow and in part will be apparent from the description, or may be learned by practice of the invention. The objects and other advantages will be realized and attained by the devices, formulations and methods disclosed in the written description and claimed by the claims, as well as the appended drawings.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
As used herein, when a quantity, concentration, percentage, or other relationship is said to be “about” a particular value, it means that it is within +/- 10% of that value. So, for example, a concentration of about 20% would be between 18% and 22%. As used herein, a kit refers to a set of articles or equipment which can be utilized together for a particular purpose. The articles in a kit may be manufactured, marketed, or sold together or separately.
Fingernails and toenails are made of keratin, a polymer. The nail plate is produced by the nail matrix which created cells that become the nail plate as they pushed older cells forward. This nail growth is on average about 3.5 mm per month for finger nails and about 1.6 mm per month for toe nails.
Onychomycosis is a fungal infection of the nail, mostly caused by dermatophytes. These fungi affect the nail plate, nail bed and matrix as they require keratin for growth. This infection is rather common and affects about 10% of global population. This infection is difficult to treat due the low ability of most drugs to effectively penetrate the nail - inhibiting an effective treatment. At the same time the low growth rate of the nail, which also further decreases with age, leads to extremely long treatment durations of about a full year to allow the regrowth of a full new unaffected nail. These prolonged treatments require significant patient compliance and adherence over a long period of time. In-office interventions are extremely time consuming and costly due to the duration of the intervention needed.
As disclosed herein, these limitations may be overcome by introducing a new method, device, formulation and kit which enable a highly effective treatment of onychomycosis while showing no side effects and good patient compliance.
The methods and systems disclosed herein provide many advantages over the state of art. Specifically, a highly effective treatment of onychomycosis is enabled through a highly effective penetration formulation of a photoactive dye deep into the nail plate in combination with a very compact and flexible illumination system. In some embodiments, the formulation and the illumination system (including embodiments described below) may be packaged or otherwise provided, marketed, or sold together as a kit or other product. They may also be provided separately and combined into a kit by an end user.
Diffusion of the nail plate is a standard problem for transungual drug delivery. This is also the mayor hurdle for the development of nail lacquers for onychomycosis as it is difficult to get the antifungal drug delivered deep into the affected nail pate in concentrations high enough to be effective. Factors impacting transungual diffusion are molecular size, hydro & lipophilicity, exposure duration, as well as pH and solute charge of the drug and formulation. There are also physical methods to enhance nail penetration which include iontophoresis, etching, micro laser drilling or hydration and occlusion.
For the photodynamic treatment of onychomycosis, overnight occlusion and hydration was clinically used to potentially soften the nail. This was followed by a short staining cycle of a dye like MB in H2O.
On the other hand,
The formulation utilized for extremely high diffusion of MB as shown in
This formulation is applied directly to the nail and utilizes a long penetration duration of 6-12 hours. Covering the area during this period is essential for several reasons. First, the formulation should not dry out during the staining process as its moisture and increased water content of the nail plate allows the deep integration and penetration of the dye. Second, the cover prevents the stain from spreading to unwanted areas. Possible solutions can range from regular tapes and drapes, to more advanced coverings which include depot areas within the cover to store extra formulation. However, a full finger or toe cover is also possible.
It is important to point out that this new formulation not only works with one specific stain but generally applies to a wide range of possible photodynamic stains.
The tremendous gain of the dye concentration within the nail plate of this new formulation is also very visible in the direct comparison with the standard stain method on the same nail.
It is also important to point out that with this novel formulation the dye is deeply integrated into the nail plate and does not diffuse or leak out over a short period of time. To demonstrate that, the nail of
Beneficially, dye concentration in the novel formulation ranges from 0.01% to 10%; more specifically it is preferred that it be from about 0.1% to about 5%. The final concentration depends on the linear absorption created within the nail plate due to the diffusion of the dye. A concentration which is too high is not advisable as all the light will get absorbed within the superficial layer of the nail plate, while a concentration which is too low might allow good light penetration but might be too low in concentration to effectively treat the underlying root cause through photoactivation. The preferred concentration is configured to allow an effective treatment while still allowing deep light penetration into the stained nail bed. However, this also depends on the wavelength utilized as UV light and blue wavelength light have difficulty penetrating into the nail due to increased light scattering. Light in the red or near IR wavelengths is preferred in that sense, but also here a balance needs to be taken into account between high quantum yield which typically happens with higher energetic UV or blue light photons and the good light penetration of longer wavelengths.
Good dye candidates but not limited are MB and RF but also indocyanine green (ICG). Other possible candidates are Verteporfin, Redaporfin, Padeliporfin, as well as Zinc- or Aluminum Phthalocyanine Tetrasulfonates.
Besides the novel formulation of allowing a deeper and long lasting penetration of the photoactive dye into the nail plate, the system 600, which activates the dye, may also novel features. Illuminator 200 of systems 600 and 600A as illustrated in
Candidates for light sources include light emitting diodes (LEDs), diode lasers, vertical cavity surface emitting lasers (VECSELs) or VECSEL-arrays. LEDs have the advantage that they are now powerful enough to deliver these irradiances at a low cost point but come with a broader light spectrum. Diode lasers or VECSLs are higher in price but are able to specifically target the peak absorption wavelengths of the photoactive dye in use.
Beneficially, these light sources are arranged so that they can emit a uniform light distribution at the target. This allows a uniform activation of the dye.
Instead of, or in addition to the array of
Illuminator 200 is driven and controlled by dedicated driver and control electronics 300, which is configured to enable a correct activation as well as timing of the light exposure and the control of the light intensity output. Beneficially, driver and control electronics 300 is implemented by an electronics board which is operatively coupled to illuminator 200. Beneficially, driver and control electronics 300 includes a timer to control on - off timing of illuminator 200. The timer may comprise, for example, a small microcontroller (e.g., a PIC16F15244) or a timing module like a TI-555 timer. The on duration for a single exposure setting can be in the range of 3 sec to 3 hours, but is typically 5-30 minutes. Beneficially, driver and control electronics 300 includes a brightness control mechanism for controlling an intensity of light 700 emitted by illuminator 200, which in some embodiments may be adjusted under user control, for example by a control knob, a slide mechanism, or the like. In some embodiments, the brightness control mechanism includes a voltage-to-current converter configured to supply current to illuminator 200. In some embodiments, the brightness control mechanism includes a pulse with modulator for applying pulse width modulation (PWM) to the drive current supplied to illuminator 200.
Driver and control electronics 300 can also serve other additional functions, such as driving an IO system such as display 350 as shown in
Driver and control electronics 300 is powered through battery 400, which may be a rechargeable battery like a LiPo battery. The use of a battery or rechargeable battery also allows the full mobility of the device to be used wherever the user decides to perform treatment. With battery 400, no power supply or cables are needed during operation. As indicated in
The electronics can be activated through initiator 500 which is operatively coupled to drive and control electronics 300. This allows the user to activate system 600, and in particular illuminator 200.
Overall the system 600 is encased to allow the illumination of the nail 110 of a finger or toe 100. This includes mechanical means to block parts of the light 700 from exiting the system other than the aperture used for illuminate the nail plate 110. This allows an overall light-safe operation of the system 600 which emits quite significant amounts of light which need to be mitigated to be eye-safe for example. This can be achieved through a base plate underneath the finger or toe 100, and other light limiting shields.
Different usage flow charts and scenarios may be employed. As depicted in
In another embodiment, the treatment cycle runs through a fixed number of cycles as depicted in
The various components and modules of the system described above may be implemented by electrical circuitry including logic circuits, and/or processors which execute computer executable program code stored in computer readable non-volatile memories and other tangible, non-volatile media.
It will be apparent to those skilled in the art that various modification and variations can be made in the methods, system, and formulations disclosed herein. Thus, it is intended that the present invention be defined by the appended claims, including the recited elements and their equivalents.
