WO1997020596A1

WO1997020596A1 - Therapy apparatus and method

Info

Publication number: WO1997020596A1
Application number: PCT/EP1996/005268
Authority: WO
Inventors: Robert M. Sayre; James G. Shepherd
Original assignee: Glaxo Group Limited
Priority date: 1995-12-01
Filing date: 1996-11-28
Publication date: 1997-06-12
Also published as: AU1094597A

Abstract

A medical illuminator apparatus for photodynamic therapy (PDT) comprising a high pressure sodium lamp having a power output between 100-500 watts and wherein at least 35-40 % of the unfiltered emission is usable for the PDT. A mirror is positioned adjacent to the lamp for collecting light and reflecting it along a predetermined pathway, and filter means is provided for filtering the light into a wavelength band of a predetermined desired width wherein at least 90 % of the filtered emission is in the desired wavelength band for the PDT. Lens means is provided for focusing the light onto a desired treatment area on a patient.

Description

THERAPYAPPARATUSANDMETHOD

The present invention relates to photodynamic therapy (PDT) and more particularly to an improved apparatus and method for photodynamic therapy utilising a high pressure sodium lamp for illumination.

As is well known in the medical field of dermatology, certain medicinal compounds can be photoactivated by light in a treatment called photodynamic therapy (PDT). Photodynamic therapy (PDT) involves the use of light sources to treat a variety of skin disorders such as cancer, psoriasis, keratosis and other types of related skin disorders. The general theory behind PDT is the therapeutic use of light so as to obtain a photoreaction of tissue to the radiation source or, altematively, to obtain the activation of a topically or systemically administered drug which is light sensitive. For example, it is presently known to treat psoriasis by exposing a patient to ultraviolet radiation in combination with a topically or systemically applied medicament that sensitises the skin to ultraviolet radiation. See, for other examples, U.S. Patent No. 5,079,262; U.S. Patent No. 5,211 ,938; and PCT International Publication No. WO 95/11059.

Normally, a photosensitive drug is administered systemically, topically or by injection into a target site such as a tumour in photodynamic therapy (PDT). Irradiation of a target site by an appropriate light source (e.g., an argon-pumped dye laser or a sunlamp) will induce a cytotoxic effect on the cells of the target site by one of two basic treatment procedures that are followed in photodynamic therapy (PDT). In type one photoactivation, the irradiated drug substance reacts directly with the biological substrate, forming radicals which can initiate subsequent radical reactions which in turn induce cytotoxic damage. Alternatively, in type two photoactivation, energy is transferred from the irradiated drugs to oxygen which thereby produces singlet molecular oxygen which in turn produces cytotoxic oxygenated products. One representative example of such a PDT technique involves the photoactivation of a family of dyes known as porphycenes. In general, the light source for photodynamic therapy (PDT) is selected depending upon the target tissue to be irradiated, the nature of the skin disorder to be treated and/or the photoactivated drug to be delivered to the patient. As is well known to those skilled in the art, certain light sources are selected on the basis of the wavelength of light required to treat a particular skin disorder (e.g., a UV light source to treat psoriasis).

In PDT treatment regimens where the light source is used to activate a particular chemical compound, the light source is generally selected so that it emits light energy in the optimal wavelength range required to photoactivate the medicinal compound. The rationale for designing and selecting light sources for use in activating light-activated PDT drugs is based upon the absorption spectrum of the drug in the skin and providing light that is primarily absorbed directly by the drug. A secondary concern in PDT therapy is to minimise the irradiation of patients with any light or radiation that can produce an adverse effect or which is absorbed by tissue not being treated with the drug.

While various light sources may be used to activate a medicinal compound of interest in PDT since almost all light sources would have some light energy within the wavelength band at which a compound is activated, it is clearly preferential to select a light source which emits wavelengths of light which most closely overlap with the range in wavelengths (or the wavelength band) at which a medicinal compound is activated. For example, the prior art suggests the use of lasers to emit light wherein it is desirable to have light energy emitted in a concentrated narrow beam that is highly specific with regard to wavelength and focused on a restricted surface area. While such an approach is good for matching wavelength with a medicinal compound undergoing photoactivation, it suffers a shortcoming of only allowing for the irradiation of a very small treatment surface area on a patient. As is well known, this is not satisfactory for many PDT treatment regimens that call for the exposure of larger treatment surface areas on a patient.

To provide exposure of larger PDT treatment surface areas on a patient, there is knowledge of only four primary light sources that have been used for PDT to date. These light sources consist of quartz tungsten- halogen, mercury arc, mercury-metal halide and xenon arc lamps. These four known light sources are generally less than optimal for a variety of reasons including that typically a vast amount of their light energy emissions are outside of the desired wavelength region or band that will be absorbed by the PDT medicinal compound during activation thereof. Moreover, all of these light sources (with the exception of quartz tungsten-halogen lamps) pose some risk of explosion so as to require protective housings as well as being difficult to reignite once they have been turned off. Consequently, for most medicinal patient treatment applications, the mercury arc, mercury- metal halide and xenon arc light sources must be shuttered while adjustments are made for additional exposure treatment sites on a patient.

Even more significantly, the primary shortcoming of all of the aforementioned light sources is the relatively small amount of light output that is actually available for photoactivation of a medicinal compound. For example, if a quartz tungsten-halogen light source is utilised, only about 10% of the light energy will typically be utilised for activation of a PDT medicinal compound and the remaining 90% of light energy will be dissipated in the form of heat. More specifically, in the case of the light wavelength band absorbed by a PDT medicinal compound such as the dye

ATMPn (9-acetoxy-2,7,12,17-tetrakis(methoxyethyl)porphycene) only about 10% of the light energy emitted is actually used to activate the medicinal compound. Accordingly, these four familiar light sources require considerable optical filtration in order to achieve the desired wavelength band to photoactivate a therapeutic compound and considerable cooling capacity to remove the unwanted heat from the environment of the light source.

An additional shortcoming of the aforementioned light sources for broad surface PDT application is the relatively low amount of power available in the desired wavelength band from the light source to photoactivate the medicinal compound. Thus, the use of a high power light source (typically 1 ,000 watts or more) is necessary in order to provide effective PDT treatment. In other words, the known light sources do not have enough power or light energy within the desired wavelength band required to photoactivate a PDT compound without significantly increasing the light source wattage to levels of 1,000 or more watts. The high wattage light sources suffer well-known disadvantages including high maintenance expenses due to increased power use and high replacement costs relative to lower wattage light sources. As an alternative to the high wattage required by known PDT light sources for broad surface PDT treatment, the light sources could be utilised with lower wattage and lengthened patient exposure time. For example, effective PDT therapy with a poφhycene medicinal compound requires at least 60 Joules of power in a desired wavelength band to reach the medicinal compound. If a light source emits 100 milliwatts of power in the desired wavelength band it would take 600 seconds of irradiation time to deliver the appropriate light treatment energy dose to the patient. On the other hand, if the power level of the emitting source is only 10 milliwatts, then the patient should be exposed to irradiation for 6,000 seconds for comparable treatment efficacy. However, such lengthy patient exposure time is clearly undesirable for obvious reasons, and thus a desirable PDT objective would be to achieve a minimal power level to deliver adequate light energy in the desired wavelength band to a patient in a reasonable amount of time.

Accordingly, there is a long-felt need in PDT for a cost-effective light source that provides broad treatment surface exposure of light energy in the desired wavelength band while minimising patient exposure time and heat dissipation requirements inherent in high wattage light sources. In accordance with the present invention, there is provided an improved medical illuminator apparatus for activation of a photoactivated compound during photodynamic therapy (PDT) comprising a high pressure sodium lamp having a power output between 100 - 500 watts and wherein at least 35% - 40% of the unfiltered emission is usable for the PDT. A mirror is positioned adjacent to the lamp for collecting light from the lamp and reflecting it along a predetermined pathway, and filter means is provided for filtering the light from the sodium lamp into a wavelength band of a predetermined desired width wherein at least 90% of the filtered light emission is in the desired wavelength band for the PDT. Lens means is provided for focusing the light onto an area on a patient.

Also, in accordance with the present invention, an improved method of photodynamic therapy (PDT) is provided for a patient including the steps of administering to a patient a drug that is delivered to a selected patient skin area and which is activated by light in a wavelength band of a predetermined width. Next, a high pressure sodium lamp having a power output between 100 - 500 watts is energised and the emitted light is collected and reflected away from the lamp, and the reflected light is passed through selected light filters so as to form a filtered wavelength band of a predetermined width wherein at least 90% of the filtered light is in the desired wavelength band for the PDT. The light is caused to be focused onto an area on the treated skin of a patient to effect the photodynamic therapy (PDT).

It is, therefore, the object of the present invention to provide an improved medical illuminator apparatus for photodynamic therapy (PDT). It is another object of the present invention to provide an improved medical illuminator apparatus that utilises a low power requirement light source to deliver adequate light energy in the desired wavelength band to a patient in an acceptable period of time.

It is another object of the present invention to provide an improved medical illuminator apparatus that utilises a light source that provides light energy in a desired wavelength band to a broad treatment surface while minimising patient exposure time and obviating the necessity of dissipating a high percentage of light energy in the form of heat.

It is yet another object of the present invention to provide an improved medical illuminator apparatus utilising a light source that provides a very high proportion of its light emissions in the desired wavelength band for activation of a selected PDT medicinal compound.

It is yet another object of the present invention to provide an improved medical illuminator apparatus that uses a light source that while providing excellent PDT treatment generally has a relatively low power requirement and consequently obviates explosion risks and the necessity for protective housing for the light source.

It is still another object of the present invention to provide an improved medical illuminator apparatus that utilises a low cost and low power requirement light source that provides a high percentage of light emissions in the desired wavelength band for PDT without requiring complex light filtering and heat dissipating assemblies.

Some of the objects of the invention having been stated, other objects will become evident as the description proceeds, when taken in connection with the accompanying drawings described hereinbelow. Figure 1 is a schematic diagram of the medical illuminator apparatus for PDT according to the present invention;

Figure 2 is a graph of the light intensity vs. wavelength for selected high pressure sodium lamps; Figure 3 is a graph of the absorption spectrum of photoactivated medicinal compound ATMPn.

Referring now to the drawings in more detail, the present invention provides an improved medical illuminator 10 (Figure 1 ) for activation of a selected photoactivated medicinal compound in photodynamic therapy (PDT). Illuminator 10 includes a high pressure sodium lamp 12 surrounded by an elliptical (or parabolic) mirror 14 which serves to direct the emitted light outwardly from high pressure sodium lamp 12. The emitted light is passed through first infrared reflective filter 16 that acts to reflect a portion of the infrared light from high pressure sodium lamp 12. The emitted light next travels through Fresnel lens 18 that serves to focus the light onto the treatment surface area of a patient's skin. The focused light from Fresnel lens 18 is filtered by second infrared reflective filter 20 and subsequently passes through red additive cut-off filter 22 to provide a light wavelength band of a predetermined desired width to photoactivate a medicinal compound on the treatment skin area of a patient. Shutter 24 is provided between red additive cut-off filter 22 and the patient's skin to control the duration of the light exposure to the treatment skin area. It is noted, however, that other lens and filter configurations could be utilised and are intended to be within the scope of the instant invention. It is contemplated that an emergency on/off control switch (not shown) will be provided to both the patient being treated and to clinicians attending to treatment of the patient. Also, illuminator 10 may be suitably mounted in a protective housing (not shown) as a matter of design choice.

Preferably, illuminator 0 utilises a 100 watt PHILIPS brand WHITE SON high pressure sodium lamp or a conventional 100 watt PHILIPS brand high pressure sodium lamp available from Philips Lighting Company located in Somerset, New Jersey. Mirror 14 may be any suitable elliptical (or parabolic) mirror or reflector such as an AUGUST JORDAN brand Part No. 4653.15 available from August Jordan Gmbh & Company. Infrared reflective filter 16 and infrared reflective filter 20 are most suitably 20.25 square inch BALZERS THIN FILM PRODUCTS brand Part No. Calflex 3000, available from Balzers Thin Film Products. Fresnel lens 18 is most suitably a FRESNEL brand lens available from Edmund Scientific Company and has a 5 inch diameter and a 5 inch focal length. Red additive cut-off filter 22 is a 2 x 2 inch square SCHOTT GLASS brand Part No. OG-590 red additive cut-off filter available from Corion Corporation.

It is contemplated that illuminator 10 using high pressure sodium lamp 12 can be used to photoactivate many different types of photoactivated medicinal compounds in order to treat a variety of skin disorders such as cancer, photoaged skin and psoriasis. More particularly, it is contemplated that illuminator 10 with high pressure sodium lamp 12 is particularly well adapted to photoactivate a class of medicinal compound known as porphycenes in the treatment of skin disorders. Even more specifically, it is contemplated that illuminator 10, utilising high pressure sodium lamp 12, is particularly well adapted to photoactivate a topically applied porphycene compound ATMPn (9-acetoxy-2,7,12,17-tetrakis(methoxyethyl)porphycene) manufactured by Chemsyn Science Laboratories of Lenexa, Kansas.

It has been discovered that photoactivation of ATMPn is preferably accomplished with illuminator 10 by utilising a 100 watt PHILIPS brand WHITE SON high pressure sodium lamp filtered by first and second infrared reflective filters 16 and 20 and red additive cut-off filter 22 to provide a band of red light from 600 to 700 nanometres (nm) in band width. As will be seen hereinafter, the filtered light from illuminator 10 with PHILIPS brand WHITE SON lamp 12 provides a very high percentage of emissions (94.35%) between 600 and 700 nanometres (see Table 1 ) so as to be particularly effective in photoactivating the ATMPn medicinal compound. Although high pressure sodium lamp 12 is preferably the 100 watt PHILIPS brand WHITE SON high pressure sodium lamp, any high pressure sodium lamp will perform satisfactorily provided that the power requirement is at least 100 watts and does not exceed 500 watts. Table 1

Light spectrum of filtered light from PHILIPS WHITE SON 100 watt lamp

WAVEBAND PERCENT OF TOTAL

200-800 nm 100%

250-500 nm 0.01%

500-600 nm 2.31 %

600-700 nm 94.35%

700-800 nm 3.33%

Thus, it can be appreciated that the preferred embodiment of illuminator 10 of the present invention lends itself particularly well to photoactivation of the porphycene compound ATMPn. However, it is not intended or contemplated that the invention be limited to use with any specific photoactivated PDT medicinal compound.

High pressure sodium lamp 12 provides at least 35% - 40% (see Table 2) of emitted light within the region generally desired for photoactivation of medicinal compounds in photodynamic therapy (PDT). In the specific case of ATMPn, high pressure sodium lamp 12 could most probably be utilised without any additional filtration by illuminator 10. However, most preferably, filtration is provided in order to remove wavelengths of light which are not directly absorbed into the ATMPn and thereby to lower the total light intensity reaching a patient's treatment skin surface and also to reduce the possible risk of eye damage. The filtered emitted light from high pressure sodium lamp 12 should result in greater than 90% of the emitted light being within the light wavelength band desired for photoactivation of a medicinal compound in photodynamic therapy (e.g., 94.35% for ATMPn). Table 2

Light spectra from selected high pressure sodium lamps (100 watt; 150 watt; and 100 watt WHITE SON)

10Owsod 150wsod whitson7s

UV 1.1 % 0.9% 0.7%

400-500 7.5% 7.7% 8.1%

500-600 43.8% 49.6% 25.5%

600-700 38.3% 34.6% 45.2%

590-700 48.7% 46.6% 45.6%

700-800 9.3% 7.1% 20.2% total 100.0% 100.0% 100.0%

Table 2 above shows the spectra of light from 100 watt and 150 watt PHILIPS brand high pressure sodium lamps and a 100 watt PHILIPS brand WHITE SON high pressure sodium lamp. As can be seen, between about 35% and 45% of the unfiltered light emission is useful for PDT with ATMPn. Moreover, it has been discovered that the PHILIPS brand WHITE SON 100 watt high pressure sodium lamp 12 has a rated lifetime of more than 10,000 hours, and thus can be expected to last at least 1 year or more in clinical usage as opposed to a quartz tungsten-halogen lamp expected lifetime of less than 1 week.

High pressure sodium lamp 12 is utilised by illuminator 10 so as to make use of the predominance of red wavelengths available in high pressure sodium light sources. By contrast, for example, light sources which use quartz tungsten-halogen lamps emit only about 5% of their total power in the red part of the light spectrum. High pressure sodium lamps emit 20% or more of their total power in the highly desirable red part of the light spectrum.

As noted hereinbefore, the preferred embodiment of illuminator 10 uses a 100 watt PHILIPS brand WHITE SON lamp 12 filtered so as to provide a band of red light from about 600 to 700 nanometres in width, and that wavelength band is particularly well adapted to photoactivate the PDT medicinal drug ATMPn. Preferably light emitted from illuminator 10 passes through an aperture A therein defining an area of 2 cm². Most suitably, lamp 12 is warmed before use and shutter 24 is manually opened and closed to provide the desired exposure time of a treatment skin area to the emitted light from illuminator 10. The filtered and focused light from illuminator 10 is most suitably used to illuminate an exposure area of about 144 cm² which is achieved by masking the exposure area to the size of the desired skin treatment area using opaque film. Spectral uniformity to be achieved over the treatment area is + 15% with illuminator 10.

The intensity (see Figure 2) of high pressure sodium lamp 12 can be changed by adjusting the position of Fresnel lens 18 This can be accomplished by measuring the intensity of the emitted light and adjusting the position of Fresnel lens 18 relative to aperture A Exposure of light is controlled by operating manual shutter 24 in conjunction with exposure duration timed using a conventional stopwatch.

Typically, the photoactive drug or dye to be utilised in PDT with illuminator 10 would be placed in a suitable pharmaceutical vehicle and applied to the area to be treated, although the drug can also be administered systemically or by injection in a manner that is well known to one skilled in the art. After a period of time that may vary from minutes to hours, the excess drug or dye on the skin surface is removed Light with an emission spectrum suitable for being absorbed by inactivating the drug or dye is directed towards the skin treatment area Both the power density (Mw/cm²) and total light dose (Joules/cm²) from illuminator 10 may vary A typical range for the power density of the light emitted from the illuminator is about 20-190Mw/cm² and a typical range for the total light dose per treatment of light emitted from the illuminator is from about 20-400

Joules/cm².

After irradiation by light from illuminator 10, the treated skin area may be protected by application of gauze bandage or the like and protected from light by other materials such as a patch or dark cloth or aluminium foil Depending upon the type of treatment response which develops in the length of time the drug or dye remains in the skin tissue, the bandage or covering may be removed after a period of time

As previously described, although many photoactivated compounds may be used with the instant invention, the invention is particularly well suited for photoactivation of a class of compounds known as porphycenes, and even more particularly for photoactivation of the topically applied photoactivated porphycene compound 9-acetoxy-2,7,12,17-tetrakis- (methoxyethyl)porphycene (ATMPn). In reference thereto, the absorption spectrum of ATMPn is shown in Figure 3 of the drawings. Based on this absorption spectrum, light of any wavelength longer than 500 nanometres and shorter than 700 nanometres might be considered acceptable for activating ATMPn in PDT applications. Other drugs used and proposed for use in PDT applications absorb light at slightly different wavelengths, but illuminator 10 can be utilised to provide optimal wavelengths for many photoactivated drugs (and for all porphyrin-based light activated drugs or dyes) by simply altering the filtration of high pressure sodium lamp 12 to maximise the desired emission wavelengths for the drug or dye selected.

Generally, visible light by itself without the presence of any light activated drug does not pose any health or safety risk for normal individuals. However, recent reports on light absorbed directly into capillaries and the haemoglobin of normal blood indicates that lasers and perhaps other light sources emitting at 577 nanometres can produce undesirable changes with relatively low total exposure. Thus, while light exposure using 577 nm from high pressure sodium lamp 12 might be useful in activating ATMPn, illuminator 10 is most suitably filtered to provide a light wavelength band from about 600 to 700 nanometres in width to effectively photoactivate ATMPn for optimum efficacy at minimum risk.

It will be understood that various details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation— the invention being defined by the claims.

Claims

1 A medical illuminator apparatus for activation of a photoactivated compound during photodynamic therapy (PDT), comprising (a) a high pressure sodium lamp having a power output between 100 -

500 watts and wherein at least 35% - 40% of the unfiltered emission is usable for the PDT,

(b) mirror means positioned adjacent to said lamp for collecting the light from said sodium lamp and reflecting it along a predetermined pathway, (c) filter means for filtering the light from said sodium lamp into a wavelength band of a predetermined desired width wherein at least 90% of the filtered emission is in the desired wavelength band for the PDT, and (d) lens means for focusing the light onto an area on a patient

2 A medical illuminator as claimed in claim 1 wherein said sodium lamp has a power output of 100 watts

3 A medical illuminator as claimed in claim 1 or claim 2 wherein said mirror means comprises a parabolic mirror

4 A medical illuminator as claimed in any one of claims 1 to 3 wherein said filter means filters light from said sodium lamp into a wavelength band from about 600 to 700 nanometres (nm) in width

5 A medical illuminator as claimed in any one of claims 1 to 4 wherein said filter means comprises one or more infrared reflecting filters and a red cut-off filter

6 A medical illuminator as claimed in claim 5 wherein said filter means comprises along the optical path a first infrared reflecting filter positioned prior to said lens means, a second infrared reflecting filter positioned subsequent to said lens means, and wherein the red cut-off filter is positioned subsequent to said second infrared reflecting filter

7. A medical illuminator as claimed in any one of claims 1 to 6 wherein said lens means comprises a Fresnel lens.

8. A medical illuminator as claimed in claim 7 wherein said Fresnel lens has a diameter of 5 inches and a focal length of 5 inches

9 A medical illuminator as claimed in claim 7 or claim 8 wherein said

Fresnel lens focuses the light onto an area of 144 cm²

10 A medical illuminator as claimed in any one of claims 1 to 9 further comprising a shutter for selectively providing the desired exposure time of a patient to light from said illuminator apparatus

11. A medical illuminator as claimed in any one of claims 1 to 10 for use in photodynamic therapy (PDT) wherein the therapy comprises the following steps.

(a) administering to a patient a PDT drug that is delivered to a selected patient skin area and which is activated by light in a wavelength band of a predetermined width; (b) irradiation of said skin area and consequent activation of said drug by means of light from a medical illuminator apparatus as claimed in any one of claims 1 to 10

12. A medical illuminator as claimed in claim 11 wherein the PDT drug is topically, systemically or intravenously administered

13 A medical illuminator as claimed in claim 11 or claim 12 wherein the drug is a porphycene compound, preferably 9-acetoxy-2,7,12,17- tetrakιs(methoxyethyl)porphycene.

14 A method of photodynamic therapy (PDT) for a patient comprising the steps

(a) administering to a patient a PDT drug that is delivered to a selected patient skin area and which is activated by light in a wavelength band of a predetermined width, (b) irradiation of said skin area and consequent activation of said drug by means of light from a medical illuminator apparatus as claimed in any one of claims 1 to 10.

15. A method as claimed in claim 14 wherein the PDT drug is topically, systemically or intravenously administered.

16. A method as claimed in claim 14 or claim 15 wherein the said drug is a porphycene compound, preferably 9-acetoxy-2,7,12,17-tetrakis (methoxyethyl)-porphycene.