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WO2006047868A1 - Methode de traitement photodynamique des micro-organismes dans la cavite buccale mettant en oeuvre une source de lumiere non coherente - Google Patents

Methode de traitement photodynamique des micro-organismes dans la cavite buccale mettant en oeuvre une source de lumiere non coherente Download PDF

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WO2006047868A1
WO2006047868A1 PCT/CA2005/001673 CA2005001673W WO2006047868A1 WO 2006047868 A1 WO2006047868 A1 WO 2006047868A1 CA 2005001673 W CA2005001673 W CA 2005001673W WO 2006047868 A1 WO2006047868 A1 WO 2006047868A1
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light
photosensitizer
predetermined
carrier
azure
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John Kennedy
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0061—5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A61N2005/0606—Mouth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0659—Radiation therapy using light characterised by the wavelength of light used infrared
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent

Definitions

  • the invention relates to methods of treating microorganisms in the oral cavity employing photodynamic therapy (PDT).
  • PDT photodynamic therapy
  • Periodontitis is associated with colonization of predominantly Gram- negative microorganisms, including the black-pigmented anaerobes Porphyromonas gingivalis and Prevotella intermedia.
  • Halitosis is typically a consequence of volatile sulphur compounds (VSC).
  • VSCs are produced by oral anaerobic Gram-positive bacteria by degradation of sulphur containing proteinaceous substrates in the saliva. The VSCs are released into the oral environment where they are mixed with air expired from the lungs resulting in a unpleasant oral odour.
  • the above mentioned proteinaceous substrates may come from the intake of foods, such as meat, fish, spices, vegetables, dairy products, etc.
  • Volatile Sulphur Compounds such as, for instance, diallyl sulfide (a thioether), can be found in garlic, which is known to cause bad breath.
  • PDT photodynamic therapy
  • PACT photoactive chemical therapy
  • photosensitizer a photoreactive drug capable of binding or being in close proximity to the targeted cells.
  • photosensitizer means a molecule that absorbs light to enter an excited, highly reactive state, enabling it to catalyse the formation of reactive oxygen species (ROS) that are able to damage cell membranes and DNA.
  • ROS reactive oxygen species
  • Synthetic photosensitizers including methylene blue, toluidine blue O (TBO), and other newly synthesized chemicals can absorb red laser light and are bactericidal for multiple species.
  • TBO is a cell membrane active photosensitizer.
  • TBO is the drug of choice in studies focusing on PDT susceptibility of P. gingivalis, and each study has demonstrated marked reductions in viable bacteria following laser-based PDT.
  • a drawback of using lasers as the light source is the inherent safety concerns associated with laser therapy and the requirement for individual pocket irradiation, which may be somewhat invasive, laborious and time-consuming. This makes it a less attractive alternative to other available antimicrobial therapies.
  • halitosis consists of eliminating or controlling the underlying cause. Proper diet and dental hygiene are often helpful. Mouthwashes and scented toothpastes mask the condition but do not alleviate it.
  • the invention provides a method of treating microorganisms in the oral cavity, including those causing periodontal disease, comprising the steps of:
  • AU or a portion of the steps may be repeated as often as required at predetermined intervals until the target microorganism populations are reduced to a desired level or eliminated.
  • the steps (i) (a), (c) and (d); or (ii) (b), (c) and (d); or all steps may be repeated every day, or every 2 days, or every 3 days.
  • Irradiation of the whole interior of the mouth in step (d) is performed by manipulating the light emitting treatment device such that all accessible interior surfaces are irradiated.
  • This task may be simplified by using light sources capable of delivering light to a wide area inside the mouth and, in some cases, it will be sufficient to irradiate only such wide areas, rather than every accessible area.
  • individual pockets may be irradiated directly to supplement the whole mouth irradiation.
  • the predetermined wait period in step (c) may be from about 1 to about 60 minutes, or from about 5 to about 20 minutes, or from about 10 to about 20 minutes.
  • the photosensitizer may be chosen from toluidene blue, methylene blue, arianor steel blue, tryptan blue, crystal violet, azure blue cert, azure B chloride, azure 2, azure A chloride, azure B tetrafluoroborate, thionin, azure A eosinate, azure B eosinate, azure mix sice, azure II eosinate, haematoporphyrin HCl, haematoporphyrin ester, aluminium disulphonated phthalocyanine, chlorins, photoactive fuUerenes (e.g.
  • the photosensitizer is toluidene blue or methylene blue.
  • the photosensitizer may be present in a concentration of from about 2 ⁇ g/ml to about 500 ⁇ g/ml, or from about 10 ⁇ g/ml to about 50 ⁇ g/ml, or from about 10 ⁇ g/ml to about 15 ⁇ g/ml.
  • the photosensitizer composition for use in step (a) comprises a suitable carrier to improve adhesion to and within the periodontal pockets.
  • the carrier is preferably a gel carrier, but may also be in the form of a cream or paste.
  • the carrier is one which has a transmittance effective to transmit light of wavelengths absorbable by the photosensitizer and the desired rheology, pH, absorbability, and the like and may include at least one of propylene glycol, polyethylene glycol, ethanol and glycerin, and a guar hydroxypropyl derivative.
  • the photosensitizer composition for use in step (b) comprises a suitable carrier and is in the form of an oral rinse, atomized spray, or mouthwash which may comprise at least one of polypropylene glycol, polyethylene glycol, ethanol and glycerin in a concentration of from 2 to 20% w/w, more preferably from 5 to 10% w/w, of the solution. It may also comprise a guar hydroxypropyl derivative. It is preferred but not essential that the the composition of step (b) is less viscous than the composition of step (a).
  • the light used in step (d) may have a peak wavelength ranging from about 600 nm to about
  • the intensity of the light used in step (d) may range from about 10 mW/cm 2 to about 300 mW/cm 2 , or from about 10 mW/cm 2 to about 200 mW/cm 2 , from about 10 mW/cm 2 to about 150 mW/cm 2 , from about 25 mW/cm 2 to about 100 mW/cm 2 , or from about 95 mW/cm 2 to about 105 mW/cm 2 .
  • the light dose used in step (d) may range from about 2 J/cm 2 to about 60 J/cm 2 , or from about 2 J/cm 2 to about 30 J/cm 2 , or from about 6 J/cm 2 to about 25 J/cm 2 , or from about 6 J/cm 2 to about 12 J/cm 2 .
  • the microbial organisms that may be targeted include but are not limited to Porphyromonas gingivalis 381; Prevotella intermedia 25611; Actinobacillus actinomycetemcomitans UT32; Fusobacterium nucleatum 1213; and Bacteroides forsythus 43037 ' .
  • the invention further provides, in accordance with a second aspect, a method of treating halitosis comprising the following steps which may be repeated at predetermined intervals as often as is required until the symptoms of halitosis are reduced to a desired level or eliminated: (a) applying a photosensitizer to the interior of the mouth, including the tongue, buccal mucosa and gum regions, and, optionally, the interior of the periodontal pockets;
  • the invention provides a kit for treating microorganisms in the oral cavity comprising:
  • At least one light emitting treatment device operable to emit non-coherent light at a wavelength spectrum absorbable by the photosensitizer and at a predetermined light intensity
  • instructions for performing the method according to the first and/or second aspects of the invention including instructions concerning the time of irradiation in each irradiation step whereby the predetermined light dose is delivered in each of these steps.
  • the invention provides the use of a light emitting treatment device operable to emit non-coherent light in combination with a photosensitizer to inactivate oral microorganisms, including those that cause various forms of periodontitis as well as halitosis, the light having a wavelength spectrum absorbable by the photosensitizer and a peak wavelength that may range from about 600 nm to about 730 ran, or from about 610 nm to about 690 nm.
  • Figure 1 illustrates the level of kill of P. gingivalis under various in vitro conditions.
  • P. gingivalis was incubated in 50 ⁇ g/ml TBO for 5 minutes prior to irradiation by either the red-filtered xenon lamp or He-Ne laser (2.2 J/cm 2 ).
  • the symbol "*” indicates a statistically significant (p ⁇ 0.05) decline in bacterial survival compared to respective No TBO controls.
  • Mean ⁇ SD; « 3.
  • Figure 2 illustrates the effect of varying xenon-lamp light intensities on P. gingivalis survival.
  • P. gingivalis was incubated with 50 ⁇ g/ml TBO for 5 minutes prior to xenon lamp irradiation at either 10, 25 or 100 mW/cm 2 respectively (total light dose 2.2 J/cm 2 ) with No TBO controls used for comparison.
  • Each light intensity produced a significant decline in P. gingivalis survivors (p ⁇ 0.05) compared to their respective controls.
  • the symbol "*" indicates a significant increase in bacterial killing compared with the 10 mW/cm 2 light intensity treatment with TBO O ⁇ 0.05).
  • Mean ⁇ SD; ra 3.
  • FIG. 3 illustrates the effect of altered xenon-lamp light doses on P. gingivalis survival in the presence and absence of TBO.
  • TBO 50 ⁇ g/ml
  • the detectable limit of the assay was reached (2.48 log cfu/ml). The linear relation could not be extended from 0 to 2.2 J/cm 2 .
  • Mean ⁇ SD; n 2>.
  • Figure 4 illustrates the effect of various conditions on the survival of serum suspended P. gingivalis.
  • the FBS/P. gingivalis suspension was treated at 6.3 J/cm 2 and 100 mW/cm 2 using a non- laser xenon lamp following incubation with 12.5 ⁇ g/ml TBO.
  • the symbol "*” indicates a significant decline in bacterial survival from controls (p ⁇ 0.05).
  • Mean ⁇ SD; « 3.
  • Figure 5 A illustrates the effects of light dose effected by a xenon lamp on survival of blood suspended P. gingivalis.
  • Def ⁇ brinated sheep's blood was used to resuspend P. gingivalis prior to treatment (lamp at 100 mW/cm 2 with 12.5 ⁇ g/ml TBO) with 0, 6.3, 10, 15 or 20 J/cm 2 .
  • All light doses, except the no light control produced significant reductions in bacterial survivors (p ⁇ 0.05) when TBO was present.
  • There is a strong linear relationship from 0 to 10 J/cm 2 (r 2 0.999) that stabilized to an approximate 3 log kill compared to TBO absent controls at higher light doses.
  • Mean ⁇ SD; n 3.
  • Figure 5B illustrates the effect of blood dilution or concentration on P. gingivalis survival following TBO incubation and radiation with a xenon lamp.
  • Def ⁇ brinated sheep's blood was diluted to 1/2, 1/4 and 1/8 with PBS, and a PBS only solution was used as a positive control.
  • the bacterial suspension was incubated for 5 min. with 12.5 ⁇ g/ml TBO and then treated with a non-laser xenon lamp light dose of 10 J/cm 2 and 100 mW/cm 2 .
  • Mean ⁇ SD; 77 3.
  • Figure 6 illustrates the effect of serum washout on P. gingivalis survival following PDT with a xenon lamp at varying light doses.
  • P. gingivalis was washed and resuspended in PBS.
  • P. gingivalis was then treated with 12.5 ⁇ g/ml TBO and irradiated with a 6.3 or 10 J/cm 2 light dose at 100 mW/cm 2 .
  • the symbol "*" indicates a significant decline in P. gingivalis survivors compared to their respective No TBO controls (p ⁇ 0.05).
  • Mean ⁇ SD; n 3.
  • Figure 7 illustrates the relationship of P. gingivalis kill to TBO concentration.
  • Figure 8 illustrates the effectiveness of xenon lamp initiated PDT on different oral pathogens.
  • A. actinomycetemcomitans (Aa); B. forsythus (Bf); F. nucleatum (Fn); P. intermedia (Pi) and P. gingivalis (Pg) were incubated in FBS for one hour at room temperature. Each bacterial species was then washed and resuspended in PBS prior to treatment with 12.5 ⁇ g/ml TBO and a 100 mW/cm 2 10 J/cm 2 light dose. P. gingivalis LD- and LD treatments were used as a comparison for killing efficacy.
  • Figure 9 illustrates the attenuation of light traveling through gingival tissue as measured in a patient.
  • Transillumination spectroscopy was performed by delivering white light to the gingival exterior and collecting light intensity measurements via a fiber optic probe placed inside the gingival pocket. Six locations in the mouth of this subject were examined. The results indicated that for the spectral region of 600 to 1000 nm, approximately 10% to 50% of the light incident on the outer gingival tissue penetrated into a typical 5-7 mm pocket.
  • the bottom image illustrates the relative placement of the light source to the fiber optic probe placed inside the gingival pocket.
  • the light source was a fiber coupled tungsten halogen lamp coupled to an "elbowed" light guide which emitted ⁇ 5 mW of power over a spot with a 3 mm diameter.
  • the light source and the fiber optic probe were calibrated against known intensities of light.
  • Liquid tissue was comprised of a scattering material (Intralipid) and a dye (India ink) in order to match typical tissue optical properties.
  • the liquid tissue simulated phantoms of known absorption and scattering properties. Measurements of the intensity of light were made at several distances from the source fiber. Monte Carlo simulations were conducted using the light intensity values measured throughout the phantom. To determine the correction factor needed between the measured signal and the actual intensity of light, the results of the Monte Carlo simulations were compared to the signals obtained by the detector.
  • a photosensitizer composition is applied in gel form to periodontal pockets in the mouth.
  • the composition comprises (i) at least one photosensitizer (which may include a mixture of photosensitizers), such photosensitizers including at least one of toluidine blue (TBO; also known as tolonium chloride), methylene blue, or any other photosensitizer determined to be effective, (ii) a gel carrier comprising propylene glycol and, optionally, (iii) other orally suitable ingredients.
  • the gel carrier allows simple and stable delivery of the photosensitizer into periodontal pockets as well as to mucosal surfaces so that it would not be washed out prior to light activation and has a transmittance effective to transmit light of wavelengths absorbable by the photosensitizer.
  • the photosensitizer is present in a concentration of 12.5 ⁇ g/ml.
  • the photosensitizing composition is introduced using a syringe; however, any other suitable device such as a cannula can be used.
  • a less viscous photosensitizing composition in the form of a mouthwash or oral rinse solution is introduced to all accessible interior surfaces of the mouth external to the periodontal pockets, including the tongue, buccal mucosa and gum regions.
  • the mouthwash also includes 12.5 ⁇ g/ml of the photosensitizer in an orally acceptable solution.
  • the patient gargles the mouthwash and holds it in his or her mouth for a tolerable period of time (i.e. from about 30 seconds to a minute). This process is repeated from 1 to 5 times to maximize exposure of oral tissues to the photosensitizer.
  • the solution may be applied in other suitable ways such as by manual or assisted irrigation.
  • a light emitting treatment device is used to irradiate the whole mouth (including the periodontal pockets) to activate the photosensitizer applied inside and outside of the periodontal pockets.
  • the light device emits non ⁇ coherent light having a wavelength spectrum matching the absorption curve of the photosensitizer. TBO and methylene blue can absorb light in the red region having a peak wavelength ranging from about 610 nm to about 690 nm.
  • the wavelength of light emitted by the light emitting diodes peaks at 633 nm when using TBO or about 668 nm when using methylene blue.
  • Such light can penetrate gum tissues to activate the photosensitizer contained in the periodontal pockets.
  • the device is adapted to deliver light to all regions of the oral cavity, including under the tongue and through the flesh covered lingual, labial, anterior and posterior areas of the oral cavity and through the bite surface.
  • the light intensity of the light device is 100 mW/cm 2 and the irradiation time is about 100 seconds for each surface such that a light dose of at least 10 J/cm 2 is delivered.
  • the device is connected to a microprocessor which is used to control the light intensity and time of illumination, and therefore also the light dose.
  • the device is sterilized after each use using a suitable disinfectant.
  • alternative light devices could be either disposable or bagged for infection control purposes.
  • the patient gargles once again with the photosensitizing mouthwash solution and the entire mouth is irradiated again, using the same light device to deliver the same light dose, to treat resident microbial organisms or those which might have been released following mechanical procedures, such as scaling or root planing.
  • microbial organisms may cause reinfection of the treated periodontal pockets and typically include the following organisms: Porphyromonas gingivalis 381; Prevotella intermedia 25611; Actinobacillus actinomycetemcomitans UT32; Fusobacterium nucleatum 1213; and Bacteroides forsythus 43037.
  • the entire procedure or portions thereof may be repeated at predetermined intervals until symptoms of bacterial infection are reduced to a desired level or eliminated.
  • the patient can gargle with a photosensitizer mouthwash solution at home and self-irradiate using a home kit according to the present invention (described further below) every 3 days until the symptoms of periodontal disease are reduced to the desired level.
  • the patient can return to the dentist's office to have the periodontal pockets filled with the photosensitizer gel composition followed by further transdermal and transtooth irradiation.
  • a method of killing bacteria responsible for halitosis involves gargling with the above described photosensitizer based mouthwash solution, waiting 5 to 20 minutes and then and irradiating the whole interior of the mouth using the light emitting device. Again, light is applied for at least 1 to 10 minutes to all accessible surfaces such that a light dose of at least 10 J/cm 2 is delivered. These steps are repeated every day until the symptoms are reduced to a desired level. Alternatively or additionally, these steps may be performed every day to keep halitosis causing bacteria to acceptable levels.
  • a third preferred embodiment of the invention is a kit for use in treating microorganisms in the oral cavity.
  • the kit can be designed for professional or home use.
  • the kit comprises the photosensitizer mouthwash solution described above, the above described light emitting device, and instructions for using the components to reduce oral microorganisms to acceptable or desired levels.
  • the instructions in this case, would direct the user to perform the above described method of gargling with the mouthwash solution, waiting the predetermined period of time, and irradiating all accessible surfaces within the oral cavity for the minimum period required to deliver the minimum light dose.
  • a kit designed for professional use may further include the photosensitizer in gel form (as described above), a syringe, cannula or other suitable device for applying the photosensitizer gel to the periodontal pockets, and additional instructions for performing the method according to the first preferred embodiment of the invention described above.
  • the kit may also include two or more alternative light sources designed to reach different areas within the oral cavity.
  • Alternative light sources include light emitting treatment devices capable of irradiating large portions of the oral cavity at once, such as those described in U.S. patent numbers 5,487,662 to Kipke at al., 4,867,682 to Hammesfahr et al., 5,316,473 to Hare and 4,553,936 to Wang.
  • light emitting treatment devices which can be manually manipulated to deliver light to various regions in the mouth which can be used include fibre optic wands, guns or light guides, remote light engines utilizing light generation means in the form of quartz halogen, mercury xenon, xenon, metal halide, sulfur based or other light emitting diode (LED) technology, flexible lightpipes composed of a number of individual fiber optic elements or liquid lightpipes, and other dental impression trays containing light emitting diodes. While various light devices may be used, it will be appreciated that the light device must be capable of delivering an effective dose of light at an effective wavelength. Thus, higher intensities may be used in combination with pulsed light delivery, or lower intensities with continuous light delivery.
  • LED light emitting diode
  • the spectrum of light emitted by the light emitting treatment device would be selected to match the particular absorption curve of the photosensitizer used.
  • a bandpass filter could be used to eliminate wavelengths not absorbed by the photosensitizer.
  • Preferred light emitting treatment devices are expected to be LED based as such can be made into a variety of shapes that will be comfortable for patients and simple to apply for dentists and/or dental hygienists. LED light sources will also reduce the potential for the generation of potentially uncomfortable heat, and would therefore be much more acceptable to patients. It is expected that a suitable light device can be made from a standard dental mouth plate carrying an encapsulated scattering gel (as is known in the art), which gel is pressed up against the gums when the device is in use.
  • LEDs can be embedded directly into the gel and positioned to face the gingival tissue.
  • the scattering medium should ensure that the light is delivered in a uniform cross-section to the gingival tissue surface.
  • Electronic connections to the LEDs can be made to the dental plate out the front of the mouth.
  • the light source may be in the form of optical fibers or other light guides coupled to LEDs with their terminus within the scattering gel.
  • Tests were conducted to investigate the effectiveness of a red-filtered xenon lamp, in combination with TBO, in suppressing P. gingivalis. The results were compared to results of tests employing a He-Ne laser in vitro. Further dosimetric and environmental analyses were performed using the xenon lamp to identify the optimal parameters for in vivo applications. Finally, the parameters were tested on four other species of periodontal pathogens.
  • intermedia strains were subcultured weekly in Todd Hewitt Broth (available commercially from Fisher Scientific; Nepean, Ontario, Canada; hereinafter referred to as Fisher) supplemented with 5 ⁇ g/ml hemin (Sigma- Aldrich Co.; Oakville, Ontario, Canada; hereinafter referred to as Sigma) and 1 ⁇ g/ml menadione (Sigma).
  • A. actinomycetemcomitans was subcultured in Tryptic Soy Broth (Fisher) containing 6g/l yeast extract (Fisher) and 8 ml of 1.5% sodium bicarbonate, filter sterilized (Fisher).
  • F. nucleatum was subcultured in Todd Hewitt Broth.
  • a 100 Watt red-filtered xenon fibre optic light source having a bandwidth of 620-640 nm (available commercially from EXFO, Inc.; Mississauga, Ontario, Canada) was used in these experiments.
  • Laser light irradiation was provided by a diode laser at 635 nm (sold by High Powered Devices).
  • Light dose for each source was calculated by the cross product of the TBO absorption spectrum and light spectrum. Hence, light doses calculated for each source were such that the photons absorbed by each source would be equivalent for a given light dose for the He-Ne laser.
  • the photosensitizer TBO (Sigma) was dissolved in Dulbecco's Phosphate Buffered Saline (PBS) (Sigma) to a concentration of 1 mg/ml under ambient light.
  • PBS Dulbecco's Phosphate Buffered Saline
  • the solution was filter sterilized, aliquoted and stored in dark tubes at -20 0 C for up to 3 months without a loss in potency.
  • the stock was diluted to appropriate concentrations with PBS as required.
  • the perfusion chamber was 500 ⁇ m thick, and so attenuation of the treatment light by the TBO was only 30% at 50 ⁇ g/ml. For most treatments at a concentration of 12.5 ⁇ g/ml TBO, the attenuation of treatment light was only 9%.
  • the inoculated perfusion chamber was irradiated under the desired conditions with a light beam whose diameter covered the perfusion chamber's transparent surface. Upon completion, the mixture was removed and serially diluted in PBS and each dilution was plated on the following media: for P. gingivalis, P. intermedia, and F.
  • nucleatum Trypticase Soy Agar (Fisher) supplemented with 5g/l yeast extract, 5 ⁇ g/ml hemin, 1 ⁇ g/ml menadione, 50 ml/1 defibrinated sheep's blood (Oxoid, Inc.; Nepean, Ontario, Canada); for B. forsythus, Trypticase Soy Agar supplemented with 4 g/L yeast extract, 4 g/L trypticase peptone (Fisher), N-acetymuramic acid (10 mg/ml stock filter sterilized into medium to 10 mg/1); and for A. actinomycetemcomitans, Tryptic Soy Agar. Once plated, P.
  • gingivalis, P. intermedia, F. nucleatum and B. forsythus were grown in dark anaerobic jars containing 10% H 2 :CO 2 and the balance N 2 (BOC Gases Canada, Ltd.; Toronto, Ontario, Canada) for 6 days at 37°C in the presence of catalyst.
  • A. actinomycetemcomitans was grown overnight at 37°C in 10% CO 2 with the balance air. Colony counts determined the number of bacterial survivors and they were expressed as cfu/ml.
  • fetal bovine serum FBS
  • defibrinated sheep's blood After the final PBS wash and was then used in the PDT assay at a final concentration of 50% (v/v).
  • PDT of a patient's periodontal pocket is likely to cause some degree of washout when TBO is added.
  • the bacteria was prepared as described and the suspension was incubated for 1 hour at room temperature in an appropriately adjusted volume of sterile serum. The serum/bacteria mixture was then centrifugated and washed as before using PBS to resuspend the pellet.
  • Figure 2 illustrates the effect of altered light intensity on P. gingivalis survival.
  • 10 mW/cm achieved a kill of 2.12 ⁇ 0.36 logs; 25 mW/cm and 100 mW/cm each achieved a kill of over 3 logs (3.34 ⁇ 0.41 logs and 3.41 ⁇ 0.58 logs respectively).
  • the detectable limit of the assay (300 cfu/ml or 2.48 log cfu/ml bacterial survivors) was reached at 10 J/cm , at which point no bacterial colonies were visible.
  • the target of 5 logs bacterial kill was achieved at the lower light dose of 6.3 J/cm , which was used in later experiments.
  • GCF gingival crevicular fluid
  • the set PDT parameters (10 J/cm , 100 mW/cm and 12.5 ⁇ g/ml TBO) were used in tests concerning other bacterial species.
  • P. intermedia 5.33 + 0.62 logs kill
  • F. nucleatum 4.7 ⁇ 0.72 logs kill
  • A. actinomycetemcomitans (5.51 + 1.34 logs kill).
  • PDT can be used effectively to kill periodontal pathogens when utilizing a xenon lamp at 10 J/cm , 100 mW/cm , and 12.5 ⁇ g/ml TBO, even in the presence of serum and blood at high concentrations.
  • the attenuation of light traveling through gingival tissue was measured using trans- illumination spectroscopy. Measurements were made on typical pockets of patients suffering from periodontal disease. Low intensity white light was delivered to the exterior of gingival pocket sites using an elbowed light guide. Light in the pocket was collected by a cylindrical diffusing tipped optical fiber probe, inserted into the gingival pocket at depths between 4-7 mm. This light was delivered to a portable spectrometer system. The apparatus was calibrated to measurements in tissue simulating liquid phantoms of known optical properties and comparing these results with calculations of the expected light intensity in the phantoms.
  • Figure 9 shows the transmission spectra measured on one patient along with the measurement location in the mouth for each spectrum. Approximately 10-50% of the incident light penetrates into the gingival pocket, with attenuation greater for pockets located between teeth, and less attenuation for pockets located on facial or lingual sides.
  • an alternative light source i.e. a conventional red- filtered xenon lamp
  • a conventional red- filtered xenon lamp is at least as effective an inducer of PDT as a laser and may even provide a significantly improved kill when testing P. gingivalis in vitro.
  • the ten-fold increase in killing could be due to a broad-spectrum effect provided by the xenon lamp compared to the He- Ne laser.
  • the lamp although filtered for light in the red spectrum, is not as precise as laser light and it was necessary to increase the lamp delivered light by 10% in order to deliver an equal amount of photons in the upper red spectrum compared to the laser.
  • This 10% increase in light delivered would include an increase in low wavelength lamp light, which may weakly activate additional TBO molecules since the excitation wavelength of TBO excitation can vary from 620-660 nm, depending on TBO molecular stability. This additional excitation may then cause the additional bacterial killing witnessed when compared to the laser.
  • Light intensity and light dose were both shown to contribute significantly to bacterial killing. Light intensity would be expected to significantly affect light penetration into the periodontal pocket. For these experiments, the near maximum intensity available (100 mW/cm 2 ) was used since higher intensities provided improved penetrance and shorter irradiation periods. A consideration in using this light intensity with the xenon lamp is the generation of heat. For in vivo use, the intensity would be selected to keep the heat generation to levels tolerable by the patient. The time of irradiation would be increased as required to deliver the required light dose.
  • Total light received by the TBO/bacteria mixture is a significant determinant of the amount of kill, as is evident by their linear relationship. This relationship was demonstrated previously with a He-Ne laser and reiterated in these experiments for the xenon lamp. However, from 0 to 2.2 J/cm 2 the relationship is skewed. It may be argued that the relationship is not linear for this light dose range. The effectiveness of light doses below 2.2 J/cm 2 could be limited by a threshold effect, whereby the number of photons absorbed by lower light doses is insufficient to provide killing, and above this threshold light dose cell death increases linearly. Preliminary studies have also shown that enough light can be delivered into periodontal pockets using transperiodontal illumination/irradiation that would be capable of activating TBO.

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Abstract

L'invention concerne une méthode et un kit de traitement des micro-organismes dans la cavité buccale. Ces micro-organismes comprennent les micro-organismes contribuant à la parodontopathie et à l'halitose. Cette méthode consiste: à appliquer un photosensibilisateur sur l'intérieur de la cavité buccale, à l'intérieur et/ou à l'extérieur des poches parodontales; à attendre pendant une durée prédéterminée; et à irradier tout l'intérieur de la bouche au moyen d'une lumière non cohérente présentant un spectre de longueurs d'onde pouvant être absorbé par le photosensibilisateur, à une intensité de lumière prédéterminée et pendant une durée prédéterminée, suffisante pour libérer une dose de lumière prédéterminée.
PCT/CA2005/001673 2004-11-02 2005-11-02 Methode de traitement photodynamique des micro-organismes dans la cavite buccale mettant en oeuvre une source de lumiere non coherente Ceased WO2006047868A1 (fr)

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