Patent Application
20080069781
The present invention provides a method and composition for disinfecting or sterilizing tissues in the oral cavity or a wound or lesion in the oral cavity. The method comprises applying a photosensitizing compound in a timed release formulation, as well as a formulation which provides locally high concentrations of primary protected photosensitizers, to the tissues, wound or lesion. Photosensitizers that produce highly reactive singlet oxygen upon activation by irradiation are known to be effective in destroying unwanted (bacterial) species and thereby disinfecting and sterilizing lesions and wounds as well as implants in the oral cavity. The timed release is characterized by providing a sustained concentration of the photosensitizer in or around a treatment area during a prolonged time period in which the photosensitizer can be activated one or several times by irradiating the tissues, wound or lesion with laser light at a wavelength absorbed by the photosensitizing compound.
This long term formulation is characterized by its ability to maintain a certain concentration of the photosensitizer drug over a prolonged period of time, and it thus provides the ability to repeatedly activate the photosensitive compound after a single application and thereby achieve healing due to repeated treatments over an extended time period with only one application of the formulation. An alternative description of this action is that only a portion of the photosensitizer is available for activation by a first irradiation of treatment site. In one embodiment, a long term effect is achieved by administering the photosensitive drug bound to particles or molecules which release the drug slowly, or by coating the respective surfaces with a specially modified dye. In another embodiment, the photosensitive molecules are included in and released from micro- or nanoparticles by controlled diffusion. Biodegradable nanoparticles can be used to avoid the step of actively releasing the molecules. In that case, the duration of the timed release would be limited and would vary depending on the composition of the nanoparticles. In another embodiment, release from some or all of the micro- or nanoparticles can be actively and controllably induced by the user or practitioner as part of the treatment.
These formulations are especially useful in treating chronic diseases like periodontal lesions where repeated treatments are necessary to achieve healing. After a photosensitizer in a timed release formulation is administered to the affected area, it is left in contact with the microbes for a period of time to enable the microbes to take up some of the photosensitizer and become sensitive to the laser light. The photosensitizers are subsequently activated by radiation at suitable wavelengths for one or more treatments to destroy the target microbes. The activation can be carried out by a dental practitioner or even by the patient at home with, for example, a laser toothbrush, operating at a wavelength which activates the photosensitizer.
In preferred aspects of the invention, the described treatment with photosensitizing compounds and laser irradiation can be applied to a variety of tasks including:
the destruction of disease-related microbes in a periodontal pocket in order to treat chronic periodontitis;
the destruction of disease-related microbes in the region between the tooth and gingiva (gingival crevice or gingival margin) in order to treat or prevent inflammatory periodontal diseases including chronic periodontitis, gingivitis and the like; and
the disinfection or sterilization of dental implants and dental and/or gingival tissues in other dental surgical procedures.
The advantage of the use of photosensitive compounds over other methods, such as antibiotic treatments, is the ability to controllably activate the compound with radiation and therefore enhance treatment effects. The long term use of antibiotics often promotes the development of resistance rendering the agents clinically ineffective. Additionally, high concentrations of antibiotics may have undesired side effects in the tissue and on the oral microflora. Since the photosensitive compound shows no toxicity without irradiation, the application of high concentrations and short and possibly repeated activation times show enhanced therapeutic effects and reduced side effects. High concentrations of the photosensitizer can be achieved, for example, by the use of specialized micro- and nano-particles such as dendrimers. Moreover, the ability of the compound to destroy only the unwanted species and leave healthy tissue intact can be enhanced by modifying the compound with targeting moieties. These modifications can affect chemical or physical properties that show an affinity to areas such as the cell membranes of unwanted bacterial species. Other targeting methods including coupling with antibodies or other affinity molecules are conceivable.
It is preferred that the photosensitizers used in the method of the present invention are activatable by light at the red end of the visible spectrum or at longer wavelengths, preferably between 630 and 800 nm. Light at these wavelengths is better able to penetrate tissues surrounding a wound or lesion, such as oral tissues, and, in particular, blood which may be present in the sites to be treated. This may be particularly useful in treating Alcove-like regions having honeycomb-like pockets. Several “second generation” photosensitive compounds with these spectral absorption properties are known to date, and include porphyrins, chlorins, pheophorbides, bacteriopheophorbides, phthalocyanines, naphthalocyanines, thiazines, xanthenes, pyrrylium dyes, psoralens, quinones. Other compounds may also be used with the present invention, including photosensitizer precursors such as aminolevulinic acid (ALA), which naturally in a mammalian body converts to a photosensitizer, protoporphyrin IX.
In a preferred embodiment, the timed release characteristic of the present formulation is due to the inclusion of polymeric micro- or nanoparticles, constructed with polymers, that contain the photosensitizer molecules. Release of photosensitizers from these polymers can occur by two general mechanisms. The first mechanism is diffusion resulting in the gradual release of the photosensitive molecules from the implant surface. The second mode of release occurs by the cleavage of the polymer backbone, defined as bulk erosion. Release can also be induced by a number of other processes. Such processes include radiation, ultrasonics, agitation through brushing, and chemical release such as with a solvent.
The micro- or nanoparticles consist of molecules building up polymers that are tolerable and non-toxic to the human or animal body. Several such compositions are known to date, among them are biodegradable and non-biodegradable compositions. Non-biodegradable particles must be removed after a certain time and thus the duration of the deposit effect can be chosen. The life time of biodegradable compounds is limited but can be chosen in a certain time range by varying the composition and size of the polymer. The molecular weight of the polymers has an important effect on the period of drug release and degradation of the microspheres. The products of degradation processes such as hydrolysis of the particles are biologically compatible and metabolizable moieties which are eventually removed from the body. Polymer biodegradation products are formed at a very slow rate, and hence do not affect normal cell function. Moreover, the deposit effect can be achieved by coating the affected areas such as teeth, implants or periodontal pockets with the photosensitizer.
In addition to the advantage of being able to house and gradually or periodically release photosensitizers, nanoparticles offer an additional benefit. Many photosensitizers suffer from significant inhibition in effectiveness from exposure to saliva, white blood cells, and other natural defenses in the mouth. This especially can prove a significant problem in maintaining an effective concentration of photosensitizers in the mouth for an extended period of time. Because photosensitizers are encased in nanoparticles before treatment, they are shielded from these bodily fluids and thus do not degrade as quickly as they would if left unprotected. Non-biodegradable micro- or nanoparticles serve to protect photosensitizers until the photosensitizers are released. Likewise, biodegradable nanoparticles also protect photosensitizers until they degrade to the point where they release the photosensitizers. In this way, micro- or nanoparticles further serve to prolong the period of time that photosensitizers can remain in the oral cavity.
It should be noted that the photosensitizer has to be in a certain concentration at the site of treatment and, for instance in the treatment of periodontal pockets and wounds where the treatment site may be flooded with body fluid such as saliva or blood, it might be necessary to apply the photosensitizers in greater concentration so as to achieve an effective concentration after dilution by the body fluid. Moreover, the treatment is more effective if the photosensitizer is applied in higher concentrations. These concentrations can be achieved by using highly specialized micro- and nanoparticles like dendrimer-photosensitizer complexes. Since the photosensitive compounds do not show any dark toxicity, these concentrations can be applied without side effects. Because exposure of the surrounding tissues of the oral cavity to the activated photosensitizer will generally be of short duration and highly localized, it may also be acceptable to use compounds which have some slight toxicity to these tissues.
It is a further object of the present invention to enhance the selectivity of the timed release photosensitizer towards unwanted species such as bacteria. The targeting is either achieved by chemically modifying the chemical or physical properties of the photosensitizer, or by coupling the molecule to a targeting moiety such as an antibody. It is generally preferred that the photosensitizer selected for use has a positive charge under physiological conditions since such photosensitizers are more readily taken up by the target microbes. Other targeting moieties that specifically recognize components of the bacterial cell membranes are known.
The present invention is further illustrated by the following examples, but is not limited thereby.
A dentist or patient can treat periodontal disease in various stages, or self-apply the treatment for prevention of diseases arising from microbes within the oral cavity. A composition containing photosensitizers encased in micro- or nanoparticles is administered either by a dentist or by the patient. For patient application, a mouthwash is used containing a high concentration of the nanoparticles. The patient takes a prescribed dose of the mouthwash, and applies it as one would apply traditional mouthwashes to coat the mouth. Patient would then wait a prescribed period, typically 4 to 6 hours, or apply the mouthwash before bedtime. During this time, the mouth's natural saliva would serve to flush most of the micro- or nanoparticles from the mouth, leaving only those particles which are associated with the biofilms or trapped in existing periodontal pockets. After the prescribed period, the dentist/patient would then administer radiation using a laser toothbrush (as seen in, for example, U.S. Pat. No. 5,658,148) to apply laser radiation for a prescribed duration or other means to direct irradiation to the treated sites within the oral cavity. The application would be similar in duration to the time taken to brush one's teeth. A prescribed frequency of about 2 times a day would effectively destroy harmful bacteria in the mouth. Merely to prevent recurrences a less frequent activation might be proposed of once a day or two.
A dental practitioner applies the photosensitizer formulation. A gel containing the above-described micro- or nanoparticles is applied by the dentist directly to the periodontal pockets. This is preferable for patients with more advanced stages of periodontal disease, in that the dentist can insure that sufficient photosensitizer reaches the deeper pockets. In one preferred embodiment a gel is chosen which hardens after application, so that photosensitizer is set to slowly release over an extended period of time such as days/weeks etc. The pockets themselves should act to retain the photosensitizer for an extended period of time. The patient returns for periodic radiation treatments or in an alternative case self-applies radiation at prescribed intervals as described in Example 1 using a laser toothbrush, as mentioned above, or other suitable means.
Having described preferred embodiments of the invention, it is to be understood that the invention is not limited to the precise embodiments, and that various changes and modifications may be effected therein by those skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims.
