KR100846912B1 - Method for photodynamic therapy and applicator for carrying out said therapy - Google Patents

Abstract

The present invention relates to light energy therapy (PDT) which can be used in medicine, in particular in tumors and skin diseases.

Pathological surface tissue characterized by superimposing the surface of the pathological site by superimposing an applicator containing 5-aminolevulinic acid (5-ALA) and irradiating the sensitized site with therapeutic light radiation in the 625-700 nm spectral range. An optical energy therapy of is proposed, wherein an applicator is used which is transparent in the spectral range of at least 625 to 700 nm and irradiation is carried out through the applicator.

The therapeutic irradiation can be carried out under the control of fluorescence intensity on tissue at the pathological site, the tissue being irradiated in the spectral range of 625 to 635 nm and the fluorescence intensity measured in the range of 635 to 700 nm via the applicator. .

In the above method, an applicator that is transparent in at least one of the spectral range of 390 to 460 nm, 510 to 540 nm or 570 to 590 nm can be used. The applicator used in the proposed method consists of a photosensitive layer having a base of a bioinner material and a carrier and 5-aminolevulinic acid dissolved or dispersed in the carrier. The base is prepared in the form of a film of a biointegral polymer that is permeable in the spectral range of at least 625 to 700 nm, wherein the carrier has a monomer link ratio of (20-35): (35-60): (20-30), respectively. ) In the form of a film layer of biocompatible hydrophilic trimers of N-vinylpyrrolidone, acrylic acid amide and acrylic acid ethyl ether, having a weight percent of 20,000 to 1,000,000 Daltons.

 The bioinertia polymer may also be transparent in at least one of the spectral ranges from 390 to 460 nm, 510 to 540 nm or 570 to 590 nm. This polymer is regenerated cellulose, polyethylene terephthalate or polyamide.

Applicators for implementing the proposed photoenergy therapy and methods can improve the efficiency of photoenergy therapy and reduce the consumption of 5-aminolevulinic acid.

Photo Energy Therapy, Applicator, 5-ALA

Description

TECHNICAL FOR PHOTODYNAMIC THERAPY AND APPLICATOR FOR CARRYING OUT SAID THERAPY}

The present invention relates to light energy therapy (PDT) which can be used in medicine, in particular in tumors and skin diseases.

A method for photoenergy therapy of pathological surface areas is disclosed in PCT Publication No. WO 95/07077 (IPC A61K 31/195), hereinafter referred to as "Publication 1," dated March 16, 1995. According to the present invention, the applicator is applied onto a liquid ointment base (containing an optically opaque coating layer on top of this layer) containing 5-aminolevulinic aud (5-ALA). Place, remove the ointment layer after a predetermined time, laser-fluorescence analysis of the concentration of the sensitizer (porphyrin derivative) in the tissue at the pathological site, and with optical radiation in the spectral range from 625 to 700 nm. It is characterized in that the surface of the pathological site is sensitized practically by irradiating the site.

The conventional applicator disclosed in Publication 1 includes a carrier in ointment form having a gel-like suspension or emulsion form of a fluid and 5-ALA dissolved or dispersed in the carrier.

The drawbacks of the conventional PDT method and the conventional applicator disclosed in the publication 1 are that it is not possible to conduct therapeutic investigation of the pathological site surface, to control the accumulation of sensitizers in the tissue during the sensitization process, and the surface of the pathological site. The application of 5-ALA at the correct dose to the bed is complicated, and the ointment must be removed prior to irradiation, resulting in an unproductive consumption of 5-ALA, particularly by the removal of substantial pathological areas that require sensitization. The ointment can be accidentally removed when placed in the patient's body part. All these drawbacks reduce the treatment efficiency of PDT.

The drawbacks of the photoenergy therapy and applicator of the pathological surface area disclosed in Publication 1 above, which are related to the possibility of accidental removal of ointment and the complexity of the application of the correct dose of 5-ALA on the surface of the pathological site, due to the concentration of the ointment, 1995 And partially removed from the dynamic therapy and applicator of the pathological surface area disclosed in PCT Publication No. WO 95/05813 (IPC A61K 31/195) (hereinafter referred to as "Publication 2"), dated March 2, 2011. These are most similar to those proposed by the present invention. The applicator disclosed in Publication 2 includes a base of a bioinertial material, and a sensitizing layer having a polymer carrier and 5-ALA dissolved or dispersed in the carrier. Since metal foils, polyesters, rubber sponges, foam polymers or other materials, which are absorbents or dispersants, which are impermeable to light radiation are used therein as bases of bioinnerative materials, The applicator is optically opaque. This makes it impossible in the known method to carry out a therapeutic investigation or fluorescence analysis of the sensitizer concentration of the pathological site surface during the sensitization process, since this operation is only performed with the applicator removed. As in Publication 1, all this reduces the treatment efficiency of PDT.

The purpose of using the applicator on the base of sensitized 5-aminolevulinic acid to improve the efficiency of photoenergy therapy of the pathological surface area is to optimize the sensitization and irradiation process of the pathological site and also to the 5-aminolevulinic acid. It is achieved by the present invention to reduce the consumption of.

An object of the present invention is to superimpose the surface of a pathological site by superimposing an applicator containing 5-aminolevulinic acid (5-ALA) and to irradiate the site sensitized by therapeutic light radiation in the 625 to 700 nm spectral range. In photoenergy therapy of pathological surface forming sites, a transparent applicator is used in the spectral range of at least 625 to 700 nm and irradiation is carried out through the applicator.

It is also an object of the present invention that the therapeutic irradiation can be carried out under the control of the fluorescence intensity of the tissue at the pathological site, whereby the tissue is irradiated in the spectral range of 625 to 635 nm and the fluorescence intensity is By measuring in the range of 635 to 700 nm via an applicator.

It is also an object of the present invention to monitor the fluorescence intensity of pathological site tissue by measuring the fluorescence intensity in the range of 635 to 700 nm through an applicator and one of the spectral range of 390 to 460 nm, 510 to 540 nm or 570 to 590 nm. This is achieved by using an applicator that is also transmissive in at least one of the above spectral ranges, while performing during irradiation at. The above object is aimed at an applicator comprising a base of a bioinner material and a photosensitive layer having a carrier and 5-aminolevulinic acid dissolved or dispersed in the carrier, the base having a spectral range of at least 625 to 700 nm. It is prepared in the form of a bioinerative polymer film permeable to the carrier, wherein the carrier is a film layer of a biocompatible hydrophilic copolymer of an acrylic acid derivative and N-vinylpyrrolidone, wherein the copolymer has a monomer link ratio of (20 35): (35-60): (20-30) by weight and a molecular weight of 20,000 to 1,000,000 daltons, terpolymers of N-vinylpyrrolidone, acrylate amide and acrylate ethyl ether .

In addition, the biointerior polymer may also be transparent in at least one of the spectral ranges from 390 to 460 nm, 510 to 540 nm or 570 to 590 nm.

As the bioenerual polymer, regenerated cellulose, polyethylene terephthalate or polyamide can be used.

The proposed method is carried out by the following method.

The applicator in the form of a film is placed on the surface of the pathological site with respect to the shape and size for the topology of the site presumed to be sensitized according to the chosen treatment method. The applicator is a copolymer of an acrylic acid derivative and N-vinylpyrrolidone, with a base in the form of a bioinner polymer film (e.g., regenerated cellulose, polyethylene terephthalate or polyamide) that is transparent in the spectral range of at least 625 to 700 nm. And a photosensitive layer having a biocompatible hydrophilic copolymer and 5-aminolevulinic acid (5-ALA) dissolved or dispersed therein. The applicator is placed on the surface of the pathological site and held on the surface by an adhesive. After a certain time has elapsed, for example after 2-3 hours, the concentration of the sensitizer (porphyrin derivative) on the sensitized site is 390-460 nm, 510-540 nm, 570-590 nm, or 625-635 nm. It is controlled by irradiating through the film by light emission in one of the spectral ranges of and measuring the fluorescence intensity of the porphyrin derivative in the spectral range of 635 to 700 nm. According to this measurement, if the concentration of the sensitizer corresponds to or exceeds the treatment level selected according to the treatment method, the sensitized site is irradiated through the film by therapeutic light emission in the 625 to 700 nm spectral range. However, if the concentration of the sensitizer in the tissue is insufficient, further sensitization continues with monitoring (periodically or continuously) until the concentration of the sensitizer reaches the required level, followed by a therapeutic investigation.

Biocompatible hydrophilic polymers are prepared by copolymerization of N-vinylpyrrolidone, acrylic acid amide, and ethyl acrylate ethyl ["Copolymerization of vinyl heterocyclic monomers and acrylic acid derivatives in the production of biosoluble polymers). (Co-authored by Davidov OB and Kharomov GL), 1973, Kazan, Thesis of the Allied Conference on the 18th Polymer Compound, p. 19]. In order to obtain polymers of the required molecular weight, the polymerization is carried out in solution or in "solvent-precipitant" systems. By varying the weight ratios of the monomers and taking into account their copolymerization constants, biocompatible polymers are obtained by different hydrophilic-hydrophobic balances of monomeric links in the macromolecules.

Embodiments implementing the method.

Example 1                 

In order to perform sensitization of pathologies with basal cell skin carcinoma having a thickness of about 3.5 mm and a diameter of about 20 mm, an applicator permeable in the spectral range of 625 to 700 nm is used, The applicator is N-vinylpyrrolidone, acrylic acid amide and acrylic acid with a ratio of 25: 50: 25% by weight and a molecular weight of 320,000 Daltons in the form of a circular film having a diameter of 28 mm made from recycled cellulose. It has a photosensitive layer containing a carrier which is a trimer of ethyl ether (30 mg / cm ² of 5-ALA is dissolved in the carrier). The applicator is pressed against the surface of the pathological site. After 3 hours, the pathological site was irradiated through the applicator by laser radiation with a wavelength of 633 nm, the fluorescence intensity was monitored in the spectral range from 635 to 700 nm, and the concentration of the sensitizer was evaluated based on the measurement. After the sensitizer reached the therapeutic concentration, the pathology site was irradiated through the applicator by laser radiation with a wavelength of 628 nm, a power density of 100 mW / cm ² and a dose density of 60 J / cm ² . One day after the treatment investigation, repeated diagnostic fluorescence studies of the pathological site indicated that the tumor tissue necrosis over substantially the entire area of the tumor examined except for one small portion where the tumor tissue remained. At the remaining tumor tissue site, due to the sensitizing action of the applicator, a high concentration of sensitizer was maintained, which was confirmed by the results of fluorescence studies. Repeated irradiation of the detected portion through the applicator was performed by therapeutic laser radiation with a wavelength of 628 nm, a power density of 100 mW / cm ² and a dose density of 20 J / cm ² . After 2 days, dry crusts formed over the entire surface of the pathological site. Data on histopathologic studies of tissue at the site of pathology showed necrosis of tumor tissue at depths up to 4 mm. After PDT, studies of the tissue at the site of pathology showed complete degeneration of the tumor.

Example 2

In order to perform sensitization of pathological sites with basal cell carcinoma having a thickness of about 1.5 mm and a diameter of about 10 mm, an applicator permeable in the spectral range of 625 to 700 nm and 510 to 540 nm was used. The applicator has a photosensitive layer containing a base in the form of a regenerated cellulose film and a carrier in the form of a circular film having a diameter of 18 mm, wherein the carrier film has a monomer link ratio of 25: 55: 20% by weight and a molecular weight of It is prepared from trimers of N-vinylpyrrolidone, acrylic acid amide and acrylic acid ethyl ether, which are 300,000 daltons, and 20 mg / cm ² of 5-ALA is dissolved in the film. The applicator is pressed against the surface of the pathological site. After 3 hours, the pathological site was irradiated through the applicator by laser radiation with a wavelength of 532 nm, the fluorescence intensity in the spectral range from 635 to 700 nm was monitored, and the concentration of the sensitizer was evaluated based on the measurement. After the sensitizer reached the therapeutic concentration, the pathology site was irradiated through the applicator by laser radiation with a wavelength of 628 nm, a power density of 100 mW / cm ² and a dose density of 60 J / cm ² . Data on histopathologic studies of tissue at the pathological site showed necrosis of tumor tissue, complete degeneration of tumor at depths up to 1.5 mm.

Example 3

In order to perform sensitization of pathological sites with basal cell carcinoma of the nose having a thickness of about 1.5 mm and a diameter of about 10 mm, an applicator permeable in the spectral range of 625 to 700 nm was used. The applicator is N-vinylpyrrolidone, acrylic acid amide, and the like, wherein the ratio of the base and monomer links in the form of a circular film having a diameter of 18 mm made from recycled cellulose is 33:38:29 wt% and the molecular weight is 970,000 Daltons; It has a photosensitive layer containing a carrier which is a trimer of ethyl acrylate ether (30 mg / cm ² of 5-ALA is dissolved in the carrier). The applicator is pressed against the surface of the pathological site. After 4 hours, the pathological site was irradiated through the applicator by laser radiation with a wavelength of 633 nm, the fluorescence intensity in the spectral range from 635 to 700 nm was monitored, and the concentration of the sensitizer was evaluated based on the measurement. After the sensitizer reached the therapeutic concentration, the pathology site was irradiated through the applicator by laser radiation with a wavelength of 628 nm, a power density of 100 mW / cm ² and a dose density of 60 J / cm ² . One day after the treatment investigation, repeated diagnostic fluorescence studies of the pathological site indicated that the tumor tissue necrosis over substantially the entire area of the tumor examined, except for one small portion where the tumor tissue remained. In the remaining tumor tissues, due to the photosensitization of the applicator, a high concentration of sensitizer was maintained, which was confirmed by the results of the fluorescence study. Repeated irradiation of the detected portion through the applicator was performed by therapeutic laser radiation with a wavelength of 628 nm, a power density of 100 mW / cm ² and a dose density of 20 J / cm ² . Two days after irradiation, a dry crust formed over the entire surface of the pathology site. Data on histopathological studies of tissue at the pathological site showed necrosis of tumor tissue at depths up to 2 mm. Studies on the tissue at the pathological site after PDT showed complete degeneration of the tumor.

Example 4

In order to perform sensitization of pathological sites with skin transition of mammary carcinoma with a thickness of about 3.5 mm and a diameter of about 10 mm, an applicator permeable in the spectral range of 625 to 700 nm and 390 to 460 nm was used. The applicator has a photosensitive layer containing a base in the form of a polyethylene terephthalate film and a carrier in the form of a circular film having a diameter of 50 mm. The carrier film was made from trimers of N-vinylpyrrolidone, acrylic acid amide and ethyl acrylate ethyl having a monomer link ratio of 21: 59: 20% by weight and a molecular weight of 300,000 Daltons, and 30 mg / cm ² 5-ALA is dissolved. The applicator is pressed against the surface of the pathological site. After 4 hours, the pathological site was irradiated through the applicator by laser radiation with a wavelength of 442 nm, the fluorescence intensity in the spectral range from 635 to 700 nm was monitored, and the concentration of the sensitizer was evaluated based on the measurement. After the sensitizer reached the therapeutic concentration, the pathology site was irradiated through the applicator by laser radiation with a wavelength of 628 nm, a power density of 100 mW / cm ² and a dose density of 120 J / cm ² . Data on histopathologic studies of tissue at the pathological site showed necrosis of tumor tissue at depths up to 4 mm.

Example 5

In order to perform sensitization of pathological sites with recurrent basal cell carcinoma with a thickness of about 1.5 mm and a diameter of about 10 mm, an applicator permeable in the spectral range from 570 to 700 nm was used. The applicator has a photosensitive layer containing a base in the form of a polyamide film and a carrier in the form of a circular film having a diameter of 20 mm. The carrier film is made from trimers of N-vinylpyrrolidone, acrylic acid amide and ethyl acrylate ethyl, with a monomer link ratio of 21: 59: 20% by weight and a molecular weight of 22,000 daltons, the film having 30 mg / cm ² 5-ALA is dissolved. The applicator is pressed against the surface of the pathological site. After 4 hours, the pathological site was irradiated through the applicator by laser radiation with a wavelength of 578 nm, the fluorescence intensity in the spectral range from 635 to 700 nm was monitored, and the concentration of the sensitizer was evaluated based on the measurement. After the sensitizer reached the therapeutic concentration, the pathology site was irradiated through the applicator by laser radiation with a wavelength of 630 nm, a power density of 100 mW / cm ² and a dose density of 120 J / cm ² . Data on histopathologic studies of tissue at the pathological site showed necrosis of tumor tissue at depths up to 2.5 mm.

The permeability of the applicator and the possibility of irradiation through the applicator is mainly due to the tumor being irradiated during the course of sensitization, for example due to insufficient concentration of the sensitizer, specificity of the site of pathology or insufficient dose at the start of the therapeutic injection. In cases where tumors are not completely destroyed by the presence of a tumor cell site where the sensitizer is continuously accumulated due to the influx of 5-aminolevulinic acid from the proposed applicator, and additional therapeutic investigations may be performed as needed. Makes it possible to perform. In addition, irradiation at the beginning of the course of sensitization may result in additional accumulation of sensitizers in tumor tissues (Patent RF 2146159, IPC A61N 5/06, which gives priority to April 11, 1996). The foregoing offers the possibility of improving the effectiveness of the PDT. According to this, since the applicator fixed to the site prior to the initiation of this action is used during the entire course of action on the pathological site, both the risk of trauma or infection to the pathological site and the consumption of 5-aminolevulinic acid are reduced.

The proposed photoenergy therapy and applicator for practicing the same can be used during the treatment of both surface tumors (eg basal cell skin carcinoma) and benign diseases of the skin envelope (especially psoriasis and others).

Claims (6)

delete delete delete  The base is made in the form of a bioinertial polymer film that is permeable in the spectral range of at least 625 to 700 nm, and the carrier is made in the form of a film layer of a biocompatible hydrophilic copolymer of acrylic acid derivatives and N-vinylpyrrolidone. The copolymers include N-vinylpyrrolidone, acrylic acid amide, wherein the ratio of monomer links is (20-35): (35-60): (20-30)% by weight, and the molecular weight is 20,000 to 1,000,000 Daltons, and An applicator for photoenergy therapy comprising a photosensitive layer having a base of a bioinner material, characterized in that it is a trimer of ethyl ether, and a 5-aminolevulinic acid dissolved or dispersed in the carrier. 5. The applicator of claim 4, wherein said bioinner polymer is also transparent in at least one of the spectral ranges of 390-460 nm, 510-540 nm or 570-590 nm. The applicator according to claim 4 or 5, wherein as the bioinner polymer, recycled cellulose, polyethylene terephthalate or polyamide is used.