MXPA02001530A - Improved topical medicaments and methods for photodynamic treatment of disease - Google Patents

Abstract

New photodynamic, topically-applicable medicaments and certain medical uses of such photodynamic medicaments for treatment of human or animal tissue are described, wherein a primary active component of such medicaments is a halogenated xanthene. The halogenated xanthenes constitute a family of potent photosensitizers that become photoactivated upon illumination of the treatment site with visible wavelengths of light. In preferred embodiments, such medicaments are used for treatment of a variety of conditions affecting the skin and related organs;the mouth and digestive tract and related organs;the urinary and reproductive tracts and related organs;the respiratory tract and related organs;various other internal or external tissue surfaces, such as tissue surfaces exposed during surgery;and for treatment of a variety of conditions related to microbial or parasitic infection. In another preferred embodiment, such medicaments are produced in various formulations including liquid, semisolid or aerosol delivery vehicles.

Description

TOPICAL MEDICATIONS IMPROVED AND METHODS FOR THE PHOTODYNAMIC TREATMENT OF DISEASE Background of the invention This application claims the benefit of the provisional application of United States Patent No. 60 / 149,015 filed August 13, 1999 which is a continuation in part of the USSN 08 / 989,231, filed on December 11. of 1997, USSN 09 / 130,041, filed on August 6, 1998, USSN 09 / 184,388, filed on November 2, 1998 and USSN 09 / 216,787, filed on December 21, 1998, which are incorporated herein by reference reference in its entirety. The present invention relates to certain photodynamic, topically applicable medicaments and methods for the treatment of human or animal tissue using photodynamic therapy (PDT). PDT was originally developed to treat cancer and other diseases with the promise to limit the Or the invention of therapeutic intervention and diminish potential collateral damage to normal, non-diseased tissue. In its simplest form, PDT is the combination of a photosensitive agent with special forms of illumination to produce a therapeutic response in certain tissues, such as a tumor. The agent achieves an active state, excited when it absorbs one or more photons and then becomes or becomes more effective. The key elements of a successful PDT regimen include either the selective application or selective uptake of a photosensitive agent in the diseased tissue and the site-specific application of the activation light. PDT agents are typically applied systemically (e.g., via intravenous injection or oral administration) or via topical application localized directly to diseased tissues (e.g., via creams topics, ointments or sprays). Subsequent to the administration of the agent (typically 30 minutes to 72 hours, later), an activation light is applied to the disease site, locally activating the agent, and destroying diseased tissue. Light is typically applied by direct illumination of the site, or by distribution of light energy to internal locations using a fiber optic catheter or similar device. Most current PDT regimens are based on systemic application of agents based on ^^^ 20 porphyrin or topical or systemic application of psoralen-based agents. Examples of porphyrin-based agents include sodium porfimer (PHOTOFRIN®), hematoporphyrin derivative (HPD), benzoporphyrin derivative (BPD), Lutex, BOPP, 5-aminolevulinic acid (ALA), and SnET2.

PHOTOFRIN® is one of the few agents currently licensed by the North American FDA. In general, agents based on porphyrin. they are derived from complex mixtures of natural or synthetically prepared materials and may contain components that are lipophilic. As a possible result of this lipophilicity, porphyrin-based agents have shown a slight tendency to accumulate preferentially in some tumors and other diseased tissues. However, the targeting of these agents to diseased tissues is still unacceptably low compared to uptake in normal tissue (ie, at most 2-10X increased uptake in diseased tissue relative to normal tissue). Psoralens, such as 8-MOP, 5-MOP, trioxsalen and AMT, are nucleic acid intercalators that work by damaging the cellular physiology. This intercalation appears to be relatively indiscriminate in terms of tissue type, and as a result, these agents also exhibit minimal specificity for diseased tissue. In this way, current agents have failed to exhibit sufficient specificity, and may exhibit additional disadvantages, including systemic or localized photosensitivity, persistent, systemic or localized toxicity, and unacceptable treatment cost (due to the high cost of the agent or excessive dose requirements.) 25 The inherent disadvantages of the various agents of Current PDT and drugs containing these agents have made difficult or impossible the acceptable treatment based on PDT of various human and animal conditions.These disadvantages are particularly serious in the case of indications that affect the external or internal surface or superficial tissues close, where it would be desirable to have the appropriate medications for the selective, localized treatment of the desired tissues. These indications include a variety of conditions that affect the skin and related organs, the mouth and digestive tract and related organs, the urinary and reproductive tracts and related organs, the respiratory tract and related organs, as well as various other tissue surfaces, such as tissue surface exposed during the surgery. Therefore, it is an object of the present invention to provide new medicaments, medical uses for these medicaments based on a sought application of these medicaments and methods for the treatment using these drugs, which result in this efficiency and increased safety and reduced cost of treatment.

Brief description of the invention The present invention relates to new photodynamic, topically applicable medicaments and certain medical uses of these photodynamic drugs or methods for the treatment using these medicaments for the treatment of human or animal tissue, wherein an active component Primary of these drugs is a halogenated xanthene, and more preferably Bengal Rose or its derivative. The halogenated xanthenes constitute a family of powerful photosensitizers that become photoactivated in the illumination with wavelengths of visible light. These medications can also be called pharmaceutical compositions or agents. The inventors of the present invention have found that these medicaments are useful for the treatment of a variety of conditions that affect the skin and related organs, the mouth and digestive tract and related organs, the urinary and reproductive tracts and related organs, the respiratory tract and related organs, as well as various other tissue surfaces, such as the surface of tissue exposed during the Or 20 surgery. These medications are applied in several formulations that include liquid, semi-solid or aerosol dispensing vehicles. The photoactivation of photoactive ingredients in these drugs produces a desirable medical response, such as destruction of microbial infection, reduction or elimination of tissue irritation, reduction or elimination of hyperproliferative tissue, reduction or elimination of cancerous or precancerous tissue, reduction or elimination of superficial or sub-surface lipocytes or lipid deposits, and many other similar indications . In a preferred embodiment, these medicaments are used for the treatment of a variety of conditions that affect the skin and related organs. In another preferred embodiment, these medicaments are used for the treatment of a variety of conditions affecting the mouth and digestive tract and related organs. In another preferred embodiment, these medicaments are used for the treatment of a variety of conditions affecting the urinary and reproductive tracts and related organs. In another preferred embodiment, these medicaments are used for the treatment of a variety of conditions that affect the respiratory tract and related organs. ^ - ^ 20 In another preferred embodiment, these medicaments are used for the treatment of a variety of conditions affecting various other internal or external tissue surfaces, such as tissue surfaces exposed during surgery. In another preferred embodiment, these medicaments are used for the treatment of a variety of conditions related to microbial or parasitic infection. In another preferred embodiment, these medicaments are produced in various formulations including liquid, semisolid or aerosol delivery vehicles.

Brief Description of the Figures In describing the preferred embodiments, reference is made to the accompanying drawings, in which: Figure 1 (a) shows the generalized chemical structure of halogenated xanthenes. Figure 1 (b) shows the chemical structure of Bengal Rose. Figure 2 shows the absorbance spectrum of example of several halogenated xanthenes.

DETAILED DESCRIPTION OF THE CURRENTLY PREFERRED EMBODIMENTS The present invention is directed to new OR 20 photodynamic drugs, topically applicable and to certain clinical uses of these photodynamic drugs or methods for the treatment using these drugs for the treatment of human or animal tissue, where a primary active component of these drugs is a halogenated xanthene. These halogenated xanthenes, discussed infra, are capable of exhibiting a desirable photodynamic effect when applied to or otherwise distributed to certain human or animal tissues, and subject to photodynamic activation in these tissues in illumination 5 with visible light, and in particular green light. These desirable effects include reduction or elimination of disease or other undesirable conditions including eradication of cancerous or pre-cancerous tumors and infectious agents, and are applicable to a variety of connections affecting the skin and related organs, the mouth and digestive tract and organs. related, the urinary and reproductive tracts and related organs, the respiratory tract and related organs, and various other internal or external tissue surfaces, such as tissue surface exposed during surgery. In a preferred embodiment, these medicaments are produced in various formulations including liquid, semisolid or aerosol dispensing vehicles. 1. Properties of preferred photoactive components and drug formulations. Applicants have discovered that a certain class of photoactive agents are widely applicable to produce topically applicable medicaments for the treatment of certain human and animal tissues. These The photoactive agents are referred to as halogenated xanthenes and are illustrated in Figure la, where the symbols X, Y and Z represent several elements present in the desired positions and the symbols R1 and R2 represent various functionalities present in the desired positions. 5 The selected chemical and physical properties (such as the chemical constituents at the XY, and Z positions and the R1 and R2 functionalities together with the molar weight and photochemical characteristics) of the representative halogenated xanthenes are summarized in the Table 1 attached. The general properties of this class of agents are analyzed in further detail in USSN 09 / 130,041, filed on August 6, 1998, USSN 09 / 184,388, filed on November 2, 1998 and USSN 09 / 216,787, filed on November 21, 1998. December 1998, which is incorporated in the present as a reference in its entirety. In general, halogenated xanthenes are characterized by low dark cytotoxicity (toxicity to cells or tissues in the absence of photoactivation), high light cytotoxicity (toxicity to cells or tissues in photoactivation) and chemical and photochemical properties that are substantially unaffected by the local chemical environment or the binding of functional derivatives at the R positions! and R2. This makes these chemical agents, and in particular the formulated drugs of these agents, excellent PDT agents for the treatment of human and animal tissues. Thus, a preferred embodiment of the present invention is a topically applicable medicament to be produced, which contains, as an active ingredient at a concentration of more than about 0.001% to less than about 20%, at least one xanthene halogenated It is further preferred that this medicament includes the halogenated xanthene, Bengal Rose (4,5,6,7- 10 tetrachloro-2 ', 4', 5 ', 7-tetraiodofluorescein, illustrated in Figure Ib). O Other exemplary halogenated xanthenes which can be used in the present invention include, without limitation, one or more of: Fluorescein; 4 ', 5' - Dichlorofluorescein; 2 ', 7' - Dichlorofluorescein; 4.5, 6, 7-Tetrachlorofluorescein, 2 ', 4', 5,, 7'- Tetrachlorofluorescein; Dibromofluorescein; Red Solvent 72; Diyodofluorescein; Eosin B; Eosina Y; Ethyl-Eosin; Erythrosin B; Floxin B; Bengal Rose; 4,5,6,7 - ^ - ^^ 20 Tetrabromoerythrosine; Mono-, Di-, or Tri-bromoerythrosine; Mono-, Di-, or Tri-chloroerythrosine; Mono-, Di-, or Trifluoroerythrosine; 2 ', 7' -Dichloro-4, 5,6,7- Tetrafluorofluorescein; 2", 4, 5, 6,7, 7 '- Hexafluorofluorescein, and 4, 5, 6, 7-Tetrafluorofluorescein.

In addition, as evidenced by the data shown in Table 1 and Figure 2, it is clear that halogenated xanthenes share common spectroscopic properties, including a cross section with a high concentration of individual photons exceeding about 500 nm at 600 nm. These properties are substantially unchanged despite the state of derivatization (for example, at positions R and R2) or the chemical or biological environment. This feature facilitates photoactivation with visible light sources commonly available, such as Cw or pulse laser or lamps, operating in the band of approximately 500 nm Or at 600 nm, and avoids the need to substantially change the sources if the specific photoactive component of the drug is varied or modified, as described in present. Additionally, the inventors of the present invention have shown that halogenated xanthenes are capable of being activated using non-linear, multiphoton excitation under certain conditions when light is used in the near infrared band from about 700 nm to 1200 nm (using methods, such as, for example, those taught in USSN 08 / 989,231, filed on December 11, 1997, USSN 09 / 196,832 filed June 12, 1998, which are incorporated herein by reference). These excitation methods provide additional utility in the activation of formulated drugs of these agents. such, for example when it is desirable to increase the depth of photoactivation to positions substantially below an exposed tissue surface. As an example of these desirable chemical, biochemical and physical properties, the inventors have found that the phototypic halogenated xanthene, Bengal Rosa, will preferentially accumulate in (ie, target) some tumors and other diseased and pathogenic tissues, has cytotoxicity in the dark negligible, high cytotoxicity with light in visible light illumination, a relatively low cost and Or the ability to quickly cleanse the body. In addition, the inventors have discovered that the ease with which halogenated xanthenes select As targeting specific tissues or other sites, it can be further optimized by the binding of specific functional derivatives at positions R3 and R2, to change the chemical partition or biological activity of the agent. For example, binding of a target selection portion ^^ 20 or more at the R or R2 positions can be used to improve targeted targeting of specific tissues, such as cancerous tumor tissues or sites of localized infection. An example of this is the esterification of the R1 position with an aliphatic alcohol Short, such as n-hexanol, to produce a derivatizing agent that exhibits enhanced cleavage in tumor tissues with high lipid content. Thus, it is a preferred embodiment that at least one of the at least one halogenated xanthene active ingredient includes at least one targeting portion, selected from the group including DNA, RNA, amino acids, proteins, antibodies, ligands. , haptens, carbohydrate receptors or complexing agents, ligand receptors or formation agents of complexes, protein receptors or complex formation agents, chelators, encapsulation vehicles, Or short or long chain aliphatic or aromatic hydrocarbons, including those containing aldehydes, acetones, alcohols, esters, amides, amines, nitriles, azides, or other hydrophilic or hydrophobic portions. A further example of this modality is the derivatization of Bengal Rose with a lipid (in position R1, via esterification), to increase the lipophilicity of Bengal Rose, and to modify this way its properties of selection in a patient. Because halogenated xanthenes and their derivatives are, in general, solid in their pure form, it is preferred that, for proper distribution to desired tissues, these agents be formulated in carriers of appropriate distribution. The approaches to this formulation will be known in general to those skilled in the art. Specifically, these formulations are preferred to facilitate contact of the agent with, and distribution to, desired tissues to be treated. In this manner, it is a further preferred embodiment of the present invention that at least one halogenated xanthene or halogenated xanthene derivative is formulated as a medicament in a topically applicable form, such as a liquid, semi-solid, solid distribution vehicle in aerosol, which include aqueous suspensions, non-aqueous or in the form of nanoparticles, solutions, creams, ointments, Or gels, syrups, suppositories or micro-drop sprays. In at least one halogenated xanthene or halogenated xanthene derivative can be dissolved or dispersed in this vehicle of distribution, wherein this vehicle can, in addition to at least one halogenated xanthene or halogenated xanthene derivative, include various fillers, stabilizers, emulsifiers or dispersants, preservatives, buffers, electrolytes and softening agents or ^ - ^ 20 tissue penetration . These components of the delivery vehicle may be present as the primary component (by weight or volume) of the medicament, or as a minor component serving in an adjuvant role in the distribution of the agent. For example, suitable binders include cellulose or cellulose derivatives such as starch and alginates. Examples of suitable stabilizers, emulsifiers or dispersants include liposomes, nanoparticles and nanodispersions, microparticles and microdispersions, as well as various lipids, detergents and other surfactants. Examples of suitable preservatives include benzalkonium chloride, thimerosal and urea. Examples of suitable buffers include monobasic or dibasic phosphate salts, salts of Or citrate, bicarbonate salts and ethanolamine. Examples of suitable electrolytes include sodium, potassium, calcium and magnesium chlorides, phosphates and nitrates. Examples of fabric penetration, softening or solvating agents and adjuvants include. • various sulfoxides, such as DMSO and 20 decylmethylsulfoxide; • various fatty and aliphatic alcohols, such as ethanol, propanol, hexanol, octanol, benzyl alcohol, decyl alcohol, lauryl alcohol, and stearyl alcohol; • various saturated and unsaturated linear and branched fatty acids, such as lauric acid, capric acid, capric acid, myristic acid, stearic acid, oleic acid, isovaleric acid, neopentanoic acid, trimethyl-hexanoic acid, neopentanoic acid, trimethyl- hexanoic, neodecanoic acid and isostearic acid; 5 • several esters of aliphatic and alkyl fatty acids, including isopropyl n-butyrate, isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl myristate, isopropyl palmitrate, octyldodecyl myristate, ethyl acetate, butyl acetate , methyl acetate 10, methyl valerate, methyl propionate, diethyl sebacate and ethyl oleate; OR • various polyols such as propylene glycol, polyethylene glycol, ethylene glycol, and ethylene glycol, triethylene glycol, dipropylene glycol, glycerol, propanediol, butanediol, pentanediol and hexanotriol; • various amides, such as urea, dimethylacetamide, diethyl toluamide, dimethylformamide, dimethyloctamide, dimethodecamide; biodegradable cyclic urea, such as 1-alkyl-4-imidazolin-2-one; pyrrolidone derivatives, such ^ - ^ 20 as l-methyl-2-pyrrolidone, 2-pyrrolidone, l-lauryl-2-pyrrolidone, l-methyl-4-carboxy-2-pyrrolidone, l-hexyl-4-carboxy-2-pyrrolidone, -lauryl-4-carboxy-2-pyrrolidone, 1-methy1-4-methoxycarbonyl-2-pyrrolidone, 1-methyl-4-methoxycarbonyl-2-pyrrolidone, 1-lauryl-4-methoxycarboni1-2- 25 pyrrolidone, N- cyclohexylpyrrolidone, N-dimethylaminopropylpyrrolidone, N-cocoalkylpyrrolidone, N- bait-alkylpyrrolidone; biodegradable pyrrolidone derivatives, such as fatty acid esters of N- (2-hydroxyethyl) -2-pyrrolidone; cyclic amides, such as 1- 5 -dodecylazacycloheptane-2-one (Azone®), 1- geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one, l-geranylgeranylazacycloheptan-2-one, 1- (3,7-dimethyloctyl) ) azacycloheptan-2-one; 1- (3, 7, 11-trimethyldodecyl) azacycloheptan-2-one, 1- 10 geranylazacyclohexan-2-one, l-geranylazacyclopentan-2, 5-dione, 1-fernesylazacyclopentan-2-one; hexamethylenelauramide O and its derivatives; and diethanolamine and triethanolamine; • various surfactants, such as anionic surfactants, including sodium laurate and . sodium lauryl sulfate; cationic agents, including cetyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium chloride, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, nonionic surfactants, such as Polaxamer (231). , 182, 184), Brij (30, 93, 96, 99), Span (20, 40, 60, 80, 85), Tween (20, 40, 60, 80), Myrj (45, 51, 52), Migiyol 840, various bile salts, such as sodium cholate, sodium salts of taurocholic acids, Glycolic, deoxycholic; lecithin; • various terpenes, including hydrocarbons, such as D-limonene, α-pinene, β-carene; various terpene alcohols, including a-Terpineol, terpinen-4-ol, carbol; Various terpene-ketone, including carvone, pulegone, piperitone, menthone; various terpene oxides including cyclohexane oxide, limonene oxide, β-pinene oxide, cyclopentene oxide, 1,8-cineole; various terpene oils, including ylang ylang, anis, chenopodium, eucalyptus; 10 • various alkanones, such as N-heptane, N-octane, N-nonane, N-decane, N-undecane, N-dodecane, N-tridecane, N- O tetradecane, N-hexadecane; • various organic acids, such as salicylic acid and salicylates (such as methyl ester and propyl glycol derivatives), citric and succinic acid. In addition to the examples cited herein, other topically applicable formulations familiar to those skilled in the art, including various simple or complex combinations of vehicles and adjuvants, will be useful in improving the distribution of the photoactive component of the drug to target tissues. The background to these vehicles and adjuvants can be found, for example, in: E. W. Smith and H.l. Maibach, "Percutaneous Penetration Enhancers: The Fundamentals"; 25 S.C. Chattaraj and R.B. Walker, "Penetration Enhancer Classification"; and B.J. Aungst, "Fatty Acids as Skin Permeation Enhancers"; in E.W. Smith and H.I. Maibach (eds.), Percutaneous Penetration Enhancers CRC Press, Boca Raton, 1995. These references are incorporated herein by reference in their entirety. Additionally, appropriate topically applicable drug formulations may, for example, incorporate several complex distribution vehicles, including several commercial vehicles, such as those available from Paddock Laboratories, including Dermabase®, Hydrocream, Aquabase, Liquaderm-A, Liqua-Gel, O Ora-Plus®, Ora-Sweet® and Ora-Sweet SF, Suspendol-S, Fattibase and Polybse, as well as several patented vehicles, such as propylene glycol with one or more agents of Adjuvant distribution, to improve the distribution of at least one halogenated xanthene or halogenated xanthene derivative to the desired tissues to be treated. A comparison of the distribution properties for various formulations of examples is given in Table 2, which shows that both the amount of the active ingredient distributed to various tissues and the depth of the distribution beyond the application point can be control substantially by the formulation of medication. 25 2. Methods and medical use of this medicine for the treatment of conditions that affect - the skin and related organs. Applicants have discovered that the 5 medicaments described herein are broadly applicable to the improved treatment of various conditions that affect the skin and related organs of humans and animals. The drug can be applied directly to, or substantially next to, the tissues that are going to treat, including those of the skin, nails, scalp and oral cavity. The example indications Or include treatment for: Psoriasis and Pustular Psoriasis; Reiter's Syndrome, Skin Ulcers, including Stasis Dermatitis; Ulcers for Stasis, Ulcers Eschemic, Leg Ulcers for Sick Cells, Diabetic Ulcers, Inflammatory Ulcers; Eczematous Disease and Eczematous Reaction; several Ichthyoses; Atopic dermatitis; Surface wrinkles; Close Surface Fat Reduction; Benign and Malignant Proliferative Disorders, such as Benign Epithelial Tumors and Hemartomas; Premalignant and Malignant Epithelial Tumors including Actinic Keratosis, Carcinoma of Basal Cells, Squamous Cell Carcinoma and Keratoacanthoma; Benign and Malignant Adnexal Tumors; Tumors of cells that produce pigment, including Malignant Melanoma, Solar Lentiginis, Nevi and Café-au-lait; Sarcomas; Limfornas; Vascular Disorders, such as Hemangiomas and Port Spot; Microbial infection, such as bacterial infections. Fungal, Yeast, Parasitic or Other; Warts; and Acne. In an example of a preferred embodiment of this method of treatment or. medical use, the applicants have found that the application of a cream or solution containing Bengal Rose at a concentration of approximately 0.1% P / V to persistent leg ulcers, followed, after a latency period of 0-72 hours, and more preferably 0-1 hour, by illumination with Or approximately 10 to 200 J / cm2 of continuous green light or with pulses in the 500-600 nm band, leads to substantial or complete healing of persistent leg ulcers, with little or no lateral effect on the surrounding tissue. The present invention, however, is not limited to this preferred embodiment, since other medicaments described herein may also be used. Additionally, other formulations of xanthenes halogenated as described herein have similar applications for the specific indications described herein and for several other similar indications including those related to cosmetic therapeutic treatment of the skin and related organs of humans and animals. 3. Methods and medical use of the present medicament for the treatment of conditions affecting the mouth and digestive tract and related organs Applicants' have discovered that the 5 medicaments described herein are broadly applicable to the improved treatment of various conditions affecting the mouth and treatment digestive and related organs of humans and animals. The medication can be applied directly to, or substantially close to, tissues to be treated, including those of the mouth, gums, tongue, larynx, pharynx, esophagus, stomach, Or intestines and colon. Exemplary indications include treatment for: Benign Esophageal Lesions, Barrett's Esophagus, and Other Esophageal Hyperplasias and Dysplasias, and Esophageal Cancer, including Squamous Cell Carcinoma, Adenocarcinoma, Carsinosarcoma, Pseudosarcoma, and Sarcoma; Gastric Ulcers, Leiomyomas, Polyps, Neoplasms, Lymphoma and Pseudolymphoma, Adenocarcinoma, Primary Lymphoma, Leiomyosarcoma, Oral and Oropharyngeal Cancer and ^ 20 Pre-malignancies, Ulcers and Inflammatory Lesions, including Squamous Cell Carcinoma, Lymphoma, Actinic Cheilitis, Nicotine Stomatitis, Leukoplakia, Erythropasia; Periodontal and Gum Disease, including Gingivitis; Laryngeal Hyperplasia, Dysplasia and Neoplasms; Colorectal Cancer and Polyps.

In an example of a preferred embodiment of this method of medical treatment or use, applicants have found that the application of a solution containing Bengal Rose at a concentration of about 1% P / V 5 in saline to esophageal tissue, followed, after a latency period of 0-72 hours, and more preferably 0-1 hour, by illumination with approximately 10 to 200 J / cm2 of green or continuous light or with pulses in the 500-600 nm band, leads to substantial or complete eradication of diseased tissues, such as those present in the Barretts esophagus, with little or no side effect Or in the surrounding tissue. The present invention, however, is not limited to this preferred embodiment, since other medicaments described herein can also be used. Additionally, other formulations of the halogenated xanthenes as described herein have similar applications for specific indications described herein, and for various other similar indications, including those related to cosmetic therapeutic treatment of the mouth and digestive tract and related organs of humans and animals. 4. Methods and medical use of the present drug for the treatment of conditions affecting the urinary and reproductive tracts and related organs. Applicants have discovered that the 5 medicaments described herein are broadly applicable to the improved treatment of various conditions affecting the urinary and reproductive tracts and related organs of humans and animals. The medication can be applied directly to, or substantially close to, the tissues to be treated including those of the urethra, bladder, ureter, kidneys, vulva, vagina, cervix, Or fallopian tube, ovaries, penis, testes, vas deferens, prostate, and epididymis. Example indications include treatment for: tract disease urinary, including cancerous and pre-cancerous hyperplasia, dysplasia and neoplasms. Tumors and other growths, inflammation and infection of the bladder, ureter, urethra, and kidney; cancerous, and pre-cancerous hyperplasia, dysplasia and neoplasms and other growths, inflammation and infection ^ - ^ 20 of the cervix, endometrium, myometrium, ovaries, fallopian tubes, uterus, vulva and vagina; cancerous hyperplasia and pre-cancerous dysplasia and neoplasm, tumors and other growths, inflammation and infection of prostate and testes, reproductive tract infections including Tinea Cruris, candidiasis, congenital condyloma, contagious molluscs, genital infection of Herpes Simplex, Infogranuloma venerio, chancrela, graniloma inginal, eritazma; psoriasis, and lichen planus and lichen sclerosus. In an example of a preferred embodiment of this method of medical treatment or use, applicants have found that the solution containing Bengal Rose at a contemplation of about 1% W / V to the tissue, followed, after a period of latency of 0-72 hours, and preferably 0-1 hours, by lighting with approximately 10 to 200 J / cm2 of continuous green light or with pulses from the 500-600 nm band leads to a Or complete substantial eradication of diseased tissues, such as those present in bladder tumors with little or no side effect in the surrounding tissue. The The present invention is, however, not limited to this preferred embodiment, since other medicaments described herein can also be used. Additionally, the formulations of the halogenated xanthenes as described herein have similar applications for the specific indications described herein, and for several other similar indications, including those related to the cosmetic therapeutic treatment of the reproductive urinary tracts. and related organs of humans and animals.

. Methods and medical use of this medication for the treatment of conditions that affect respiratory and related organs. Applicants have discovered that the 5 medicaments described herein are broadly applicable to the improved treatment of various conditions affecting the respiratory tract and related organs to humans and animals. The drug can be applied directly to, or substantially in close proximity to, or tissues that will be treated. Example indications include treatment for: hyperplasia, neoplasia dysplasia, cancer, O inflammation and infection of the nasal cavity, sinuses for nasals, lacrimal ducts, eustachian tubes, nasopharynx, hypopharynx, larynx, trachea, bronchi, lung, and alveoli. In an example of a preferred embodiment of this method of medical treatment or use, applicants have found that the application of a solution containing Bengal Rose or a concentration of about 1% P / V ^^ 20 to the tissue, followed by, after of a lag period 0-72 hours, more preferably 0-1 hour, by illumination with approximately 10 to 200 j / cm2 of green or continuous light or pulses in the 500-600 nm band leads to a substantial eradication or complete of the tissues patients, such as those present in tracheal tumors, with little or no lateral effect on the surrounding tissue. The present invention, however, is not limited to this preferred embodiment, since other medicaments described herein may also be used. Additionally, other formulations of the halogenated xanthenes as described herein as described herein have similar applications for the specific indications described herein, and for several other similar indications, including those related to therapeutic or cosmetic treatments of the same. respiratory tract and related organs of Or humans and animals. 6. Methods and clinical use of the medicament agent 15 for the treatment of conditions affecting various other internal or external tissue surfaces,. such as tissue surface exposed during surgery. Applicants have discovered that the medicaments described herein are broadly applicable to the improved treatment of various conditions that affect various other internal or external tissue surfaces of humans and animals, such as tissue surfaces exposed during surgery, including surgery. endoscopic or other endoscopic procedures. The drug can be applied directly to substantially next to, the tissues to be treated. Exemplary indications include treatment for: inflammation of joints such as arthritis; beads of .tumor extracted from the head and other 5 head and neck, thoracic or abdominal tumors, cardiac and pericardial tissues and circulatory tissues, including arteries and veins, including plaques and infections of these tissues, such as bacterial endocarditis; metastatic tumors such as metastases from breast tumors to the skin and several other substantially similar indications.

OR In an example of a preferred embodiment of that method of medical treatment or use, applicants have found that the application of a solution containing Bengal Rose at a concentration of approximately 10% P / V micro molar to breast adenocarcinoma and sarcoid tissues, followed, after a latency period of 0-72 hours and more preferably 0-1 hour, by illumination with approximately 10 to 200 J / cm2 of green light ^ - ^ 20 or continuous or with pulses of the band of 500-600 nm, leads to a substantial or complete radiation of these tissues, with little or no side effect in the surrounding tissue. The present invention, however, is not limited to this preferred embodiment, since it is also can use other medications described herein.

Additionally, other formulations of the halogenated xanthenes as described herein have similar applications for the specific indications described herein, and for several other similar indications including those related to the cosmetic therapeutic treatment of various other internal or external human and tissue surfaces. or animals, such as tissue surfaces, exposed during surgery. 7. Methods and clinical use of this medicine for the treatment of conditions related to microbial or parasitic infection. Applicants have discovered that the medications described herein are widely applicable to the improved treatment of various conditions related to microbial or parasitic infection of humans or animals, including those infections resistant to conventional treatments. The medicament can be applied directly to, or substantially subjacent to, the tissues to be treated. Example indications include treatment for: bacterial infection and resistant bacterial infection antibiotics, including those caused by Gram positive and Gram negative, Streptomycetes, Actinomycetes, Staphylococcus, Streptococcus, Pseudomonas, Escherichia coli.

Mycobacteria and others; infections caused by filamentous fungi and non-filamentous fungi, such as Cryptosporidium, Histoplasma, Aspergillus, Blastomyces, Candida and others; parasitic infection caused by amoebas, 5 (including for the use in lysis and annihilation of amoeba amoebic cysts) Trichinella, Dirodfilaria (heartworm in dogs) and others. An example of a preferred embodiment of this method of medical treatment or use, applicants have found that the application to an aqueous solution contains Bengal Rose at a concentration of approximately 1 to 10 O micromolar or greater to Staphylococcus aureus resistant antibiotics, Escherichia coli, several other Gram-negative Gram-positive bacteria and several yeasts, followed, after a lag period of 0-72 hours and more preferably 0-1 hour, by illumination with approximately 10 to 200 J / cm "of continuous green light or with pulse in a band of 500-600 nm leads to substantial or complete eradication of these microbes with little or no side effect on the surrounding tissue The present invention, however, is not limited to this preferred embodiment, since other medicaments described herein may also be used. , other formulations of halogenated xanthenes as describe in the following have similar applications for the specific indications described herein and for several other similar indications, including those related to the cosmetic therapeutic treatment of various other conditions related to microbial or parasitic infection of humans or animals- or TABLE 1 Physical and photochemical chemical properties of some halogenated xanthenes of e em lo Table 2.- Efficiency of relative distribution of exemplary transdermal distribution formulations of a halogenated xanthene; Pink flare is used as the agent at indicated concentrations [RB]. The formulation is applied to murine skin for 30 minutes under exclusive conditions. Relative efficacy indicates an estimate of the Or amount of pink flare distributed in the tissue, based on fluorescent measurement on the surface and in the cross sections of the tissue. Depth indicates the depth Relative penetration of rose bengal: LP = Penetration to lamina propria; D + = penetration to dermis and more Or there.

OR This description has been offered for illustrative purposes only and is not intended to limit the invention of this application, which is defined in the claims below. What is claimed as new and that is desired to be protected by patent laws is set forth in the appended claims. or

Claims (37)

1. CLAIMS 1. A medicament for topical application, the medicament is characterized in that it comprises at least one halogenated xanthene as a primary active component, 5 wherein the medicament is useful for the photodynamic treatment of human and animal tissue.
2. 2. The medicament according to claim 1, characterized in that the halogenated xanthene is present in a concentration of more than 10 0.001% less than 20%.
3. 3. The medication in accordance with Or claim 1, characterized in that the halogenated xanthene comprises Rose Bengal.
4. 4. The medicament according to claim 1, characterized in that the halogenated xanthene includes at least one compound selected from the group consisting of fluorescein; 4 ', 5' dichlorofluorescein; 2 ', 7' -dichloroflurescein; 4, 5, 6, 7-tetrachlorofluorescein; 2 ', 4', 5 ', 7' -tetrachlorofluorescein; dibromofluorescein; ^ - ^ red solvent 72; diiodofluorescein; Eosin B; Eosina Y; ethyl eosin; Erythrosin B; phloxin B; pink flare; 4, 5, 6, 7-tetraboroeritrosin; mono-, di, or tri-bromoerythrosine; mono-, di-, or tri-coloroerythrosine; mono-, di-, or trifluoroerythrosine; 2 ', 7', -dichloro-4, 5,6,7, -25 tetrafluoroflorescein; 2 ', 4, 5, 6, 7, 7', - hexafluoroflorescein; and 4, 5, 6, 7-tetrafluorofluorescein.
5. 5. The medicine according to claim 1, characterized in that it also comprises at least one selection portion coupled to the xanthene. 5 halogenated.
6. The medicament according to claim 5, characterized in that the selection ratio selects the group consisting of DNA, RNA, amino acids, protein, antibodies, ligands, haptens, 10 carbohydrate receptors or complex formation agents, lipid receptors or formation agents O complex protein receptors or complex formation agents, burners, encapsulation vehicles, aliphatic or short chain aromatic hydrocarbons or Long, aldehydes, ketones, alcohols, esters, amides, amines, nitriles, azides, and other hydrophilic or hydrophobic portions.
7. 7. The medicament according to claim 1, characterized in that the medicament is X ^ 20 formulates in a distribution vehicle selected from the group consisting of semi-solid liquids, solids and aerosols.
8. 8. The medicament according to claim 8, characterized in that the vehicle 25 selects the group consisting of suspensions, aqueous, non-aqueous and nanoparticle solutions, creams, ointments, ice creams, syrups, suppositories and micro-drop aerosols.
9. The medicament according to claim 1, characterized in that the halogenated xanthene is in a distribution vehicle including an adjuvant selected from the group consisting of fillers, stabilizers, emulsifiers, dispersants, preservatives, buffers, electrolytes, penetrating agents of tissue and tissue softening agents.
10. 10. The medicament according to claim 1, characterized in that the medicament is Or useful for the treatment of indications selected from the group consisting of conditions that affect the skin and related organs, conditions that affect the mouth and 15 digestive tract and related organs, conditions that affect the urinary and reproductive tracts and related organs, conditions that affect the respiratory tracts and related organs conditions that affect other internal and external tissue surfaces, or XX 20 conditions that affect tissue surface exposed during Surgery and conditions related to microbial and parasitic infection.
11. 11. The medicament according to claim 1, characterized in that the medicament is 25 useful for photodynamic treatment using a green activation light.
12. The medicament according to claim 11, characterized in that the green light has a wavelength of approximately 500 nm and 600 nm.
13. 13. The use of a halogenated xanthene in the preparation of topical medicament for the treatment of human and animal tissue using photodynamic therapy.
14. 14. The use according to claim 13, for the preparation of a medicament for the treatment of indications selected from the group consisting of conditions affecting the skin and organs. Or related, conditions that affect the mouth and digestive tract and related organs, conditions that affect the reproductive urinary tracts and related organs, 15 conditions that affect the respiratory tracts and related organs, affecting other surfaces of internal and external tissue conditions that affect surfaces of tissue exposed during surgery and conditions related to microbial or parasitic infection. and ^ 20
15. 15. Use in accordance with the claim 13, characterized in that the halogenated xanthene comprises Bengal Rose.
16. 16. The use according to claim 13, characterized in that this medicament is for photodynamic therapy with green activation light.
17. 17. The use of a xanthene comprising: administering a therapeutically effective amount of a halogenated xanthene to or close to human or animal tissue and photoactivation of the halogenated xanthene present in or proximate to this tissue.
18. 18. The use according to claim 17, characterized in that this halogenated xanthene comprises Bengal Rose.
19. 19. The use according to claim 10 17, characterized in that this halogenated xanthene is photoactivated with green activation light. OR
20. 20. The use according to claim 19, characterized in that the green light has a wavelength of between about 500 nm and 600 nm.
21. 21. A pharmaceutical composition for topical administration comprising a halogenated xanthene for treatment using photodynamic therapy.
22. 22. The pharmaceutical composition according to claim 21, characterized in that the xanthene ^ - ^ 20 halogenated is present in concentration of greater than 0.001% to less than 20%.
23. 23. The pharmaceutical composition according to claim 21, characterized in that the halogenated xanthene comprises Bengal Rose.
24. 24. The pharmaceutical composition according to claim 21, characterized in that the halogenated xanthene includes at least one compound selected from the group consisting of fluorescein; 4 ', 5' dichloroflurescein; 2 ', 7' -dichloroflurescein; 4,5,6,7- 5 tetrachlorofluorescein; 2 ', 4', 5 ', 7' -tetrachlorofluorescein; dibromofluorescein; red solvent 72; diiodofluorescein; Eosin B; Eosina Y; ethyl eosin; Erythrosin B; phloxin B; pink flare; 4, 5, 6, 7-tetrabromoerythrosine; mono-, di, or tribromoeritrosine; mono-, di-, or trichloroerythrosine; raono-10, di-, or trifluoroerythrosine; 2 ', 7', -dichloro-4, 5, 6, 7, -tetrafluorofluorescein; 2 ', 4, 5, 6,7,7', - O hexafluorofluorescein; and 4, 5, 6, 7-tetrafluorofluorescein.
25. 25. The pharmaceutical composition according to claim 21, characterized in that it comprises 15 additionally at least one target portion coupled to the halogenated xanthene.
26. 26. The pharmaceutical composition according to claim 25, characterized in that the target portion is selected from the group consisting of ^ - ^ 20 of DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, lipid receptors or complex formation agents protein receptors or complexing agents, burners, vehicles of encapsulation, aliphatic or aromatic hydrocarbons of short or long chain, aldehydes, ketones, alcohols, esters, amides, amines, nitriles, azides, and other hydrophilic or hydrophobic portions.
27. 27. The pharmaceutical composition according to claim 21, characterized in that the pharmaceutical composition is formulated in a distribution vehicle selected from the group consisting of semisolid, solid and aerosol liquids.
28. 28. The pharmaceutical composition according to claim 27, characterized in that the vehicle selects the group consisting of suspensions, aqueous, not Or aqueous and nanoparticle solutions, creams, ointments, ice creams, syrups, suppositories and micro-drop sprays.
29. 29. The pharmaceutical composition in accordance with claim 21, characterized in that the halogenated xanthene is in a distribution vehicle that includes an adjuvant selected from the group consisting of fillers. stabilizers, emulsifiers, dispersants, preservatives, buffers, electrolytes, tissue penetration agents and tissue softening agents.
30. 30. The pharmaceutical composition according to claim 21, characterized in that the photodynamic therapy uses green activation light.
31. 31. ' The pharmaceutical composition according to claim 30, characterized in that the green light has a wavelength of between about 500 and 600 nm.
32. 32. A method of treatment comprising: topically applying a medicament that includes at least one halogenated xanthene at or close to human or animal tissue; and illuminating the human or animal tissue to activate the halogenated xanthene present within or approximating the tissue.
33. 33. The method according to claim 32, characterized in that the human or animal tissue comprises the skin and related organs, the O mouth and digestive tract and related organs, urinary and reproductive tracts and related organs, 15 respiratory tracts and related organs, other external and internal tissue surfaces, tissue surfaces exposed during surgery, and tissue with microbial infection or parasitic
34. 34. The method according to XX 20 claim 32, characterized in that the illumination step uses green activation light
35. 35. The method according to claim 34, characterized in that the green light has a wavelength of approximately 500 at 600 nm.
36. 36. A topically applicable medicament comprising at least one halogenated xanthene as a primary active component, characterized in that the medicament is useful for the photodynamic treatment of human or animal tissue.
37. 37. A topically applicable medicament comprising at least one halogenated xanthene as a primary active component, characterized in that the medicament is useful for the indications selected from a group consisting of conditions affecting the skin and the 10 related organs, conditions that affect the mouth and the digestive tracts and related organs, conditions that affect the urinary and reproductive tracts and related organs, conditions that affect the respiratory tracts and related organs, other conditions that 15 affect the surfaces of external and internal tissue, conditions that affect tissue surfaces exposed during surgery, and conditions related to microbial and parasitic infection. twenty