Intracorporeal medicaments for photodynamic treatment of disease
http://www.pharmcast.com/Patents200/Yr2008/June200 [2008-7-14]
Tag : Butyl Glycol
Abstract
New intracorporeal photodynamic medicaments and certain medicaluses and methods for use of such photodynamic medicaments fortreatment of disease in human or animal tissue are described,wherein a primary active component of such medicaments is ahalogenated xanthene or halogenated xanthene derivative. Inpreferred embodiments, such medicaments are used for treatment of avariety of conditions affecting the skin and related organs, themouth and digestive tract and related organs, the urinary andreproductive tracts and related organs, the respiratory tract andrelated organs, the circulatory system and related organs, the headand neck, the endocrine and lymphoreticular systems and relatedorgans, various other tissues, such as connective tissues andvarious tissue surfaces exposed during surgery, as well as varioustissues exhibiting microbial or parasitic infection. In anotherpreferred embodiment, such medicaments are produced in variousformulations including liquid, semisolid, solid or aerosol deliveryvehicles.
Description of the Invention
SUMMARY OF THE PRESENT INVENTION
The present invention is directed to new intracorporealphotodynamic medicaments and certain medical uses of suchmedicaments, and methods for treatment using such medicaments, fortreatment of human or animal tissue, wherein a primary activecomponent of such medicaments is a halogenated xanthene or ahalogenated xanthene derivative, and more preferably Rose Bengal ora functional derivative of Rose Bengal. The halogenated xanthenesconstitute a family of potent photosensitizers that becomephotoactivated upon illumination of the treatment site with visiblewavelengths of light. Such medicaments are suitable forintracorporeal administration, and are thus intracorporealmedicaments. Such medicaments can also be called pharmaceuticalcompositions or agents.
In a preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting theskin and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting themouth and digestive tract and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting theurinary and reproductive tracts and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting therespiratory system and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting thecirculatory system and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting thehead and neck.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting theendocrine and lymphoreticular systems and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting variousother tissues, such as connective tissues and various tissuesurfaces exposed during surgery.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions related tomicrobial or parasitic infection.
In another preferred embodiment, such medicaments are produced invarious formulations including liquid, semisolid, solid or aerosoldelivery vehicles, as well as in tablet, capsule, suppository, andother similar forms.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
The present invention is directed to new photodynamic medicamentsand certain medical uses of such photodynamic medicaments, andmethods for photodynamic treatment using such medicaments, fortreatment of human or animal tissue, wherein a primary activecomponent of such medicaments is a halogenated xanthene orhalogenated xanthene derivative. The inventors of the presentinvention have discovered that such halogenated xanthenes, asdiscussed in more detail infra, exhibit desirable photodynamiceffects when applied to or otherwise delivered to certain human oranimal tissues. The desirable effects include reduction orelimination of disease or diseased tissue or other undesirableconditions, including eradication of cancerous or pre-canceroustumors and infectious agents. The treatment is applicable to avariety of conditions affecting the skin and related organs, themouth and digestive tract and related organs, the urinary andreproductive tracts and related organs, the respiratory tract andrelated organs, the circulatory system and related organs, the headand neck, the endocrine and lymphoreticular systems and relatedorgans, various other tissues, such as tissues exposed duringsurgery, as well as various tissues exhibiting microbial, viral,fungal or parasitic infection.
In a preferred embodiment, such medicaments are produced in variousformulations suitable for intracorporeal administration, includingin various liquid, semisolid, solid or aerosol delivery vehicles,as well as in tablet, capsule, suppository, and other similarforms. Such medicament formulations are suitable for delivery viavarious conventional modes and routes (hereafter defined asintracorporeal administration), including intravenous injection(i.v.), intraperitoneal injection (i.p.), intramuscular injection(i.m.), intracranial injection (i.c.), intratumoral injection(i.t.), intraepithelial injection (i.e.), transcutaneous delivery(t.c.), and per oesophageal (p.o.) administration; additionaladministrative modes and routes include intraabdominal,intraapendicular, intraarterial, intraarticular, intrabronchial,intrabuccal, intracapsular, intracardial, intracartilaginous,intracavitary, intracephalic, intracolic, intracutaneous,intracystic, intradermal, intraductal, intraduodenal,intrafascicular, intrafat, intrafilar, intrafissural, intragastric,intraglandular, intrahepatic, intraintestinal, intralamellar,intralesional, intraligamentous, intralingual, intramammary,intramedullary, intrameningeal, intramyocardial, intranasal,intraocular, intraoperative, intraoral, intraosseous, intraovarian,intrapancreatic, intraparietal, intrapelvic, intrapericardial,intraperineal, intraperitoneal, intraplacental, intrapleural,intrapontine, intraprostatic, intrapulmonary, intrarachidian,intrarectal, intrarenal, intrascleral, intrascrotal,intrasegmental, intrasellar, intraspinal, intrasplenic,intrasternal, intrastromal, intrasynovial, intratarsal,intratesticular, intrathoracic, intratonsillar, intratracheal,intratubal, intratympanic, intraureteral, intraurethral,intrauterine, intravaginal, intravascular, intraventricular,intravertebral, intravesical, or intravitreous administration. Suchmedicaments will thus be referred to as intracorporeal medicaments(i.e., medicaments suitable for intracorporeal administration).
1. Properties of the Preferred Photoactive Components andMedicament Formulations.
The inventors of the present invention have discovered a class ofphotoactive agents that are broadly applicable for producingintracoporeal medicaments for photodynamic treatment of disease incertain human and animal tissues. These photoactive agents arereferred to as halogenated xanthenes and are illustrated in FIG. 1a(see Original Patent), where the symbols X, Y, and Z representvarious elements present at the designated positions, and thesymbols R.sup.1 and R.sup.2 represent various functionalitiespresent at the designated positions.
Selected chemical and physical properties (such as chemicalconstituents at positions X, Y, and Z and functionalities R.sup.1and R.sup.2, along with molecular weight and photochemicalcharacteristics) of representative halogenated xanthenes aresummarized in attached Table 1 (see Original Patent). Certaingeneral properties of this class of agents are discussed in furtherdetail in U.S. Ser. No. 09/130,041, filed on Aug. 6, 1998, U.S.Ser. No. 09/184,388, filed on Nov. 2, 1998, and U.S. Ser. No.09/216,787, filed on Dec. 21, 1998, which are herein incorporatedby reference in their entirety. In general, the halogenatedxanthenes are characterized by a low dark cytotoxicity (toxicity tocells or tissues in the absence of photoactivation), by high lightcytotoxicity (toxicity to cells or tissues upon photoactivation)and by chemical and photochemical properties that are substantiallyunaffected by the local chemical environment or by the attachmentof functional derivatives at positions R.sup.1 and R.sup.2. Suchfactors make these chemical agents, and in particularintracorporeal medicaments formulated from such agents, excellentPDT agents for the treatment of disease in human and animaltissues.
One preferred embodiment of an intracorporeal medicament accordingto the present invention contains an active ingredient, at aconcentration of from greater than approximately 0.001% to lessthan approximately 20%, of at least one halogenated xanthene,including for example one or more of: Fluorescein;4',5'-Dichlorofluorescein; 2',7'-Dichlorofluorescein;4,5,6,7-Tetrachlorofluorescein; 2',4',5',7'-Tetrachlorofluorescein;Dibromofluorescein; Solvent Red 72; Diiodofluorescein; Eosin B;Eosin Y; Ethyl Eosin; Erythrosin B; Phloxine B; Rose Bengal;4,5,6,7-Tetrabromoerythrosin; Mono-, Di-, or Tribromoerythrosin;Mono-, Di-, or Trichloroerythrosin; Mono-, Di-, orTrifluoroerythrosin; 2',7'-Dichloro-4,5,6,7-Tetrafluorofluorescein;2',4,5,6,7,7'-Hexafluorofluorescein; and4,5,6,7-Tetrafluorofluorescein. It is further preferred that thismedicament include Rose Bengal(4,5,6,7-tetrachloro-2',4',5',7'-Tetraiodofluorescein, illustratedin FIG. 1b (see Original Patent)).
Further, as evidenced by the data shown in Table 1 (infra) and inFIG. 2 (see Original Patent), halogenated xanthenes share commonspectroscopic properties, including a high single-photoncross-section extending from approximately 500 nm to 600 nm. Theseproperties are substantially invariant regardless of state offunctional derivatization (for example, at positions R.sup.1 andR.sup.2) or of chemical or biological environment. This featurefacilitates photoactivation with commonly available visible lightsources operating in the band from approximately 500 nm to 600 nmand circumvents the need to substantively change sources if thespecific photoactive component of the medicament is varied ormodified, as discussed herein. Furthermore, the inventors of thepresent invention have shown that the halogenated xanthenes arecapable of being activated using non-linear, multi-photonexcitation under certain conditions when using light in the nearinfrared band from approximately 700 nm to 1200 nm (using methodssuch as, for example, those taught in U.S. Pat. No. 6,042,603 andin U.S. Ser. No. 09/096,832, filed Jun. 12, 1998 (entitled"Improved Methods And Apparatus For Multi-PhotonPhoto-Activation Of Therapeutic Agents"), both of which isincorporated herein by reference in their entireties). Suchexcitation methods provide additional utility in the activation ofmedicaments formulated from these agents, for example when it isdesirable to increase the depth of photoactivation to positionssubstantially beyond that readily accessible using visible lightexcitation methods.
As an example of these desirable chemical, biochemical, andphysical properties, the inventors have found that the prototypicalhalogenated xanthene, Rose Bengal, will accumulate preferentiallyin (i.e. target) some tumors and other tissues and pathogenicentities, has negligible dark cytotoxicity, high light cytotoxicityupon illumination with visible light, relatively low cost, and theability to clear rapidly from the body.
For example, it is possible to estimate an agent's potential fortissue accumulation based on the partition coefficient, K.sub.p.This in vitro parameter is purported to have predictive valuerelating to in vivo agent delivery at the cellular level. Inparticular, a value greater than unity is considered to indicateagents capable of localizing in tumor or other diseased tissue, andmore specifically in plasma membranes of cells composing suchtissue, and thereby being capable of exhibiting enhancedphotodynamic efficacy in such tissue. K.sub.p is determined bymeasuring the ratio of equilibrium concentrations of an agent in alipophilic phase (n-octanol) contacted with an aqueous phase(phosphate buffered saline, PBS, pH=7.4). Comparative values ofK.sub.p are shown in Table 2 (see Original Patent), infra. Thelarge K.sub.p values for the halogenated xanthenes relative to manyof the porphyrin-based PDT agents suggest that the halogenatedxanthenes will exhibit an enhanced tendency to concentrate oraccumulate in tumor or other diseased tissue, and should thereby becapable of exhibiting superior photodynamic efficacy in suchtissue.
The following examples illustrate this preference for accumulationin tumor tissue by the halogenated xanthenes:
Initially, tumor cell suspensions (e.g. melanoma, breast tumor,liver tumor, renal carcinoma, gall bladder tumor or prostate tumor)were injected subcutaneously into the flanks of nude mice resultingin formation of primary tumors, within a few weeks, at theinjection site having a volume of approximately 0.1 cm.sup.3 to 0.5cm.sup.3.
Thereafter, a solution of Rose Bengal (10-30 .mu.L of 10% RoseBengal, i.e., 1-3 mg Rose Bengal p.o.) was administered peroesophageal to the mice, followed by illumination of the tumor 3-48hours post administration using light at 532 nm (50-200 J/cm.sup.2at the tumor surface). This resulted in selective destruction oftumor tissue with no substantive effect in healthy surroundingtissue. These example results are summarized in Table 3 (seeOriginal Patent), infra.
Intratumoral injection (i.t.) of a similar Rose Bengal formulationresulted in persistent accumulation and retention of Rose Bengaluniformly throughout the tumor volume, with more than 75% ofinjected Rose Bengal dose remaining in the tumor after severalweeks. As in the per oesophageal example above, illumination usinglight at 532 nm resulted in selective tumor destruction (see Table4, infra (see Original Patent)).
Peritumoral injection (i.e., injection into normal tissue aroundthe outside margins of the tumor) exhibited no such retention innormal tissue, with less than 1% of Rose Bengal remaining in thevicinity of the tumor after 24 hours.
In contrast, i.t. administration of a different class of agent,indocyanine green (K.sub.p=99), showed that within 24 hours thisagent had substantively migrated out of the tumor, and insteadexhibited a tendency to accumulate in peritumoral tissues. Hence,while the K.sub.p value for indocyanine green is nearly ten-foldlarger than that of Rose Bengal (and as such, indocyanine green is,by the conventional model based on K.sub.p, expected to accumulatestrongly in tumor tissue), the tissue localization properties ofthe two agents are clearly completely different.
Thus, the inventors of the present invention have shown that thehalogenated xanthenes, and in particular Rose Bengal, exhibit anunexpectedly marked preference for accumulation and retention intumor and other diseased tissue upon intracorporeal administration,and that once present in such tissue, said halogenated xanthenescan be utilized as potent, highly tissue or disease specific PDTagents.
In addition to superior suitability for direct administration intodesired targeted tissue to be treated, such as a focal tumor, thepreference of the halogenated xanthenes for accumulation in certaintypes of tissues provides a basis for highly-selective, systemicdelivery of the halogenated xanthenes to such tissues. For example,Rose Bengal's relatively large partition coefficient is indicativeof a preference for accumulation in lipophilic tissue, such ascutaneous lipocytes. The inventors of the present invention havefound that systemic administration of Rose Bengal, for example asan aqueous solution administered via intraperitoneal injection(i.p.) or per oesophagus (p.o.) administration, resulted in highlyselective accumulation of said agent in certain tissues, such as inthe cutaneous fat deposits of obese laboratory mice. Histologicexamination of skin samples from such animals showed thataccumulated agent is substantively limited to cutaneous lipocytes.Furthermore, illumination of the skin of such animals with light atapproximately 532 nm resulted in photodynamic activation of thisaccumulated agent only in such lipocytes. Such photodynamicactivation of accumulated agent precipitated selective photodynamicdestruction of such lipocytes with no effect in overlying skin orunderlying muscle tissue.
Moreover, the inventors of the present invention have discoveredthat the facility with which the halogenated xanthenes targetspecific tissues or other sites can be further optimized byattachment of specific functional derivatives at positions R.sup.1and R.sup.2 (see e.g. FIG. 1), so as to change the chemicalpartitioning and/or biological activity of the agent. For example,attachment of one targeting moiety or more at positions R.sup.1 orR.sup.2 can be used to improve targeting to specific tissues, suchas cancerous tumor tissues or sites of localized infection. Anexample of this is esterification at position R.sup.1 with a shortaliphatic alcohol, such as n-hexanol, to produce a derivatizedagent exhibiting enhanced partitioning into lipid-rich tumortissues.
It is thus a further preferred embodiment to include a targetingmoiety in at least one of the at least one halogenated xantheneactive ingredients, such targeting moiety being selected from agroup that includes deoxyribonucleic acid (DNA), ribonucleic acid(RNA), amino acids, proteins, antibodies, ligands, haptens,carbohydrate receptors, carbohydrate complexing agents, lipidreceptors, lipid complexing agents, protein receptors, proteincomplexing agents, chelators, encapsulating vehicles, short-chainaliphatic hydrocarbons, long-chain aliphatic hydrocarbons, aromatichydrocarbons, aldehydes, ketones, alcohols, esters, amides, amines,nitriles, azides, hydrophilic moieties and hydrophobic moieties. Afurther example of this embodiment is derivatization of Rose Bengalwith a lipid (at position R.sup.1, via esterification), so as toincrease the lipophilicity of Rose Bengal, and thereby modify itstargeting properties in a patient. An additional further example ofthis embodiment is derivatization of Rose Bengal with folate (atposition R.sup.1, via esterification or other modes of attachment),so as to increase selective targeting of cancer and other cellsexhibiting enhanced folate receptor activity or folate metabolism.
As a further example of the desirable chemical, biochemical, andphysical properties of the halogenated xanthenes and halogenatedxanthene derivatives, the inventors of the present invention haveshown that these agents exhibit a remarkable combination of lowdark cytotoxicity and high light cytotoxicity. This is evidenced bythe following: addition of Rose Bengal and other halogenatedxanthenes to procaryotic or eucaryotic cell cultures atconcentrations equivalent to or greater than 100 mg/kg generallyresulted in no measurable effect on the viability of such cultures.However, subsequent illumination of such cultures with light atwavelengths between about 500 nm and 600 nm generally resulted inan immediate and complete kill of such cell cultures.Intracorporeal administration of these agents at these levels intotumor-bearing laboratory animals resulted in negligible biologicaleffects in the absence of illumination. However, illumination oftumor tissue in these animals subsequent to this administrationresulted in marked destruction of such tumor tissue. Further, theinventors of the present invention have shown that these agents arereadily cleared from healthy tissues in a matter of several hoursand are known to be rapidly excreted in bile, urine and feces,without doing damage to those healthy tissues while it was there.This is in dramatic contrast to most conventional PDT agents, someof which exhibit half-lives in healthy tissues on the order of manyweeks.
Further examples of the desirable properties of the halogenatedxanthenes and halogenated xanthene derivatives are as follows:halogenated xanthenes and halogenated xanthene derivatives areeasily synthesized using simple, low-cost synthetic methods, can bereadily purified and exhibit excellent stability (such as a longshelf life without need for refrigeration or storage under an inertatmosphere).
Because the halogenated xanthenes and their derivatives are, ingeneral, fine solid powders in their pure form, it is preferredthat, for proper delivery to desired tissues, such agents beformulated in appropriate delivery vehicles. Approaches to suchformulation will be generally known to those of ordinary skill inthe art. Specifically, such formulations are preferred so as tofacilitate agent delivery into the body and subsequent contactwith, and delivery to, desired tissues to be treated.
It is thus a further preferred embodiment of the present inventionthat at least one halogenated xanthene or halogenated xanthenederivative be formulated as an intracorporeal medicament in a formsuitable for intracorporeal administration via various conventionalmodes and routes. Such suitable forms include, for example,medicaments formulated in a liquid, semisolid, solid or aerosoldelivery vehicle, including in vehicles of the following natures:aqueous suspensions, non-aqueous suspensions, solutions, creams,ointments, gels, syrups, micro-droplet sprays, suppositories,tablets and capsules. The at least one halogenated xanthene orhalogenated xanthene derivative may be dissolved or suspended insuch delivery vehicle, wherein this vehicle may, in addition to theat least one halogenated xanthene or halogenated xanthenederivative, include various builders, stabilizers, emulsifiers ordispersants, preservatives, buffers, electrolytes, and tissuepenetrating or softening agents. Such components of the deliveryvehicle may be present as the primary component (by weight orvolume) of the medicament, or as a minor component that serves inan adjuvant role in agent delivery with no adverse affect on tissueor treatment outcome.
For example, appropriate builders include cellulose and cellulosederivatives, such as starch, methylcellulose,carboxymethylcellulose, and alginates.
Examples of appropriate stabilizers, emulsifiers or dispersantsinclude liposomes, nanoparticulates and nanodispersions,microparticulates and microdispersions, as well as various lipids,detergents and other surfactants.
Examples of appropriate preservatives include benzalkoniumchloride, thimerosal, quaternary amines and urea.
Examples of appropriate buffers include monobasic or dibasicphosphate salts, citrate salts, bicarbonate salts, andethanolamine.
Examples of appropriate electrolytes include sodium, potassium,calcium and magnesium chlorides, phosphates, and nitrates.
Examples of appropriate tissue penetrating, softening or solvatingagents and adjuvants include: various sulfoxides, such as DMSO anddecylmethylsulfoxide; various aliphatic and fatty alcohols, such asethanol, propanol, hexanol, octanol, benzyl alcohol, decyl alcohol,lauryl alcohol, and stearyl alcohol; various linear and branched,saturated and unsaturated fatty acids, such as lauric acid, caproicacid, capric acid, myristic acid, stearic acid, oleic acid,isovaleric acid, neopentanoic acid, trimethyl hexanoic acid,neodecanoic acid and isostearic acid; various aliphatic and alkylfatty acid esters, such as isopropyl n-butyrate, isopropyln-hexanoate, isopropyl n-decanoate, isopropyl myristate, isopropylpalmitate, octyldodecyl myristate, ethyl acetate, butyl acetate,methyl acetate, methylvalerate, methylpropionate, diethyl sebacateand ethyl oleate; various polyols, such as propylene glycol,polyethylene glycol, ethylene glycol, diethylene glycol,triethylene glycol, diproplyene glycol, glycerol, propanediol,butanediol, pentanediol and hexanetriol; various amides, such asurea, dimethylacetamide, diethyltoluamide, dimethylformamide,dimethyloctamide, dimethyldecamide; biodegradable cyclic urea, suchas 1-alkyl-4-imidazolin-2-one; pyrrolidone derivatives, such as1-methyl-2-pyrrolidone, 2-pyrrolidone, 1-lauryl-2-pyrrolidone,1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4-carboxy-2-pyrrolidone,1-lauryl-4-carboxy-2-pyrrolidone,1-methyl-4-methyoxycarbonyl-2-pyrrolidone,1-methyl-4-methyoxycarbonyl-2-pyrrolidone,1-lauryl-4-methyoxycarbonyl-2-pyrrolidone, N-cyclohexylpyrrolidone,N-dimethylaminopropylpyrrolidone, N-cocoalkypyrrolidone,N-tallowalkylpyrrolidone; biodegradable pyrrolidone derivatives,such as fatty acid esters of N-(2-hyroxyethyl)-2-pyrrolidone;cyclic amides, such as 1-dodecylazacycloheptane-2-one (Azone.RTM.),1-geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one,1-geranylgeranylazacycloheptan-2-one,1-(3,7-dimethyloctyl)azacycloheptan-2-one,1-(3,7,11-trimethydodecyl)azacycloheptan-2-one,1-geranylazacyclohexane-2-one, 1-geranylazacyclopentan-2,5-dione,1-farnesylazacyclopentan-2-one; hexamethylenelauramide and itsderivatives; and diethanolamine and triethanolamine; varioussurfactants, such as anionic surfactants, including sodium laurateand sodium lauryl sulfate; cationic surfactants, includingcetyltrimethyl ammonium bromide, tetradecyltrimethylammoniumbromide, benzalkonium chloride, octadecyltrimethylammoniumchloride, cetylpyridinium chloride, dodecyltrimethylammoniumchloride, hexadecyltrimethylammonium chloride; nonionicsurfactants, 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), Miglyol 840; various bile salts, such as sodium cholate,sodium salts of taurocholic, glycholic, desoxycholic acids;lecithin; various terpenes, including hydrocarbons, such asD-limonene, .alpha.-pinene, .beta.-carene; various terpenealcohols, including .alpha.-Terpineol, terpinen-4-ol, carvol;various terpene ketones, including carvone, pulegone, piperitone,menthone; various terpene oxides, including cyclohexane oxide,limonene oxide, .alpha.-pinene oxide, cyclopentene oxide,1,8-cineole; various terpene oils, including ylang ylang, anise,chenopodium, eucalyptus; various alkanones, such as N-heptane,N-octane, N-nonane, N-decane, N-undecane, N-dodecane, N-tridecane,N-tetradecane, N-hexadecane; various organic acids, such assalicylic acid and salicylites (including their methyl, ethyl, andpropyl glycol derivatives), citric and succinic acid.
The present invention is not limited to the above recited examples,as other formulations familiar to those of ordinary skill in theart, including various simple or complex combinations of vehiclesand adjuvants, are also useful for improving delivery of thephotoactive component of the medicament to target tissues.
2. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Skin and RelatedOrgans.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the skin and relatedorgans of humans and animals. The medicament can be applied, usingconventional intracorporeal administration modes, directly orindirectly to, or substantially proximal to, tissues to be treated,including those of the skin, nails and scalp. Such administrationmodes provide direct delivery of medicament to, into orsubstantially proximal to, tissues to be treated, or systemicdelivery of medicament to, into or substantially proximal to,tissues to be treated.
Example indications include treatment for: Psoriasis and PustularPsoriasis; Reiter's Syndrome; Skin Ulcers, including StasisDermatitis, Stasis Ulcers, Ischemic Ulcers, Sickle Cell Leg Ulcers,Diabetic Ulcers, Inflammatory Ulcers; Eczematous Disease andEczematous Reaction; various Ichthyoses; Atopic Dermatitis;Superficial Wrinkles; Near Surface Fat Reduction; Benign andMalignant Proliferative Disorders, such as Benign Epithelial Tumorsand Hamartomas; Premalignant and Malignant Epithelial Tumors,including Actinic Keratoses, Basal Cell Carcinoma, Squamous CellCarcinoma, and Keratoacanthoma; Benign and Malignant AdnexalTumors; Tumors of Pigment-Producing Cells, including MalignantMelanoma, Solar Lentigines, Nevi, and Cafe-au-lait; Sarcomas;Lymphomas; Vascular Disorders, such as Hemangiomas and Port WineStain; Microbial Infection, such as Bacterial, Fungal, Yeast,Parasitic or Other Infections; Warts; and Acne. These examples areprovided for illustrative purposes, as the present invention is notlimited to the recited examples and includes other indicationsknown to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that per oesophagealadministration of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V to mice exhibiting cutaneoustumors, followed by illumination of such tumors with green light inthe 500-600 nm band, leads to substantial or complete photodynamiceradication of such tumors. The present invention, however, is notlimited to this preferred embodiment, as other medicamentsdisclosed herein can also be used. Further, other formulations ofthe halogenated xanthenes as described in the present applicationhave similar applications for the specific indications describedherein, and for various other similar indications, including thoserelated to therapeutic or cosmetic treatment of the skin andrelated organs of humans and animals.
3. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Mouth andDigestive Tract and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the mouth and digestivetract and related organs of humans and animals. The medicament canbe applied, using conventional intracorporeal administration modes,directly or indirectly to, or substantially proximal to, tissues tobe treated, including those of the mouth, gums, tongue, larynx,pharynx, esophagus, stomach, intestines and colon. Suchadministration modes provide direct delivery of medicament to, intoor substantially proximal to, tissues to be treated, or systemicdelivery of medicament to, into or substantially proximal to,tissues to be treated.
Example indications include treatment for: Benign EsophagealLesions, Barretts Esophagus and other Esophageal Hyperplasia andDysplasia, and Esophageal Cancer, including Squamous CellCarcinoma, Adenocarcinoma, Carsinosarcoma, Pseudosarcoma, andSarcoma; Gastric Ulcers, Leiomyomas, Polyps, Neoplasms, Lymphomaand Pseudolymphoma, Adenocarcinoma, Primary Lymphoma,Leiomyosarcoma; Oral and Oropharynx Cancer and Premalignancies,Ulcers and Inflammatory Lesions, including Squamous Cell Carcinoma,Lymphoma, Actinic Cheilitis, Nicotine Stomatitis, Leukoplakia,Erythroplakia; Gum and Other Peridontal Disease, includingGingivitis; Laryngeal Hyperplasia, Dysplasia and Neoplasms;Colorectal Cancer and Polyps. These examples are provided forillustrative purposes, as the present invention is not limited tothe recited examples and includes other indications known to thoseskilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that per oesophagealadministration of a medicament solution containing Rose Bengal at aconcentration of approximately 1.0% W/V to canines, followed byillumination of a region of esophageal tissue with green light inthe 500-600 nm band, leads to controlled, localized photodynamicdestruction of tissues in the treated region. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic or cosmetic treatment of the mouth and digestivetract and related organs of humans and animals.
4. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Urinary andReproductive Tracts and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the urinary andreproductive tract and related organs of humans and animals. Themedicament can be applied, using conventional intracorporealadministration modes, directly or indirectly to, or substantiallyproximal to, tissues to be treated, including those of the urethra,bladder, ureter, kidneys, vulva, vagina, cervix, uterus, fallopiantubes, ovaries, penis, testes, vas deferens, prostate, andepididymis. Such administration modes provide direct delivery ofmedicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Urinary Tract Disease,including Cancerous and Pre-Cancerous Hyperplasia, Dysplasia andNeoplasms, Tumors and other Growths, Inflammation, and Infection ofthe Bladder, Ureter, Urethra, and Kidney; Cancerous andPre-Cancerous Hyperlasia, Dysplasia and Neoplasms, Tumors and otherGrowths, Inflammation, and Infection of the Cervix, Endometrium,Myometrium, Ovaries, Fallopian Tubes, Uterus, Vulva, and Vagina,including Vaginal Warts; Cancerous and Pre-Cancerous Hyperlasia,Dysplasia and Neoplasms, Tumors and other Growths, Inflammation,and Infection of the Prostate and Testes; Cancerous andPre-Cancerous Hyperlasia, Dysplasia and Neoplasms, Tumors and otherGrowths, Inflammation, and Infection of the Breast; ReproductiveTract Infections, including Tinea Cruris, Candidiasis, CondylomataAcuminata, Molluscum Contagiosum, Genital Herpes Simplex Infection,Lymphogranuloma Venereum, Chancroid, Granuloma Inguinale,Erythrasma; Psoriais; and Lichen Planus and Lichen Sclerosus. Theseexamples are provided for illustrative purposes, as the presentinvention is not limited to the recited examples and includes otherindications known to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a prostate tumor, followed by illumination of said tumortissue with green light in the 500-600 nm band, leads tocontrolled, localized photodynamic eradication of such tumors. Thepresent invention, however, is not limited to this preferredembodiment, as other medicaments disclosed herein can also be used.Further, other formulations of the halogenated xanthenes asdescribed herein have similar applications for the specificindications described herein, and for various other similarindications, including those related to therapeutic or cosmetictreatment of the urinary and reproductive tracts and related organsof humans and animals.
5. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the RespiratoryTract and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the respiratory tract andrelated organs of humans and animals. The medicament can beapplied, using conventional intracorporeal administration modes,directly or indirectly to, or substantially proximal to, tissues tobe treated, including those of the lung and alveoli, bronchi,trachea, hypopharynx, larynx, nasopharynx, tear ducts, sinuses andnasal cavities. Such administration modes provide direct deliveryof medicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Hyperplasia, Dysplasiaand Neoplasia, Cancer, Inflammation and Infection of the NasalCavity, Paranasal Sinuses, Tear Ducts, Eustachian Tubes,Nasopharynx, Hypopharynx, Larynx, Trachea, Bronchi, Lung andAlveoli. These examples are provided for illustrative purposes, asthe present invention is not limited to the recited examples andincludes other indications known to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a lung tumor, followed by illumination of such tumor withgreen light in the 500-600 nm band, leads to controlled, localizedphotodynamic eradication of such tumors. The present invention,however, is not limited to this preferred embodiment, as othermedicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic treatment of the respiratory tract and relatedorgans of humans and animals.
6. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the CirculatorySystem and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the circulatory systemand related organs of humans and animals. The medicament can beapplied, using conventional intracorporeal administration modes,directly or indirectly to, or substantially proximal to, tissues tobe treated, including those of the heart, kidneys, liver and bloodvessels. Such administration modes provide direct delivery ofmedicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Disease of Cardiac andPericardial Tissues and Circulatory Tissues, including Arteries andVeins, including Plaques and Infections of such tissues, such asBacterial Endocarditis; and destruction of unwanted blood vessels,such as spider veins. These examples are provided for illustrativepurposes, as the present invention is not limited to the recitedexamples and includes other indications known to those skilled inthe art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that per oesophagealadministration of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V leads to transient elevationof serum levels of Rose Bengal; such circulating Rose Bengal canaccumulate in lipophilic deposits, such as those in arterialplaques, and can thereby potentiate destruction of such plaquesupon illumination with green light in the 500-600 nm band. Thepresent invention, however, is not limited to this preferredembodiment, as other medicaments disclosed herein can also be used.Further, other formulations of the halogenated xanthenes asdescribed herein have similar applications for the specificindications described herein, and for various other similarindications, including those related to therapeutic treatment ofthe circulatory system and related organs of humans and animals.
7. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Head and Neck.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photo dynamictreatment of various conditions affecting the head and neck ofhumans and animals. The medicament can be applied, usingconventional intracorporeal administration modes, directly orindirectly to, or substantially proximal to, tissues to be treated,including those of the head, neck, brain, eyes and ears. Suchadministration modes provide direct delivery of medicament to, intoor substantially proximal to, tissues to be treated, or systemicdelivery of medicament to, into or substantially proximal to,tissues to be treated.
Example indications include treatment for: Tumors or Resected TumorBeds of Intra-cranial and other Head and Neck Tumors; OphthalmicTumors and other diseases, including Macular Degeneration andDiabetic Retinopathy; Metastatic Tumors, such as Metastases ofMelanoma, Breast or Other Tumors to the Skin of the Head or Neck.These examples are provided for illustrative purposes, as thepresent invention is not limited to the recited examples andincludes other indications known to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a metastatic breast tumor, followed by illumination of suchtumor with green light in the 500-600 nm band, leads to controlled,localized photodynamic eradication of such tumor. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic or cosmetic treatment of the head and neck of humansand animals.
8. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Endocrine andLymphoreticular Systems and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the endocrine andlymphoreticular systems and related organs of humans and animals.The medicament can be applied, using conventional intracorporealadministration modes, directly or indirectly to, or substantiallyproximal to, tissues to be treated, including those of the thyroidgland, the thalamus and hypothalamus, the pituitary gland, lymphnodes and lymphoreticular system. Such administration modes providedirect delivery of medicament to, into or substantially proximalto, tissues to be treated, or systemic delivery of medicament to,into or substantially proximal to, tissues to be treated.
Example indications include treatment for: Hyperplasia, Dysplasiaand Neoplasia, Cancer, Inflammation and Infection of the Thyroid,Thalamus and Hypothalamus, Pituitary Gland, Lymph Nodes andLymphoreticular system, including Graves' Disease. These examplesare provided for illustrative purposes, as the present invention isnot limited to the recited examples and includes other indicationsknown to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a thyroid tumor, followed by illumination of such tumorwith green light in the 500-600 nm band, leads to controlled,localized photodynamic eradication of such tumor. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic treatment of the endocrine and lymphoreticularsystems and related organs of humans and animals.
9. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting Various OtherTissues such as Connective Tissues and Various Tissue SurfacesExposed During Surgery.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting various other internal orexternal tissues of humans and animals, such as connective tissuesand various tissue surfaces exposed during surgery. The medicamentcan be applied, using conventional intracorporeal administrationmodes, directly or indirectly to, or substantially proximal to,tissues to be treated, including those of tissue surfaces exposedduring surgery, including endoscopic surgery or other endoscopicprocedures. Such application modes provide direct delivery ofmedicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Joint Inflammation, suchas that of Arthritis; Resected Tumor Beds of Thoracic, Abdominal,or other Tumors; Metastatic Tumors, such as Metastases of BreastTumors to the Skin; Tumors or Infections of the Pleura, Peritoneumor Pericardium; and various other substantially similarindications. These examples are provided for illustrative purposes,as the present invention is not limited to the recited examples andincludes other indications known to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a metastatic breast tumor, followed by illumination of suchtumor with green light in the 500-600 nm band, leads to controlled,localized photodynamic eradication of such tumor. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic or cosmetic treatment of conditions affectingvarious other tissues of humans and animals, such as connectivetissues and various tissue surfaces exposed during surgery.
10. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Related to Microbial ViralFungal or Parasitic Infection.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions related to microbial, viral, fungalor parasitic infection of humans and animals. The medicament can beapplied, using conventional intracorporeal administration modes,directly or indirectly to, or substantially proximal to, tissues tobe treated, including those of tissue surfaces exposed duringsurgery, including endoscopic surgery or other endoscopicprocedures. Such administration modes provide direct delivery ofmedicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Bacterial and AntibioticResistant Bacterial Infection, including those caused by GramPositives and Gram Negatives, Streptomycetes, Actinomycetes,Staphylococci, Streptococci, Pseudomonas, Escherichia coli,Mycobacteria and others; Infection caused by Filamentous Fungi andNon-filamentous Fungi like Cryptosporidium, Histoplasma,Aspergillus, Blastomyces, Candida and others; Parasitic Infectioncaused by Amoeba (including for use in lysing and killing amoeba inamoebic cysts), Trichinella, Dirodfilaria (Heart worm in dogs) andvarious other substantially similar indications. These examples areprovided for illustrative purposes, as the present invention is notlimited to the recited examples and includes other indicationsknown to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that application of anaqueous solution containing Rose Bengal at a concentration ofapproximately 1 to 10 micromolar to antibiotic resistantStaphylococcus aureus, Escherichia coli, various other grampositive and gram negative bacteria, and various yeasts, followedby illumination with green light in the 500-600 nm band, leads tosubstantial or complete eradication of such microbes. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic or cosmetic treatment of microbial, viral, fungal orparasitic infection of humans and animals.
Claim 1 of 23 Claims
1. An intracorporeal photodynamic medicament, the medicamentcomprising of a halogenated xanthene as a primary active component,wherein said halogenated xanthene is disodium4,5,6,7-Tetrabromoerythrosin, and wherein said medicament is forphotodynamic treatment of human tissue.
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Abstract
New intracorporeal photodynamic medicaments and certain medicaluses and methods for use of such photodynamic medicaments fortreatment of disease in human or animal tissue are described,wherein a primary active component of such medicaments is ahalogenated xanthene or halogenated xanthene derivative. Inpreferred embodiments, such medicaments are used for treatment of avariety of conditions affecting the skin and related organs, themouth and digestive tract and related organs, the urinary andreproductive tracts and related organs, the respiratory tract andrelated organs, the circulatory system and related organs, the headand neck, the endocrine and lymphoreticular systems and relatedorgans, various other tissues, such as connective tissues andvarious tissue surfaces exposed during surgery, as well as varioustissues exhibiting microbial or parasitic infection. In anotherpreferred embodiment, such medicaments are produced in variousformulations including liquid, semisolid, solid or aerosol deliveryvehicles.
Description of the Invention
SUMMARY OF THE PRESENT INVENTION
The present invention is directed to new intracorporealphotodynamic medicaments and certain medical uses of suchmedicaments, and methods for treatment using such medicaments, fortreatment of human or animal tissue, wherein a primary activecomponent of such medicaments is a halogenated xanthene or ahalogenated xanthene derivative, and more preferably Rose Bengal ora functional derivative of Rose Bengal. The halogenated xanthenesconstitute a family of potent photosensitizers that becomephotoactivated upon illumination of the treatment site with visiblewavelengths of light. Such medicaments are suitable forintracorporeal administration, and are thus intracorporealmedicaments. Such medicaments can also be called pharmaceuticalcompositions or agents.
In a preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting theskin and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting themouth and digestive tract and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting theurinary and reproductive tracts and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting therespiratory system and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting thecirculatory system and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting thehead and neck.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting theendocrine and lymphoreticular systems and related organs.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions affecting variousother tissues, such as connective tissues and various tissuesurfaces exposed during surgery.
In another preferred embodiment, such medicaments are used forphotodynamic treatment of a variety of conditions related tomicrobial or parasitic infection.
In another preferred embodiment, such medicaments are produced invarious formulations including liquid, semisolid, solid or aerosoldelivery vehicles, as well as in tablet, capsule, suppository, andother similar forms.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
The present invention is directed to new photodynamic medicamentsand certain medical uses of such photodynamic medicaments, andmethods for photodynamic treatment using such medicaments, fortreatment of human or animal tissue, wherein a primary activecomponent of such medicaments is a halogenated xanthene orhalogenated xanthene derivative. The inventors of the presentinvention have discovered that such halogenated xanthenes, asdiscussed in more detail infra, exhibit desirable photodynamiceffects when applied to or otherwise delivered to certain human oranimal tissues. The desirable effects include reduction orelimination of disease or diseased tissue or other undesirableconditions, including eradication of cancerous or pre-canceroustumors and infectious agents. The treatment is applicable to avariety of conditions affecting the skin and related organs, themouth and digestive tract and related organs, the urinary andreproductive tracts and related organs, the respiratory tract andrelated organs, the circulatory system and related organs, the headand neck, the endocrine and lymphoreticular systems and relatedorgans, various other tissues, such as tissues exposed duringsurgery, as well as various tissues exhibiting microbial, viral,fungal or parasitic infection.
In a preferred embodiment, such medicaments are produced in variousformulations suitable for intracorporeal administration, includingin various liquid, semisolid, solid or aerosol delivery vehicles,as well as in tablet, capsule, suppository, and other similarforms. Such medicament formulations are suitable for delivery viavarious conventional modes and routes (hereafter defined asintracorporeal administration), including intravenous injection(i.v.), intraperitoneal injection (i.p.), intramuscular injection(i.m.), intracranial injection (i.c.), intratumoral injection(i.t.), intraepithelial injection (i.e.), transcutaneous delivery(t.c.), and per oesophageal (p.o.) administration; additionaladministrative modes and routes include intraabdominal,intraapendicular, intraarterial, intraarticular, intrabronchial,intrabuccal, intracapsular, intracardial, intracartilaginous,intracavitary, intracephalic, intracolic, intracutaneous,intracystic, intradermal, intraductal, intraduodenal,intrafascicular, intrafat, intrafilar, intrafissural, intragastric,intraglandular, intrahepatic, intraintestinal, intralamellar,intralesional, intraligamentous, intralingual, intramammary,intramedullary, intrameningeal, intramyocardial, intranasal,intraocular, intraoperative, intraoral, intraosseous, intraovarian,intrapancreatic, intraparietal, intrapelvic, intrapericardial,intraperineal, intraperitoneal, intraplacental, intrapleural,intrapontine, intraprostatic, intrapulmonary, intrarachidian,intrarectal, intrarenal, intrascleral, intrascrotal,intrasegmental, intrasellar, intraspinal, intrasplenic,intrasternal, intrastromal, intrasynovial, intratarsal,intratesticular, intrathoracic, intratonsillar, intratracheal,intratubal, intratympanic, intraureteral, intraurethral,intrauterine, intravaginal, intravascular, intraventricular,intravertebral, intravesical, or intravitreous administration. Suchmedicaments will thus be referred to as intracorporeal medicaments(i.e., medicaments suitable for intracorporeal administration).
1. Properties of the Preferred Photoactive Components andMedicament Formulations.
The inventors of the present invention have discovered a class ofphotoactive agents that are broadly applicable for producingintracoporeal medicaments for photodynamic treatment of disease incertain human and animal tissues. These photoactive agents arereferred to as halogenated xanthenes and are illustrated in FIG. 1a(see Original Patent), where the symbols X, Y, and Z representvarious elements present at the designated positions, and thesymbols R.sup.1 and R.sup.2 represent various functionalitiespresent at the designated positions.
Selected chemical and physical properties (such as chemicalconstituents at positions X, Y, and Z and functionalities R.sup.1and R.sup.2, along with molecular weight and photochemicalcharacteristics) of representative halogenated xanthenes aresummarized in attached Table 1 (see Original Patent). Certaingeneral properties of this class of agents are discussed in furtherdetail in U.S. Ser. No. 09/130,041, filed on Aug. 6, 1998, U.S.Ser. No. 09/184,388, filed on Nov. 2, 1998, and U.S. Ser. No.09/216,787, filed on Dec. 21, 1998, which are herein incorporatedby reference in their entirety. In general, the halogenatedxanthenes are characterized by a low dark cytotoxicity (toxicity tocells or tissues in the absence of photoactivation), by high lightcytotoxicity (toxicity to cells or tissues upon photoactivation)and by chemical and photochemical properties that are substantiallyunaffected by the local chemical environment or by the attachmentof functional derivatives at positions R.sup.1 and R.sup.2. Suchfactors make these chemical agents, and in particularintracorporeal medicaments formulated from such agents, excellentPDT agents for the treatment of disease in human and animaltissues.
One preferred embodiment of an intracorporeal medicament accordingto the present invention contains an active ingredient, at aconcentration of from greater than approximately 0.001% to lessthan approximately 20%, of at least one halogenated xanthene,including for example one or more of: Fluorescein;4',5'-Dichlorofluorescein; 2',7'-Dichlorofluorescein;4,5,6,7-Tetrachlorofluorescein; 2',4',5',7'-Tetrachlorofluorescein;Dibromofluorescein; Solvent Red 72; Diiodofluorescein; Eosin B;Eosin Y; Ethyl Eosin; Erythrosin B; Phloxine B; Rose Bengal;4,5,6,7-Tetrabromoerythrosin; Mono-, Di-, or Tribromoerythrosin;Mono-, Di-, or Trichloroerythrosin; Mono-, Di-, orTrifluoroerythrosin; 2',7'-Dichloro-4,5,6,7-Tetrafluorofluorescein;2',4,5,6,7,7'-Hexafluorofluorescein; and4,5,6,7-Tetrafluorofluorescein. It is further preferred that thismedicament include Rose Bengal(4,5,6,7-tetrachloro-2',4',5',7'-Tetraiodofluorescein, illustratedin FIG. 1b (see Original Patent)).
Further, as evidenced by the data shown in Table 1 (infra) and inFIG. 2 (see Original Patent), halogenated xanthenes share commonspectroscopic properties, including a high single-photoncross-section extending from approximately 500 nm to 600 nm. Theseproperties are substantially invariant regardless of state offunctional derivatization (for example, at positions R.sup.1 andR.sup.2) or of chemical or biological environment. This featurefacilitates photoactivation with commonly available visible lightsources operating in the band from approximately 500 nm to 600 nmand circumvents the need to substantively change sources if thespecific photoactive component of the medicament is varied ormodified, as discussed herein. Furthermore, the inventors of thepresent invention have shown that the halogenated xanthenes arecapable of being activated using non-linear, multi-photonexcitation under certain conditions when using light in the nearinfrared band from approximately 700 nm to 1200 nm (using methodssuch as, for example, those taught in U.S. Pat. No. 6,042,603 andin U.S. Ser. No. 09/096,832, filed Jun. 12, 1998 (entitled"Improved Methods And Apparatus For Multi-PhotonPhoto-Activation Of Therapeutic Agents"), both of which isincorporated herein by reference in their entireties). Suchexcitation methods provide additional utility in the activation ofmedicaments formulated from these agents, for example when it isdesirable to increase the depth of photoactivation to positionssubstantially beyond that readily accessible using visible lightexcitation methods.
As an example of these desirable chemical, biochemical, andphysical properties, the inventors have found that the prototypicalhalogenated xanthene, Rose Bengal, will accumulate preferentiallyin (i.e. target) some tumors and other tissues and pathogenicentities, has negligible dark cytotoxicity, high light cytotoxicityupon illumination with visible light, relatively low cost, and theability to clear rapidly from the body.
For example, it is possible to estimate an agent's potential fortissue accumulation based on the partition coefficient, K.sub.p.This in vitro parameter is purported to have predictive valuerelating to in vivo agent delivery at the cellular level. Inparticular, a value greater than unity is considered to indicateagents capable of localizing in tumor or other diseased tissue, andmore specifically in plasma membranes of cells composing suchtissue, and thereby being capable of exhibiting enhancedphotodynamic efficacy in such tissue. K.sub.p is determined bymeasuring the ratio of equilibrium concentrations of an agent in alipophilic phase (n-octanol) contacted with an aqueous phase(phosphate buffered saline, PBS, pH=7.4). Comparative values ofK.sub.p are shown in Table 2 (see Original Patent), infra. Thelarge K.sub.p values for the halogenated xanthenes relative to manyof the porphyrin-based PDT agents suggest that the halogenatedxanthenes will exhibit an enhanced tendency to concentrate oraccumulate in tumor or other diseased tissue, and should thereby becapable of exhibiting superior photodynamic efficacy in suchtissue.
The following examples illustrate this preference for accumulationin tumor tissue by the halogenated xanthenes:
Initially, tumor cell suspensions (e.g. melanoma, breast tumor,liver tumor, renal carcinoma, gall bladder tumor or prostate tumor)were injected subcutaneously into the flanks of nude mice resultingin formation of primary tumors, within a few weeks, at theinjection site having a volume of approximately 0.1 cm.sup.3 to 0.5cm.sup.3.
Thereafter, a solution of Rose Bengal (10-30 .mu.L of 10% RoseBengal, i.e., 1-3 mg Rose Bengal p.o.) was administered peroesophageal to the mice, followed by illumination of the tumor 3-48hours post administration using light at 532 nm (50-200 J/cm.sup.2at the tumor surface). This resulted in selective destruction oftumor tissue with no substantive effect in healthy surroundingtissue. These example results are summarized in Table 3 (seeOriginal Patent), infra.
Intratumoral injection (i.t.) of a similar Rose Bengal formulationresulted in persistent accumulation and retention of Rose Bengaluniformly throughout the tumor volume, with more than 75% ofinjected Rose Bengal dose remaining in the tumor after severalweeks. As in the per oesophageal example above, illumination usinglight at 532 nm resulted in selective tumor destruction (see Table4, infra (see Original Patent)).
Peritumoral injection (i.e., injection into normal tissue aroundthe outside margins of the tumor) exhibited no such retention innormal tissue, with less than 1% of Rose Bengal remaining in thevicinity of the tumor after 24 hours.
In contrast, i.t. administration of a different class of agent,indocyanine green (K.sub.p=99), showed that within 24 hours thisagent had substantively migrated out of the tumor, and insteadexhibited a tendency to accumulate in peritumoral tissues. Hence,while the K.sub.p value for indocyanine green is nearly ten-foldlarger than that of Rose Bengal (and as such, indocyanine green is,by the conventional model based on K.sub.p, expected to accumulatestrongly in tumor tissue), the tissue localization properties ofthe two agents are clearly completely different.
Thus, the inventors of the present invention have shown that thehalogenated xanthenes, and in particular Rose Bengal, exhibit anunexpectedly marked preference for accumulation and retention intumor and other diseased tissue upon intracorporeal administration,and that once present in such tissue, said halogenated xanthenescan be utilized as potent, highly tissue or disease specific PDTagents.
In addition to superior suitability for direct administration intodesired targeted tissue to be treated, such as a focal tumor, thepreference of the halogenated xanthenes for accumulation in certaintypes of tissues provides a basis for highly-selective, systemicdelivery of the halogenated xanthenes to such tissues. For example,Rose Bengal's relatively large partition coefficient is indicativeof a preference for accumulation in lipophilic tissue, such ascutaneous lipocytes. The inventors of the present invention havefound that systemic administration of Rose Bengal, for example asan aqueous solution administered via intraperitoneal injection(i.p.) or per oesophagus (p.o.) administration, resulted in highlyselective accumulation of said agent in certain tissues, such as inthe cutaneous fat deposits of obese laboratory mice. Histologicexamination of skin samples from such animals showed thataccumulated agent is substantively limited to cutaneous lipocytes.Furthermore, illumination of the skin of such animals with light atapproximately 532 nm resulted in photodynamic activation of thisaccumulated agent only in such lipocytes. Such photodynamicactivation of accumulated agent precipitated selective photodynamicdestruction of such lipocytes with no effect in overlying skin orunderlying muscle tissue.
Moreover, the inventors of the present invention have discoveredthat the facility with which the halogenated xanthenes targetspecific tissues or other sites can be further optimized byattachment of specific functional derivatives at positions R.sup.1and R.sup.2 (see e.g. FIG. 1), so as to change the chemicalpartitioning and/or biological activity of the agent. For example,attachment of one targeting moiety or more at positions R.sup.1 orR.sup.2 can be used to improve targeting to specific tissues, suchas cancerous tumor tissues or sites of localized infection. Anexample of this is esterification at position R.sup.1 with a shortaliphatic alcohol, such as n-hexanol, to produce a derivatizedagent exhibiting enhanced partitioning into lipid-rich tumortissues.
It is thus a further preferred embodiment to include a targetingmoiety in at least one of the at least one halogenated xantheneactive ingredients, such targeting moiety being selected from agroup that includes deoxyribonucleic acid (DNA), ribonucleic acid(RNA), amino acids, proteins, antibodies, ligands, haptens,carbohydrate receptors, carbohydrate complexing agents, lipidreceptors, lipid complexing agents, protein receptors, proteincomplexing agents, chelators, encapsulating vehicles, short-chainaliphatic hydrocarbons, long-chain aliphatic hydrocarbons, aromatichydrocarbons, aldehydes, ketones, alcohols, esters, amides, amines,nitriles, azides, hydrophilic moieties and hydrophobic moieties. Afurther example of this embodiment is derivatization of Rose Bengalwith a lipid (at position R.sup.1, via esterification), so as toincrease the lipophilicity of Rose Bengal, and thereby modify itstargeting properties in a patient. An additional further example ofthis embodiment is derivatization of Rose Bengal with folate (atposition R.sup.1, via esterification or other modes of attachment),so as to increase selective targeting of cancer and other cellsexhibiting enhanced folate receptor activity or folate metabolism.
As a further example of the desirable chemical, biochemical, andphysical properties of the halogenated xanthenes and halogenatedxanthene derivatives, the inventors of the present invention haveshown that these agents exhibit a remarkable combination of lowdark cytotoxicity and high light cytotoxicity. This is evidenced bythe following: addition of Rose Bengal and other halogenatedxanthenes to procaryotic or eucaryotic cell cultures atconcentrations equivalent to or greater than 100 mg/kg generallyresulted in no measurable effect on the viability of such cultures.However, subsequent illumination of such cultures with light atwavelengths between about 500 nm and 600 nm generally resulted inan immediate and complete kill of such cell cultures.Intracorporeal administration of these agents at these levels intotumor-bearing laboratory animals resulted in negligible biologicaleffects in the absence of illumination. However, illumination oftumor tissue in these animals subsequent to this administrationresulted in marked destruction of such tumor tissue. Further, theinventors of the present invention have shown that these agents arereadily cleared from healthy tissues in a matter of several hoursand are known to be rapidly excreted in bile, urine and feces,without doing damage to those healthy tissues while it was there.This is in dramatic contrast to most conventional PDT agents, someof which exhibit half-lives in healthy tissues on the order of manyweeks.
Further examples of the desirable properties of the halogenatedxanthenes and halogenated xanthene derivatives are as follows:halogenated xanthenes and halogenated xanthene derivatives areeasily synthesized using simple, low-cost synthetic methods, can bereadily purified and exhibit excellent stability (such as a longshelf life without need for refrigeration or storage under an inertatmosphere).
Because the halogenated xanthenes and their derivatives are, ingeneral, fine solid powders in their pure form, it is preferredthat, for proper delivery to desired tissues, such agents beformulated in appropriate delivery vehicles. Approaches to suchformulation will be generally known to those of ordinary skill inthe art. Specifically, such formulations are preferred so as tofacilitate agent delivery into the body and subsequent contactwith, and delivery to, desired tissues to be treated.
It is thus a further preferred embodiment of the present inventionthat at least one halogenated xanthene or halogenated xanthenederivative be formulated as an intracorporeal medicament in a formsuitable for intracorporeal administration via various conventionalmodes and routes. Such suitable forms include, for example,medicaments formulated in a liquid, semisolid, solid or aerosoldelivery vehicle, including in vehicles of the following natures:aqueous suspensions, non-aqueous suspensions, solutions, creams,ointments, gels, syrups, micro-droplet sprays, suppositories,tablets and capsules. The at least one halogenated xanthene orhalogenated xanthene derivative may be dissolved or suspended insuch delivery vehicle, wherein this vehicle may, in addition to theat least one halogenated xanthene or halogenated xanthenederivative, include various builders, stabilizers, emulsifiers ordispersants, preservatives, buffers, electrolytes, and tissuepenetrating or softening agents. Such components of the deliveryvehicle may be present as the primary component (by weight orvolume) of the medicament, or as a minor component that serves inan adjuvant role in agent delivery with no adverse affect on tissueor treatment outcome.
For example, appropriate builders include cellulose and cellulosederivatives, such as starch, methylcellulose,carboxymethylcellulose, and alginates.
Examples of appropriate stabilizers, emulsifiers or dispersantsinclude liposomes, nanoparticulates and nanodispersions,microparticulates and microdispersions, as well as various lipids,detergents and other surfactants.
Examples of appropriate preservatives include benzalkoniumchloride, thimerosal, quaternary amines and urea.
Examples of appropriate buffers include monobasic or dibasicphosphate salts, citrate salts, bicarbonate salts, andethanolamine.
Examples of appropriate electrolytes include sodium, potassium,calcium and magnesium chlorides, phosphates, and nitrates.
Examples of appropriate tissue penetrating, softening or solvatingagents and adjuvants include: various sulfoxides, such as DMSO anddecylmethylsulfoxide; various aliphatic and fatty alcohols, such asethanol, propanol, hexanol, octanol, benzyl alcohol, decyl alcohol,lauryl alcohol, and stearyl alcohol; various linear and branched,saturated and unsaturated fatty acids, such as lauric acid, caproicacid, capric acid, myristic acid, stearic acid, oleic acid,isovaleric acid, neopentanoic acid, trimethyl hexanoic acid,neodecanoic acid and isostearic acid; various aliphatic and alkylfatty acid esters, such as isopropyl n-butyrate, isopropyln-hexanoate, isopropyl n-decanoate, isopropyl myristate, isopropylpalmitate, octyldodecyl myristate, ethyl acetate, butyl acetate,methyl acetate, methylvalerate, methylpropionate, diethyl sebacateand ethyl oleate; various polyols, such as propylene glycol,polyethylene glycol, ethylene glycol, diethylene glycol,triethylene glycol, diproplyene glycol, glycerol, propanediol,butanediol, pentanediol and hexanetriol; various amides, such asurea, dimethylacetamide, diethyltoluamide, dimethylformamide,dimethyloctamide, dimethyldecamide; biodegradable cyclic urea, suchas 1-alkyl-4-imidazolin-2-one; pyrrolidone derivatives, such as1-methyl-2-pyrrolidone, 2-pyrrolidone, 1-lauryl-2-pyrrolidone,1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4-carboxy-2-pyrrolidone,1-lauryl-4-carboxy-2-pyrrolidone,1-methyl-4-methyoxycarbonyl-2-pyrrolidone,1-methyl-4-methyoxycarbonyl-2-pyrrolidone,1-lauryl-4-methyoxycarbonyl-2-pyrrolidone, N-cyclohexylpyrrolidone,N-dimethylaminopropylpyrrolidone, N-cocoalkypyrrolidone,N-tallowalkylpyrrolidone; biodegradable pyrrolidone derivatives,such as fatty acid esters of N-(2-hyroxyethyl)-2-pyrrolidone;cyclic amides, such as 1-dodecylazacycloheptane-2-one (Azone.RTM.),1-geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one,1-geranylgeranylazacycloheptan-2-one,1-(3,7-dimethyloctyl)azacycloheptan-2-one,1-(3,7,11-trimethydodecyl)azacycloheptan-2-one,1-geranylazacyclohexane-2-one, 1-geranylazacyclopentan-2,5-dione,1-farnesylazacyclopentan-2-one; hexamethylenelauramide and itsderivatives; and diethanolamine and triethanolamine; varioussurfactants, such as anionic surfactants, including sodium laurateand sodium lauryl sulfate; cationic surfactants, includingcetyltrimethyl ammonium bromide, tetradecyltrimethylammoniumbromide, benzalkonium chloride, octadecyltrimethylammoniumchloride, cetylpyridinium chloride, dodecyltrimethylammoniumchloride, hexadecyltrimethylammonium chloride; nonionicsurfactants, 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), Miglyol 840; various bile salts, such as sodium cholate,sodium salts of taurocholic, glycholic, desoxycholic acids;lecithin; various terpenes, including hydrocarbons, such asD-limonene, .alpha.-pinene, .beta.-carene; various terpenealcohols, including .alpha.-Terpineol, terpinen-4-ol, carvol;various terpene ketones, including carvone, pulegone, piperitone,menthone; various terpene oxides, including cyclohexane oxide,limonene oxide, .alpha.-pinene oxide, cyclopentene oxide,1,8-cineole; various terpene oils, including ylang ylang, anise,chenopodium, eucalyptus; various alkanones, such as N-heptane,N-octane, N-nonane, N-decane, N-undecane, N-dodecane, N-tridecane,N-tetradecane, N-hexadecane; various organic acids, such assalicylic acid and salicylites (including their methyl, ethyl, andpropyl glycol derivatives), citric and succinic acid.
The present invention is not limited to the above recited examples,as other formulations familiar to those of ordinary skill in theart, including various simple or complex combinations of vehiclesand adjuvants, are also useful for improving delivery of thephotoactive component of the medicament to target tissues.
2. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Skin and RelatedOrgans.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the skin and relatedorgans of humans and animals. The medicament can be applied, usingconventional intracorporeal administration modes, directly orindirectly to, or substantially proximal to, tissues to be treated,including those of the skin, nails and scalp. Such administrationmodes provide direct delivery of medicament to, into orsubstantially proximal to, tissues to be treated, or systemicdelivery of medicament to, into or substantially proximal to,tissues to be treated.
Example indications include treatment for: Psoriasis and PustularPsoriasis; Reiter's Syndrome; Skin Ulcers, including StasisDermatitis, Stasis Ulcers, Ischemic Ulcers, Sickle Cell Leg Ulcers,Diabetic Ulcers, Inflammatory Ulcers; Eczematous Disease andEczematous Reaction; various Ichthyoses; Atopic Dermatitis;Superficial Wrinkles; Near Surface Fat Reduction; Benign andMalignant Proliferative Disorders, such as Benign Epithelial Tumorsand Hamartomas; Premalignant and Malignant Epithelial Tumors,including Actinic Keratoses, Basal Cell Carcinoma, Squamous CellCarcinoma, and Keratoacanthoma; Benign and Malignant AdnexalTumors; Tumors of Pigment-Producing Cells, including MalignantMelanoma, Solar Lentigines, Nevi, and Cafe-au-lait; Sarcomas;Lymphomas; Vascular Disorders, such as Hemangiomas and Port WineStain; Microbial Infection, such as Bacterial, Fungal, Yeast,Parasitic or Other Infections; Warts; and Acne. These examples areprovided for illustrative purposes, as the present invention is notlimited to the recited examples and includes other indicationsknown to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that per oesophagealadministration of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V to mice exhibiting cutaneoustumors, followed by illumination of such tumors with green light inthe 500-600 nm band, leads to substantial or complete photodynamiceradication of such tumors. The present invention, however, is notlimited to this preferred embodiment, as other medicamentsdisclosed herein can also be used. Further, other formulations ofthe halogenated xanthenes as described in the present applicationhave similar applications for the specific indications describedherein, and for various other similar indications, including thoserelated to therapeutic or cosmetic treatment of the skin andrelated organs of humans and animals.
3. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Mouth andDigestive Tract and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the mouth and digestivetract and related organs of humans and animals. The medicament canbe applied, using conventional intracorporeal administration modes,directly or indirectly to, or substantially proximal to, tissues tobe treated, including those of the mouth, gums, tongue, larynx,pharynx, esophagus, stomach, intestines and colon. Suchadministration modes provide direct delivery of medicament to, intoor substantially proximal to, tissues to be treated, or systemicdelivery of medicament to, into or substantially proximal to,tissues to be treated.
Example indications include treatment for: Benign EsophagealLesions, Barretts Esophagus and other Esophageal Hyperplasia andDysplasia, and Esophageal Cancer, including Squamous CellCarcinoma, Adenocarcinoma, Carsinosarcoma, Pseudosarcoma, andSarcoma; Gastric Ulcers, Leiomyomas, Polyps, Neoplasms, Lymphomaand Pseudolymphoma, Adenocarcinoma, Primary Lymphoma,Leiomyosarcoma; Oral and Oropharynx Cancer and Premalignancies,Ulcers and Inflammatory Lesions, including Squamous Cell Carcinoma,Lymphoma, Actinic Cheilitis, Nicotine Stomatitis, Leukoplakia,Erythroplakia; Gum and Other Peridontal Disease, includingGingivitis; Laryngeal Hyperplasia, Dysplasia and Neoplasms;Colorectal Cancer and Polyps. These examples are provided forillustrative purposes, as the present invention is not limited tothe recited examples and includes other indications known to thoseskilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that per oesophagealadministration of a medicament solution containing Rose Bengal at aconcentration of approximately 1.0% W/V to canines, followed byillumination of a region of esophageal tissue with green light inthe 500-600 nm band, leads to controlled, localized photodynamicdestruction of tissues in the treated region. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic or cosmetic treatment of the mouth and digestivetract and related organs of humans and animals.
4. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Urinary andReproductive Tracts and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the urinary andreproductive tract and related organs of humans and animals. Themedicament can be applied, using conventional intracorporealadministration modes, directly or indirectly to, or substantiallyproximal to, tissues to be treated, including those of the urethra,bladder, ureter, kidneys, vulva, vagina, cervix, uterus, fallopiantubes, ovaries, penis, testes, vas deferens, prostate, andepididymis. Such administration modes provide direct delivery ofmedicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Urinary Tract Disease,including Cancerous and Pre-Cancerous Hyperplasia, Dysplasia andNeoplasms, Tumors and other Growths, Inflammation, and Infection ofthe Bladder, Ureter, Urethra, and Kidney; Cancerous andPre-Cancerous Hyperlasia, Dysplasia and Neoplasms, Tumors and otherGrowths, Inflammation, and Infection of the Cervix, Endometrium,Myometrium, Ovaries, Fallopian Tubes, Uterus, Vulva, and Vagina,including Vaginal Warts; Cancerous and Pre-Cancerous Hyperlasia,Dysplasia and Neoplasms, Tumors and other Growths, Inflammation,and Infection of the Prostate and Testes; Cancerous andPre-Cancerous Hyperlasia, Dysplasia and Neoplasms, Tumors and otherGrowths, Inflammation, and Infection of the Breast; ReproductiveTract Infections, including Tinea Cruris, Candidiasis, CondylomataAcuminata, Molluscum Contagiosum, Genital Herpes Simplex Infection,Lymphogranuloma Venereum, Chancroid, Granuloma Inguinale,Erythrasma; Psoriais; and Lichen Planus and Lichen Sclerosus. Theseexamples are provided for illustrative purposes, as the presentinvention is not limited to the recited examples and includes otherindications known to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a prostate tumor, followed by illumination of said tumortissue with green light in the 500-600 nm band, leads tocontrolled, localized photodynamic eradication of such tumors. Thepresent invention, however, is not limited to this preferredembodiment, as other medicaments disclosed herein can also be used.Further, other formulations of the halogenated xanthenes asdescribed herein have similar applications for the specificindications described herein, and for various other similarindications, including those related to therapeutic or cosmetictreatment of the urinary and reproductive tracts and related organsof humans and animals.
5. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the RespiratoryTract and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the respiratory tract andrelated organs of humans and animals. The medicament can beapplied, using conventional intracorporeal administration modes,directly or indirectly to, or substantially proximal to, tissues tobe treated, including those of the lung and alveoli, bronchi,trachea, hypopharynx, larynx, nasopharynx, tear ducts, sinuses andnasal cavities. Such administration modes provide direct deliveryof medicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Hyperplasia, Dysplasiaand Neoplasia, Cancer, Inflammation and Infection of the NasalCavity, Paranasal Sinuses, Tear Ducts, Eustachian Tubes,Nasopharynx, Hypopharynx, Larynx, Trachea, Bronchi, Lung andAlveoli. These examples are provided for illustrative purposes, asthe present invention is not limited to the recited examples andincludes other indications known to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a lung tumor, followed by illumination of such tumor withgreen light in the 500-600 nm band, leads to controlled, localizedphotodynamic eradication of such tumors. The present invention,however, is not limited to this preferred embodiment, as othermedicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic treatment of the respiratory tract and relatedorgans of humans and animals.
6. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the CirculatorySystem and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the circulatory systemand related organs of humans and animals. The medicament can beapplied, using conventional intracorporeal administration modes,directly or indirectly to, or substantially proximal to, tissues tobe treated, including those of the heart, kidneys, liver and bloodvessels. Such administration modes provide direct delivery ofmedicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Disease of Cardiac andPericardial Tissues and Circulatory Tissues, including Arteries andVeins, including Plaques and Infections of such tissues, such asBacterial Endocarditis; and destruction of unwanted blood vessels,such as spider veins. These examples are provided for illustrativepurposes, as the present invention is not limited to the recitedexamples and includes other indications known to those skilled inthe art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that per oesophagealadministration of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V leads to transient elevationof serum levels of Rose Bengal; such circulating Rose Bengal canaccumulate in lipophilic deposits, such as those in arterialplaques, and can thereby potentiate destruction of such plaquesupon illumination with green light in the 500-600 nm band. Thepresent invention, however, is not limited to this preferredembodiment, as other medicaments disclosed herein can also be used.Further, other formulations of the halogenated xanthenes asdescribed herein have similar applications for the specificindications described herein, and for various other similarindications, including those related to therapeutic treatment ofthe circulatory system and related organs of humans and animals.
7. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Head and Neck.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photo dynamictreatment of various conditions affecting the head and neck ofhumans and animals. The medicament can be applied, usingconventional intracorporeal administration modes, directly orindirectly to, or substantially proximal to, tissues to be treated,including those of the head, neck, brain, eyes and ears. Suchadministration modes provide direct delivery of medicament to, intoor substantially proximal to, tissues to be treated, or systemicdelivery of medicament to, into or substantially proximal to,tissues to be treated.
Example indications include treatment for: Tumors or Resected TumorBeds of Intra-cranial and other Head and Neck Tumors; OphthalmicTumors and other diseases, including Macular Degeneration andDiabetic Retinopathy; Metastatic Tumors, such as Metastases ofMelanoma, Breast or Other Tumors to the Skin of the Head or Neck.These examples are provided for illustrative purposes, as thepresent invention is not limited to the recited examples andincludes other indications known to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a metastatic breast tumor, followed by illumination of suchtumor with green light in the 500-600 nm band, leads to controlled,localized photodynamic eradication of such tumor. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic or cosmetic treatment of the head and neck of humansand animals.
8. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting the Endocrine andLymphoreticular Systems and Related Organs.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting the endocrine andlymphoreticular systems and related organs of humans and animals.The medicament can be applied, using conventional intracorporealadministration modes, directly or indirectly to, or substantiallyproximal to, tissues to be treated, including those of the thyroidgland, the thalamus and hypothalamus, the pituitary gland, lymphnodes and lymphoreticular system. Such administration modes providedirect delivery of medicament to, into or substantially proximalto, tissues to be treated, or systemic delivery of medicament to,into or substantially proximal to, tissues to be treated.
Example indications include treatment for: Hyperplasia, Dysplasiaand Neoplasia, Cancer, Inflammation and Infection of the Thyroid,Thalamus and Hypothalamus, Pituitary Gland, Lymph Nodes andLymphoreticular system, including Graves' Disease. These examplesare provided for illustrative purposes, as the present invention isnot limited to the recited examples and includes other indicationsknown to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a thyroid tumor, followed by illumination of such tumorwith green light in the 500-600 nm band, leads to controlled,localized photodynamic eradication of such tumor. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic treatment of the endocrine and lymphoreticularsystems and related organs of humans and animals.
9. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Affecting Various OtherTissues such as Connective Tissues and Various Tissue SurfacesExposed During Surgery.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions affecting various other internal orexternal tissues of humans and animals, such as connective tissuesand various tissue surfaces exposed during surgery. The medicamentcan be applied, using conventional intracorporeal administrationmodes, directly or indirectly to, or substantially proximal to,tissues to be treated, including those of tissue surfaces exposedduring surgery, including endoscopic surgery or other endoscopicprocedures. Such application modes provide direct delivery ofmedicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Joint Inflammation, suchas that of Arthritis; Resected Tumor Beds of Thoracic, Abdominal,or other Tumors; Metastatic Tumors, such as Metastases of BreastTumors to the Skin; Tumors or Infections of the Pleura, Peritoneumor Pericardium; and various other substantially similarindications. These examples are provided for illustrative purposes,as the present invention is not limited to the recited examples andincludes other indications known to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that intratumoralinjection of a medicament solution containing Rose Bengal at aconcentration of approximately 10% W/V into tumor tissue, such asthat of a metastatic breast tumor, followed by illumination of suchtumor with green light in the 500-600 nm band, leads to controlled,localized photodynamic eradication of such tumor. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic or cosmetic treatment of conditions affectingvarious other tissues of humans and animals, such as connectivetissues and various tissue surfaces exposed during surgery.
10. Methods and Medical Use of the Subject Medicament forPhotodynamic Treatment of Conditions Related to Microbial ViralFungal or Parasitic Infection.
The inventors have discovered that the intracorporeal medicamentsdisclosed herein are broadly applicable to improved photodynamictreatment of various conditions related to microbial, viral, fungalor parasitic infection of humans and animals. The medicament can beapplied, using conventional intracorporeal administration modes,directly or indirectly to, or substantially proximal to, tissues tobe treated, including those of tissue surfaces exposed duringsurgery, including endoscopic surgery or other endoscopicprocedures. Such administration modes provide direct delivery ofmedicament to, into or substantially proximal to, tissues to betreated, or systemic delivery of medicament to, into orsubstantially proximal to, tissues to be treated.
Example indications include treatment for: Bacterial and AntibioticResistant Bacterial Infection, including those caused by GramPositives and Gram Negatives, Streptomycetes, Actinomycetes,Staphylococci, Streptococci, Pseudomonas, Escherichia coli,Mycobacteria and others; Infection caused by Filamentous Fungi andNon-filamentous Fungi like Cryptosporidium, Histoplasma,Aspergillus, Blastomyces, Candida and others; Parasitic Infectioncaused by Amoeba (including for use in lysing and killing amoeba inamoebic cysts), Trichinella, Dirodfilaria (Heart worm in dogs) andvarious other substantially similar indications. These examples areprovided for illustrative purposes, as the present invention is notlimited to the recited examples and includes other indicationsknown to those skilled in the art.
In an example of a preferred embodiment of this method of treatmentor medical use, the inventors have found that application of anaqueous solution containing Rose Bengal at a concentration ofapproximately 1 to 10 micromolar to antibiotic resistantStaphylococcus aureus, Escherichia coli, various other grampositive and gram negative bacteria, and various yeasts, followedby illumination with green light in the 500-600 nm band, leads tosubstantial or complete eradication of such microbes. The presentinvention, however, is not limited to this preferred embodiment, asother medicaments disclosed herein can also be used. Further, otherformulations of the halogenated xanthenes as described herein havesimilar applications for the specific indications described herein,and for various other similar indications, including those relatedto therapeutic or cosmetic treatment of microbial, viral, fungal orparasitic infection of humans and animals.
Claim 1 of 23 Claims
1. An intracorporeal photodynamic medicament, the medicamentcomprising of a halogenated xanthene as a primary active component,wherein said halogenated xanthene is disodium4,5,6,7-Tetrabromoerythrosin, and wherein said medicament is forphotodynamic treatment of human tissue.
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