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WO2002011539A1 - Methodes et compositions de traitement d'ulceres cutanes par therapie photodynamique topique - Google Patents

Methodes et compositions de traitement d'ulceres cutanes par therapie photodynamique topique Download PDF

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Publication number
WO2002011539A1
WO2002011539A1 PCT/US2001/041611 US0141611W WO0211539A1 WO 2002011539 A1 WO2002011539 A1 WO 2002011539A1 US 0141611 W US0141611 W US 0141611W WO 0211539 A1 WO0211539 A1 WO 0211539A1
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WIPO (PCT)
Prior art keywords
aryl
photosensitizing dye
alkyl
light
poφhycene
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Ceased
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PCT/US2001/041611
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English (en)
Inventor
Rolf-Markus Szeimies
Christoph Abels
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Cytopharm Inc
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Cytopharm Inc
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Priority to AU2001285419A priority Critical patent/AU2001285419A1/en
Publication of WO2002011539A1 publication Critical patent/WO2002011539A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines

Definitions

  • This invention relates to methods and compositions for treating skin ulcers by topical application of a photosensitizing dye to an ulcer, combined with activation of the photosensitizing dye with light.
  • Skin ulcers such as diabetic foot ulcers, pressure sores, and chronic venous leg ulcers, are open sores or lesions of the skin characterized by the wasting away of tissue and sometimes accompanied by formation of pus. Skin ulcers may have different causes, and affect different populations, but they all tend to heal very slowly, if at all, and can be quite difficult and expensive to treat.
  • DFUs diabetic foot ulcers
  • Pressure sores are particularly common in the disabled, elderly and bedridden population of hospitals and nursing homes. Up to one-third of all patients in the hospital over the age of 70 have pressure sores. The essential cause is ischaemia due to sustained or repeated pressure applied to the skin surface. Nearly all pressure ulcers develop over the following sites: sacral bone, greater trochanter, ischial tuberosity, tuberosity of the calcaneus and lateral malleolus. Management and treatment comprises mainly prevention and relief of pressure. Bedsores are often under treatment for months and sometimes even years with daily application of generally ineffective anecdotal therapies.
  • Such anecdotal therapies range from mechanical devices such as cotton filled doughnuts, air filled mattresses, rotating beds, Clinitron beds, foam mattresses and air suspension mattresses, to a variety of topical preparations which are applied locally to the wound area including "debriders" or enzyme preparations to eat away the dead cells so that the living cells may survive, topical antibiotics to treat infections of the area, betadine washes, normal saline rinses, hydrogen peroxide soaks, wet to dry dressings, occlusive dressings, silvadine ointments, elase ointments and travase ointment. In cases of persisting ulcers classical topical therapies as for chronic venous leg ulcers or diabetic ulcers are commonly used.
  • Therapeutic approaches to healing chronic leg ulcers aim first of all to restore the impaired venous flow in the leg by compression or surgical intervention. However, an adjuvant local therapy is mandatory to accelerate the healing of the ulcer. The first step is to cleanse the ulcer, second to fight local superinfection and third to stimulate both granulation via influencing the cytokine network and reepithelization of the ulcer.
  • Photodynamic Therapy is a bimodal treatment, employing a photosensitizer and a light source, and has been used historically primarily for treating superficial non- melanoma skin cancer (von Tappeiner and Jesionek, Therapeutician thoughtse mit fluorescirenden Stoffen, Mtinch Med Klischr 47:2042-2044, 1903; Karrer et al., The use of photodynamic therapy for skin cancer, Onkologie 21:20-27, 1998). Recently, however, PDT has also been shown to be effective in the treatment of inflammatory dermatoses, e.g.
  • psoriasis Boehncke et al., Treatment of psoriasis by topical photodynamic therapy with polychromatic light, Lancet, 343: 801, 1994
  • scleroderma Topical photodynamic therapy for localized scleroderma, Acta Derm Venerol (Stockh) 80: 26-27, 2000, not responding to conventional therapy.
  • the PDT technique is based upon the delivery to the target tissue of the photosensitizer, normally a photosensitizing dye.
  • the dye is then exposed to light comprised of a wavelength corresponding to an absorption band of the dye, whereupon the dye molecules are exited to an excited singlet state.
  • the dye molecule can either decay back to the ground state (either by fluorescence or non-radiative decay processes), or by intersystem crossing processes enter an excited triplet state.
  • the dye molecules can transfer energy to other molecules, such as oxygen. In the latter case, energy transfer to oxygen results in the formation of singlet oxygen and other reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • the photosensitizer may be applied either systemically or topically.
  • the first modern photosensitizer to receive regulatory approvals in numerous countries is Photofrin ® which, however, is administered by intravenous injection.
  • Photofrin ® has been approved for use in PDT treatment of oesophageal, lung and bladder cancers, plus other solid tumors.
  • i.v. injection of Photofrin ® a complex mixture of many porphyrinoid derivatives, is known to cause occasional generalized cutaneous photosensitisation for up to 8 weeks, sometimes giving rise to severe phototoxic reactions. In dermatology, this major side effect is not acceptable for the treatment of superficial skin cancer or inflammatory dermatoses. Therefore a topical application is preferred.
  • a new extensively studied photosensitizer which can be applied topically is 9-Acetoxy-2,7,12,17-tetrakis-( ⁇ -methoxyethyl)porphycene (ATMPn), a porphycene with functionalized side chains, which already has shown its effectiveness in clinical trials for PDT treatments of psoriasis.
  • ATMPn 9-Acetoxy-2,7,12,17-tetrakis-( ⁇ -methoxyethyl)porphycene
  • one object of the present invention is a method of treating skin ulcers by topical application of a photosensitizing dye to an ulcer followed by activation with light.
  • Another object of the present invention is a topical composition comprising a photosensitive dye.
  • photosensitizing dyes applied topically for short periods of time to otherwise slow- healing sores and ulcers and combined with short exposures to light, can accelerate wound- healing.
  • Suitable photosensitive dyes are those compounds which, upon irradiation with light of an appropriate wavelength, convert oxygen into singlet oxygen.
  • Suitable compounds include porphycenes, porphyrins, chlorins, phthalocyanmes, naphthalocyanines, texaphyrins, purpurins, biogenetic precursors of endogenous protoporphyrin IX (acid modified ⁇ - aminolevulinic acids), and mixtures thereof.
  • Acid modified ⁇ -aminolevulinic acid may describe modification of the free carboxylic acid function (e.g., as an ester or amide; in its free form ⁇ -aminolevulinic acid acts as an unacceptable irritant to ulcerated tissue or wounds).
  • the photosensitive dye is a porphycene compound.
  • porphycene compounds there are compounds of the formula :
  • R 1 , R 2 , R 3 and R 4 are each independently
  • Z is H or a substituent covalently bound to the porphycene macrocycle through an oxygen atom or a nitrogen atom, as exemplified by ethers (-OR, where R is alkyl, aryl, or aralkyl), esters, amides, etc., and may bear at least one carboxylic acid function through which Z may be conjugated to a poly ly sine moiety via an amide link.
  • ATMPn is a preferred porphycene compound according to formula I, where R 1 , R 2 , R 3 , and R 4 all are CH 3 OCH 2 CH 2 -, and Z is CH 3 CO 2 -; typically in an amount of 0.001 to 5.0 wt.%, preferably in an amount of 0.01 to 1.0 wt.%.
  • Non-limiting examples of suitable porphycene compounds are disclosed in U.S. 4,913,907, 5,015,478, 5,132,101, 5,179,120, 5,244,671, 5,262,401, 5,409,900, 5,610,175, and 5,637,608 as well as U.S. 09/289,637, filed on April 12, 1999, the relevant portion of each is which describes the porphycene compounds are hereby incorporated by reference.
  • Other useful photoactivatable compounds include Photofrin ® and Photosan ® , verteporfin, chlorins, texaphyrins, purpurins, phthalocyanmes, methylene blue, hypericin, etc.
  • Photofrin ® and Photosan ® are a complex mixture of porphyrinoid molecules derived from processed bovine or porcine blood. Photophrin ® is available from QLT Therapeutics and Photosan ® is available in Germany from SeeLab. The structure of a benzoporphyrin derivative, verteporfin, available from QLT Therapeutics is shown below. Chlorins are po hyrin- or chlorophyll-derived compounds which strongly absorb light at wavelengths of more than 650 nm.
  • chlorin structures i.e., mono-aspartyl chlorin e6, produced by Nippon Petrochemical, meso-tetra(m-hydroxyphenyl)chlorin, produced by Ontario Pharmaceuticals, and meso-tetra(m-hydroxyphenyl)bacteriochlorin are shown below.
  • Purpurin has the structure shown below.
  • the tin etiopurpurin derivative (SnEt 2 ) is available from Miravant.
  • Representative phthalocyanmes have the structures shown below.
  • the zinc phthalocyanine complex is available from Ciba-Geigy (Novartis).
  • porphycene compounds suitable for the present method may be made by conventional methods known to those of ordinary skill in the art, such as by analogy to the techniques taught in the references cited above.
  • topically applied PDT compositions containing a photosensitizing dye such as ATMPn
  • a photosensitizing dye such as ATMPn
  • a photosensitizing dye such as ATMPn
  • a short incubation interval on the wound area prevents deep penetration of the photosensitizing dye (Karrer et al., Topical application of a first porphycene dye for photodynamic therapy —penetration studies in human perilesional skin and basal cell carcinoma, Arch Dermatol Res, 289: 132-137, 1997).
  • the bandage is then removed and the area is irradiated with light at a wavelength corresponding to the absorption band of the photosensitizing dye.
  • porphycene dyes such as ATMPn absorb at a wavelength of approximately 640 nm.
  • the energy intensity of the light applied is lower than that typically used for tumor destruction, about 5-40 J/cm 2 .
  • the light source may be either a coherent source, such as a laser, or an incoherent or polychromatic light source.
  • a non-limiting example of the light source may be an incoherent light source, such as the Waldmann PDT 1200L, made by Waldmann Medizintechnik, Villingen-Schwenningen, FRG. This light source can be used to deliver light having an intensity of 1-250 mW/cm 2 . More typically, light of 40 mW/cm 2 intensity is employed. Light sources manufactured by other companies having similar light intensities may also be employed.
  • the total light dose applied to the ulcer may be, for example, 10 J/cm 2 . Different light doses may be used depending on the nature of the ulcer treated and the photosensitizing dye employed.
  • light doses of up to 20 J/cm 2 may be employed.
  • a light dose of 20 J/cm 2 may typically require irradiation of the ulcer for approximately 5.5 min., using a light source with an intensity of 60 mW/cm 2 . This process can be repeated two to three times a week until the ulcer heals.
  • a topical formulation containing approximately 0.1% ATMPn is applied to the ulcer, at a dosage of approximately 20-100 ⁇ l of the formulation per cm 2 of ulcer surface. Contamination of adjacent tissue may be avoided, however, since the composition typically has low penetration properties for intact skin. Contamination of adjacent tissues does not result in tissue damage.
  • the ulcer site is then covered with an opaque and liquid-tight bandage.
  • plastic films such as polyvinylidene chloride, polyethylene, etc., cloth, or aluminum foil may be employed as components of the bandage.
  • the ulcer site is then incubated for a varying time period, depending on the composition of the formulation. Typically, incubation times of 3-6 hours are preferred.
  • the residual photosensitizing dye is removed from the surface of the ulcer, for example by wiping the ulcer with sterile gauze or a sterile swab.
  • the ulcer may then be irradiated with a suitable light source.
  • the ulcer is then covered with a standard wound dressing, for example a wet wound dressing.
  • the above PDT schedule may be repeated 2 to 3 times per week.
  • the PDT treatments could be carried out on a Monday/Thursday schedule (two treatments per week), or a Monday/Wednesday/Friday schedule (three treatments per week).
  • any photosensitizing dye that can be activated by a light source to generate ROS is suitable, provided that the dye, and/or a formulation containing the dye, is not unacceptably toxic or a severe irritant.
  • other photosensitizing dyes may be employed.
  • the actual dose of the dye, the duration of contact with the ulcer prior to illumination, and the wavelength and intensity of the light source used are all factors which must be specifically optimized for each dye selected.
  • the photosensitizing dye is Photofrin ® , it may be mixed into a gel base at a concentration of 1 mg Photofrin ® /ml of gel.
  • the formulation may be applied either at a medical facility, by a doctor or nurse, or may be applied by the patient.
  • the topical composition used in the present process comprises a photosensitizing dye in a carrier.
  • porphycene compounds of the present invention may be formulated for topical application in penetrating solvents or in the form of a lotion, cream, ointment, spray or gel containing a sufficient amount of the porphycene compound to be effective for PDT therapy.
  • Topical vehicles may include water and pharmaceutically acceptable water-miscible organic solvents such as ethyl alcohol, isopropyl alcohol, propylene glycol, glycerin, propylene carbonate, and the like, and mixtures of these solvents.
  • These compositions should not be toxic to the ulcer tissue, and may also contain conventional additives such as humectants, emollients, lubricants, stabilizers, and perfumes, provided that the additives do not interfere with the therapeutic properties of the composition.
  • the vehicle does not substantially contribute to irritation of the wound, and for this reason ethyl alcohol and isopropyl alcohol are not preferred.
  • Suitable humectants include, but are not limited to aloe vera gel, squalane, glycerol stearate, polyethylene glycol, cetyl alcohol, stearic acid, propylene glycol, glycerin, sorbitan, and the like, and mixtures thereof. Humectants, when employed, may be present in amounts from about 0-20% by weight, preferably about 0-10%, by weight of the composition.
  • Suitable emollients include, but are not limited to guerbet alcohols (such as isocetyl alcohol or isostearyl alcohol); esters (such as isopropyl palmitate, isopropyl isostearate, octyl stearate, hexyl laurate and isostearyl lactate); a liquid mixture of hydrocarbons which are liquids at ambient temperatures (such as petroleum distillates and light mineral oils); and ethanol.
  • Emollients when employed, may be present in amounts of 0-70%, by weight, preferably 0-25% of the total weight of the composition
  • Suitable lubricants may include, for example, the polyglycerylmethacrylate lubricants available under the trademark Lubrajel® from Guardian Chemical Corporation, 230 Marcus Boulevard., Hauppage, N.Y. 11787.
  • Suitable Lubrajels include Lubrajel TW, Lubrajel CG and Lubrajel MS, Lubrajel WA, Lubrajel DV and so-called Lubrajel Oil.
  • Suitable stabilizers include oil-soluble antioxidants, for example butyl hydroxytoluene, butyl hydroxyanisole, -, ⁇ -, ⁇ -, and ⁇ -tocopherol, nordihydrogualaretin, propyl gallate, fatty acid esters of ascorbic acid, ascorbic acid salts, isoascorbic acid, isoascorbic acid salts, sorbic acid and sorbic acid salts.
  • oil-soluble antioxidants for example butyl hydroxytoluene, butyl hydroxyanisole, -, ⁇ -, ⁇ -, and ⁇ -tocopherol, nordihydrogualaretin, propyl gallate, fatty acid esters of ascorbic acid, ascorbic acid salts, isoascorbic acid, isoascorbic acid salts, sorbic acid and sorbic acid salts.
  • the topical formulations contain a sufficient amount of the porphycene compound to be effective in PDT therapy. Generally, concentrations in the range of 0.001 to 5 wt. %, preferably from about 0.025 to 1 wt. %, may be used.
  • Topical formulations may be prepared in gel form by combining the porphycene with a solvent such as propylene carbonate, polyethylene glycol, diethyltoluamide (DEET), diisopropyl adipate (DIP A), or combinations thereof, and adding a gelling agent.
  • a preferred gelling agent is fumed silica (CAB-O-SIL.RTM., Cabot Corp., Tuscola, 111.), and particularly grade M-5.
  • the gelling agent is generally used in amounts of about 5-12 wt % to obtain a gel with the desired viscosity. Obviously, gels containing more or less gelling agent will have slightly higher or lower viscosity.
  • additives such as cosolvents and/or surfactants, frequently improve the gel properties and may be added as desired.
  • Suitable cosolvents/surfactants include propylene glycol and glycerine.
  • the additives may be incorporated into the gel by mechanically mixing the additives into a mixture of solvent and gelling agent.
  • the topical PDT composition to be administered will, in any event, contain a quantity of the photosensitizing dye sufficient to achieve the desired therapeutic effect.
  • Topical application is a critical factor when treating skin sores using PDT, since it limits penetration of the dye below surface tissues.
  • BPD-MA verporfin
  • CASP a phthalocyanine
  • the efficacy of the topical PDT can be determined by planimetric measurements of the wound area from digital images of the wound (using conventional image processing techniques) and the bacterial colonization can be measured prior to, during, and after treatment. Insight into the pathophysiological changes in the microcirculation induced by PDT can also be obtained by assessing the tissue oxygenation (tpO2) using planar sensors. In addition, observation of the morphology and the quantification of the skin capillaries of the ulcer margin before and after topical PDT can be undertaken.

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Abstract

On traite des ulcères cutanés en appliquant sur la peau une composition topique contenant une quantité efficace sur le plan thérapeutique de colorant de photosensibilisation, ce qui permet à ladite composition de rester sur l'ulcère cutané. Ainsi, ledit ulcère peut absorber une quantité thérapeutique de colorant de photosensibilisation. On irradie ensuite la composition topique de lumière à partir d'une source de lumière qui émet au moins une longueur d'onde correspondant à une bande d'absorption dudit colorant, pendant une période de temps suffisant à la libération d'une dose thérapeutique d'énergie lumineuse dans ledit colorant. La composition topique se présente sous forme de gel, de crème, d'onguent, de solution, de liposome, de pulvérisateur ou d'aérosol contenant un colorant de photosensibilisation.
PCT/US2001/041611 2000-08-08 2001-08-08 Methodes et compositions de traitement d'ulceres cutanes par therapie photodynamique topique Ceased WO2002011539A1 (fr)

Priority Applications (1)

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AU2001285419A AU2001285419A1 (en) 2000-08-08 2001-08-08 Methods and compositions for treating skin ulcers by topical photodynamic therapy

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US63463300A 2000-08-08 2000-08-08
US09/634,633 2000-08-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015000058A1 (fr) * 2013-07-03 2015-01-08 Klox Technologies Inc. Compositions biophotoniques comprenant un chromophore et un agent gélifiant pour traiter des plaies
US10207029B2 (en) 2014-04-01 2019-02-19 Klox Technologies Inc. Tissue filler compositions and methods of use
US11421349B2 (en) 2014-10-31 2022-08-23 Klox Technologies Inc. Photoactivatable fibers and fabric media

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5079262A (en) * 1989-07-28 1992-01-07 Queen's University At Kingston Method of detection and treatment of malignant and non-malignant lesions utilizing 5-aminolevulinic acid
US5484778A (en) * 1990-07-17 1996-01-16 University Hospitals Of Cleveland Phthalocyanine photosensitizers for photodynamic therapy and methods for their use
US6063108A (en) * 1997-01-06 2000-05-16 Salansky; Norman Method and apparatus for localized low energy photon therapy (LEPT)
US6107326A (en) * 1999-04-12 2000-08-22 Cytopharm, Inc. Porphycenes for treatment of microbial populations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5079262A (en) * 1989-07-28 1992-01-07 Queen's University At Kingston Method of detection and treatment of malignant and non-malignant lesions utilizing 5-aminolevulinic acid
US5484778A (en) * 1990-07-17 1996-01-16 University Hospitals Of Cleveland Phthalocyanine photosensitizers for photodynamic therapy and methods for their use
US5484778C1 (en) * 1990-07-17 2001-05-08 Univ Cleveland Hospitals Phthalocynine photosensitizers for photodynamic therapy and methods for their use
US6063108A (en) * 1997-01-06 2000-05-16 Salansky; Norman Method and apparatus for localized low energy photon therapy (LEPT)
US6107326A (en) * 1999-04-12 2000-08-22 Cytopharm, Inc. Porphycenes for treatment of microbial populations

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015000058A1 (fr) * 2013-07-03 2015-01-08 Klox Technologies Inc. Compositions biophotoniques comprenant un chromophore et un agent gélifiant pour traiter des plaies
US10881736B2 (en) 2013-07-03 2021-01-05 Klox Technologies Inc. Biophotonic compositions comprising a chromophore and a gelling agent for treating wounds
US10207029B2 (en) 2014-04-01 2019-02-19 Klox Technologies Inc. Tissue filler compositions and methods of use
US10772990B2 (en) 2014-04-01 2020-09-15 Klox Technologies Inc. Tissue filler compositions and methods of use
US11421349B2 (en) 2014-10-31 2022-08-23 Klox Technologies Inc. Photoactivatable fibers and fabric media

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