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EP2259794A1 - Procédé de traitement de la photosensibilité et de la phototoxicité - Google Patents

Procédé de traitement de la photosensibilité et de la phototoxicité

Info

Publication number
EP2259794A1
EP2259794A1 EP09713206A EP09713206A EP2259794A1 EP 2259794 A1 EP2259794 A1 EP 2259794A1 EP 09713206 A EP09713206 A EP 09713206A EP 09713206 A EP09713206 A EP 09713206A EP 2259794 A1 EP2259794 A1 EP 2259794A1
Authority
EP
European Patent Office
Prior art keywords
alpha
msh
analogue
photosensitivity
phototoxicity
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09713206A
Other languages
German (de)
English (en)
Inventor
Philippe Wolgen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clinuvel Pharmaceuticals Ltd
Original Assignee
Clinuvel Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2008900858A external-priority patent/AU2008900858A0/en
Application filed by Clinuvel Pharmaceuticals Ltd filed Critical Clinuvel Pharmaceuticals Ltd
Publication of EP2259794A1 publication Critical patent/EP2259794A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to compositions and methods for treating photosensitivity and phototoxicity following the administration of a photosensitizing agent.
  • Alpha melanocyte stimulating hormone (alpha-MSH) is released from UVR exposed keratinocytes in human skin following exposure to ultraviolet radiation. It is understood to act on the melanocortin-1 -receptors (MClR) to, exclusively in melanocytes, induce synthesis of the brownish-black melanin pigment. MClR are expressed on keratinocytes as well as number of other cells including, but not exclusively, immunological cells such as dendritic / Langerhans cells, neutrophils, microglia and monocytes as well as astrocytes, and endothelial cells.
  • MlR melanocortin-1 -receptors
  • Nle 4 -D-Phe 7 -alpha- MSH (afamelanotide)
  • Nle 4 -D-Phe 7 -alpha- MSH contains two amino acid substitutions and is approximately 10 to 1, 000-fold more potent than the native hormone at inducing pigmentation in experimental systems such as the frog skin bioassay or in cultured human keratinocytes.
  • the present invention provides the administration of a super-potent derivative of alpha-MSH, Nle 4 -D-Phe 7 -alpha-MSH (afamelanotide; WHO 2008, INN) as a method for prophylactically or therapeutically treating photosensitive and phototoxic reactions following the administration of photosensitizers, for instance such as in systemic or local photodynamic therapy (PDT).
  • PDT photodynamic therapy
  • a method of treating photosensitivity and/or phototoxicity in a patient due to administration of a photosensitizing agent comprising administering to the patient a therapeutically effective amount of an agent which causes an increase in the level of melanin in the skin of the patient, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.
  • a second aspect of the present invention there is provided the use of an effective amount of an agent which causes an increase in the level of melanin in the skin of a patient for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient, wherein the photosensitivity and/or phototoxicity is due to administration of a photosensitizing agent, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.
  • composition comprising a photosensitizing agent and an agent which causes an increase in the level of melanin in the skin.
  • Ranges may be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • references in the specification and concluding claims to parts by weight, of a particular element or component in a composition or article denotes the weight relationship between the element or component and any other' elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent of a component is based on the total weight of the formulation or composition in which the component is included.
  • contacting is meant an instance of exposure by close physical contact of at least one substance to another substance.
  • contacting can include contacting a substance, such as a pharmacologic agent, with a cell,
  • a cell can be contacted with a test compound, for example, an analogue of alpha-MSH, by adding the agent to the culture medium (by continuous infusion, by bolus delivery, or by changing the medium to a medium that contains the agent) or by adding the agent to the extracellular fluid in vivo (by local delivery, systemic delivery, intravenous injection, bolus delivery, or continuous infusion).
  • the duration of contact with a cell or group of cells is determined by the time the test compound is present at physiologically effective levels or at presumed physiologically effective levels in the medium or extracellular fluid bathing the cell.
  • prophylactic treatment means the administration of an active compound or composition to a subject at risk for an undesirable condition.
  • the condition can include a disease, disorder or reaction, or a predisposition to a disease, disorder or reaction.
  • Prophylactic treatment can range from a reduction in the risk for the condition or of the severity of the condition to the complete prevention of the condition.
  • therapeutic treatment and “treating” mean the administration of an active compound or composition to a subject having an undesirable condition such as a disease, disorder or reaction.
  • Therapeutic treatment can range from reduction in the severity of the condition in the subject to the complete recovery of the subject from the condition.
  • an effective amount and time means a therapeutic amount and time needed to achieve the desired result or results, e.g., preventing or treating photosensitivity and phototoxicity associated with photosensitisation following photodynamic therapy (PDT) in a subject.
  • PDT photodynamic therapy
  • induce means initiating a desired response or result that was not present prior to the induction step.
  • induce also includes the term “potentiate”.
  • intermittent means administering an active compound or composition in a series of discreet doses over a determined period, e.g., a period of sustained release of more than 4 hours, preferably more than 8 hours, more preferably more than 16 hours or 24 hours of an alpha-MSH analogue every two months.
  • potentiate means sustaining a desired response at the same level prior to the potentiating step or increasing the desired response over a period of time.
  • melanogenesis as referred to herein is defined as the ability of a subject to produce melanin by melanin-producing cells, or melanocytes.
  • epithelial tissue as referred to herein includes in particular the skin of a subject.
  • These and other materials are disclosed herein, and it is understood that, when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.
  • Described herein are methods for prophylactically or therapeutically treating photosensitivity and phototoxicity associated photosensitisation of skin and eyes following photodynamic therapy (PDT).
  • PDT photodynamic therapy
  • an alpha-MSH analogue is used to reduce or ameliorate photosensitivity and/or phototoxicity in a patient due to administration of a photosensitizing agent. Also according to the invention an alpha-MSH analogue is used for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient due to administration of a photosensitizing agent. The above used reduces or ameliorates photosensitivity and phototoxicity following the treatment with photodynamic therapy (PDT).
  • PDT photodynamic therapy
  • the photosensitizer compounds is selected from delta-aminolevulinic acid (ALA-PpIX), benzoporphyrin derivative monoacid A (BCP-MA), mono-aspertyl chlorine 6 (MACE), meta- tetrahydroxyphenylchlorin (mTHPC), a silicon phtalocyanine (Pc4), porphyrin sodium (Photofrin), metallopurin derivaties, fluorine-based derivatives, Temoporfin, Hypocrellins, tetracycline, Thiazide Diurectics, Hypoglycemic agents, Sulfonamides, Phenothiazines, Nalidixic Acid, Quinidine, Quinine, Lomotil, Griseofulvin, Psoralens, Oil of Bergamot, deodorants soaps, and figs, limes, celery, parsnips plants.
  • ALA-PpIX delta-aminolevulinic acid
  • BCP-MA benzo
  • the alpha-MSH-analogue is Nle 4 -D-Phe 7 -alpha-MSH and/or the alpha-MSH-analogue _ _
  • the alpha-MSH-analogue exhibits agonist activity for MClR and/or upregulates the melanocortin-1 receptor (MClR).
  • the photosensitizing agent may be activated or excited at a wavelength of between 280 ran and 800 nm, and preferably between 390 nm and 800 nm.
  • Photosensitivity and phototoxicity may arise due to administration of photosensitizers following PDT in patients undergoing treatment for lesions, ulcerations, aberrations, stricture, stenosis,
  • dystrophy 10 dystrophy, hypertrophy, dysplasia, metaplasia, anaplasia, cancer precursors, actinic keratosis, carcinoma in situ, Bo wens' disease, basal cell carcinoma, squamous cell carcinoma, bile duct lesions and strictures, other lesions of the urinary tract, gastrointestinal tract, and reproductive system, psoriasis, viral inactivation, macular degeneration, ocular anomalies, glaucoma and various vascular diseases.
  • the present invention provides for a method of treating photosensitivity and/or phototoxicity due to photosensitizing agents, by increasing level of melanin in the skin of the patient.
  • the present invention provides for a method of administering an alpha-MSH analogue that increases melanin in the skin before, simultaneously or subsequent to administering of a photosensitizing agent.
  • the alpha-MSH analogue may be administered intermittently.
  • composition comprising a 2.5 photosensitizing agent and an alpha-MSH-analogue which causes an increase in the level of melanin in the skin.
  • a method of treating photosensitivity and/or phototoxicity in a patient due to administration of a photosensitizing agent comprising administering to the patient a therapeutically effective amount of an agent which causes an increase in the level of melanin in the skin of the patient, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.
  • a second aspect of the present invention there is provided the use of an effective amount of an agent which causes an increase in the level of melanin in the skin of a patient for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient, wherein the photosensitivity and/or phototoxicity is due to administration of a photosensitizing agent, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 ran and 800 nm, and preferably between 390 nm and 800 ran.
  • a second aspect of the present invention there is provided the use of an effective amount of an agent which causes an increase in the level of melanin in the skin of a patient for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient, wherein the photosensitivity and/or phototoxicity is due to and following the administration of a photosensitizing agent, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.
  • composition comprising a photosensitizing agent and an agent which causes an increase in the level of melanin in the skin.
  • the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.
  • the agent which increases the level of melanin in the skin of the patient upregulates the melanocortin-1 receptor (MClR).
  • MlR melanocortin-1 receptor
  • the agent which increases the level of melanin in the skin of the patient is an alpha-MSH analogue.
  • the agent which increases the level of melanin in the skin of the patient is Forskolin and/or an analogue thereof.
  • the alpha-MSH analogue is administered in a manner such as to maintain an effective plasma level of the alpha-MSH analogue for a period of at least 24 hours wherein the level is less than 100 ng/ml.
  • the administration of the alpha- MSH analogue to the subject is intermittent administration.
  • the subject is a human subject.
  • the agent which causes an increase in the level of melanin in the skin of the patient may be administered before, simultaneously or subsequent to the administration of the photosensitizing agent.
  • the photosensitizing agent will typically be administered topically, locally, systemically orally or parentally.
  • the purpose of the agent is to cause photosensitivity such as in photodynamic therapy, however, in some cases photosensitivity is simply a side effect of administration of the agent.
  • Photosensitivity and phototoxicity are conditions of the skin and eyes that are associated with photosensitisation the use and or administration of photosensitizing drugs, in particular following photodynamic therapy (PDT).
  • Photosensitizing drugs exhibit photosensitivity due to their chemical structure and composition. Photosensitivity and phototoxicity may arise due to the administration of photosensitizers following PDT in patients undergoing treatment for lesions, ulcerations, aberrations, strictures, stenosis, dystrophy, hyperplasia, hypertrophy, dysplasia, metaplasia, anaplasia, cancer precursors, actinic keratosis, carcinoma in situ, Bowens' disease, basal cell carcinoma, squamous cell carcinoma, epithelioma, endothelioma, urethelioma, small lung cell carcinoma, ovarian carcinoma, bile duct lesions and strictures, other lesions of the urinary tract, gastrointestinal tract, and reproductive system.
  • photosensitivity and phototoxicity of the skin and or eyes may occur after photodynamic treatment of psoriasis, viral inactivation, macular degeneration, ocular' anomalies, glaucoma and various vascular diseases. These anomalies may be due to some acquired or genetic defect in a subject.
  • photodynamic therapy of the aforementioned tracts and anomalies photosensitivity and phototoxicity of the skin and eyes due to the administration of other photosensitizing agents and pharmacologically active compounds and molecules have been recognized. Further information regarding PDT may be found in Triesscheijn, M., Baas, P., Schellens, J. H M., and Stewart, F. A. (2006) Photodynamic Therapy in Oncology. The Oncologist 71:1034-1044.
  • the present invention extends to treatment of all such anomalies by photodynamic therapy using photosensitizers, whether the photosensitivity associated with the condition arises from administration of the photosensitizer to be used in photodynamic therapy or not.
  • photosensitizer compounds used in photodynamic therapy include delta- _
  • ALA-PpIX aminolevulinic acid
  • BPD-MA benzoporphyrin derivative monoacid A
  • MACE mono- aspertyl chlorine 6
  • mTHPC meta-tetrahydroxyphenylchlorin
  • Pc4 silicon phtalocyanine
  • Photofrin poiphin sodium
  • metallopurin derivatives fluorene-based derivatives
  • Temoporfin and Hypocrellins aminolevulinic acid
  • BPD-MA benzoporphyrin derivative monoacid A
  • MACE mono- aspertyl chlorine 6
  • mTHPC meta-tetrahydroxyphenylchlorin
  • Pc4 silicon phtalocyanine
  • Photofrin poiphin sodium
  • metallopurin derivatives fluorene-based derivatives
  • Temoporfin Temoporfin and Hypocrellins.
  • Phenothiazines (Phenergan, Thorazine, Stelazine, Compazine)
  • the methods of the present invention help to reduce or ameliorate phototoxicity and/ or photosensitivity following administration or application of certain photosensitizer compounds to a patient.
  • alpha-MSH analogue referred to herein is defined as a derivative of alpha-MSH which exhibits agonist activity for MClR, the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte.
  • Such derivatives include derivatives in which (i) one or more amino acid residues are deleted from the native alpha-MSH molecule at the N-terminal end, the C-terminal end, or both; and/or (ii) one or more amino acid residues of the native alpha- MSH molecule are replaced by another' natural, non-natural or synthetic amino acid residue; and/ or (Hi) an intramolecular interaction forms as a cyclic derivative.
  • the alpha-MSH analogue may be a compound as disclosed in Australian Patent No. 597630, selected from compounds of the formula:
  • M is Met, NIe or Lys
  • Ri is Ac-GIy-, Ac-Met-Glu, Ac-NIe-GIu-, or Ac-Tyr-Glu-;
  • W is -His- or -D-His-;
  • X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pNO 2 )D-Phe 7 -,
  • Y is -Arg- or -D-Arg-;
  • Z is -Trp- or -D-Trp-; and
  • R 2 is -NH 2 ; -GIy-NH 2 ; or -GIy-LyS-NH 2 .
  • the alpha-MSH analogue may be selected from cyclic analogues which are disclosed in Australian Patent No. 618733 where an intramolecular interaction (such as a disulfide or other covalent bond) exists (1) between the amino acid residue at position 4 and an amino acid residue at position 10 or 11, and/or (2) between the amino acid residue at position 5 and the amino acid residue at position 10 or 11.
  • an intramolecular interaction such as a disulfide or other covalent bond
  • the alpha-MSH analogue may be a linear analogue as disclosed in US Patent No. 5,674,839, selected from the group consisting of:
  • the alpha-MSH analogue may also be a cyclic analogue as disclosed in US Patent No. 5,674,839, selected from the group consisting of:
  • Ala alanine
  • Arg arginine
  • Dab 2,4-diaminobutyric acid
  • Dpr 2,3-diaminopropionic acid
  • GIu glutamic acid
  • GIy glycine
  • His histidine
  • Lys lysine
  • Met methionine
  • NIe norleucine
  • Orn ornithine
  • Phe phenylalanine
  • (pNC>2)Phe paranitrophenylalanine
  • PIg phenylglycine
  • Pro proline
  • Ser serine
  • Trp tryptophan
  • TrpFor N 1 - formyl-tryptophan
  • Tyr tyrosine
  • VaI valine.
  • the alpha-MSH analogue can be any organic compound.
  • the alpha-MSH analogue can be any organic compound.
  • the alpha-MSH analogue is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the alpha-MSH analogue is [NIe 4 , D-Phe 7 ] -alpha-MSH.
  • the alpha-MSH analogue may be administered in a sustained-release delivery system a disclosed in International Patent Application No. PCT/AU2005/000181 (WO 2006/012667), or topically using a transdermal delivery system as disclosed in International Patent Application No. PCT/AU2005/001552 (WO 2006/037188).
  • the alpha-MSH analogue is administered in an amount which is effective to prophylactically or therapeutically treat photodermatoses, particularly if due to and following the administration of photosensitizing agents.
  • any of the alpha-MSH analogues useful herein can be administered to a subject using a variety of administration or delivery techniques known in the art. It is desirable to maintain low concentrations of the alpha-MSH analogue in the plasma of the subject to induce prophylactically or therapeutically treatment of photodermatoses in the subject. Therefore, the mode of administration will depend upon the subject to be treated and the alpha-MSH analogue selected. In various aspects, the alpha-MSH analogues can be administered orally or parenterally.
  • oral is used herein to encompass administration of the compounds via the digestive tract.
  • parenteral is used herein to encompass any route of administration, other than oral administration, by which the alpha-MSH analogue is introduced into the systemic circulation which includes, but is not limited to, intravenous, intramuscular, subcutaneous, intraperitoneal, intradermal, ocular 1 , inhalable, rectal, vaginal, transdermal, topical, buccal, sublingual, or mucosal administration.
  • mucosal encompasses the administration of the compounds by methods that employ the mucosa (mucous membranes) of the human body-such as, but not limited to, buccal, intranasal, gingival, vaginal, sublingual, pulmonary, or rectal tissue.
  • transdermal encompasses the administration of the compounds that go into the skin or go through the skin using formulations such as, but not limited to, transdermal formulations, buccal patches, skin patches, or transdermal patches.
  • topical encompasses administration by applying conventional topical preparations such as creams, gels, or solutions for localized percutaneous delivery and/or by solution for systemic and/or localized delivery to areas such as, but not limited to the eye, skin, rectum, and vagina.
  • delivery systems composed of devices or compositions containing an alpha-MSH analogue can be manufactured that allow for the controlled-release, extended-release, modified- — I o — release, sustained-release, pulsatile-release, or programmed-release delivery of the alpha-MSH analogue in order to maintain concentration of the alpha-MSH analogue in the plasma of the subject.
  • drugs or active pharmaceutical ingredients can be delivered for hours, weeks, or months following a single administration.
  • Drug-delivery devices include, but are not limited to pumps, needle-free injectors, metered-dose inhalers, and the like.
  • Transdermal compositions with or without penetration enhancers include but are not limited to transdermal patches, microneedles, and transdermal formulations that achieve drug delivery using inotophoresis, sonophoresis, electroporation, thermoporation, perfusion, adsorption and absorption.
  • Other delivery systems include, but are not limited to, biodegradable or nonbiodegradable rods or other shaped implants, fibers, microparticles, microspheres, microcapsules, nanospheres, nanocapsules, porous silicon nanoparticles, in situ gelling formulations, in situ bolus forming compositions, quick dissolving tablets and the like, buccal patches, films, tablets, capsules, osmotic pressure driven formulations, liquid filled capsules, liposomes and other lipid based compositions and the like, pegalation and the like, hydrogel formulations, emulsions, microemulsions, and suspensions.
  • polymeric delivery systems can be microparticles including, but not limited to microspheres, microcapsules, nanospheres and nanoparticles comprising biodegradable polymeric excipients, non-biodegradable polymeric excipients, or mixtures of polymeric excipients thereof, or the polymeric delivery systems can be, but not limited to rods or other various shaped implants, wafers, fibers, films, in situ forming boluses and the like comprising biodegradable polymeric excipients, non-biodegradable polymeric excipients, or mixtures thereof
  • These systems can be made from a single polymeric excipient or a mixture or blend of two or more polymeric excipients.
  • a suitable polymeric excipient includes, but is not limited to, a poly(diene) such as poly(butadiene) and the like; a poly(aikene) such as polyethylene, polypropylene, and the like; a poly(acrylic) such as poly(acrylic acid) and the like; a poly(methacrylic) such as poly(methyl methacrylate), a poly(hydroxyethyl methacrylate), and the like, a poly(vinyl ether); a polyvinyl alcohol); a poly(vinyl ketone); a poly(vinyl halide) such as polyvinyl chloride) and the like; a poly(vinyl nitrile), a polyvinyl ester) such as poly(vinyl acetate) and the like; a poly(vinyl pyridine) such as poly(2-vinyl pyridine), poly(5-methyl-2 -vinyl pyridine) and the like; a poly(styrene
  • cellulose ester such as cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, and the like
  • poly(saccharide) a protein, gelatin, starch, gum, a resin, and the like. These materials may be used alone, as physical mixtures (blends), or as co-polymers. Derivatives of any of the polymers listed above are also contemplated
  • the polymeric excipient of the delivery system includes a biocompatible, nonbiodegradable polymer such as, for example, a silicone, a polyacrylate; a polymer of ethylene- vinyl acetate; an acyl substituted cellulose acetate; a non-degradable polyurethane; a polystyrene; a polyvinyl chloride; a polyvinyl fluoride; a poly(vinylimidazole), a chlorosulphonate polyolefm; a polyethylene oxide; or a blend or copolymer thereof.
  • a biocompatible, nonbiodegradable polymer such as, for example, a silicone, a polyacrylate; a polymer of ethylene- vinyl acetate; an acyl substituted cellulose acetate; a non-degradable polyurethane; a polystyrene; a polyvinyl chloride; a polyvinyl fluoride; a poly(vinylimidazole),
  • the polymeric excipient includes a biocompatible, biodegradable polymer such as, for example, a poly(lactide); a poly(glycolide); a poly(lactide-co-glycolide); a poly(lactic acid); a poly(glycolic acid), a poly(lactic acid-co-glycolic acid); a poly(caprolactone); a poly(orthoester); a poly(phosphazene), a poly(hydroxybutyrate) or a copolymer containing a poly(hydroxybutarate); a poly(lactide-co-caprolactone); a polycarbonate; a polyesteramide; a polyanhydride; a poly(dioxanone); a poly(alkylene alkylate), a copolymer of polyethylene glycol and a polyorthoester, a biodegradable polyurethane; a poly(amino acid), a polyetherester; a polyace
  • the delivery system comprises a gel or liquid formulation or an implant or rod, wherein the implant or rod comprises a biodegradable polymer, wherein the alpha-MSH analogue is embedded within the implant or rod.
  • the alpha-MSH analogue is encapsulated in an implant or rod composed of poly(lactide-co-glycolide), poly(lactide), poly(glycolide), or a mixture thereof.
  • Lactide/glycolide polymers for drug-delivery formulations are typically made by melt polymerization through the ring opening of lactide and glycolide monomers. Some polymers are available with or without carboxylic acid end groups.
  • the end group of the poly(lactide-co-glycolide), poly(lactide), or poly(glycolide) is not a carboxylic acid, for example, an ester, then the resultant polymer is referred to herein as blocked or capped.
  • the unblocked polymer conversely, has a terminal carboxylic group.
  • linear lactide/glycolide polymers are used; however star polymers can be used as well,
  • high molecular weight polymers can be used for medical devices, for example, to meet strength requirements.
  • low molecular weight polymers can be used for drug-delivery and _ _
  • the lactide portion of the polymer has an asymmetric carbon.
  • Commercially racemic DL-, L-, and D- polymers are available.
  • the L-polymers are more crystalline and resorb slower than DL- polymers.
  • copolymers of L-lactide and DL-lactide are available.
  • homopolymers of lactide or glycolide are available.
  • the amount of lactide and glycolide in the polymer can vary.
  • the biodegradable polymer contains 0 to 100 mole %, 40 to 100 mole%, 50 to 100 mole%, 60 to 100 mole%, 70 to 100 mole%, or 80 to 100 mole% lactide and from 0 to 100 mole%, 0 to 60 mole %, 10 to 40 mole%, 20 to 40 mole%, or 30 to 40 mole% glycolide, wherein the amount of lactide and glycolide is 100 mole%,.
  • the biodegradable polymer can be poly(lactide), 8.5:15 poly(lactide-co-glycolide), 75:25 poly(iactide-co-glycolide), or 65:35 ⁇ oly(lactide-co-glycolide) where the ratios axe mole ratios.
  • the biodegradable polymer when the biodegradable polymer is poly(lactide-co-glycolide), poly(lactide), or poly(glycolide), the polymer has an intrinsic viscosity of from 0.15 to 1.5 dL/g, 0.25 to 1.5 dL/g, 0.25 to 1.0 dL/g, 0.25 to 0,8 dL/g, 0.25 to 0.6 dL/g, or 0.2.5 to 0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL at 30 0 C.
  • the amount of alpha-MSH analogue that is encapsulated or incorporated in the biodegradable polymer will vary depending upon the selection of the biodegradable polymer, the encapsulation or incorporation technique, and the amount of alpha-MSH to be delivered to the subject.
  • the amount of alpha-MSH analogue encapsulated in the microcapsule, implant, or rod can be up to 50% by weight of the delivery system.
  • the amount of alpha-MSH analogue encapsulated in the microcapsule, implant, or rod can be from 5 to 60%, 10 to 50%, 15 to 40%, or 15 to 30% by weight of the delivery system.
  • the amount of alpha-MSH analogue in the formulation can be from 0.001 to 10%, or 0.05 to 5% by weight of the formulation.
  • the pharmaceutically- 2. _L — acceptable component can include, but is not limited to, a fatty acid, a sugar, a salt, a water- soluble polymer such as polyethylene glycol, a protein, polysaccharide, or carboxmethyil cellulose, a surfactant, a plasticizer, a high- or low-molecular-weight porosigen such as polymer or a salt or sugar, or a hydrophobic low-molecular-weight compound such as cholesterol or a wax.
  • a fatty acid a sugar, a salt, a water- soluble polymer such as polyethylene glycol, a protein, polysaccharide, or carboxmethyil cellulose, a surfactant, a plasticizer, a high- or low-molecular-weight porosigen such as polymer or a salt or sugar, or a hydrophobic low-molecular-weight compound such as cholesterol or a wax.
  • the delivery system comprises an implant or rod, wherein the alpha-MSH analogue is [NIe 4 , D-Phe 7 ]-alpha-MSH in the amount from 15% to 45% by weight of the implant or rod, wherein the rod or implant comprises poly(lactide) or poly(lactide-co-glycolide) such as, for example, 85:15 poly ⁇ actide-co-glycolide).
  • the delivery system can be administered subcutaneously to the subject.
  • the duration of administration can vary depending upon the amount of alpha-MSH analogue that is encapsulated and the biodegradable polymer selected.
  • the delivery system is administered subcutaneously to the subject and releases the alpha-MSH analogue for a period of at least 2, 4, 6, 8, 10 or 12 days.
  • the delivery system releases the alpha- MSH analogue in the subject for 1 up to three months.
  • the delivery system releases the alpha-MSH analogue in the subject for 10 days, 15 days, 20 days, 25 days, or 30 days.
  • any of the alpha-MSH analogues can be combined with at least one pharmaceutically-acceptable carrier to produce a pharmaceutical composition.
  • the pharmaceutical compositions can be prepared using techniques known in the art.
  • the composition is prepared by admixing the alpha-MSH analogue with a pharmaceutically- acceptable carrier.
  • admixing is defined as mixing the two components together so that there is no chemical reaction or physical interaction.
  • admixing also includes the chemical reaction or physical interaction between the alpha-MSH analogue and the pharmaceutically-acceptable carrier.
  • Pharmaceutically-acceptable earners are known to those skilled in the art. These most typically would be standard carriers for administration to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH.
  • Molecules intended for pharmaceutical delivery may be formulated in a pharmaceutical composition.
  • Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice, _ _
  • compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.
  • Preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles if needed for collateral use of the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils
  • intravenous vehicles if needed for collateral use of the disclosed compositions and methods, include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like.
  • Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Formulations for topical administration may include ointments, lotions, creams, gels, drops, ointments, suppositories, sprays, liquids and powders
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • the alpha- MSH analogue can be admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, propellants, or absorption enhancers as may be required or desired.
  • compositions for topical applications e g., viscous compositions that can be creams or ointments, as well as compositions for nasal and mucosal administration.
  • the formulation can be in the form of a drop, a spray, an aerosol, or a sustained release format.
  • the spray and the aerosol can be achieved through use of the appropriate dispenser.
  • the sustained release format can be an ocular' insert, credible microparticulates, swelling mucoadhesive particulates, pH sensitive microparticulates, nanoparticles/latex systems, ion- exchange resins and other polymeric gels and implants (Ocusert, Alza Corp., California; Joshi, A., S. Ping and K J. Himmelstein, Patent Application WO 91/19481).
  • a patient may suffer from photosensitivity and or phototoxicity of skin and or eyes pre- and post- treatment, These patients will need to avoid outdoors, incandescent and/or fluorescent light sources indoors.
  • the first step in evaluating a photosensitive patient is based on the dose and time of photosensitizer administered.
  • Photosensitivity and phototoxicity of skin and or eyes is an acquired symptom or side effect following the administration of a photosensitizer used in photodynamic therapy. It is most often the accumulation of (proto)porphyrin in the skin and eyes that, is is responsible for cutaneous and ocular photosensitivity and phototoxicity leading to (i) pain, (ii) swelling, (iii) discrete scarring and (iv) formation of ulcers or lesions, In the presence of light at 380 nm and above, (protoporphyrin or porphyrin are being excited (brought in state of excitation) and generates reactive oxygen species resulting in the typical phototoxic reactions.
  • Subjects were recruited from a database of EPP patients. According to the main criteria for entry into the study, eligible subjects are adult male or female patients (aged 18-70 years) with a diagnosis of EPP (confirmed by elevated free protoporphyrin in peripheral erythrocytes and/or ferrochelatase mutation) of sufficient severity that they have requested treatment to alleviate symptoms. Written informed consent was obtained from each patient prior to the performance of any study-specific procedure.
  • afamelanotide (20 mg/implant contained in a poly(D,L-lactide implant core, giving sustained release of study drag over 10 days) on Days 0, 30, 60, 120, 180, 240 and 300.
  • the primary efficacy endpoint of this study is the time taken for the development of symptoms provoked during phototesting.
  • the primary efficacy analysis will compare the "time to appearance of provoked symptoms" before (Day -7) and after CUV 1647 treatment (Days 0, 30, 90, 150, 240, 300 and 360) and in each patient by an appropriate statistical method.
  • H 0 there is no difference in "time taken to develop provoked symptoms" before and after treatment.
  • Secondary efficacy endpoints include:
  • Treatment-emergent adverse events will be summarized by MedDRA preferred term and body system for each treatment group. Treatment-emergent events will be further summarized by intensity, seriousness, outcome and relationship to study drug.
  • Table 1 Measurements of response time, melanin density and PPIX concentration ( ⁇ mol/L) at Days 0, 30, 60 and 90 following administration of afamelanotide
  • the first step in evaluating a photosensitive patient is based on the dose and time of photosensitizer administered.
  • Photosensitivity and phototoxicity of skin and or eyes is an acquired symptom or side effect following the administration of a photosensitizer used in photodynamic therapy. It is most often the accumulation of (proto)porphyrin in the skin and eyes that, is responsible for cutaneous and ocular photosensitivity and phototoxicity leading to (i) pain, (ii) swelling, (iii) discrete scarring and (iv) formation of ulcers or lesions, In the presence of light at 380 nm and above, (proto)porphyrin or porphyrin are being excited (brought in state of excitation) and generates reactive oxygen species resulting in the typical phototoxic reactions.
  • the primary objective of this study was to determine under conditions of use of a single-dose the efficacy and safety of afamelanotide 16 mg as a subcutaneous formulation to reduce the susceptibility of patients following PDT treatment with a systemically administered photosensitizer. Endpoints were erythema and pain of the skin upon controlled provocation to light and UV, as tested through specially fabricated gloves.
  • the study was conducted in accordance with the Declaration of Helsinki and its revisions, ICH guidelines for Good Clinical Practice (GCP) governing the conduct of studies, and all applicable local regulations.
  • GCP Good Clinical Practice
  • Subjects were recruited from a database of the French Cancer Registry, diagnosed with recurrent Barretts' esophagus and cholangio carcinoma. According to the main criteria for entry into the study, eligible subjects are adult male or female patients (aged 18-70 years) with a positive diagnosis of aforementioned disease states. Written informed consent was obtained from each patient prior to the performance of any study-specific procedure.
  • afamelanotide (16 mg/implant contained in a poly(D,L-lactide implant core, giving sustained release of study drug over 10 days) on Day -7.
  • a male middle-aged patient of Caucasian skintype was suffering from Barrett's esophagus exhibited photosensitivity and or phototoxicity of skin and eyes immediately after the administration of a porphyrin-related photosensitizing drug used in the art of systemically administered PDT.
  • This patient was forced to stay indoors, obliged to shield from the effects of UV and visible light during 90 days post-therapy. His inability to comply with the strict light- avoiding measures resulted in a second degree burn to his left arm following moderate sun exposure 42 days post-PDT treatment. His skin remained photosensitive for the duration of 4 years.
  • the primary efficacy endpoint of this study is defined as the time taken for the development of symptoms provoked during phototesting under conditions of use.
  • the primary efficacy analysis will compare the "time to appearance of provoked symptoms" before (Day 0) and after afamelanotide treatment (Days 0, 30, 60, 90.) and the two groups of patients, using an appropriate statistical method.
  • Treatment-emergent adverse events are being summarized by MedDRA preferred term and body system for each treatment group. Treatment-emergent events will be further summarized by intensity, seriousness, outcome and relationship to study drug.

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Abstract

La présente invention porte sur l'utilisation d'un analogue alpha-MSH pour réduire ou améliorer la photosensibilité et/ou la phototoxicité chez un patient en raison de l'administration d'un agent photosensibilisant, et sur l'utilisation d'un analogue alpha-MSH pour la fabrication d'une préparation thérapeutique ou prophylactique pour traiter la photosensibilité et/ou la phototoxicité chez le patient en raison de l'administration d'un agent photosensibilisant.
EP09713206A 2008-02-22 2009-02-20 Procédé de traitement de la photosensibilité et de la phototoxicité Withdrawn EP2259794A1 (fr)

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AU2008900858A AU2008900858A0 (en) 2008-02-22 Method for treatment of photosensitivity and phototoxicity following the use of photosensitizers in photodynamic therapy
AU2008900857A AU2008900857A0 (en) 2008-02-22 Method for treatment of photosensitivity and phototoxicity followng the use of photosensitizing agent
PCT/EP2009/052093 WO2009103816A1 (fr) 2008-02-22 2009-02-20 Procédé de traitement de la photosensibilité et de la phototoxicité

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