US20050090481A1 - Compositions comprising a photosensitizer and a skin-penetration enhancer and their use in photodynamic treatment - Google Patents

Compositions comprising a photosensitizer and a skin-penetration enhancer and their use in photodynamic treatment Download PDF

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US20050090481A1
US20050090481A1 US10494786 US49478604A US2005090481A1 US 20050090481 A1 US20050090481 A1 US 20050090481A1 US 10494786 US10494786 US 10494786 US 49478604 A US49478604 A US 49478604A US 2005090481 A1 US2005090481 A1 US 2005090481A1
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skin
photosensitizer
composition according
composition
penetration enhancer
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Ronald Boch
Peter Lutwyche
John North
Wendy Monk
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Novelion Therapeutics Inc
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Novelion Therapeutics Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/49Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/555Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K41/00Medicinal preparations obtained by treating materials with wave energy or particle radiation; Therapies using these preparations
    • A61K41/0057Photodynamic 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
    • A61K41/0071PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/0616Skin treatment other than tanning
    • A61N5/0617Hair treatment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/062Photodynamic therapy, i.e. excitation of an agent
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q7/00Preparations for affecting hair growth
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/42Colour properties
    • A61K2800/43Pigments; Dyes
    • A61K2800/434Luminescent, Fluorescent; Optical brighteners; Photosensitizers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/81Preparation or application process involves irradiation

Abstract

The present invention relates to a composition comprising a photosensitizing agent and a skin-penetration enhancer. The composition herein show improved delivery of the photosensitizer through the stratum corneum. In addition, the composition of the present invention show improved stability and a reduced incidence of skin photosensitivity.

Description

    TECHNICAL FIELD
  • The present invention relates to a composition comprising photosensitizing agents.
  • BACKGROUND OF THE INVENTION
  • Photodynamic therapy is a diverse field of medical treatment. Generally, PDT involves the delivery of a photosensitizer to the target tissue and, subsequently, irradiating the target area with light of an appropriate wavelength to activate the PS. This activation results in an agent that modifies or destroys the target tissues. The PS is usually delivered systemically although it has been proposed to deliver it locally.
  • Local delivery has the advantage that the PS is delivered directly to the target tissue and, consequently, high concentrations of the drug in the target tissue can be achieved. However, local delivery also has some disadvantages. Photosensitizing agents do not easily penetrate the stratum corneum. In addition, the PS agents are relatively reactive so it is difficult to formulate a stable composition.
  • At the time of writing, one product that is marketed for topical PDT is Levulan® Kerastick®. This product is used for the treatment of non-hyperkeratotic actinic keratosis lesions on the face or scalp. The photosensitizer in this product is a pro-drug and is converted into the active in situ. The product is supplied in a plastic applicator tube containing two sealed glass ampules. One ampule contains the a solution to act as the vehicle and the other the photosensitizing agent as a dry solid. The applicator tube is enclosed in a protective cardboard sleeve and cap. Immediately prior to application, the two ampules are crushed and the solution is mixed with the photosensitizer. The contents are then shaken for several minutes until the drug is dissolved. The solution containing dissolved drug must be discarded two hours after mixing due to the short stability of the product
  • Thus there remains a need for a stable photosensitizer composition suitable for topical application to the skin.
  • It has also been found that topical photosensitizer compositions can cause skin-photosensitivity reactions. In addition, it has been problematic to deliver the photosensitizer to the correct target tissue because often the stratum corneum is difficult to penetrate.
  • SUMMARY OF THE INVENTION
  • The present invention relates to a composition comprising a photosensitizing agent and at least one skin-penetration enhancer. The compositions herein show improved delivery of the photosensitizer through the stratum corneum. In addition, the compositions of the present invention show improved stability.
  • The photosensitizers of the present compositions are able to penetrate the stratum corneum. Consequently, when light energy is delivered, the photosensitizer is activated at the target tissue rather than at the surface. This means that the compositions are more efficacious. In addition, it has surprisingly been found that, when using the compositions of the present invention, administration of light does not cause substantial skin photosensitivity. While not wishing to be bound by theory, it is thought that this the fact that the photosensitizer distributes to the epidermis, rather than in the dermis, means there is less skin photosensitivity.
  • Unless otherwise specified, all documents referred to are incorporated herein by reference.
  • Unless otherwise specified, all percentages herein are expressed as weight percentages.
  • DETAILED DESCRIPTION
  • The present invention provides compositions comprising a photosensitizing agent and a skin penetration enhancer. These elements will be described in more detail below.
  • The compositions of the present invention are preferably substantially free of water. As used herein, the term “substantially free of water” means that the composition comprises less than about 5%, preferably less than about 3%, by weight, of free water. It is preferred that the compositions herein do not have a total water content (i.e. free water plus any water of hydration) of more than about 15%, preferably less than about 10%.
  • Photosensitizer
  • Any suitable photosensitizing agent may be used herein. Generally, these will absorb radiation in the range of from 400 nm to 800 nm, typically from 600 nm to 750 nm.
  • As used herein, “photosensitizer” or “photosensitizing agent” means a chemical compound which, when accumulated in selected target tissues and contacted by radiation, absorbs the light and induces changes to, or destruction of, the target. Virtually any chemical compound that ca be taken up by target cells or tissues and absorbs light may be used in this invention. Preferably, the chemical compound is nontoxic to the animal to which it is administered or is capable of being formulated in a nontoxic composition. Preferably, the chemical compound in its photodegraded form is also nontoxic. A listing of photosensitive chemicals may be found in Kreimer-Bimbaum, Sem. Hematol. 26:157-73, 1989 (incorporated herein by reference) and in Redmond and Gamlin, Photochem. Photbiol. 70 (4): 391-475 (1999).
  • In preferred embodiments of the invention, the photosensitizer is selected from a particularly potent group of photosensitizers known as green porphyrins, which are described in detail in U.S. Pat. No. 5,171,749 (incorporated herein by reference). The term “green porphyrins” refers to porphyrin derivatives obtained by reacting a porphyrin nucleus with an alkyne in a Diels-Alder type reaction to obtain a mono-hydrobenzoporphyrin. Such resultant macropyrrolic compounds are called benzoporphyrin derivatives (BPDs), which is a synthetic chlorin-like porphyrin with various structural analogues, as shown in U.S. Pat. No. 5,171,749. Typically, green porphyrins are selected from a group of tetrapyrrolic porphyrin derivatives obtained by Diels-Alder reactions of acetylene derivatives with protoporphyrin under conditions that promote reaction at only one of the two available conjugated, nonaromatic diene structures present in the protoporphyrin-IX ring systems (rings A and B). Metallated forms of a Gp, in which a metal cation replaces one or two hydrogens in the center of the ring system, may also be used in the practice of the invention. The preparation of the green porphyrin compounds useful in this invention is described in detail in U.S. Pat. No. 5,095,030 (hereby incorporated by reference).
  • Preferably, the BPD is a benzoporphyrin derivative diester di-acid (BPD-DA), mono-acid ring A (BPD-MA), mono-acid ring B (BPD-MB), or mixtures thereof. These compounds absorb light at about 692 nm wavelength and have improved tissue penetration properties. The compounds of formulas BPD-MA and BPD-MB may be homogeneous, in which only the C ring carbalkoxyethyl or only the D ring carbalkoxyethyl would be hydrolyzed, or may be mixtures of the C and D ring substituent hydrolyzates. A number of other BPD B-ring derivatives may also be used in the present methods. These derivatives have the following general formula:
    Figure US20050090481A1-20050428-C00001
  • wherein; R5 is vinyl, R1 and R6 are methyl, and n is 2. X1, X2, and X3 are listed in the tables below:
    TABLE 1
    Hydrophilic BPD B-ring analogs
    Drug X1 X2 X3
    QLT0061 COOH COOH COOH
    QLT0077 CONH(CH2)2N+(CH3)3I CONH(CH2)2N+(CH3)3I COOCH3
    QLT0079 CONH(CH2)2N+(CH3)2((CH2)3CH3 CONH(CH2)2N+(CH3)2((CH2)3CH3) COOCH3
    QLT0086 CONHCH(COOH)CH2COOH CONHCH(COOH)CH2COOH COOCH3
    QLT0092 CONH(CH2)2NH(CH3)2 CONH(CH2)2NH(CH3)2 COOCH3
    CF3COO CF3COO−
    QLT0094 CONHCH2COOH CONHCH2COOH CONHCH2COOH
  • TABLE 2
    Lipophilic BPD B-ring analogs
    Drug X1 X2 X3
    QLT0060 CO(O(CH2)2)0H CO(O(CH2)2)0H COOCH3
    QLT0069 COOCH3 COOCH3 COOH
    QLT0074 CO(OCH2CH2)0H CO(OCH2CH2)0H COOCH3
    QLT0078 CO(O(CH2)2)20H CO(O(CH2)2)20H COOCH3
    QLT0080 CO(O(CH2)2)3OH CO(O(CH2)2)3OH COOCH3
    QLT0081 CO(O(CH2)2)2OCH3 CO(O(CH2)2)2OCH3 CO(O(CH2)2)2OCH3
    QLT0082 CO(O(CH2)2)2OH CO(O(CH2)2)2OH CO(O(CH2)2)2OH
    QLT0083 CO(O(CH2)2)3OH CO(O(CH2)2)3OH CO(O(CH2)2)3OH
    QLT0087 CO(O(CH2)2)4OH CO(O(CH2)2)4OH COOCH3
    QLT0088 COOCH3 COOCH3 CONH(C6H4)(C5H10N)
    QLT0090 CO(O(CH2)2)5OH CO(O(CH2)2)5OH COOCH3
    QLT0093 CO(O(CH2)2)5OH CO(O(CH2)2)5OH CO(O(CH2)2)5OH

    Preferred photosensitizers are the benzoporphyrin derivative mono-acid (BPD-MA), EA6, also known as QLT 0074, (as set forth in U.S. Pat. No. 5,929,105) and B3 (as set forth in U.S. Pat. No. 5,990,149). BPD-MA, for example, is lipophilic and a potent photosensitizer. EA6 and B3 have the following structures:
    Figure US20050090481A1-20050428-C00002

    wherein; R5 is vinyl, R1 and R6 are methyl, and n is 0, 1, 2, or 3. Preferably, n is 2.
  • Additionally, the photosensitizers used in the invention may be conjugated to various ligands to facilitate targeting. These ligands include receptor-specific ligands as well as immunoglobulins and fragments thereof. Preferred ligands include antibodies in general and monoclonal antibodies, as well as immunologically reactive fragments of both.
  • Dimeric forms of the green porphyrin and dimeric or multimeric forms of green porphyrin/porphyrin combinations can be used. The dimers and oligomeric compounds of the invention can be prepared using reactions analogous to those for dimerization and oligomerization of porphyrins per se. The green porphyrins or green porphyrin/porphyrin linkages can be made directly, or porphyrins may be coupled, followed by a Diels-Alder reaction of either or both terminal porphyrins to convert them to the corresponding green porphyrins. Of course combinations of two or more photosensitizers may be used in the practice of the invention.
  • In addition to the above mentioned preferred photosensitizing agents, additional examples of photosensitizers useful in the invention include, but are not limited to, green porphyrins disclosed in U.S. Pat. Nos. 5,283,255, 4,920,143, 4,883,790, 5,095,030, and 5,171,749; and green porphyrin derivatives, discussed in U.S. Pat. Nos. 5,880,145 and 5,990,149. Several structures of typical green porphyrins are shown in the above cited patents, which also provide details for the production of the compounds.
  • The amount of photosensitizer used herein will depend on a variety of factors such as the specific type of PS and the type of activation energy source. However, it is preferred that the compositions herein comprise from about 0.0001% to about 50%, more preferably from about 0.001% to about 5%, even more preferably from about 0.01% to about 2%, still more preferably from about 0.1% to about 1%, by weight, of photosensitizer.
  • Skin-Penetration Enhancer
  • The compositions herein must comprise a skin-penetration enhancer. As used herein, the term “skin-penetration enhancer” means a substance or mixture of substances that aids in the delivery of the photosensitizing agent through the Stratum Corneum of the skin.
  • Any skin-penetration enhancer suitable for aiding the delivery of the photosensitizing agent can be used herein. A list of skin-penetration enhancers can be found in “Pharmaceutical Skin Penetration Enhancement” (1993) Walters, K. A., ed.; Hadgraft, J., ed—New York, N.Y. Marcel Dekker and in “Skin Penetration Enhancers cited in the Technical Literature” Osbourne, D. W. Pharmaceutical Technology, November 1997, pp 59-65, both of which are incorporated herein by reference. Highly preferred for use in the compositions herein are hydrophobic skin-penetration enhancers.
  • Preferred skin-penetration enhancers are selected from glycol ethers, fatty acids, fatty acid esters, glycol esters, glycerides, azones, polysorbates, alcohols, dimethylsulfoxide, and mixtures thereof.
  • Preferred skin-penetration enhancers for use herein include, but are not limited to, diethylene glycol monoethyl ether (Transcutol®), Oleyl alcohol, Oleic acid, Azone (Laurocapram or 1-n-Dodecyl azacycloheptan-2-one), Propylene glycol mono- and diesters of fats and fatty acids (e.g. propylene glycol monocaprylate, propylene glycol monolaurate), Triglycerides and lipids (e.g. linoleic acid), Macrogolglycerides or Polyethylene glycol glycerides and fatty esters (e.g. stearoyl macrogolglycerides, oleoyl macrogolglycerides, lauroyl macrogolglycerides, Oleyl macrogol-6-glycerides, Lauroyl macrogol-6 glycerides), Glycerides and fatty acid esters of polyethylene glycol (e.g. caprylocaproyl macrogolglycerides, capryl-caproyl macrogolglycerides, oleoyl macrogolglycerides), Polyoxyl 40 Hydrogenated Castor Oil (Cremophor RH 40), Polysorbate 80 (Tween 80), Dodecylazacycloheptanone, SEPA® such as described in U.S. Pat. No. 4,861,764 (e.g. 2-n-nonyl-1,3-dioxolane), and mixtures thereof.
  • Most preferred is diethylene glycol monoethyl ether (available from Gattefosse under the tradename Transcutol).
  • It is preferred that the compositions herein comprise from about 0.1% to about 99%, preferably from about 0.1% to about 90%, more preferably from about 5% to about 90%, even more preferably from about 15% to about 75%, by weight of skin penetration enhancer.
  • It is preferred that the ratio of photosensitizer to skin-penetration enhancer is from about 1:20 to about 1:10000, more preferably from about 1:60 to 1:300, on the basis of percentages by weight of total composition.
  • It is highly preferred that the compositions of the present invention have a viscosity at 20° C. of from about 50 cps to about 50000 cps, more preferably from about 500 cps to about 40000 cps, even more preferably from about 5000 cps to about 30000 cps.
  • Solubilizer
  • It is highly preferred that the compositions herein comprise a solubilizer. This is especially true when the photosensitizer is hydrophobic. Some solubilizers are also penetration enhancers and it is preferred that the compositions herein comprise a penetration enhancer that is also a solubilizer for the photosensitizer.
  • Preferably the solubilizer is selected from glycol ethers, polyethylene glycol, polyethylene glycol derivatives, propylene glycol, propylene glycol derivatives, fatty alcohols, aromatic alcohols, propylene glycol, glycerols, oils, surfactants, glucosides, and mixtures thereof.
  • More preferably the solubilizer is selected from diethylene glycol monoethyl ether (Transcutol®), polyethylene glycol of average molecular weight from 100 to 5000, triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, septaethylene glycol, octaethylene glycol, propylene glycol, propylene glycol mono- and diesters of fats and fatty acids (e.g. propylene glycol monocaprylate, propylene glycol monolaurate), benzyl alcohol, glycerol, oleyl alcohol, mineral oil, lanolin/lanolin derivatives, petrolatum or other petroleum products suitable for application to the skin, propylene glycol mono- and diesters of fats and fatty acids, macrogols, macrogolglycerides or polyethylene glycol glycerides and fatty esters (e.g. stearoyl macrogolglycerides, oleoyl macrogolglycerides, lauroyl macrogolglycerides, linoleoyl macrogolglycerides), ethoxylated castor oil (e.g. Cremophor—a polyoxyl hydrogenated castor oil), C6-C30 triglycerides, natural oils, glucosides (e.g. cetearyl glucoside), surfactants, and mixtures thereof.
  • More preferable the solubilizer is selected from diethylene glycol monoethyl ether (Transcutol®), PEG-200, oleyl alcohol, and mixtures thereof.
  • It is preferred that the compositions herein comprise from about 0.1% to about 99%, more preferably from about 1% to about 75%, by weight of solubilizer.
  • Viscosity Modifyinq Agents
  • The compositions herein preferably comprise a viscosity modifying agent. Preferred viscosity modifiers are selected from polyethylene glycols, acrylic acid-based polymers (carbopol polymers or carbomers), polymers of acrylic acid crosslinked with allyl sucrose or allylpentaerythritol (carbopol homopolymers), polymers of acrylic acid modified by long chain (C10-C30) alkyl acrylates and crosslinked with allylpentaerythritol (carbopol copolymers), poloxamers also known as pluronics (block polymers; e.g. Poloxamer 124, 188, 237, 338, 407), waxes (paraffin, glyceryl monostearate, diethylene glycol monostearate, propylene glycol monostearate, ethylene glycol monosterate, glycol stearate), hard fats (e.g. Saturated C8-C18 fatty acid glycerides), xantham gum, polyvinyl alcohol, solid alcohols, and mixtures thereof. More preferably the viscosity modifiers are selected from high molecular weight polyethylene glycols, especially PEG-3350.
  • Optional Ingredients
  • The compositions herein may comprise a variety of optional components. Any suitable ingredient may be used herein but typically these optional component will render the compositions more cosmetically acceptable or provide additional usage benefits. Some examples of preferred optional ingredients include, but are not limited to, emulsifiers, humectants, emollients, surfactants, oils, waxes, fatty alcohols, dispersants, skin-benefit agents, pH adjusters, dyes/colourants, analgesics, perfumes, preservatives, and mixtures thereof.
  • Examples of suitable preservatives include but are not limited to parabens, benzyl alcohol, quaternium 15, imidazolidyl urea, disodium EDTA, methylisothiazoline, alcohols, and mixtures thereof. Examples of suitable emulsifiers include but are not limited to waxes, sorbitan esters, polysorbates, ethoxylated castor oil, ethoxylated fatty alcohols, macrogolglycerides or polyethylene glycol glycerides and fatty esters (e.g. stearoyl macrogolglycerides, oleoyl macrogolglycerides, lauroyl macrogolglycerides), esters of saturated fatty acids (e.g. diethylene glycol parmitostearate), macrogols of cetostearyl ether (e.g. macrogol-6-cetostearyl ether), polymers of high molecular weight, crosslinked acrylic acid-based polymers (carbopols or carbomers) , and mixtures thereof. Examples of suitable emollients include but are not limited to propylene glycol dipelargonate, 2-octyidodecyl myristate, non-polar esters, triglycerides and esters (animal and vegetable oils), lanolin, lanolin derivatives, cholesterol, glucosides (e.g. cetearyl glucoside), pegylated lanolin, ethoxylated glycerides, and mixtures thereof. Examples of suitable surfactants include but are not limited to sorbitan esters, polysorbates, sarcosinates, taurate, ethoxylated castor oil, ethoxylated fatty alcohols, ethoxylated glycerides, caprylocaproyl macrogol-8 glycerides, polyglyceryl-6 dioleate, and mixtures thereof. Examples of suitable oils include but are not limited to propylene glycol monocaprylate, medium chain triglycerides (MCT), 2-octyl-dodecyl myristate, cetearyl ethylhexanoate, and mixtures thereof. Examples of suitable fatty alcohols include but are not limited to cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof.
  • Also useful in the compositions herein are lipids and triglycerides (e.g. concentrates of Seed Oil Lipids, Concentrates of Marine Oil Lipids, high purity triglycerides and esters), alkyl ether sulfates, alkyl polyglycosides, alkylsulfates, amphoterics cream bases, and mixtures thereof.
  • A preferred embodiment of the present invention comprises green-porphyrin photosensitizer, low molecular weight PEG such as PEG200, diethylene glycol monoethyl ether (Transcutol®), high molecular weight PEG such as PEG3350 and fatty alcohol such as oleyl alcohol. While not wishing to be bound by theory it is believed that the PEG3350 acts as a viscosity modifier while the Transcutol, PEG 200, and oleyl alcohol act to deliver the photosensitizer through the stratum corneum.
  • Method of Use
  • The present invention also relates to a method of using a compositions as described hereinabove. Said method comprises:
      • (i) applying to the skin a composition comprising a photosensitizing agent and a carrier wherein the carrier comprises a skin-penetration enhancer,
      • (ii) allowing time for at least some of the photosensitizer to penetrate through the stratum corneum,
      • (iii) washing the skin to which the composition has been applied, and
      • (iv) irradiating with activation energy at a wavelength appropriate to activate the photosensitizer.
  • The washing step can be performed with any suitable substance.
  • The washing step can be performed using a composition comprising at least one of the ingredients of the carrier. Preferably, the wash composition comprises two or more, more preferably all, of the ingredients of the carrier. It is preferred that the levels of ingredient(s) in the wash composition are at the same or similar levels as in the carrier.
  • While not wishing to be bound by theory, it is believed that the washing step removes excess photosensitizer which might otherwise mask the target preventing the activation energy from reaching the target. The utilization of a composition similar to the carrier is believed to aid with the penetration of the photosensitizer composition through the creation of a concentration gradient.
  • Process
  • The present compositions can be made by any suitable process. Preferably, the photosensitizer is lyophilized. A preferred process for production of the present compositions comprises:
      • a) Preparation of lyophilized photosensitizer,
      • b) Manufacture of base composition comprising a skin penetration enhancer and, optionally, a solubilizer,
      • c) Addition of the photosensitizer to the base with stirring.
  • In an alternative process the photosensitizer is first dissolved in a solubilizer with heating. As mentioned above it is preferred that the solubilizer is also a skin-penetration enhancer. After cooling any remaining ingredients are added.
  • Method of Treatment
  • The compositions of the present invention may be used for promoting hair growth. The present method comprises applying a composition of the present invention to a suitable target and activating the photosensitizing agent. Typically, from about 0.1 g to about 50 g, preferably from about 1 g to about 10 g, of the composition is applied to the target. The activation energy can be from an suitable energy source.
  • The compositions of the present invention can be used for the treatment of androgenetic alopecia. The present method comprises applying a composition of the present invention to a suitable target and activating the photosensitizing agent. Typically, from about 0.1 g to about 50 g, preferably from about 1 g to about 10 g, of the composition is applied to the target. The activation energy can be from an suitable energy source.
  • The compositions of the present invention can be used for the treatment of alopecia areata. The present method comprises applying a composition of the present invention to a suitable target and activating the photosensitizing agent. Typically, from about 0.1 g to about 50 g, preferably from about 1 g to about 10 g, of the composition is applied to the target. The activation energy can be from an suitable energy source.
  • The compositions of the present invention can be used for the treatment of skin cancers. The present method comprises applying a composition of the present invention to a suitable target and activating the photosensitizing agent. Typically, from about 0.1 g to about 50 g, preferably from about 1 g to about 10 g, of the composition is applied to the target. The activation energy can be from an suitable energy source.
  • The compositions of the present invention can be used for the treatment of acne. The present method comprises applying a composition of the present invention to a suitable target and activating the photosensitizing agent. Typically, from about 0.1 g to about 50 g, preferably from about 1 g to about 10 g, of the composition is applied to the target. The activation energy can be from an suitable energy source.
  • The compositions of the present invention can be used for the treatment of psoriasis. The present method comprises applying a composition of the present invention to a suitable target and activating the photosensitizing agent. Typically, from about 0.1 g to about 50 g, preferably from about 1 g to about 10 g, of the composition is applied to the target. The activation energy can be from an suitable energy source.
  • The compositions of the present invention can be used for the treatment of atopic dermatitis. The present method comprises applying a composition of the present invention to a suitable target and activating the photosensitizing agent. Typically, from about 0.1 g to about 50 g, preferably from about 1 g to about 10 g, of the composition is applied to the target. The activation energy can be from an suitable energy source.
  • The compositions of the present invention can be used for the treatment of endometrial ablation. The present method comprises applying a composition of the present invention to a suitable target and activating the photosensitizing agent. Typically, from about 0.1 g to about 50 g, preferably from about 1 g to about 10 g, of the composition is applied to the target. The activation energy can be from an suitable energy source.
  • EXAMPLES
  • It will be understood that the following embodiments of the present invention are intended to be illustrative of some of the possible applications or principles. Various modifications may be made by the skilled person without departing from the true spirit and scope of the invention.
    Example 1 Example 2 Example 3 Comparative
    (wt %) (wt %) (wt %) Example (wt %)
    QLT0074 0.5 0.25 0.75 0.5
    PEG-200 54 50 58 54
    Transcutol ®1 20 24 16 0
    PEG-3350 15.5 10 15.5 15.5
    Oleyl Alcohol 10 15.75 10 30

    1Diethylene glycol monethyl ether available from Gattefosse Canada Inc., Baie D'Urfé, Québec, H9X 2T3, Canada
  • The above compositions were prepared in the following way:
    • a) Preparation of cryodessicated photosensitizer—the QLT0074 is dissolved in Glacial Acetic Acid. The solution is then frozen in a dry icelisopropanol bath and the acetic acid is removed by lyophilization. The resultant material is a fine fluffy powder which goes into topical solution easily.
    • b) Manufacture of base—the PEG 200 is warmed to 80-90° C. with stirring. PEG 3.35K is added with stirring followed by oleyl alcohol, then where present the transcutol®. Stirring is continued until solution is clear.
      • c) Addition of photosensitizer—base composition is cooled to approx. 50° C. and the photosensitizer is added with stirring. Stirring is continued with cooling until homogeneous paste is achieved. The resulting formulation is checked for the absence of undissolved photosensitizer crystals by phase contrast microscopy.
  • It was found that Examples 1-3 gave good penetration of the QLT0074 through the stratum corneum while the comparative example did not.

Claims (20)

1. A composition comprising:
a photosensitizer and a skin-penetration enhancer.
2. A composition according to claim 1 wherein the photosensitizer is a polypyrrolic macrocycle.
3. A composition according to claim 1 wherein the photosensitizer is a green-porphyrin.
4. A composition according to claim 1 where the photosensitizer is present at a level of from about 0.0001% to about 50%.
5. A composition according to claim 1 wherein the skin-penetration enhancer comprises glycol ethers, fatty acids, fatty acid esters, glycol esters, glycerides, azones, polysorbates, alcohols, dimethylsulfoxide, or mixtures thereof.
6. A composition according to claim 1 wherein the skin-penetration enhancer comprises diethylene glycol monoethyl ether, polyethylene glycol of average molecular weight from 200 to 4000, oleyl alcohol, or mixtures thereof.
7. A composition according to claim 1 where the skin-penetration enhancer is present at a level of from about 0.1% to about 90%.
8. A composition according to claim 1 wherein the skin-penetration enhancer is a solubilizer for the photosensitizer.
9. A composition according to claim 1 wherein the composition comprises a solubilizer selected from a group, consisting of diethylene glycol monoethyl ether, polyethylene glycol of average molecular weight from 200 to 4000, oleyl alcohol, and mixtures thereof.
10. A composition according to claim 1 wherein the composition has a viscosity at 20° C. of from about 50 cps to about 50000 cps.
11. A composition comprising green-porphyrin photosensitizer, low molecular weight polyethylene glycol, diethylene glycol monoethyl ether, high molecular weight polyethylene glycol, and fatty alcohol.
12. The use of a composition according to claim 1 for application to the skin for the purposes of photodynamic therapy.
13. The use of a composition according to claim 1 for the photodynamic treatment of androgenetic alopecia, alopecia areata, skin cancers, acne, psoriasis atopic, dermatitis, endometrial ablation, or for promoting hair growth.
14. A method of treating androgenetic alopecia, skin cancers, acne, or for promoting hair growth, said method comprising applying a composition according to claim 1 to the target tissue and irradiating the target tissue with activation energy of a appropriate wavelength to activate the photosensitizer.
15. A method of photodynamic therapy comprising:
(i) applying to the skin a composition comprising a photosensitizing agent and a carrier wherein the carrier comprises a skin-penetration enhancer,
(ii) allowing time for at least some of the photosensitizer to penetrate through the stratum corneum,
(iii) washing the skin to which the composition has been applied, and
(iv) irradiating with activation energy at a wavelength appropriate to activate the photo sensitizer.
16. A process of the manufacture of a composition according to claim 1, said process comprising:
manufacturing a base composition comprising a skin penetration enhancer and
adding a lyophilized photosensitizer to the base with stirring.
17. The use of a composition according to claim 11 for application to the skin for the purposes of photodynamic therapy.
18. The use of a composition according to claim 11 for the photodynamic treatment of androgenetic alopecia, alopecia areata, skin cancers, acne, psoriasis atopic, dermatitis, endometrial ablation, or for promoting hair growth.
19. A method of treating androgenetic alopecia, skin cancers, acne, or for promoting hair growth, said method comprising applying a composition according to claim 11 to the target tissue and irradiating the target tissue with activation energy of a appropriate wavelength to activate the photosensitizer.
20. The process according to claim 16, wherein the base composition comprises a solubilizer.
US10494786 2001-11-09 2002-11-08 Compositions comprising a photosensitizer and a skin-penetration enhancer and their use in photodynamic treatment Abandoned US20050090481A1 (en)

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