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WO1996006602A1 - COMPOSITIONS ET PROCEDES POUR L'ADMINISTRATION D'ACIDE δ-AMINOLEVULINIQUE ET DE SES EQUIVALENTS PHARMACEUTIQUES - Google Patents

COMPOSITIONS ET PROCEDES POUR L'ADMINISTRATION D'ACIDE δ-AMINOLEVULINIQUE ET DE SES EQUIVALENTS PHARMACEUTIQUES Download PDF

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Publication number
WO1996006602A1
WO1996006602A1 PCT/US1995/010879 US9510879W WO9606602A1 WO 1996006602 A1 WO1996006602 A1 WO 1996006602A1 US 9510879 W US9510879 W US 9510879W WO 9606602 A1 WO9606602 A1 WO 9606602A1
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WO
WIPO (PCT)
Prior art keywords
adhesive
pharmaceutical composition
acid
ala
pharmaceutical
Prior art date
Application number
PCT/US1995/010879
Other languages
English (en)
Inventor
Juan A. Mantelle
Allyn L. Golub
Original Assignee
Noven Pharmaceuticals, Inc.
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 US08/112,330 external-priority patent/US5446070A/en
Application filed by Noven Pharmaceuticals, Inc. filed Critical Noven Pharmaceuticals, Inc.
Priority to AU34168/95A priority Critical patent/AU3416895A/en
Publication of WO1996006602A1 publication Critical patent/WO1996006602A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide

Definitions

  • 5-Aminolevulinic acid also referred to as £- aminolevulinic acid or 5-amino-4-oxopentanoic acid
  • ALA has been known for over 40 years to be a precursor in the metabolic pathway to he e in humans and to chlorophyll in plants.
  • ALA has been of limited usefulness, namely, use limited to porphyrin research.
  • ALA was proposed for use as a photodynamic herbicide. It has been discovered recently that ALA can be used by various routes of administration to detect and treat certain conditions involving rapidly metabolizing cells, namely hyperproliterative cells. It is especially useful in the treatment of malignant and non-malignant abnormal growths.
  • ALA has been administered by various routes known for use in drug administration, but especially by topical application to the skin and epithelium of various body cavities.
  • Application of ALA results in the selective accumulation of clinically significant amounts of protoporphyrin IX, another precursor in the metabolic pathway to heme.
  • protoporphyrin IX Activation of protoporphyrin IX by light, depending on the wavelength of the light, will cause the protoporphyrin IX either to fluoresce (which can be used as the basis of a detection method) , or to decompose (which can be used as the basis of treatment for cells that need to be removed) .
  • ALA previously has been used in clinical testing on humans and other mammals in aqueous and non-aqueous fluid vehicles such as creams (oil in water emulsions) and lotions for application to the skin and orally for the diagnosis and treatment of skin cancers.
  • ALA has been used in clinical studies in aqueous solution for application to the endometrial cavity.
  • ALA has been reported to inhibit degradation of the drug calcitonin by the nasal mucosa peptides in U.S. 5,026,825 .
  • Preparations in the examples of that patent show a combination of calcitonin and ALA in aqueous solutions containing one or more of benzalkonium chloride, citric acid, sodium citrate, hydrochloric acid, sodium acetate and acetic acid.
  • the organic acids and their salts appear to be used as buffers, to adjust the pH of the resulting solution to about 4.
  • ALA has a tendency to decompose in a wide variety of vehicles used in clinical testing including both water containing"vehicles, anhydrous fluid vehicles and water and oil emulsions.
  • the lower the pH of the fluid vehicle the more rapid the degradation.
  • addition of about 10% by weight ALA in the form the hydrochloride salt into an alkaline solution, left at room temperature results in almost complete degradation in about one week.
  • Precursors or prodrugs of ALA have been reported for use in conditions similar to that as reported for ALA.
  • the invention relates to a pharmaceutical composition of increased stability, which comprises ALA and a pharmaceutically acceptable, flexible, finite carrier suitable for administration to the skin or other dermal membrane of a mammal, optionally containing a stabilizing amount of an organic weak proton donor or a saccharide.
  • the pharmaceutically acceptable carrier in solid formulation for topical delivery to the skin is desirably a skin patch, many forms and types of which are known and used in the art. It is preferable that the composition be prepared without - and essentially contain no - water. Not only are these formulations using a topical solid carrier stable after prolonged storage, but use of the formulations appear to improve the fluorescence produced after exposing treated skin to activating light, as compared with the fluorescence produced with ALA in a fluid carrier. In particular, the pattern of fluorescence is more even and uniform over the area of application than with topical creams or salves, and may even provide increased fluorescence.
  • a proton donor such as a weak organic acid
  • Suitable organic acids are mono- and polycarboxylic acids such as citric acid, oxalic and ascorbic acids. Weak organic acids are preferred because they are less irritating and less likely to affect the stability of the ALA.
  • the additive also can be a saccharide. If the solid preparation contains water, it is essential to include the stabilizing amount of a proton donor or saccharide-containing substance. Anhydrous preparations, however, are preferred.
  • stabilizing amount when applied to the mild organic proton donor or the saccharide-containing substance of the present invention, means a concentration sufficient to prevent or minimize the degradation of ALA over the expected storage time for the composition, typically 6 months to two years. In general, this amount should be an amount at least equal in weight to the ALA present, although concentrations as high as four times the weight of ALA can be used.
  • the saccharide-containing substance can be a complex saccharide such as starch, a gum or a polysaccharide or it can be less complex saccharide such as a monosaccharide.
  • the mechanism by which the solid topical formulation stabilizes the ALA is unknown.
  • the mechanism by which the weak organic proton donor such as the weak organic acid or the saccharide-containing substance increases the stability of ALA also is unknown. It cannot be explained merely as a reducing effect which prevents the oxidation of ALA, since other anti-oxidants, such as Vitamin E, BHT, BHA, ascorbic acid and sodium bisulfite used in an aqueous solution, were not found to be effective at increasing the stability of ALA. It is unknown whether this effect is one of protection by the saccharide- containing substance of the degradation sites on the ALA.
  • This invention also comprises the method of stabilizing ALA by mixing the same with an anhydrous, flexible, finite, pharmaceutically acceptable carrier for topical administration.
  • the carrier also may comprise a weak organic proton donor or saccharide, a solid polymer, or two or more of the foregoing.
  • ALA can be prepared in a stable formulation for topical use by incorporation into a topical drug delivery carrier, optionally containing a mild organic proton donor or saccharide containing substance.
  • the delivery carrier is contained in a patch.
  • Use of topically acting ALA in a patch is unusual since, because of the increased costs associated with manufacture of patches. Typically, because of these costs, patches are used only for prescription drugs intended for systemic effect, but which are given topically to avoid degradation by the liver or to prolong the rate and extent of distribution.
  • a £-aminolevulinic acid refers to ALA, pharmaceutically acceptable salts thereof and prodrugs, which are considered pharmaceutical equivalents for purposes of this invention.
  • the nature of such salts and prodrugs are known to skilled workers in the arts.
  • the pharmaceutically acceptable salts include, but are not limited to, acid addition salts with inorganic and organic acids as well as quaternary ammonium salts of ALA.
  • Suitable inorganic salts include hydrochloride, hydrobromide, sulfate, carbonate, hydrogen carbonate, hydrogen sulfate and like inorganic salts known for use with pharmacologically active substances.
  • Suitable organic acids are those mono- and polycarboxylie acids such as citric acid, ascorbic acid, oxalic acid and benzoic acid which are weak acids and can also act as a proton donor.
  • a suitable quaternary ammonium salt is olealkonium chloride and other quaternary ammonium salts that are generally recognized as safe and effective
  • the other pharmaceutically acceptable prodrugs of ALA include the pharmaceutically acceptable esters - amides and other masked forms or derivatives thereof - that are metabolized in vivo to yield ALA or a solubilized form thereof.
  • esterification of ALA with an aliphatic alcohol which is normally catalyzed by a strong acid, is not preferred. Esterification may, however, be accomplished by an alternate route.
  • the amino group is protected by a carbobenzoxy group by reaction with carbobenzoxysuccinimide.
  • the CBZ-ALA is reacted with a diazoalkane such as diazomethane %,o produce CBZ-ALA ester.
  • the CBZ group is then removed by hydrogenolysis to produce an ALA carboxylie acid ester.
  • “Pharmaceutically acceptable ester” refers to those esters which retain, upon hydrolysis of the ester bond in vivo, the biological effectiveness and properties of the carboxylic acid and are not biologically or otherwise undesirable.
  • ester formation can be accomplished via conventional synthetic techniques. (See, e.g., March Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons, New York (1985) p. 1157 and references cited therein, and Mark et al. , Encyclopedia of Chemical Technology, John Wiley & sons.
  • the ester component of the carboxylie acid ester will generally comprise (i) a C1-C22 alkane that can also contain one or more double bonds and can contain branched carbon chains or (ii) a C7-C12 aromatic or heteroaromatic group.
  • This invention also contemplates the use of those compositions which are both esters as described herein and at the same time are the pharmaceutically acceptable acid addition salts thereof.
  • “Pharmaceutically acceptable amide” refers to those amides which retain, upon hydrolysis of the amide bond, the biological effectiveness and properties of the carboxylic acid or amine and are not biologically or otherwise undesirable.
  • pharmaceutically acceptable amides as prodrugs, see Bundgaard, H. , ed. , (1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam. These amides are typically formed from the corresponding carboxylic acid and an amine. Generally, amide formation can be accomplished via conventional synthetic techniques. (See e.g., March Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons, New York (1985) p.
  • compositions which are both amides as described herein and at the same time are the pharmaceutically acceptable acid addition salts thereof.
  • the stability of ALA may be increased by incorporating it into a solid, pharmaceutically acceptable carrier, preferably a topical carrier and more preferably in an anhydrous adhesive topical carrier.
  • the solid carrier can optionally contain an organic weak proton donor such as a weak organic acid, or a saccharide-containing substance.
  • pharmaceutically acceptable carrier used here with reference to topical administration refers to the wide variety of carriers known for use for application to the skin or body cavity to a dermal membrane. Such carriers are well known in the art.
  • organic weak proton donor refers to an organic substance known to function as a weak acid which does not, at the same time, degrade the ALA. Whether the organic substance will degrade the ALA can be determined easily by placing the substance at the concentration intended for use with the ALA, then analyzing for residual ALA.
  • Suitable organic weak proton donors are organic weak acids such as mono- and polycarboxylic acids such as citric acid, oxalic acid, ascorbic acid and benzoic acid.
  • Suitable stabilizers are gums such as guar gum, xanthan gum, karaya gum, British gum, starch gum, tragacanth gum, pectin gum and derivatives thereof, saccharides such as complex saccharides such as cellulose, polysaccharides such as dextran and dextrin, and monosaccharides such as dextrose, fructose, maltose, D-glucose and L-glucose.
  • Corn syrup composed of dextrin and glucose is particularly useful, but its use is limited by the fact that it generally contains water.
  • the solid topical forms of the present invention include all the known types of devices, including both the adhesive matrix and reservoir devices. Matrix devices are preferred because the minimization of the number of layers of the device results in ease of preparation.
  • the matrix devices are prepared by methods known in the art. The most convenient form for manufacture of a matrix device is one in which the ALA is dispersed in a pressure sensitive adhesive.
  • the matrix devices are preferably prepared using commercially supplied organic solvents containing the polymer. The additional ingredients are added to the mixture and then the solvents are removed to form the patch. This avoids the use of or inclusion of water in the composition and the need to perform a cross-linking step after the mixing, such as is necessary for emulsion polymerization.
  • Pressure sensitive adhesives useful in preparing the preferred topical compositions include a wide variety of polymeric adhesives includingpharmaceutically acceptable acrylics, vinyl acetate, silicone and synthetic or natural rubber adhesives and mixtures thereof.
  • Acrylic adhesives include Gelva adhesives GMS 1430, 788 available from Monsanto Co. and various Durotak adhesives such as 87-2852 manufactured by National Starch.
  • Vinylacetate adhesives including Flexbond 149 and 150 from Air Products are of limited usefulness because they contain water. Rubber based adhesives such as the Morstiks from Morton Thiokol, Ins. or Vistanex manufactured by Exxon Chemicals can be used. Numerous silicone based adhesives are available from Dow-Corning. These and other pressure sensitive adhesives suitable for topical application will be apparent to one skilled in the art.
  • the polymer blend is applied to a suitable backing material impermeable to the drug or the other components of the polymer matrix.
  • the backing materials which are preferably water resistant, and occlusive or non-occlusive, can be selected from such material as foam, metal foil, polyester, low density polyethylene, copolymers of vinyl chloride and polyvinylidene chloride and laminates thereof.
  • the topical device is a reservoir-type device
  • the ALA in a solvent preferably in a non-aqueous solvent such as an alkanediol or an organic acid such as citric acid is used to fill the reservoir.
  • a gelling agent such as hydroxypropyl cellulose
  • a suitable rate-controlling membrane such as an ethylene- vinyl acetate copolymer membrane, which membrane preferably has a face layer of a pressure sensitive adhesive as described above.
  • Backing materials are similar to those described above for matrix devices.
  • Both adhesive matrix and reservoir devices contain a release liner impermeable to the drug and any solvents present in the system in order to protect the adhesive layer until the patch is to be applied to the skin.
  • Typical materials for release liners are polyester, polyethylene, and polyethylene coated paper, preferably silicon-coated to facilitate removal.
  • the adhesive matrices of the present invention contain 0.5 to 50% ALA by weight, preferably 5 to 20%, and most preferably 10 to 20%; 50 to 95% adhesive, preferably 60 to 90% and more preferably 70 to 90%.
  • An optional carrierand may contain from 0 to 40% by weight of other components, such as a proton donor, penetration enhancer and other substances known for use in transdermal formulations. Since the ALA in the solid formulation is used for a topical effect, there is in fact no maximum limitation as to the amount of ALA that can be used in the patch except to the extent that the adhesiveness or stability of the patch is affected.
  • a preferred method for preparing adhesive matrix topical devices of the present invention comprises coating a thin layer of the adhesive polymer containing the ALA optionally in an anhydrous solvent and optionally containing a mild organic proton donor such as saccharide-containing substance or a mild organic acid onto the material to be used as a release liner, cross- linking the polymer blend in the case of an adhesive to be cross-linked, drying the release liner containing the polymer mixture, then laminating the backing material to the resultant adhesive layer.
  • the preferred proton donor for the ALA is any liquid material or a saccharide- containing substance or an organic acid such as citric acid in a non-aqueous solvent. Additional substances which increase the passage of the drug into the skin also can be added. Suitable sized patches can then be cut out and the patches preferably sealed in protective pouches.
  • the layer of polymer mixture cast on the release liner according to the preferred method of this invention is about 5 mils to about 30 mils thick.
  • the coated layer is preferably dried at a temperature of about 80 degrees Centigrade.
  • One mil 0.0254 mm.
  • the size of the topical device of the present invention depends on the dose of ALA to be utilized, with the preferred patch area being about 2.5 to 20 cm 2 , preferably 5 to 15 cm 2 .
  • the preferred delivery rate for ALA is at least 0.1 ⁇ g. per cm 2 per hour, giving a preferred daily dosage of at least 0.25 mg. per day applied to the area of the skin to be diagnosed or treated for about 2-48 hours.
  • the optimum concentration of ALA in a patch is at least 0.1-3.0 mg. per cm 2 .
  • the topical device must contain a pharmacologically effective amount of ALA. Generally, this is at least 0.25 mg.
  • the duration of application is that period sufficient to achieve ALA penetration into the diseased tissue and that permits high localized concentrations of protoporphyrin IX resulting from the conversion of ALA. This period may be about 3-24 hours and, preferably, is 12-16 hours.
  • the effective amount and duration will vary depending on the nature of the lesion and may be determined empirically by those skilled in the art by testing localized fluorescence of the lesion after administration. If fluorescence is insufficient, longer application or higher ALA concentrations may be used.
  • Topical ALA photodynamic therapy involves the exposure of the ALA-treated lesion with light.
  • a suitable wavelength is 400 nm, 634 nm or 600-700 run, at an intensity of 10-100 milliwatts per centimeter squared (mW/cm 2 ) to provide a light dose of 10-100 Joules/cm 2 .
  • Exposure time may vary from 3 to 30 minutes, but preferably is about 10 minutes.
  • activation of protoporphyrin IX leads to in situ breakdown of protoporphyrin IX and the generation of singlet oxygen, leading to the destruction of diseased cells.
  • the target tissues for which the present invention may be used are any visible, cutaneous lesion or other undesired rapidly growing cells.
  • these include, but are not limited to, neoplastic, aplastic and hyperplastic skin conditions such as basal cell carcinoma, actinic keratosis, psoriasis and similar conditions.
  • GMS Gelva multipolymer system
  • the ALA, propylene glycol, lecithin and glycerin are blended at about 70 to 90°C until all the drug is dissolved.
  • the solution is then cooled to about 20 to 35°C prior to adding the karaya gum.
  • the final composition is applied to a suitable backing material such as a non- woven polyester film (for example, the film sold under the trademark Sontara 8100, manufactured by DuPont de Nemours, Wilmington, DE) and warmed to about 100°C to accelerate the formation of the gel into its final, finite form.
  • a suitable backing material such as a non- woven polyester film (for example, the film sold under the trademark Sontara 8100, manufactured by DuPont de Nemours, Wilmington, DE) and warmed to about 100°C to accelerate the formation of the gel into its final, finite form.
  • a thirty-two year old female is diagnosed with basal cell carcinoma. A single lesion is evident on her right forearm covering approximately 22 mm 2 , and topical aminolevulinic acid photodynamic therapy (ALA PDTTM) is prescribed.
  • ALA PDTTM topical aminolevulinic acid photodynamic therapy
  • the patch is left in place for 18 hours, which is sufficient to permit adequate penetration of ALA into the lesion and for the formation of protoporphyrin IX ("PpIX”) , the active end product of topical ALA administration.
  • PpIX protoporphyrin IX
  • the lesion is wiped with an alcohol swab to remove any residual adhesive.
  • the lesion is then exposed to activating UV light using a conventional Woods lamp to determine if the fluorescence levels, and hence the PpIX levels, are sufficient. Finding the levels suitable, the lesion is then exposed to a 634 nm wavelength light source at 100 mW/cm 2 for 15 minutes.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique de stabilité accrue, qui comporte de l'acide aminolévulinique ou ses équivalents pharmaceutiques ainsi qu'un vecteur souple pharmaceutiquement acceptable, de taille définie, et convenant à l'administration à la peau ou une autre membrane dermique d'un mammifère, contenant éventuellement une quantité stabilisante d'un donneur de protons organiques faibles ou d'une substance renfermant du saccharide. En formulation solide, ce vecteur pharmaceutiquement acceptable peut être un disque transdermique dont de multiples formes et types sont connus et utilisés dans la technique. Il est préférable que la composition soit anhydre. Ces formulations semblent améliorer la fluorescence obtenue après exposition de la peau traitée à une photoactivation, par rapport à la fluorescence obtenue avec de l'acide aminolévulinique dans un vecteur fluide. En particulier, l'aspect de fluorescence est plus régulier et uniforme sur la région d'application qu'avec des crèmes ou pommades à usage local et peut constituer une fluorescence accrue.
PCT/US1995/010879 1993-08-27 1995-08-28 COMPOSITIONS ET PROCEDES POUR L'ADMINISTRATION D'ACIDE δ-AMINOLEVULINIQUE ET DE SES EQUIVALENTS PHARMACEUTIQUES WO1996006602A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34168/95A AU3416895A (en) 1994-08-26 1995-08-28 Compositions and methods for the administration of delta-aminolevulinic acid and pharmaceutical equivalents thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/112,330 US5446070A (en) 1991-02-27 1993-08-27 Compositions and methods for topical administration of pharmaceutically active agents
USPCT/US94/09466 1994-08-26
PCT/US1994/009466 WO1995005813A1 (fr) 1993-08-27 1994-08-26 Compositions et procedes d'administration d'acide delta-aminolevulinique

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WO1996006602A1 true WO1996006602A1 (fr) 1996-03-07

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6269818B1 (en) 1997-05-27 2001-08-07 The University Of British Columbia Photoactivation of endogenous porphyrins for treatment of psoriasis
US6313181B1 (en) 1999-05-26 2001-11-06 Color Access, Inc. Cosmetic compositions containing optical brighteners
WO2001085125A2 (fr) * 2000-05-10 2001-11-15 Radiumhospitalets Forskningsstiftelse Preparation dermatologique
DE10034673C1 (de) * 2000-07-17 2002-04-25 Medac Klinische Spezialpraep Dermales Applikationssystem für Aminolävulinsäure und seine Verwendung
EP1238652A1 (fr) * 1999-12-14 2002-09-11 Cosmo Oil Co., Ltd Compositions de peeling
WO2002078687A2 (fr) * 2001-03-30 2002-10-10 Biochimici Psn S.P.A. Acide delta-aminolevulinique a usage therapeutique et cosmetique
WO2003061621A2 (fr) * 2002-01-23 2003-07-31 Photonamic Gmbh & Co. Kg Systeme d'administration dermique de derives d'acide aminolevulique
WO2004064827A1 (fr) 2003-01-17 2004-08-05 Gerhard Saalmann Utilisation de substances de la synthese de porphyrine pour la mise en oeuvre de la phototherapie et pour le traitement de maladies de la peau et des articulations
EP1444977A1 (fr) * 2003-02-07 2004-08-11 Novosis AG Système thérapeutique transdermique contenant un butenolide
US7247655B2 (en) 1995-03-10 2007-07-24 Photocure Asa Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
US7530461B2 (en) 1995-03-10 2009-05-12 Photocure Asa Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy
US8187628B2 (en) 1999-01-14 2012-05-29 Noven Pharmaceuticals, Inc. Dermal composition for controlling drug flux comprising two acrylic adhesive polymers having different functionalities and different solubility parameters
US8216606B2 (en) 1999-01-14 2012-07-10 Noven Pharmaceuticals, Inc. Dermal composition for controlling drug flux comprising two acrylic adhesive polymers having different functionalities and different solubility parameters
WO2013030129A1 (fr) * 2011-08-31 2013-03-07 Lts Lohmann Therapie-Systeme Ag Système thérapeutique transdermique pour le chlorhydrate d'acide 5-aminolévulinique
EP3085359A1 (fr) * 2015-04-22 2016-10-26 ASKLEPION - Lasercentrum Praha s.r.o. Film polymère photosensible sur la base de l'acide 5-aminolévulinique et de ses dérivés et son utilisation
US11446512B2 (en) 2015-10-15 2022-09-20 Dusa Pharmaceuticals, Inc. Adjustable illuminator for photodynamic therapy and diagnosis
US11571478B2 (en) 2018-01-12 2023-02-07 Dusa Pharmaceuticals, Inc. Methods for photodynamic therapy
US11904180B2 (en) 2015-10-15 2024-02-20 Dusa Pharmaceuticals, Inc. Adjustable illuminators and methods for photodynamic therapy and diagnosis
US12290700B2 (en) 2022-08-16 2025-05-06 Sun Pharmaceutical Industries, Inc. Adjustable illuminator for photodynamic therapy and diagnosis

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US5369142A (en) * 1993-01-15 1994-11-29 The Ohio State University Water soluble polymers containing amino acid residues for dental restoratives

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US5369142A (en) * 1993-01-15 1994-11-29 The Ohio State University Water soluble polymers containing amino acid residues for dental restoratives

Cited By (39)

* Cited by examiner, † Cited by third party
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