Classifications

• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to a solution of a 5-aminolevulinic acid ester (E-ALA) for the production of a pharmaceutical preparation which can be used for the diagnosis and / or the treatment of tissue and / or cellular lesions by local irradiation using radiation emitted by a light energy source followed, in the case of diagnosis, by detection of the fluorescence emitted by substances of which 5-aminolevulinic acid (ALA) or E-ALA are precursors , in particular protoporphyrin IX (PplX).
• E-ALA 5-aminolevulinic acid ester
• the administration of the solution can be carried out orally or parenterally, for example in the form of an intradermal, subcutaneous, intraperitoneal or intravenous injection. This administration can also be done topically, for example locally, by exposing the surface of the organ to be treated to a solution of E-ALA or ALA. A tampon soaked in such a solution can also be used for topical administration.
• the concentration of the ALA ester solution (E-ALA) recommended in this publication is between 1 and 50% and preferably between 15 and 30%. However, this concentration essentially does not generate PplX in some of the organs mainly affected by this type of treatment, in particular the urinary bladder.
• the product used in the treatments is ALA and not an ester of ALA, which is very different in terms of concentrations. Indeed, the concentrations of ALA used are at least 45 to 60 times higher than those necessary in the case of the use of an ALA ester solution (E-ALA).
• the aim of the present invention is to overcome these drawbacks by developing a solution intended for the diagnosis and / or treatment of cancerous lesions, in particular in the field of urology, administered at concentrations which do not carry not detrimental to the biosynthesis of the active compounds, and which demonstrates great efficiency when applied for sufficient relatively short times to authorize treatment, if not on an outpatient basis, at least in day clinics, or even in medical offices.
• This solution must in particular allow a strong accumulation of PplX in a minimum of time and a very good distribution of this PplX through the treated tissues.
• E-ALA 5-aminolevulinic acid ester
• the ALA ester (E-ALA) giving the best results is ALA hexyl hydrochloride (h-ALA).
• the solution is produced by dissolving an ALA ester (E-ALA) in a solvent compatible with the human or animal organism.
• E-ALA ALA ester
• Said solvent is advantageously chosen from one of the following substances: sterilized filtered water, physiological NaCl solution, phosphate buffer solution, alcohol.
• the solution comprises a component for adjusting the PH to a physiological value of between 4.8 and 8.1.
• the solution can comprise a complementary substance to prevent the transformation of PplX into heme by complexing of iron in living cells.
• Said complementary substance can be an EDTA (diaminoethyl tetra acetate), deferroxamine or desferal.
• a 5-aminolevulinic acid (E-ALA) ester solution is prepared by dissolving this substance, for example in the form of an amorphous powder or in crystalline form, in a suitable solvent, compatible with in vivo use.
• this solution can be sterilized demineralized water, a physiological NaCl solution containing approximately 9% of NaCl, a phosphate buffer solution, an alcohol or a solution containing an alcohol or the like.
• This solution is preferably adjusted in PH to a so-called physiological value which depends on the application and mainly on the organ to be treated concerned.
• This PH value is usually between 4.8 and 8.1.
• the PH is preferably between 5.3 and 7.4.
• the solution can be supplemented by the addition of a complementary substance to prevent the transformation of PplX into heme by complexing of iron in living cells.
• This complementary substance can be an EDTA (diaminoethyl tetra acetate), deferroxamine or desferal.
• the administration of the solution can be topical, in contact with the internal walls of the organ.
• the bladder is filled with approximately 50 ml of solution of ALA ester (E-ALA) or of ALA hexylester (h-ALA) of low concentration, namely a concentration ⁇ (by weight) of between 0, 01% and 0.5% and preferably equal to 0.2%.
• the instillation can have a duration of between 1 hour and 7 hours, but preferably between Vz hour and 4 hours. It has been surprisingly found that, under these low concentrations which are very different from the concentrations of 15 to 30% currently used in this same field, the ALA ester (E-ALA) exhibits greater efficiency, which is measurement by an increased presence of fluorescent protoporphyrin IX (PplX) appearing at the sites of lesions on the interior walls of the bladder and a better distribution of this protoporphyrin in the cellular layers.
• PplX fluorescent protoporphyrin IX
• the cytotoxicity is reduced, which considerably reduces the risks of undesirable side effects. In particular, this reduced cytotoxicity promotes the generation of photosensitive and / or fluorescent substances of which E-ALA or free ALA are precursors.
• this maximum generation of PplX reduces the time between the administration of the solution and the intervention itself.
• a variant of the mode of application can be defined under the name "fractional topical method”. It includes for example the following steps:
• screening and / or fluorescence treatment of the bladder can take place.
• Topical application of the ALA ester (E-ALA) or ALA hexylester (h-ALA) solution may also be replaced by systemic administration.
• the solution is administered orally or parenterally with or without combination with components called transporters, such as for example dimethylsulfoxide, glycine or the like, intended to promote the absorption and / or migration of the active substance, in this case the ester of ALA (E-ALA) or of hexylester d 'ALA (h-ALA), by tissues and / or cells.
• transporters such as for example dimethylsulfoxide, glycine or the like
• a means of activating tissue or cell penetration of the ALA ester (E-ALA) or the ALA hexylester (h-ALA) can consist of practicing iontophoresis on the walls of the organ concerned. .
• phase 1 are followed by one or more phases of phototherapy treatment and / or fluorescence treatment.
• the walls of the organ concerned are irradiated with light radiation called excitatory light, monochromatic or not, continuously or sequentially, which is preferably located in the field spectral between 300 and 900 nanometers, and preferably between 350 and 650 nanometers.
• the illumination E applied to the walls of the bladder which is the light power per unit area, is between 0.1 mW / cm 2 and 1W / cm 2 , and preferably between 5mW / cm 2 and 500 mW / cm 2 .
• This light induces a phototoxic reaction due to the presence of protoporphyrin IX (PplX) in particular and / or its photoproducts in the tissues.
• the illumination doses can be applied homogeneously over the entire wall of the organ or collimated only on the sites which have been identified as having lesions.
• the walls of the bladder are irradiated by means of radiation whose spectral width is between 300 and 700 nanometers, and preferably between 350 and 650 nanometers.
• the illumination E applied to the walls of the bladder (light power per unit area) is included between 1mW / cm and 1W / cm and preferably between 50mW / cm 2 and 500 mW / cm 2 .
• This exciting light induces the fluorescence of substances in which E-ALA, and in particular h-ALA, is a precursor, in particular PplX.
• This fluorescence is collected by an optical system and detected by eye, or by a point, linear or matrix detector such as a camera.

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• Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Emergency Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Investigating Or Analysing Biological Materials (AREA)
• Medicinal Preparation (AREA)
• Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

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Cited By (12)

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Citations (1)

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• 1998
  • 1998-04-22 FR FR9805425A patent/FR2777782B1/fr not_active Expired - Fee Related
• 1999
  • 1999-04-22 JP JP2000544365A patent/JP4630395B2/ja not_active Expired - Lifetime
  • 1999-04-22 US US09/673,871 patent/US7348361B2/en not_active Expired - Lifetime
  • 1999-04-22 WO PCT/CH1999/000163 patent/WO1999053962A1/fr not_active Ceased
  • 1999-04-22 ES ES99913060T patent/ES2188146T3/es not_active Expired - Lifetime
  • 1999-04-22 AT AT99913060T patent/ATE228018T1/de active
  • 1999-04-22 DE DE69904033T patent/DE69904033T2/de not_active Expired - Lifetime
  • 1999-04-22 EP EP99913060A patent/EP1073472B1/fr not_active Expired - Lifetime
  • 1999-04-22 CA CA002327393A patent/CA2327393C/fr not_active Expired - Lifetime
• 2010
  • 2010-03-09 JP JP2010051284A patent/JP2010163445A/ja active Pending

Patent Citations (1)

Non-Patent Citations (5)

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