Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• • 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
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

• the fluorescein diester is contained in the solutions according to the invention in particular in a concentration of up to about 200 micromol / 1 (200 ⁇ mol / 1), preferably in a concentration of about 40 to about 200 micromol / 1, in particular in a concentration of up to about 100 micromol / 1, and most preferably at a concentration of about 60 to about 100 micromol / 1.
• partially etherified ⁇ -cyclodextrins are used which, in addition to the hydroxyalkyl radicals, can also contain alkyl radicals, namely methyl or ethyl radicals, up to a degree of substitution of 0.05 to 2.0, preferably 0.2 to 1.5.
• the degree of substitution for the alkyl radicals is particularly preferably from about 0.5 to about 1.2.
• the solubility of the fluorescein diesters is increased in particular by the fact that form the etherified ß-cyclodextrins inclusion compounds.
• the partially etherified ⁇ -cyclodextrins are therefore contained in the formulations according to the invention in an amount which ensures that the amount of fluorescein diester used is completely dissolved.
• the partially etherified ⁇ -cyclodextrins in the formulations according to the invention are preferably present in an amount of about 1 to about 20 percent by weight, particularly preferably in an amount of about 5 to about 12 percent by weight.
• the invention relates to a solution containing a fluorescein din-lower alkyl ester and a partially etherified ⁇ -cyclodextrin, the ether substituents of which are hydroxypropyl groups.
• the present invention also relates to a dry formulation comprising a fluorescein din-lower alkyl ester and a partially etherified ⁇ -cyclodextrin, the ether substituents of which are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups.
• non-ionic tonicity enhancers such as e.g. Urea, glycerin, sorbitol, mannitol, aminoethanol or propylene glycol.
• ionic tonicity enhancers such as sodium chloride are rather unsuitable in connection with this invention.
• a tonicity enhancer is contained in the solutions according to the invention in an amount which leads to the formation of an approximately isotonic solution.
• An approximately isotonic solution is understood here to mean a solution that has an osmolarity of approximately 300 milliosmol (mOsm), i.e. 300 ⁇ 10% mOsm. It should be noted that all components of the solution contribute to osmolarity.
• the non-ionic tonicity enhancers, if present, are added in customary amounts, ie in particular in amounts of about 1 to about 3.5 percent by weight, preferably in amounts of about 1.5 to about 3 percent by weight.
• Suitable acids are, for example, ganic mono- or dicarboxylic acids such as acetic acid, citric acid, tartaric acid, lactic acid or propionic acid, or inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid.
• ganic mono- or dicarboxylic acids such as acetic acid, citric acid, tartaric acid, lactic acid or propionic acid, or inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid.
• a solvent is not absolutely necessary in the finished solution according to the invention. However, it does an excellent job in making the solutions.
• a solution of the fluorescein diester in a solvent is advantageously mixed with an aqueous solution of the ⁇ -cyclodextrin derivative.
• the solvent can be removed again after mixing the aqueous ⁇ -cyclodextrin phase and the solvent phase containing the fluorescein diester, for example by gentle evaporation or by lyophilization.
• the solvent can remain in the solution, preferably if it is ophthalmologically acceptable.
• Suitable solvents are polar organic aprotic solvents, e.g. Ethyl acetate, dimethyl sulfoxide, dimethylformamide or acetone.
• Solvents, if present in the solutions according to the invention are used in amounts of up to 5 percent by weight, preferably in amounts of up to 1 percent by weight.
• Thickeners can also be added to the solutions according to the invention in customary amounts, such as, for example, organic cellulose ethers, e.g. Hydroxypropyl methyl cellulose, or hyaluronic acid salts such as hyaluronic acid sodium salt. Common buffers can also be added in customary amounts.
• organic cellulose ethers e.g. Hydroxypropyl methyl cellulose
• hyaluronic acid salts such as hyaluronic acid sodium salt.
• Common buffers can also be added in customary amounts.
• the solution according to the invention can be stored in the frozen state (unchanged after 3 months of storage). In the fridge, i.e. at about 8 ° C, it is stable for at least 3 months, at room temperature about 2 to 3 weeks.
• Another object of the invention relates to the use of the solution according to the invention in the photodynamic therapy of living cells, in particular in the prophylaxis of secondary cataracts.
• Fluorescein diacetate has already been mentioned in connection with therapeutic methods.
• EP-A-279.757 contains the teaching, i.a. Use fluorescein diacetate in the selective destruction of transformed cells or tumor cells.
• a substance such as fluorescein diacetate is introduced into tumor cells by microinjection. The tumor cells are killed by subsequent irradiation.
• EP-A-279.757 does not contain any concrete information on the type and concentration of the solution of fluorescein diacetate to be used. Neither is there any indication of an application in the prophylaxis of secondary cataracts.
• Methocel E4M 40.00 g are dissolved in 960.00 g of water (aqua ad iniectabilia). The solution is autoclaved. The two solutions are mixed in a ratio of 1: 1. In this way, a solution with a pH of 4.5 ⁇ 0.3 and an osmolarity of about 300 mOsmol / kg is obtained.
• the intracellular fluorescein concentration is 0.004 to 0.005 mmol / 1 after 0.01 mmol 1 FDA, 0.007 to 0.009 mmol / 1 after 0.02 mmol / 1 FDA and 0.019 mmol / 1 after 0.04 mmol / 1 FDA.
• Example 8 The cytotoxic effect of the irradiation of intracellular fluorescein with 488 nm laser light (argon) is investigated in vivo on the cornea of the rabbit eye. For this purpose, the Comea is dripped with FDA solution for 10 minutes, washed with physiological saline, then the radiation is carried out.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Veterinary Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nanotechnology (AREA)
• Molecular Biology (AREA)
• General Engineering & Computer Science (AREA)
• Medical Informatics (AREA)
• Biotechnology (AREA)
• Crystallography & Structural Chemistry (AREA)
• Biophysics (AREA)
• Biochemistry (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Publications (1)

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• 1992
  • 1992-09-19 TW TW081107414A patent/TW251236B/zh active
• 1993
  • 1993-09-02 JP JP6506874A patent/JPH08503928A/ja active Pending
  • 1993-09-02 AU AU49561/93A patent/AU4956193A/en not_active Abandoned
  • 1993-09-02 EP EP93919243A patent/EP0663838A1/de not_active Ceased
  • 1993-09-02 KR KR1019950700947A patent/KR950703365A/ko not_active Withdrawn
  • 1993-09-02 WO PCT/EP1993/002367 patent/WO1994005331A1/de not_active Application Discontinuation
  • 1993-09-02 CA CA002143115A patent/CA2143115A1/en not_active Abandoned
  • 1993-09-02 FI FI951092A patent/FI951092A7/fi not_active Application Discontinuation
  • 1993-09-02 US US08/392,993 patent/US5573773A/en not_active Expired - Fee Related

Non-Patent Citations (1)

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