EP0697863A1 - Verwendung von dihydroliponsäure als ophthalmologicum und zur unterdrückung von unverträglichkeitsreaktionen im grenzbereich von implantaten mit lebendem körpergewebe - Google Patents

Verwendung von dihydroliponsäure als ophthalmologicum und zur unterdrückung von unverträglichkeitsreaktionen im grenzbereich von implantaten mit lebendem körpergewebe

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Publication number
EP0697863A1
EP0697863A1 EP94913566A EP94913566A EP0697863A1 EP 0697863 A1 EP0697863 A1 EP 0697863A1 EP 94913566 A EP94913566 A EP 94913566A EP 94913566 A EP94913566 A EP 94913566A EP 0697863 A1 EP0697863 A1 EP 0697863A1
Authority
EP
European Patent Office
Prior art keywords
acid
implants
body tissue
living body
reactions
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Withdrawn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
EP94913566A
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German (de)
English (en)
French (fr)
Inventor
Heinz Ulrich
Erich Franz Elstner
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.)
Asta Medica GmbH
Original Assignee
Asta Medica GmbH
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 DE19934317173 external-priority patent/DE4317173C2/de
Application filed by Asta Medica GmbH filed Critical Asta Medica GmbH
Publication of EP0697863A1 publication Critical patent/EP0697863A1/de
Withdrawn legal-status Critical Current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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • 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
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • dihydrolipoic acid as an ophthalmologic and to suppress intolerance reactions in the border area of implants with living body tissue
  • the present invention relates to the use of dihydrolipoic acid (6,8-dimercapto-octanoic acid) in eye diseases and in the case of intolerance reactions of the eye with implants, such as e.g. Vitreous and lens replacement materials.
  • Dihydrolipoic acid can also be used in the event of intolerance reactions of the remaining body tissue with endoprostheses and implants.
  • Dihydrolipoic acid the reduced form of ⁇ -lipoic acid, is involved in the regulation of the cellular redox state under physiological conditions. Oxidation reactions due to certain highly reactive oxygen compounds have been recognized as triggers of various clinical pictures due to cell and tissue damage.
  • This regulatory system includes low molecular weight compounds such as vitamin A (retinol), vitamin C (ascorbic acid), vitamin E ( ⁇ -tocopherol), uric acid and glutathione as well as special enzymes with antioxidative radio tion. If this system is weakened or chronically overloaded, it should be supplemented from the outside with added antioxidants in order to achieve continuous protection against damage.
  • dihydrolipoic acid is known from DE-A-40 35 456 for combating retroviruses, in particular the HIV virus.
  • a combination with another antiretroviral active substance can also be used.
  • the object of the present invention is to provide pharmaceuticals which are used for the treatment or prophylaxis of eye diseases. diseases and for suppressing and preventing intolerance reactions in the border area of implants with living body tissue.
  • This object is achieved by using dihydrolipoic acid or its physiologically tolerable salts for the production of pharmaceutical compositions for the treatment of radical-induced disorders in living body tissue.
  • the disorders are in particular eye diseases, for example cataracts, retinopathy or retrolental fibroplasia, and intolerance reactions in the border area of implants and endoprostheses with living body tissue.
  • Ophthalmic implants are particularly preferred.
  • the treatment can also be prophylactic, in particular to avoid the incompatibility reactions in the border area of implants or endoprostheses. to avoid or reduce living body tissue.
  • Dihydrolipoic acid is capable of favorably influencing the pathobiochemical processes caused by the occurrence of reactive radicals in these disease processes.
  • the intensive exposure of the lens conceivable chemical processes triggered by radiation, in which reactive, in particular oxygen-containing, radicals are formed.
  • the lens also contains substances such as riboflavin (vitamin B) and N-formyl kynurenin, which trigger radiation-related reactions as light sensitizers, the stress situation in the eye is very high.
  • discoloration and covalent protein cross-linking occur during aging but with cataractogenesis (pathological cloudiness due to cataracts), in the lens.
  • the proportion of antioxidants such as ascorbate and glutathione and protective enzymes such as glutathione peroxidase is significantly higher in healthy lenses than in cataract lenses. There is also a higher proportion of hydrogen peroxide here.
  • a continuous oxidation of cysteine and methionine occurs in the lens.
  • Radical-mediated protein degradations similar to those in lens tissue also occur in the vitreous body of the eye in various metabolic diseases, such as diabetes mellitus, as well as in old age and on the floor of various partly unknown causes.
  • various metabolic diseases such as diabetes mellitus
  • old age and on the floor of various partly unknown causes In premature and newborn babies, who are exposed to increased oxygen partial pressures in the incubator due to a pulmonary disturbance, so-called retrolental fibroplasia develops through oxidative stress.
  • dihydrolipoic acid according to the invention is used for therapy
  • radicals can also be demonstrated when inserting implants and endoprostheses. These arise from the release or abrasion of the smallest metal or plastic species (ions or particles) that are able to induce foreign body reactions. All of these processes can lead to a delay or disruption and prevention of the healing process. Foreign body granulomas or excessive connective tissue can form around the implant or endoprosthesis, which lead to mechanical, optical, electrical or chemical and other functional impairments, or the desired function can only be achieved later or only for be possible for a limited time. In the case of subdermal implantation, these processes can also lead to cosmetically disruptive scar formation with subsequent shrinkage processes and restrictions on movement.
  • the release of implant material is also observed with ocular implants.
  • the inflammatory foreign body reactions induced thereby can also lead to disturbance and delay in healing and the formation of poorly (or not at all translucent) scar tissue in the vicinity of the implant and thus, for example, completely or partially prevent its function of maintaining or improving the visual acuity.
  • the intra- and extraocular foreign body reactions represent a uniform reaction of all body tissues or organs to a foreign body stimulus. It is known from various publications that only quantitative differences exist here.
  • the biocompatibility of implants and endoprostheses is checked by animal experiments in which the implants are introduced into the subcutaneous tissue or through intraocular implantation. It has been found that by administering dihydrolipoic acid in the form of a pharmaceutical composition when testing for biocompatibility, the intolerance reactions can be suppressed or significantly reduced. Because of the corresponding disturbances in the case of implants in the subcutaneous tissue, in the case of intramuscular implantation and in the case of intraocular implantation, the use according to the invention is generally suitable for the treatment of acute diseases as well as for prophylaxis in the event of possible intolerance reactions of implants and endoprostheses.
  • dihydrolipoic acid was demonstrated by examining the effects of UV radiation on a homogeneous extract of beef eye lenses.
  • the molecular weight composition and the proportion of free SH groups in the extract were determined.
  • the molecular weight composition changes towards higher aggregates, as a result of which the proportion of free SH groups which bring about crosslinking decreases. Irradiation was carried out with and without the addition of riboflavin and then with increasing concentration of dihydroliponic acid.
  • activated leukocytes release myeloperoxidase into the phagosome, where the myeloperoxidase reacts with H 0 and CI to form hypochlorous acid H0C1. It is a highly active bactericide and inactivator of numerous enzymes.
  • the lenses are isolated from the beef bulb and, after removal of adhering glass and ciliary body residues, temporarily stored in physiological NaCl solution. Then you determine the drained weight of the lenses (plastic sieve).
  • the lenses are homogenized in a grinding bowl (on ice) precooled with a little liquid nitrogen and mixed with cooled, physiological NaCl solution in a ratio of 1 g of lenses per 1 ml of saline. The mixture is then centrifuged at 15,000 g for 30 minutes and the aqueous supernatant, which contains the water-soluble protein portion, is filtered through sterile filters (0.22 ⁇ m) in brown screw-top vials (20 ml). Before sealing the vials, the lens homogenate is overlaid with gaseous nitrogen in order to keep oxidation reactions due to atmospheric oxygen as low as possible. The lens homogenate obtained in this way is stored at -20 ° C. until used.
  • the Bio-Rad Protein Assay is used for the quantitative detection of proteins in solutions.
  • the assay corresponds to the method described by Bradford (1976), which is based on the shift in the absorption maximum of a phosphoric acid, methanolic solution of Coomassie Brilliant Blue G 250 from 465 nm to 595 nm if this dye is based on protein or Amino groups binds.
  • Bovine serum albumin (BSA) is used as the standard protein.
  • the assay 5 ml of the 1: 5 diluted dye reagent are mixed with 0.1 ml sample solution and then 15 min. Incubation at room temperature, the absorbance at 595 nm was determined.
  • 0.1 ml of solvent of the protein is used as a sample solution in the assay.
  • the color reagent is subject to aging, particularly in its thinned form. For this reason, the dilution of the detection reagent is always freshly prepared and with each new dilution a new calibration line with BSA is created.
  • the calibration solutions contain between 0.1 and 0.8 mg / ml BSA.
  • the extinction values obtained photometrically are converted on the basis of the calibration curve to mg protein per ml lens homogenate.
  • the protein content is on average 110-130 mg per ml lens homogenate.
  • Lentil proteins are exposed together with riboflavin and then examined by means of FPLC (gel filtration). This shows a change in the molecular weight composition of the lens homogenate as a function of the exposure time, with high molecular weight aggregates increasingly being produced. This model reaction simulates a possible photodynamic change in lens proteins during cataractogenesis.
  • the batch volume was 2.00 ml; Reaction temperature
  • This test is based on an ELLMAN method
  • Free SH groups reductively convert the colorless, disulfide El l an's reagent DTNB (5,5 '-dithio-bis-2-nitro-benzoic acid, dissolved in methanol) into the strongly yellow-colored chromogen 2-nitro-5- mercaptobenzoate free (SEKLAK & LINDSAY, 1968).
  • the extinction of this dye at 412 nm correlates linearly with the SH concentration used in the range from 10-100 ⁇ M SH.
  • a typical assay is composed as follows:
  • the detection reaction is started by adding DTNB and the resulting dye is determined photometrically (E) after 30 minutes at room temperature.
  • Oxidation of free thiol groups in the lens homogenate Lens proteins have a comparatively high concentration of free SH groups. If lens proteins are exposed to oxidative stress, the SH group decrease can serve as an indication of the extent of the damage caused. It is checked whether the dihydrolipoic acid can intervene in the oxidation processes. Exposed riboflavin serves as an oxidative system.
  • the SH groups are quantified using the modified Ellman method.
  • Fresh lens homogenate has an SH concentration of 2.25 ⁇ 0.12 mM, which decreases steadily despite storage at -20 ° C and overlaying with nitrogen. After 8 weeks of storage, 1.93 ⁇ 0.05 mM SH can still be detected in the lens homogenate, which corresponds to a loss of around 14%. At room temperature, the SH decrease takes place much faster: after 24 hours, about 5-10% is already oxidized. If the SH concentration is related to the protein content of the lens homogenate, the following absolute values result:
  • the NAP-25 columns separate in the range of 1 to 5 dcal, i.e. Proteins with a molecular weight of over 5 kdal are eluted with the eluent. However, this also has the consequence that the glutathione of the lens homogenate and small SH-containing peptides are also removed. In addition, the samples are diluted by gel filtration, but this is compensated for by a higher sample aliquot in the Ellman approach. Dihydrolipoic acid inhibits the SH group oxidation of the lens proteins in a concentration-dependent manner.
  • Fig. 2 shows these results of the oxidation of SH groups in the lens homogenate by exposed riboflavin and the influence of dihydrolipoic acid.
  • the SH loss of the control resulting from gel filtration is 7.1 ⁇ 0.4 ⁇ M (approx. 15%). Comparing the protein contents before and after gel filtration, so there is a loss of 0.52 ⁇ 0.06 mg / ml (approx. 18%). Check the elution of a standard protein
  • the yield in the 3.5 ml eluate is 98.5 ⁇ 3.4%.
  • dihydroliponic acid or its physiologically tolerable salts are formulated together with customary auxiliaries to give medicaments which can be applied, the salt former also being able to be used in excess, i.e. in a higher amount than equimolar.
  • 1 4, 1 4 mean like mono- and diethanolamine, l-amino-2-propanol, 3-amino-l-propanol; AI kylendiamine with an alkylene chain of 2-6 carbon atoms such as ethylenediamine or hexamethylenetetramine, saturated cyclic amino compounds with 4-6 ring carbon atoms such as piperidine, piperazine, pyrrolidine, morpholine; N-methylglucamine, creatine, trometamol.
  • AI kylendiamine with an alkylene chain of 2-6 carbon atoms such as ethylenediamine or hexamethylenetetramine, saturated cyclic amino compounds with 4-6 ring carbon atoms such as piperidine, piperazine, pyrrolidine, morpholine; N-methylglucamine, creatine, trometamol.
  • the application of the dihydroliponic acid as a pharmaceutical composition can take place on the skin or mucous membrane or inside the body, for example orally, enterally, pulmonally, nasally, lingually, intravenously, intra-arterially, intracardially, intramuscularly, intraperitoneally, intra-cutaneously, subcutaneously and in the vitreous or. the anterior chamber.
  • dihydrolipoic acid topical application of dihydrol iponic acid solutions, suspensions, emulsions and gels corneal and conjunetical can also take place.
  • the substances can also be applied by means of release via a medicament reservoir located in the conjunctival sack or subconjunetival, dermal, subdermal, intraoeular, articular or in other body tissue.
  • application can also be carried out by applying the substances in sustained and non-sustained release form to endoprostheses and implants.
  • antioxidants that can be used include, for example, sodium sulfite, sodium bisulfite, sodium metabulit, ascorbic acid, ascorbyl palate, myristate, stearate, galic acid, gal bind by complex formation, for example lecithin, ascorbic acid, phosphoric acid, ethylenediaminotetraacetic acid, citrates, tartrates) can be used.
  • the addition of the synergists significantly increases the antioxidant effect of the antioxidants.
  • Sorbic acid, p-hydroxybenzoic acid esters (for example lower alkyl esters), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride, chlorhexidine and formalin derivatives can also be used as preservatives.
  • Polyphenols can also be used as additives. Rutin, quercetin and morin or a mixture thereof are particularly suitable.
  • chelating agents such as ethylenediaminotetraacetic acid, nitrotriesriacetic acid, diethylenetriaminepentaacetic acid and their salts.
  • Complexing agents which also include dihydrolipoic acid in a cavity can also be used.
  • Examples include urea, thiourea, cyclodextrins, amylose.
  • the pharmaceutical composition for stabilizing the active substance molecules is preferably adjusted to a pH range of about 6-9 with physiologically compatible bases or buffers.
  • a pH that is as neutral as possible to weakly basic up to pH 8 is preferred.
  • parenteral preparation forms are, in particular, sterile or sterilized formulations.
  • the carriers and auxiliaries are gelatin, natural sugars such as cane sugar or milk sugar, lecithin,.
  • Pectin, starch eg maize starch or amylose
  • cyclodextrins and cyclodextrin derivatives dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, lycopodium, silicic acid (eg colloidal), cellulose, cellulose derivatives (eg cellulose ether, in which the cellulose hydroxyl groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyalcohols, for example methyloxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate); Fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12-22 carbon atoms, especially the saturated ones (eg stearates),
  • glycerol hydroxy groups are completely or only partially esterified (e.g. mono-, di- and triglycerides); pharmaceutically acceptable monohydric or polyhydric alcohols and polyglycols such as polyethylene glycols (molecular weight range, for example, 300 to 1500) and derivatives thereof, polyethylene oxide, esters of aliphatic saturated or unsaturated fatty acids (2-22 carbon atoms, in particular 10-18 carbon atoms Atoms) with monohydric aliphatic alcohols (1-20 C atoms) or polyhydric alcohols such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol etc., which may also be etherified, esters of citric acid with primary ⁇ alcohols, acetic acid, urea, benzyl benzoate, dioxolanes, glycerin formals, tetrahydrofurfuryl alcohol, poly
  • Lactamides lactates, ethyl carbonates, silicones (in particular medium-viscosity polydimethylsiloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium arbonate and the like.
  • Substances which cause the disintegration of solid formulations such as: crosslinked polyvinylpyrrolidone, sodium boxoxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose can also be used as further auxiliaries.
  • Known coating materials can also be used, for example polymers and copolymers of acrylic acid and / or methacrylic acid and / or their esters; Copolymers of acrylic and methacrylic acid esters with a low content of ammonium groups (eg Eudragit RS), copolymers of acrylic and methacrylic acid esters and trimethylammonium methacrylate (eg Eudragit RL); Polyvinyl acetate; Fats, oils, waxes, fatty alcohols; Hydroxypropyl methyl cellulose phthalate or acetate succinate; Cellulose acetate phthalate, starch acetate phthalate and polyvinyl acetate tatphthalate; Carboxymethyl cell ulose; Methylcel 1 ulose phthalate, methyl cellulose succinate, phthalate succinate and methyl cellulose phthalic acid semiesters; Zein; Ethyl cellulose and ethylcel 1 ulosesuccinate; Shellac, gluten;
  • Citric and tartaric acid esters acetyl triethyl citrate, acetyl tributyl, tributyl, triethyl citrate); Glycerin and glycerol esters (glycerol diacetate, triacetate, acetylated monoglycerides, castor oil); Phthalic acid esters (dibutyl, diamyl, diethyl, diethyl, dipropyl phthalate), di (2-methoxy or 2-ethoxyethyl) phthalate, ethylphthalylglycolate, butylphthalylethylglycolate and butylglycolate; Alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl adipate, di - (2-methoxy- or 2-ethoxyethyl) adipate); Benzophenone; Diethyl and dibutyl sebacate
  • water or physiologically compatible organic solvents can be used, such as, for example, alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example silicone oil, peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soybean oil oil, castor oil, cattle foot oil), paraffins, dimethyl sulfoxide, triglycerides and the like.
  • alcohols ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives
  • fatty alcohols for example silicone oil, peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soybean oil oil, castor oil, cattle foot oil
  • paraffins dimethyl sulfoxide, triglycerides and the like.
  • Non-toxic, parenterally compatible diluents or solvents are used, such as, for example: water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols in a mixture with water, glycerol, Ringer's solution, isotonic saline solution or also hardened oils, including synthetic mono- or diglycerides or fatty acids such as oleic acid.
  • solubilizers or emulsifiers can be used in the preparation of the preparations.
  • the following may be used as solubilizers and emulsifiers: polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated olefins, trioleate, polyoxyethylated, polyoxyethylated, polyoxyethylated Oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or l-methyl-l- (2-hydroxyethyl jimidazole idon- (2).
  • Polyoxyethylated here means that the substances in question contain polyoxyethylene chains, the Degree of polymerization is generally between 2 to 40 and in particular between 10 and 20.
  • Such polyoxyethylated substances can be obtained, for example, by reacting compounds containing hydroxyl groups (for example mono- or diglycerides or unsaturated compounds such as, for example, those containing oleic acid residues) with ethylene oxide n (e.g. 40 moles of ethylene oxide per 1 mole of glyceride).
  • oleotriglycerides examples include olive oil, peanut oil, castor oil, sesame oil, construction wool seed oil, corn oil.
  • the daily doses in the use according to the invention are carry 0.01 to 800 mg, preferably 0.1 to 600 mg and in particular 0.2 to 200 mg dihydroliponic acid in the form of the racemate.
  • the maximum daily dose should not exceed 800 mg.
  • the daily doses can be used in the form of a single administration of the total amount or in the form of 1 to 6, in particular 1 to 4, partial doses per day. In general, administration from 1 to 4 times, in particular 1 to 3 times a day is preferred.
  • the preferred daily dose for the dihydrolipoic acid is preferably 80 mg for the parenteral administration form and 200 mg for the oral form. In particular, the daily dose for the parenteral administration form is 50 mg and 150 mg for the oral form.
  • the dihydrolipoic acid can in particular also be applied in the form of a solution, for example orally, topically, parenterally (intravenously, intra-articularly, intramuscularly, subcutaneously), inhalatively, rectally, transdermally or vaginally, into the vitreous body of the eye , intraocularly in the anterior chamber of the eye or in the conjunctival sac of the eye.
  • a solution for example orally, topically, parenterally (intravenously, intra-articularly, intramuscularly, subcutaneously), inhalatively, rectally, transdermally or vaginally, into the vitreous body of the eye , intraocularly in the anterior chamber of the eye or in the conjunctival sac of the eye.
  • the drugs containing dihydroliponic acid as the active ingredient can e.g. in the form of tablets, capsules, pills or dragees, granules, suppositories, pellets, plasters, solutions or emulsions, the active ingredient being combined with corresponding auxiliaries and excipients.
  • these contain, for example, 0.5 to 20% by weight, preferably 1 to 10% by weight, dihydroliponic acid.
  • the dosage unit of the medicament with the dihydroliponic acid or a therapeutically usable salt of The same can include, for example:
  • parenteral drug forms e.g. intraocular or intravenous, intramuscular or intra-articular
  • the doses can be administered, for example, 1 to 6, preferably 1 to 4, in particular 1 to 3 times a day.
  • dihydroliponic acid preferably 0.1 to 250 mg, in particular 0.2 to 200 mg dihydroliponic acid.
  • the doses can be administered, for example, 1 to 6, preferably 1 to 4, in particular 1 to 3 times a day.
  • galenical preparations can also be prepared which contain the above-mentioned dosage units 2 to 10 times, for example.
  • Ins Special capsules contain 20 to 600 mg, pellets or granules 20 to 400 mg, suppositories 20 to 300 mg dihydrolipoic acid.
  • the weight amounts given above relate to the pure dihydrolipoic acid, i.e. not on the salts. If salts are used, the dose amounts in question must correspond to and be increased in accordance with the changed molecular weight.
  • Dihydroliponic acid or a pharmaceutically usable salt of dihydroliponic acid mixed or homogenized together with customary carriers and / or diluents or auxiliaries and, if appropriate, the mixture thus obtained is poured into hollow cells of the appropriate size or filled into capsules of the appropriate size or size nulated and then, optionally with the addition of further customary auxiliaries, compressed into tablets or filled into capsules, containing 0.01 to 800 mg of dihydroliponic acid or a pharmaceutically usable salt of dihydroliponic acid in the metering unit.
  • This formulation is prepared at temperatures between 0 and 120 ° C, preferably 20 to 80 ° C.
  • dihydroliponic acid or a pharmaceutically usable salt of dihydroliponic acid optionally with an antioxidant and optionally with one or more of the following substances: starch, cyclodextrin, urea, cellulose, lactose, for alin-casein, modified starch, magnesium stearate, Calcium hydrogen phosphate, silicic acid mixed, the mixture obtained optionally granulated with an aqueous solution which contains at least gelatin, starch, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and / or polyoxyethylene sorbitan monooleate, the granulate if appropriate with one or more of the above-mentioned auxiliary Homogenized substances, and this mixture pressed into tablets or filled into capsules, the tablets or capsules in the dosage unit each containing 0.01 to 800 mg of active ingredient dihydroliponic acid or a salt thereof.
  • This formulation is prepared at temperatures between 0 and 120 ° C, preferably 20 to 80 °
  • Dihydroliponic acid or a pharmaceutically usable salt of dihydroliponic acid optionally with 0.001 to 1 part by weight (based on 1 part by weight of dihydroliponic acid) of antioxidant and optionally with the addition of one or more emulsifiers and / or complexing agents with at least one of the following substances to form a mixture , which contains 0.5 to 20 percent by weight dihydroliponic acid, homogenized and optionally emulsified: water, glycerol, paraffin, petroleum jelly, aliphatic alcohol with 12 to 25 C atoms, aliphatic monocarboxylic acid with 15 to 20 C atoms, sorbitan monopalmitate, Polyoxyethylene polyol fatty acid ester, mono- or polyvalent low molecular weight aliphatic alcohol, fatty acid glyceride, wax, silicone, polyethylene glycol, polyethylene oxide. This formulation is produced at temperatures between 20 and 120 ° C.
  • polyphenols such as rutin, quercetin or morin or mixtures thereof or a pharmaceutically usable salt can be added.
  • Dihydroliponic acid or a pharmaceutically usable salt of dihydroliponic acid optionally with 0.001 to 1 part by weight (based on 1 part by weight of dihydroliponic acid) of antioxidant, and optionally with the addition of a complexing agent and / or an emulsifier in water, physiologically acceptable alcohols, dimethyl sulfoxide, polyethylene glycol or Oils or mixtures thereof dissolved and, if appropriate, the solution thus obtained filled with enough water, alcohol, dimethyl sulfoxide, polyethylene glycol or oil that the final solution, final suspension or final emulsion contains 0.5-20 percent by weight of active ingredient dihydroliponic acid.
  • This formulation is produced at temperatures between 30 and 100 ° C.
  • polyphenols such as rutin, quercetin or morin or mixtures thereof or a pharmaceutically usable salt can be added.
  • polyoxyethylene-40-stearate (trade name: Myrj 52), 80 g of cetylstearyl alcohol, 200 g of white petroleum jelly, 50 g of viscous paraffin and 5 g of dimethicone are melted together in a homogenization apparatus. 1.26 g of methyl 4-hydroxybenzoate and 0.533 g of propyl 4-hydroxybenzoate are dissolved in the melt.
  • preservatives for the production of eye drops, it is preferred to add preservatives, lubricants and well-wetting agents to the preparation.
  • Suitable preservatives are, for example, benzalkonium chlorides, which have an antiseptic and surface-active effect. Furthermore, it is preferred to use the eye drop glycerol and physiological saline to admit.
  • Glycerin and / or dextran 0.100 g sterile water up to 100 ml
  • Stabilizers preservatives in sufficient quantities.
  • the topical application is carried out drop by drop directly into the eye.
  • the frequency of use varies from one to five times a day.
  • Another possible application is to deliver the above-mentioned formulation to the eye via a carrier. Keratin discs or soft contact lenses, which are applied after preincubation, are suitable as carriers.
  • liposome preparations can also be added to the eye drops for direct or application on a carrier.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP94913566A 1993-05-22 1994-04-11 Verwendung von dihydroliponsäure als ophthalmologicum und zur unterdrückung von unverträglichkeitsreaktionen im grenzbereich von implantaten mit lebendem körpergewebe Withdrawn EP0697863A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4317173 1993-05-22
DE19934317173 DE4317173C2 (de) 1993-05-22 1993-05-22 Verwendung von Dihydroliponsäure als Ophthalmologicum
PCT/EP1994/001110 WO1994027592A1 (de) 1993-05-22 1994-04-11 Verwendung von dihydroliponsäure als ophthalmologicum und zur unterdrückung von unverträglichkeitsreaktionen im grenzbereich von implantaten mit lebendem körpergewebe

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EP0697863A1 true EP0697863A1 (de) 1996-02-28

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EP94913566A Withdrawn EP0697863A1 (de) 1993-05-22 1994-04-11 Verwendung von dihydroliponsäure als ophthalmologicum und zur unterdrückung von unverträglichkeitsreaktionen im grenzbereich von implantaten mit lebendem körpergewebe

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US (1) US5691379A (enrdf_load_stackoverflow)
EP (1) EP0697863A1 (enrdf_load_stackoverflow)
JP (1) JPH08511246A (enrdf_load_stackoverflow)
AU (1) AU6566794A (enrdf_load_stackoverflow)
CA (1) CA2162467A1 (enrdf_load_stackoverflow)
DE (1) DE4345199C2 (enrdf_load_stackoverflow)
IL (1) IL109701A0 (enrdf_load_stackoverflow)
PH (1) PH31652A (enrdf_load_stackoverflow)
TW (1) TW265264B (enrdf_load_stackoverflow)
WO (1) WO1994027592A1 (enrdf_load_stackoverflow)
ZA (1) ZA943514B (enrdf_load_stackoverflow)

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US5965618A (en) * 1997-11-17 1999-10-12 Perricone; Nicholas V. Treatment of scar tissue using lipoic acid
US6905707B2 (en) * 1998-05-28 2005-06-14 Medical Research Institute Controlled release arginine alpha ketoglutarate
US20040259895A1 (en) * 1998-05-28 2004-12-23 Medical Research Institute Oral formulation of lipid soluble thiamine and lipoic acid
US6197340B1 (en) * 1998-05-28 2001-03-06 Medical Research Institute Controlled release lipoic acid
US20050085498A1 (en) * 1998-05-28 2005-04-21 Byrd Edward A. Oral formulation of lipid soluble thiamine, lipoic acid, creatine derivative, and L-arginine alpha-ketoglutarate
US6191162B1 (en) 1998-05-28 2001-02-20 Medical Research Institute Method of reducing serum glucose levels
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US6136339A (en) * 1998-08-21 2000-10-24 Gardiner; Paul T. Food supplements and methods comprising lipoic acid and creatine
AU5601300A (en) * 1999-06-09 2000-12-28 Department Of The Army, U.S. Government Method and compositions for treating and preventing retinal damage
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US20050112113A1 (en) * 2000-08-16 2005-05-26 Till Jonathan S. Presbyopia treatment by lens alteration
US8647612B2 (en) * 2008-03-05 2014-02-11 Encore Health, Llc Dithiol compounds, derivatives, and treatment of presbyopia
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US8697109B2 (en) 2000-08-16 2014-04-15 Encore Health, Llc Caged mercaptan and seleno-mercaptan compounds and methods of using them
US8557868B2 (en) 2000-11-04 2013-10-15 Fxs Ventures, Llc Ophthalmic and contact lens solutions using low molecular weight amines
US9492582B2 (en) * 2000-11-08 2016-11-15 Fxs Ventures, Llc Ophthalmic and contact lens solutions containing simple saccharides as preservative enhancers
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US9492581B2 (en) 2000-11-08 2016-11-15 Fxs Ventures, Llc Ophthalmic and contact lens solutions containing simple saccharides as preservative enhancers
US20070098813A1 (en) * 2000-11-08 2007-05-03 Fxs Ventures, Llc Ophthalmic and contact lens solutions with a peroxide source and a preservative
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PT1331902E (pt) * 2000-11-08 2008-12-02 Fxs Ventures Llc Soluções oftálmicas e para lentes de contacto melhoradas contendo formas de vitamina b
US9308264B2 (en) 2000-11-08 2016-04-12 Fxs Ventures, Llc Ophthalmic contact lens solutions containing forms of vitamin B
US20070110782A1 (en) * 2000-11-08 2007-05-17 Fxs Ventures, Llc L-histidine in ophthalmic solutions
DE10229995A1 (de) * 2002-07-03 2004-01-15 Beiersdorf Ag Kosmetische oder dermatologische Zubereitungen mit einem Gehalt an alpha-Liponsäure
WO2004091438A2 (en) * 2003-04-15 2004-10-28 Fxs Ventures, Llc Improved ophthalmic and contact lens solutions containing peptides as representative enhancers
ITLO20060004A1 (it) * 2006-08-08 2008-02-09 River Pharma Srl "lapille" e una nuova invenzione avente per oggetto una nuova combinazione chimica stabile per uso cosmetico e farmaceutico contenente come ingredienti attivi l'acido alfa-lipoico ed il dimetilsulfossido, in grado di migliorare l'assorbimento, la bio
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Also Published As

Publication number Publication date
WO1994027592A1 (de) 1994-12-08
US5691379A (en) 1997-11-25
CA2162467A1 (en) 1994-12-08
DE4345199C2 (de) 1995-10-12
IL109701A0 (en) 1994-08-26
TW265264B (enrdf_load_stackoverflow) 1995-12-11
PH31652A (en) 1999-01-12
DE4345199A1 (de) 1994-12-01
JPH08511246A (ja) 1996-11-26
ZA943514B (en) 1995-02-02
AU6566794A (en) 1994-12-20

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