EP1830803A2 - Arzneimittel zur hygienischen applikation im ohr - Google Patents

Arzneimittel zur hygienischen applikation im ohr

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Publication number
EP1830803A2
EP1830803A2 EP05816509A EP05816509A EP1830803A2 EP 1830803 A2 EP1830803 A2 EP 1830803A2 EP 05816509 A EP05816509 A EP 05816509A EP 05816509 A EP05816509 A EP 05816509A EP 1830803 A2 EP1830803 A2 EP 1830803A2
Authority
EP
European Patent Office
Prior art keywords
acid
medicament
medicament according
weight
pharmaceutical formulation
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Withdrawn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
EP05816509A
Other languages
German (de)
English (en)
French (fr)
Inventor
Iris Heep
Gert Daube
Ernst Böttcher
Dirk Mertin
Georg Schulte
Ulrike Umgelder
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.)
Bayer Intellectual Property GmbH
Original Assignee
Bayer Healthcare AG
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
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1830803A2 publication Critical patent/EP1830803A2/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Withdrawn legal-status Critical Current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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D7/00—Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body

Definitions

  • the invention relates to a system as a medicament for the hygienic application of an ear medication - especially in animals - which is reproducible even at low volumes and which is not ejected even when shaking the head again.
  • causes of the complex disease in the dog is usually a combination of predisposing factors (eg lop-eared ears, strong earwax production), primary factors (underlying disease such as atopy or food allergy, seborrhoea) and preserving factors (bacterial and yeast propagation in the ear canal), in a circulus vitiosus from microbial growth on the one hand and inflammation on the other.
  • predisposing factors eg lop-eared ears, strong earwax production
  • primary factors underlying disease such as atopy or food allergy, seborrhoea
  • preserving factors bacterial and yeast propagation in the ear canal
  • the treatment of otitis occurs after diagnosis and initial therapy by the veterinarian usually by the owner.
  • the object of the invention was therefore to find a drug that allows the dosing accurate, hygienic and easy treatment of the ear.
  • thixotropic formulations are described in these documents, they are taken either orally as capsules orally, thereby ensuring reproducible dosing, or the agents are filled in larger containers with higher proportions of active ingredient (FR 2790200) also a reproducible dosage considerably easier.
  • the restoring force in the descriptions of the thixotropic formulations is solely for the purpose of filling the capsules, but not the specific application at the patient's ear (WO 00/01371).
  • the subject of the invention is therefore:
  • a medicament for the treatment of diseases of the ear in humans or animals comprising:
  • Anti-infective agents are in particular antibacterial compounds such as penicillins, cephalosporins, aminoglycosides, sulfonamides and especially quinolones.
  • Quinolones preferably fluoroquinolones, include compounds as disclosed in the following documents: US 4,670,444 (Bayer AG), US 4,472,405 (Riker Labs), US 4,730,000 (Abbott), US 4,861,779 (Pfizer U.S. 4,382,892 (Daiichi), U.S.
  • fluoroquinolones are those of the formula (I) or (IT):
  • X is hydrogen, halogen, Ci. 4- alkyl, C 1-4 -alkoxy, NH 2 ,
  • R 4 is optionally substituted by hydroxy or methoxy straight or branched Ci-Gi-alkyl, cyclopropyl, acyl having 1 to 3 carbon atoms,
  • R 5 is hydrogen, methyl, phenyl, thienyl or pyridyl
  • R 6 is hydrogen or C M -alkyl
  • R 7 is hydrogen or Ci -4 -alkyl
  • R 8 is hydrogen or Ci -4 -alkyl
  • R 1 is an alkyl radical having 1 to 3 carbon atoms, cyclopropyl, 2-fluoroethyl, methoxy, 4-fluorophenyl, 2,4-difluorophenyl or methylamino,
  • R 2 is hydrogen or optionally methoxy or 2-methoxyethoxy-substituted alkyl having 1 to 6 carbon atoms and cyclohexyl, benzyl, 2-oxopropyl, phenacyl, ethoxycarbonylmethyl, pivaloyloxymethyl,
  • R 3 is hydrogen, methyl or ethyl
  • the compounds of formulas (I) and (IT) may be in the form of their racemates or in enantiomeric forms.
  • R 1 is optionally halogen-substituted C 1 -C 6 -alkyl or cyclopropyl
  • R is 2-4 I stands for hydrogen or alkyl C Y for residues of the structures
  • R 4 represents optionally hydroxyl-substituted straight or branched C r C 3 alkyl, oxalkyl having 1 to 4 carbon atoms,
  • R 5 is hydrogen, methyl or phenyl
  • R 7 is hydrogen or methyl
  • R 6 and R 8 are hydrogen
  • R! represents cyclopropyl
  • R 2 is hydrogen, methyl or ethyl
  • R 4 is methyl, optionally substituted by hydroxy ethyl, R 5 is hydrogen or methyl,
  • R 7 is hydrogen or methyl
  • R 6 and R 8 are hydrogen
  • Suitable salts are pharmaceutically usable acid addition salts and basic salts.
  • Examples of pharmaceutically usable salts are the salts of hydrochloric acid, sulfuric acid, acetic acid, glycolic acid, lactic acid, succinic acid, citric acid, tartaric acid, methanesulfonic acid, 4-toluenesulfonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid.
  • the compounds according to the invention can be bound to acidic or basic ion exchangers.
  • Suitable pharmaceutically usable basic salts are the alkali metal salts, for example the sodium or potassium salts, the alkaline earth metal salts, for example the magnesium or calcium salts; the zinc salts, the silver salts and the guanidinium s' Alze called.
  • Hydrates are understood as meaning both the hydrates of the fluoroquinolones themselves and the hydrates of their salts.
  • fluoroquinolones which may be mentioned are the compounds described in WO 97/31001, in particular 8-cyano-1-cyclopropyl-7 - ((1S, 6S) -2,8-diazabicyclo [4.3.0] nonan-8-yl) 6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid (pradofloxacin) having the formula
  • Pradofloxacin is preferred in its free form as anhydrate, e.g. In modification B (see WO 00/31076) or as trihydrate (cf., WO 2005/097789).
  • the preferred quinolone anti-infective agents are marbofloxacin, orbifloxacin, difloxacin and ibafloxacin.
  • Penicillins are e.g. Benzylpenicillin, ampicillin, amoxicillin, oxacillin, piperacillin, ticarcillin.
  • Cephalosporins are z. B. Ceefalexin, Cefadroxil, Cefazolin, Cefoxitin, Ceftiofur.
  • macrolide is e.g. called erythromycin, spiramycin, tylosin, tilmicosin.
  • sulfonamides are, for example: called trimethoprim and " sulfadiazine " (preferably used in Kömbinuschiün).
  • aminoglycosides may be mentioned gentamicin, kanamycin, streptomycin, neomycin and spectinomycin.
  • antibiotic Lmcosamid called clindamycin.
  • the anti-infective agent is typically used in the formulation in an amount of 0.001-6% by weight, preferably 0.01-1.0% by weight, particularly preferably 0.1-0.8% by weight.
  • anti-infective agents in the context of this invention are derived from silver, z.
  • colloidal silver silver nitrate or silver sulfadiazine.
  • these may be used in combination with one of the anti-infective agents described above and / or, as described below, optionally a corticosteroid.
  • the drug according to the invention in addition to the anti-infective as another pharmaceutically active ingredient contains an antimycotic, such.
  • an imidazole or a triazole in particular z. Clotrimazole, miconazole or bifonazole.
  • the antimycotic agent is typically used in the formulation in a proportion of 0.01-10% by weight, preferably 0.1-5% by weight, particularly preferably 0.5-2% by weight. Furthermore, it is advantageous if the medicament according to the invention also contains a corticoid in addition to the anti-infective and optionally the antimycotic. It can be used both the corticosteroids and their derivatives usually used for pharmaceutical purposes, in particular the esters. Examples of corticosteroids are hydrocortisone, prednisolone, betamethasone, mometasone, flumethasone; preferred betamethasone, triamcinolone and especially dexamethasone called.
  • the hydroxyl groups on C17 and / or C21 are usually esterified with short-chain organic acids, this increases the potency of the corticosteroids, the higher lipophilicity leads to a better penetration into the cells and at the same time the accumulation in the skin is improved.
  • Hydrocortisone for example, is one of the weakest, while hydrocortisone 17-butyrate is one of the strong glucocorticoids. Similar effects are to be expected with the glucocorticoids dexamethasone / dexamethasone 21-acetate and betamethasone / betamethasone 17-valerate.
  • Korticoidester are Aclometasonpropionat, beta methasondipropionat, hexanoate betamethasone, clobetasol propionate, clobetasone, Clocortolon-, Clocortolonpivalat, Dexamethasonaceatat, diflucortolone, diflucortolone, flumetasone, Fluocortolonhexanoat, fluocortolone pivalate, fluprednidene, fluticasone propionate, buteprat hydrocortisone, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone, Methylprednisolone aceponate, mometasone furoate, prednicarbate and prednisolone acetate.
  • corticoid esters are betamethasone-17-valerate and especially dexamethasone-21-acetate.
  • Another particularly preferred example of a corticosteroid derivative is triamcinolone acetonide, a ketal.
  • corticoid in its broadest sense also encompasses derivatives such as the esters and ketals detailed above.
  • the corticoid is typically used in the formulation in a proportion of 0.001-2.0% by weight, preferably 0.005-0.5% by weight, particularly preferably 0.05-0.2% by weight.
  • pradofloxacin a particularly preferred active ingredient combination
  • clotrimazole a particularly preferred active ingredient combination
  • dexamethasone preferably in the form of its 21-acetate
  • Optically active substances can be used in the form of their stereoisomers or as a mixture of stereoisomers, for example as pure or enriched enantiomers or as racemates.
  • the fluid base may be oily or aqueous.
  • natural (animal or vegetable), synthetic and semi-synthetic oils or fats can be used. These include soybean, sunflower, cottonseed, olive, peanut, safflower, palm, rapeseed, coconut, corn germ, castor and jojoba oils.
  • medium-chain triglycerides triglycerides with saturated fatty acids, preferably the octane and decanoic acid
  • propylene glycol diesters of caprylic / capric acid low-viscosity paraffin or sesame oil
  • particularly preferably used are the medium-chain triglycerides and propylene glycol diesters of caprylic / capric acid.
  • these oils and fats can also be used as mixtures.
  • aqueous base water, glycerin, propylene glycol or polyethylene glycols can be used. Mixtures of these substances are also usable.
  • An oily foundation is preferred.
  • the oily or aqueous base is typically used in an amount of 99.9-72% by weight, preferably 99.4-89.5% by weight, more preferably 97.9-94.0% by weight. used.
  • a fluid drug formulation is filled in a primary packaging.
  • the formulations may in principle be solutions, emulsions, suspensions, pastes or gels.
  • the formulations may contain thickening agents, e.g. Cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose,
  • Carboxymethyl cellulose microcrystalline cellulose; Bentonites, kaolin, pectin, starches, modified starches, waxes, agar, paraffins, gelatin, alginates, polyvinylpyrrolidone,
  • Crospovidone cetyl alcohol, stearates such as magnesium stearate, zinc stearate or glyceryl stearate, saturated or unsaturated long-chain fatty acids (C 8 -C 2) , high molecular weight polyethylene glycols (eg polyethylene glycol 2000) or preferably silicas such as hydrophilic, precipitated, highly dispersed, precompressed or hydrophobic, methylated silicas and mixed oxides
  • Silica and alumina and more preferably fumed silicas.
  • thickeners is z. B. advantageous if one or more active ingredients do not dissolve sufficiently or in the fluid base, so that a suspension must be used.
  • the thickener then serves to stabilize the suspension against sedimentation.
  • the thickener is used in the formulations typically in a proportion of 0.1 to 10 wt .-%, preferably 0.5 to 5 wt .-%, particularly preferably 1.0 to 3.0 wt .-%.
  • the formulation is adjusted to have thixotropic properties, that is, it becomes thinner by agitation, and at rest the viscosity rebuilds.
  • Thixotropic formulations are prepared by adding a corresponding additive to the formulation base (fluid base) insofar as the fluid base is not itself thixotropic.
  • a suspension stabilizer or thickener such as e.g. the fumed silicas or hydrophobic silica (eg, methylated silica).
  • the degree of thixotropy can be adjusted by varying the concentration.
  • the primary packaging means according to the invention are single dose containers. These are filled with a volume of 0.1-5.0 ml, preferably 0.2-4.0 ml, particularly preferably 0.3-2.0 ml of removable content of fluid formulation.
  • the formulations may contain other customary, pharmaceutically acceptable additives and auxiliaries. As examples may be mentioned
  • Preservatives such as carboxylic acids (sorbic acid, propionic acid, benzoic acid, lactic acid), phenols (cresols, p-hydroxybenzoic acid esters such as methylparaben,
  • Propylparaben, etc. aliphatic alcohols (benzyl alcohol, ethanol, butanol, etc.), quaternary ammonium compounds (benzalkonium chloride, cetylpyridinium chloride)
  • Antioxidants such as sulfites (Na sulfite, Na-metabisulfite), organic sulfides (cystine, cysteine, cysteamine, methionine, thioglycerol, thioglycolic acid, thiolactic acid) phenols (tocopherols, as well as vitamin E and vitamin E TPGS ( d-alpha-tocopherylpolyethylene glycol 1000 succinate), butylhydroxyanisole, butylhydroxytoluene, gallic acid or its derivatives (propyl, octyl and dodecyl gallate), organic acids (ascorbic acid, citric acid, tartaric acid, lactic acid) and their salts and esters ,
  • sulfites Na sulfite, Na-metabisulfite
  • organic sulfides cystine, cysteine, cysteamine, methionine, thioglycerol, thiogly
  • Wetting agents or emulsifiers for example fatty acid salts, fatty alkyl sulfates, fatty alkyl sulfonates, linear alkylbenzenesulfonates, fatty alkyl polyethylene glycol ether sulfates, fatty alkyl polyethylene glycol ethers, alkylphenol polyethylene glycol ethers, alkyl polyglycosides, fatty acid N-methylglucamides, polysorbates, sorbitan fatty acid esters, lecithins and poloxamers. • Pharmaceutically acceptable dyes such as iron oxides, carotenoids, etc.
  • the formulations may also contain co-solvents, which may also lower the viscosity. These are usually used in proportions of 0.1 to 40 wt .-%, preferably from 1 to 10 wt .-%.
  • cosolvents which may be mentioned are: pharmaceutically acceptable alcohols, such as ethanol or benzyl alcohol, dimethyl sulfoxide, ethyl lactate,
  • Hexyl dodecanol, decyl oleate, dibutyl adipate, dimethicone, glyceryl ricinoleate, octyldodecanol, octyl stearate, propylene glycol dipelargonate and preferably isopropyl myristate or isopropyl palmitate can be used as spreading agents.
  • Penetration enhancers improve the transdermal application of drugs and are in principle known in the art (see, for example, Chapter 6 of
  • spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils or their copolymers with polyethers, fatty acid esters (for example oleic acid oloxyl esters), triglycerides, fatty alcohols and linolenes.
  • DMSO N-methylpyrrolidone, 2-pyrrolidone, dipropylene glycol monomethyl ether, octyldodecanol, oleylmacrogol glycerides or propylene glycolollaurate may also be used.
  • acids are basically inorganic and organic acids in question.
  • inorganic acids are hydrochloric acid, sulfuric acid, sulfurous acid and phosphoric acid.
  • organic acids are formic acid, acetic acid, propionic acid,
  • the primary packaging usually has the form of a tube (tube tubes, laminate tubes, Blastuben or spray stretch tubes).
  • the disposable container can be made of polypropylene, polyethylene, aluminum (Al), laminate or mixtures of these materials.
  • the most common material for plastic tubes in general is currently polyethylene, namely PE-LD (polyethylene low density) and also PE-HD (high density).
  • Laminate tubes are multilayer tubes made of aluminum or silicon oxide (SiOx) and plastic laminates. The composites usually consist of PE-LD / AL / PE-LD and other layers.
  • the aluminum layer can also be replaced by barrier films such as thermoplastics or barrier plastics, in particular by E / V AL (EfVOH, ethylene-vinyl alcohol) and silicon oxide (SiOx).
  • barrier films such as thermoplastics or barrier plastics, in particular by E / V AL (EfVOH, ethylene-vinyl alcohol) and silicon oxide (SiOx).
  • Tubes of polyethylene, polypropylene or laminate, more preferably of laminate or in particular polypropylene are preferably used according to the invention.
  • Specifically sterilizable polypropylene tubes provide e.g. Tubes made of PP / E / VAL / PP.
  • the tubes are by Abmosh, screw or plug with or without additional sealing membrane by means of piercing membrane including mandrel, for example. in the cap, by means of peelable sealing e.g. opened in the form of a film or by means of breakable or tear-off seal.
  • the tubes are screwed or screwed on e.g. in the cap Domes open in the sealing membrane of the tube.
  • the tip of the applicator should also be of a certain length when opened and be rounded at the front end to prevent injuries.
  • Fig. 1 shows an example of a tube according to the invention suitable as a single dose container.
  • the described formulations filled in single-dose containers are particularly suitable for the hygienic treatment of otitis externa on dogs and cats. It should be emphasized in particular that the formulation can be taken in a well reproducible manner. If thickeners are used in suspension formulations, sedimentation of the suspended constituents can generally be prevented. Thixotropic formulations are particularly advantageous since, after shaking the single-dose containers, the formulation is taken out particularly well reproducibly, even with low active ingredient concentrations, the formulation is simply and hygienically applied to the animal's ear by the thixotropy and the single-dose container and yet not, for example, by the usual shaking of the head can be thrown out.
  • the formulations are prepared by dispersing the active ingredients or adjuvants to be dissolved or suspended in the base. If appropriate, an agitator or preferably a homogenizer or high-pressure homogenizer is used for dispersion. The order of addition of individual ingredients may be varied depending on the formulation. After dispersing all formulation ingredients, the finished formulation is stored intermediately or filled directly into the single-dose containers, which are then sealed.
  • the medicaments according to the invention are generally suitable for use in humans and animals. Preferably, they are used in livestock and animal breeding in livestock, breeding, zoo, laboratory, experimental and hobby animals, especially in mammals.
  • the livestock and breeding animals include mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as e.g. Mink, chinchilla, raccoon, as well as birds such as e.g. Chickens, geese, turkeys, ducks, pigeons and ostriches.
  • mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as e.g. Mink, chinchilla, raccoon, as well as birds such as e.g. Chickens, geese, turkeys, ducks, pigeons and ostriches.
  • preferred farm animals are beef, sheep, pork and chicken.
  • Laboratory and experimental animals include dogs, cats, rabbits and rodents such as mice, rats, guinea pigs and golden hamsters.
  • the hobby animals include dogs, cats, horses, rabbits, rodents such as golden hamsters, guinea pigs, mice, reptiles, amphibians and birds for home and zoo keeping.
  • the medicaments according to the invention are preferably used in pets, in particular in dogs and cats.
  • the application can be both prophylactic and therapeutic.
  • formulations described here are intended for local application in the ear canals. Other applications are possible but in principle such. As the dermal, oral, rectal, vaginal or nasal application. Examples
  • the percentages for the formulations described herein are given by weight per volume (grams of the subject substance per 100 ml of finished formulation).
  • the medium-chain triglycerides to be used are the triglycerides of the CapryW capric esters, for example Miglyol® 812 from Sasol / Witten (used, for example, in Examples 3 and 6).
  • betamethasone valerate 0.5 g are suspended with 1.5 g of pradofloxacin, 5 g of bifonazole in 973 g Propylenglykoloctanoatdecanoat and then treated with 20 g of fumed silica. Subsequently, the suspension is homogenized with a homogenizer for 10 min.
  • 10 g of enrofloxacin are suspended with 2 g of triamcinolone acetonide, 20 g of clotrimazole in 1932 g of medium-chain triglycerides and then mixed with 36 g of fumed silica. Subsequently, the suspension is homogenized with a homogenizer for 10 min.
  • dexamethasone 21 acetate 1.0% clotrimazole 0.8% hydroxyethylcellulose 20% lactic acid 19% isopropanol
  • 200 g of isopropanol and 16 g of benzyl alcohol are mixed in 500 g of propylene glycol.
  • 1 g of dexamethasone acetate, 3 g of pradofloxacin and 10 g of clotrimazole are suspended therein and then treated with 200 g of lactic acid.
  • 8 g of hydroxyethyl cellulose are stirred in and adjusted to the final weight with 62 g of propylene glycol. Subsequently, the suspension is homogenized with a homogenizer for 10 min.
  • pradofloxacin 3 g are suspended with 0.3 g of dexamethasone acetate and 10 g of clotrimazole in 968.7 g medium-chain triglycerides and then mixed with 18 g of fumed silica. Subsequently, the suspension is homogenized with a homogenizer for 10 min.
  • n-butanol 0.5 g is mixed in 241 g of medium chain triglycerides.
  • 0.25 g of dexamethasone acetate, 1.25 g of enrofloxacin and 2.5 g of bifonazole are dispersed and then added to the approach with 4.5 g of fumed silica.
  • the suspension is then homogenized with a homogenizer for 10 min.
  • Silica are dispersed in this solution and the remaining mid-chain triglycerides (22.9 kg) added. Subsequently, the suspension is homogenized with a homogenizer for about 10 min.
  • methylated silica (Aerosil® R 972, fumed silica hydrophobized with dimethyldichlorosilane from Degussa) ad 100% medium-chain triglycerides
  • sorbic acid 0.5 kg of clotrimazole and 0.05 kg of dexamethasone 21 acetate are dissolved in 95.64 kg of medium-chain triglycerides. 0.114 kg of pradofloxacin trihydrate and 3.6 kg of hydrophobic silica are dispersed in this solution. Subsequently, the suspension is homogenized with a homogenizer for about 10 min.
  • methylated silica (Aerosil® R 974, fumed silica hydrophobized with dimethyldichlorosilane from Degussa) ad 100% medium-chain triglycerides 0.1 kg sorbic acid, 0.5 kg clotrimazole and 0.05 kg dexamethasone 21 acetate are reported in 96, 66 kg medium-chain triglycerides dissolved. 0.114 kg of pradofloxacin trihydrate and 2.7 kg of hydrophobic silica are dispersed in this solution. Subsequently, the suspension is homogenized with a homogenizer for about 10 min.

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  • Wood Science & Technology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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EP05816509A 2004-12-09 2005-12-03 Arzneimittel zur hygienischen applikation im ohr Withdrawn EP1830803A2 (de)

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DE102005055385A DE102005055385A1 (de) 2004-12-09 2005-11-17 Arzneimittel zur hygienischen Applikation im Ohr
PCT/EP2005/012978 WO2006061156A2 (de) 2004-12-09 2005-12-03 Arzneimittel zur hygienischen applikation im ohr

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PL2802209T3 (pl) * 2012-01-10 2021-07-05 Entrx LLC Preparaty do uszu
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BR112018013504B1 (pt) 2015-12-29 2022-08-09 Galderma S.A. Método para desacetilação pelo menos parcial de glicosaminoglicano compreendendo grupos acetila, glicosaminoglicano pelo menos parcialmente desacetilado, uso de hidroxilamina para desacetilação pelo menos parcial de glicosaminoglicano e método para preparar produto de hidrogel
CN109689027A (zh) * 2016-06-29 2019-04-26 奥德纳米有限公司 甘油三酯耳用制剂及其用途
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RU2431486C2 (ru) 2011-10-20
AR052990A1 (es) 2007-04-18
WO2006061156A2 (de) 2006-06-15
BRPI0518855A2 (pt) 2008-12-09
IL183744A0 (en) 2008-04-13
DE102005055385A1 (de) 2006-06-14
CR9142A (es) 2007-12-04
JP2008522998A (ja) 2008-07-03
PE20061145A1 (es) 2006-12-29
RU2007125570A (ru) 2009-01-20
CA2594103A1 (en) 2006-06-15
NZ555640A (en) 2009-12-24
WO2006061156A3 (de) 2006-08-24
US20090011045A1 (en) 2009-01-08
GT200500361A (es) 2006-11-07
KR20070086799A (ko) 2007-08-27
AU2005313602A1 (en) 2006-06-15
MX2007006689A (es) 2007-08-14
NO20073148L (no) 2007-08-22

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