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EP1744738A1 - Topische zubereitung enthaltend ambroxol - Google Patents

Topische zubereitung enthaltend ambroxol

Info

Publication number
EP1744738A1
EP1744738A1 EP05739626A EP05739626A EP1744738A1 EP 1744738 A1 EP1744738 A1 EP 1744738A1 EP 05739626 A EP05739626 A EP 05739626A EP 05739626 A EP05739626 A EP 05739626A EP 1744738 A1 EP1744738 A1 EP 1744738A1
Authority
EP
European Patent Office
Prior art keywords
ambroxol
topical
pharmaceutical compositions
acceptable salts
compositions according
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Withdrawn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
EP05739626A
Other languages
German (de)
English (en)
French (fr)
Inventor
Anke Esperester
Frieder Ulrich Maerz
Claudia Mueller
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34966914&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1744738(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of EP1744738A1 publication Critical patent/EP1744738A1/de
Withdrawn legal-status Critical Current

Links

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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to topical pharmaceutical compositions containing ambroxol or one of its pharmacologically acceptable salts, preferably in the form of its hydrochloride, for direct application or application to the skin and / or mucosa having antiinflammatory and local anesthetic properties.
  • Ambroxol lozenges are known for the treatment of pain in the throat and throat (EP 1200070, WO 03/072094).
  • Topical formulations of anesthetically or anti-inflammatory compounds often show side effects.
  • topical pharmaceutical compositions containing ambroxol or one of its pharmacologically acceptable salts for direct application or application to the skin and / or mucous membrane possess anti-inflammatory and local anesthetic properties.
  • the excellent toxicological profile of ambroxol also allows a large-scale and prolonged use of such formulations.
  • the present invention relates to topical pharmaceutical compositions containing ambroxol or one of its pharmacologically acceptable salts for direct application or application to the skin and / or mucous membrane, preferably to the skin or oral mucosa, more preferably to the skin, with anti-inflammatory and local anesthetic properties.
  • topical pharmaceutical compositions in the form of a formulation selected from the group consisting of gels, hydrophilic pastes, shake mixtures and solutions, preferably gels and hydrophilic pastes.
  • topical pharmaceutical compositions in the form of a formulation selected from the group consisting of gels, hydrophilic pastes, shaking mixtures and solutions in which the content of ambroxol is from 0.1% to 20% (w / w), preferably 0.5% to 5% (w / w).
  • Topical pharmaceutical compositions in the form of a formulation selected from the group consisting of suppositories, hydrophobic pastes, ointments, creams, lotions and sticks, preferably suppositories, hydrophobic pastes and sticks.
  • a preferred embodiment of the invention consists in topical pharmaceutical compositions in the form of mucoadhesive patches, buccal strips or mucoadhesive tablets, preferably mucoadhesive patches or buccal strips.
  • a likewise preferred embodiment of the invention consists in topical compositions, wherein the content of ambroxol in mucoadhesive patches of 1% -50% (w / w) based on the total mass of the hydrophilic carrier layer, preferably 5% to 40% (w / w), particularly preferably from 10 to 30% (w / w).
  • topical compositions described above wherein the residence time of ambroxol or one of its pharmaceutically acceptable salts on the skin and / or mucosa is prolonged over that of a 0.1% ambroxol-containing nonionic hydrophilic cream according to the 2003 edition of the German Pharmacopoeia.
  • Another object of the present invention is the use of ambroxol or one of its pharmacologically acceptable salts for the preparation of a pharmaceutical composition for the topical treatment of pain, burning or itching of the
  • Skin and / or mucous membrane preferably from pain and burning of the mucous membrane or itching and burning of the skin, particularly preferably from pain and burning of the mucous membrane.
  • ambroxol or one of its pharmacologically acceptable salts for the preparation of a pharmaceutical composition for the topical treatment of inflammation.
  • Another object of the present invention is the use of ambroxol or one of its pharmacologically acceptable salts for the preparation of a pharmaceutical composition for the topical treatment of conditions selected from the group consisting of painful inflammation in the mouth or vaginal area, mosquito bites, skin allergic, immunological or idiopathic origin and itchy or burning hemorrhoids, preferably painful inflammations in the mouth or vaginal area and itchy or burning hemorrhoids.
  • Suitable acids for salt formation of ambroxol are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid and methanesulfonic acid, preferably hydrochloric acid.
  • the gels, hydrophilic pastes, shaking mixtures and solutions according to the invention contain different proportions of water, one or more auxiliaries from the group consisting of natural, semisynthetic or synthetic polymers, inorganic gelling compounds, flavors, fragrances, sweeteners, colorants, preservatives, lower alcohols, polyols, pH regulators, permeation enhancers and solubilizers.
  • auxiliaries from the group consisting of natural, semisynthetic or synthetic polymers, inorganic gelling compounds, flavors, fragrances, sweeteners, colorants, preservatives, lower alcohols, polyols, pH regulators, permeation enhancers and solubilizers.
  • polymers pharmaceutically acceptable compounds selected from the group consisting of gum arabic, cellulose, cellulose derivatives, preferably nonionic and mucoadhesive cellulose derivatives, more preferably methylcellulose (MC), carboxymethylcellulose (CMC) or its salts, hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC ), Hydroxypropylmethylcellulose (HPMC) or methylethylcellulose (MEC), polyvinylalkylether-co-maleic anhydride or its salts, gelatin, pectin, polyethylene glycols (PEG), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), tragacanth, carrageenan, xanthan, chitosan, Chitosan chloride, agarose, agar-agar, alginates, poloxamers, starch, starch derivatives, guar gum, galactomannan, polyacrylates, cross-linked acrylic polymers, poly (hydroxyeth
  • Suitable inorganic gels are colloidal silicas or bentonite.
  • Suitable polyols are compounds selected from the group consisting of ethylene glycol, propylene glycol, glycerol and sugar alcohols, preferably glycerol, sorbitol and maltitol.
  • pH regulators and permeation enhancers correspond to the auxiliaries listed in the section hydrophilic ointments, pastes, creams and lotions.
  • Solubilizers, perfumes, dyes, sweeteners and preservatives may be added in pharmaceutically acceptable amounts.
  • finely ground insoluble inorganic compounds for example zinc oxide, titanium dioxide can be added.
  • the mucoadhesive patches according to the invention consist of at least one hydrophilic layer and optionally a more hydrophobic cover layer, which is optionally linked to the mucoadhesive layer via a separate bonding layer.
  • the hydrophilic layer contains ambroxol or one of its pharmaceutically acceptable salts, for example in a concentration range of 1% to 50% (w / w), preferably from 5% to 40% (w / w), more preferably from 10% to 30% (w / w) ambroxol, based on the total weight of the dried hydrophilic Layer.
  • the hydrophilic mucoadhesive layer contains one or more natural, semi-synthetic or synthetic hydrocolloid polymers and optionally one or more
  • the overcoat layer comprises a natural, semi-synthetic or synthetic film-forming compound which is insoluble or poorly soluble in water and has lower mucoadhesive properties than the hydrocolloid polymer in the hydrophilic layer, preferably from the group of polyacrylates and cellulose derivatives.
  • the topcoat further contains one or more plasticizers and optionally flavors, perfumes, sweeteners and dyes.
  • the film-forming component can be used in the form of an aqueous dispersion which contains further additives for stabilizing the dispersion and / or promoting film formation, for example surfactants, preservatives or defoamers.
  • the topcoat may contain separately prepared and pharmaceutically acceptable plastic materials, for example, polyethylene, polyethylene terephthalate, polypropylene, and / or polyvinyl chloride.
  • the mucoadhesive patch may further include a tie layer for attachment of the functional layers.
  • the tie layer comprises a polymer having suitable adhesiveness and optionally plasticizers, dyes and other adjuvants affecting adhesiveness and / or flexibility.
  • Hydrocolloid polymers are compounds selected from the group consisting of mucoadhesive cellulose derivatives, for example methylcellulose (MC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), methylethylcellulose (MEC), gelatin, soluble Starch and its pharmacologically acceptable derivatives, pectin, tragacanth, alginic acid and its pharmaceutically acceptable salts, guar gum, karaya gum, poly (ethylene oxide), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyvinyl acetate, polyvinyl alkyl ether co-maleic anhydride and its pharmacologically acceptable salts, polyacrylates, crosslinked acrylic polymers, poly (hydroxyethyl) methacrylate, poly (hydroxypropyl) methacrylate, poly (hydroxypropylmethyl) methacrylate, and mixtures of these compounds
  • Regenerated cellulose cellophane
  • hydrophobic cellulose derivatives for example hydroxypropylcellulose (HPC), ethylcellulose (EC) or cellulose acetate
  • polyacrylates polymethacrylates, poly (hydroxyethyl) methacrylate, poly (hydroxypropyl) methacrylate or poly (hydroxypropylmethyl) methacrylate can be used as the film-forming compounds.
  • plasticizers it is possible to use phthalates, for example dibutyl phthalate, sebacates, for example dibutyl sebacate, adipates, for example dibutyl adipate, polyols, for example alkylene glycols, glycerol or polyethylene glycol, sugar alcohols, for example sorbitol or maltitol, triacetin or triethyl citrate.
  • phthalates for example dibutyl phthalate
  • sebacates for example dibutyl sebacate
  • adipates for example dibutyl adipate
  • polyols for example alkylene glycols, glycerol or polyethylene glycol
  • sugar alcohols for example sorbitol or maltitol, triacetin or triethyl citrate.
  • the polymeric binder can be selected from agarose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylate, polymethacrylate, poly (hydroxyethyl) methacrylate, poly (hydroxypropyl) methacrylate or poly (hydroxypropylmethyl) methacrylate, as well as cellulose derivatives, for example methylcellulose (MC), carboxymethylcellulose (CMC) or hydroxypropylmethylcellulose (HPMC ) consist.
  • MC methylcellulose
  • CMC carboxymethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • Suitable pH regulators and permeation enhancers are compounds as described under hydrophilic ointments, pastes, creams and lotions, below.
  • solubilizers, flavorings, dyes, sweeteners and preservatives used according to the invention are pharmaceutically acceptable excipients.
  • the mucoadhesive tablets according to the invention contain ambroxol or one of its pharmaceutically acceptable salts in a concentration of 0.1% to 30% (w / w), preferably 1% to 20% (w / w) ambroxol. Furthermore, they contain at least one mucoadhesive polymer and optionally further auxiliaries, for example binders, fillers, flow agents and lubricants. Optionally, they may contain pH regulators and / or permeation enhancers. Furthermore, perfumes, flavors, sweeteners and / or dyes may be added.
  • Suitable mucoadhesive polymers according to the invention are cellulose or derivatives thereof, preferably nonionic cellulose derivatives, for example methylcellulose (MC),
  • Carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose
  • HEC hydroxypropylmethylcellulose
  • MEC methylethylcellulose
  • polyvinylalkylether-co-maleic anhydride or its salts
  • gelatin pectin
  • PEG polyethylene glycol
  • PVA polyvinyl alcohol
  • PVP polyvinylpyrrolidone
  • polyvinylacetate tragacanth
  • carrageenan xanthan
  • Chitosan chitosan chloride
  • agarose agar agar, alginic acid or its salts
  • poloxamers starch, starch derivatives, guar gum, galactomannan, polyacrylate, polymethacrylate, poly (hydroxyethyl) methacrylate, poly (hydroxypropyl) methacrylate or poly (hydroxypropylmethyl) methacrylate.
  • binders and fillers used are pharmaceutically acceptable auxiliaries, for example starch or starch derivatives, cellulose or derivatives thereof, dextrin, tragacanth, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, sugars such as sucrose or lactose, sugar alcohols or calcium phosphates.
  • auxiliaries for example starch or starch derivatives, cellulose or derivatives thereof, dextrin, tragacanth, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, sugars such as sucrose or lactose, sugar alcohols or calcium phosphates.
  • Plasticizers and lubricants are preferably selected from pharmaceutically acceptable compounds selected from the group consisting of talc, colloidal silica, stearic acid or its salts, fats, for example glyceryl tribehenate, waxes, polyethylene glycols and fumaric acid.
  • the flavorings, dyes and sweeteners used according to the invention are pharmaceutically acceptable excipients.
  • Suitable pH regulators and permeation enhancers are compounds as described under hydrophilic ointments, pastes, creams and lotions, below.
  • the ointments, pastes and suppositories according to the invention consist of a lipophilic base in which ambroxol or one of its pharmaceutically acceptable salts is dissolved or dispersed.
  • they may contain pharmaceutically acceptable hydrocolloids. They may also contain pharmaceutically acceptable fragrances, sweeteners, colorants, permeation enhancers, as well as preservatives and / or antioxidants.
  • the lipophilic base is selected from the group consisting of synthetic or natural hydrocarbons, for example paraffins, polyethylenes or Vaselingelen, from vegetable or animal oils or fats, hydrogenated fats, synthetic glycerides, waxes and liquid polyalkylsiloxanes.
  • the pharmaceutically acceptable hydrocolloids are selected from the group consisting of cellulose and derivatives thereof, preferably nonionic and mucoadhesive derivatives, for example methylcellulose (MC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) and Methylethylcellulose (MEC), from poly (alkyl vinyl ether maleic anhydride) and its salts, gelatin, pectin, poly (ethylene oxide), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), tragacanth, carrageenan, xanthan, chitosan, chitosan chloride , Agarose, agar-agar, alginic acid and its salts, poloxamer, starch, starch derivatives, guar gum, karaya gum, galactomannan, polyacrylate, polymethacrylate, poly (hydroxyethyl
  • antioxidants and permeation enhancers those listed among the following hydrophilic ointments, pastes, creams and lotions are suitable.
  • Hydrophilic ointments Hydrophilic ointments, pastes, creams and lotions
  • the fiction, contemporary hydrophilic ointments, pastes, creams and lotions consist of a lipophilic base and surfactants of the type of O / W and / or W / O emulsifiers.
  • water can be contained in different amounts. Depending on the amount of water and emulsifier type, the system may be in the form of an O / W or W / O type emulsion. Products in the sense of this
  • Invention contain ambroxol or its salts in a concentration between 0.1% and 50%, preferably between 1% and 40%, more preferably in the range of 1.5% to 5% in aqueous systems and 5% to 30% in anhydrous systems ,
  • ambroxol and its pharmaceutically acceptable salts preservatives, Antioxidants, permeation enhancers, polyols, spreading agents, thickeners, dyes, flavors and fragrances and pH regulators are incorporated.
  • hydrocarbons for example white vaseline, yellow vaseline, thin and viscose paraffin, hard paraffin, microcrystalline paraffin, paraffin oil, polyethylene, squalene or perhydrosqualene,
  • Glycerides for example, partial glycerides, polyglycerides, mono-, di- or triglycerides, fatty acids, for example stearic acid, palmitic acid or oleic acid,
  • Fatty oils of vegetable origin for example borage seed, safflower, peanut, coconut or maize germ oil, fatty oils (of semi) synthetic origin such as medium chain triglycerides,
  • Fats and hardened glycerides of vegetable origin for example hardened peanut oil, castor oil or cocoa butter,
  • Fats of animal origin for example lard, or fats of semi-synthetic origin, such as hard fat or shea butter,
  • Waxes of natural and synthetic origin for example yellow wax, bleached wax, microcrystalline wax, beeswax, cetyl palmitate or its derivatives, preferably acetylated wax, polyethylene wax, cetyl ester wax or GHG wax,
  • Resins for example rosin, or
  • Silicones for example, silicone oil, dimethicone, simethicone or cyclomethicone.
  • auxiliaries can be used as surface-active substances:
  • anionic emulsifiers for example alkali stearate, preferably potassium stearate or metal stearate, preferably aluminum monostearate, amine soaps, preferably triethanolamine or triethanolamine lauryl sulfate, and alkyl sulfates, preferably sodium dodecyl sulfate,
  • cationic emulsifiers for example quaternary ammonium compounds, preferably benzalkonium chloride or cetylpyridinium chloride, amphoteric emulsifiers, for example natural or synthetic phospholipids, in particular lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglyceride, phosphatidylinositol, phosphatidylserine or sphingomyeline or betaine nonionic emulsifiers, for example higher fatty alcohols, preferably cetyl alcohol, stearyl alcohol or cetylstearyl alcohol, partial esters of polyhydric alcohols, preferably ethylene / propylene glycol fatty acid esters , particularly preferably ethylene glycol monostearate, distearate or propylene glycol, glycerol, preferably glycerol monopalmitate, Glyceroldipalmitat, Glyceroltripalmitat
  • Suitable preservatives according to the invention are: alcohols and phenols, such as ethanol, isopropanol, benzyl alcohol, chlorobutanol, phenylethyl alcohol, phenoxyethanol, phenol, chlorocresol, thymol or triclosan, Carboxylic acids and their salts, such as benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, PHB esters (4-hydroxybenzoic acid esters), preferably methyl 4-hydroxybenzoate, ethyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate or butyl 4-hydroxybenzoate and their sodium compounds, Nitrogen compounds such as benzalkonium chloride, chlorhexidine gluconate, pyrithione zinc or cisyl (3-chloroallyl-3,5,7-triaza-1-azonia-adamatanchlorid, or
  • Antioxidants are natural antioxidants such as ascorbic acid, salicylic acid or - tocopherol, semi-synthetic antioxidants such as ascorbic acid or gallic acid esters, especially palmitoyl ascorbic acid or propyl gallate, synthetic antioxidants such as butylated hydroxyanisole, butylhydroxytoluene or sulfites, in particular sodium bisulfite, complexing agents such as editic acid or sodium EDTA, and mixtures of two or more of said antioxidants, according to the invention suitable.
  • natural antioxidants such as ascorbic acid, salicylic acid or - tocopherol
  • semi-synthetic antioxidants such as ascorbic acid or gallic acid esters, especially palmitoyl ascorbic acid or propyl gallate
  • synthetic antioxidants such as butylated hydroxyanisole, butylhydroxytoluene or sulfites, in particular sodium bisulfite
  • complexing agents such as editic acid or sodium EDTA, and mixtures
  • Glycerol sugar alcohols such as sorbitol, mannitol, maltitol or isomalt are used as polyols.
  • Ethylene glycol, propylene glycol, hexylene glycol or polyethylene glycols suitable according to the invention are Ethylene glycol, propylene glycol, hexylene glycol or polyethylene glycols suitable according to the invention.
  • Myristyl myristate, isopropyl myristate, isopropyl palmitate, isopropyllanoate, diisopropyl adipate and dibutyl adipate are suitable according to the invention as spreading agents.
  • pH regulators are acids such as acetic acid, tartaric acid, citric acid, lactic acid, hydrochloric acid, sulfuric acid or phosphoric acid, bases such as ammonia, sodium hydroxide, potassium hydroxide, lithium hydroxide, aluminum hydroxide or trometamol and salts such as sodium bicarbonate, Natriummonohydrogenphophat, Natriumdihydrogenphophat, Kaliummonohydrogenphophat, potassium dihydrogen phosphate, sodium chloride, sodium citrate Sodium oxalate, sodium lactate, calcium lactate, magnesium sulfate, ammonium monohydrogen citrate or diammonium hydrogen citrate are suitable according to the invention.
  • permeation enhancers are urea, dimethyl sulfoxide, hyaluronic acid sodium salt, alkanols such as lauryl alcohol or oleyl alcohol, alkanoic acids such as oleic acid, 1-dodecylazacycloheptan-2-one, ethylene glycol, propylene glycol or menthol, and other permeation enhancers from the material groups of 1-acylglycosides, 1-acyl-polyoxyethylenes, 1-acyl-saccharides, 2-n-acyl-cyclohexanones, 2-n-acyl-1,3-dioxolanes (SEPA), 1,2,3-triacyl-glycerols, 1 Alkanols, 1-alkanoic acids, 1-alkyl-acetates, 1-alkyl-amines, 1-alkyl-n-alkyl-polyoxyethylenes, 1-alkyl-alkylates, n-alkyl-beta-D-thio
  • flavoring agents, dyes and fragrances used according to the invention are pharmaceutically acceptable excipients.
  • Pens for the purposes of this invention contain 0.1% to 50% (w / w), preferably 1% to 45% (w / w) and more preferably 2% to 40% (w / w) ambroxol or its pharmaceutically usable salts. In addition, they contain 4% to 8% (w / w) sodium soaps, especially sodium soaps of palmitic acid, stearic acid, stearic acid amides and stearic monoethanolamines and
  • Ethanol, isopropanol and / or water in varying proportions by weight may also be in a base consisting of one or more
  • Polyethylene glycols of different chain lengths are processed in the form of a pen.
  • emulsifiers preservatives, antioxidants, spreading agents, polyols, permeation enhancers and perfumes may be included. From the groups mentioned adjuvants, as described above under “Hydrophilic ointments, pastes, creams and lotions", can be selected.
  • formulations according to the invention can be prepared by methods known from the literature.
  • Example 1 The formulations of the invention are to be illustrated by the following examples. The examples are illustrative and not limiting. Examples: Example 1
  • the non-swelling content substances are dissolved in water.
  • the gel-forming components are added and allowed to swell.
  • the mixture is stirred gently to form a homogeneous solution or a homogeneous gel.
  • the ingredients are dissolved in a suitable solvent, for example isopropanol and / or water, and poured onto a suitable non-stick backing to form a film of the desired layer thickness and allowed to dry.
  • a suitable solvent for example isopropanol and / or water
  • the HydrokoUoid Har and the cover layer can be prepared separately and adhered to each other with the binder solution, or the layers can be cast directly onto each other.
  • the HydrokoUoid harsh was poured so that their basis weight after drying was about 0.02 g / cm.
  • the topcoat had about 0.015 g / cm 2 in Example 5 and 0.06 g / cm 2 in Example 6. 0.02 g / cm 2 was used for the tie layer.
  • the layer thicknesses can vary, so that the dosage per unit area and the technological properties of the film, such as adhesiveness or flexibility, are optimally adaptable.
  • the ingredients are mixed and pressed as tablets of the desired shape, preferably flat flat or slightly convex to a thickness of about 0.5 to 2 mm, on a tableting machine.
  • the hard fat is melted in a water bath.
  • Ambroxol HCl is suspended in the molten base, poured into a suitable mold, and allowed to cool until the suppositories harden.
  • Example 13 White vaseline, medium-chain triglycerides, cetyl alcohol and glycerol monostearate are melted in a water bath. Purified water, propylene glycol and polyethylene glycol 100-glycerol monostearate are mixed and heated to about the temperature of the oily phase. Ambroxol HCl is dissolved in the aqueous mixture. The hydrophilic phase is then added to the lipophilic phase. The mixture is stirred until cold.
  • Polyethylene glycol 1000 and polyethylene glycol 600 are melted in a water bath, ambroxol HCl is suspended therein and the solution is poured into a suitable mold.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Emergency Medicine (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP05739626A 2004-05-03 2005-04-22 Topische zubereitung enthaltend ambroxol Withdrawn EP1744738A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004021992A DE102004021992A1 (de) 2004-05-03 2004-05-03 Topische Zubereitung enthaltend Ambroxol
PCT/EP2005/004343 WO2005107732A1 (de) 2004-05-03 2005-04-22 Topische zubereitung enthaltend ambroxol

Publications (1)

Publication Number Publication Date
EP1744738A1 true EP1744738A1 (de) 2007-01-24

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MXPA06012655A (es) 2007-01-16
ECSP066970A (es) 2006-12-29
AR049036A1 (es) 2006-06-21
UA87841C2 (ru) 2009-08-25
BRPI0510600A (pt) 2007-10-30
AU2005239809A1 (en) 2005-11-17
RU2381794C2 (ru) 2010-02-20
DE102004021992A1 (de) 2005-11-24
CN1950076A (zh) 2007-04-18
TW200603787A (en) 2006-02-01
JP2007536296A (ja) 2007-12-13
RU2006142735A (ru) 2008-06-20
IL178975A0 (en) 2007-03-08
US20050266058A1 (en) 2005-12-01
PE20060214A1 (es) 2006-04-26
ZA200608017B (en) 2008-07-30
MD4093B1 (ro) 2011-02-28
KR20070005020A (ko) 2007-01-09
CA2565183A1 (en) 2005-11-17
SG152257A1 (en) 2009-05-29
WO2005107732A1 (de) 2005-11-17

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