EP1744738A1

EP1744738A1 - Topical preparation containing ambroxol

Info

Publication number: EP1744738A1
Application number: EP05739626A
Authority: EP
Inventors: Anke Esperester; Frieder Ulrich Maerz; Claudia Mueller
Original assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim International GmbH; Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2004-05-03
Filing date: 2005-04-22
Publication date: 2007-01-24
Also published as: JP2007536296A; CA2565183A1; WO2005107732A1; DE102004021992A1; IL178975A0; ZA200608017B; TW200603787A; AR049036A1; RU2381794C2; CN1950076A; ECSP066970A; RU2006142735A; SG152257A1; KR20070005020A; MXPA06012655A; PE20060214A1; AU2005239809A1; BRPI0510600A; US20050266058A1; MD4093B1

Abstract

The invention relates to topical pharmaceutical compositions containing ambroxol or one of its pharmacologically compatible salts, preferably in the form of its hydrochloride, for direct application or for application to the skin and/or mucosa, said compositions having anti-inflammatory and local anaesthetic characteristics.

Description

Topical preparations containing ambroxol

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.

In pharmacy various basic formulations for the application of drugs to the skin and mucosa are known. For a review, common textbooks of pharmaceutical technology, e.g. U Schöffing, "Arzneiformenlehre", German Apotheker Verlag Stuttgart, 4th Edition 2003 or Gurny / Junginger, "Bioadhesion - Possibilities and Future Trends", Scientific Publishing Company Stuttgart, 1990. WO 00/38653 describes an improved formulation for the transdermal administration of corticosteroids, In addition to many other antioxidants, ambroxol is also mentioned as a suitable excipient to protect against oxidative spoilage. Ambroxol lozenges are known for the treatment of pain in the throat and throat (EP 1200070, WO 03/072094). Pharmaceutically effective formulations with ambroxol or its salts as active ingredient for direct local application to and treatment of the skin or mucosa, however, are not described in the prior art. Topical formulations of anesthetically or anti-inflammatory compounds often show side effects.

It is therefore the object of the present invention to prepare topical formulations which, in addition to good anti-inflammatory and anesthetic activity, show little or no side-effects.

Description of the invention

Surprisingly, it has been found that 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.

Preferred are topical pharmaceutical compositions wherein ambroxol is in the form of its hydrochloride.

Further preferred are 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.

Particular preference is given to 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).

Particularly preferred are 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). Most preferred are 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.

Likewise provided by 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 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.

Gels, hydrophilic pastes. Shaking mixtures and solutions

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. As 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 (hydroxyethyl), poly (hydroxypropyl) and poly (hydroxypropylmethyl) methacrylates.

Suitable inorganic gels are colloidal silicas or bentonite.

As lower alcohols in the present invention, ethanol, 1-propanol and 2-

Propanol called.

Suitable polyols are compounds selected from the group consisting of ethylene glycol, propylene glycol, glycerol and sugar alcohols, preferably glycerol, sorbitol and maltitol.

Compounds suitable as 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.

For the preparation of the above-described hydrophilic pastes or shaking mixtures, 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

Plasticizers. Furthermore, pharmaceutically acceptable auxiliaries, for example adhesion and / or flexibility influencing adjuvants, crystallization inhibitors, flavors, fragrances, sweeteners, dyes, preservatives, lower alcohols, permeation enhancers, pH regulators and / or solubilizers may be included. 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. Preferably, the topcoat further contains one or more plasticizers and optionally flavors, perfumes, sweeteners and dyes.

For the production of the cover layer, 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 with polyisobutylene.

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.

As 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.

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.

Suitable pH regulators and permeation enhancers are compounds as described under hydrophilic ointments, pastes, creams and lotions, below.

The solubilizers, flavorings, dyes, sweeteners and preservatives used according to the invention are pharmaceutically acceptable excipients.

Mucoadhesive tablets

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 (HPMC) or methylethylcellulose (MEC), polyvinylalkylether-co-maleic anhydride) or its salts, gelatin, pectin, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), 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.

The 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.

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.

Hydrophobic ointments, pastes and suppositories

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. In addition to improving mucoadhesion and / or preventing recrystallization, 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) methacrylate, poly (hydroxypropyl) methacrylate and poly (hydroxypropylmethyl) methacrylate.

As preservatives, antioxidants and permeation enhancers, those listed among the following hydrophilic ointments, pastes, creams and lotions are suitable.

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. In addition, optionally 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 , In addition to ambroxol and its pharmaceutically acceptable salts, preservatives, Antioxidants, permeation enhancers, polyols, spreading agents, thickeners, dyes, flavors and fragrances and pH regulators are incorporated.

The following pharmaceutically acceptable auxiliaries or mixtures selected therefrom are suitable as lipophilic bases: 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.

The following pharmaceutically acceptable 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, glycerol monostearate, Glycerolmonoisostearat, glycerol distearate, Glyceroldiisostearat, glycerol tristearate, Glyceroltrihydroxystearat, glycerol monooleate or glycerol dioleate, sorbitan fatty acid ester, preferably sorbitan laurate, sorbitan stearate Sorbitpalmitat, sorbitan monooleate, sorbitan sesquioleate, or sorbitan trioleate, Ethers and esters of polyethylene glycol, preferably Polyethylenglycolfettalkoholether, preferably polyethylene glycol lauryl ether, Polyethylenglycolcetylether, Polyethylenglycolstearylether, Polyethylenglycolcetylstearylether or Polyethylenglycolmyristylcetylstearylether, polyethylene glycol, preferably polyethylene glycol monolaurate, polyethylene glycol monostearate, polyethylene glycol distearate, Polyethylenglycolstearylstearat or Polyefhylenglycolricinooleat, Polyethylenglycolsorbitanfettsäureester, preferably polysorbates, Polyethylenglycolglycerolfettsäureester, preferably Polyethylenglycolglycerolmonostearat, Polyethylenglycolglyceroldistearat, Polyethylenglycolglycerolhydroxystearat, Polyethylenglycolglyceroltripalmitat, Polyethylenglycolglyceroltrilinolat, Polyethylenglycolglyceroltrioleat , Polyethylene glycol glycerol ricinoleate or polyethylene glycol glycerol coccoate, stearic alcohols, preferably cholesterol or wool wax alcohol, block copolymers of polyoxyethylene / polyoxypropylene, preferably poloxamers, wool wax or wool wax alcohols and mixtures of two or more of said emulsifiers.

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

- Propylene carbonate and mixtures of two or more of the said preservatives.

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.

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.

Myristyl myristate, isopropyl myristate, isopropyl palmitate, isopropyllanoate, diisopropyl adipate and dibutyl adipate are suitable according to the invention as spreading agents.

As 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.

As 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-thioglycosides, l-alkyl-glycerides , 1-alkyl-propylene glycols, 1-alkyl-polyoxyethylenes, 1-alkyl-2-pyrrolidones, alkyl-acetoacetates, alkylene glycols, alkylmethyl sulfoxides, alkyl propionates, alkyl sulfates, diacylsuccinates, diacyl-N, N-dimethylaminoacetates (DDAA), diacyl- N, N-dimethylaminoisoρrppionate (DDAIP) and phenylalkylamines suitable according to the invention.

As thickening agents, natural, semisynthetic polymers, synthetic

Polymers, inorganic gel-forming compounds as listed in the description of the gels and hydrophilic pastes listed above.

The flavoring agents, dyes and fragrances used according to the invention are pharmaceutically acceptable excipients.

pencils

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. Alternatively, the active ingredient 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.

Furthermore, 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.

The formulations according to the invention can be prepared by methods known from the literature.

The formulations of the invention are to be illustrated by the following examples. The examples are illustrative and not limiting. Examples: Example 1

Example 2

Example 3

Example 4

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.

Example 5

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. The HydrokoUoidschicht 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. For the above examples, the HydrokoUoidschicht 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.

Example 7

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.

Example 8

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 9

Example 10

The HydrocoUoide are mixed and introduced into the gel consisting of the polyethylene and paraffin. Ambroxol hydrochloride is suspended in this base. Example 11

White vaseline, liquid paraffin, cetostearyl alcohol and sodium cetostearyl sulfate are melted in a water bath. Ambroxol HCl is suspended therein and the mixture is stirred until cold.

Example 12

White vaseline, liquid paraffin, cetostearyl alcohol and sodium cetostearyl sulfate are melted in a water bath. Ambroxol HCl is dissolved in the heated water, added to the mixture and stirred until it cools.

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.

Example 14

Stearic acid, glycerol and sodium hydroxide are dissolved in ethanol (96%). • Ambroxol HCl is added and the solution poured into a suitable mold.

Example 15

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.

Claims

claims

1. Topical pharmaceutical compositions containing ambroxol or one of its pharmacologically acceptable salts for direct application or application to the skin and / or mucous membrane with anti-inflammatory and local anesthetic properties.

2. Topical pharmaceutical compositions according to claim 1, wherein ambroxol is in the form of its hydrochloride.

3. Topical pharmaceutical compositions according to claim 1 or 2 in the form of a formulation selected from the group consisting of gels, hydrophilic pastes, shaking mixtures and solutions.

4. Topical pharmaceutical compositions according to claim 3, characterized in that the content of ambroxol is from 0.1% to 20%.

5. Topical pharmaceutical compositions according to claim 1 or 2 in the form of a formulation selected from the group consisting of suppositories, hydrophobic pastes, ointments, creams, lotions and sticks.

6. Topical pharmaceutical compositions according to claim 1 or 2 in the form of mucoadhesive patches, Buccalstreifen or mucoadhesive tablets.

7. Topical compositions according to claim 6, characterized in that the content of ambroxol in mucoadhesive patches of 1% to 50% (w / w) based on the total mass of the hydrophilic support layer.

8. Topical compositions according to any one of claims 1 to 7, wherein the residence time of the ambroxol or one of its pharmaceutically acceptable salts on the skin and / or mucous membrane is prolonged compared to a 0, 1% ambroxol containing nonionic hydrophilic cream according to edition 2003 of the German Pharmacopoeia.

9. Use of ambroxol or one of its pharmacologically acceptable salts for the preparation of a composition according to any one of claims 1 to 7 for the topical treatment of pain, burning or itching of the skin and / or mucous membrane.

10. Use of ambroxol or one of its pharmacologically acceptable salts for the preparation of a composition according to any one of claims 1 to 7 for the topical treatment of inflammation.

11. Use of ambroxol or one of its pharmacologically acceptable salts for the preparation of a composition according to any one of claims 1 to 7 for the topical treatment of conditions selected from the group consisting of painful or itchy mouth sores, burning or itching inflammations in the vaginal area, mosquito bites, reddening of the skin allergic, immunological or idiopathic origin and itchy or burning hemorrhoids.