Immediate wettability water soluble film or water soluble layer for oral application

The present invention discloses a preparation pharmaceutical active ingredients and / or the breathing refreshing contain active ingredients, for use in the oral cavity. Of the Carrier comprises water-soluble polymers in combination with certain ingredients and has a therapeutic and / or cosmetic effect. The film will be using brushed existing coating technologies and dried and has an instant wettability, followed by rapid dissolution / degradation in application in the oral cavity.

which adhere to the mucosa (mucoadhesive) Dosing for use in the oral cavity, with which therapeutic discharged and / or cosmetic active substances to the oral mucosa to be, known in the art. US Patent 5,047,244 describes an on the oral mucosa adherent support for the controlled delivery of a the therapeutic agent through the mucosal tissue, of an anhydrous but hydratable polymer matrix and amorphous silica. Optionally, a water-insoluble film are attached, to the surface to make non-adhesive. WO 91/06270 of the same inventor discloses a three-layer film for prolonged release of an active The active ingredient in the oral cavity. Similarly, US 4,876,092 discloses a sheet-like, adhesive composition comprising an adhesive layer, which certain water-soluble and water-insoluble polymers and contains a water-insoluble carrier, which at the oral mucosa adhere and thereby an active ingredient write to the oral cavity.

All of these aforementioned devices are not completely water soluble and remain in the oral cavity, even to achieve goal, and prepare the Patient some discomfort in the mouth, mainly is caused by the carrier layer containing a insoluble Residue in the mouth leaves.

A series of experiments was undertaken to the uneasy reduce feeling in the oral cavity, which by the causes rigidity and inflexibility of the support layer was by introducing soft film supports. The Documents EP 0200508 and EP 0381194 suggest the use of polyethylene films, polyvinyl acetate, ethylene-vinyl acetate copolymers, Metal foils, laminates of cloth or paper and a plastic film, and similar materials as soft modes, in which synthetic resins such as polyethylene, Vinyl acetate homopolymers and ethylene-vinyl acetate preferred materials are. Similarly, CA 1,263,312 discloses the use of Polyolefins such as polyethylene, polypropylene, polyester, PVC, and nonwoven fabrics as soft support materials. Nevertheless leave this to the patient a considerable Amount of residues of water-insoluble support film and therefore still cause an uncomfortable feeling. An obvious solution to overcome this problem was the development of mucosa-adhesive films, which completely disintegrate or dissolve in saliva. Fuchs and Hilmann (DE 24 49 865.5) prepared homogeneous, water-soluble Films for buccal delivery of hormones ago. They proposed the use of water-soluble cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose or methylhydroxypropylcellulose ago as film formers.

The two patents DE 36 30 603 and EP 0219762 disclose the use of swellable polymers such as gelatin or corn starch as film formers, which after application slowly disintegrate in the oral cavity, while a release active agent which included in the film is. The same polymers can also be used, to produce films, which are intended for dental care, as described in EP 0 452 446. You However, these preparations also call an uneasy Feeling in the mouth out, especially caused by their initial rigidity and delayed softening. From this results in a need for a composition for use in the oral cavity, which in the need for a well-being wearing mouth invoice. The present invention discloses methods and compositions, be avoided by an unpleasant feeling can, by providing an / an immediate Wettability having film / layer for application to the oral mucosa, and by a tensile strength in -free film is obtained which has a trouble-free coating, Processing and packaging of a consumer-friendly Product allows.

The present invention relates to a / a faster-acting (n) Film / layer of / adhered to the oral cavity while a pharmaceutical or cosmetic active ingredient emits, wherein the film / the layer water-soluble polymers, one or more polyols and one or more pharmaceutically or cosmetic active ingredients contains. Optionally, the formulation is a combination of certain plasticizers or surfactants, Dyes, sweeteners, flavors, flavor enhancers contain or other Corrigenzien, as commonly used for modification of the taste of for application in the oral cavity certain formulations be used. The resulting film is characterized by immediate wettability which the Film immediately upon application to the mucosal tissue can soften, whereby the patient experiences a longer lasting discomfort is prevented in the mouth, and by a normal coating, cutting, Aufschneid- and packaging operations suitable tenacity.

contains the mucoadhesive film of the present invention as essential components a water-soluble polymer or a combination of water-soluble polymer, a or more plasticizers or surfactants, one or more polyols and a pharmaceutical or cosmetic active ingredient. include The polymers used for the mucoadhesive film hydrophilic and / or water-dispersible polymers. Preferred Polymers are water-soluble cellulose derivatives. Hydroxypropylmethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose are, alone or mixed, especially prefers. Examples of other, optional, polymers hereinafter, without limiting the invention: Polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, Sodium alginate, polyethylene glycol, natural gums as xanthan gum, tragacanth, guar gum, acacia resin, gum arabic, water-dispersible polyacrylates like polyacrylic acid, Methyl methacrylate copolymer, carboxyvinyl copolymers. The concentration of water-soluble polymer in the finished Film may be between 20 and 75 wt .-%. A preferred Concentration is between 50 and 75 wt .-%.

The surfactants used for the mucoadhesive film Substances, one or more nonionic surface active his materials. When using a combination of surfactants, the first component a Polyethoxysorbitan fatty acid ester or an α-hydro-ω-hydroxypoly (ethoxy) -poly (propoxy) poly (ethoxy) block copolymer be, while the second component is a Polyethoxyalkylether or a polyethoxy rizinusöld be erivat can. is preferably the HLB value of Polyethoxysorbitanfettsäurester be between 10 and 20 with a portion 13 to 17 is particularly preferred. The α-hydro-ω-hydroxypoly (ethoxy) poly (propoxy) poly (ethoxy) block copolymer should be at least 35 propoxy units, preferably at least 50 propoxy units. The Polyethoxyalkylether should have an HLB value between 10 and 20 have, preferably not less than 15. The polyethoxy castor oil should have an HLB value between 14 and 16 have. In order to achieve the desired, instant wettability, is the ratio between the first and second Component of a binary surfactant mixture between 1 held, preferably between 1: 1 and 1:10 5 and 1: 3. The total concentration of the surfactants in the final film depends on the properties of the other Ingredients, but is usually between 0.1 and 5 wt .-%, respectively. The polyol is required to provide the desired degree of softness the film through. Examples of polyalcohols include glycerol, polyethylene glycol, propylene glycol, Glycerol monoesters with fatty acids or other pharmaceutically Polyalcohols used. The concentration of polyalcohol in the dry matter of the film is usually 0.1 to 5 wt .-%.

The film is especially suitable for dispensing a wide Range of pharmaceutically active agents through the Mucosal membranes of a patient, in particular by the buccal mucosa. Therapeutic agents, absorption problems due to limited solubility, degradation in the gastrointestinal tract or have extensive metabolism, are particularly well suited. As examples of usable therapeutic agents are to be mentioned: hypnotics, sedatives, antiepileptics, waking amines, Psychoneurotropica, Neuro-muscular blockers, antispasmodics, Antihistamines, antiallergics, cardiotonics, antiarrhythmics, Diuretics, hypotensive agents, vasopressors, antitussives, Expectorants, thyroid hormones, sex hormones, antidiabetics, Antitumor agents, antibiotics and chemotherapeutics and narcotics. The Be Stored in the amount of film of active ingredient depends on their type and is usually , Between 0.01 and 20 wt .-%, it can, however, if to achieve the desired effect required higher lie.

Cosmetic agents include breath fresheners such as menthol, other flavors, aromas or fragrances, as they are commonly be used for oral hygiene, and / or Agents for dental care and / or oral hygiene, for example, quaternary ammonium bases. The effect of flavors and flavorings, by flavor enhancers such as tartaric acid, Citric acid, vanillin, or the like reinforced will. Dyes which are optionally added to the film, must be safe toxicity and should for Use permitted in cosmetics by the competent authorities be.

The inventive mucoadhesive film may follow getting produced:

The polyalcohol, surfactants, plasticizers, and Other possible components except the / the water-soluble or water dispersible polymers with a sufficient dissolved amount of a compatible solvent. Examples a compatible solvent include water, alcohols or mixtures thereof. After a clear solution is the water-dispersible polymer or the mixture wasserdispersibler polymers slowly with stirring and, if necessary heat was added until a clear and homogeneous solution is formed. This is coated on a support and dried to a film. The support material must have a have surface tension which allows the polymer solution evenly across the intended coating width distribute without the solution is sucked and thus a destructive bond between the carrier and coating arises. Examples of suitable materials include nichtsilikonisierte Polyethylene terephthalate films, nichtsiliconisiertes Kraft paper, polyethylene-impregnated kraft paper or nichtsiliconisierten polyethylene film. The application of the solution to the support material can with any conventional device are executed. specially preferred application technique relates to a knife over roller coater. The thickness of the resulting film layer depends on the concentration the solids in the coating solution and on the gap width of the coating machine and can between 5 and 200 vary. The drying of the film is in a hot-air using a Trokkenofens, Drying tunnel, vacuum drier, or other appropriate made drying devices which effect the of / the active ingredient / active ingredients or flavorings not adversely affect results. To an unpleasant feeling reliably to avoid the mouth, to the film thickness not exceed 70 microns. For better use relief the film may be in pieces of suitable size and shape slicing and packaging.

The invention is illustrated by the following examples.

Example 1:

15 g of sorbitol, 6 g of glycerol, 0.5 g of polysorbate 80 (Tween 80) 2 g Brij 35, 25 g lemon mint flavor, 3 g of aspartame, 15 g 1-menthol and 3 g of citric acid at 60 ° C in a Mixture of 250 g of water and 250 g ethanol stirred, has formed a clear solution to be. To the solution, 30 g of hydroxypropyl methylcellulose slowly added with stirring until a clear and homogeneous formed solution. The resulting solution is then to allowed to cool to room temperature and using a conventional coating / drying device on a suitable carrier material painted on, for example, nichtsiliconisiertes polyethylene coated kraft paper. Coating gap and web speed have controlled be that a dry film thickness between 20 and 50 is achieved by. The drying temperature depends on the length the drying oven and the material speed and from should be adjusted so that the solvent completely, or at least substantially completely removed from the film will. The resulting film is detached from the support and for use in pieces of suitable size and Mold parts.

Example 2:

3 g sorbitol, 1.5 g Kollidon 30 (supplier: BASF), 5 g glycerol, 5 g propylene glycol, 5 g polyethylene glycol, 4 g polysorbate 80 (Tween 80), 8 g Brij 35, 12 g peppermint flavor, 0.8 g aspartame are g in a mixture of 400 water and 400 g of ethanol dissolved at 60 ° C with stirring. To the clear solution 28 g hydroxypropyl methylcellulose Stirring slowly added. After complete dissolution of The polymer is cooled to room temperature and the solution on a support under the same coating and Drying conditions painted as in Example 1st Of the dry film is again in pieces of a suitable size and form parts.

Example 3:

15 g sorbitol, 22.5 g glycerol, 2,5 propylene glycol, 2.5 g of Brij 35, 2.5 g poloxamer 407, 3.5 g Cremophor RH 40, 9 g Herb mint flavor, 0.5 g aspartame are under constant Stirring at 60 ° C in a mixture of 250 g of water and 250 g of ethanol. To the clear solution, 75 g of hydroxypropyl cellulose stirring constantly slowly added. The clear solution is again coated and dried under the conditions described as in Example 1; the dry film is suitably in pieces of Size and shape of parts.

Example 4:

3.6 Tween 80, 3.6 g glycerol, 39 g menthol, and 171 g Kollidon 30 are at room temperature and under stirring in a Solution of 600 ml of water and 2800 ml of ethanol. 247.5 g of hydroxypropyl methylcellulose are slowly and added in portions at 50-55 ° C; make up to complete dissolution stirred. After cooling the mixture are, as a result, 90 g lemon mint flavor followed by a Solution / suspension of 27.13 g aspartame, 18 g of citric acid and 0.17 g FD & C yellow # 5 in 120 ml of water with stirring added. The clear solution is below the example in painted and dried 1 specified conditions; the dry film into pieces for the intended Use of appropriate size and shape of parts.

Example 5:

165.4 g Kollidon 30 are at room temperature in a solution from 720 ml of water and 2660 ml of ethanol with stirring. Then, 220.5 g hydroxypropyl methylcellulose added at 55-60 ° C and stirred vigorously to the solution is clear and homogeneous. After cooling the mixture are, as a result, 78.75 g flavor followed by a Mixture of 26.88 g nicotine salicylate and 31.5 g Karamelflüssigkeit added in 120 ml water with stirring. The clear, yellowish brown liquid is among the Example brushed described conditions 1 and dried and the dry film into pieces of appropriate Size and shape parts, to deliver a dose of nicotine from 1-2 mg per piece. <sl><li>1. Preparation for application in the oral cavity with a / a at the mucosal pressure-sensitive adhesive layer or film, characterized in that the pressure-sensitive adhesive layer or the pressure-sensitive adhesive film containing a homogeneous mixture comprising of a water soluble polymer, a polyalcohol, a cosmetic or pharmaceutical active substance, and a Flavor or flavoring.</li><li>2. A preparation according to 1, characterized in that the water-soluble polymer is hydroxypropylmethylcellulose, Hydroxyethyl cellulose, hydroxypropyl cellulose, Polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, Sodium alginate, polyethylene glycol, xanthan gum, tragacanth, Guar gum, acacia resin, gum arabic, polyacrylic acid, Methyl methacrylate copolymer, carboxyvinyl copolymers or their Mixtures comprising.</li><li>3. A preparation according to 1, characterized in that the Concentration of water-soluble polymer in the dry matter the film layer is between 20 and 75 wt .-% is.</li><li>4. The preparation according to 1, characterized in that the Mix as optional ingredients one or more Plasticizers or surface-active substances.</li><li>5. A preparation according to 4, characterized in that the first Component of a mixture of surfactants one Polyethoxysorbitan fatty acid ester or an α-hydro-ω-hydroxypoly (ethoxy) poly (propoxy) poly (ethoxy) - block copolymer is.</li><li>6. A preparation according to 4, characterized in that the second A component of the surfactant Polyethoxyalkylether or Polyethoxyrizinusölderivat is. </li><li>7. A preparation according to 1, characterized in that the Polyalcohol is selected from glycerol, polyethylene glycol, Propylene glycol or glycerol monoesters with fatty acids.</li><li>8. A preparation according to 1, characterized in that the therapeutic agent is selected from the group of Hypnotics, sedatives, antiepileptics, Weckaminen, Psychoneurotropica, neuro-muscular blocking agents, antispasmodics, Antihistamines, antiallergics, cardiotonics, antiarrhythmics, Diuretics, hypotensive agents, vasopressors, antitussives, Expectorants, thyroid hormones, sex hormones, antidiabetics, Antitumor agents, antibiotics and chemotherapeutics or narcotics.</li><li>9. A preparation according to 1, characterized in that the cosmetic active breath fresheners such as menthol, flavorings, Flavoring or fragrance as commonly for oral hygiene are used, and / or active substances for dental or includes oral care, such as quaternary ammonium bases.</li></sl>