Water-soluble instantly wettable film or layer for use in oral administration

The present invention relates to a preparation for use in the mouth, in the form of a mucoadhesive film or layer, comprising pharmaceutical active substances and / or breath freshening substances. The carrier is a water-soluble polymer in combination with certain ingredients and has a therapeutic and / or cosmetic effect. The film is created using existing technologies and dried. The membrane exhibits immediate wettability, followed by dissolution / decomposition after oral administration.

Mucosal adhesive (mucoadhesive) dispensing systems are known for use in the mouth, allowing delivery of therapeutic and / or cosmetic active substances to the oral mucosa. U.S. Pat. No. 5,047,244 describes a support

190 376 adhesive for the oral mucosa, intended for the controlled administration of the active therapeutic substance through the mucosa, containing an anhydrous but hydrolysable polymer matrix and amorphous silicon dioxide.

Alternatively, a water-insoluble film with a non-stick surface can also be used. WO 91/06270 discloses a three-layer membrane for sustained release of the active substance in the oral cavity.

U.S. Pat. No. 4,876,092 discloses a flat adhesive formulation having an adhesive layer containing certain water-soluble and water-insoluble polymers, and a water-insoluble carrier, adhering to the oral mucosa and releasing the active substance into the mouth.

All the above-mentioned preparations are not completely water-soluble and remain in the oral cavity after reaching the therapeutic goal, and as a result, patients feel a certain disgust, mainly caused by the carrier layer leaving the insoluble part in the mouth.

A number of attempts have been made to introduce soft membrane carriers to reduce the unpleasant sensation in the mouth caused by the rigidity and insufficient elasticity of the carrier layer. EP 0 200 508 and EP 381 194 propose the use as soft carriers of polyethylene films, polyvinyl acetate, ethylene vinyl acetate copolymers, metal foils, laminates of material or paper with a plastic coating, and similar materials, with preferred materials being are synthetic resins such as polyethylene, vinyl acetate homopolymer, and ethylene vinyl acetate copolymer.

Patent description CA 1 263 312 discloses the use of polyolefins such as polyethylene, polypropylene, polyesters, PVC as well as nonwovens as soft carrier materials.

However, these materials leave patients with a significant amount of water-insoluble residue in the carrier membrane, with the result that there is always a feeling of distaste. The emerging solution to this problem was the development of mucosal membranes that completely break down or dissolve in saliva. DE 24 49 865 describes homogeneous, water-soluble membranes for buccal introduction of hormones. The use of water-soluble cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose or methyl hydroxypropyl cellulose as film-forming substances has been proposed.

DE 36 30 603 and EP 0 219 762 disclose the use of swellable polymers, such as gelatin and corn starch, as film-forming substances that slowly degrade in the oral cavity with the release of the active substance contained in this membrane. According to EP 0 452 446, such polymers can also be used for the preparation of dental care membranes. However, these preparations also cause an unpleasant mouth feel, especially due to their initial stiffness and prolonged softening time. Thus, there is a need for a composition for use in the mouth that provides a pleasant mouth feel.

Surprisingly, it was found that a formulation with the desired properties was obtained by using certain surfactants.

Thus, the invention relates to a preparation for use in the oral cavity, in the form of a mucoadhesive film or layer having immediate wettability, and which dissolves or disintegrates in the mouth, which film or layer comprises a homogeneous mixture of at least one water-soluble polymer, a mixture of nonionic surface substances active at least one polyalcohol, at least one cosmetic or pharmaceutical active substance and at least one flavoring or aroma substance, and one or more plasticizers as optional ingredients, wherein the preparation is characterized in that it contains a mixture of non-ionic surfactants consisting of two ingredients, where the first component is a polyoxyethylene sorbitan fatty acid ester or <x-hydroxy-cTihydroxypolyoxyctylceio) -poli (okkypiOpyicno) -poll (oxyethylene) block copolymer,

190 376 and the second component is polyoxyethylene alkyl ether or polyoxyethylene castor oil, the ratio of the first component to the second component in this binary surfactant mixture is 1:10 to 1: 1.

Preferably, the preparation according to the invention contains hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth, acrylic gum, polyacrylate, acanthate, polyacrylate, acanthate, gum, acanthate, polyacrylate, gum carboxyvinyl copolymers or mixtures thereof.

Preferably, the concentration of the water-soluble polymer in the dry weight of the film layer is 20-75% by weight.

The formulation according to the invention preferably contains a polyalcohol selected from glycerin, polyethylene glycol, propylene glycol and fatty acid glycerol monoester.

A preferred formulation according to the invention contains a therapeutic active substance selected from the group consisting of sleeping pills, sedatives, anti-epileptics, stimulants, psychoneurotropic agents, neuromuscular blockers, spasmolytics, antihistamines, antiallergic agents, cardiac agents, antiarrhythmics, diuretics, hypotension agents. , vasopressors, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetic agents, active substances with anti-cancer effect, antibiotics as well as chemotherapeutics and drugs.

The formulation of the invention as the cosmetic active ingredient preferably contains breath fresheners such as menthol, flavors, aromatics or fragrances, typically used in oral hygiene, and / or oral and / or oral care active ingredients, such as quaternary ammonium bases.

The effect of flavors or flavors may be enhanced by taste enhancers such as tartaric acid, citric acid, vanillin or the like.

The formulations according to the invention are convenient to use, since the unpleasant sensation after application to the oral mucosa of the membrane / layer exhibiting immediate wettability is avoided. In addition, due to the high tear strength of the free film, it is possible to coat easily, further process and package convenient products.

The preparation is in the form of a rapidly dissolving oral adhesive film / layer and releasing a pharmaceutical or cosmetic active substance, said film / layer comprising water-soluble polymers, one or more polyalcohols and one or more pharmaceutical or cosmetic active substances. The formulation may optionally contain a number of specific plasticizers or surfactants, dyes, sweeteners, flavors, flavor enhancers or other property correctors that are typically used to modify the taste of preparations intended for use in the oral cavity. The membrane formed from these ingredients is characterized by immediate wettability, thanks to which the membrane softens immediately after application to the mucosa, which prevents unpleasant sensation in the mouth for longer. Such a film also has a tear resistance suitable for coating, cutting, cutting and packaging operations.

The preparation according to the invention in the form of a mucoadhesive film as the main components comprises a water-soluble polymer or series of water-soluble polymers, one or more plasticizers or surfactants, one or more polyalcohols and a pharmaceutical or cosmetic active substance.

The polymers used in the mucoadhesive film are hydrophilic and / or water dispersible polymers. Preferred polymers are water-soluble cellulose derivatives, especially those mentioned above, alone or in a mixture. Other types of polymers may also be used, including e.g. water dispersible polyacrylates. The concentration of the water-soluble polymer in the finished film can be 20-75% by weight. The preferred concentration is 50-75% by weight.

190 376

The mucoadhesive membrane may contain one or more nonionic surfactants, the essential ingredients being polyoxyethylene sorbitan fatty acid ester or α-hydro- <o-hydroxypols (ethoxy) -poli (propoxy) -poli (ethoxy) block polymer and ether polyoxyethylene alkyl or polyoxyethylene castor oil.

Preferably the HLB value of the fatty acid polyoxyethylene sorbitan ester should be 10-20, with a range of 13-17 being particularly preferred. Α-hydro-o-hydroxypols (oxyethylene) -poli (oxypropylene) -poli (oxyethylene) block copolymer should contain at least 35 oxypropylene units, preferably at least 50 oxypropylene units.

The HLB value of polyoxyethylene alkyl ether should be 10-20, preferably not less than 15. The HLB value of polyoxyethylene castor oil should be 14-16.

To achieve the desired immediate wettability, the ratio of the first component to the second component of the binary surfactant mixture should be kept in the range from 1:10 to 1: 1, preferably from 1: 5 to 1: 3.

The concentration of all surfactants in the finished film depends on the properties of the other ingredients, but should usually be 0.1-5% by weight.

Polyalcohol is needed to achieve the desired degree of membrane softening. In addition to the above-mentioned preferred polyalcohols, other pharmaceutical polyalcohols may be useful. The dry film concentration of polyalcohol is usually 0.1-5% by weight.

The membrane is particularly well suited for delivering a wide group of pharmaceutically active substances through the patient's mucosa, in particular through the buccal mucosa.

Particularly suitable therapeutic active substances are difficult to absorb because of limited solubility, degradation in the gastrointestinal tract or extensive metabolism. Preferable examples of possible therapeutic active ingredients are listed above. The amount of active substance introduced into the film depends on the nature of the substance and is usually 0.01-20% by weight, however this amount may be higher if it is necessary to achieve the desired effect.

Dyes, possibly added to the membrane, must be safe in terms of toxicity and should be approved by the appropriate authority for use in cosmetics.

The preparation according to the invention in the form of a mucoadhesive film can be prepared in the following manner.

The polyalcohol, surfactants, plasticizer and other optional ingredients, in addition to the water-soluble or water-dispersible at least one polymer, are dissolved in a sufficient amount of a suitable solvent. Examples of a suitable solvent are water, alcohols or mixtures thereof. After the formation of a clear solution with continuous stirring and, if necessary, heating, water-dispersible polymer or a mixture of water-dispersible polymers is slowly added until a clear and homogeneous solution is formed. This solution is applied to the carrier and dried, resulting in a film. The support material must have a surface tension such that it is possible to evenly distribute the polymer solution over the intended width of the coating, without sucking in the solution and creating a destructive bond between the support and the coating

Examples of such suitable material are non-silicone polyethylene terephthalate membranes, non-silicone kraft paper, polyethylene impregnated kraft paper or non-silicone polyethylene film.

The solution can be applied to the carrier material using any device usually used for this purpose. A particularly preferred method is application in a roller coater with a squeegee.

The thickness of the produced film layer depends on the concentration of solids in the applied solution and the width of the gap in the coater and can vary in the range of 5 - 200 pm. Drying is carried out in a stream of hot air in drying ovens, tunnel driers, vacuum driers and other suitable drying devices that do not adversely affect the action of the active substance (s) or flavors. To reliably avoid unpleasant sensations in the mouth,

190 376 the thickness of the coating should not exceed 70 pm. For ease of use, the film can be cut into pieces of the right size and shape and packaged properly.

The invention is illustrated by the following examples.

Example 1 g sorbitol, 6 g glycerin, 0.5 g polysorbate 80 (Tween 80), 2 g Brij 35 (polyoxyethylene monolauryl ether), 25 g lemon mint flavor, 3 g aspartame, 15 g 1-menthol and 3 g acid lemon mixture in a mixture of 250 g water and 250 g ethanol was stirred at 60 ° C until a clear solution was formed.

While stirring, 30 g of hydroxypropyl methylcellulose was slowly added to the solution until a clear and homogeneous solution was formed. The resulting solution was cooled to room temperature and was applied to a suitable support material, e.g., unsilted, polyethylene-coated kraft paper, using a conventional coating and drying device. The coating gap and belt speed were adjusted to obtain a dry film thickness of 20-50 pm. The drying temperature depends on the length of the drying oven and the material speed, and should be set to completely or at least largely remove the solvent from the film. The resulting film was separated from the carrier and divided into pieces of suitable size and shape for use.

Example 2 g sorbitol, 1.5 g collidone 30 (BAS supplier), 5 g glycerin, 5 g propylene glycol, 5 g polyethylene glycol, 4 g polysorbate 80 (Tween 80), 8 g Brij 35, 12 g peppermint aroma and 0.8 g of aspartame was dissolved in a mixture of 400 g water and 400 g ethanol at 60 ° C and under stirring. With continued stirring, 28 g of hydroxypropyl methylcellulose was slowly added to the clear solution. After the polymer had completely dissolved, the solution was cooled to room temperature and applied to the support under the same coating and drying conditions as in Example 1. The dried film was again divided into pieces of suitable size and shape.

Example 3 g sorbitol, 22.5 g glycerin, 2.5 g propylene glycol, 2.5 g Brij 35, 2.5 g poloxamer 407. 3.5 g cremophore RH 40, 9 g mint aroma and 0.5 g aspartame dissolved in a mixture of 250 g water and 250 g ethanol, at 60 ° and under stirring. With continued stirring, 75 g of hydroxypropyl cellulose was slowly added to the clear solution. The clear solution was applied to the carrier and dried under the conditions described in Example 1. The dried film was divided into pieces of suitable size and shape.

Example 4

3.6 g of Tween 80, 3.6 g of glycerin, 39 g of menthol and 171 g of collidone were dissolved in a solution of 600 ml of water and 2800 ml of ethanol at room temperature and under stirring. Then 247.5 g hydroxypropyl methylcellulose was slowly added portionwise at 50-55 ° C; the solution was stirred until the added substance completely dissolved. After cooling the mixture, 90 g of lemon-mint aroma was successively added with stirring, followed by a solution / suspension of 27.13 g of aspartame, 18 g of citric acid and 0.17 g of FD&C yellow # 5 in 120 ml of water. The clear solution was applied to the carrier and dried under the conditions given in Example 1. The dried film was divided into pieces of a size and shape appropriate for the intended application.

Example 5

165.4 g collidone 30 were dissolved in a solution of 720 ml water and 2660 ml ethanol, at room temperature and with stirring. Then 220.5 g of hydroxypropyl methylcellulose was added at 50-55 ° C and the mixture was vigorously stirred until a clear and homogeneous solution was formed. After cooling the mixture, 78.75 g of flavor was successively added with stirring, followed by a mixture of 26.88 g of nicotine salicylate and 31.5 g of liquid caramel in 120 ml of water. The clear, yellow-brown liquid was applied to the carrier and dried under the conditions described in Example 1. The dried film was divided into pieces of suitable size and shape, each of which allows nicotine to be administered at a dose of 1-2 mg.

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