MXPA99005548A - Individually dosed foil-form presentation which decomposes rapidly on contact with liquid and contains an active substance, in particular an aromatic substance - Google Patents

Abstract

The invention concerns an individually dosed foil-form presentation which decomposes rapidly on contact with liquid and contains an active substance, in particular an aromatic substance, said aromatic substance being an inner fat-soluble phase distributed in the form of liquid droplets in an outer solid but water-soluble phase. The presentation is characterized in that the outer phase comprises at least 40%(g/g) polyvinylalcohol and between 0 and 30%(g/g) of a surfactant, and in that the proportion of the inner phase relative to the outer phase is between 0.1 and 30%(g/g), in each case relative to anhydrous portions.

Description

METHODS OF ADMINISTRATION BY LAYER MODE CONTAINING ACTIVE AND PARTICULAR SUBSTANCES CONTAINING INDIVIDUAL DOSING FLAKES AND FAST DECOMPOSITION WHEN ENTERING CONTACT WITH A LIQUID DESCRIPTION OF THE INVENTION The present invention relates to a form of administration in the form of a sheet containing active substances and in particular containing flavorings, of individual dosage and rapid decomposition when coming into contact with a liquid, in which the flavoring agent it is distributed within a solid exterior phase, soluble in water, as a liposoluble inner phase in the form of liquid droplets. The flat presentation forms to be applied in the mouth and on the oral mucous membranes and on the oral mucous membranes are already known. U.S. Patent 3,444,858 discloses medicine strips based on a gelatinous material. In the early 1970s, drugs in the form of a lamina have already been described, for example in the New England Journal of Medicine, 289, 533-535 (1973). Patent document DE 244 49 865 discloses medical active substance carriers in the form of a sheet containing different active substances and active substance concentrations. US 4,128,445 describes technical solutions for filling the support material with active substances, and in doing so deals with the subsequent addition of preparations of REF: 30589 active substance on prefabricated preparations in the form of a sheet. The filling process is described in dry and wet form with the aim of uniform subsequent distribution of active substance on a layer. In the Canadian patent application no. No. 492040 describes a process for the preparation of preparations in the form of a lamina using active substance with gelatin or agar, gluten, carboxyvinyl polymer, polyhydric alcohol, vegetable ucilago, wax or water. Application proposals are also known for laminates filled with active substance outside the field of medicines. This is described in EP 0 219 762 a water-soluble film based on starch, gelatin, glycerin or sorbitol which is coated by a roller application process. There it is mentioned that these administration forms can also be prepared containing chemical reagents, flavoring agents and the like. DE 36 30 606 envisages making a flat administration form on a support material (separation film), which can be removed between doses. There are also known systems in the form of a sheet containing medicaments, as well as their advantages, by US Pat. No. 5,047,244 with a two-layer structure based on a water-swellable layer and a water-insoluble barrier film. It is also known to use polymers such as polyethylene glycol, the use of colloidal silicon dioxide, bioadhesive polymers (for example carboxy-functional polymers) but also polyvinyl alcohol and a number of other auxiliary substances. EP 0 460 588 discloses a formulation suitable for the preparation of preparations in the form of a sheet containing flavoring. Special advantages are seen in a composition based on 20 to 60% by weight of a film-forming element, 2 to 4% by weight of a gel-forming element, 0.1 to 35% by weight of active or flavoring substances and a maximum of 40% by weight of an inert filler. As the gel-forming element, polyvinyl alcohol is mentioned among other substances. It turns out, however, that the gel-forming properties of polyvinyl alcohol are only conditionally compatible with the film-forming elements, which are cited in that writing. A proportion of 20 and more parts by weight of the film-forming element, generally a derivative of sugar, polyethylene glycol, etc. resulted in considerable loss of aroma and this even during the drying conditioned by thin layer processing. Microcapsules are known application forms for the protection of volatile or incompatible products, finely divided, wrapping them with a solid phase (for example Bauer / Frómming, Pharmazeutische Technologie, Stuttgart 1986, 563-566). In the case of microencapsulated flavors, the different drops of liquid are prepared by wrapping them, for example so that they can fall in the form of rain. These forms have already been proposed to be applied in the buccal area, for example according to US 5 286 496. In this case, however, these are intermediate products of fine granulation for the manufacture of larger final products. Also known are flat administration forms containing flavorings for application in the buccal area, by EP 0452 446, no measures are described therein on how to avoid evaporation of the flavor during its manufacture and / or storage. According to US Pat. No. 4,946,684, it has been proposed to use sugar alcohols to increase the hygrostatic stability, for forms that do not have a lamellar nature but do appear as flat, rigid, open-pored foams. According to our own knowledge, the high proportions of these additives that increase the solubility for the preparation of the flavorings give rise to significant loss of aroma. The known processes for the manufacture and production of supports in the form of flavored sheets therefore suffer from fundamental drawbacks: On the one hand, the mechanical strength is not satisfactory, in particular the resistance to bending and the tear resistance of the sheets obtained is not enough for comfortable routine applications for the user. With a softer setting, the sheets have the phenomenon of "cold creep", that is, they tend to stick together. This property is inconvenient because then the objectives are no longer usable or individually usable for the user. However, the main drawback is that the sheets according to the state of the art that contain flavors suffer considerable loss of aroma during manufacture and storage, conditioned by their structure and by the choice of auxiliary substances. These losses are due to the total quantitative loss of flavorings due to migration / diffusion through the base material and its subsequent evaporation. But at the same time, the quality of the flavor impression also changes since certain volatile components that determine the quality are preferably lost. Starting from this current level of the technique, the invention aims to offer individually dosable administration forms of the kind indicated in the general concept of claim 1, and that avoiding the aforementioned drawbacks and difficulties, present improved mechanical characteristics and some losses of minimum aroma during manufacturing and storage. The problem is solved according to the present invention according to the features of claim 1.

For them, the interior phase containing the active substance is introduced, where the aromatizing agent is present in the form of liquid droplets, in a solid but water-soluble outer phase, which according to the characterizing part of claim 1 contains parts of polyvinyl alcohol , surface-active substances and fillers, the ratio in amount of the interior phase to the exterior phase being between 0.1 and 30% by weight. In this way and with the use of important proportions of polyvinyl alcohol, the incorporation of the flavorant into the foil takes place, forming a two-phase system. The administration form according to the invention decomposes in the mouth within a maximum period of 5 minutes, then releasing all the flavors it contains, being preferably available as an aid in cosmetic, pharmaceutical and food applications. The products obtained according to the invention have surface stability, are flexible and resistant to rupture and considerably resistant to tearing. The rough surfaces that reduce the adhesion only have a low adhesion friction and practically do not present "cold creep". The objective according to the invention is normally achieved when the outer phase is composed essentially of polyvinyl alcohol and the proportion by quantity of the inner phase containing the flavorant, with respect to the outer phase, is between 0.1 and 30% (w / w) ), preferably between l and 5% (w / w), always referred to the anhydrous portions. Below a proportion of 0.1% by weight, the phases are soluble with each other, and above 30% by weight the outer phase becomes greasy and no longer allows to form film. Adding to the outer phase up to 30% (w / w) of a surfactant that can improve the uniformity of distribution of the droplets and their size that can be between less than 1 μm approx. 100 μm. Adding up to 40% (w / w) of a filling material does not cancel out the advantages according to the invention but extends the field of applications, for example also for use as dry toothpaste. Suitable for these are the silicon dioxide, titanium dioxide, calcium carbonate, calcium sulfate, talc, calcium phosphate or mixtures of these substances without the relationship being exhaustive. To improve the flavor impression, flavor enhancing substances such as sodium saccharin, other sweeteners, salt and sugar derivatives as well as low molecular weight organic acids such as for example maleic acid, adipic acid, citric acid or glutamic acid are also suitable. The products prepared in the form of a sheet preferably have a thickness between 20 and 300 μm and their size may advantageously be from 5 to 8 cm.

The polyvinyl alcohol used will advantageously be a partially hydrolyzed form in which 1% and 20% of the hydroxyl groups are substituted by acetyl groups, with 12% being especially preferred. The core of the invention is the form of the flavors contained in the base material, these substances are mainly essential oils (volatile water-insoluble distillates of aromatic components of plants) and other volatile flavoring substances which have a limited miscibility with water. As an example, mention may be made, for example, of phenylethanol as a component of the aromas of roses, menthol, camfeno and pines in fresh mint-like flavors, appetite-stimulating flavors, spice flavors such as n-butylfidade or cineole, but also medicinal flavorings such as eucalyptus oil and eucalyptus oil and thyme oil. A very wide field is occupied by the essences and / or aromas that are used as additives for food products and in the prefabricated additives for food products. Here, for example, the so-called fruit ether but also other flavorings such as ethyl vanillin can be cited as examples., 6-methylcoumarin, citronella oil or also n-butyl ester of acetic acid. The flavorings mentioned above as examples, which for the most part can be mixed with each other but not with the base substance formed by the polyvinyl alcohol or with water in any proportion, are according to the invention embedded in an encapsulated form of small drops in the base material. This state is characterized in that in an inner phase the flavorant is in the form of tiny droplets within the otherwise monolithic solid phase of the dry polyvinyl alcohol and possibly other additives. Although certainly the distribution of a liquid active substance in the form of a droplet in a solid support material has been known technically for some time, but until now it has been used exclusively in the coacerbation processes in spray drying, spray dosing and other processes resulting in final products in powder form. However, the present invention describes a state of distribution in which the outer phase is macroscopically tangible and therefore allows a simple monolithic structure of the product to be elaborated. The advantages of the product object of the invention in regard to its manufacturing technique are also evident: In this it avoids that the previous products in the form of droplets, which are sensitive to humidity are altered in their entirety during their transformation to move to a form of administration as a sheet. Intermediate phases of production of high energy consumption are also avoided. The simultaneous use of the auxiliary substance, polyvinyl alcohol, which is characterized by a particularly low diffusibility for essential oils and other flavorings, ensures both during manufacture and storage of the finished product the best possible preservation of the contained flavors and their protection for prevent dissemination outside of the administration form. Although the mechanical strength of the system is given especially by the use of polyvinyl alcohol, a proportion of up to 20% of other water-soluble polymers is innocuous for the quantity of the product object of the invention. Advantageous properties can also be achieved with a view to adjusting the mechanical characteristics of the product, by the addition of polyethylene glycol and other additional plasticizing substances. The manufacture and the transformation of the product object of the invention can be carried out following procedures known to the person skilled in the art. For this purpose, reference is particularly made to the state of the art known from EP 0 460 and DE 26 30 603. In a preferred process, a 40% (w / w) solution of polyvinyl alcohol in water is first prepared. In this phase, the previously weighed quantity of flavoring is slowly stirred. For this, a shaking movement that is very sharp must be avoided. Adjusting the temperature to less than 30-40 ° C and with relatively small additions of substances that facilitate the solution, the dissolution and evaporation of the delicate flavors is avoided. In general, the liquid mass only maintains its physical stability for a few hours, and has to spread rapidly on a support, for example a sheet material or a metal cylinder, preferably with a layer thickness of approximately 200-300 μm, letting it dry. The drying can be done in a tunnel dryer in which the temperature increases but does not exceed 80 ° C, until reaching the desired hardness for the product. If a reduced surface adhesion is desired, a matt surface can be obtained in the product by means of a coating of non-adhesive materials that roughen the surface. The two-phase structure makes it possible to surprisingly obtain a transparent to translucent appearance for the sheets that have pigments and other additives that scatter light that prevent it. The refractive indices of the light of the usual aromatizers are close to the refractive indexes of polyvinyl alcohol, whereby light scattering does not occur. However, microscopically, the dispersed state of the flavorant can be demonstrated at all times by placing the interior phase using lipophilic dyes, for example Sudan red. Example; Preparation of a method of administration according to the invention 17.0 g of polyvinyl alcohol (degree of hydrolysis 88%) are completely dissolved in 60.0 g of water with stirring at approx. 90 ° C. After cooling, 8.0 g of mint essentials are added and stirred slowly for 60 minutes. A uniformly turbid viscous mass is obtained which extends with a layer thickness of 400 μm on a 200 μm thick polyethylene terephthalate sheet. The layer is first dried for 10 minutes at room temperature and then subjected to subsequent drying at 50 ° C for 8.0 minutes. It is a clear, transparent, monolithic-looking sheet that dissolves completely in 0 seconds when adding water. After balancing for 24 hours with a relative humidity of 60%, the sheet remains stable for a radius of curvature of 1 mm. The surface is dry and can slide allowing its permanent conservation in a stacked form. After a week of unpackaged storage at 65 ° C and 60% relative humidity, the taste impression remains subjectively perfect. The invention is described in more detail below by means of a figure: In the cross section of a method of administration according to the invention, they mean: 1 - Water-soluble outer phase of the administration form in the form of a sheet.

- Liposoluble interior phase that contains the flavorings.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (10)

1. CLAIMS Having described the invention as above, it is claimed as property contained in the following claims: l.- Form of administration as a sheet containing active substances and in particular flavoring, individual dosage and rapid decomposition when coming into contact with a liquid wherein the flavorant is distributed within a solid but water-soluble outer phase, as an internal phase soluble in fat, in the form of liquid droplets, characterized in that the outer phase contains: - a minimum of 40% (w / w) of polyvinyl alcohol - or to 30% (w / w) of a surfactant, and because the proportion of the inner phase in relation to the outer phase is between 0.1 and 30% (w / w), always referred to the anhydrous parts.
2. 2. Method of administration according to claim 1, characterized in that the outer phase contains up to 40% (w / w) of a filler.
3. 3. Method of administration according to claims 1 or 2, characterized in that the ratio of the inner phase to the outer phase is between 1 and 5% (p / p) always referred to the anhydrous phase.
4. 4. Method of administration according to claim 3, characterized in that the filler material is composed of silicon dioxide, titanium dioxide, calcium carbonate, calcium sulfate, talc, calcium phosphate or mixtures of these substances.
5. 5. - Method of administration according to one or more of claims 1 to 4, characterized in that it is present as a sheet with a thickness between 20 and 300 μm.
6. 6. - Method of administration according to one or more of claims 1 to 5, characterized in that it is present as a sheet with a surface of between 0.5 and 8 cm2.
7. 7. - Method of administration according to one or more of claims 1 to 5, characterized in that it has at least one of the faces a rough surface that reduces adhesion.
8. 8. - Method of administration according to claim 1, characterized in that the polyvinyl alcohol is present in a partially hydrolyzed form in which up to 20% of the hydroxyl groups are substituted by acetyl groups.
9. 9. - Method of administration according to claim 1, characterized in that it contains up to 20% of water-soluble polymers.
10. 10. Method of administration according to claim 1, characterized in that it contains plasticizing additives.