Active ingredient support in the form of a film

CA 02339836 2001-02-07

The invention, relates to a film-shaped active substance carrier with particles of an active substance-containing substrate, which particles can be applied to the surface thereof .

Administration forms to be applied in the oral region and on the mucous membranes thereof are known.

US 3,444,858 describes medicament strips based on a gelatinlike material.

Already in 1937, film-shaped medicaments were described in the New England Journal of Medicine, volume 289, pages 533 to 535.

From DE-OS 24 49 865 are known medicinal active substance carriers in the form of films containing, side by side, different active substances and active substance concentrations.

EP 0 216 762 describes a water-soluble film of starch, gelatin, glycerin or sorbite which is coated by means of a roll coating process. It is mentioned in this connection that these administration forms can also be produced for chemical reagents, flavourings, etc.

Canadian patent application 492 040 describes a process for making film-shaped preparations using active substances, along with gelatin or agar, gluten, carboxyvinyl polymer, polyvalent alcohol, a vegetable mucilage, or wax and water. EP 0 460 588 discloses a formulation suitable for the manufacture of film-shaped systems. Here, a preparation of 20 to 60%-wt. of film former, 2 to 40%-wt. of gel former, 0.1 to 35%-wt of active substance and maximally 40%-wt. of an inert filler is of particular advantage. Among other substances, polyvinyl alcohol is mentioned as a gel former.

According to DE-OS 36 30 603 it is particularly advantageous to apply a flat-shaped dosage form to a carrier material, which is formed as a release film, in such a manner that it can be peeled off in doses.

CA 02339836 2001-02-07

US 4,128,445 and US 4,197,289 discuss possible technical solutions of loading carrier material with active substance. They describe loading processes in dry and moist environment, which aim at attaining a uniform distribution of active substances on these layers, or can be carried out making use of electrostatics.

US Re 31764 discloses a detailed description of possibilities of applying pharmaceutical active substances on flat substrates in drops. In this connection the document describes mechanisms of piezoelectrical application of active substances with the aid of electrical fields.

US 5,089,307 describes a hot-sealable, edible film based on water-soluble polysaccharides, polyvalent alcohols and water. However, only food applications but not medicinal applications are described therein.

From US 5,714,007 it is known to supply surfaces of pharmaceutical formulations with pulverulent active substances. To this end, active substance loading of planar layers is carried through by means of electrostatic charging of active substance particles, with the active substance carrier having opposite charge, said loading being controlled by voltage, polarity or duration.

US 4,851,394 describes edible films based on glucomannane and glycerin as a covering of soft capsules or as food packages which dissolve when being consumed.

US 5,232,704 discloses oral pharmaceutical forms wherein a lifting force caused by the generation of gas brought about by admission of liquid is used as a means for attaining a prolonged retention time in the stomach with the aim of achieving a prolonged duration of action.

US 5,047,244 describes film-shaped systems which, advantageously, have a two-layer structure of a waterswellable layer and a water-insoluble barrier layer. The document reports on the use of polymers such as polyethylene glycol, the use of colloidal silicon dioxide, bioadhesive,

CA 02339836 2001-02-07

e.g. carboxyfunctional, polymers, polyvinyl alcohol and other auxiliaries.

The above-described preparations, however, do not meet the below listed requirements of pharmaceutical administration forms of the kind mentioned at the outset, or they meet these requirements only in a very dissatisfactory manner. Said requirements comprise:

it must be possible to prepare the active substance preparation in an extremely accurate and in a precisely reproducible manner;

the finished administration form must contain the active substance unchangeably as to the amount and quality thereof, and it is to have a the desired mechanical stability;

the administration forms must release the active substance to the organism in a predetermined manner, not immediately and uncontrollably, but evenly and over a prolonged period of time;

in the case of oral application, the retention time in the stomach must be increased in accordance with a desired duration of action;

the dissolution rate of slightly soluble active substance components should be increased;

where film pieces are used as a finished administration form for oral application, these should retain their flat shape and avoid curling, such curling being a phenomenon frequently to be expected in the case of cast films.

These requirements are not satisfactorily met by the systems and formulations of the prior art mentioned. Consequently, the invention has the object of providing a film-shaped

CA 02339836 2007-01-04 active substance carrier for controlled release of active substance, comprising a carrier film with an active substance-containing substrate fixedly connected thereto as well as a further water vapor-diffusible film-shaped layer covering the said carrier film, whereby the carrier film and the further film-shaped layer are sealed on top of one another such that the film-shaped active substance carrier is configured as a pouch in whose interior space there are gas-forming components, which enables both an accurate and a precisely reproducible active substance dosage as well as an accurate and precisely reproducible active substance release at a predetermined delivery rate, and which contains the active substance, protected against premature detachment, on or in a mechanically stable filmshaped active substance carrier.

This object is achieved by the invention in a film-shaped active substance carrier of the kind mentioned initially in that the particles of the active substance-containing substrate are fixedly connected with the said substrate. One embodiment of the invention provides for the particles to be fixed on the substrate with the aid of a solvent. In this case the anchoring of the particles on the carrier film is effected by preliminary interaction with moisture or solvent vapor, or under action of pressure and/or temperature.

One advantageous embodiment of the invention makes use of the fact that by applying a further film-shaped layer one achieves an encapsulation of the drug particles. Application of this additional layer can be effected by calendaring with or without the use of solvent or heat. It is also of advantage that by using fusible particles of an active substance-containing preparation, the adhesion of the particles on or in the carrier layer can be optimally realized. In this embodiment of the film-shaped active substance carrier it is of essential importance with regard to the invention that the further film-shaped layer is water vapour-diffusible. Here, the second film-shaped layer applied provides for additional protection of the particles applied to the surface of a carrier, and when selecting a suitable film the rate of active substance release is controlled by reason of the fact that it is possible to adjust the active substance release characteristics, which characteristics can

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CA 02339836 2001-02-07 be predetermined in the process and which, in particular, are retarded.

When in this process the two films which are used for lamination are sealed upon each other at their edge contour, it is possible - by employing gas-generating components in, for example, aqueous environment - to use the laminate as a gas-filled, floatable pouch in the stomach as a gastroretentive system.

A further retardation of the active substance release can be achieved by a specific embodiment of the invention in that at least one further film-shaped body is contained in the space of the active substance carrier, which space is inflated due to the generation of gas, on whose surface are present active substance-containing particles which are fixedly connected with the said body.

Furthermore, additional film-shaped bodies may be present in the cavity of the active substance carrier which are adapted as auxiliary substance carriers for the generation of gas.

The use of the film-shaped active substance carrier is provided for as an administration form, for cosmetic, pharmaceutical or food-technological products.

Further details and advantages of the invention will become evident from the following explanation of some of the examples of embodiments schematically shown in the drawings. The drawings show:

Figure 1 to Figure 6 : sectional and side views of different but similar embodiments of film-shaped active substance carriers according to the invention.

Figure 1: a sectional view of a film-shaped active substance carrier (2) provided with particles (1) of an active substance-containing substrate, which particles are fixedly

CA 02339836 2001-02-07 anchored on the carrier. When using slightly soluble active substances it is possible here to employ the measure of homogeneously applying to the surface a micronized form of the active substance at particle sizes of below 50 pm, preferably below 5 pm, and - avoiding agglomeration - fixing the same on the surface. In this case, a base may be chosen for the film-shaped drug carrier which is freely soluble in water.

Figure 2 shows another embodiment of the film-shaped active substance carrier, with active substance particles (1), the film-shaped carrier (2) and a further film-shaped carrier (3) laminated thereon.

Figure 3 shows an alternative embodiment of the film-shaped active substance carrier (2), with active substance particles (1) fixedly connected with the surface thereof, which active substance carrier (2) is covered or encapsulated with a filmshaped layer (3), thus forming a cavity (4).

According to Figure 4 the film-shaped active substance carrier (2) and the film-shaped layer (3) covering said carrier form a cavity (4) wherein an additional film-shaped element (2’), comprising active substance particles (1) fixed on the surface thereof, is embedded. In the cavity (4) are provided film-shaped auxiliary substance carriers (5, 6) for generation of gas. To render the latter activatable by admission of moisture, the film-shaped layer (3) is formed using water vapour-diffusible material. The active substance carrier (2) may be provided with active substance particles fixed on the surface thereof.

As shown in Figure 5, a further alternative embodiment of the device according to the invention is provided with a filmshaped active substance carrier (2) and a water vapourdiffusible layer (3), forming a cavity (4) which contains

CA 02339836 2001-02-07 film-shaped active substance carriers (5, 6). The active substance particles (1) are fixed on the inner surfaces of the layers (2, 3).

Figure 6 shows the separation of a strand consisting of layers (2, 3) and provided with active substance particles (1), using a separating device (7).

The drug carriers (2, 2') shown in Figures 1 to 6 consist of a film of film-forming materials such as, for example, polyvinyl alcohol, preferably in partially hydrolized form, wherein between 1 and 20%, particularly preferred 12%, of the hydroxyl groups are replaced by acetyl groups, of cellulose derivatives, gelatin, pullulan or other saccharides, vegetable gums and polyvinylpyrrolidone. Furthermore, sugar, glucose, sorbite, polyethylene glycol and other water-soluble additives may advantageously be added to regulate the dissolution properties. Additives of up to 30%-wt. of a surfactant can improve the wetting to the active substancecontaining particles (1).

Adding up to 40%-wt. of a filler does not eliminate the advantages of the invention and is likewise suitable for modification of the dissolution properties. Without claiming to be exhaustive, suitable substances for this purpose are silicon dioxide, titanium dioxide, calcium carbonate, calcium sulfate, calcium phosphate, talcum or mixtures of these substances.

To improve acceptance, it is also possible to add flavours which advantageously form a drop-shaped internal phase in the layer.

Furthermore, flavour-enhancing substances such as sodium saccharinate, other sweeteners, salt or sugar derivatives can be used to improve the impression of taste, such as also, for example, low-molecular organic acids, for example malic acid, adipic acid or citric acid. Further, stabilizers such as antioxidants improve the shelf-life of the adhering active substance particles.

CA 02339836 2001-02-07

These may consist of the above-mentioned base components of the film itself but also of more lipophile, e.g. wax- or resin-like, portions.

Thermoplastic components, as well as water-soluble polymers such as polyethylene, are suitable for embedding after application onto a carrier film.

Typically the active substances may be applied to a carrier in pure and optionally in micronized form.

The film-shaped products or initial products preferably have a thickness of 20 to 300 pm; their size is advantageously 0.5 to 8 cm².

Through the application according to the invention of a second film-shaped layer (3) to an active substance carrier (2) it is possible to protect and encapsulate the particles (1) applied on the surface. Depending on the base material as well as the sensitivity to temperature, this can be effected by hot-calendering, bonding with the aid of solvents, or other methods known to those skilled in the art.

By further processing, for example by means of contour rolls or similar shaping devices, the film laminate can obtain a desired geometrical contour, for example a shape suitable for filling into capsules. In this manner, it is possible to obtain, for example, markedly delayed active substance release characteristics.

If two films intended for lamination are sealed with each other at the edge contour, it is thereby possible to achieve further special effects.

On the one hand, it is thereby possible to achieve an extreme delay of the active substance release rate, and on the other hand the laminate can be used as a gastroretentive therapeutic product in the stomach or the intestinal tract by employing gas-generating components in the interior space of

CA 02339836 2001-02-07 a device according to the invention which is shaped as a pouch and has water vapour-diffusible layers.

The film-shaped active substance carrier according to the invention has a wide range of applications, it can be produced in industrial production processes with high outputs at moderate costs, and it solves the task mentioned at the outset in an optimal manner.