Stock material or miscellaneous articles – Web or sheet containing structurally defined element or... – Adhesive outermost layer
Reexamination Certificate
2002-01-14
2004-08-24
Tarazano, D. Lawrence (Department: 1773)
Stock material or miscellaneous articles
Web or sheet containing structurally defined element or...
Adhesive outermost layer
C343S823000, C343S823000, C343S823000, C343S823000, C424S443000, C424S447000, C424S448000, C424S449000, C427S002310
Reexamination Certificate
active
06780504
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an active substance-containing multi-layer film of film-forming polymers with a cover layer, at least one active substance-containing layer and an adherent layer, a process and a device for its production, as well as its use.
The release of active substances from active substance-containing multi-layer films is nowadays becoming increasingly important. These multi-layer films consist of a cover layer that protects the multi-layer film against, inter alia, undesirable influences, an active substance-containing layer and an adherent layer by means of which the multi-layer film is secured to the site at which the active substance is to be released.
In particular the administration of medicaments via transmucosal application by means of a multi-layer film has proved very effective both for local therapy as well as systemic therapy.
The production of films that satisfy the requirements for use in the buccal cavity as regards thickness, flexibility, mucoadhesion, control of the release of active substances and compatibility has however up to now encountered serious technological difficulties. Thus for example, in order to maintain the long-term effect an insolubility in the aqueous medium of the application site is required, especially moreover as regards the cover layer. This necessitates the use of water-insoluble polymers such as for example ethylcellulose, poly(methyl methacrylates), etc.; in other words, substances that can be suitably processed only in organic solvents or in the form of complicated latex or pseudolatex dispersions, which however leads to both ecological and economic disadvantages. Since these multi-layer films are in this connection produced by a casting process, considerable problems moreover also arise in the scaling-up of the production process from the laboratory to the mass production level.
SUMMARY OF THE INVENTION
It is an object of the invention to provide an improved multi-layer film containing at least one active substance, as well as a process and an apparatus for producing such a film.
Another object of the invention is to provide a multi-layer film containing at least one active substance which avoids or overcomes the disadvantages of the prior art, as well as a process and an apparatus for producing such a film.
These an other objects are achieved in accordance with the present invention by providing a multi-layer film of film-forming polymers comprising a cover layer, at least one active substance-containing layer and an adherent layer, wherein the cover layer and/or the active substance-containing layer consists of hydrophilic polymers crosslinked in situ that are no longer water-soluble or are possibly only still water-swellable.
As used herein, the term “crosslinked in situ” means that the film-forming polymer and a suitable crosslinking agent are applied separately from one another to a preferably smooth surface where they are mixed, resulting in an in situ crosslinking after they have been mixed.
The cover layer serves to mechanically stabilize the multi-layer film, to protect the active substance incorporated in the active substance-containing layer, and also as a barrier to prevent diffusion of the active substance, so that a unidirectional release of the active substance takes place through the adherent layer to the site where the multi-layer film is attached.
The cover layer may be produced from any known suitable film-forming, water-soluble polymer(s) and suitable crosslinking agent(s). Suitable polymers and crosslinking agents are disclosed, for example, in Abletshauser, C.; Schneider, R.; Rupprecht, H.: Film coating of pellets with insoluble polymers obtained by “in situ” crosslinking in the fluidized bed, J. Control. Rel. 27, 149-156 (1993) or in Abletshauser, C.; Rupprecht, H.: Self supporting polymer films crosslinked “in situ” by simultaneous spraying of component solutions, Farm. Vestn. 45, 297-309 (1994), which are incorporated herein by reference and are thus part of the disclosure.
Preferably, however, the cover layer is based on cellulose ethers, preferably hydroxyethylcellulose and/or methylcellulose, particularly preferably methylhydroxy-propylcellulose. The cellulose ethers are preferably crosslinked with phenolic substances, particularly preferably with tannin. In order to optimize the film properties, the quantitative ratio of polymer to crosslinking agent may be varied in a wide range. Preferably the quantitative ratio is however 4:1 to 1:1. Most particularly preferably the cover layer is based on methylhydroxypropylcellulose crosslinked with tannin, the quantitative ratio being between 4:1 and 1:2.
Also, the cover layer may preferably be based on anionic polymers, preferably sodium carboxymethylcellulose, polyacrylates or carragenates, particularly preferably sodium alginate. The anionic polymers preferably are crosslinked with inorganic ions, particularly preferably calcium ions, or preferably with polycations, particularly preferably chitosan.
Further preferred cover layer materials are films formed from mixtures of methylhydroxypropylcellulose crosslinked with tannin together with latex dispersions of ethylcellulose, suitable poly(methyl methacrylates) such as for example Eudragit RS, Eudragit E, etc., from Röhm Pharma GmbH, Darmstadt, Germany.
Particularly preferred as cover layers also include prefabricated sheets of water-impermeable materials with hydrophobic surfaces, such as polyamides. The cover layer may also be produced from a mixture of polymers in order for example to optimize the properties of this layer.
The function of the cover layer can according to the invention be expanded further by incorporating colored pigments such as for example iron oxides, titanium oxide, etc. and/or sweetening agents and/or aromas, as well as optionally by further auxiliary substances in order to optimize the properties of use, preferably as a medicament form.
Preferably the layer thickness of the cover layer is between 30 and 100 &mgr;m, particularly preferably between 40 and 60 &mgr;m.
The multi-layer film has according to the invention at least one active substance-containing layer that is joined directly to the cover layer. This layer serves according to the invention as an active substance matrix.
The active substance-containing layer may be produced from a suitable film-forming, water-soluble polymer and suitable crosslinking agents, such as are described for example in Abletshauser, C.; Schneider, R.; Rupprecht, H.: Film coating of pellets with insoluble polymers obtained by “in situ” crosslinking in the fluidized bed. J. Control. Rel. 27, 149-156 (1993) or in Abletshauser, C.; Rupprecht, H.: Self supporting polymer films crosslinked “in situ” by simultaneous spraying of component solutions. Farm. Vestn. 45, 297-309 (1994), which are included here by way of reference and are thus part of the disclosure.
Preferably, however, the active substance-containing layer is based on cellulose ethers, preferably hydroxyethylcellulose and/or methylcellulose, particularly preferably methylhydroxypropylcellulose. The cellulose ethers preferably are crosslinked with phenolic substances, particularly preferably with tannin.
In order to optimize the film properties, the quantitative ratio of polymer to crosslinking agent may be varied over a wide range. Preferably, however, the quantitative ratio is from 4:1 to 1:1.
Also preferably, the active substance-containing layer is based on anionic polymers, preferably sodium carboxymethylcellulose, polyacrylates or carragenates, particularly preferably sodium alginate. The anionic polymers preferably are crosslinked with inorganic ions, particularly preferably calcium ions, or with polycations, particularly preferably chitosan.
The active substance-containing layer may also be produced from a mixture of polymers in order for example to optimize the release of active substance from this layer and/or its stability. Preferably the active substance-containing layer is based on methylhydroxypropylcellulose crosslinked with tannin, to
Rupprecht Herbert
Zinzen Stephan
Crowell & Moring LLP
Gruenenthal GmbH
Tarazano D. Lawrence
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