United States Patent:  6,063,404

Assignee:  Jenapharm GmbH & Co. KG (Jena, DE)

Filed:  July 29, 1998

This invention relates to a bioadhesive tablet containing at least one bioadhesive adjuvant and at least one lubricant, with at least one surface of the tablet comprising concentric or parallel, straight and/or curved depressions, and to a method for producing the bioadhesive tablets as well as to pharmaceuticals in the form of the bioadhesive tablets.

SUMMARY OF THE INVENTION

This problem is solved according to the invention by a bioadhesive tablet containing at least one bioadhesive adjuvant and at least one lubricant, with at least one surface of said tablet comprising concentric or parallel, straight and/or curved depressions.

The bioadhesive tablets of the invention are decomposed in such a way that they or their decomposition products do not impair by swelling the passage of the active agents they contain through the mucosa. The tablets of the invention are a solid substance but nevertheless constitute a bioadhesive form of pharmaceutical in the organism that protects its active agents against microbial attacks, and from which said active agents are made available for resorption across an extensive tissue area of the target organ.

The bioadhesive tablets of the invention nearly completely release the active agent they contain and stimulate its resorption by the tissue while not entering into any undesirable interaction with the biological tissue.

The bioadhesive adjuvant should preferably be a substance that develops adhesion when coming into contact with the mucosa, such as a cellulose, a cellulose derivative, a carboxyvinyl polymer, a derivative of a carboxyvinyl polymer, a lectin or natural material or mixtures of said substances.

It is furthermore considered advantageous that the lubricant facilitates tabletting of cohesive mixtures as do talc, a metallic soap, a fatty acid, or mixtures of said substances.

Furthermore, it is advantageous according to the invention that the content of bioadhesive adjuvant of a tablet is between 5 and 65 percent by weight, preferably between 10 and 45 percent by weight, and the lubricant content between 0.05 and 5 percent by weight, preferably between 1 and 3 percent by weight, and that the lubricant/bioadhesive adjuvant ratio is between 1:1300 and 1:1, preferably between 1:10 and 1:15.

It is particularly advantageous that the tablet surface comprises 2 to 12, preferably 3 to 5, concentric or parallel straight and/or curved depressions with a depth between 0.1 mm and 1.0 mm, preferably between 0.3 mm and 0.6 mm, measured from the surface of the tablet, said depressions being at a spacing between 0.5 and 5 mm, preferably between 1.5 and 2.5 mm, and shaped like notches, the flanks of said notches having a circular convexity the radius of which is in the range from 0.1 to 0.9 mm, preferably 0.5 mm, and/or the aperture angle of said notches being between 45 and 135^o  preferably 90^o.

Another object of the present invention is a method for producing bioadhesive tablets which includes intermixing at least one bioadhesive adjuvant with at least one lubricant and pressing a tablet having at least one surface with concentric or parallel straight and/or curved depressions.

A preferred method according to the invention for producing bioadhesive tablets is characterized in that the bioadhesive adjuvant is a substance that develops adhesion when it comes into contact with the mucosa, such as a cellulose, a cellulose derivative, a carboxyvinyl polymer, a derivative of a carboxyvinyl polymer, a lectin or natural material or mixtures of said substances.

Another preferred method for producing bioadhesive tablets is characterized in that the lubricant facilitates tabletting of cohesive mixtures as do talc, a metallic soap, a fatty acid, or mixtures of said substances.

Particularly preferred is a method according to the invention for producing bioadhesive tablets wherein the content of bioadhesive adjuvant of a tablet is between 5 and 65 percent by weight, preferably between 10 and 45 percent by weight, and the lubricant content between 0.05 and 5 percent by weight, preferably between 1 and 3 percent by weight, and wherein the lubricant/bioadhesive adjuvant ratio is between 1:1300 and 1:1, preferably between 1:10 and 1:15.

Particularly preferred is a method for producing bioadhesive tablets in which the tablet surface comprises 2 to 12, preferably 3 to 5, concentric or parallel straight and/or curved depressions with a depth between 0.1 mm and 1.0 mm, preferably between 0.3 mm and 0.6 mm, measured from the surface of the tablet, said depressions being at a spacing between 0.5 and 5 mm, preferably between 1.5 and 2.5 mm, and shaped like notches, the flanks of said notches having a circular convexity the radius of which is in the range from 0.1 to 0.9 mm, preferably 0.5 mm, and/or the aperture angle of said notches being between 45 and 135^o, preferably 90^o.

Another object of the present invention are pharmaceuticals that are present in the form of the bioadhesive tablets according to the invention and that contain active agents of the most varied fields of indication.

An object of the present invention are, in particular, pharmaceuticals in the form of the bioadhesive tablets according to the invention containing as active agents antirheumatics, analgesics, antiparkinson agents, .beta.-adrenergic receptor blockers, sexual hormones, contraceptives, cardiovascular agents, sleeping and hypophyseal hormones, antidiabetics, immunotherapeutic agents, or anticoagulants.

The bioadhesive tablets of the invention can be produced in a known way. Any active agent, especially medicinal substances, can be moulded into tablets that adhere to the mucosa by adding a bioadhesive adjuvant, a lubricant, and optionally other adjuvants common in tabletting using a simple technique. In the organism, the bioadhesive tablet is to adhere to the mucosa immediately upon contacting it, to develop as large a contact area as possible with the mucosa, while containing exclusively toxicologically safe adjuvants that favour resorption of the active agents.

The medicinal substances that can be used are all those for which a guaranteed or controlled bioavailability can be useful. No specification is made as to their intensity or sphere of action so that, for example, antirheumatics, analgesics, antiparkinson agents, .beta.-adrenergic receptor blockers, sexual hormones, especially contraceptives, cardiovascular agents, sleeping and hypophyseal hormones, antidiabetics, immunotherapeutic agents, anticoagulants and other medicinal substances can be included in bioadhesive tablets produced in accordance with the method of the invention. In addition, no specification is made as to the place of resorption of this form of pharmaceutical. The invention is preferably suited for producing bioadhesive pharmaceuticals administered perorally and vaginally.

An object of the present invention are therefore pharmaceuticals for oral, peroral, rectal, or vaginal application containing a pharmaceutically active agent besides the common substrates and diluents.

The pharmaceuticals according to the invention are produced in a generally known way at an appropriate dosage depending on the intended application using the common solid or liquid substrates or diluents and adjuvants commonly used in pharmaceutical engineering. Preferred preparations are those forms suitable for oral, rectal, or vaginal administration. Suitable techniques are described, for example, in "Hagers Handbuch der pharmazeutischen Praxis, 4th edition, 1967-89, Springer Verlag, Berlin".

The respective tablets can be produced, for example, by intermixing the active substance with known adjuvants, for example, inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, blasting agents such as maize starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talcum and/or materials by which to produce a depot effect such as carboxyl polymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may consist of several layers.

Claim 1 of 15 Claims

1. A bioadhesive tablet containing at least one bioadhesive adjuvant, at least one pharmaceutically active agent and at least one lubricant, with at least one surface of said tablet comprising concentric or parallel, straight or curved depressions or both, said depressions being shaped like notches, the aperture angle of said depressions being between about 45^o and about 135^o, the flanks of said depressions having a circular convexity which is in the range from about 0.1 to about 0.9 mm, and said depressions having a depth which is in the range from about 0.1 mm to about 1.0 mm.

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