Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2001-03-09
2004-01-13
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000
Reexamination Certificate
active
06676962
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
A large group of the so-called non-steroid antirheumatic agents are active substances which are to be considered derivatives of acetic acid and of propionic acid.
2. Description of the Prior Art
Examples of acetic acid derivatives are—without claim to exhaustiveness—indomethacin, acemetacine, tolmetin, diclofenac and lonazolac; examples of propionic acid derivatives (profens) are ibuprofen, flurbiprofen, fenoprofene, ketoprofen, naproxen and tiaprofen.
The free carboxyl group is significant to the action of this class of substances as it leads to accumulation of the active substances in inflammatory tissues having a decreased pH value.
For peroral administration, however, it is frequently not the free acids which are used but the salts, since these have better solubility in aqueous environment. For topical administration, however, the free acids are better suited since electrically neutral substances have a greater capability of penetrating the stratum corneum of the human skin than electrically charged salts.
As a side effect, the occurrence of stomach trouble and hemorrhages in the gastrointestinal region have been described for all of the above-mentioned substances. In the case of local complaints it is therefore advantageous not to administer these substances systemically but locally.
Such complaints are, for example, inflammatory-rheumatic diseases of the joints and the spinal column, swellings and inflammations of the soft tissue in the vicinity of joints, shoulder stiffness, low back pain, lumbago, as well as sports injuries and accidental injuries.
For local administration, gels, ointments or self-adhesive patch systems may be used, with the self-adhesive patch systems having the advantage over ointments and gels that they do not contaminate a person's clothing and that the patches—provided that they are correspondingly designed—must be applied only once every 1-2 days.
Such patches for topical application at the site of action typically consist of an active substance-containing, self-adhesive, so-called matrix layer, a—frequently textile—backing layer, and a protective layer—to be removed prior to use—for the matrix.
By reason of the action being only topical at the site of application, such patches have a size starting from about 70 cm
2
and reaching up to about 250 cm
2
. This means that the physical properties of the backing layer are of great significance for the wearing characteristics of the patch. Especially in the case of application in the region of joints, it emerges that the backing layer must be elastic in one direction at least, in order to, on the one hand, have sufficient adherence in this region, and, on the other hand, to not excessively restrict freedom of movement. Film-type materials are either non-elastic or, if they are elastic, they are made of materials that are not inert to the ingredients of the matrix of the patch.
In addition, with films, the water vapor permeability in dependence on the selected materials frequently poses a problem since occlusion, and sweating, which is connected therewith, can significantly affect the adhesive properties.
Textile materials are also not without problems since materials such as cotton or polyurethane tend to bind active substances or diffusible auxiliary substances. Polyurethanes, in particular, tend to change their physical properties in an inadmissible manner.
The adhesive also has to fulfill specific requirements. Its most important function is to anchor the system safely on the skin for the time for which the patch is intended to be worn, without causing pain or leading to torn-off skin when the patch is removed. The adhesive should have no occlusive action since, as occlusion increases, skin compatibility is decreased. Since the adhesive has intimate contact with the active substance, it must be sufficiently inert thereto, in order to have a patch that is stable for at least two years. The composition of the adhesive must be appropriately geared to the given chemical composition of the active substances and auxiliary substances. Not least, the adhesive must have adequate solubility for the active substances. Since the permeation rate is fundamentally dependent on thermodynamic activity, one has to aim at an active substance concentration that is as near to the saturation concentration as possible.
Generally, by reason of the amount of active substance to be released being, after all, relatively large, one should aim at a solubility of at least 5% (w/w), and, for reasons of active substance economy, not more than 30%, better: not more than 15% (w/w).
All of these demands are best met by polyacrylate adhesives. These adhesives are produced by radical polymerization of acrylic or methacrylic acid, and their derivatives. Additionally possible monomers are vinyl compounds such as, for example, vinyl acetate or maleic acid.
Apart from the more technical aspects, skin compatibility is of great importance to topical systems. While systemically active transdermal therapeutic systems (TTS) are applied to varying skin areas, in the case of topical patches the application site is determined by the complaint. This means that in such patches only ingredients having good skin-tolerance can be used for the matrix. Moreover, the adhesive behavior must be adapted such that, on the one hand, the patch reliably adheres to the skin for the intended application time, and, on the other hand, no excessive mechanical irritation of the skin occurs when the patch is removed.
As a matter of course, the patches must be capable of releasing enough active substance in order to achieve sufficiently high tissue levels in the tissues lying underneath the patches, i.e. at the site of action.
It is likewise a matter of course that the administration form must meet the demand of having sufficient stability with respect to the active substance content, the release of active substance and the adhesive behavior.
In summary, topical patches should substantially fulfill the following requirements as optimally as possible:
sufficiently high permeation rate for obtaining therapeutically effective tissue levels at the site of application,
good skin compatibility in the case of multiple application at the same site,
good, but not too firm, adherence, and no stripping on removal,
elasticity in at least one direction, to enable application in the joint region,
stability for at least 2 years,
simple and cost-effective production.
It is the object of the present invention to provide a topical patch with non-steroid antirheumatic agents having free carboxyl groups, which fulfills the above-mentioned requirements.
SUMMARY OF THE INVENTION
This object has surprisingly been solved, for the active substance group of the non-steroid antirheumatic agents having free carboxyl groups, by means of a patch comprising a backing layer made of a material that is elastic in at least one direction and is inert to the active substance, a self-adhesive, active substance-containing matrix layer containing fatty acid based on a polyacrylate adhesive, which is cross linked with multivalent metal ions and has free carboxyl groups, and a protective sheet to be removed prior to use. The matrix has one layer and is free of hydroxyl groups and the backing layer is made of an elastic polyester woven fabric or polyester knitted fabric, or a non-woven, woven or knitted fabric of polyethylene terephthalate, or a closed-cell, elastic foam.
In the patent literature, topical patches are described that also comprise non-steroid active substances. Patches based on hydrogels have not been taken into account since by reason of their low adhesive power their use without additional fixing bandages is limited.
GB 2 273 044 describes patches, for example, which also comprise ketoprofen as active ingredient. In these, the active substance is combined in the matrix with substances improving permeation through the skin, said substances belonging to the group of fatty acid esters, polyoxethylene derivatives, glycerides, fatty acid est
Hochberg D. Peter
Kishore Gollamudi S.
LTS Lohmann Therapie-Systeme
Mellino Sean
Vieyra Katherine R.
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