Patch local actions with non-steroidal antirheumatic drugs containing acid group

 

The invention relates to medicine. As the active substance patch contains non-steroidal Antirheumatic agent. It consists of inert with respect to the current substance of the substrate, self-adhesive matrix layer based adhesive polyacrylate containing the active substance, and a protective film which is removed before use. While non-steroidal Antirheumatic remedy contains a free carboxyl group. Matrix patch comprises an adhesive polyacrylate, crosslinked with polyvalent ions of the metal, and contains free carboxyl groups. The matrix also contains a fatty acid. The substrate consists of a material having elasticity in at least one direction. The invention improves the rate of penetration of the drug stability. 10 C.p. f-crystals, 2 Il.

The so-called non-steroidal Antirheumatic funds represent the largest group of active substances which should be regarded as derivatives of acetic and propionic acids.

Non-exhaustive examples of derivatives of acetic acid are indomethacin, acemetacin, tolmetin, diclofenac and lonazolac; Primerose and cuprofen.

The free carboxyl group has a significant impact on the effects of substances of this class, as it leads to the accumulation of active substances in inflamed tissues, the pH of which is reduced.

However, when oral administration is often used not free acid, salt, because they have better solubility in aqueous medium. However, for local use better free acid, as electrically neutral substances have a better than electrically charged salts, the ability to penetrate the corneal layer of the skin.

For all the above-mentioned substances are characterized by adverse effects, consisting in the defeat of the stomach and bleeding in the area of the gastrointestinal tract. In this regard, in the case of local complaints, it is advisable to prescribe these drugs for local and not systemic use.

Such complaints, for example, associated with acute articular rheumatism and acute rheumatic diseases of the spine, swelling and inflammation of the soft tissues near the joints, stiffness of joints, pain in the lumbar region, lumbago, sports injuries and accidentally received injuries.

For local the self-adhesive patches compared with ointments and gels is they do not stain the clothing of the user and corresponding structures should be used only once within 1-2 days.

These patches are intended for local application in the field of their actions usually consist of so-called self-adhesive matrix layer containing the active substance, substrate, often consisting of textiles, and protects the matrix layer that must be removed before using the patch.

Because these patches have only a local effect in the field of their application, their size ranges from about 70 sq. cm to about 250 square see This means that the physical properties of the substrate substantially affect the characteristics of wear resistance of the patch. This applies particularly to applications in the joints, because the substrate must be flexible at least in one direction, so that, on the one hand, to possess a sufficient level of adhesion in the areas of overlap, and on the other hand, not to restrict the freedom of movement of the user. Materials such as film does not have the elasticity or, if they are flexible, they are made of substances other than inert to the ingredients of the matrix patch.

In addition, the problem is with this corking and sweating can negatively affect the adhesion ability.

Textile materials also pose some problems, because materials such as cotton or polyurethane capable of binding the active substances or able to diffuse excipients. In particular, polyurethanes capable unacceptable way to change physical properties.

The adhesive material must also meet certain requirements. Its most important function is to securely fix the system during such time as the patch should stay on the skin without causing pain or breaks in the skin when removing the patch. The adhesive material should not have obstructive actions, because with increasing blockage reduces the compatibility of the skin. Since the adhesive material is in close contact with the active ingredient, it must be sufficiently inert with respect thereto, so that the patch remained stable for at least two years. The composition of the adhesive material must meet the specified chemical composition of active substances and excipients. The adhesive material must also have the appropriate ability to dissolve active ingredients. Since the rate of permeation main VA was as close as possible to the saturation concentration. In General, due to the fact that the amount of the released active substance in the end, is relatively high, it is necessary that its solubility was at least 5 wt.%, and for reasons of economy, the active substance is not more than 30%, preferably not more than 15 wt.%.

All of these requirements are best suited adhesive materials based on polyacrylate. Such adhesive materials are produced by the method has radical-chain polymerization of acrylic or methacrylic acid and their derivatives. As additional monomers can be used vinyl compounds such as, for example, vinyl acetate or maleic acid.

In addition, for the most part, the technical aspects, an important role in systems designed for local use, plays a compatible skin. Transdermal therapeutic system (TTS), which has a systemic effect, applied to different areas of the skin, whereas the site of application patches for local application determines, based on the patient's complaints. This means that for the manufacture of a matrix can be used only ingredients that have good skin tolerance. In addition, the adhesive must be adjusted the other hand, was not excessive mechanical irritation of the skin when removing the patch. Assume that the patches must be capable of releasing the residual quantity of the active ingredient to penetrate sufficiently deep layers of tissue beneath the patch, i.e., in the place of his action was quite high.

This also implies that the form of application must meet the requirement to provide sufficient stability with respect to the content of the active substance, its release and behavior of adhesive material.

In General, plasters local actions should mainly as much as possible to meet the following requirements: - possess a high rate of penetration in order to achieve therapeutically effective layers of tissue at the site of application of the patch, is to have good compatibility with the skin in case of multiple applications on the same site, is to have good, but not excessive level of adhesion and do not delaminate when removed, can differ elasticity, at least in one direction, so that it can be applied in the area of the joint to be stable for at least two years, - f has a local effect of the patch, containing non-steroidal Antirheumatic tools with free carboxyl groups and meet the above requirements.

This goal was achieved through the use of groups of active substances containing non-steroidal Antirheumatic means with the free carboxyl groups in the form of a patch according to the characteristics of the present invention.

In the patent literature describes with local action plasters, also containing non-steroidal active agents. Patch-based hydrogels are not taken into account, since their use without additional fixing bandages are limited due to their low adhesion.

In the patent, for example, great Britain GB 2273044 described plasters, as active ingredient containing Ketoprofen. The active ingredient in these patches contained in the matrix in combination with substances that enhance penetration through the skin, these substances belong to the group of esters of fatty acids, derivatives of polyoxyethylene, glycerides, esters of fatty acids propylene glycol series and a derivative of pyrrolidone. The adhesive substance in this case can also be selected from a group is as a material for the textile substrate mentioned cotton fabric which, however, ties a significant portion of the active substance contained in the matrix, which negatively affects the release of the active substance. Not described functional acid groups, and the use of plasticizers or permeation enhancers containing carboxyl groups.

In German patent DE-OS 19527306 described patch local action containing Ketoprofen as the active substance. This patch is characterized by the presence of multi-layered matrix, the individual layers of which have different abilities to absorb water.

In U.S. patent US 5702720 described plaster containing flurbiprofen as an active ingredient. The matrix of such a patch also includes an adhesive substance on the basis of polyacrylate, as an additional component containing polyvinylpyrrolidone. In this case, the presence of polyvinylpyrrolidone should be seen as a disadvantage, since this polymer has very good interaction with carboxyl groups, fenoline hydroxyl groups. This improves the adhesion of the patch to the skin, however, this comes at the expense of release of the active substance or, respectively, increase calderai ibuprofen as the active ingredient. In this case, the matrix consists of two different polymers, polyacrylate and, besides the active substance, optionally includes diethylphthalate. In this case, diethylphthalate cannot be considered safe from the point of view of toxicology substance, as it in large quantities, can penetrate into the skin. Not described the presence in the matrix of acid plasticizer in combination with the acid functional groups, and non-steroidal Antirheumatic agent with free carboxyl groups.

None of the techniques known from the patch does not contain the optimal form all the elements necessary for the patch.

It has been found that the combination of the active substance with a free carboxyl group, structured adhesive substance on the basis of acrylate with a free carboksilnami groups from the group comprising polymerized acrylic or methacrylic acid, and fatty acid as a plasticizer or amplifier permeation get a matrix of physical properties that optimally meet all the requirements.

Structuring the adhesive substance on the basis of acrylate is carried out using cation polivalente aluminiumalloy. Organic connection part is removed along with the solvent during the drying of the adhesive substance, after which the carboxyl group of adhesive substance forming counter-ions relative to the cations of aluminum. The resulting structuring should be considered as reversible. Obviously, the acidic active ingredient, as well as acid plasticizer, also interact with aluminium ions, thereby giving an appropriate adhesive matrix, which in this case does not become too soft and as a result are subject to the so-called plastic deformation. Such deformation, on the one hand, a negative impact on the stability and on the other hand, creates inconvenience lies in the fact that after removal of the patch with the skin, it leaves traces on the boundary of the overlay adhesive substance.

In addition, it is expected that the present fatty acids will block the sites of the polymer, can also interact with the acidic active ingredient and thereby affect the ability to release the acidic active ingredient. An additional advantage is that due to the presence of fatty acids of dissoc is indirectly contributing to the formation of the neutral form of the active substance, are better able to penetrate the skin.

In General, there are a number of interacting circumstances, the combination of which gives the matrix of optimum physical properties.

The substrate of the patch consists of a woven or knitted material based on polyester having elasticity in at least water direction, or elastic foam with closed cells.

Such woven or knitted materials become more elastic due to the use of polyester threads. Due to this they differ from non-woven polyester material with little elasticity. Such nonwovens are made, however, their disadvantage is the fact that they remain sufficiently elastic only at very small thickness, otherwise they are not able to sufficiently cover the adhesive matrix and to provide protection from her bonding with packing material or clothing during use of the patch. Even quite thick (about 150 g/square m) woven or knitted materials based on polyester have sufficient ability to be stretched in order that they can be used as a textile underlay patch. However, Myung-woven or knitted materials, polyester is the most inert in respect able to diffuse ingredients of the matrix. Because of this he is superior to materials such as cotton, viscose, polyamide or polyvinyl acetate. Even after storage for three years the rate of release of the patch that contains ibuprofen, and Ketoprofen, as proves example, remains unchanged provided that its substrate comprises polyester. This implies that the material is absolutely not absorb the active ingredient.

Within a specified period of time, the composition of the active substance remains unchanged, even if the patch is stored at elevated temperatures. Not observed the appearance of degradation products. This is further evidence of the excellent stability of these patches.

As prove conducted in vitro tests on the ability of penetration through the epidermis of human skin, the release of the active substance into the skin is also quite large. This is illustrated by the example of testing the penetrating ability of the patches, manufactured according to examples 2 and 3.

The permeation velocity can be further increased through the use of a substrate of foam with closed cells * this is an increase in the degree of blockage, which generally increases the rate of permeation. Despite the fact that when used as a substrate such foamed materials it is impossible to achieve high elasticity and the same ease of use as when using woven materials based on polyester, their advantage lies in the higher efficiency due to higher speed of release of the active substance patch.

In Fig. 2 higher permeation velocity was confirmed in comparative studies penetrating ability in human epidermis for example, the active ingredient Ketoprofen.

Medication in the form of patches according to the invention is illustrated in examples 1-3. Such a drug may contain any non-steroid active substances with acidic groups, however, for each individual active substance is necessary to find the appropriate concentration.

EXAMPLE 1: a PATCH CONTAINING KETOPROFEN AS the active SUBSTANCE TO 500 grams Durotak 387-2251 with a solids content of 48 wt.% added 58 grams of oleic acid and 26 grams of Ketoprofen, the mixture was stirred until until Ketoprofen has not disappeared entirely.

Then to the mixture was added 90 is tion.

Then for making a layer of the matrix solution was applied to a siliconized film, and the solvents removed in the process lasted 20 minutes drying at a temperature of 50oC. the coating Thickness was chosen so that the specific gravity of the dried matrix film coating was 80 g/sq m

After that, the dried layer of the matrix thin layer caused woven material based on polyester having elasticity in two directions; from the obtained laminate hole cut out of the finished patch.

EXAMPLE 2.

To 500 g of Durotak 387-2251 with a solids content of 48 wt.% added 58 grams of oleic acid and 30 grams of flurbiprofen, the mixture was stirred until until Ketoprofen has not disappeared entirely.

Then to the mixture was added 90 grams of a solution (4 wt.%) aluminiumalloy and brought the solution to the homogeneous by stirring.

Then for making a layer of the matrix solution was applied to a siliconized film, and the solvents removed in the process lasted 20 minutes drying at a temperature of 50oC. the coating Thickness was chosen so that the specific gravity of the dried matrix film coating was 80 g/sq m

After that, NCU in two directions; from the obtained laminate hole cut out of the finished patch.

EXAMPLE 3: PLASTER CONTAINING IBUPROFEN AS the active SUBSTANCE TO 500 grams Durotak 387-2251 with a solids content of 48 wt.% added 58 grams of oleic acid and 41 grams of ibuprofen, the mixture was stirred until until Ketoprofen has not disappeared entirely.

Then to the mixture was added 90 grams of a solution (4 wt.%) aluminiumalloy and brought the solution to the homogeneous by stirring.

Then for making a layer of the matrix solution was applied to a siliconized film, and the solvents removed in the process lasted 20 minutes drying at a temperature of 50oC. the coating Thickness was chosen so that the specific gravity of the dried matrix film coated was 150 g/square m

After that, the dried layer of the matrix thin layer caused woven material based on polyester having elasticity in two directions; from the obtained laminate hole cut out of the finished patch.

Shown in Fig.1 the results of the penetrating abilities were obtained as a result of in vitro tests on human epidermis using the well-known cone of Ftve active ingredient containing non-steroidal Antirheumatic means with a free carboxyl group consisting of inert with respect to the current substance of the substrate, made of material having elasticity at least in one direction, contains the active substance is a self-adhesive matrix layer on the basis of polyacrylate adhesive substance, crosslinked with polyvalent metal ions and containing free carboxyl groups, while the matrix contains fatty acid, the protective layer is removed before use, characterized in that the matrix containing the active substance consists of a single layer, and the substrate is made of elastic woven or knitted material based on polyester or non-woven, woven or knitted material based on poly (ethylene terephthalate), or elastic foam with closed cells.

2. Having a local effect of the patch on p. 1, wherein the non-steroidal Antirheumatic remedy is a derivative of propene.

3. Having a local effect of the patch on p. 2, characterized in that the active substance is a Ketoprofen, ibuprofen, fluprofen or naproxen.

4. Having a local effect of the patch on p. 3, characterized in that the active substance is a Ketoprofen or fluprofen and is contained in the Mat that the active substance is a Ketoprofen is present in the matrix in dissolved form at a concentration of 6-10 wt. %.

6. Having a local effect of the patch on p. 1, wherein the fatty acid is an oleic, linoleic or linolenic acid.

7. Having a local effect of the patch on p. 6, wherein the fatty acid is an oleic acid present in the matrix of the patch at a concentration of 5 to 20 wt. %.

8. Having a local effect of the patch on p. 1, characterized in that the polyacrylate adhesive substance is obtained using at least 2-ethylhexyl acrylate and acrylic acid.

9. Having a local effect of the patch on p. 1, characterized in that the polyacrylate adhesive substance is obtained using at least 2-ethylhexyl acrylate, vinyl acetate, acrylic acid, butyl acrylate.

10. Having a local effect of the patch on p. 1, characterized in that the substrate consists of a woven material based on poly (ethylene terephthalate) having elasticity in both directions.

11. Having a local effect of the patch on p. 1, characterized in that the plastic foam with closed cells is made of polyethylene, polypropylene, polyvinyl chloride or a copolymer of ethylene and vinyl acetate.

 

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