MXPA01009422A - Transdermal therapy system and method for producing the same - Google Patents

Abstract

The invention relates to a transdermal therapy system (TTS) which comprises the following essential characteristics:a back layer which faces away from the skin and is impermeable to the active agent, at least one active agent deposit, a matrix which is connected to said active agent deposit and which controls the release of the active agent;and an adhesive fixing device for fixing the therapy system on the skin. The deposit and/or the matrix also contain support materials consisting of paper. The invention also relates to a method for producing the inventive transdermal therapy system and to the use of the same.

Description

SYSTEM OF TRANSDERMAL THERAPY AND METHOD TO PRODUCE THE SAME DESCRIPTIVE MEMORY The invention relates to a transdermal therapeutic system (TTS) and to a process for its production. Therapeutic systems for transdermal administration of pharmaceuticals are known, such as nicotine, nitroglycerin, sex hormones, scopolamine, fentanyl. Suitable systems have been described, for example, in International application DE 84/00372 (WO 88/01516). Said systems contain as essential features a backing layer which is remote from the skin and is impermeable to the active substance, at least a deposit of active substance, a distribution device of active substance which is in contact with the reservoir of the active substance. active substance, a control device that controls the supply of the active substance by the system, and a pressure-sensitive adhesive attachment device for the therapeutic system in the skin. The active substance distribution device may be combined with the control device to produce a reservoir matrix which has one or more separate active substance reservoirs disposed in a spatially defined manner with respect to each other and having a concentration of active substance higher than that which is present in the deposit matrix.

It is stated in WO 88/01516 that the reservoir may also contain inert adjuvants such as support materials which render the deposition of active substance insensitive with respect to the application of pressure and tension, and vehicles. In accordance with the patent specification of E.U.A. 5,820,876, the support material can be a flat fabric (support fabric) as an inert adjuvant, by which the distribution of the active substance within the reservoir is made and favored. A particular embodiment is also described in figure 5 of both documents, according to which an adhesive layer is provided on a backing layer, in which the active substance is present, if desired with adjuvants, such as material to facilitate the processing capacity of the active substance, or carrier materials such as fabrics. The support fabric may also be present, such as a non-woven fabric (fleece). In the examples, the fleece materials are described as suitable (50:50 of rayon-cotton fiber combination with a substance weight of 80 g / m2, Paratex II / 80 from the company Lohmann GmbH &Co. KG, or a 70:30 combination of rayon-cotton fiber with a substance weight of 40 g / m2, Paratex III / 40 from Lohmann GmbH &Co. KG). In both examples, it is further established that the fleece material acts as a support fabric and also contributes to the uniform distribution of the nicotine, as an inert adjuvant as defined in the introduction of the specification. The patent specification of E.U.A. 4,597,961 describes a different form of a transdermal therapeutic system. In this system, the supply of the active substance is generally controlled by a microporous membrane. It is stated in the description of Figure 2 that the reservoir 114 may contain a suitable absorbent material 122, such as a sponge or cotton in which the desired amount of liquid nicotine is absorbed. Furthermore, it is pointed out in Example 4, that the reservoir 114 contains a dense matrix of porous material or inert fiber, such as cotton, to prevent loss of nicotine. However, the term "matrix" is used in this context for a completely different technical characteristic than in WO 88/01516 and in the patent specification of E.U.A. 5,820,876. A TTS for nicotine is also known from the patent specification of E.U.A. 4,915,950, in which a reservoir layer (13) is disposed between an adhesive (14), which acts as a control device, and a fixing adhesive (12). The active substance deposit layer may consist of a nonwoven fabric (fleece) for example polyester, polyethylene, polypropylene, polyamides, rayon or cotton and may consist particularly of a non-woven fabric of 100% polyester. In this specification or through it, there is no description or indication of the use of paper. It has now been found that a TTS with a substantially improved quality compared to the known state of the art is obtained if instead of the known support materials, which include particularly fabrics such as fleece, the carrier material is paper. The paper is fundamentally distinguished from fabrics that include (fleece) non-woven by the fact that in this, the cellulose fibers are bonded together to form a thin layer by means of strength. The cohesion of the fibers in the paper is carried out, in addition to the mechanical adhesion and the hook connection of the fibers, through chemical bonds (hydrogen bonds) which are formed between the hydroxyl groups of the cellulose molecules in the course of paper making. This chemical bond is so strong that the tensile strength of the paper can even exceed that of ordinary construction steel (RM Consult Papiersmaschinen Info - http://home.t-online.de/home/rm.consult/rm-info .htm of November 17, 1988). In addition, paper has the advantage that it has a high absorption capacity for liquid phases which is characterized by DIN ISO 8787 for the suction height. In this way, the suction height in the direction determined for paper with a basis weight of 26 g / m2 was 146 mm / 10 min and in the transverse direction 143 mm / 10 min compared to values of approximately 110 and 80 mm / 10 min for the aforementioned fleece material Paratex NI / 40, where the values for the fleece varied to an important degree in the series tests. The paper ordinarily does not contain a binder, so that incompatibilities between the active substance and the binder can not occur. Therefore, the aim of the invention is a transdermal therapeutic system which contains as essential features: a) a remote backing layer of the skin and impermeable to the active substance, b) at least one deposit of active substance, c) a matrix that makes contact with the active substance reservoir and controls the supply of the active substance, and d) a pressure-sensitive adhesive fixation device for the therapeutic system on the skin, the reservoir or the matrix or both contain support materials , where the support material consists of paper. The use of paper as a support material and inert adjuvant according to the invention has several advantages. When fabrics are used, such as fleeces, there is always a certain scale of deviation from the amount of active substance transferred to the single TTS, this despite a good dosing technique. For example, it has been observed that the amounts of nicotine transferred to the single TTS have a deviation scale of about 4% when a fleece is used (70:30 combination of viscose-cotton fiber, substance weight 40 g / m2). If paper is used according to the invention, the deviation scale is considerably smaller; depending on the paper surface weight, it is significantly below 2%, for example with paper having a basis weight of 23 g / m below 1.9% and with paper having a basis weight of 26 g / m2 including below 1.2%. The preferred papers have a basis weight of 90 to 60, preferably 15 to 40 and particularly 20 to 35 g / m2. The use of paper as a support material in TTS according to the invention, however, is of importance not only for the uniformity of the TTS produced, but also for the production technique. According to a known method, a defined amount of the active substance is transferred to the support material by means of a stopper. This implies that in this process, a certain amount of the support material is removed by the stopper and is transported with the detachment of the stopper from the support material. This requires that the plug be cleaned at certain levels and in this way, the production process has to be interrupted. When paper according to the invention is used, abrasion is significantly reduced, which can be explained by the fact that paper fibers are more firmly bonded together than, for example, fibers in a fleece or other fabric . It is known that the fibrous fractions emanate from each fabric. It may be possible by the use of paper according to the invention, that the capacity of the plug to function is prolonged at least 10 times, even preferably 50 to 100 times, so that its cleaning and consequently, an interruption of the process of production are required much less frequently. TTS according to the invention, can have different configurations. The suitable modalities are shown in the attached figures 1 and 2, although other modalities are possible, which are described for example in the international application WO 88/01516. According to figures 1 and 2, the TTS consists of a backup layer (10), a reservoir matrix (12), one or more reservoirs (14) and a fixation device (16) which are provided with a protection sheet that is removed before administration, so that the system is then fixed to the skin (18). The protection sheet also has to be impermeable for the active substance. For the backing layer, the deposit matrix, the fixing device and the protection sheets, materials known to those skilled in the art are used.

The object of the invention is furthermore a process for the improved production of transdermal therapeutic systems with a reduced scale of deviation of the quantities of active substance applied, wherein the active substance is applied in a conventional manner by means of a stopper to a material of Support consisting of paper. According to a preferred embodiment, the deviation (relative standard deviation) of the amount of active substance applied, such as that achieved through the method of the invention, is less than 2%, particularly less than 1.2%. A final objective of the invention consists in the use of paper as a support and means of distribution in transdermal therapeutic systems. The systems according to the invention are in principle suitable for any active substance that can be used transdermally. In particular, it can be mentioned, in addition to those mentioned above, lidocaine, diphenylhydramine hydrochloride, salbutamol, 5-fluorouracil and as sex hormone estradiol and also gestagens such as norethindrone acetate, levonorgestrel.

EXAMPLE 1 First, a pressure sensitive adhesive preparation is made HS when homogenizing a) 933 g of a commercial product (© Durotak 387-2516 from the company National Starch and Chemical, Zutphen, The Netherlands - this is a 40% solution of a self-interlacing acrylate polymer based on acrylate 2- ethylhexyl, vinyl acetate, acrylic acid and titanium chelate ester in a solvent mixture of ethyl acetate, ethanol, heptane methanol) with b) 8 g of a triglyceride of fractionated coconut fatty acids (Cs-Cío; © Miglyol 812 of the company Hüls AG, Witten Germany). In addition, 6210 g of Durotak 387-2516, 553 g of ethyl acetate and 311 g of ethanol are combined with 66 g of the aforementioned triglyceride and with 626 g of an acrylic resin prepared from dimethylaminoethyl methacrylate and acid esters neutral methacrylic (© Eudragit E 100 from the company Róhm-Pharma, Darmstadt, Germany) and homogenized (adhesive composition MS). In addition, 72 g of © Eudragit E 100 are introduced into 101 g of nicotine and dissolved therein. In this way, the preparation of active substance is obtained. The pressure adhesive composition HS is applied to a protective layer finished without adhesive (A), so that after evaporation of the solvents, a pressure-sensitive adhesive layer is formed with a substance weight of 40 g / m2 . The adhesive composition MS is applied to an additional protective layer finished without adhesive (B) so that after the evaporation of the solvents, a film having a substance weight of 220 g / m2 is produced. This film is laminated to the pressure sensitive adhesive layer applied to the protective layer (A). In this way, the lower sheet is obtained.

In an additional coating step, the adhesive composition MS is applied to an additional protective layer finished without adhesive (C), so that after the evaporation of the solvents a film having a substance weight of 110 g / m2 is produced. in which the impermeable backing layer for the active substance is laminated. Here the upper sheet is produced. After removal of the finished protective layer without adhesive (B) from the lower sheet, centrally placed discs are made of a fleece fabric (70:30 combination of viscose-cotton rayon fiber, with substance weight 40 g / m2) or paper (26 or 24 g / m2 respectively). Subsequently, the preparation of active substance is dosed in the disks of fleece or paper material, respectively. After the removal of the finished protective layer without adhesive (C), the topsheet is laminated to the bottom sheet (finished with discs of fleece or paper material and provided with preparation of active substance), and from this the transdermal therapeutic systems are punctured. The results are evident from the following table: As is evident from the table, this is possible when fleece material is used to produce only 1, 200 transdermal therapeutic systems. Then, the cleaning of the device is required to transfer the active substance (plug). Contrary to this, more than 100,000 transdermal therapeutic systems can be produced when paper is used, without the need to stop the machinery because cleaning becomes necessary.

EXAMPLE 2 Transdermal therapeutic systems were produced according to example 1 and the precision of the dosage was determined. The amount of nicotine contained in the simple therapeutic systems was determined and the results were evaluated statistically. It was found that the transdermal therapeutic systems that had been produced using paper have a significantly lower relative standard deviation (S-rel (%)) (see Figure 3).

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A transdermal system containing as essential features: (a) a backing layer (10) impermeable to the active substance, remote from the skin, (b) at least one deposit of active substance (14), (c) a matrix that is in communication with the active substance reservoir and controls the release of the active substance, and (d) a fixation device (16) addable to the therapeutic system on the skin (18), still containing the reservoir and / or the matrix supporting materials, characterized in that the support material consists of paper and the active substance is lidocaine, diphenylhydramine hydrochloride, salbutamol, 5-fluorouracil, but in particular one or more sex hormones, or progestagens or fentanyl.

2. The transdermal therapeutic system according to claim 1, further characterized in that the active substance is estradiol, norethindrone acetate or levonorgestrel.

3. The transdermal therapeutic system according to claim 1 or 2, further characterized in that the paper has a surface weight of 9-60, preferably 15-40, in particular 20-35 g / m2.

4. A process for the improved production of transdermal therapeutic systems with a dispersion of the applied amounts of active substance below 2%, further characterized in that the active substance is applied in a conventional manner by means of a stopper on a support material, which It consists of paper.

5. The method according to claim 4, further characterized in that the dispersion of the applied amounts of active ingredient is below 2%.

6. The process according to claim 4 or 5, further characterized in that the paper has a surface weight of 9-60, preferably 15-40, in particular 20-35 g / m2.