JP4861553B2 - Transdermal therapeutic system and manufacturing method thereof - Google Patents

Description

【００１８】
この表から明らかなように、フリース材料を使用するときは僅かに１２００の経皮治療システムしか製造できない。続いて、活性物質を移す手段（タンポン）の清掃が必要であった。これとは異なり、紙を使用するときは１００,０００より多くの経皮治療システムを製造することができ、清掃が必要になるために機械を停止する必要はなかった。
【００１９】
実施例２
実施例１に従って経皮治療システムを製造しそして投与量の精度を確かめた。単一の経皮治療システム中に含まれるニコチンの量を測定しそして結果を統計的に評価した。紙を使用して製造した経皮治療システムは著しく小さい相対標準偏差（Ｓ−rel(％)）を有することがわかった（図３参照）。
【図面の簡単な説明】
【図１】 本発明の経皮治療システム（ＴＴＳ）の好適な態様を示す。
【図２】 本発明の他の経皮治療システムの好適な態様を示す。
【図３】 支持材料による経皮治療システムのニコチン投与量の精度の変動を示す。[0001]
The present invention relates to a transdermal therapeutic system (TTS) and to a method of manufacturing the same.
Treatment systems are known for transdermal administration of pharmaceuticals such as nicotine, nitroglycerin, sex hormones, scopolamine, and fetanyl. Suitable systems are described, for example, in the international patent application DE 87/00372 (WO 88/01516). Such a system comprises a backing layer that is remote from the skin and is not permeable to the active substance, at least one active substance depot, an active substance dispersing device in contact with it, a control device that controls the delivery of the active substance by the system, And a pressure sensitive adhesive fixation device for a therapeutic system on the skin. The active substance dispersion device is combined with a control device to define one or more discrete active substances having a spatial arrangement relative to each other and having an active substance concentration greater than that of the active substance within the reservoir matrix. A reservoir matrix having an active substance depot can be formed.
[0002]
WO 88/01516 describes a support material that desensitizes the active substance depot to the application of pressure and tension, and that inert depots such as carriers may also include the depot. Yes. According to US Pat. No. 5,820,876, the support material may be a flat cloth (support cloth) as an inert auxiliary, which advantageously distributes the active substance in the depot. FIG. 5 of both of these documents also shows a specific embodiment, according to which, if desired, an auxiliary agent which is a material for facilitating the functioning of the active substance, or a support material such as a cloth. At the same time, an adhesive layer is provided on the backing layer on which the active substance is present. The support fabric may exist as a non-woven fabric (fleece). In examples, a fleece material (50:50 viscose rayon-cotton fiber blend with a substance weight of 80 g / m ² , Paratex II / 80 from the company Lohman GmbH & Co. KG, or a substance weight of 40 g / m ² One 70:30 viscose rayon-cotton fiber blend, Paratex II / 80 from the company Lohman GmbH & Co. KG) is disclosed as suitable. In both examples, it is further stated that the fleece material acts as a support fabric and also serves as an inert aid as defined in the introductory part of the specification to help uniform distribution of nicotine.
[0003]
US Pat. No. 4,597,961 discloses a different form of transdermal therapeutic system. In this system, the delivery of the active substance is generally controlled by a microporous membrane. In the illustration of FIG. 2, reservoir 114 may include a suitable absorbent material 122, such as sponge or cotton, into which a desired amount of liquid nicotine is absorbed. Furthermore, in Example 4, it is pointed out that the reservoir 114 may include an inert fibrous or porous dense matrix such as cotton, which prevents the loss of nicotine. However, in this context, the term “matrix” is used for technical features that are quite different from those in WO 88/01516 and US Pat. No. 5,820,876.
[0004]
From U.S. Pat. No. 4,915,950 a TTS for nicotine is further known, in which a depot layer (13) is placed between an adhesive (14) acting as a control device and a fixing adhesive (12). Yes. The active material deposit layer may consist of a non-woven fabric (fleece) such as polyester, polyethylene, polypropylene, polyamide, rayon or cotton, and in particular a 100% polyester non-woven fabric. There is no disclosure or suggestion regarding the use of paper in this specification.
[0005]
It has now been found that when the support material is paper instead of known support materials, particularly including fabrics such as fleece, a TTS is obtained that has substantially improved quality compared to the known state of the art. It was. Paper is fundamentally distinguished from fabrics that include nonwovens (fleece) by the fact that by reinforcement, the cellulose fibers together form a thin layer in the paper. The aggregation of fibers in the paper is carried out by chemical bonds (hydrogen bonds) formed between the hydroxyl groups of the cellulose molecules during the manufacture of the paper, in addition to the mechanical adhesion and interconnection of the fibers. This chemical bond is so strong that the tensile strength of the paper even exceeds the tensile strength of ordinary building steel (RM Consult Papiermaschinen Info-http: //home.-online.de/home/rm.consult/rm-info .htm, November 17, 1998). In addition, the paper has the advantage that it has a high absorption capacity for the liquid phase, which is characterized by DIN ISO 8787 as wicking height. The measured longitudinal suction height for paper having a reference weight of 26 g / m ² is 146 mm / 10 minutes and 143 mm / minute in the transverse direction, which is the Paratex III / 40 of the fleece material described above. Compared to about 110 and 80 mm / min. In this case, the value for the fleece changes very significantly in a series of tests. Usually, paper does not contain a binder and therefore no incompatibility can occur between the active substance and the binder.
[0006]
The subject matter of the present invention is an essential component:
a) a backing layer that is far from the skin and is not permeable to the active substance,
b) at least one active substance depot,
c) a matrix that contacts the active substance depot and controls the delivery of the active substance, and d) a therapeutic system comprising a pressure sensitive adhesive fixation device for the therapeutic system on the skin, where the depot or matrix or both are paper A support material consisting of
[0007]
There are various advantages to using paper as a support material and inert adjunct in accordance with the present invention. When using a fabric such as a fleece, there is a range of variation in the amount of active substance transferred to a single TTS, which occurs despite good dosing techniques. For example, the amount of nicotine transferred to a single TTS is found to vary in the range of about 4% when using a fleece (70:30 viscose-cotton fiber blend, material weight 40 g / m ² ). ing. In accordance with the present invention, when the paper is used instead, the scope of variation is quite small, this range depending on the area weight of the paper is considerably less than 2%, in the paper for example, the reference weight is 23 g / m ² 1 It is even less than 1.2% for papers of less than 9.9% and a basis weight of 26 g / m ² . Desired paper 9~60g / m ^2, preferably a basis weight of 15 to 40 g / m ² and particularly 20 to 35 g / m ^2.
[0008]
However, the use of paper as a support material in the TTS of the present invention is important not only for the homogeneity of the manufactured TTS, but also for the manufacturing technology. When following known methods, a defined amount of active substance is transferred to the support material by a tampon. This means that in this way an amount of support material is scraped off by the tampon and entrained in releasing the tampon from the support material. For this reason, it is necessary to clean the tampon at certain time intervals and therefore the manufacturing process must be interrupted. When using paper according to the present invention, the fretting is significantly reduced, which can be explained by the fact that the paper fibers are more strongly connected to each other than, for example, a fleece or other fabric. It is known that fibrous pieces emerge from all fabrics. By using paper in accordance with the present invention, the ability of the tampon to function can be extended by at least 10 times, mostly 50-100 times, thus requiring cleaning of the tampon and thus interrupting the manufacturing process. It becomes less frequent.
[0009]
The TTS of the present invention may be of various shapes. A preferred embodiment is shown in the attached FIGS. However, other embodiments are possible, as disclosed, for example, in international application WO 88/01516. According to FIGS. 1 and 2, the TTS consists of a backing layer (10), a reservoir matrix (12), one or more depots (14) and an anchoring device (16), which is prior to dispensing. There is a protective foil that is removed, and then the system is secured to the skin (18). Of course, this protective foil must also not be permeable to the active substance.
Materials known to those skilled in the art are used for the backing layer, reservoir matrix, anchoring device and protective foil.
[0010]
The subject of the invention is also an improved method of manufacturing a transdermal therapeutic system with a small range of variation in the amount of active substance applied, in which case the active substance is applied in a conventional manner by means of a tampon to a support material consisting of paper. Applied. In a preferred embodiment, the variation in the amount of active substance applied (relative standard deviation) achieved with the method of the invention is less than 2%, in particular less than 1.2%.
The final subject of the present invention is the use of paper in the transdermal therapeutic system as a support and dispersion medium.
[0011]
The system according to the invention is in principle suitable for all active substances which can be administered transdermally. In addition to those mentioned above, lidocaine, diphenylhydramine hydrochloride, salbutamol, 5-fluorouracil can be mentioned, and sex hormones can include estradiol and also gestagens such as norethindrone acetate, levonorgestrel.
[0012]
Example 1
First a) commercial product (Netherlands Zutphen Company, National Starch and Chemical of Durotak ^(R) 387-2516─ This self-crosslinking of 2-ethylhexyl acrylate, vinyl acetate, based on acrylic acid and titanium chelate ester 933 g of a acrylate polymer in a solvent mixture of ethyl acetate, ethanol, heptane and methanol) b) Triglycerides of rectified coconut oil fatty acid (C ₈ -C ₁₀ ; Huels AG, German company Witten, Germany) Of Miglyol ^(R) 812) 8g
A pressure sensitive adhesive formulation HS was prepared by homogenizing with.
[0013]
Furthermore, Durotak of 6210g ^(R) 387-2516, ethyl acetate 553g and ethanol 311g of the above triglyceride 66g and also acrylic resin made from methacrylic acid esters of dimethylaminoethyl methacrylate and neutral (in Darmstadt, Germany company, Roehm- blended with Eudragit E ^{(R) 100)} 626g of Pharma, and homogenized (adhesive composition MS).
Furthermore, by introducing Eudragit E ^(R) 100 72g to 101g nicotine and dissolved thereto. In this way an active substance formulation was obtained.
[0014]
The pressure-sensitive adhesive composition HS was applied to the non-adhesive protective layer (A) so that a pressure-sensitive adhesive layer having a material weight of 40 g / m ² was formed after evaporation of the solvent.
The adhesive composition MS was applied to another non-adhesive protective layer (B) so that after evaporation of the solvent, a film with a material weight of 220 g was produced. This film was laminated on the pressure-sensitive adhesive layer applied to the protective layer (A). In this way, a lower sheet was obtained.
[0015]
In another coating step, the adhesive composition MS is applied to another protective layer (C) that is dehesively finished so that after evaporation of the solvent, a film having a mass of 110 g is produced. Thereafter, a backing layer having no permeability to the active substance was laminated. Thus, the upper sheet was obtained.
After removing the non-adhesive protective layer (B) from the lower sheet, a fleece fabric (70:30 viscose rayon-cotton fiber blend, material weight 40 g / m ² ) or paper (26 or 24 g / m respectively) The disc made from m ² ) was placed in the center.
[0016]
The active substance formulation was then dispensed into each of the fleece material or the paper disc.
After removing the non-adhesive protective layer (C), the upper sheet is laminated onto the lower sheet (prepared with a fleece material or paper disc and provided with the active substance formulation). And from now on, I cut through the transdermal therapeutic system. The results are clear from the table below.
[0017]
[Table 1]

[0018]
As can be seen from this table, only 1200 transdermal therapeutic systems can be manufactured when using fleece materials. Subsequently, cleaning of the means for transferring the active substance (tampon) was necessary. Unlike this, when using paper, more than 100,000 transdermal treatment systems could be manufactured and the machine did not have to be stopped because cleaning was required.
[0019]
Example 2
A transdermal therapeutic system was manufactured according to Example 1 and dose accuracy was verified. The amount of nicotine contained in a single transdermal therapeutic system was measured and the results were evaluated statistically. A transdermal therapeutic system manufactured using paper was found to have a significantly smaller relative standard deviation (S-rel (%)) (see FIG. 3).
[Brief description of the drawings]
FIG. 1 shows a preferred embodiment of the transdermal therapeutic system (TTS) of the present invention.
FIG. 2 shows a preferred embodiment of another transdermal therapeutic system of the present invention.
FIG. 3 shows the variation in accuracy of nicotine dosage in a transdermal therapeutic system with a support material.

Claims (6)

As essential constituents: a) A backing layer (10) that is remote from the skin and is not permeable to the active substance,
b) at least one active substance depot (14),
c) a matrix (12) in contact with the active substance depot and controlling the delivery of the active substance;
d) including a pressure sensitive adhesive anchoring device (16) for the treatment system on the skin (18), including a support material consisting of paper with a depot and / or matrix having a basis weight of 9-60 g / m ² And the active substance is lidocaine, diphenylhydramine hydrochloride, salbutamol, 5-fluorouracil, or one or more sex hormones or gestagens, or fentanyl.   The transdermal therapeutic system according to claim 1, wherein the active substance is estradiol, norethindrone acetate or levonorgestrel. Transdermal therapeutic system according to claim 1 or 2 paper having a basis weight of 1 5 to 40 g / m ^2. Active substance to a support material consisting of paper thus applied to the tampon down, less than the variation of 2% of the amount of active material applied, the transdermal therapeutic system according to any one of claims 1 3 Improved manufacturing method.   5. A process according to claim 4, wherein the variation in the amount of active substance applied is less than 1.2%. 6. A method according to claim 4 or 5, wherein the paper has a basis weight of 15 to 40 g / m < ² >.

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