Percutaneous therapeutic system based on nicotine, additionally containing monoterpenes

 

The invention relates to the field of drugs. Proposed percutaneous therapeutic system consisting of a substrate, at least one containing nicotine layer or region can have the ability to stick when pressed, as well as removable protective layer containing at least one essential oil, extracted from one of the varieties of mint, or at least one monoterpenes contained in these essential oils. A way to mask the unpleasant smell percutaneous therapeutic system caused contains nicotine. The proposed system is the most neutral and pleasant to use compared with the known technical solutions. 2 C. and 7 C.p. f-crystals, 1 tab., 1 Il.

The present invention relates to the addition to percutaneous therapeutic system based on nicotine substances, improve their smell. More precisely the invention relates to transdermal therapeutic systems based on nicotine containing such additives, as well as to a method of masking the unpleasant odor of such systems and the use of which improves the smell of the substances to disguise mariacristina therapeutic system based on nicotine widely used in the treatment of nicotine addiction. However, industrially produced systems are characterized by their strong smell of nicotine, especially felt when removing the system from the package and how to use them.

During storage, the period is usually from 2 to 3 years, as a result of partial decomposition of the smell increased and becomes extremely unpleasant.

In the application WO 95/08324 A1 disclosed a method of manufacturing a transdermal therapeutic systems comprising at least two layers, using as the sole solvent vysokoletuchih ingredient. Such transdermal therapeutic system containing several active substances, including nicotine, and other menthol or other volatile derivatives of terpenes as substances that enhance penetration through the skin. The application is not described any particular effect of such additives on the smell of percutaneous therapeutic systems based on nicotine. As for the “volatile derivatives of terpenes”, it does not make any difference between monoterpenic alcohols and Monteriggioni.

In the European patent EP 356382 A2 discloses a percutaneous therapeutic system on the basis of certain block copolymers, in which a researcher is moved to use eucalyptol or eucalyptus oil, at the same time as the main component are especially encouraged to use cineole; the ingredients included in the composition of oils of peppermint, are not considered. Also not addressed the problem of odor patches nicotine.

In U.S. patent US 5599554 And disclosed compositions for crosslisted or percutaneous application of nicotine, which may also contain aromatic substances or fragrances. Mentioned characteristic of nicotine smell, but it is not described as a drawback. As additional ingredients mentioned aromatic compounds, such as menthol or eucalyptol, but not mentioned essential oils of peppermint or techenclave. Not disclosed to the role of such additives. Presumably they serve to improve the taste of compositions intended for oral administration.

In U.S. patent US 5593684 And disclosed a method of treatment based on the simultaneous crosslisted and percutaneous application of nicotine. In this case, for masking the unpleasant taste of nicotine use selected from the containing terpenes plant essential oils in the form of tablets for oral administration.

In U.S. patent US 4933184 disclosed transdermal therapeutic system, different improved percutaneous ol the matter. No mention of any other substances contained in essential oils of various species of mint, such as monoterpenes. Peppermint oil was seen as reinforcing agents and as an alternative to menthol, but, oddly enough, did not provide the expected effect. In the rest of this publication applies only to improve the penetration of the active substance, and not the way to improve the smell of transdermal therapeutic systems.

Thus, the aim of the present invention according to the preamble of claim 1 is neutralizing or masking characteristic odor percutaneous therapeutic systems based on nicotine by adding the corresponding aromatic substances with a more pleasant smell.

The solution to this problem was found by adding the essential oils of various species of mint or their components, in particular monoterpenes. In accordance with the invention, such additives can be used to disguise or improve odor percutaneous therapeutic systems based on nicotine. Transdermal therapeutic system according to the invention contain at least one essential oil containing mainly monoterpenes and extracted from odnri this content monoterpenes (s) in nicotine basis is from 0.1 to 5.0 wt.%.

Components of essential oils of various species of mint are basically the products of metabolism of terpenes, more precisely monoterpene.

Peppermint oils are generally pleasant, refreshing scent. Examples of used oils are peppermint oil, peppermint oil curly or preimenovao oil extracted from various plants.

Typical monoterpene contained in such oils can be divided into monoterpenic alcohols and monoterpenes.

Typical monoterpenic alcohols are menthol, isomenthol, neomenthol, neosolaniol and isopulegol.

Typical monoterpene are Menton, isomenthone, carvon, piperitone, pulegone and isopulegol.

Almost all of them are present as a mirror isomers in optical levogyrate, and programada forms.

As representatives of this group were studied peppermint essential oil (Oleum Mentae peperitae), curly mint (Oleum Mentae crispae) and (Japanese) mint (Oleum Mentae arvensis).

In peppermint oil and mint features mainly contains monoterpenic alcohols, in particular menthol. In contrast, peppermint oil curly for the most part contains monoterpenes, especially carvon (see Europeat], and also, Schneider, Pharmazeutische Biologie [Pharmaceutical biology], 2nd edition, 1988, pages 342-345).

As individual substances were tested (-)-menthol and (-)-menthone, which is typical of monoterpenic alcohol and typical monoterpenes.

Examples:

To study the action of such additives was modeled simplified test system to the smell.

Nicotine in concentrations equal to 7 wt.%, mixed with megliola 812. Miglyol 812 represents a saturated triglyceride, serving as odorless carrier. Mass concentration of nicotine equal to 7%, roughly corresponds to the concentration of the active substance used in transdermal therapeutic systems at a concentration of 5-10 wt.%. Mixing nicotine with megliola carried out under vapor pressure comparable to the pressure percutaneous therapeutic systems, which provided a similar odor intensity. In this test mixture was added 5 test substances or mixtures:

(-) - menthol and (-) - menthone, peppermint oil (according to the quality requirements of the European Pharmacopoeia), peppermint oil curly (according to the quality requirements of the pharmaceutical Code of the Federal Republic of Germany) and peppermint oil (according to the requirements of the quality of the 15 samples tested. In addition, one sample was obtained without the use of additives that improve the smell.

The smell mentioned 16 samples were evaluated by six persons, in this case it was not known which and how many of the relevant additives contained in the samples.

Below are the evaluation criteria and associated points:

1. The smell of nicotine: invisible (4); weak (3);

moderate (2); clear (1)

2. Overall impression: unpleasant odour (1); neutral smell (2);

pleasant smell (3); aromatic smell (4)

Before both the assessments made by each taster, were summed for each sample, the scores for the criterion “overall impression” were multiplied by a factor of 2 in order to give them more meaning than by the criterion of "the smell of nicotine". A higher score indicates a more favorable evaluation. The scoring system was used to calculate the mean score. The minimum theoretical estimate is 3.0, and the maximum theoretical score to 12.0. The results are shown in table 1.

The sample, containing no additives, received a score of 4.0.

In the drawing, the test results are displayed in graphical form.

The table clearly follows that Menton has undeniable advantages the left menthol (see, Schneider, Pharmazeutische Biologic [Pharmaceutical biology], 2nd edition, 1988, page 345), were rated lower than the samples containing peppermint oil, mainly to 32% of Menton (see the European Pharmacopoeia, 1997).

Finally, the highest scores were received samples containing peppermint oil curly, mainly carvon, and does not contain menthol.

In General, this shows a clear advantage of monoterpenes or mixtures of monoterpenic alcohols and monoterpenes over monoterpenic alcohols in pure form.

In practice, the process of adding substances according to the invention in percutaneous therapeutic system on the basis of nicotine is associated with certain difficulties due to the high volatility of these substances; however, these difficulties can be overcome if you follow the instructions from application PCT/WO 95/08324.

According to the invention, the number of monoterpenes (s) or essential oils contained in the nicotine-based transdermal therapeutic system with improved odor, is in the range from 0.1 to 5.0 wt.%, preferably from 0.5 to 2 wt.%.

Thus, the addition of substances according to the present invention in percutaneous therapeutic system based nicotine is effective properties described in the preamble of paragraph 1, are different, as mentioned above, the fact that they contain at least one essential oil selected from one of the species of mint, or monoterpenes contained in these essential oils.

Preferably monoterpenes represents one of the compounds of the group comprising carvon, dihydrocarvone, Menton, isopulegol, isomenthone, neomenthol, neotomodon or piperitone. Monoterpenes can be used as a mirror isomers in pure form or as mixtures thereof.

Particularly preferable as the essential oils used peppermint oil curly (Oleum Mentae crispae).

The content of monoterpenes (s) or essential oils containing nicotine basis is preferably from 0.5 to 2 wt.%. The invention also relates to a method for masking the unpleasant odor percutaneous therapeutic system caused contains nicotine. This method is characterized in that the percutaneous therapeutic system based on nicotine add at least one improves the smell of the substance constituting the essential oil containing mainly monoterpenes and extracted from one of the varieties of mint, or monoterpenes, stergiadou nicotine base in an amount of from 0.1 to 5.0 wt.%.

In this case, the above-mentioned monoterpenes or peppermint oil can preferably be used respectively as monoterpenes or essential oils. It is possible to use monoterpenes as the mirror isomers in pure form or as mixtures thereof.

The content of monoterpenes (s) or essential oils(oils) in nicotine basis is preferably from 0.5 to 2 wt.%.

In addition, the invention relates to the use of essential oils extracted from one of the varieties of mint, and/or monoterpenes contained in the essential oil, extracted from one of the varieties of mint, for masking the unpleasant odor percutaneous therapeutic system caused contains nicotine.

Preferably use monoterpenes, representing one of the compounds of the group comprising carvon, dihydrocarvone, Menton, isopulegol, isomenthone, neomenthol, neotomodon or piperitone. Monoterpenes can be used as a mirror isomers in pure form or as mixtures thereof.

Particularly preferable as the essential oils used peppermint oil curly (Oleum Mentae crispae).

According to this etancelin (s) or essential oils are added to nicotine base, preferably in quantities of from 0.1 to 5.0 wt.%, particularly preferably, in quantities of from 0.5 to 2 wt.%.

Claims

1. Percutaneous therapeutic system consisting of a substrate, at least one layer containing nicotine or area, possess the ability to stick when pressed, as well as removable protective layer, characterized in that it contains at least one essential oil containing mainly monoterpenes and extracted from one of the varieties of mint, or at least one monoterpenes contained in essential oils, the content of monoterpenes(s) in nicotine basis is from 0.1 to 5.0 wt.%.

2. Transdermal therapeutic system according to p. 1, characterized in that monoterpenes represents one of the compounds of the group comprising carvon, dihydrocarvone, Menton, isopulegol, isomenthone, neomenthol, neotomodon or piperitone.

3. Transdermal therapeutic system according to p. 2, characterized in that monoterpenes used as a mirror isomers in pure form or as mixtures thereof.

4. Transdermal therapeutic system according to p. 1, characterized in that the quality of the essential oil use oil of mint curly (Oleum is connected with the fact, the content of monoterpenes(s) in nicotine-based ranges from 0.5 to 2 wt.%.

6. Way to mask the unpleasant smell percutaneous therapeutic system caused contains nicotine, characterized in that percutaneous therapeutic system based on nicotine add at least one improves the smell of the substance constituting the essential oil containing mainly monoterpenes and extracted from one of the varieties of mint, or monoterpenes contained in the essential oil, extracted from one of the varieties of mint, with monoterpenes(s) is added to nicotine base in an amount of from 0.1 to 5.0 wt.%.

7. The method according to p. 6, wherein the essential oil is an oil of mint curly (Oleum Mentae crispae).

8. The method according to p. 6, characterized in that monoterpenes represents one of the compounds of the group comprising carvon, dihydrocarvone, Menton, isopulegol, isomenthone, neomenthol, neotomodon or piperitone.

9. The method according to p. 8, characterized in that monoterpenes(s) is added to nicotine base in an amount of from 0.5 to 2 wt.%.

 

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