WO2004069231A1

WO2004069231A1 - Transdermal therapeutic system with improved adhesion to the skin

Info

Publication number: WO2004069231A1
Application number: PCT/EP2004/000490
Authority: WO
Inventors: Reinhold Meconi; Frank Seibertz
Original assignee: Lts Lohmann Therapie-Systeme Ag
Priority date: 2003-02-07
Filing date: 2004-01-22
Publication date: 2004-08-19
Also published as: DE10304988A1

Abstract

The invention relates to a transdermal therapeutic system (TTS) containing a backing and at least one layer that is in contact with the skin, the latter layer containing a pharmaceutical active ingredient and at least one polymer and ensuring adhesion to the skin of the user during the use of the transdermal therapeutic system. The layer that is in contact with the skin is characterised by the presence of a substance that modifies the adhesive force, such as carbopol, dexpanthenol, lanolin or tylose. In preferred embodiments, the lanolin and/or dexpanthenol content of the layer that is in contact with the skin is at least 0.5 wt. %.

Description

Transdermal therapeutic system with improved

Skin stickiness

The present invention relates to a transdermal therapeutic system (TTS) which contains at least one active pharmaceutical ingredient, preferably nicotine.

Transdermal therapeutic systems (TTS) have been known for years and are used for the prophylaxis of angina pectoris, for hormone replacement therapy, for pain treatment, for pregnancy prevention and to support smoking cessation. Well-known products are Nicotinell ^® , Habitrol ^® , Nicoderm ^® , Nicorette ^® , Prostep ^® and Nicotrol ^® . These systems have a layered structure and contain a nicotine-impermeable backing layer, at least one nicotine-containing matrix or reservoir layer, possibly a support layer made of a nonwoven material, possibly a membrane controlling the release of nicotine and possibly a pressure-sensitive adhesive layer. Details of these devices are described, for example, in EP 261 402 A1, WO 89/12470 A1, EP 289 342 A2 and WO 89/07429 A1.

Due to the way a transdermal therapeutic system works, the pharmaceutical active ingredient, even if its main quantity is contained in a layer further away from the skin, must ultimately pass through a layer which is located directly on the skin and ensures the adhesion of the TTS to the skin. In this layer - referred to below as the "skin contact layer" - the concentration of the active substance (in particular nicotine) can be lower or higher than in other layers (reservoir layer, speed-controlling membrane) of the TTS.

As is known from the prior art, nitroglycerin and nicotine in particular are considered to be active ingredients which can act as plasticizers, dispersants and / or solvents for certain polymers and polymer compositions. To prevent the TTS required amount of active ingredient (or correspondingly the active ingredient concentration) now causes an undesired softening or dissolving of the skin contact layer, for the sake of simplicity the properties of the polymer used (or the polymer mixture) are dependent on the required amount of active ingredient, which may depend on the duration of use and the indication, customized.

For such an adjustment of the material properties, the person skilled in the art can on the one hand modify the degree of polymerisation (average molecular weight) and / or the degree of crosslinking of the polymer and on the other hand change the content of additional plasticizers, thickeners, solvents, permeation enhancers, fillers, tackifiers etc. Monomers with special properties can also be polymerized in different proportions, for example, it is known that the properties of ethylene-vinyl acetate copolymers can be greatly changed by the vinyl acetate content, depending on the vinyl acetate content, appropriate copolymers are used to produce composite films and stretch films , used as seals and adhesives, for hot melt adhesives and latices for emulsion paints.

It should be noted that the typical properties of the polymer (or the polymer mixture) such. B. the elasticity, flexibility, plasticity, etc., which essentially determine the physical-physical nature of the skin contact layer of the TTS, may only change slightly by the release of the active ingredient (e.g. nitroglycerin, nicotine) during use. As a result of this adaptation of the properties of the polymer (or polymer mixture) to the amount of active ingredient required in the TTS, a skin-containing layer contains an active ingredient-containing (in particular nicotine-containing) polymer mixture which largely maintains its consistency over the entire period of use and thus essentially constant drug release enables.

The most important properties of the polymer (or the polymer mixture) of the skin contact layer can be considered to be cohesion and adhesion. The Cohesion causes the internal strength of the polymer (or the polymer mixture). The adhesion allows the polymer (or the polymer mixture) to adhere to a material surface. In the case of a TTS, pressure-sensitive polymers or pressure-sensitive polymer mixtures are used to make intimate and permanent contact with the skin surface of the user. Ultimately, it is the properties of cohesion and / or adhesion of a polymer (or the polymer mixture) that are modified by the said adaptation of the material properties to the required amount of nicotine.

As a rule of thumb, it can be said that if the cohesion is too low, an increase in the degree of crosslinking and / or the degree of polymerization can result in an increase. If the adhesion is too low, this can usually be increased by adding plasticizers, solvents and / or tackifiers. However, these two properties can usually not be designed completely independently of one another. For example, the measures for a desired increase in adhesion can bring about an undesirable reduction in cohesion and vice versa. The person skilled in the art will usually optimize the properties (for example cohesion, adhesion) of the polymer or the polymer mixture of the skin contact layer on the other constituents of this layer by means of series tests.

It has now been shown that the adhesive force of the skin contact layer can be impaired by transdermal therapeutic systems on the skin if external factors - for example excessive sweating of the skin (increased sweating), the higher humidity in the tropical and subtropical regions of the earth or higher Temperatures - can influence this during the application and / or storage of the transdermal therapeutic systems. There are indications that in particular nicotine-containing transdermal therapeutic systems in tropical and subtropical regions do not adhere satisfactorily to the skin of many users. This can have the consequence that the TTS falls off before the end of the predetermined application period and / or that the TTS does not cover the entire area of the Skin sticks. These two consequences of insufficient skin adhesion can have a negative impact on the success of the therapy.

The object of the present invention is therefore to improve the adhesive strength of the skin contact layer of a transdermal therapeutic system (TTS) without the need to carry out a completely new adjustment of the material properties of the polymer (or the polymer mixture). In particular, the adhesion of this layer to the skin is to be improved in a simple manner. The release behavior of the active pharmaceutical ingredient, which is an important pharmacological quality feature of a TTS, should not be impaired.

The object is achieved by a transdermal therapeutic system (TTS), which contains a backing layer and a skin contact layer, which contains a pharmaceutical active ingredient and at least one polymer and ensures the adhesion of the TTS to the skin, this skin contact layer containing at least one substance which Modified adhesive strength. Lanolin, dexpanthenol, carbopol and tylose are particularly suitable as such a substance that modifies the adhesive strength (“adhesive force modifier”). The adhesive force modifiers themselves are not pressure-sensitive adhesive.

The proportion of the adhesive strength modifier in the skin contact layer is at least 0.1% by weight. However, the skin contact layer preferably contains larger amounts, in particular 0.5% by weight of lanolin and / or 0.5% by weight of dexpanthenol and / or 0.1% by weight of Carbopol and / or 0.1% by weight of tylose , The skin contact layer preferably contains 1 to 20% by weight of lanolin and / or 1 to 30% by weight of dexpanthenol and / or 0.1 to 3% by weight of Carbopol and / or 0.1 to 2% by weight of tylose. Quantities between 3 and 10% by weight of lanolin or 2 to 20% by weight of dexpanthenol or 1 to 2% by weight of Carbopol or 0.1 to 1% by weight of tylose are particularly preferred. Any active pharmaceutical ingredient which can be administered transdermally can be considered as the active ingredient, preferably acetylsalicylic acid, buprenorphine, clonindine, estradiol, fentanyl, levonorgestrel, methylphenidate, nicotine, nitroglycerin, noretistherone acetate, oxybutinin, ropinirole and scotaminophenol, testosterone, rotigotonafil, testosterone, testosterone. The active substances nitroglycerin and nicotine are particularly preferred, since these are known to have a pronounced behavior as plasticizers for polymers.

Lanolin (also: Adeps Lanae, Wollwachs) is obtained from the secretion of the sebum glands of the sheep. Extraction of the sheep fleece gives the unpurified preliminary stage. After specific cleaning stages, including neutralization and deodorization, the "neutral wool wax" is obtained. After its drainage, the water-free quality is obtained. Subsequent, additional high vacuum distillation can be used to obtain products of the highest quality. Lanolin contains natural cholesterol esters that give it its hydrophilic character. The anhydrous lanolin has a water absorption capacity of 200 - 300%, which enables it to form stable W / O emulsions. Lanolin consists of a mixture of esters, di-esters and hydroxy esters. So far, 69 aliphatic C-κ-C- ₃₆ alcohols and 6 sterols (cholesterol, dihydrocholesterol, lanosterol, dihydroianosterol, agnosterol and dihydroagnosterol) and 138 C _δ -Cι fatty acids have been extracted from lanolin. Lanolin has the CAS number [8006-54-0].

Chemically speaking, dexpanthenol is (R) -2,4-dihydroxy-N- (3-hydroxypropyl) -3,3-dimethylbutanoic acid amide, also (R) -2,4-dihydroxy-3,3-dimethylbutyric acid Called -3-hydroxypropylamide. Other names are D-panthenol, pantothenol, D-pantothenyl alcohol, provitamin B5. Undiluted dexpanthenol is a clear, colorless and highly viscous liquid that attracts water (somewhat hygroscopic properties) and can form crystalline deposits or even solidify after prolonged storage. The CAS number is: [81- 13-0]. Carbopol ^® is a highly acidic, cross-linked acrylic acid polymer with a high molecular weight. The CAS number is: [9003-01-4] Carbopol 934 P is particularly preferred.

Tylose ^® is cellulose ether, in particular methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, methyl hydroxypropyl cellulose, ethyl hydroxyethyl cellulose and carboxymethyl cellulose, which can differ from one another in the type and degree of etherification and in their viscosity range.

The following are suitable as polymers: polyacrylates, polyisobutylenes, ethylene-vinyl acetates, polyurethanes, polyisoprenes, polyvinyl alkyl ethers, polyvinyl alcohols, polyvinyl acetates, polyvinyl pyrrolidones, polyacrylonitrile, polybutadiene, polybutene, polycarbonate, polychlorotrifluoroethylene, polydialkylsiloxane, polyethyleneglycol, polyethylene, polyisglyophenyl, poly, glycol, polyisglyoxene, polyethylene, polyisglyophenyl, poly, glycol, poly, glycol, poly, glycol, poly, glycol, poly, glycol, poly, glycol, poly, glycol, poly, glycol, poly, glycol, Polyethylene glycol ether, polyglycol ester, polyisobutene, polypeptides, polypropylene, polystyrene, polytetrafluoroethylene, polyurethane, polyvinyl alcohol, polyvinyl chloride, polyvinyl ester, polyvinyl ether, polyvinylidene chloride, proteins, vinyl acetate-ethylene acrylate copolymers, styrene-isoprene-styrene block polymers, carrageenanextrin, carrageenane, carrageenanine, carrageenanine Rubber, alginates, pectin, synthetic and natural polysaccharides, vegetable gums, gum arabic, cellulose, starch, gelatin, or mixtures of at least two of these polymers.

Polyacrylates are particularly preferred, in particular those which can be obtained by polymerizing at least one of the following monomers: acrylic acid, methacrylic acid, n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate, tert-butyl acrylate, sec. -Butyl acrylate, tert-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate, isopropyl methacrylate, glycidyl methacrylate and vinyl acetate. Also particularly preferred are mixtures of two polyisobutylenes, the first of which has a low average molecular weight (LMW-PIB) between 1,000 and 450,000 and the second a high average molecular weight (HMW-PIB) between 450,000 and 1,600,000 in a ratio of 60- 95: 40-5. Mixtures of two polyisobutylenes, of which the first has an average molecular weight between 20,000 and 50,000 and the second an average molecular weight between 1,000,000 and 1,400,000 in a ratio of 80-90: 20-10 (LMW-PIB: HMW- PIB).

These polymers are pressure-sensitive adhesives, the adhesive properties of the polymers being able to be increased if appropriate by adding tackifiers. Tackifiers are known to the person skilled in the art. These include tackifying resins such as abitol, esters of (hydro-) abietic acid, hydroabietyl alcohol, etc.

The advantage of this solution is that the adhesion of the skin contact layer can be increased by adding the adhesive strength modifier (lanolin, dexpanthenol, carbopol, tylose) without the composition of the other components of the skin contact layer having to be changed and without the release behavior of the active pharmaceutical ingredient being significant being affected. This means that the release behavior ensures the "bioequivalence" of a transdermal therapeutic system modified in this way. In particular, the material properties of the polymer or the polymer mixture of the skin contact layer need not be changed, and the proportions of auxiliaries such as plasticizers, tackifiers, fillers etc. The cohesion of the skin contact layer was also not significantly impaired by the addition of the adhesive strength modifiers.

The following examples serve to illustrate the solution according to the invention. Transdermal therapeutic systems (TTS) were produced, which have a backing layer, an active substance-containing matrix layer and a skin contact layer. The skin contact layer was covered with a removable protective layer during storage of the TTS. The compositions of the total of 21 different skin contact layers are given in Figure 1 = Table 1.

To carry out the adhesive tests, the TTS were worn over a period of 24 hours in the area of the chest or lumbar spine (approx. 30 subjects in 3 groups). 7-8 TTS were glued to each subject. All subjects were made to sweat during exercise during exercise. The subjects were then able to take a shower. The adhesive behavior was then assessed. (Figure 2 = Table 2 and Figure 3 = Table 3)

The releasability was assessed using the evaluation scheme given in Table 3. After the end of the gestation period, the subjects had to assess the adhesive behavior of the (full-surface adhesive) plasters according to this scheme. The mean value resulted from the formation of the quotient from the sum of the evaluation numbers by the number of fully adhering plasters. For the standard plaster used in this experiment (formulation 16), this gave a rating of 4.73.

As can be seen, the formulations with lanolin, carbopol, dexpanthenol and tylose achieve values in the range between 4.79 and 5.14. Values below 4.73 were regarded as a deterioration in the adhesive strength. Lanolin and dexpanthenol have the advantage that they can be used over a relatively wide range of parts by weight, while Carbopol and Tylose, on the other hand, achieve a change in the adhesive force even with small amounts in the skin contact layer.

It should be understood that this example cannot represent the full scope of the invention and, therefore, should not be construed as limiting the invention.

Claims

claims

1. Transdermal therapeutic system (TTS) for the controlled release of a pharmaceutical active substance, comprising a backing layer and a skin contact layer, which contains a pharmaceutical active substance and at least one polymer and ensures its adhesion to the skin during use of the TTS, characterized in that the skin contact layer contains at least 0.1% by weight of a substance which modifies the adhesive force.

2. Transdermal therapeutic system according to claim 1, characterized in that the adhesive modifying substance from the group comprising carbopol, dexpanthenol, lanolin and tylose or a mixture thereof.

3. Transdermal therapeutic system according to claim 1 or 2, characterized in that the skin contact layer contains at least 0.5 wt .-% lanolin and / or dexpanthenol.

4. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the skin contact layer contains between 1 and 20% by weight of lanolin and / or between 1 and 30% by weight of dexpanthenol.

5. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the pharmaceutical active ingredient from the group comprising acetylsalicylic acid, buprenorphine, clonidine, estradiol, fentanyl, levonorgestrel, methylphenidate, nicotine, nitroglycerin, norethisterone acetate, oxybutirolin, rotopininirinol, rinotinirinol, rinopinorphinol Scopolamine, Sildenafil and Testosterone is selected.

6. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the skin contact layer is a polymer from the group of polyacrylates, polyisobutylenes, ethylene-vinyl acetates, polyurethanes, polyisoprenes, polyvinyl alkyl ethers, polyvinyl alcohols, polyvinyl acetates, polyvinyl pyrrolidones, polyacrylonitrile, polybutadiene, polybutadiene , Polycarbonate, polychlorotrifluoroethylene, polydialkylsiloxane, polyisoprene, polyisobutadienes, polyether, polyethylene, Polyethylene glycol, polyethylene glycol ester, polyethylene glycol ether, polyglycol ester, polyisobutene, polypeptides, polypropylene, polystyrene, polytetrafluoroethylene, polyurethane, polyvinyl alcohol, polyvinyl chloride, polyvinyl ester, polyvinyl ether, polyvinylidene chloride, proteins, vinyl acetate-ethylene acrylate copolymers. Styrene-isoprene-styrene block polymers, carrageenan, carrageen, dextrins, polypeptides, rubber, alginates, pectin, synthetic and natural polysaccharides, vegetable gums, gum arabic, cellulose, starch, gelatin, hydroxypropylmethyl cellulose or a mixture of at least two of these polymers ,

7. The transdermal therapeutic system as claimed in one or more of the preceding claims, characterized in that the polymer is a polyacrylate which is obtained by polymerizing at least one of the monomers from the group comprising acrylic acid, methacrylic acid, n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2 -Ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate, tert.-butyl acrylate, sec.-butyl acrylate, tert.-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate methacrylate, isopropyl acrylate methacrylate, isopropyl acrylate methacrylate, isopropyl acrylate methacrylate, isopropyl methacrylate, isopropyl acrylate methacrylate,

8. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the polymer is a mixture of two polyisobutylenes, the first of which has an average molecular weight (LMW-PIB) between 1,000 and 450,000 and the second an average molecular weight (HMW- PIB) between 450,000 and 1,600,000, in a ratio of 60-95: 40-5 (LMW-PIB: HMW-PIB).

9. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that the polymer is a mixture of two polyisobutylenes, the first of which has an average molecular weight (LMW-PIB) between 20,000 and 50,000 and the second an average molecular weight (HMW- PIB) between 1,000,000 and 1,400,000, in a ratio of 80-90: 20-10 (LMW-PIB: HMW-PIB).

10. Transdermal therapeutic system according to one or more of the preceding claims, characterized in that it is additionally contains at least one further layer from the group comprising the active substance-containing matrix layer, reservoir, nonwoven layer, speed-controlling membrane and barrier layer.

11.Method for modifying the adhesive force of a pressure-sensitive adhesive polymer layer on the skin, characterized in that during the production of the pressure-sensitive adhesive skin contact layer, a substance which modifies the adhesive force in a content of at least 0.1% by weight (based on the weight of the dry skin contact layer ) is added.

12. The method according to claim 11, characterized in that the adhesive modifying substance is selected from the group comprising carbopol, dexpanthenol, lanolin and tylose or a mixture thereof.

13. Use of a substance that modifies the adhesive force to improve the adhesive force of an active substance-containing skin contact layer of a transdermal therapeutic system.

14. Use according to claim 13, wherein the adhesive modifying substance is selected from the group consisting of carbopol, dexpanthenol, lanolin and tylose.