DE29923242U1 - Transdermal therapeutic system (TTS) containing tolterodine - Google Patents

Description

-1- Transdermal Therapeutic System (TTS) containing tolterodine

Description

The present invention relates to a transdermal therapeutic system (TTS) for the transcutaneous administration of tolterodine over several days.

The bioavailability of orally or intravenously administered active substances is often unsatisfactory. The hepatic metabolism of many active substances can lead to undesirable concentration ratios, toxic by-products and a reduction in the effect or even a loss of effect during the first passage through the liver. Transdermal administration of active substances has various advantages over oral administration. The supply of active substances can be better controlled over a longer period of time, which avoids large fluctuations in blood levels. In addition, the required therapeutically effective dose can usually be significantly reduced. In addition, patients often prefer a patch to taking tablets once or several times a day.

In the past, in order to overcome the aforementioned disadvantages of non-transdermal administration of active substances, a variety of transdermal therapeutic systems (TTS) with different structures for different active substances for the treatment of different diseases were developed.

The technical documents listed below describe the parenteral administration of a wide variety of systemically or locally reacting active substances based on either dose-controlled or general release systems. Examples of these are U.S. P. (U.S. patent numbers)

3,598,122 A; 3,598,123 A; 3,731,683 A; 3,797,494 A; 4,031,894A; 4,201,211A; 4,286,592 A; 4,314,557 A; 4,379,454 A; 4,435,180A; 4,559,222 A; 4,568,343 A;

4,573,995A, 4,588,580A; 4,645,502 A; 4,702,282 A; 4,788,062 A; 4,816,258 A; 4,849,226 A; 4,908,027A; 4,943,435 A and 5,004,610 A.

In the late 1960s, it was originally theoretically assumed that any active substance with a short half-life but high potency and good skin permeability was suitable for safe and effective administration via a TTS. However, these initial expectations regarding the possibilities of transdermal administration of active substances via TTS could not be fulfilled. The main reason for this is that the skin is naturally endowed with a vast variety of properties in order to maintain its function as an intact barrier against the penetration of non-endogenous substances into the body. (See: Transdermal Drug Delivery: Problems and Possibilities, B.M. Knepp et al., CRC Critical Review and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987)).

Therefore, transdermal administration is only available for those few active substances that have a suitable combination of many favorable characteristics. However, for a specific active substance, these required characteristics, which are intended to ensure safe and effective transdermal administration, are not predictable.

The requirements for an active substance suitable for transdermal administration are:

- skin permeability,

- no impairment of the adhesive properties of the plaster by the active ingredient,

- Avoid skin irritations,

- Avoiding allergic reactions,

- favourable pharmacokinetic properties,
- favourable pharmacodynamic properties,

- a relatively wide therapeutic window,

- Metabolism characteristics consistent with therapeutic use during continuous administration.

Undoubtedly, the above list of requirements is not exhaustive. In order for an active substance to be available for transdermal administration, the "right" combination of all these requirements is desirable.

The above for the active ingredients applies equally to the TTS composition containing the respective active ingredient and its structural design.

Transdermal therapeutic systems (TTS) are usually patches that are equipped with an impermeable cover layer, a removable protective layer and a matrix containing the active substance or a reservoir containing the active substance with a semi-permeable membrane. In the first case they are called matrix patches, in the second case they are called membrane systems.

Polyester, polypropylene, polyethylene, polyurethane, etc. are usually used for the top layer, which can also be metallized or pigmented. Polyester, polypropylene or paper with a silicone and/or polyethylene coating can be used for the removable protective layer.

For the pharmaceutically or medically common active ingredient-containing matrices, substances based on polyacrylate, silicone, polyisobutylene, butyl rubber, styrene/butadiene copolymer or styrene/isoprene copolymer are used.

The membranes used in membrane systems can be microporous or semipermeable and are usually formed on the basis of an inert polymer, in particular polypropylene, polyvinyl acetate or silicone.

While the active ingredient-containing matrix compositions can be self-adhesive, depending on the active ingredient used, active ingredient-containing matrices can also be non-self-adhesive, so that as a result the patch or TTS must be structurally provided with an overtape.

To ensure the required flux rate of the active ingredient, skin penetration enhancers such as aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols, each mono- or polyhydric and each containing up to 8 C atoms, are often used.

Alcohol/water mixture, a saturated and/or unsaturated fatty alcohol with up to 18 carbon atoms each, a saturated and/or unsaturated fatty acid with 8 to 18 carbon atoms each and/or their esters as well as vitamins as additives are required.

Furthermore, stabilizers such as polyvinylpyrrolidone, a-tocopherol succinate, propyl gallate, methionine, cysteine and/or cysteine hydrochloride are often added to the active ingredient-containing matrix.

As the above list shows, numerous TTS designs and materials used for them are known. However, many interacting requirements must be taken into account if a drug in the form of a TTS is to meet a medical need.

The following issues must be considered when developing drug-containing TTS:

1. The skin permeability for the active ingredient is too low to achieve the therapeutically necessary penetration rate and/or the lag time until the therapeutically required plasma levels are reached is too long, with the consequence that additives to accelerate skin penetration must be administered.

2. The polymer matrix loaded with active ingredients and possibly additionally loaded with skin penetration enhancers is not physically stable during long-term storage. In particular, active ingredient recrystallization can occur, which leads to an uncontrollable decrease in the active ingredient release capacity of the TTS.

3. A high loading of the polymer carrier with active ingredient and/or skin penetration enhancers makes it difficult to achieve optimal adhesive properties of the transdermal system in self-adhesive polymer films.

4. The drug absorption rate decreases to an unacceptable level when applied over several days, so that additional control layers and/or components are required.

5. It is also known from the literature that the fatty acid esters of polyhydric alcohols frequently used to promote penetration through the skin are of varying quality and contain impure diluents. This leads to penetration increases that are difficult to reproduce (Burkoth et al. 1996, DE 196 22 902 A1). 5

The problems described therefore require a variety of embodiments of transdermal therapeutic systems, which are reflected in the state of the art in this field.

DE 196 53 606 A1 describes an adhesive and binder for TTS consisting of defined mass proportions of the components a) (meth)acrylate polymer, which may contain quaternary ammonium groups, b) an organic di- or tricarboxylic acid and c) a plasticizer, which may be a citric acid triester.

As the above list shows, many patch designs and the materials used for them are known. Nevertheless, there is still a great need to provide TTS for many active ingredients processed in transdermal therapeutic systems that enable the therapeutically required drug release without being structurally complex and that represent an optimal relationship between their components. This also applies to the active ingredient tolterodine if it is to be administered transcutaneously.

Tolterodine is the generic name (INN) for the R-isomer of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine (lUPAC name (+)-(R)-2-{a[2-(diisopropylamino)ethyl]benzyl}4-methylphenol). In the following, tolterodine refers to N ₁ N-diisopropyl-3-(2-hydroxy-5-ethylphenyl)-3-phenylpropylamine. As far as the individual isomers, i.e. the R or S isomer thereof or the racemic mixture of R and S isomers are concerned, these are referred to as R-, S- or R,S-tolterodine.

Tolterodine is used therapeutically to treat unstable bladder associated with the symptoms of urinary urgency, pollakiuria and urge incontinence. The recommended dose is 2 mg of tolterodine administered orally twice daily.

After oral administration, tolterodine is metabolized to a very different extent during the first passage through the liver. The absolute bioavailability of tolterodine is 65% in slow metabolizers, but only 17% in fast metabolizers. Since the resulting 5-hydroxymethyl metabolite is also pharmacologically active, the lower blood levels of tolterodine in fast metabolizers do not result in a loss of effectiveness to the same extent. Nevertheless, it is desirable to avoid such inter-individual fluctuations and to avoid any resulting differences in effectiveness. Furthermore, different plasma levels arise when tolterodine is administered with or without food. These problems can basically be avoided by transdermal administration of tolterodine, since the active ingredient is delivered directly to the bloodstream, bypassing the gastrointestinal tract and the first passage through the liver. Transdermal administration can avoid plasma fluctuations with high concentration peaks that occur with oral administration, which can lead to undesirable side effects such as dry mouth, dyspepsia, vomiting, accommodation disorders and confusion. Likewise, drug levels falling below the threshold of effectiveness and involuntary urination around the clock can be avoided. In addition, bypassing the first liver passage results in a significantly lower load of the drug on the liver, which is particularly desirable for patients with previously damaged livers, such as patients with liver cirrhosis.

WO 98/03067 A1 teaches the use of S-tolterodine for the treatment of bladder emptying disorders including incontinence. Transdermal application is also suggested for the administration of the active ingredient. However, a technical teaching for carrying out the transdermal application or an embodiment aimed at this are not included.

Transdermal therapeutic systems for the administration of tolterodine are not described in the prior art.

Surprisingly, a TTS preparation for tolterodine has now been found which is structurally simple, well tolerated by the skin and physically and chemically stable over long periods of storage and application, has good adhesive properties and releases as much active ingredient as possible onto and through the skin per unit area.

A transdermal therapeutic system (TTS) is therefore provided for the transcutaneous administration of tolterodine, which contains a self-adhesive, layered matrix mass that contains an ammonium-containing (meth)acrylate copolymer, at least one plasticizer and up to 25% by weight of tolterodine. Surprisingly, tolterodine is released from this onto and through the skin at such a high rate that this is only known for other active substances in conjunction with skin penetration enhancers. The therapeutically required dosage can thus be achieved with TTS with a small release area without having to accept an increased risk of skin irritation caused by skin penetration enhancers.

For the purposes of this application:

a) "several days": the TTS can be applied to the skin for therapeutic use from 1 to 7, preferably 1 to 4 days.

b) “solid solution”: the pharmaceutical active ingredient is molecularly present in the TTS matrix

dispersed distributed.

According to a further advantageous embodiment, the TTS described above can additionally be surrounded, with the exception of the release area of its tolterodine-containing matrix on the skin, by a larger, but active ingredient-free skin patch for fixation at the application site (overtape).

This structure has the advantage that different skin types and climate zones can be taken into account. Furthermore, the KO'/adhesion properties of the TTS on the one hand and the drug solubility, drug dissolution rate and release behavior on the other hand can be optimized largely separately from one another.

Preferably, the active ingredient matrix contains R-tolterodine or R,S-tolterodine.

According to a further embodiment of the invention, the matrix mass contains deuterated tolterodine as an active ingredient. Deuterated tolterodine is present when tolterodine contains

-8th-

or several hydrogen atoms are replaced by its isotope deuterium. In principle, each of the hydrogen atoms contained in tolterodine can be replaced by deuterium. Preferably, the methyl substituent of the aromatic compound and/or this aromatic compound itself contains at least one deuterium atom.

An example of this is 2-(3-diisopropylamino-1-phenylpropyl)-4-[ ² H3]methylphenol.

Surprisingly, it was found that the skin penetration rate of deuterated tolterodine is significantly increased compared to non-ideuterated tolterodine, which already has a very high skin penetration rate.

According to a further development, the matrix mass preferably contains 10-20 wt.% tolterodine.
15

Finally, the tolterodine-containing matrix mass can be a solid solution.

The formation of a solid solution of tolterodine in the ammonium group-containing (meth)acrylate polymer was not foreseeable and is all the more surprising as many active ingredients in polymers do not form solid solutions (with molecularly dispersed distribution), but are deposited in the respective polymer in the form of solid particles that can be seen under electron microscopy. In contrast to solid solutions, crystalline active ingredients also show a Debye-Scherrer diagram.

According to a further embodiment of the invention, the tolterodine-containing matrix mass contains at least one citric acid triester. The citric acid triester preferably contains short-chain alkanoic acids. In particular, methanoic acid, ethanoic acid, n-propanoic acid, i-propanoic acid, n-butanoic acid, sec. butanoic acid and tert. butanoic acid come into consideration here.

According to a preferred embodiment, the tolterodine-containing matrix mass contains citric acid(n) butyl ester, citric acid ethyl ester or a mixture thereof.

• · · ♦

Due to the composition according to the invention and the structural design of the TTS, it is surprising that despite high active substance concentrations of tolterodine in the polymer matrix, sufficient physical stability of the system is ensured during long-term storage.
5

It was not expected that the polymer used as the active ingredient-containing polymer matrix would create an intimate contact between the active ingredient matrix and the skin immediately after the TTS was applied, which would be of such quality that a TTS would result that would adhere independently for several days and meet both the therapeutic and the commercial, in particular the business, requirements.

This takes patient compliance into account excellently.

If you choose the version with a skin patch/overtape that does not contain any active ingredients, only very small-area skin patches with an adhesive edge that is only a few mm wide are required.

This is advantageous both economically and in terms of patient compliance.

According to a further embodiment of the invention, the carrier film of the TTS has a metal vapor or oxide coating on the matrix side.

The structure of the TTS according to the invention, seen from the application site, is:

a) in the version without overtape:

The polymer matrix containing the active ingredient is located on a removable protective film and is covered by a cover film;

b) in the version with overtape:

The polymer matrix containing the active ingredient is located on a removable protective film, which is covered by a cover film. Above this cover film is the overtape, which consists of a carrier film and an adhesive film.

The TTS according to the invention can be produced by the so-called "solvent-based process". For this purpose, the polymer, active ingredient and the other ingredients are dissolved in a common solvent and the resulting solution is spread in a thin layer on a carrier. The coated carrier is dried to remove the solvent contained in the polymer matrix, covered with another film and then cut into pieces of the desired size.

Alternatively, the TTS can also be produced using the so-called "hot-melt process". For this, the polymer is melted, mixed with the active ingredient and the other excipients, the resulting mixture is spread in a thin layer on a carrier film (= removable protective film) and left to cool. It is then covered with another film (cover film) and cut into pieces of the desired size.

The tolterodine-containing matrix mass is preferably produced by melt extrusion, whereby the active ingredient is continuously added as a solid substance to a melt of polymer and plasticizer and the resulting active ingredient-containing polymer melt is continuously coated on a removable protective layer with a thickness of 0.02 to 0.5 mm immediately after the active ingredient has been added and the resulting 2-layer laminate is provided with a cover layer on the other side of the matrix. The active ingredient-containing matrix mass is advantageously produced and further processed in a continuous and cost-saving operation with short process times. The thermal load on the active ingredient-containing polymer mass is reduced to a minimum so that decomposition reactions are excluded.

The following examples serve to further explain:

example 1

2.52 g Eudragit RS 100, (= poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride)) with a molar ratio of the monomer units of 1:2:0.1 1.16 g tributyl citrate and

0.65 g R-tolterodine are added with

8.00 g of ethyl acetate dissolved in a beaker by stirring. 35

The resulting polymer solution is spread with a doctor blade onto a removable polyester film (= carrier film) that is approximately 100 μηι thick and has been vapor-coated with aluminum and siliconized on both sides. The film is then dried for 30 minutes at 45 ^° C in a circulating air drying cabinet to produce a tolterodine-containing polymer film with a basis weight of 110 g/m ² . This is then covered with a polyester film (= cover film) approximately 19 μηι thick. 5 cm ² transdermal systems (TTS) are punched out of the resulting 3-layer laminate, consisting of removable protective film, polymer film containing the active ingredient and cover film.

B · B

• t

-12-

Tolterodine flux measurements in vitro Flux measurements through mouse skin

A TTS with a punched-out area of 2.55 cm ² is fixed in a horizontal diffusion cell on the horny layer side of the abdominal and dorsal skin of hairless mice. Immediately afterwards, the acceptor chamber of the cell is filled with phosphate buffer solution (0.066 molar) pH 6.2 pre-tempered to 32°C without air bubbles and the release medium is thermostatted to 32 ± 0.5 ⁰ C.
10

At the sampling times (after 3, 6, 24, 30, 48, 54 and 72 hours) the release medium is exchanged for fresh medium thermostatted at 32 ± 0.5°C.

Flux measurements through human skin
The test was carried out in a flow cell according to the method of Tiemessen (Harry LGM

Thiemessen et al., Acta Pharm. Technol. 34 (1998), 99-101) on freshly prepared human skin of approximately 200 μηι thick, which rests on a silicone membrane on the acceptor side (acceptor medium: phosphate buffer solution (0.066 molar) pH 6.2;

thermostated to 32 ± 0.5 ⁰ C).
20

Sampling was performed after 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72 hours.

The content of R-tolterodine base in the release or acceptor medium in the human and mouse skin permeation tests is determined by high performance liquid chromatography under the conditions listed below. Stationary phase: Cg reverse phase, 3.9 x 150 mm, 5 μηδ; column temperature: room temperature; eluent: 700 volumes of sodium dihydrogen phosphate buffer (0.05 mol) pH 3.0, 300 volumes of acetonitrile; detection: UV at 220 nm; flow rate: 1.2 ml/min; injection volume: 50 μηδ at 15°C.

The results of the investigations are shown in Table 1 for Example 1.

· t • ·«· • • ··· · • • • • · ■ • •

Table 1:

R-Tolterodine Base Flux Rates through Excised Skin Preparations (Example 1, Ch. Ref. INZ 006)

Content of R- Steady State Average cumulative flux 849.0 ^g/cm ² ] Tolterodine base Flux rate after [Wt.%] ^g/cm ² h] 24 hours 48 hours 460.1 72 hours Mouse skin 15.0 14.6 524.2 1036.4 (η = 4) Human skin 15.0 12.7 130.5 731.0 (η = 3)

Example 2

9.71 g Eudragit RS 100, (=poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride)) with a molar ratio of the monomer units of 1:2:0.1 4.76 g tributyl citrate and

2.50 g (R,S)-tolterodine are added with

32.00 g of ethyl acetate are dissolved in a beaker by stirring.

The resulting polymer solution is spread with a doctor blade onto a removable polyester film (= carrier film) that is vapor-coated with aluminum and siliconized on both sides and is approximately 100 µm thick. The film is then dried for 30 minutes at 45°C in a circulating air drying cabinet to produce a tolterodine-containing polymer film with a basis weight of 125 g/m ² . This is then covered with a polyester film (= cover film) approximately 19 µm thick. 5 cm ² TTSs are punched out of the resulting 3-layer laminate, consisting of removable protective film, active ingredient-containing polymer film and cover film.

Tolterodine flux measurements in vitro Flux measurements through mouse skin

A TTS with a punched-out area of 2.55 cm ² is fixed in a horizontal diffusion cell on the horny layer side of the abdominal and dorsal skin of hairless mice. Immediately afterwards, the acceptor chamber of the cell is filled with phosphate buffer solution (0.066 molar) pH 6.2 pre-tempered to 32 ⁰ C without air bubbles and the release medium is thermostatted to 32 ± 0.5 ⁰ C.
10

At the sampling times (after 3, 6, 24, 30, 48, 54 and 72 hours) the release medium is exchanged for fresh medium thermostatted at 32 ± 0.5 ⁰ C.

Flux measurements through human skin
The test was carried out in a flow cell according to the method of Tiemessen (Harry LGM

Thiemessen et al., Acta Pharm. Technol. 34_(1998), 99-101) on freshly prepared human skin of approximately 200 μηι thick, which rests on a silicone membrane on the acceptor side (acceptor medium: phosphate buffer solution (0.066 molar) pH 6.2;

thermostated to 32 ± 0.5 ⁰ C).
20

Sampling was performed after 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69 and 72 hours.

The content of (R,S)-tolterodine base in the release or acceptor medium in the human and mouse skin permeation tests is determined by high performance liquid chromatography under the conditions listed below. Stationary phase: Cs reverse phase, 3.9 x 150 mm, 5 μl; column temperature: room temperature; eluent: 700 volumes of sodium dihydrogen phosphate buffer (0.05 mol) pH 3.0, 300 volumes of acetonitrile; detection: UV at 220 nm; flow rate: 1.2 ml/min; injection volume: 50 μl at 15 ⁰ C.

The results of the investigations are shown in Table 2 for Example 2.

Table 2:

(R.S)-Tolterodine Base Flux Rates through Excised Skin Preparations

Content of (R,S) Steady State Average cumulative flux 1110.4 ^g/cm ² ] Tolterodine base Flux rate after [Wt.%] [μg/cm ² · h] 24 hours 48 hours 718.9 72 hours Mouse skin 15.0 17.9 648.8 1302.0 (η =4) Human skin 15.0 21.2 208.4 1219.4 (π =4)

Example 3

9.71 g Eudragit RS 100, (=poly (ethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride)) with a molar ratio of the monomer units of 1:2:0.1 4.76 g tributyl citrate and

2.50 g of R-(+)-2-(3-diisopropylamino-1-phenyl-propyl)-4- [ ² H ₃ ]methylphenol(R-(D ₃ )-tolterodine) are added with

32.00 g of ethyl acetate are dissolved in a beaker by stirring.

The resulting polymer solution is spread with a doctor blade onto a removable polyester film (= carrier film) that is approximately 100 μm thick and has been vapor-coated with aluminum and siliconized on both sides. The film is then dried for 30 minutes at 45°C in a circulating air drying cabinet to produce a tolterodine-containing polymer film with a basis weight of 125 g/m ² . This is then covered with a polyester film (= cover film) approximately 19 μm thick. 5 cm ² TTSs are punched out of the resulting 3-layer laminate, consisting of removable protective film, polymer film containing the active ingredient and cover film.

-16-

Tolterodine flux measurements in vitro Flux measurements through mouse skin

A TTS with a punched-out area of 2.55 cm ² is fixed in a horizontal diffusion cell on the horny layer side of the abdominal and dorsal skin of hairless mice. Immediately afterwards, the acceptor chamber of the cell is filled with phosphate buffer solution (0.066 molar) pH 6.2 pre-tempered to 32 ⁰ C without air bubbles and the release medium is thermostatted to 32 ± 0.5 ⁰ C.

At the sampling times (after 3, 6, 24, 30, 48, 54 and 72 hours) the release medium is exchanged for fresh medium thermostatted at 32 ± 0.5 ⁰ C.

The content of R-(D ₃ )-tolterodine base in the release or acceptor medium in the mouse skin permeation tests is determined by high performance liquid chromatography under the conditions listed below. Stationary phase: Cs reverse phase, 3.9 x 150 mm, 5 μηγ; column temperature: room temperature; eluent: 700 volumes of sodium dihydrogen phosphate buffer (0.05 mol) pH 3.0, 300 volumes of acetonitrile; detection: UV at 220 nm; flow rate: 1.2 ml/min.; injection volume: 50 μηγ at 15 ⁰ C.

The results of the investigations are shown in Table 3 for Example 3.

Table 3:
R-(D3)-Tolterodine Base Flux Rates through Excised Skin Preparations

Salary of Steady State Average cumulative flux 1388.4 [μ9/ ^0ΓΠ2 ] R-(D ₃ )- Flux rate after Tolterodine base ^g/cm ² h] 24 hours 48 hours 72 hours [Wt.%] 872.0 1737.4 Mouse skin 15.0 (n = 4)

Claims (8)

1. Transdermal therapeutic system (TTS) for the transcutaneous administration of tolterodine over several days, characterized in that the TTS has a self-adhesive, layered matrix mass which contains an ammonium group-containing (meth)acrylate copolymer, at least one plasticizer and up to 25% by weight of tolterodine. 2. (TTS) according to claim 1, characterized in that, with the exception of its release area, it is surrounded at the application site by a larger, drug-free plaster for fixation to the skin. 3. TTS according to claims 1-2, characterized in that the active substance-containing matrix mass contains (R,S)-tolterodine or R-tolterodine. 4. TTS according to claims 1-3, characterized in that the active substance-containing matrix mass contains deuterated tolterodine. 5. TTS according to claims 1-4, characterized in that the tolterodine-containing matrix mass is a solid solution. 6. TTS according to claims 1-5, characterized in that the tolterodine-containing matrix mass contains at least one citric acid triester as a plasticizer. 7. TTS according to claim 6, characterized in that citric acid tributyl ester is contained as plasticizer, alone or in a mixture with citric acid triethyl ester. 8. TTS according to claims 1-7, characterized in that the carrier film has a metal vapor or oxide coating on the matrix side.