NO333619B1 - Transepicutaneous administration to treat restless leg syndrome - Google Patents

Abstract

The invention relates to a trans-epicutaneous pharmaceutical composition containing Rotigotin for effective treatment of Restless Leg Syndrome (RLS), especially in the form of a transdermal therapeutic system (TDS) based on acrylate or silicone having a surface of 2.5 - 20 cm<2> and containing 1.125 9.0 mg/cm<2> Rotigotin as an active component against Restless Leg Syndrome, which, according to the International Restless Leg Syndrome Study Group (IRLSSG) Rating Scale, results in an improvement in the conditions of human Restless Leg Syndrome patients in comparison with a placebo treatment of 2 units or more, after administration over a period of time of at least 8 days.

Description

The invention relates to the use of rotigotine for the preparation of a drug in a transepicutaneous application form, particularly in the form of a transdermal therapeutic system (TDS), for the treatment of "Restless Leg" syndrome.

Restless Leg Syndrome, hereafter also referred to as RLS, is a neurological disorder and manifests itself as paresthesia in the legs followed by a strong urge to move. RLS manifests itself as a tingling, pricking, pulling, itching, burning, spasm or pain and causes an overwhelming need to move in the affected persons. These ailments often occur when the affected person is resting.

These sensory disorders and the resulting urge to move lead to restlessness and sleep disturbances, especially at night when falling asleep and during nocturnal sleep.

RLS can occur at any age, however, it occurs more often with increasing age. Prevalence in the general population is approx. 10%. Due to the type of symptoms, RLS is one of the most frequent causes of sleep disorders. RLS is the cause of sleep/wake disorders in 5% of 20-40 year olds, in 20% of 40-60 year olds and in 35% of those over 60.

If the patient's quality of sleep or quality of life is increasingly limited by RLS or if the patient suffers from fatigue during the day, this is an indication that therapy is necessary. The need for therapy generally occurs at the age of 40-50.

In therapy studies, monotherapies using dopamine agonists, opiates, benzodiazepines, carbamazepine, clonidine or levodopa (L-DOPA) in combination with a dopadecarboxylase inhibitor had varying degrees of success.

The use of L-DOPA for RLS was investigated most often. There was a clear reduction in complaints during long-term treatment with L-DOPA and the quality of life and sleep quality improved. However, the disadvantage of the therapy is that the effect only lasts for a short time in a number of patients due to the short half-life of L-DOPA. Long-term use further leads to a reduction in effect (development of tolerance) and/or a shift of the RLS symptoms to the morning (rebound) or to a worsening of the symptoms, where the disorder also occurs during the day (reinforcement).

Amplification, rebound and tolerance are detailed for RLS as follows:

a) Reinforcement.

In patients with RLS include augmentation

- onset of RLS symptoms earlier in the evening than was the case before treatment; - the symptoms occur during the day; - other body parts, typically the arms are affected;

or

- a more rapid development of the symptoms than in untreated cases.

A form of reinforcement in RLS patients is particularly undesirable. It is described as an increase in the severity of RLS symptoms respectively during the day, followed by a reduction of symptoms at night if the medicine is taken in the evening.

b) Rebound

This phenomenon is equivalent to amplification and manifests itself in particular in that

RLS symptoms appear in the morning, shortly after waking up when the level of the effect is decreasing.

c) Tolerance

This can be described in RLS patients as adaptation to an active substance-based therapy.

It manifests itself in that either ever-increasing doses of active substance must be administered to the patient in order to relieve the same symptoms of RLS or that the same amount of active substance does not relieve the symptoms to the same extent as was the case at the beginning of the therapy.

Additional individual dopamine agonists were investigated for their therapeutic utility in short-term therapy studies. Among the investigated dopamine agonists were: bromocriptine, cabergoline, alphadihydroergocriptine, lisuride, pergolide, pramipkesol and ropinirole. All these dopamine agonists were found to be effective, however, they have the disadvantage of causing side effects such as nausea, vomiting, dizziness, hypotension, constipation and insomnia, which generally occur at the beginning and are dose-dependent.

Benzodiazepines and opiates are also used for RLS. However, due to the risk of habituation and the development of tolerance, these substances are only available for therapy to a limited extent.

The efficacy of transdermally administered clonidine, 2-(2,6-dichloroanilino)-4,5-dihydroimidazole originally developed as a hypertensive and miotic agent, was investigated in the treatment of RLS. It was thereby found that although sleep onset latency was reduced, sleep quality, frequency of awakening and periodic leg movements during sleep (PLMS) on the other hand were not affected. Since more effective drugs are available as a monotherapy, clonidine is currently only limitedly recommended as an alternative form of therapy.

Most of the available monotherapies, e.g. therapy with L-dopa has the disadvantage that the amount of the corresponding active substance must be increased depending on the duration of the therapy to ensure therapeutic success. A therapy is therefore necessarily connected with increasing active substance tolerance.

Combination therapies should thus overcome the disadvantages linked to monotherapies.

WO 01/13903 describes e.g. a combination of active substances contained, among other things, in a TDS for the treatment of "Restless Leg" syndrome, which consists of an a2-agonist and a further neuropsychological drug that reduces the symptoms of RLS in a monotherapy.

Mentioned among others as a neuropsychological drug in the group of dopamine agonists is S(-)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxy-tetralin (eg as N-0923) as a component of the combination of active substance. However, design examples that support this are lacking.

WO 01/13902 defines a combination of active substances, among other things, for transdermal use, which consists of the a2-agonist clonidine and the dopamine agonist pramipexole for the treatment of Restless Leg syndrome.

The design example in both documents describes the treatment of two patients using a combination therapy consisting of pramipexole and clonidine.

Pramipexole is fundamentally recognized for the treatment of sensorimotor RLS symptoms.

Fatigue, impaired digestion (dyspepsia), headache and secretory congestion have been reported as more significant additional adverse effects (side effects) for this drug.

However, since clonidine present in the combination of active substances - as proposed in the WO descriptions - has no influence on sleep quality, awakening frequency or periodic leg movements during sleep, the active substance clonidine therefore does not contribute essentially to the relief of RLS.

As mentioned above, the α2-agonist clonidine is therefore the second choice in the treatment of

RLS.

This is confirmed by the US American Restless Leg Syndrome Foundation in its "RLF medical bulletin".

In the chapter headed 'treatment', 'secondary pharmacological treatments' are dealt with after 'primary pharmacological treatments'. "Secondary pharmacological treatments" are qualified therein as treatments that are not well established or whose effectiveness in treating RLS is limited.

In addition to other active substances, clonidine is also mentioned as not being sufficiently effective for the disease RLS.

It has been concluded that the use of clonidine for the treatment of RLS cannot be recommended with conviction. Patients would have to understand that experience for the use of this drug is minimal.

In conclusion, treatment with combination therapy as described in the two WO descriptions cited above was only performed on a total of 2 test subjects (in each case one (1) male and one (1) female test subject), and it is thus not possible to make any decisions with consideration of the therapy and its course.

The proposed plaster formulations are also either troublesome to make, technically difficult to realize or financially cost-intensive.

If, as confirmed in the mentioned WO descriptions, the two active substances are each applied in a separate plaster, the treatment becomes troublesome for the patient and there is no sufficient compliance. Among other things, there is a risk that the patches can be confused and therefore that the patient will use two (2) patches that have the same active substance.

If the two active substances are stored as a mixture on the same patch, it cannot be ensured that the therapeutically necessary dose for each individual component will be able to have an effect. The necessary efficiency is thus not sufficiently ensured.

If the two active substances are stored separately in the patch, the production of such a patch is complex in terms of construction and costs.

In conclusion, a therapy for a disease should occur as far as possible with individual substances to keep interactions with other administered substances as low as possible. This therapeutic requirement is significant for RLS since this disease - as mentioned above - occurs with increasing age when multimorbidity often occurs.

A number of disadvantages must be overcome in the case of medication against RLS.

E.g. when levodopa is administered, only a limited and irregular absorption in the intestine, especially in the duodenum, is possible, and thus reproducible plasma levels cannot be achieved. This is especially the case if food is consumed at the same time.

Most active substances that can be used for the disease RLS are subject to first-pass metabolism in the liver when administered orally.

These factors may result, in the case of oral administration, in a delayed and non-reproducible onset of action and an unpredictable duration of action. The resulting fluctuating levodopa/plasma concentrations are particularly undesirable. Peak plasma concentration values often correlate with the onset of unwanted side effects, however, no effect occurs if the plasma level is too low. L-dopa must therefore be administered several times a day, which can lead to compliance problems.

The disadvantages of oral administration cited above led to the search for other more effective ways of administering levodopa or other active substances against the disease RLS. The following non-oral routes of administration were considered: intravenous, transdermal, subcutaneous, intramuscular, intracerebroventricular, intranasal, pulmonary, sublingual or intrarectal.

None of these ways, however, have until now led to therapeutically satisfactory administration systems or to therapeutic success.

The proposed non-oral administration methods in particular have the limitations that some of them are invasive and complications can occur. This was e.g. case of long-term intraduodenal administration of a levodopa solution. Changing catheter tips is particularly often associated with wounds and pain.

Continuous intravenous or subcutaneous infusion is also not therapeutically satisfactory. Although stable plasma concentrations can be achieved e.g. with subcutaneously administered infusions of apomorphine, unacceptable local irritations occur if apomorphine must be administered several times daily over a long period of time.

There was therefore still a need to provide an active substance for therapy in RLS:

• which is well tolerated,

• which can be used as monotherapy, and

• which is present in a pharmaceutical/technical formulation that meets the therapeutic requirements, and

with which the active substance-containing formulation can be produced in a favorable way in terms of both technology and costs.

It has been surprisingly and unexpectedly found that a transepicutaneous form of administration containing rotigotine, particularly in the form of a TDS, is of therapeutic value for the treatment of RLS. This form of administration is therapeutically effective, especially in the treatment of RLS patients who are dependent on a continuous long-term treatment of RLS symptoms and who are prone to RLS amplification.

Description of the invention

The present invention therefore relates to the use of rotigotine for the preparation of a pharmaceutical composition in the form of a transepicutaneous pharmaceutical preparation, in particular in the form of a transdermal therapeutic system (TDS), which avoids the disadvantages known from the prior art with regard to present monotherapies with orally administered active substances.

It has surprisingly been shown that the administration of rotigotine as a monotherapy agent in a transepicutaneous composition, particularly in the form of the pharmaceutical composition of a TDS, causes suppression and reduction of the symptoms of RLS, where the active substance rotigotine, in contrast to monotherapies known up to now, is also able to be administered in very low doses over a long period and is well tolerated.

The form of administration according to the invention is particularly suitable for the treatment of moderate to severe RLS complaints.

Rotigotine is the INN (international non-proprietary name) of the chemical (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-l-naphthol.

The compound (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol is obtained in a manner known per se. The above-mentioned compound is prepared as described in EP 0 168 505 Bl. Reference is hereby made to the entire range thereof for the present invention.

It is already known that (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol can be used as an agent to treat Parkinson's disease.

However, it is significant to note in this connection that the disorder RLS is not a form of Parkinson's disease, but rather a different disorder.

It has now been found that administration of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-l-naphthol in a transepicutaneous form of administration has a beneficial influence on the disease Restless Leg Syndrome.

The compound to be used according to the invention surprisingly shows a specific effect even in very low doses, which makes it possible to be used for the treatment of Restless Leg syndrome. The compound is superior to known substances effective for the indication Restless Leg Syndrome with regard to both strength of action and its specificity.

Such an effective and specific effect was not known until now with regard to all the agents against RLS used in monotherapy known in the prior art, and thus the use of the compound in the form of administration according to the invention as a therapeutic agent for Restless Leg Syndrome an enrichment for pharmacy and medicine.

The form of administration according to the invention provides, in a therapeutically advantageous manner, constant plasma levels which avoid the pulsating plasma levels that occur with oral forms of administration. In particular, no interaction with food is known from L-dopa therapy, which has the consequence that plasma levels and therapeutic effects cannot be reproduced.

An advantage of the invention is that by using the active substance rotigotine in a transdermal application form for the treatment of Restless Leg Syndrome, low doses alone are sufficient to improve the patient's condition without intolerable, unwanted effects (side effects) that occur as a result; it is especially important for reinforcement to be suppressed. This is particularly desirable since in approx. Half of the RLS patients with exacerbation require a change in medication. Susceptibility and response rates in patients with RLS were further improved. The active substance is used in an amount of 1.0-10 mg, preferably in an amount of 0.5-5 mg per day, which is particularly advantageous according to the invention.

A further advantage in terms of administration according to the invention is due to the convenient provision of the active substance rotigotine over at least 24 hours with constant plasma levels.

The active substance is applied to the patient's skin in the form of a transepicutaneous application, either as an ointment, gel or cream, it is however preferably administered as a TDS in the form of a patch.

According to the invention, the transdermal therapeutic system has a back layer which is inert with regard to the components of the matrix, an adhesive matrix layer containing (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2- thienyl)ethyl]amino]-l-naphthol and a protective film to be removed before use, characterized in that said matrix layer: a) contains as a base a non-aqueous acrylate or silicone-based polymer adhesive, b) has a solubility of > 5% (g/g) for the free base (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol, and c) contains the free the base (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol in an effective amount.

According to a further development, matrix in TDS contains less than 0.5%

(g/g) of inorganic silicate particles.

According to a particularly advantageous further development, the transdermal therapeutic system contains < 0.05% (w/w) of inorganic silicate particles in the matrix.

According to one embodiment of the invention, the transdermal system contains an acrylate-based polymer adhesive which comprises at least two of the following monomers: acrylic acid, acrylamide, hexyl acrylate, 2-ethylhexyl acrylate, hydroxyethyl acrylate, octyl acrylate, butyl acrylate, methyl acrylate, glycidyl acrylate, methacrylate, methacrylamide, hexyl methyl acrylate , 2-ethylhexyl methacrylate, octyl methacrylate, methyl methacrylate, glycidyl methacrylate, vinyl acetate or vinyl pyrrolidone.

According to an advantageous further development of the invention, the transdermal system comprises a silicone-based polymer adhesive with additions to improve the solubility of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl ]amino]-1-naphthol in the form of hydrophilic polymers or glycerin derivatives.

According to a further design according to the invention, in the transdermal system (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol is contained in the acrylate-based polymer adhesive in a concentration of 10-35% [w/g] or in the silicone-based polymer adhesive in a concentration of 5-40% [w/g].

According to a further development of the invention, the transdermal system contains substances which improve the permeability of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1 -naphthol in human skin.

According to the invention, the penetration-promoting substance for the transdermal system is selected from the group consisting of fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerin or derivatives thereof, N-methylpyrrolidone, terpenes or terpene derivatives.

According to one embodiment of the invention, the penetration-promoting substance in the transdermal therapeutic system is oleic acid or oleyl alcohol.

According to the invention, the hydrophilic polymer in the transdermal system is advantageously polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, polyethylene glycol, polypropylene glycol or a copolymer of ethylene and vinyl acetate.

In a further design, the hydrophilic polymer in the transdermal system is contained in the active substance-containing matrix layer in the form of soluble polyvinylpyrrolidone and at a concentration of 1.5-5% (w/w).

According to the invention, the transdermal system can further contain inert filler materials in the matrix to improve the binding force.

The transdermal therapeutic system can be produced as described in detail in the design examples in EP 1 033 978 Bl.

A pharmaceutical product according to the present invention comprises a backing layer which is inert with respect to the matrix components, an adhesive matrix layer comprising an effective amount of rotigotine or rotigotine hydrochloride and a protective film which must be removed before use.

Design example 1

Polyacrylate system with (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol 66 g of a 50% solution of Eudragit El00 in ethyl acetate are placed to 264 g of a solution of a polyacrylate adhesive with a solids content of 50%, and a subsequent addition of 36 g of oleyl alcohol, after which the mass is homogenized by stirring.

89.65 g of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol is then dissolved in 200 ml of methyl ethyl ketone and is added to the above mass while stirring. When the mass is homogenized, it is coated on a siliconized polyester film using a suitable coating knife. The thickness of the moist film must be dimensioned so that the subsequent removal of the solvent by means of drying for 30 min. at 50°C, results in a coating weight of 60 g/m<2>.

The dried matrix film is now laminated with a 13 thick polyester film. The finished plaster is now stamped out of the resulting plaster laminate in a desired size and is packed in packaging bags.

The concentration of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol in the plaster matrix is 30.8%. Suitable polyacrylate adhesives are e.g. Durotak 387-2051, Durotak 387-2287, Durotak 387-2353 and Durotak 387-2516, all from National Starch & Chemical.

Design example 2

Silicone system with (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-l-naphthol 18 g of (-)-5,6,7,8 -tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol dissolved in 40 g of ethanol is added to 24 g of a 25% solution of Kollidon 90F and the mass is homogenized. 251 g of a solution of an amine-resistant silicone adhesive having a solids content of 70% is then added to this mass and the mass is homogenized by further stirring.

The mass is then coated onto a polyester film provided with an adhesive (Scotchpak 1022) using a suitable coating knife to a thickness that results in a coating weight of 50 g/m<2> after removal of the solvent by drying for 30 min. at 50°C.

The dried matrix film is now laminated with a 13 nm thick polyester film. The finished plasters are stamped out of the resulting plaster laminate in a desired size and packed in packaging bags.

The concentration of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol base in plaster matrix is 9%.

Suitable amine-resistant silicone adhesives are e.g. BIO-PSA Q7-4301 and BIO-PSA Q7-4201, both from Dow Corning.

Design example 3

25 g of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol hydrochloride are stirred together with 14.7 g of sodium metasilicate or 16 .8 g of sodium trisilicate in 40 ml of ethanol at room temperature for 48 hours. The active substance solution is now optionally filtered and 9.2 g of oleyl alcohol, 63.2 g of a 52% solution of a polyacrylate adhesive (Durotak 387-2287 from the company National Starch & Chemical) and 22.8 g of a 40% (g /g) solution of Eudragit El00 (Rohm-Pharma) is added and the mass is then homogenized by means of mechanical stirring.

The mass is then coated on a suitable polyester film provided with an adhesive to produce plaster matrix and the solvent is removed by drying for 20 min. at 50°C. The coating weight of the dried matrix film is 80 g/m<2>.

The dried matrix film is laminated with a 23 thick polyester film. The individual patches are stamped out of the complete laminate.

According to the invention, it is finally exceptionally advantageous to use a silicone-based transdermal therapeutic system which must contain at least one amino-resistant silicone compound as the main component.

The silicone compound is normally a pressure-sensitive adhesive or a mixture thereof and forms a matrix in which the other components of the TDS are embedded. Furthermore, the adhesive(s) should preferably be pharmaceutically acceptable so that they are biocompatible, non-sensitizing and non-irritating to the skin. Particularly advantageous silicone adhesives for use according to the invention should further meet the following requirements: - that the adhesive is durable and has bondable properties in the presence of moisture or sweat within normal temperature fluctuations, - good compatibility with rotigotine as well as with other carriers used in the formulation, in particular should not the adhesive react with the amine group of rotigotine.

It has been shown that pressure sensitive adhesives of the type which form a soluble polycondensed polydimethylsiloxane (PDMS)/resin network, the hydroxy end groups are protected, e.g. with trimethylsilyl (TMS) groups, and are particularly useful according to the invention. Preferred adhesives of this type are BIO-PSA pressure sensitive silicone adhesives manufactured by Dow Corning, particularly Q7-4201 and Q7-4301 grades. However, other silicone adhesives can be used in the same way.

In addition, and preferably, a silicone-based transdermal therapeutic system is also provided according to the invention for the same application, comprising two or more silicone resins as adhesive main components. It can be advantageous for such a mixture of silicone adhesives to include at least one adhesive with high tack and at least one adhesive with medium tack to ensure an optimal balance between good tack and low cold flux. Extensive cold flux can lead to excessively soft plaster that easily sticks to the packaging material or to the patient's clothing. Such a mixture of adhesives further appears to be particularly useful for achieving an effective transdermal therapeutic system. A mixture of the above-mentioned amine-resistant pressure-sensitive silicone adhesives Q7-4201 (medium tack) and Q7-4301 (high tack) in approx. equal amounts have been found to be particularly useful according to the invention.

In a further preferred embodiment, the silicone-based transdermal therapeutic system comprises a dissolving agent. Various surfactant-like or amphiphilic substances can be used as solubility-promoting agents. They should be pharmaceutically acceptable and approved for use in medicinal products. It is advantageous if the dissolution promoting agent also causes an improvement in the binding of the transdermal therapeutic system. A particularly preferred example of such a solubility-promoting agent is soluble polyvinylpyrrolidone. Polyvinylpyrrolidone is commercially available e.g. under the trade name Kollidon<®>(Bayer AG). Other examples include copolymers of polyvinylpyrrolidone and vinyl acetate, polyethylene glycol, polypropylene glycol, glycerin and fatty acid esters of glycerin or copolymers of ethylene and vinyl acetate.

The silicone-based transdermal therapeutic system contains less than 1% by weight of inorganic silicates for use according to the invention, it is most preferred that it is completely free of inorganic silicates.

The water content of the transdermal therapeutic system for use according to the invention is preferably so low that evaporation of water is not necessary during the production of TDS. The water content of a newly manufactured plaster is typically less than 2% by weight and is preferably 1% by weight or less.

In a particularly preferred design according to the invention, the transdermal therapeutic system has a surface area of 10-30 cm<2>, preferably 5-20 cm<2>. It is understood that a TDS that has a surface area of e.g. 20 cm<2> is pharmacologically equivalent to and can be replaced with two 10 cm<2> patches or four 5 cm<2> patches that have the same amount of medicine per cm<2>. The surface areas specified in the present application must therefore be understood as relating to the total surface of all TDS simultaneously applied to a patient.

Provision and use of one or more transdermal therapeutic systems according to the invention has the pharmacological advantage over an oral therapy that the doctor responsible can titrate the optimal dose for the patient reasonably quickly, individually and accurately, e.g. by simply increasing the number or size of patches given to the patient.

If a seven-day patch is desired, higher amounts of drug are generally required. It was found that a rotigotine content in the range from approx. 0.4-0.5% by weight is particularly advantageous since it optimally utilizes the drug contained in the TTS, i.e. the amount of drug remaining in the TTS after administration is only very low. The dose administered using such a TTS is normally 50% or more of the amount of drug originally contained in the TTS, and may be as high as 80-90%.

The fact that the silicone-based transdermal therapeutic system described according to the invention causes a significant therapeutic effect on the symptoms of Restless Leg Syndrome even with surface areas of 10-20 cm<2>, especially less than 10 cm<2>, and with low amounts of medicine of approx. 0.4-0.5 mg/cm<2>, especially 0.45 g/cm<2>, must be seen as a further advantage of the invention.

The transdermal therapeutic system used according to the invention is preferably a plaster with a continuous adhesive matrix containing the drug at least in its central part. However, transdermal equivalents to such patches are also covered by the invention, i.e. a design in which the drug is placed in an inert but non-adhesive silicone matrix in the central part of the TTS and an adhesive part extends along the edges of the patch.

The invention further relates to a method for treating RLS, in which a transdermal therapeutic system having a surface area of 5-20 cm<2> is applied to a patient.

The invention and the best design will be described in more detail below.

Design example 4

A transdermal therapeutic system using a combination of pressure-sensitive silicone adhesives was prepared as follows.

(-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol hydrochloride (rotigotine hydrochloride, 150 g) was added to a solution of 17.05 g NaOH in 218 g ethanol (96%). The resulting mixture was stirred for approx. 10 minutes 23.7 g of sodium phosphate buffer solution (8.35 g of Na 2 HPO 4 x 2 H 2 O and 16.07 g of NaH 2 PO 4 x 2 H 2 O in 90.3 g of water) was then added. Insoluble or precipitated substances were separated from the mixture by filtration. The filtrate was washed with 60.4 g

ethanol (96%) to obtain a particle-free ethanol solution of rotigotine in free base form.

The solution of rotigotine in free base form (346.4 g) in ethanol (35% W/W) was mixed with 36.2 g of ethanol (96%). The resulting solution was mixed until homogeneous with 109 g of an ethanol solution containing 25% by weight of polyvinylpyrrolidone (KOLLIDON<®>90F), 0.077% by weight of liquid sodium bisulfite solution (10% by weight), 0.25% by weight of ascorbyl palmitate and 0 .63% by weight of DL-alpha-tocopherol 1. 817.2 g of an amine-resistant, highly tacky silicone adhesive (BIO-PSA<®>Q7-4301, manufactured by Dow Corning) (74% by weight solution in heptane), 851, 8 g of an amine-resistant medium tacky silicone adhesive (BIO-PSA<®>Q7-4201, manufactured by Dow Corning) (71% by weight solution in heptane) and 205.8 g of petroleum ether (heptane) were added to the mixture and all components were stirred until a homogeneous dispersion was obtained.

The dispersion was applied to a suitable polyester release layer (SCOTCHPAK<®>1022) using a suitable coating knife and the solvents were continuously removed in a drying oven at temperatures of up to 80°C for approx. 30 min. and a drug-containing adhesive matrix having a coating weight of 50 g/m<2>was thus obtained. The dried matrix film was laminated with a polyester type backing film (SCOTCHPAK<®>1109). The individual patches were punched out of the finished laminates in the desired sizes (eg 5 cm<2>, 10 cm<2>, 20 cm<2>, 30 cm<2>) and were sealed in bags under nitrogen flow .

The following table shows the composition in mg/20 cm<2> of a transdermal therapeutic system according to the invention, which contains a combination of silicone type

PSA.

Clinical tests

Rotigotine TDS prepared according to design example 4 was investigated in placebo-controlled, double-blind, randomized clinical trials at several centers and included, in a three-armed, parallel-group study, 63 patients suffering from moderate to very severe idiopathic diseases such as Restless Leg Syndrome. The average age of the patients was 58.3 years. Randomization in the three treatment groups was adequately balanced with respect to sex, age and severity of previous illnesses.

The patient was treated with rotigotine TDS after gradual and complete termination of the current therapy with L-dopa and a break in therapy (washout) of 7 + 4 days.

Over the eight (8) day treatment period, patients in one group were treated with 5 cm<2>TDS and patients in another group were treated with 10 cm<2>TDS. By way of comparison, the patients in the patient group were treated with placebo TDS. All groups received four patches as a combination of verum and placebo patches. The first group received e.g. a combination of two 2.5 cm<2>verum patches and two placebo patches and the other group received four 2.5 cm<2>verum patches. The placebo group received four placebo patches. A 2.5 cm<2>TDS comprised a rotigotine amount of 1.125 mg. 5 cm<2> therefore contained a rotigotine amount of 2.25 mg and a 10 cm<2>TDS contained 4.5 mg. About. 50% of the active substance (apparent dose) rotigotine was released to the individual patients from the respective above-mentioned active substance-containing TDS within 24 hours.

It was found that an effective relief of the symptoms of Restless Leg Syndrome in the patients suffering from this disease was achieved after only one (1) week. The patient was not receiving any other drugs effective against RLS at this time.

As a result of the pre-specified primary efficacy, the activity and motor ability of daily living changed, according to the generally accepted grading scale of the International Restless Leg Syndrome Study Group (IRLSSG), between the initial value and evaluation at the end of treatment (8th day). .

The IRLSSG measures and categorizes the following clinical parameters in patients with Restless Leg Syndrome on the basis of ten questions.

1. How would you rate the overall RLS discomfort in your arms or legs?

0 = none = no symptoms

1 = mild

2 = moderate

3 = significant

4 = very severe symptoms

2. How would you overall rate the need to move around due to the RLS symptoms?

0 = nothing

1 = mild

2 = moderate

3 = significant

4 = loud

3. How much relief from RLS arm or leg discomfort did you experience in total by moving around?

0 = no RLS discomfort should be relieved 1 = complete or almost complete

2 = moderate

3 = easy

4 = nothing

4. How severe was your sleep disturbance due to RLS symptoms?

0 - none

1 = mild

2 = moderate

3 = significant

4 = high

5. How severe was your tiredness or sleepiness during the day because of your RLS symptoms?

0 = none

1 = mild

2 - moderate

3 = significant

4 = severe

6. How severe was your RLS as a whole?

0 = none

1 = mild

2 = moderate

3 = significant

4 = severe

7. How often do you get RLS symptoms?

0 = never

1 = occasionally (ie 1 in the last 7 days)

2 = sometimes (ie 2-3 in the last 7 days)

3 = often (ie 4-5 in the last 7 days)

4 = very often (ie 6-7 in the past 7 days) 8. When you had RLS symptoms, how severe were they on average?

0 = none

1 = mild (ie for less than 1 hour in a 24 hour period)

2 = moderate (ie 1-3 hours in a 24 hour period)

3 = significant (ie for 3-8 hours in a 24 hour period)

4 = severe (ie for 8 or more hours in a 24 hour period)

9. Overall, how severe was the impact of your RLS symptoms on your ability to carry out activities of daily living, e.g. to lead a satisfactory family, private, academic or working life?

0 = none

1 = mild

2 = moderate

3 = significant

4 = high

10. How severe were your mood disturbances due to RLS symptoms - were you angry, depressed, sad, anxious or irritable?

0 = nothing

1 = mild

2 = moderate

3 = significant

4 = severe

The overall IRLSSG grade is determined from the individual values as follows: An initial value for each patient participating in the examinations is first determined. This is done by adding together the individual IRLSSG parameter values on day 0, i.e. before treatment. The IRLSSG values during treatment are then compared with this initial value and changes with regard to the initial value are recorded. Finally, the average improvement in the IRLSSG value on day 8 compared to the initial value is determined by averaging all test subjects. The resulting value is referred to as the FAS (full analysis set) randomized mean change from the initial value of the total IRLSSG grade. The term "randomized" indicates that the patient was randomized in advance in a double-blind manner with respect to the various predetermined doses.

Patients suffering from the disease Restless Leg Syndrome are known to experience a relatively strong placebo effect, i.e. even in the case of placebo treatment, the IRLSSG values of the patients with Restless Leg Syndrome improved to some extent. It is therefore important to compare any effect of the drug treatment with assessment of the IRLSSG improvement achieved with a placebo treatment over the same period. The final evaluation of the improvement was therefore carried out in relation to the effect of a placebo treatment over the same period.

Results

There was a significant, dose-related improvement in IRLSSG values between the initial value and the value 8 days after application of a TDS according to the invention. In particular, compared to the placebo group, the group treated with a TDS having a rotigotine amount of 4.5 mg (apparent dose 2.25 mg) showed therapeutically particularly favorable IRLSSG values. This result can be seen from the following table.

The value referred to as "p" in the above table represents the one-tailed p-value obtained by the statistical evaluation of test data.

At the end of the eight-day treatment, both patient groups reported that almost all of the subjective symptoms such as tingling, cramping, pain in the legs, restlessness in the legs during the night and difficulty falling or staying asleep no longer existed or were been reduced to a tolerable minimum so that the quality of daily life was no longer negatively affected.

Depending on the administered dose of the active substance rotigotine, the patients further reported that they suffered only very mildly or not at all from fatigue during the day, no nausea, dizziness, vomiting or insomnia, etc.

Rotigotine was generally well tolerated when administered using the TDS of the invention.

Skin reactions at the application site were generally very mild.

Conclusions

The above-mentioned results show for the first time in a double-blind placebo-controlled study that a dopamine agonist (rotigotine) administered transdermally once a day leads to a clear clinical improvement in patients with Restless Leg Syndrome at moderate to severe stages and is well tolerated. An advantage of this medication could especially be determined in patients whose RLS symptoms became more intense during the day.

It was not possible until now to achieve such a result with orally administered drugs in a monotherapy, whereby even an improvement in the IRLSSG value of 2 compared to placebo can be considered a success. An improvement of over 3 or 6 or more units therefore constitutes an even greater therapeutic advantage and is thus preferred according to the invention.

Long-term survey

A long-term study of over four (4) months or 120 days was conducted by maintaining the above-mentioned clinical study model.

Rotigotine TDS prepared according to design example 4 was again used.

The study was conducted in a placebo-controlled, double-blind and randomized manner as a three-arm, parallel-group study with twelve (12) patients suffering from moderate to severe idiopathic Restless Leg Syndrome.

The average age of the patients was 60 years. Randomization in the three treatment groups was adequately balanced with respect to sex, age and severity of previous illnesses.

The patients were treated with rotigotine TDS after gradual and complete termination of the ongoing therapy with L-dopa and one of the interruptions in the therapy (washout) of 8 ± 4 days.

Over the duration of the treatment of four (4) months, patients in one group were treated with 5 cm<2>TDS, the patients in another group were treated with 10 cm<2>TDS and by way of comparison, the patients in the placebo group were treated with placebo TDS. 5 cm<2>TDS had a rotigotine amount of 2.25 mg and 10 cm<2>TDS had an amount of 4.5 mg. 50% of the active substance (apparent dose) rotigotine was released to the individual patients from the respective above-mentioned active substance-containing TDS within 24 hours.

It was found that an effective relief of the symptoms of Restless Leg Syndrome in patients suffering from this disease was achieved after only one (1) week. The patients were not receiving any other drugs effective against RLS at this time.

As a result of the predetermined primary efficacy, the activities and motor skills of daily living changed, according to the International Restless Leg Syndrome Study Group (IRLSSG) generally accepted grading scale, between the initial value and an end-of-treatment evaluation (day 120).

The IRLSSG measures, as described above, categorize the clinical parameters in patients with Restless Leg symptoms on the basis of 10 questions.

Results

There was a significant dose-related improvement in the IRLSSG values between the initial value and that obtained 120 days after application of a TDS according to the invention. Compared to the placebo group, in particular the group treated with a TDS having a rotigotine amount of 4.5 mg (apparent dose 2.25 mg) showed therapeutically particularly favorable IRLSSG values.

At the end of 120 days of treatment, both patient groups reported that all the subjective symptoms and problems falling asleep or staying asleep no longer existed or had been reduced to a minimum so that their quality of life was no longer negatively affected. There was no significant enhancement. The IRLSSG value in the group treated with a TDS having 2.25 mg rotigotine was 12.8 and was 15.7 in the group treated with a TDS having 4.5 mg rotigotine.

Depending on the administered dose of the active substance rotigotine, patients further reported that during treatment they suffered very mildly or not at all from fatigue during the day, no nausea, no dizziness, no vomiting or insomnia, etc. .

Rotigotine was generally well tolerated when administered using TDS according to the invention.

Skin reactions at the application site were generally very mild. If necessary, TDS was applied elsewhere on the skin. The previous application site was quickly reduced and could be used for further treatment.

Conclusions

The above results show for the first time in a double-blind, placebo-controlled, long-term study that a dopamine agonist (rotigotine) administered transdermally once daily is well tolerated and safe and causes a significant clinical improvement in patients with moderate to severe Restless Leg Syndrome.

It was not possible to date to achieve such a result with orally administered drugs in a monotherapy, in which however an improvement in IRLSSG value of 2 compared to placebo can be considered a success. An improvement of 10 or more units therefore constitutes an even greater therapeutic advantage and is thus preferred according to the invention.

The investigation shows in particular the effectiveness of the administration form according to the invention in alleviating the disease in patients suffering from RLS, in whom an increase in RLS symptoms due to various previous medications could be observed.

Claims (19)

1. Use of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-l-naphthol for the preparation of a drug for transepicutaneous treatment of Restless Leg Syndrome . 2. Use as stated in claim 1, in which the medicine is suitable for using 0.5-10 mg of active substance per day. 3. Use as stated in claim 1 or 2, in which the drug is a transdermal therapeutic system (TDS) comprising a backing layer which is inert with respect to the components of the matrix, an adhesive matrix layer which contains (-)-5,6,7, 8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol and a protective film to be removed before use, in which said matrix layer: a) contains as a base a non-aqueous acrylate or silicone-based polymeric adhesive, b) having a solubility of > 5% (w/w) for the free base (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl ]amino]-l-naphthol, and c) contains the free base (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-l-naphthol in an effective amount. 4. Use as stated in claim 3, wherein the matrix contains less than 0.5% (w/w) of inorganic silicate particles. 5. Use as stated in claim 3, wherein the matrix contains less than 0.05% (w/w) of inorganic silicate particles. 6. Use as stated in claim 3, in which the acrylate-based polymeric adhesive comprises at least two of the following monomers: acrylic acid, acrylamide, hexyl acrylate, 2-ethylhexyl acrylate, hydroxyethyl acrylate, octyl acrylate, butyl acrylate, methyl acrylate, glycidyl acrylate, methacrylate, methacrylamide, hexylmethyl acrylate, 2- ethylhexyl methacrylate, octyl methacrylate, methyl methacrylate, glycidyl methacrylate, vinyl acetate or vinyl pyrrolidone. 7. Use as set forth in claim 3, wherein the silicone-based polymeric adhesive contains additives to improve the solubility of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino ]-1-naphthol in the form of hydrophilic polymers or glycerin or glycerin derivatives. 8. Use as stated in claim 6 or 7, wherein (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1-naphthol is contained in the acrylate-based polymeric adhesive in a concentration of 10-35% (w/g) or in the silicone-based polymeric adhesive in a concentration of 5-40% (w/g). 9. Use as stated in claim 8, wherein the TDS contains substances that improve the permeability of (-)-5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-1- naphthol into human skin, selected from the group consisting of fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerin or derivatives thereof, N-methylpyrrolidone, terpenes or terpene derivatives. 10. Use as stated in claim 9, in which the penetration-promoting substance is oleic acid or oleyl alcohol. 11. Use as stated in claim 7, wherein the hydrophilic polymer is polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, polyethylene glycol, polypropylene glycol or a copolymer of ethylene and vinyl acetate. 12. Use as stated in claim 11, in which the hydrophilic polymer is soluble polyvinylpyrrolidone and is contained in a concentration of 1.5-5% (w/w) in the active substance-containing matrix layer. 13. Use as stated in claim 3, wherein the TDS comprises a mixture of at least one silicone adhesive with high tackiness and at least one silicone adhesive with medium tackiness. 14. Use as stated in claim 13, wherein TDS further comprises a solubilizing agent. 15. Use as stated in claim 14, in which the solubilizing agent is soluble polyvinylpyrrolidone. 16. Use as stated in one of claims 13-15, wherein the TDS contains less than 1% by weight of inorganic silicates. 17. Use as stated in claim 16, wherein the TDS is free of inorganic silicates. 18. Use as stated in claim 3, in which the TDS has a size of 5-20 cm<2> and contains 0.4-0.5 mg/cm<2> of rotigotine as the active component in its matrix, which primarily comprises a mixture of at least two amine-resistant silicone adhesives. 19. Use as stated in claim 3, in which the drug is a silicone-based transdermal therapeutic system which has a surface area of 5-20 cm and which contains 0.1-3.15 mg/cm<2> of rotigotine as the active component for preparation of an anti-Restless Leg Syndrome drug which, according to the grading scale of the International Restless Leg Syndrome Study (IRLSSG) leads to an improvement of 2 units or more in human patients suffering from Restless Leg Syndrome compared to a placebo treatment after at least eight days application.