Iontophoretic delivery of rotigotine for the treatment of parkinson's disease

Description of the invention

The invention relates to the use of a composition containing rotigotine and a composition for use.

The present invention relates to the effective treatment or reduction of symptoms of Parkinson's disease, wherein iontophoretic delivery of the dopamine receptor agonist rotigotine (INN) is used.

Parkinson's disease is believed to be caused primarily by the degeneration of dopaminergic neurons in the substantia nigra, resulting in a loss of dopamine-enhancing secretion and dopamine-related modulation of the activity of neurons in the caudate and thus a deficiency of dopamine in certain regions of the brain. The resulting imbalance of the neurotransmitters acetylcholine and dopamine eventually produces symptoms related to the disease. Although usually considered a disorder of the motor system, Parkinson's disease is now considered a more complex disorder that involves both motor and non-motor systems. This disabling disease is characterized by major clinical features including tremor, slowness of movement, stiffness, dyskinesia, gait disturbance, and speech impairment. In some patients, these symptoms may be associated with dementia. Autonomic involvement of the nervous system can cause orthostatic pressure drops, paroxysmal flushing of blood to the head, problems with regulating heat, constipation, and loss of bladder and sphincter control. Psychological disorders such as loss of motivation and depression can also accompany Parkinson's disease.

Parkinson's disease is mainly a disease of middle age and beyond, and it affects both men and women equally. Parkinson's disease is most prevalent in the age group over 70 years of age, with 1.5 to 2.5% of the population having Parkinson's disease. The mean age of patients with onset disease is between 58 and 62 years, and most patients develop Parkinson's disease between the ages of 50 and 79. In the United States alone, there are approximately 800,000 people with Parkinson's disease.

Early motor deficiency in Parkinson's disease can be detected as the emerging degeneration of dopamine-releasing black cells. This neuronal degeneration produces a defect in the dopaminergic pathway that connects the black matter to the striatum. As the disease progresses, refractory autonomic and mental motor complications may develop, indicating that there is progressive degeneration of the striatal receptor mechanisms.

The clinical diagnosis of Parkinson's disease is based on the presence of characteristic psychological symptoms. The disease is known to appear gradually, slowly progressive, and changeable in clinical symptoms. The data suggest that the dopamine content in the striatum falls to 20% below the levels found in age-matched controls before onset of symptoms.

Treatments for Parkinson's disease have been attempted, including L-dopa (levodopa), which is still the gold standard in the treatment of Parkinson's disease. Levodopa crosses the blood-brain barrier as a dopamine precursor and is then converted into dopamine in the brain. L-dopa reduces the symptoms of Parkinson's disease but can cause serious side effects. In addition, the drug tends to lose effectiveness after the first two to three years of treatment. After five to six years, only 25% to 50% of patients continue to improve.

In addition, a major limitation of the current treatments for Parkinson's disease is the final manifestation of "fluctuation syndrome" leading to "all or nothing" states characterized by alternating periods of "on" motility with dyskinesia and periods of "off" with hypokinesia or akinesia. Patients who exhibit unpredictable or irregular "on-off" phenomena with oral anti-Parkinson treatment have a predictable beneficial response to IV administration of L-dopa and other dopamine agonists, suggesting that fluctuations in plasma drug concentrations are responsible for the "on-off" phenomena. The frequency of "on-off" fluctuations was also improved by continuous infusions of the dopamine receptor agonists apomorphine and lisuride. However, this mode of administration is cumbersome. Thus, other modes of administration providing more consistent plasma levels, such as topical administration, are preferred and have been suggested in the past.

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As mentioned above, one approach to treating Parkinson's disease involves dopamine receptor agonists. Dopamine receptor agonists (sometimes also referred to as dopamine agonists) are substances that, although structurally different from dopamine, bind to different sub-types of dopamine receptors and produce effects that are comparable to those of dopamine. In view of the reduced side effects, it is advantageous for the substances to bind selectively to a subset of the dopamine receptors, ie the D2 receptors.

One of the dopamine agonists that has been used to treat the symptoms of Parkinson's disease is rotigotine. It has mainly been tested as the hydrochloride salt. Rotigotine is the International Non-proprietary Name (INN) for the compound (-) - 5,6,7,8-tetrahydro-6- [propyl- [2- (2-thienyl) ethyl] amino] -1-naphthalenol having the structure shown below

<img file="PL219696B1_D0001.tif" />

Previously, it was known to administer rotigotine in passive transdermal therapeutic systems (TTS). Such passive transdermal therapeutic systems for the administration of rotigotine are described in WO94 / 07568 and WO 99/49852. However, the flow of rotigotine obtained from such passive transdermal therapeutic systems is not necessarily sufficient for all patients.

Another dopamine agonist that has been used to treat Parkinson's disease is R-apomorphine. R-apomorphine is the international non-proprietary name (INN) of the compound (R) -5, -6,6a, 7-tetrahydro-6-methyl-4H-dibenzoquinoline-11,12-diol with the structure shown below

<img file="PL219696B1_D0002.tif" />

Several approaches to the development of an iontophoretic delivery system have been described previously

R-apomorphines (see, e.g., R. van der Geest, M. Danhof, HE Bodde "lontophoretic Delivery of Apomorphine: In Vitro Optimization and Validation", Pharm. Res. (1997), 14, 1797-1802; M Danhof, R. van der Geest, T. van Laar, HE Bodde, "An integrated pharmacokinetic-pharmacodynamic approach to optimization of R-apomorphine delivery in Parkinson's disease." Advanced Drug Delivery Reviews (1998), 33, 253-263) . However, despite these efforts, only concentrations at the lower end of the therapeutic concentration range of 1.4 to 10.7 ng / ml could be achieved.

Another dopamine antagonist is ropinirole hydrochloride. Ropinirole (INN) is (4- [2-dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one) having the structure shown below

<img file="PL219696B1_D0003.tif" />

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Although iontophoretic administration of ropinirole was considered adequate, only flows at the lower end of the therapeutic range could be achieved (see A. Luzardo-Alvarez, MB

Delgado-Charro, J. Blanco-Mendez, "lontophoretic Delivery of Ropinirole Hydrochloride: Effect of Current Density and Vehicle Formulation", Pharmaceutical Research (2001), 18 (12), 1714-1720).

Many patients require concentrations that are significantly higher than those achievable with iontophoretic delivery of apomorphine or ropinirole.

Due to the wide range of Parkinson's disease symptoms and the varying severity of the disease, there is a strong need for a method that allows the adjustment of rotigotine flow through the skin while at the same time enabling the continuous stimulation of dopamine receptors in Parkinson's patients. Preferably, such a system should also allow rotigotine flows higher than that achieved by passive transdermal delivery systems.

Given the daunting experience with iontophoretic delivery of apomorphine, it was unexpected that iontophoretic delivery of rotigotine could provide plasma levels of rotigotine that are not only higher than typical passive diffusion systems, but are actually in the range that allows for pharmaceutically effective doses to be delivered. drug. The results obtained using this invention allow it to be reasonably expected that effective treatment of Parkinson's disease can be provided. It is understood that the term "treatment" in the context of this application is intended to mean the treatment or reduction of the symptoms of Parkinson's disease, and not an actual causal treatment leading to complete recovery.

The present invention provides the use of a composition comprising rotigotine and at least one chloride salt selected from NaCl, triethylammonium chloride and tributylammonium chloride at a concentration of 1 to 140 mmol / L, which has a pH in the range of 4 to 6.5 to prepare an iontophoretic device used for Parkinson's disease treatment.

Preferably the concentration of rotigotine is at least 0.5 mg / ml, more preferably 0.5 to 3 mg / ml.

Preferably the chloride salt is triethylammonium chloride or tributylammonium chloride, preferably in a concentration of 60 to 80 mmol / l.

Preferably the composition is used in the donor phase of an iontophoretic device and preferably contains rotigotine in a concentration of 0.5 to 3 mg / ml and at least one of triethylammonium chloride and tributylammonium chloride in a concentration of 60 to 80 mmol / l, and the pH of the donor phase is from 4 , 5 to 5.5.

The present invention also provides a composition comprising rotigotine and at least one pharmaceutically acceptable chloride salt selected from NaCl, triethylammonium chloride and tributylammonium chloride at a concentration of 1 to 140 mmol / L, which has a pH of 4 to 6.5, for use in the treatment of Parkinson's disease by administering by iontophoresis onto the skin of a patient in need.

Iontophoresis is the introduction of various ions into the skin by means of electricity. Compared to passive transcutaneous delivery, iontophoresis provides a number of benefits that are useful in treating Parkinson's disease:

- enables programming of the flow at the required therapeutic rate by adjusting the electric current, and

- allows the administration of a therapeutic agent to be started or terminated quickly by simply turning the iontophoretic delivery system on or off.

As the iontophoretic flow is influenced by a number of parameters, it is essential to optimize these parameters separately for optimal flow.

Surprisingly, it has been found that by using a composition having a pH of 4 to 6.5 and containing rotigotine and at least one chloride salt at a concentration of 1 to 140 mmol / L in the donor chamber of an iontophoretic device, flows can be achieved entirely within the therapeutic range.

By lowering the electrolyte concentration in the donor chamber, it was possible to achieve the target iontophoretic flow at a lower current density or to increase the percutaneous dose per unit area.

In studies conducted to evaluate the possibility of iontophoretic delivery of rotigotine, it was found that the solubility of rotigotine decreased with increasing pH. However, it was surprisingly found that a therapeutically relevant rate was achieved in the pH range of 4 to 6.5 at very low concentrations of rotigotine.

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To ensure optimal flow through the human stratum corneum, it was also necessary to provide a sufficient concentration of Cl ions^- for the electrode reaction in the donor phase. However, while maintaining the electrode reaction, the addition of the chloride salts lowers the solubility of rotigotine. Thus, a chloride salt concentration of 1 to 140 mmol / L, preferably 50 to 100 mmol / L, more preferably 60 to 80 mmol / L, has proven to be optimal.

The concentration of rotigotine can be varied according to the needs of the patient and the flow required to obtain a therapeutic effect in the treatment of Parkinson's disease. However, for optimal performance, it is preferably at least 0.5 mg / ml, more preferably 0.5 mg / ml to 3 mg / ml.

In a particularly preferred embodiment of the invention, the composition that is used as the donor phase of the iontophoretic device comprises rotigotine in a concentration of 0.5 to 3 mg / ml and at least one of triethylammonium chloride and tributylammonium chloride in a concentration of 60 to 80 mmol / l, the donor phase has pH 4.5 to 5.5.

Any conventional iontophoretic device may be used in the invention. Such iontophoretic devices are described, for example, in V. Nair, O. Pillai, R. Poduri, R. Panchagnula, "Transdermal Iontophoresis. Th. I: Basic Principles and Considerations ”Methods Find. Exp. Clin. Pharmacol.

(1999), 21 (2), 139-151.

The current density used during iontophoresis may be varied according to the needs of the patient and will depend on the iontophoretic device and composition used. The appropriate current can be determined by the attending physician. Generally, a suitable current density will be in charge₂ the range is preferably 200 to 500 µ / cm.

Example 1:

In vitro iontophoretic studies for rotigotine administration were performed with three-compartment flow diffusion cells as described by R. van der Geest et al. (R. van der Geest, M. Danhof, HE Bodde, "Validation and testing of a new lontophoretic continuous flow through transport cell ", J. Control. Release (1998), 51, 85-19). The stratum corneum of the human epidermis (SC) was placed on both sides of the acceptor compartment. A dialysis membrane having a cut-off of 5000 Da was used as a support membrane. The volume of the outer chambers was approximately 2 ml while the volume of the acceptor compartment was 0.54 ml. The two outer chambers contained a silver plate (anode) or a silver / silver chloride electron driver (cathode). The donor phase consisted of rotigotine solution buffered with 5 mM citrate buffer (2.1 mM sodium citrate dihydrate and 2.9 mM citric acid).

₂

Using this kit, pH 5 in the donor chamber, current density 500 μA / cm, pH 7.4 in the acceptor chamber, temperature 20 ° C and NaCl concentration in the donor chamber 70 mmol / L, the rotigotine flow was measured for various drug concentrations in the donor phase .

<td>Rotigotine concentration (mg / ml) (Donor solution)</td><td>Rotigotine concentration (mM) (Donor solution)</td><td>Rotigotine flow (nmol / cm²/ h)</td>

<td> 0,5</td><td> 1,4</td><td> 22,9</td>

<td> 1,0</td><td> 2,8</td><td> 30,2</td>

<td> 1,4</td><td> 3,98</td><td> 53,2</td>

Example 2:

Using a similar procedure as in Example 1 and a rotigotine concentration of 1.4 mg / ml (3.98 mM), the pH ₂ in donor chamber 5, current density 500 µA / cm, pH in acceptor chamber 7.4 and temperature 20 ° C, but by replacing triethylammonium chloride (TEACl) or tributylammonium chloride (TBACl) with NaCl, the influence of various cations on the flow was investigated. The concentration of chloride salts in the donor solution was 70 mmol / L

<td>Source of added ions</td><td>Rotigotine flow (nmol / cm²/ h)</td>

<td>NaCl</td><td> 53,2</td>

<td>TEACl</td><td> 72,8</td>

<td>TBACl</td><td> 62,0</td>

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Example 3:

Using a similar procedure and the same parameters as in Example 2, the effect of reducing the pH in the acceptor chamber from 7.4 to 6.2 was assessed for the various chloride salts. The concentration of chloride salts in the donor solution was 70 mmol / L.

<td>Source of added ions</td><td>Flow (nmol / cm²/ h) rotigotine</td>

<td>NaCl</td><td> 58,9</td>

<td>TEACl</td><td> 43,2</td>

<td>TBACl</td><td> 76,5</td>

Patent claims