EP1796610A2 - Systeme therapeutique transdermique pour la maladie de parkinson - Google Patents

Systeme therapeutique transdermique pour la maladie de parkinson

Info

Publication number
EP1796610A2
EP1796610A2 EP05802679A EP05802679A EP1796610A2 EP 1796610 A2 EP1796610 A2 EP 1796610A2 EP 05802679 A EP05802679 A EP 05802679A EP 05802679 A EP05802679 A EP 05802679A EP 1796610 A2 EP1796610 A2 EP 1796610A2
Authority
EP
European Patent Office
Prior art keywords
max
auc
rotigotine
disease
parkinson
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05802679A
Other languages
German (de)
English (en)
Other versions
EP1796610A4 (fr
Inventor
Marina Braun
Willi Cawello
Eric B. Foster
Thomas Lauterbach
Hans-Michael Wolff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Schwarz Pharma Inc
Original Assignee
Schwarz Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schwarz Pharma Inc filed Critical Schwarz Pharma Inc
Publication of EP1796610A2 publication Critical patent/EP1796610A2/fr
Publication of EP1796610A4 publication Critical patent/EP1796610A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings

Definitions

  • the present invention relates to a skin patch (also known as a Transdermal Therapeutic System (TTS)) that delivers a sufficient amount of rotigotine, at a sufficient rate, to treat or alleviate the symptoms of Parkinson's Disease or Restless Legs Syndrome.
  • TTS Transdermal Therapeutic System
  • the dopaminergic system uses dopamine as a neurotransmitter and plays a key role in the pathogenesis of a number of diseases including Parkinson's Disease, Alzheimer's Disease, Huntington's Disease and Schizophrenia (Seigel, G., et al, Basic Neurochemistry, 4 th Ed., 1989, pp 815-822 and 864-866).
  • the dopaminergic system has also been implicated with respect to depression (Dougherty, D., et al., J. Clin. Psychiatry, 1998; 59, Suppl 5:60-63), Restless Legs Syndrome (RLS) (Trenkwalder, C 1 et al. Lancet Neurol. 2005 Aug;4(8):465-75.) and Periodic Limb Movement in Sleep PLMS (O'Brien, C, CNI Review Medical Journal, Spring 1999, Volume 10, No. 1).
  • Parkinson's Disease is primarily a disease of middle age and beyond, and it affects both men and women.
  • the highest rate of occurrence of Parkinson's Disease is in the age group over 70 years old, where Parkinson's Disease exists in 1.5 to 2.5% of that population.
  • the mean age at onset is between 58 and 62 years of age, and most patients develop Parkinson's Disease between the ages of 50 and 79. There are approximately 800,000 people in the United States alone with Parkinson's Disease.
  • Parkinson's Disease is believed to be primarily caused by the degeneration of dopaminergic neurons in the substantia nigra.
  • Parkinson's Disease is now considered to be a more complex disorder that involves both motor and nonmotor systems.
  • This debilitating disease is characterized by major clinical features including tremor, bradykinesia, rigidity, dyskinesia, gait disturbances, and speech disorders. In some patients, dementia may accompany these symptoms.
  • Involvement of the autonomic nervous system may produce orthostatic hypotension, paroxysmal flushing, problems with thermal regulation, constipation, and loss of bladder and sphincter control.
  • Psychological disorders such as loss of motivation and depression may also accompany Parkinson's Disease.
  • Parkinson's Disease The clinical diagnosis of Parkinson's Disease is based on the presence of characteristic physical signs, e.g., tremor, rigidity of skeletal muscles, bradykinesia, impairment of postural reflexes, and gait distrubances.
  • the disease is known to be gradual in onset, slowly progressive, and variable in clinical manifestation.
  • Evidence suggests that the striatal dopamine content declines to 20% below levels found in age-matched controls before symptoms occur.
  • L-dopa is a compound that passes the blood-brain barrier as a precursor for dopamine and is then converted into dopamine in the brain. L-dopa improves the symptoms of Parkinson's Disease but may cause severe side effects. Moreover, the drug tends to lose its effectiveness after the first two to three years of treatment. After five to six years, only 25% to 50% of patients on L-dopa therapy maintain improvement.
  • Dopamine receptor agonists are substances which, while structurally different from dopamine, bind to dopamine receptors and trigger an effect which is comparable to that of dopamine. Due to the reduced side-effects, it is advantageous when the substances selectively bind to or interact with one or a subset of the known dopamine receptor subtypes. At present there are several classes of identified dopamine receptor subtypes, the most well characterized being the D1 , D2, and D3 receptors.
  • Rotigotine is (6S)-6- ⁇ propyl[2-(2- thienyl)ethyl]amino ⁇ -5,6,7,8-tetrahydro-1-naphthalenol (CAS No. 99755-59-6) having the structure:
  • the formulation disclosed in WO 94/07468 usually contains additional hydrophobic solvents, permeation- promoting substances, dispersing agents and, in particular, an emulsifier which is required to emulsify the aqueous solution of the active principle in the lipophilic polymer phase.
  • a TTS prepared by using such a system has been tested in healthy subjects and Parkinson patients.
  • the average drug plasma levels obtained by using this system were around 0.15 ng/mL with a 20 cm 2 patch containing 10 mg rotigotine hydrochloride. This level is considered too low to achieve a truly efficacious treatment or alleviation of the symptoms related to Parkinson's Disease.
  • the TTS used in this patent application comprises a backing layer, inert with respect to the constituents of the matrix, a self-adhesive matrix layer containing an effective quantity of rotigotine or rotigotine hydrochloride and a protective film which is removed before use.
  • the matrix system is composed of a non-aqueous polymer adhesive system, based on acrylate or silicone, with a solubility of rotigotine of at least 5% w/w.
  • the matrix system is essentially free of inorganic silicate particles.
  • Examples 1 and 2 and in FIG. 1 of WO 99/49852 two transdermal therapeutic systems are compared.
  • FIG. 1 of WO 99/49852 shows that a silicone patch releases about the same amount of active principle through the skin as an acrylate patch. This has been demonstrated by the almost identical drug flux rates in an in vitro model, independent of the adhesive test system employed. Therefore an identical flux rate through human skin was expected.
  • the drug content of the silicone patch used in WO 99/49852 was lower than the drug content used in the acrylate patch. This merely reflects the difference in drug release capacity , however, in the respective polymeric silicone and acrylate adhesives used in Examples 1 and 2 of the published PCT application, respectively. While the acrylate system is able to dissolve more drug than the silicone system, silicone allows for a faster release of the drug to the skin. As these two effects compensate each other, it has been thought that the acrylate and the silicone system used in WO 99/49852 are about equivalent in the obtainable drug plasma levels and, hence, in therapeutic efficacy.
  • RLS Symptoms of RLS include tingling, pulling, aching, itching, burning, cramps or pain, causing in the person concerned the irresistible urge to move. This disorder occurs most frequently when the person concerned is resting. It is particularly during the night's sleep that this sensory disorder with its attendant kinetic urge leads to restlessness and sleep interruptions. RLS can occur at any age but increases in frequency as persons grow older. It afflicts about 10% of the general population. Because of the nature of the symptoms, RLS is one of the most prevalent causes of sleep disturbances. In 20-40 year-olds, RLS accounts for 5%, in 40-60 year-olds for 20% and in those over 60 years of age for 35% of their sleeping-waking problem.
  • L-DOPA levodopa
  • L-DOPA therapy lies in the fact that in a great many patients its effectiveness tapers off and/or the RLS problem is shifted toward the morning hours (rebound) or the disorder is aggravated with the problem occurring even during the day (augmentation) (U.S. Patent Application Publication No. 2004/0048779, paragraph 0006).
  • a transdermal therapeutic system comprising a silicone matrix and rotigotine in its free base form produces a rotigotine pharmacokinetic profile with unexpectedly high plasma levels of rotigotine, a controlled release, substantially stable rotigotine blood plasma levels over time, and substantially uniform rotigotine plasma levels when the patch is placed at a variety of skin sites.
  • TTS transdermal therapeutic system
  • the inventors have demonstrated that a silicone-based TTS containing rotigotine in the free base form provides mean maximum drug plasma levels in the range of almost 0.5 ng/mL for a 20 cm 2 silicone patch containing 9 mg of rotigotine.
  • the invention contemplates a treatment regimen that allows for repeated daily administration that achieves a steady state plasma concentration effective for alleviating symptoms of Parkinson's Disease.
  • the methods of this invention produce continuous rotigotine plasma levels, which can be a more effective treatment than regimens producing pulsatile plasma levels.
  • the invention relates to methods for providing substantially controlled release of rotigotine and for inducing substantially steady-state rotigotine pharmacokinetic profiles over 24 hour period in a human patient in need thereof is provided, wherein the C max of rotigotine is from about 0.14 ng/mL to about 1.54 ng/mL and the AUC 0-t is from about 3.3 ng/mL*h to about 32.2 ng/mL*h, said method comprising administering rotigotine to said human patient.
  • the invention relates to methods for providing substantially controlled release of rotigotine and for inducing substantially steady-state rotigotine pharmacokinetic profiles over other and longer time periods, wherein the human patent suffers from Parkinson's Disease, Restless Legs Syndrome or another disease associated with the dopaminergic system.
  • the invention also relates to methods for multiple administrations of rotigotine patches, and to methods for providing substantially controlled release of rotigotine and for inducing substantially steady-state rotigotine pharmacokinetic profiles by placing rotigotine skin patches at various skin sites.
  • the methods of the invention encompass administration of rotigotine in various intervals effective to sustain a C max at a level from about 0.14 ng/mL to about 1.54 ng/mL and the mean area under the curve (AUC 0 -O at a level from about 3.3 ng/mL * h to about 32.2 ng/mL *h.
  • the invention also relates to methods that involve rotating the transdermal application site on a daily basis, wherein the pharmacokinetic profiles remain unchanged.
  • the invention relates to a controlled release rotigotine formulation for transdermal administration to human patients, comprising from about 4 to about 20 mg rotigotine, where the formulation provides a mean maximum plasma concentration (C max ) of rotigotine from about 0.14 ng/mL to about 1.54 ng/mL and a mean area under the curve up to the last quantifiable concentration (AUC 0-t ) from about 3.3 ng/mL*h to about 32.2 ng/mL*h.
  • C max mean maximum plasma concentration
  • AUC 0-t mean area under the curve up to the last quantifiable concentration
  • the C max of rotigotine induced by the formulation is from about 0.20 ng/mL to about 1.30 ng/mL; from about 0.30 ng/mL to about 1.20 ng/mL; from about 0.14 ng/mL to about 0.48 ng/mL; from about 0.37 ng/mL to about 0.75 ng/mL; or from about 0.84 ng/mL to about 1.54 ng/mL.
  • the induced C max is about 0.31 ng/mL ; about 0.56 ng/mL ; or about 1.19 ng/mL.
  • the induced area-under-the-curve of the pharmacokinetic profile over time "t" (“AUC 0-t ”) is from about 4.0 ng/mL * h to about 30.0 ng/mL * h; from about 5.0 ng/mL*h to about 25.0 ng/mL*h; from about 3.3 ng/mL * h to about 8.9 ng/mL*h; from about 7 ng/mL*h to about 15.2 ng/mL * h; or from about 15.2 ng/mL * h to about 32.2 ng/mL*h.
  • the induced AUC 0-t is about 6.1 ng/mL * h ; about 11.1 ng/mL*h ; or about 23.7 ng/mL*h.
  • a method for treating Parkinson's Disease in human patient comprising administering rotigotine which, upon administration, provides a C max of from about 0.14 ng/mL to about 1.54 ng/mL and wherein the AUC 0-t is from about 3.3 ng/mL * h to about 32.2 ng/mL * h.
  • a method for treating Restless Legs Syndrome in human patient comprising administering rotigotine which, upon administration, provides a C max of from about 0.14 ng/mL to about 1.54 ng/mL and wherein the AUC 0 . t is from about 3.3 ng/mL * h to about 32.2 ng/mL*h.
  • the invention relates to a controlled release rotigotine formulation for transdermal administration to human patients, wherein said formulation gives the same pharmacokinetic profile regardless of where it is applied on the body of said human patient.
  • the patient is suffering from Parkinson's disease.
  • the patient is suffering from Restless Legs Syndrome.
  • Figure 1 Mean (+/-standard deviation) rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 9.0mg rotigotine with Patch A.
  • Figure 2 Mean (+/-standard deviation) rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 18.0mg rotigotine with 2 x Patch A.
  • Figure 3 Mean (+/-standard deviation) rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 33.48mg rotigotine (state) with Patch B.
  • Figure 4 Mean (+/-standard deviation) rotigotine plasma concentrations (in ng/mL) during and after multiple transdermal administration of 4.5mg rotigotine with Patch C.
  • Figure 5 Mean (+/-standard deviation) rotigotine plasma concentrations (in ng/mL) during and after last transdermal administration of 4.5mg rotigotine with Patch C.
  • Figure 6 Mean (+/-standard deviation) rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 4.5mg rotigotine with Patch D.
  • Figure 7 Mean (+/-standard deviation) rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 4.5mg rotigotine with Patch C.
  • Figure 8 Mean plasma concentrations versus time for each of the six application sites using combined data from Days 27 and 30 (after normalization by body weight and apparent dose).
  • Figure 10 Arithmetic mean and standard deviation of the rotigotine plasma concentrations (ng/mL) during titration and maintenance phase.
  • Transdermal therapeutic systems (TTS) of the present invention may be prepared using methods known in the art or as described in Published U.S. Patent Application Nos. US2003/0026830 and US2003/0027793 and U.S. Patent No. 6,884,434, the disclosure of which as they relate to preparation of TTS's are incorporated by reference herein in their entirety.
  • a TTS of the present invention is reservoir or matrix type transdermal system composed of one or more layers.
  • the TTS includes a backing layer and a liner layer that is removed prior to use.
  • a TTS of the present invention is a thin, matrix-type transdermal system composed of three layers:
  • a flexible backing which is preferably siliconised on its inner side and is consisting of an aluminized polyester foil coated with a pigment-layer on the outer side or a transparent polyester film;
  • a self-adhesive drug matrix layer comprising of the active component rotigotine, ascorbyl palmitate, dl-alpha tocopherol, silicone adhesive, povidone, and sodium metabisulfite;
  • a protective liner comprising of a transparent fluoropolymer-coated polyester film, which liner is removed prior to application.
  • a preferred TTS of the present invention may contain from about 4 to about 20 mg of the rotigotine free base.
  • the TTS contains about 4.5 mg of the rotigotine free base, about 9 mg of the rotigotine free base, about 13.5 mg of the rotigotine free base, or about 18 mg of the rotigotine free base.
  • the TTS contains 5 - 25% (w/w) rotigotine.
  • the TTS is in the form of a patch.
  • the release surface area of the patch may be from about 10 cm 2 to about 40 cm 2 . In preferred embodiments of the present invention, the release surface area of the patch is about 10 cm 2 , about 20 cm 2 , about 30 cm 2 , or about 40 cm 2 .
  • a preferred embodiment of the invention utilizes a TTS containing one or more of the following: a pharmaceutically acceptable carrier (e.g., polyvinylpyrrolidone), sodium bisulfite, ascorbyl palmitate, DL-alpha-tocopherol, an amine resistant high tack silicone adhesive (e.g., BIO-PSA® Q7-4301 ; Dow Coming), and an amine resistant medium tack silicone adhesive (e.g., BIO-PSA® Q7-4201 , Dow Corning).
  • a pharmaceutically acceptable carrier e.g., polyvinylpyrrolidone
  • sodium bisulfite sodium bisulfite
  • ascorbyl palmitate DL-alpha-tocopherol
  • an amine resistant high tack silicone adhesive e.g., BIO-PSA® Q7-4301 ; Dow Coming
  • an amine resistant medium tack silicone adhesive e.g., BIO-PSA® Q7-4201 , Dow Corning
  • the TTS comprises a self-adhesive matrix layer containing the free base of rotigotine in an amount effective for the treatment of the symptoms of Parkinson's Disease or restless legs syndrome (RLS), wherein the matrix is based on a silicone-based polymer adhesive system in which rotigotine free base is dispersed; a backing layer inert to the components of the matrix layer; and a protective foil or sheet covering the matrix layer to be removed prior to use.
  • the TTS may also further comprise inert fillers to improve cohesion, e.g. polyvinylpyrrolidone.
  • the TTS may also further comprise additives that facilitate a homogeneous dispersion of rotigotine particles in the form of hydrophilic polymers (e.g., polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinylacetate, and a copolymer of ethylene and vinylacetate).
  • hydrophilic polymers e.g., polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinylacetate, and a copolymer of ethylene and vinylacetate.
  • the polyvinylpyrrolidone is present in the active substance-containing matrix layer in the form of insoluble particles at a concentration of 1.5 - 5% (w/w).
  • a TTS of the present invention is used to treat Parkinson's Disease or restless legs syndrome (RLS).
  • treatment is meant to designate a treatment or alleviation of the symptoms of Parkinson's Disease or RLS, rather than a real causative treatment leading to a complete cure.
  • the C 013x of rotigotine induced by the formulation is from about 0.20 ng/mL to about 1.30 ng/mL; from about 0.30 ng/mL to about 1.20 ng/mL; from about 0.14 ng/mL to about 0.48 ng/mL; from about 0.37 ng/mL to about 0.75 ng/mL; or from about 0.84 ng/mL to about 1.54 ng/mL.
  • the induced C max is about 0.31 ng/mL ; about 0.56 ng/mL ; or about 1.19 ng/mL.
  • the induced area-under-the-curve of the pharmacokinetic profile over time "t" (“AUC 0 . t ”) is from about 4.0 ng/mL * h to about 30.0 ng/mL*h; from about 5.0 ng/mL*h to about 25.0 ng/mL*h; from about 3.3 ng/mL*h to about 8.9 ng/mL*h; from about 7 ng/mL*h to about 15.2 ng/mL*h; or from about 15.2 ng/mL*h to about 32.2 ng/mL*h.
  • the induced AUC 0-t is about 6.1 ng/mL*h ; about 11.1 ng/mL*h ; or about 23.7 ng/mL*h.
  • the TTS is used in a method for treating Parkinson's Disease in humans, comprising administering rotigotine which, upon administration, provides a C max of from about 0.14 ng/mL to about 1.54 ng/mL and wherein the AUC 0 - t is from about 3.3 ng/mL*h to about 32.2 ng/mL*h.
  • the invention contemplates a TTS used to administer 0.5 mg to 20 mg rotigotine over a 24 hour period.
  • a TTS of the present invention is used to administer 2, 4, 6, or 8 mg rotigotine over a 24 hour period.
  • the TTS used to deliver the aforementioned dosages contains, at the time of application, 4.5, 9, 13.5, or 18 mg rotigotine, respectively.
  • a TTS of the present invention When applied once daily, a TTS of the present invention produces a sustained and relatively stable rotigotine plasma level.
  • Figures 1-2 show a sustained and relatively stable rotigotine plasma level over a 24 hour period after single administration of a preferred patch (described in Example 1).
  • a preferred patch described in Example 1
  • the presence of stable plasma levels of dopamine agonists such as rotigotine resulted in lower incidence of diskinesias compared to pulsatile plasma levels produced by intermittent administration.
  • Rotigotine is released at a controlled rate following application of a TTS of the present invention to the skin. Approximately 45% of the rotigotine content of the TTS is released within 24 hours. Steady-state rotigotine plasma concentrations are reached after one to two days of transdermal administration and are maintained by once daily application of the TTS, where the TTS is worn by the patient for 24 hours. In the clinical trials of rotigotine effectiveness using neuproTM, the mean trough plasma concentrations of rotigotine were stable over the six months of maintenance treatment. The bioavailability of rotigotine was similar across al! application sites. Figure 9 shows that the AUC 0 . t and the C max , for example, are comparable whether the TTS of the present invention is administered to the hip, shoulder, upper arm, thigh, abdomen or flank.
  • Rotigotine plasma levels have been determined in unconjugated blood samples or conjugated blood samples.
  • the TTS contains a controlled release rotigotine formulation for transdermal administration to human patients, comprising from about 4 to about 20 mg rotigotine, said formulation resulting in a mean maximum plasma concentration (C max ) of rotigotine from about 0.14 ng/mL to about 1.54 ng/mL and a mean area under the curve up to the last quantifiable concentration (AUC 0-t ) from about 3.3 ng/mL*h to about 32.2 ng/mL * h.
  • C max mean maximum plasma concentration
  • AUC 0-t mean area under the curve up to the last quantifiable concentration
  • the TTS contains a controlled release rotigotine formulation for transdermal administration to human patients, comprising from about 4.5 to about 18 mg rotigotine, said formulation providing a mean maximum plasma concentration (C max ) of rotigotine from about 0.14 ng/mL to about 1.54 ng/mL and a mean area under the curve up to the last quantifiable concentration (AUC 0 . t ) from about 3.3 ng/mL*h to about 32.2 ng/mL * h.
  • C max mean maximum plasma concentration
  • the TTS is used in a method for inducing a steady-state rotigotine pharmacokinetic profile over a 24 hour period in a human patient suffering from Parkinson's Disease, wherein the C max of rotigotine is from about 0.14 ng/mL to about 1.54 ng/mL and the AUC 0 - t is from about 3.3 ng/mL*h to about 32.2 ng/mL*h, said method comprising administering rotigotine to said human patient.
  • the invention relates to a method for treating Parkinson's Disease in a human patient, comprising administering to the patient a rotigotine formulation capable of providing a plasma concentration effective to alleviate the symptoms of Parkinson's Disease, wherein the C max is from about 0.14 ng/mL to about 1.54 ng/mL and wherein the mean area under the curve (AUCo-t) is from about 3.3 ng/mL * h to about 32.3 ng/mL *h.
  • the formulation is administered daily in 24 hour intervals.
  • the invention relates to a method for treating Parkinson's Disease in a human patient, comprising administering to the patient a rotigotine formulation capable of maintaining a plasma concentration effective to alleviate the symptoms of Parkinson's Disease, wherein the C max is sustained at a level from about 0.14 ng/mL to about 1.54 ng/mL and wherein the mean area under the curve (AUC o - t ) is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
  • the invention relates to a method of treating Parkinson's Disease in a human patient, comprising applying a transdermal therapeutic system (TTS) comprising rotigotine, wherein the TTS is capable of providing a plasma concentration effective to alleviate the symptoms of Parkinson's Disease, wherein the C max is from about 0.14 ng/mL to about 1.54 ng/mL and wherein the mean area under the curve (AUC 0 .,) is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
  • TTS transdermal therapeutic system
  • the invention relates to a method of treating Parkinson's Disease in a human patient comprising applying one or more transdermal patches comprising an amount of rotigotine from 4 mg to 20 mg to the human patient; so as to produce in the human patient a mean maximum plasma concentration (C max ) of rotigotine effective to alleviate the symptoms of Parkinson's Disease in the human patient, wherein the C max of rotigotine in the patient is sustained at a level from about 0.14 ng/mL to about 1.54 ng/mL and the last quantifiable concentration (AUC 0-t ) of the rotigotine in the patient is sustained at a level from about 3.3 ng/mL * h to about 32.2 ng/mL * h.
  • C max mean maximum plasma concentration
  • the invention relates to a method of treating Parkinson's Disease in a human patient comprising
  • step b) applying one or more transdermal patches comprising an amount of rotigotine from 4 mg to 20 mg to the human patient; b) removing the patch or patches of step a) and applying another patch or patches comprising an amount of rotigotine from 4 mg to 20 mg to the human patient at an interval so as to produce in the human patient a mean maximum plasma concentration (C max ) of rotigotine effective to alleviate the symptoms of Parkinson's Disease in the human patient; and c) repeating step b) as required to sustain the C max of rotigotine in the human patient at a level effective to alleviate the symptoms of Parkinson's Disease in the human patient wherein the C max of rotigotine is sustained at a level from about 0.14 ng/mL to about 1.54 ng/mL.
  • C max mean maximum plasma concentration
  • the C max of rotigotine in the human patient is sustained from 3 days to 28 weeks, from 1 to 7 days, from 1 to 6 weeks, for 7 weeks, from 8 to 28 weeks or for 28 weeks.
  • the patch or patches are removed and another patch or patches are applied daily, twice daily, weekly, twice weekly, monthly or twice monthly.
  • the C max of rotigotine in the human patient is sustained at a level from about 0.20 ng/mL to about 1.30 ng/mL; from about 0.30 ng/mL to about 1.20 ng/mL; from about 0.14 ng/mL to about 0.48 ng/mL; from about 0.37 ng/mL to about 0.75 ng/mL; or from about 0.84 ng/mL to about 1.54 ng/mL.
  • the induced C max is about 0.31 ng/mL ; about 0.56 ng/mL ; or about 1.19 ng/mL.
  • the invention relates to a controlled release rotigotine formulation for transdermal administration to human patients, wherein said formulation is capable of providing a plasma concentration effective to alleviate the symptoms of Parkinson's Disease regardless of where it is applied on the body of said human patient.
  • the patients are suffering from Parkinson's disease.
  • the patients are suffering from restless legs syndrome.
  • the patients are suffering from a disease related to the dopaminergic system.
  • the invention relates to a method for inducing a steady-state rotigotine pharmacokinetic profile over a 24 hour period in a human patient in need thereof comprising administering rotigotine to said human patient, wherein the C max of rotigotine is from about 0.14 ng/mL to about 1.54 ng/mL and the AUCo- t is from about 3.3 ng/mL *h to about 32.2 ng/mL * h, wherein the method gives the same C max and AUC 0 - t regardless of where the rotigotine is administered to the body of the human patient.
  • the invention relates to a method for treating Parkinson's Disease in a human patient, comprising administering to the patient over a 24 hr period a rotigotine formulation capable of providing a plasma concentration effective to alleviate the symptoms of Parkinson's Disease, wherein the C max is from about 0.14 ng/mL to about 1.54 ng/mL and the AUC 0-1 is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
  • the invention in another embodiment, relates to a method provides the same plasma concentration effective to alleviate the symptoms of Parkinson' disease regardless of where the rotigotine is administered to the body of the human patient.
  • the invention relates to a method of treating Parkinson's Disease in a human patient comprising applying one or more transdermal patches comprising an amount of rotigotine from 4 mg to 20 mg to the patient to provide a plasma concentration effective to alleviate the symptoms of Parkinson's Disease in the human patient, wherein the C max is sustained at a level from about 0.14 ng/mL to about 1.54 ng/mL and the mean area under the curve (AUC 04 ) of the rotigotine in the patient is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
  • a single daily dose of rotigotine should be initiated and then increased in increments to an effective dose.
  • the dose is administered with a transdermal therapeutic system (TTS).
  • TTS transdermal therapeutic system
  • the TTS is applied once a day.
  • the TTS should be applied at the same time every day.
  • the application site of the TTS should be moved on a daily basis, for example from the right side to the left side and from the upper body to the lower body.
  • the transdermal system is replaced every 48 hours preferably every 24 hours.
  • the application site does not affect the pharmacokinetic profile.
  • the TTS can be applies to the front of the abdomen, thigh, hip, flank, shoulder or upper arm.
  • the TTS is moved on a daily basis, for example from the right side to the left side, from the upper body to the lower body.
  • the TTS is not applied to the same site more than once every 7 days, 10 days, 14 days, 17 days or 21 days.
  • AUC 0 . t area under the curve from zero up to the last quantifiable concentration.
  • AUC(0-48) area under the curve from zero up to 48 hours after administration.
  • a single silicone patch A was administered to each of 14 healthy male subjects (Caucasian race, aged 18 - 50 years) for a period of 24 hours.
  • the same subjects were in randomized order administered either a single acrylic patch B for 24 hours in the second period followed another six day wash-out period and then administered two silicone patches A for 24 hours in the third period or administered two silicone patches A for 24 hours in the second period followed another six day wash-out period and then administered a single acrylic patch B for 24 hours in the third period.
  • the silicone patches had a rotigotine content of 9 mg /20 cm 2 and the acrylic patches had a rotigotine content of 33.48 mg /20 cm 2 .
  • AUC AUC(O-t) + C(t)/kel, where C(t) is the last quantificable plasma concentration.
  • Table 5 Individual rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 18.0mg rotigotine with 2 x Patch A
  • Table 6 Parameters of model independent pharmacokinetics of rotigotine during and after single transdermal administration of 18.0mg rotigotine. with 2 x Patch A
  • the silicone patches had a rotigotine content of 4.5mg/10cm 2 .
  • Table 10 Parameters of model independent pharmacokinetics of rotigotine during and after multiple transdermal administration of 4.5mg rotigotine with Patch C. subj. C max tmax AUC( 312- 336)
  • Both patch types contained 4.5 mg rotigotine/10 cm 2 .
  • patches were administered singly to the subjects for 24 hours. After a washout period of 7 days, the other patch was administered for 24 hours.
  • Tabie 11 Mean rotigotine plasma concentrations (in ng/mL) during and after transdermal administration of 4.5mg rotigotine with Patch D.
  • Table 12 Mean rotigotine plasma concentrations (in ng/mL) during and after transdermal administration of 4 5mg rotigotine with Patch C
  • Table 13 Parameters of model independent pharmacokinetics of rotigotine under administration of 4 5mg roligotine with Patch D
  • Table 14 Parameters of model independent pharmacokinetics of rotigotine under administration of 4.5mg rotigotine with Patch C
  • Rotigotine doses included 4.5mg/day (Patch D), 9.0mg/day (Patch E), 13.5mg/day (Patch F), and 18.0mg/day (2 x Patch E).
  • the trial consisted of an Eligibility Assessment (EA), a 24-day Titration Phase (4.5 to 18.0mg/day doses; incremental increases of 4.5mg/day every 6 days), a 6-day Maintenance Phase (18.0mg/day dose), a 6-day De-escalation Phase (13.5/9.0/4.5mg/day decreasing dose every 2 days), and a Safety Follow-Up visit 2 days following the last dose.
  • EA Eligibility Assessment
  • A Eligibility Assessment
  • PK primary pharmacokinetic
  • the objectives of this trial included the following: 1) to characterize the pharmacokinetic profile of rotigotine during 24 hour intervals where the skin site of patch application was rotated in subjects with early-stage Parkinson's disease, 2) to investigate the electrocardiographic effects of rotigotine over a 24 hour period under maximal anticipated therapeutic exposure in subjects with early- stage Parkinson's disease, and 3) to investigate the safety and local tolerability of a rotigotine transdermal patch under maximal anticipated therapeutic exposure.
  • the 18.0mg/day dose used 2x20 cm 2 patches. Initial doses were 4.5mg/day with weekly increases of 4.5mg/day to a maximum target dose of 18.0mg/day.
  • Table 16 reports the result of descriptive statistics of plasma concentrations for unconjugated rotigotine separated by the day of administration, the time of sampling after actual administration and the site of patch administration.
  • Table 16 Descriptive statistics of parameters of rotigotine plasma concentrations (ng/mL) under multiple dose in patients with early-stage Parkinson's disease
  • Table 18 shows the summary statistics for AUC 0 - t , Ss and C max , ss for unconjugated rotigotine for each site combined data from Day 27 and Day 30.
  • Table 18 Summary statistics of derived PK parameters for area under the curve (AUC 0- t , ss, n o rm a i ⁇ z ed ) and maximum plasma concentration (C max ,normai ⁇ zed) of unconjugated rotigotine for each patch application site after normalization for body weight and apparent dose, data from Day 27 and Day 30 combined (PKS)
  • PKS pharmacokinetic set
  • SD standard deviation
  • CV coefficient of variance
  • the doses included 4.5mg/day, 9mg/day, and 13.5mg/day of rotigotine.
  • Trial periods consisted of a 4-week pre-treatment (washout) period, a 3-week dose escalation period, a 25-week dose maintenance period, and a 4-week follow-up period for a total duration of 36 weeks.
  • Plasma samples for measurement of rotigotine concentration were collected in 56 subjects. The total number of samples was 1297. During the study blood samples for the analysis of rotigotine were taken before patch application and at 1 , 2, 3, 11 , 19, and 28 weeks after first patch application.
  • Table 19 shows the results of descriptive statistics for concentrations of rotigotine in plasma samples.
  • Figure 10 illustrates the results. This figure shows stable concentration over the maintenance phase of the study.
  • Table 19 Descriptive statistics of rotigotine plasma concentrations (ng/mL) during titration and maintenance phase
  • Min minimum
  • Max maximum
  • MP maintenance period
  • SD standard deviation
  • TP titration period.

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Abstract

L'invention concerne un système thérapeutique transdermique (TTS) qui contient de la rotigotine en tant que principe actif. Ce système thérapeutique transdermique est indiqué pour le traitement de la maladie de Parkinson du fait qu'il donne un profil pharmacocinétique comportant un taux plasmique élevé et stable de rotigotine.
EP05802679A 2004-09-29 2005-09-29 Systeme therapeutique transdermique pour la maladie de parkinson Withdrawn EP1796610A4 (fr)

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DE10361258A1 (de) 2003-12-24 2005-07-28 Schwarz Pharma Ag Verwendung von substituierten 2-Aminotetralinen zur vorbeugenden Behandlung von Morbus Parkinson
DE102004014841B4 (de) 2004-03-24 2006-07-06 Schwarz Pharma Ag Verwendung von Rotigotin zur Behandlung und Prävention des Parkinson-Plus-Syndroms
JPWO2015129527A1 (ja) 2014-02-27 2017-03-30 株式会社 メドレックス プラミペキソールを含有する神経変性疾患の治療用貼付剤

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EP1325742A1 (fr) * 2001-05-08 2003-07-09 Schwarz Pharma Ag Système thérapeutique transdermique amélioré pour le traitement de morbus Parkinson
EP1344522A1 (fr) * 2001-05-08 2003-09-17 Schwarz Pharma Ag Système thérapeutique transdermique pour l'obtention de taux plasmatiques élevés de rotigotine dans le traitement de morbus Parkinson
EP1386605A1 (fr) * 2002-07-30 2004-02-04 Schwarz Pharma Ag Systeme transdermique ameliore pour l'administration de rotigotin

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DE10234673B4 (de) * 2002-07-30 2007-08-16 Schwarz Pharma Ag Heißschmelz-TTS zur Verabreichung von Rotigotin und Verfahren zu seiner Herstellung sowie Verwendung von Rotigotin bei der Herstellung eines TTS im Heißschmelzverfahren
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WO1999049852A1 (fr) * 1998-03-30 1999-10-07 Lts Lohmann Therapie-Systeme Ag Systeme therapeutique transdermique contenant un agoniste d2 servant a traiter le syndrome parkinsonien, et son procede de production
EP1325742A1 (fr) * 2001-05-08 2003-07-09 Schwarz Pharma Ag Système thérapeutique transdermique amélioré pour le traitement de morbus Parkinson
EP1344522A1 (fr) * 2001-05-08 2003-09-17 Schwarz Pharma Ag Système thérapeutique transdermique pour l'obtention de taux plasmatiques élevés de rotigotine dans le traitement de morbus Parkinson
EP1386605A1 (fr) * 2002-07-30 2004-02-04 Schwarz Pharma Ag Systeme transdermique ameliore pour l'administration de rotigotin

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