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EP1796610A2 - Transdermal therapeutic system for parkinson's disease - Google Patents

Transdermal therapeutic system for parkinson's disease

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Withdrawn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)
French (fr)
Other versions
EP1796610A4 (en
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/en
Publication of EP1796610A4 publication Critical patent/EP1796610A4/en
Withdrawn legal-status Critical Current

Links

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

The invention provides a transdermal therapeutic system (TTS) containing rotigotine as the active ingredient. The TTS is useful in the treatment of Parkinson’s Disease because it induces a pharmacokinetic profile where the rotigotine plasma level is high and stable.

Description

U.S. PATENT APPLICATION
for
TRANSDERMAL THERAPEUTIC SYSTEM FOR PARKINSON'S DISEASE
Inventors: Marina Braun
Willi Cawello Eric B. Foster Thomas Lauterbach Hans-Michael Wolff
TRANSDERMAL THERAPEUTIC
SYSTEM FOR PARKINSON'S DISEASE
[0001] This application claims the benefit of U.S. Provisional Application Nos. 60/613,760 and 60/613,761, both filed September 29, 2004, and U.S. Serial No. 10/139,894, filed May 7, 2002, which claims the benefit of U.S. Provisional Application No. 60/363,638, filed March 12, 2002 and U.S. Serial No. 10/140,096, filed May 7, 2002 which claims the benefit of U.S. Provisional Application No. 60/363,655 filed March 12, 2002. The entire contents of these applications are herein incorporated by reference.
[0002] Various references are cited through out the application to more fully describe the subject matter of the invention. These references are hereby incorporated in their entirety.
FIELD OF THE INVENTION
[0003] 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.
BACKGROUND OF THE INVENTION
[0004] 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, 4th 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, C1 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).
[0005] 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. [0006] Parkinson's Disease is believed to be primarily caused by the degeneration of dopaminergic neurons in the substantia nigra. This, in effect, results in loss of tonic dopamine secretion and dopamine-related modulation of neuronal activity in the caudate nucleus, and thus in a deficiency of dopamine in certain brain regions. The resulting imbalance of neurotransmitters acetylcholine and dopamine eventually results in disease related symptoms. Although usually regarded as a motor system disorder, 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.
[0007] Early motor deficits of Parkinson's Disease can be traced to incipient degeneration of nigral dopamine-releasing cells. This neuronal degeneration produces a defect in the dopamineric pathway that connects the substantia nigra to the striatum. As the disease progresses, refractory motor, autonomic, and mental abnormalities may develop, which implies that there is progressive degeneration of striatal receptor mechanisms.
[0008] 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.
[0009] Treatment of Parkinson's Disease has been attempted with, inter alia, L-dopa, which still is the standard for the therapy of Parkinson's Disease. 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.
[0010] Furthermore a major drawback of currently utilized therapies for Parkinson's Disease is the eventual manifestation of the "fluctuation syndrome," which results in "all-or-none" conditions characterized by alternating "on" periods of mobility with dyskinesias and "off' periods with hypokinesia or akinesia. Patients who display unpredictable or erratic "on-off" phenomena with oral anti-Parkinson therapy have a predictable beneficial response to intravenous administration of L-dopa and other dopamine agonists, suggesting that fluctuations in plasma concentrations of drug are responsible for the "on-off" phenomena. The frequency of "on-off" fluctuations has also been improved by continuous infusions of the dopamine receptor agonists apomorphine and lisuride. However, this mode of administration is inconvenient. Therefore, other modes of administration providing a more stable plasma level would be beneficial.
[0011] As mentioned above, one treatment approach for Parkinson's Disease involves dopamine receptor agonists. Dopamine receptor agonists, sometimes also referred to as dopamine 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.
[0012] One dopamine receptor agonist which has been used to treat the symptoms of Parkinson's Disease is a compound called rotigotine. 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:
[0013] To date, various TTS's for the administration of rotigotine have been described. Published PCT Application No. WO 94/07468 discloses a transdermal therapeutic system containing rotigotine hydrochloride as active substance in a two-phase matrix which is essentially formed by a hydrophobic polymer material as the outer phase and a disperse hydrophilic phase contained therein and mainly containing the drug and hydrated silica. The silica enhances the maximum possible loading of the TTS with the hydrophilic salt. Moreover, 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 cm2 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.
[0014] Various further transdermal therapeutic systems have been described in Published PCT Application No. WO 99/49852. 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. In Examples 1 and 2 and in FIG. 1 of WO 99/49852, two transdermal therapeutic systems are compared. These are based on acrylate or silicone adhesives. 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.
[0015] It should be noted that 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.
[0016] The shortcomings of the silicone formulation disclosed in WO 94/07468 have led to clinical tests (safety and pharmacokinetic studies) of only the acrylate-based TTS of Example 1 of WO 99/49852. The mean steady flux rate across human skin in vitro of this TTS amounted to 15.3 μg/cm2/h. Even the acrylate-based TTS, however, exhibited unsatisfactory plasma levels of rotigotine that are too low to allow for a really efficacious treatment of Parkinson's Disease. A 30 mg (20 cm2) patch only yielded a mean maximum plasma concentration of 0.12 ng/mL, while a 5 cm2 patch containing 7.5 mg yielded a mean maximum plasma concentration of 0.068 ng/mL. Again, such values are too low to provide a real therapeutic progress in the treatment of Parkinson's Disease. In sum, neither the 20 cm2 silicone patch disclosed in WO 94/07468 nor the 20 cm2 acrylate patch disclosed in WO 99/49852 provided sufficient drug plasma levels to provide a satisfactory therapeutic effectiveness in the treatment of Parkinson's Disease. [0017] The Restless Legs Syndrome (RLS) is a neurological disease that expresses itself as a false sensation in the legs accompanied by a strong kinetic urge. 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. Once the quality of sleep and thus of life of a patient has increasingly deteriorated due to RLS or the patient suffers from daytime somnolence, the need for therapy is indicated. Such need for therapy usually sets in at the age of 40-50 (U.S. Patent Application Publication No. 2004/0048779, paragraphs 0002 to 0005).
[0018] Therapy studies have revealed a diversity of results obtained in monotherapeutic treatments with dopamine agonists, opiates, benzodiazepines, carbamazepine, clonidine or levodopa (L-DOPA) in combination with a dopa decarboxylase inhibitor. The use of L-DOPA for treating RLS has been the subject of a particularly large number of papers. Long-term L-DOPA therapy leads to a clear mitigation of the disorder with an improved quality of sleep and life. The drawback of L-DOPA therapy, however, 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).
[0019] Administration of rotigotine has been shown to lead to the suppression and reduction of RLS symptoms (U.S. Patent Application Publication No. 2004/0048779, paragraph 0012).
SUMMARY OF THE INVENTION
[0020] Based on the results of human clinical trials involving both healthy subjects and early-stage Parkinson's patients the inventors have found that a transdermal therapeutic system (TTS) 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. For example, 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 cm2 silicone patch containing 9 mg of rotigotine.
[0021] As such, 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. In particular, the methods of this invention produce continuous rotigotine plasma levels, which can be a more effective treatment than regimens producing pulsatile plasma levels.
[0022] 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 Cmax of rotigotine is from about 0.14 ng/mL to about 1.54 ng/mL and the AUC0-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. In other aspects, 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 Cmax at a level from about 0.14 ng/mL to about 1.54 ng/mL and the mean area under the curve (AUC0-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.
[0023] In another aspect, 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 (Cmax) 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 (AUC0-t) from about 3.3 ng/mL*h to about 32.2 ng/mL*h.
[0024] In other, preferred aspects of the invention, the Cmax 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. In yet other preferred aspects of the invention, the induced Cmax is about 0.31 ng/mL ; about 0.56 ng/mL ; or about 1.19 ng/mL.
[0025] In other aspects of the invention, the induced area-under-the-curve of the pharmacokinetic profile over time "t" ("AUC0-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. In other aspects, the induced AUC0-t is about 6.1 ng/mL*h ; about 11.1 ng/mL*h ; or about 23.7 ng/mL*h.
[0026] In another aspect of the invention, a method for treating Parkinson's Disease in human patient is provided, comprising administering rotigotine which, upon administration, provides a Cmax of from about 0.14 ng/mL to about 1.54 ng/mL and wherein the AUC0-t is from about 3.3 ng/mL*h to about 32.2 ng/mL*h.
[0027] In another aspect of the invention, a method for treating Restless Legs Syndrome in human patient is provided, comprising administering rotigotine which, upon administration, provides a Cmax of from about 0.14 ng/mL to about 1.54 ng/mL and wherein the AUC0.t is from about 3.3 ng/mL*h to about 32.2 ng/mL*h.
[0028] In one embodiment, 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. In a preferred embodiment, the patient is suffering from Parkinson's disease. In another preferred embodiment, the patient is suffering from Restless Legs Syndrome.
DESCRIPTION OF THE FIGURES
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 9 - Plasma concentration over time for all patch application sites (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.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
I. Transdermal Therapeutic Systems
[0029] 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.
[0030] In an embodiment, a TTS of the present invention is reservoir or matrix type transdermal system composed of one or more layers. In a further embodiment the TTS includes a backing layer and a liner layer that is removed prior to use.
[0031] In a preferred embodiment, a TTS of the present invention is a thin, matrix-type transdermal system composed of three layers:
(1) 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; and
(2) a self-adhesive drug matrix layer comprising of the active component rotigotine, ascorbyl palmitate, dl-alpha tocopherol, silicone adhesive, povidone, and sodium metabisulfite; and
(3) a protective liner, comprising of a transparent fluoropolymer-coated polyester film, which liner is removed prior to application.
[0032] A preferred process for making the TTS is described in U.S. Patent Application Publication No. US 2003/0026830 at paragraphs 38-42 and U.S. Patent Application Publication No. US 2003/0027793 at paragraphs 37-41 , which are incorporated herein by this reference.
[0033] A preferred TTS of the present invention may contain from about 4 to about 20 mg of the rotigotine free base. In preferred embodiments, 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. In another preferred embodiment, the TTS contains 5 - 25% (w/w) rotigotine.
[0034] In a preferred embodiment of the present invention, the TTS is in the form of a patch. The release surface area of the patch may be from about 10 cm2 to about 40 cm2. In preferred embodiments of the present invention, the release surface area of the patch is about 10 cm2, about 20 cm2, about 30 cm2, or about 40 cm2. [0035] 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). For example, a preferred 20 cm2 patch TTS contains the components in the amounts described in Table 1.
Table 1
[0036] In a particularly preferred embodiment, 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).
[0037] When the above-mentioned hydrophilic polymer is polyvinylpyrrolidone, 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).
[0038] In one preferred embodiment, a TTS of the present invention is used to treat Parkinson's Disease or restless legs syndrome (RLS). As is used herein, the term "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.
II. Rotigotine Pharmacokinetics and the TTS A. Pharmacokinetics
[0039] In an embodiment of the invention, the C013x 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. In yet other preferred aspects of the invention, the induced Cmax is about 0.31 ng/mL ; about 0.56 ng/mL ; or about 1.19 ng/mL.
[0040] In other aspects of the invention, the induced area-under-the-curve of the pharmacokinetic profile over time "t" ("AUC0.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. In other aspects, the induced AUC0-t is about 6.1 ng/mL*h ; about 11.1 ng/mL*h ; or about 23.7 ng/mL*h.
[0041] In another preferred embodiment, the TTS is used in a method for treating Parkinson's Disease in humans, comprising administering rotigotine which, upon administration, provides a Cmax of from about 0.14 ng/mL to about 1.54 ng/mL and wherein the AUC0-t is from about 3.3 ng/mL*h to about 32.2 ng/mL*h.
[0042] The invention contemplates a TTS used to administer 0.5 mg to 20 mg rotigotine over a 24 hour period.
[0043] In preferred embodiments, a TTS of the present invention is used to administer 2, 4, 6, or 8 mg rotigotine over a 24 hour period. In certain embodiments, the TTS used to deliver the aforementioned dosages contains, at the time of application, 4.5, 9, 13.5, or 18 mg rotigotine, respectively.
[0044] 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). In animal models of Parkinson's Disease, 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. Chase, T.N., Drugs 55 Suppl. 1: 1 - 9 (1998); Stocchi, F. and Olanow, C.W., Neurology 62 (1 Suppl. 1): S56 - S63 (2004).
[0045] 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 neupro™, 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 AUC0.t and the Cmax, for example, are comparable whether the TTS of the present invention is administered to the hip, shoulder, upper arm, thigh, abdomen or flank.
[0046] Rotigotine plasma levels have been determined in unconjugated blood samples or conjugated blood samples.
[0047] Exposure to rotigotine from daily application of the TTS of the present invention in healthy subjects and Parkinson's Disease patients exhibited a consistent exposure profile. Repeated daily administration resulted in stable plasma levels. After removal of the TTS, plasma levels decrease with an elimination half-life life of 5 to 7 hours.
[0048] Pharmacokinetic parameters observed after single dose or multiple dose application of a preferred TTS of the present invention to healthy subjects are summarized in Table 2.
Table 2
B. Preferred Embodiments
[0049] In a preferred embodiment of the present invention, 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 (Cmax) 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 (AUC0-t) from about 3.3 ng/mL*h to about 32.2 ng/mL*h.
[0050] In a preferred embodiment of the present invention, 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 (Cmax) 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 (AUC0.t) from about 3.3 ng/mL*h to about 32.2 ng/mL*h.
[0051] In still another preferred embodiment, 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 Cmax of rotigotine is from about 0.14 ng/mL to about 1.54 ng/mL and the AUC0-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.
[0052] In an embodiment, 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 Cmax 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. In certain embodiments, the formulation is administered daily in 24 hour intervals.
[0053] In another embodiment, 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 Cmax 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 (AUCo-t) is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
[0054] In yet another embodiment, 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 Cmax is from about 0.14 ng/mL to about 1.54 ng/mL and wherein the mean area under the curve (AUC0.,) is from about 3.3 ng/mL *h to about 32.2 ng/mL *h. [0055] In a further embodiment, 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 (Cmax) of rotigotine effective to alleviate the symptoms of Parkinson's Disease in the human patient, wherein the Cmax 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 (AUC0-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.
[0056] In a further embodiment, the invention relates to a method of treating Parkinson's Disease in a human patient comprising
a) 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 (Cmax) 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 Cmax of rotigotine in the human patient at a level effective to alleviate the symptoms of Parkinson's Disease in the human patient wherein the Cmax of rotigotine is sustained at a level from about 0.14 ng/mL to about 1.54 ng/mL.
[0057] In a preferred embodiment of the invention, the Cmax 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.
[0058] In another preferred embodiment of the invention, the patch or patches are removed and another patch or patches are applied daily, twice daily, weekly, twice weekly, monthly or twice monthly.
[0059] In other, preferred aspects of the invention, the Cmax 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. In yet other preferred aspects of the invention, the induced Cmax is about 0.31 ng/mL ; about 0.56 ng/mL ; or about 1.19 ng/mL.
[0060] In one embodiment, 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. In a preferred embodiment, the patients are suffering from Parkinson's disease. In another preferred embodiment, the patients are suffering from restless legs syndrome. In still another embodiment, the patients are suffering from a disease related to the dopaminergic system.
[0061] In another embodiment, 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 Cmax 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 Cmax and AUC0-t regardless of where the rotigotine is administered to the body of the human patient.
[0062] In another embodiment, 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 Cmax is from about 0.14 ng/mL to about 1.54 ng/mL and the AUC0-1 is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
[0063] In another embodiment, the invention 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.
[0064] In yet another embodiment, 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 Cmax is sustained at a level from about 0.14 ng/mL to about 1.54 ng/mL and the mean area under the curve (AUC04) of the rotigotine in the patient is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
[0065] In an embodiment of the invention, a single daily dose of rotigotine should be initiated and then increased in increments to an effective dose. In another embodiment, the dose is administered with a transdermal therapeutic system (TTS). In yet another embodiment, the TTS is applied once a day. In a further embodiment, the TTS should be applied at the same time every day. In another embodiment, 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.
[0066] In certain embodiments, the transdermal system is replaced every 48 hours preferably every 24 hours. The application site does not affect the pharmacokinetic profile. In non-limiting examples the TTS can be applies to the front of the abdomen, thigh, hip, flank, shoulder or upper arm. Preferably 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. Preferable the TTS is not applied to the same site more than once every 7 days, 10 days, 14 days, 17 days or 21 days.
[0067] The present invention is illustrated by the following examples, without limiting the scope of the invention.
Abbreviations
[0068] As used above, and elsewhere herein, the following terms and abbreviations have the meanings defined below:
AUC0.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.
AUCo-inf: area under the curve from zero up to infinity calculated using the area under the curve after the first 24 hours (AUCo-24) and extrapolating to infinity such that AUC0-inf = AUCo-24 + plasma concentration at 24 hours/keι.
Ctrougtv measured trough plasma concentration.
CL: total body clearance.
Cmax: maximum measured plasma concentration
CmaX|T: maximum measured plasma concentration during a dose interval ,τ.
Cmin: minimum measured plasma concentration.
Cmin,τ: minimum measured plasma concentration during a dose interval T.
CV: coefficient of variation.
ke(: rate constant of elimination.
LLQ: lower limit of quantification.
std: standard deviation
swing: fluctuation of the plasma concentration calculated by (Cmax - Cmin) / (0.5*Cmax +0.5*Cmin ) * 100%. t|ag: lag time; elapsed time until onset of absorption.
tmax: timeofCmax.
tmιn: timeofCmin-
(Site of administration: H = hip, S = shoulder, UA = upper arm, T = thigh, AB = abdomen, F = flank
EXAMPLE 1
Study Design and Subject Population
[0069] A single-center, open-label, single administration, three-way cross-over clinical trial was performed to assess the blood levels and comparative bioavailability of rotigotine from silicone and acrylic transdermal patches. The acrylic transdermal patches were made in accordance with the teachings of WO 99/49852. The silicone transdermal patches were made in accordance with the teachings of U.S. Patent Application Publication No. US 2003/0026830 at paragraphs 38-42, U.S. Patent Application Publication No. US 2003/0027793 at paragraphs 37- 41 and U.S. Patent No. 6,884,434, columns 5-6, Example 2 and comprised the following components:
Patch A
Patch B
[0070] In a first period, 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. After a six day wash-out period, 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 cm2 and the acrylic patches had a rotigotine content of 33.48 mg /20 cm2.
[0071] During each study period blood samples for the analysis of rotigotine were taken before patch application and at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 15 h, 23 h, 24 h, 25 h, 26 h, 27 h, 28 h, 30 h, 32 h, 36 h, 40 h and 48 h after first patch application.
[0072] To characterize the pharmacokinetics of rotigotine after administration of rotigotine patches in healthy volunteers, the maximum plasma concentration (Cmax) and the corresponding timepoint (tmax) were taken and the data was separated by formulation (and dose). For each sequence of plasma concentrations the AUC was calculated using the trapezoidal rule. AUC(0-t) represents the AUC from patch administration up to the last quantifiable plasma concentration (e.g., if the concentration dropped to below quantifiable levels in less than 48 hours) whereas AUC(O-48) presents the AUC from patch administration to the last sampling point, 48 h after start of administration. The total body clearance was calculated from the individual apparent dose and the corresponding AUC. AUC was the individual area under the concentration time curve extrapolated to infinity: AUC = AUC(O-t) + C(t)/kel, where C(t) is the last quantificable plasma concentration.
Plasma Concentrations of Rotigotine
[0073] Data for the rotigotine plasma concentrations and pharmacokinetic parameters measured during this clinical trial for the silicone patches are provided in Tables 3, 4, 5, and 6. Data for rotigotine plasma concentration for the acrylic patch are provided in Tables 7 and 8. Figures 1 and 2 illustrate the arithmetic mean of rotigotine plasma concentration for single dose administration of the silicone patch. Figure 3 illustrates the arithmetic mean of rotigotine plasma concentration for single dose administration of the acrylic patch. Table 3: Individual rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 9.0mg rotigotine with Patch A (n.s. = no sample).
subj. time [h] no. 25 26 27 28 30 32 36 40 48
1 0.289 0.245 0.228 0.168 0.15 0.103 0.0799 0.0376 0.0179
2 0.325 0.312 0.287 0.235 0.16 0.119 0.053 0.0476 0.0289
3 0.285 0.296 0.182 0.14 0.0798 0.0608 0.04 0.028 0.0137
4 0.489 0.426 0.335 0.277 0.168 0.143 0.0884 0.0521 0.035
5 0.513 0.422 0.382 0.361 0.23 0.149 0.0927 0.0682 0.0535
6 0.382 0.317 0.292 0.275 0.18 0.125 0.0826 0.0664 0.0355
7 0.255 0.229 0.218 0.186 0.132 0.0914 0.0467 0.0281 0.0103
8 0.282 0.281 0.237 0.193 0.145 0.0981 0.0569 0.0386 0.0187
9 0.389 0.297 0.258 0.217 0.129 0.0974 0.0544 0.0257 0.0187
10 0.186 0.162 0.13 0.107 0.0582 0.0386 0.024 0.0163 0
11 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
12 0.306 0.267 0.236 0.178 0.131 0.103 0.0617 0.0288 0.0151
15 0.58 0.516 0.413 0.328 0.166 0.109 0.0752 0.0593 0.0464
23 0.311 0.215 0.177 0.146 0.107 0.0868 0.0379 0.0182 0.0162
Dimension concentration = [ng/ml] Table 4: Parameters of model independent pharmacokinetics of rotigotine during and after single transdermal administration of 9.0mg rotigotine with Patch A
Dimension: Cmax [ng/ml] tmax, t [h] AUC [ng/ml h]
Table 5: Individual rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 18.0mg rotigotine with 2 x Patch A
Dimension concentration = [ng/ml]
Table 6: Parameters of model independent pharmacokinetics of rotigotine during and after single transdermal administration of 18.0mg rotigotine. with 2 x Patch A
Dimension: Cmax [ng/ml] tmax, t [h] AUC [ng/ml h]
Table 7: Individual rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 33.48mg rotigotine with Patch B
Dimension concentration = [ng/ml] Table 8: Parameters of model independent pharmacokinetics of rotigotine during and after single transdermal administration of 33.48mg rotigotine with Patch B
Dimension: Cmax [ng/ml] tmax, t [h] AUC [ng/ml h]
EXAMPLE 2
Study design and Subject Population
[0074] A single-center, open-label, multiple dose clinical trial was performed to assess the pharmacokinetics of a rotigotine transdermal patch during 14 days of once-daily patch administration to 30 healthy male volunteers. The subjects were treated for two days with placebo patches and then either with placebo or rotigotine patches for 14 days (i.e., days 13-16). The silicone transdermal patches were made in accordance with the teachings of U.S. Patent Application Publication No. US 2003/0026830 at paragraphs 38-42, U.S. Patent Application Publication No. US 2003/0027793 at paragraphs 37-41 and U.S. Patent No. 6,884,434, columns 5-6, Example 2 and comprised the following layers and components:
Patch C
[0075] The silicone patches had a rotigotine content of 4.5mg/10cm2.
[0076] During the study blood samples for the analysis of rotigotine were taken before patch administration and at 1 , 2, 4, 6, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 316, 320, 324, 336, 337, 338, 339, 340, 342, 344, 350, 360, 372, and 384 hours after first patch administration.
[0077] To characterize the pharmacokinetics of rotigotine after multiple dose administration of rotigotine patches in healthy volunteers the maximum plasma concentration (C013x) and the corresponding timepoint (tmax) were taken and the data separated by subject. For each time sequence of plasma concentrations the AUC was calculated using the trapezoidal rule. AUC(312- 336) represents the AUC within the dose interval of 24 hours under steady state administration. Plasma Concentrations of Rotigotine
[0078] Data for the rotigotine plasma concentrations and pharmacokinetic parameters measured during this trial are provided in Tables 9 and 10 Figures 4 and 5 illustrate the arithmetic mean of rotigotine plasma concentration during and after multiple patch administration
Table 9: Individual rotigotine plasma concentrations (in ng/mL) during and after multiple transdermal administration of 4 5mg rotigotine with Patch C
Dimension concentration [ng/ml]
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)
02 .385 320.0 7.884
03 .196 324.0 4.542
04 .233 320.0 4.18
05 .355 316.0 7.73
06 .19 336.0 3.948
07 .343 316.0 5.294
08 .479 320.0 9.356
09 .356 324.0 8.032
10 .521 324.0 10.202
11 .216 336.0 3.1964
12 .933 324.0 14.87
13 .183 336.0 4.268
14 .144 324.0 2.7528
15 .272 324.0 6.05
16 .266 336.0 5.656
17 .227 336.0 5.068
18 .283 320.0 5.986
19 .294 324.0 6.408
20 .396 320.0 7.892
21 .0756 324.0 1.7402
22 .277 324.0 5.808
23 .169 336.0 3.556
24 .194 324.0 3.912
25 .221 336.0 4.912
26 .309 316.0 5.608
27 .296 336.0 5.244
28 .495 324.0 8.958
29 .46 320.0 10.006
30 .136 320.0 2.9064
Min .0756 316.0 1.7402
Max .933 336.0 14.87
Med .277 324.0 5.608 ic .307 325.517 6.068
SD .165 7.044 2.798
Dimension : c-max [ng/ml]; t-max,t [h]; auc [ng/ml h]
EXAMPLE 3
Study Design and Subject Population
[0079] A single-center, open-label, single-dose, randomized two-way cross-over clinical trial was performed to assess bioequivalence of two different rotigotine-containing silicone patches in 30 healthy male subjects (Caucasian, aged 18-50 years). The first silicone transdermal patches (Patch C) were made in accordance with the teachings of U.S. Patent Application Publication No. US 2003/0026830 at paragraphs 38-42, U.S. Patent Application Publication No. US 2003/0027793 at paragraphs 37-41 and U.S. Patent No. 6,884,434, columns 5-6, Example 2 and comprised the following layers and components:
Patch C
[0080] The second silicone transdermal patches (Patch D) were made in accordance with the teachings of U.S. Patent Application Publication No. US 2003/0026830 at paragraphs 38-42 and U.S. Patent Application Publication No. US 2003/0027793 at paragraphs 37-41 and comprised the following layers and components:
Patch D
[0081] Both patch types contained 4.5 mg rotigotine/10 cm2. In a first period, 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.
[0082] During the study blood samples for the analysis of rotigotine were taken before patch application and at, 1 , 2, 4, 6, 8, 10, 12, 15, 23, 24, 25, 26, 27, 28, 30, 36 and 48 hours after first patch application The study was done under in-patient conditions except for the urine collection at 36 - 48 hours and the 48 h blood collection (which were performed on an ambulatory basis).
Plasma Concentrations of Rotigotine
[0083] Data for rotigotine plasma concentrations and pharmacokinetic parameters measured during this clinical are provided in Tables 11 , 12, 13, 14, and 15. Figures 6 and 7 illustrate the arithmetic mean of rotigotine plasma concentration for single patch administration. Table 15 summarizes the results of a statistical test to show that the two patch formulations are bioequivalent.
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
Table 15: Results of relative bioavailability for rotigoine after administration of Patches C and D
* = least square means, SE = standard error, Cl = confidence interval, Difference = difference on log-scale
EXAMPLE 4
Study Design and Subject Population
[0084] An open-label, multi-site, randomized trial with daily doses of rotigotine patch applied to the skin of 70 subjects was performed to evaluate the safety, tolerability, and effectiveness of placing the patch on different body sites. The study also evaluated electrocardiographic effects of patch- administered rotigotine. Each day, a fresh patch was placed on a new skin site (abdomen, flank, upper arm, shoulder, thigh, hip) in a rotating order. The silicone transdermal patches were made in accordance with the teachings of U.S. Patent Application Publication No. US 2003/0026830 at paragraphs 38-42, U.S. Patent Application Publication No. US 2003/0027793 at paragraphs 37-41 and U.S. Patent No. 6,884,434, columns 5-6, Example 2 and comprised the following layers and components:
Patches D, E and F
[0085] 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. A total of 70 subjects were enrolled and randomized; 63 subjects were analyzed for the primary pharmacokinetic (PK) variables and 58 subjects were analyzed for the primary pharmacodynamic variables.
[0086] 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.
[0087] The study used 10 cm2, 20 cm2, and 30 cm2 rotigotine transdermal patches, which correspond to 4.5mg, 9.0mg, and 13.5mg rotigotine, respectively. The silicone transdermal patches were made in accordance with the teachings of U.S. Patent Application Publication No. US 2003/0026830 at paragraphs 38-42 and U.S. Patent Application Publication No. US 2003/0027793 at paragraphs 37-41 comprised the following layers and components as disclosed above
[0088] The 18.0mg/day dose used 2x20 cm2 patches. Initial doses were 4.5mg/day with weekly increases of 4.5mg/day to a maximum target dose of 18.0mg/day.
[0089] Blood samples were collected before patch administration and on the days and at the times indicated in Table 16.
Plasma Concentrations of Rotigotine
[0090] Mean plasma concentrations versus time for each of the six application sites using combined data from Days 27 and 30 are shown in the Figure 8.
[0091] Mean plasma concentrations of unconjugated rotigotine were similar between the six application sites. Starting with a plasma concentration at Time 0 (prior to patch removal, CtrOugh) of about 1ng/ml_, the concentration decreased within 2 hours by about 0.2ng/mL, followed by an increase back up to the level of the trough plasma concentration. Figure 9 illustrates a plasma concentration over time for all patch application sites.
[0092] 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
Application Site = Hip
#Obs
Day Time n >LOQ Mean SD CV(%) Geo Mean Geo SD Median Mm Max
Day25 OH 10 10 09598 089990 938 07010 220222 05265 0271 2980
4H 10 10 08993 067741 753 06929 216680 08040 0256 2400
8H 10 10 08447 078229 926 05629 278343 06550 0114 2750
12H 10 10 09776 079679 815 06434 294450 07255 0094 2330
Day26 OH 11 11 07716 039609 513 06542 193335 07250 0187 1260
4H 11 11 05491 027813 507 04660 194460 05250 0111 0912
8H 11 11 08153 044074 541 06802 198291 07620 0230 1370
12H 11 11 09108 062860 690 06841 243929 09420 0102 2300
Day27 OH 10 10 13040 111784 857 10111 205974 08805 0375 4150
1H 10 10 12353 105886 857 09845 192688 09300 0450 3980
2H 10 10 09798 095288 973 07477 203439 07055 0292 3550
4H 10 10 10117 126502 1250 06774 227514 05055 0314 4440
5H 10 10 08224 062891 765 06431 209471 06425 0232 1970
6H 10 10 07661 045889 599 06546 180767 05935 0283 1560
7H 10 10 08542 045527 533 07356 185188 07095 0203 1730
8H 10 10 08676 043667 503 07580 178669 07310 0236 1520
1OH 10 10 09860 047824 485 08971 157901 08460 0371 2130
12H 10 10 10611 055365 522 09429 167691 08825 0380 2280
14H 10 10 10745 055728 519 09609 163250 09115 0485 2080
16H 10 10 13677 079763 583 12073 165233 10500 0634 3090
18H 10 10 11769 054621 464 10728 157672 09900 0457 2140
2OH 10 10 12121 051482 425 11143 154847 10650 0593 1970
22H 10 10 09248 045066 487 08350 161184 08890 0379 1920
235H 10 10 09600 038736 404 08745 164926 09570 0261 1750
Day28 4H 11 11 07955 046452 584 06786 182902 05510 0218 1570
8H 11 11 11237 075207 669 08577 234277 10500 0178 2300
12H 11 11 10759 065385 608 08227 244476 10000 0158 2130
Day29 OH 11 11 06160 028338 460 05494 169457 06300 0209 1070
4H 11 11 04802 028770 599 04018 191554 03910 0131 0974
8H 11 11 05221 026648 510 04468 188281 06020 0133 0900
12H 11 11 05715 029201 511 05056 170189 04600 0180 1140
Day30 OH 10 10 10048 046928 467 09083 161927 08680 0398 1930
1H 10 10 08518 036378 427 07819 156060 07840 0393 1500
2H 10 10 06981 024795 355 06594 142980 06430 0397 1100
4H 10 10 07967 068299 857 06487 185828 05950 0236 2670
5H 10 10 08458 063315 749 06787 201882 07460 0194 2420
6H 10 10 10816 152030 1406 06542 261354 05810 0140 5310 7H 10 10 07566 047940 634 06270 194917 06825 0217 1800
8H 10 10 09441 099194 1051 06780 225518 07225 0214 3640
10H 10 10 07786 056988 732 06330 196963 06990 0235 2220
12H 10 10 09966 064950 652 08291 191705 08425 0317 2510
14H 10 10 08877 048873 551 07835 167757 07380 0428 1860
16H 10 10 12098 066582 550 10564 174629 12200 0424 2670
18H 10 10 12131 063776 526 10663 171951 10250 0473 2220
2OH 10 10 12665 070594 557 11060 172835 10255 0504 2600
22H 10 10 10856 071368 657 09142 184220 09330 0380 2770
235H 10 10 08204 034090 416 07585 151856 06915 0461 1350
Days
27&30 OH 20 20 11544 084839 735 09583 182270 08730 0375 4150
Combined
1H 20 20 10436 079528 762 08774 174752 08405 0393 3980
2H 20 20 08390 069289 826 07021 173502 06575 0292 3550
4H 20 20 09042 099557 1101 06629 203165 05520 0236 4440
5H 20 20 08341 061432 737 06607 201882 06425 0194 2420
6H 20 20 09239 110489 1196 06544 217423 05905 0140 5310
7H 20 20 08054 045777 568 06791 187859 06980 0203 1800
8H 20 20 09059 074695 825 07169 199371 07225 0214 3640
1OH 20 20 08823 052297 593 07536 180455 07605 0235 2220
12H 20 20 10289 058831 572 08842 177857 08675 0317 2510
14H 20 20 09811 051907 529 08677 165125 08370 0428 2080
16H 20 20 12888 071967 558 11294 168360 11500 0424 3090
18H 20 20 11950 057821 484 10695 162781 10250 0457 2220
2OH 20 20 12393 060198 486 11101 161944 10650 0504 2600
22H 20 20 10052 058675 584 08737 170855 09280 0379 2770
235H 20 20 08902 036229 407 08144 157540 08700 0261 1750
Application Site = Shoulder
#Obs
Day Time n >LOQ Mean SD CV(%) Geo Mean Geo SD Median Mm Max
Day25 OH 11 11 08450 039342 466 07595 166491 07700 0243 1720
4H 11 11 14656 118532 809 10877 229840 11300 0276 4130
8H 11 11 15562 089190 573 12839 201651 12700 0390 2750
12H 11 11 14674 087603 597 12450 184120 14900 0534 3390
Day26 OH 11 11 0g283 080108 863 07068 215694 07510 0170 3020
4H 11 11 082Og 043510 530 07038 185972 09000 0212 1600
8H 11 11 10675 051786 485 09399 174736 11800 0338 2020
12H 11 11 11026 041510 376 10094 161600 12600 0373 1700
Day27 OH 11 11 07905 058843 744 06131 213333 05090 0188 1880
1H 11 11 07317 046938 641 06025 193539 06100 0239 1470
2H 11 11 07235 038012 525 06190 186084 06960 0223 1360
4H 11 11 07431 044194 595 06375 178507 06880 0283 1700
5H 11 11 07521 056646 753 06188 186218 05000 0293 2250
6H 11 11 07916 063449 801 06556 180693 06020 0287 2580
7H 11 11 07798 044581 572 06828 171130 06450 0258 1830
8H 11 11 08102 059484 734 06695 186679 05890 0253 2370
10H 11 11 08745 042362 484 07815 167369 08150 0290 1790
12H 11 11 08646 043447 502 07759 163179 07820 033* 1810
14H 10 10 09155 037149 406 08388 158945 09210 0357 1530
16H 11 11 10633 057402 540 09311 172241 08600 0412 2250
18H 11 11 11540 058214 504 10212 169632 10400 0431 2230
2OH 11 11 10924 045924 420 09953 161217 10400 0372 2000
22H 11 11 09357 041007 438 08398 168826 09560 0289 1670
235
11 11 09075 052690 581 07901 171665 07130 0387 1980 H
Day28 4H g g 10613 084706 798 08260 208735 06080 0323 2940
8H g 9 11016 107009 971 07720 246350 08690 0199 3710
12H g g 10689 084181 788 08423 210124 09110 0214 3100
Day29 OH 10 10 08564 037266 435 07862 155758 08040 0347 1650
4H 10 10 10285 050781 494 08838 189291 09695 0238 1640
8H 10 10 11192 082177 734 08413 234757 08730 0163 2560
12H 10 10 10289 081504 792 07421 245889 07160 0163 2620
Day30 OH 11 11 06888 032132 466 06271 157060 06710 0316 1330
1H 11 11 04812 017361 361 04525 145073 04390 0239 0745
2H 11 11 06484 031245 482 05870 159214 06530 0334 1360
4H 11 11 10701 065380 611 09207 177194 09420 0380 2720
5H 11 11 11798 086047 729 09713 188398 09560 0360 3330
6H 11 11 09113 038029 417 08369 156205 08190 0364 1530
7H 11 11 10807 045844 424 09932 155158 10800 0438 1870
8H 11 11 12537 084729 676 10561 182857 10200 0372 3410 1OH 11 11 11660 055622 477 10307 173365 10800 0369 1980
12H 11 11 11693 054122 463 10404 1 70227 10500 0401 1890
14H 11 11 12580 058500 465 11460 1 57295 12100 0580 2590
16H 11 11 12787 066304 519 11479 1 60896 10600 0600 2530
18H 11 11 13215 077932 590 11604 1 67705 11700 0577 3250
2OH 11 11 13956 119600 857 11356 1 84877 10400 0427 4810
22H 10 10 09039 043904 486 08153 1 61217 07335 0398 1770
235
11 11 10242 075976 742 08511 1 82764 08480 0405 3010 H
Days
27&30 OH 22 22 07397 046557 629 06201 1 83811 05915 0188 1880
Combined
1H 22 22 06065 036838 607 05222 1 72140 04560 0239 1470
2H 22 22 06859 034171 498 06028 1 70931 06910 0223 1360
4H 22 22 09066 056971 628 07661 1 80861 07855 0283 2720
5H 22 22 09660 074384 770 07753 1 92416 08045 0293 3330
6H 22 22 08515 051412 604 07407 1 69270 07555 0287 2580
7H 22 22 09303 046737 502 08235 1 67509 07655 0258 1870
8H 22 22 10320 074958 726 08409 1 90210 09045 0253 3410
1OH 22 22 10203 050500 495 08975 1 71434 09450 0290 1980
12H 22 22 10170 050366 495 08985 1 68374 08870 0339 1890
14H 21 21 10949 051375 469 09878 1 60647 10700 0357 2590
16H 22 22 11710 061515 525 10338 1 66506 10170 0412 2530
18H 22 22 12378 067671 547 10886 1 67256 11350 0431 3250
2OH 22 22 12440 089759 722 10632 1 71821 10400 0372 4810
22H 21 21 09206 041362 449 08280 1 63214 08480 0289 1770
235
22 22 09659 064081 663 08201 1 75077 07995 0387 3010 H
Application Site = Upper Arm # Obs
Day T Tiimmee nn >LOQ Mean SD CV (%) Geo Mean Geo SD Median Mm Max
Day 25 O OHH 1 100 10 0 8531 049953 58 6 0 7157 1 93040 07455 0219 1770
4H 10 10 0 6055 0 25103 41 5 0 5603 1 51365 05080 0366 1000
8H 10 10 0 7649 0 36745 48 0 0 6892 1 61891 06225 0354 1420
12H 10 10 0 9058 0 38785 42 8 0 8191 1 65583 08865 0283 1540
Day 26 OH 9 0 6452 0 26690 41 4 0 5823 1 69184 06370 0192 1080
4H 9 0 9841 1 16480 1184 0 6514 2 38356 04370 0290 3860
8H 9 0 8018 0 58759 733 0 6614 1 88172 06230 0292 2170
12H 9 0 9626 0 60654 63 0 0 8223 1 78312 06170 0413 2170
Day 27 OH 10 10 1 1664 0 63917 548 0 8981 2 62949 10750 0076 2060 1H 10 10 07850 0 39998 51 0 06288 242290 07060 0062 1400 2H 10 10 0 7760 0 36374 46 9 0 6493 2 16745 06835 0086 1360 4H 10 10 08503 046010 541 07529 167989 08085 0358 1920 5H 10 10 10106 065776 651 08303 195398 08270 0348 2120 6H 10 10 09577 062292 650 06714 317479 09535 0036 2160 7H 10 10 08950 053831 601 06804 257511 09335 0071 1840 8H 10 10 09987 055599 557 08537 184479 08595 0383 2030
10H 10 10 09798 051868 529 08616 171881 08135 0365 1930
12H 10 10 11466 063722 556 09701 192584 10255 0253 2290
14H 10 10 10699 058804 550 08976 197808 09335 0213 2020
16H 10 10 11540 058531 507 09705 203045 11030 0187 1910
18H 10 10 11039 060875 551 09215 202065 09330 0194 2030
2OH 10 10 11564 075476 653 09511 199892 09700 0228 2870
22H 10 10 10020 062301 622 08046 213992 08670 0190 2160
235H 10 10 09361 055459 592 07423 226567 09385 0129 1880
Day 28 4H 12 12 07681 051159 666 06211 199127 05480 0 251 1 720
8H 12 12 10700 066177 618 08703 208162 10000 0 178 2 650
12H 12 12 09082 046115 508 07892 179669 09415 0 249 1 740
Day 29 OH 11 11 10746 072989 679 08627 210510 09570 0 180 2 870
4H 11 11 08639 070262 813 06623 215445 06130 0 192 2 650
8H 11 11 11498 067779 589 09496 199607 11600 0 306 2 470
12H 11 11 12128 071743 592 10161 191241 11000 0 377 2 490
Day 30 OH 11 11 07028 023782 338 06599 147979 06920 0314 0981 1 H 11 11 06353 031713 499 05665 165855 05710 0269 1230 2H 11 11 05860 016988 290 05653 132079 05710 0375 0945 4H 11 11 06831 030322 444 06218 159139 06410 0278 1260 5H 11 11 07822 038194 488 06938 169794 08190 0314 1440 6H 11 11 08920 045884 514 07891 169564 09590 0381 1910 7H 11 11 07893 037701 478 07130 161065 08100 0358 1650 8H 11 11 09771 039344 403 09046 152119 09690 0449 1770
10H 11 11 10650 063744 599 09417 163598 09940 0562 2760
12H 11 11 11607 069159 596 10052 174277 10600 0475 2830
14H 11 11 10294 037927 368 09606 149647 10400 0488 1590
16H 11 11 09613 045864 477 08572 168573 09020 0312 1720
18H 11 11 11474 046970 409 10444 162876 12400 0351 1990
2OH 11 11 11207 059545 531 09702 180101 11300 0354 2230
22H 11 11 10576 041511 392 09806 152585 09800 0415 1850
23 5H 11 11 09245 041698 451 08333 164525 08990 0347 1670
Days
27 & 30 OH 21 21 09236 051808 561 07642 205994 08560 0076 2060
Combined
1H 21 21 07066 035798 507 05954 200405 06330 0062 1 400 2H 21 21 06765 028882 427 06038 174974 06510 0086 1 360 4H 21 21 07627 038543 505 06811 162982 07560 0278 1 920 5H 21 21 08910 053037 595 07557 180767 08190 0314 2 120 6H 21 21 09233 053011 574 07307 237307 09590 0036 2 160 7H 21 21 0.8396 0.45210 53.8 0.6973 2.05213 0.8830 0.071 1.840
8H 21 21 0.9874 0.46543 47.1 0.8800 1.66122 0.9540 0.383 2.030
1OH 21 21 1.0244 0.57108 55.7 0.9026 1.65733 0.8810 0.365 2.760
12H 21 21 1.1540 0.64955 56.3 0.9884 1.80366 1.0600 0.253 2.830
14H 21 21 1.0487 0.47745 45.5 0.9301 1.71638 1.0400 0.213 2.020
16H 21 21 1.0530 0.51872 49.3 0.9094 1.83140 0.9160 0.187 1.910
18H 21 21 1.1267 0.52684 46.8 0.9840 1.80039 1.1600 0.194 2.030
2OH 21 21 1.1377 0.65876 57.9 0.9610 1.86589 1.0600 0.228 2.870
22H 21 21 1.0311 0.51150 49.6 0.8924 1.82207 0.9360 0.190 2.160
23.5H 21 21 0.9300 0.47474 51.0 0.7887 1.92430 0.8990 0.129 1.880
Application Site = Thigh
# Obs.
Day Time n >LOQ Mean SD CV (%) Geo. Mean Geo. SD Median Min Max
Day 25 OH 11 11 0.5459 0.31177 57.1 0.4575 1.99998 0.5360 0.087 1.300
4H 11 11 0.3757 0.18016 47.9 0.3262 1.89010 0.3440 0.062 0.709
8H 11 11 0.4448 0.25511 57.4 0.3661 2.04796 0.4200 0.087 0.864
12H 11 11 0.5095 0.30534 59.9 0.4246 1.96224 0.4230 0.105 1.160
Day 26 OH 11 11 0.8664 0.48505 56.0 0.7679 1.64271 0.6140 0.398 1.950
4H 11 11 0.5822 0.24421 41.9 0.5363 1.53465 0.4920 0.299 0.961
8H 11 11 0.8017 0.50124 62.5 0.6800 1.81246 0.5910 0.280 1.850
12H 11 11 0.8817 0.32211 36.5 0.8316 1.43050 0.8790 0.466 1.550
Day 27 OH 9 9 0.7659 0.22662 29.6 0.7316 1.39657 0.8240 0.429 1.010
1 H 9 9 0.6961 0.22690 32.6 0.6580 1.45179 0.7110 0.337 0.998
2H 9 9 0.6704 0.22674 33.8 0.6336 1.44547 0.6660 "0.326 1.040
4H 9 9 0.7407 0.55140 74.4 0.6006 1.95373 0.5670 0.234 1.970
5H 9 9 0.6593 0.40489 61.4 0.5593 1.84149 0.4930 0.238 1.450
6H 9 9 0.6381 0.59883 93.8 0.4821 2.10452 0.3660 0.215 2.120
7H 9 9 0.6203 0.40515 65.3 0.5063 1.98142 0.4170 0.239 1.290
8H 9 9 0.6990 0.50385 72.1 0.5434 2.14173 0.3970 0.244 1.440
10H 9 9 0.6318 0.52626 83.3 0.4670 2.30320 0.4510 0.149 1.780
12H 9 9 0.7850 0.51311 65.4 0.6231 2.13741 0.8430 0.220 1.690
14H 9 9 0.8909 0.60851 68.3 0.7309 1.94514 0.7750 0.297 2.080
16H 9 9 1.0051 0.49241 49.0 0.8930 1.69568 1.0200 0.441 1.690
18H 9 9 0.9699 0.45472 46.9 0.8590 1.73615 1.1100 0.357 1.540
2OH 9 9 0.9627 0.52371 54.4 0.8240 1.87126 1.0600 0.273 1.940
22H 9 9 0.7457 0.41963 56.3 0.6414 1.81633 0.6860 0.271 1.450
23.5H 9 9 0.6751 0.30935 45.8 0.6187 1.54714 0.5870 0.374 1.260
Day 28 4H 9 9 0.6501 0.33546 51.6 0.5898 1.57382 0.6110 0.306 1.450
8H 9 9 0.9154 0.50750 55.4 0.7880 1.83625 0.8720 0.285 1.940
12H 9 9 0.9857 0.53062 53.8 0.8741 1.67978 0.9300 0.398 2.140
Day 29 OH 12 12 0.8323 0.49058 58.9 0.6904 1.98820 0.7905 0.185 1.930
4H 12 12 0.5280 0.23157 43.9 0.4816 1.57708 0.4215 0.206 0.892 8H 12 12 0.6492 0.37254 57.4 0.5579 1.79230 0.5430 0.200 1.340
12H 12 12 0.7147 0.33321 46.6 0.6404 1.65449 0.6585 0.295 1.240
Day 30 OH 11 11 0.8924 0.30631 34.3 0.8464 1.40745 0.8610 0.495 1.520
1 H 11 11 0.7264 0.35752 49.2 0.6565 1.59424 0.6090 0.348 1.530
2H 11 11 0.6491 0.21364 32.9 0.6178 1.39147 0.6190 0.390 0.974
4H 11 11 0.6865 0.33996 49.5 0.6107 1.67154 0.6760 0.307 1.210
5H 11 11 0.7082 0.40994 57.9 0.6160 1.72547 0.5880 0.297 1.600
6H 11 11 0.6519 0.33980 52.1 0.5638 1.80838 0.6090 0.212 1.250
7H 11 11 0.7899 0.51478 65.2 0.6252 2.13852 0.7930 0.207 1.730
8H 11 11 0.9367 0.58856 62.8 0.7401 2.17202 0.8650 0.233 1.780
10H 11 11 0.7395 0.50770 68.7 0.5829 2.11814 0.6200 0.189 1.770
12H 11 11 0.8881 0.77808 87.6 0.6636 2.20837 0.6830 0.218 2.900
14H 11 11 1.0653 0.92586 86.9 0.8037 2.17880 0.8560 0.258 3.450
16H 11 11 0.9864 0.51673 52.4 0.8481 1.85590 0.9840 0.245 2.040
18H 11 11 1.1151 0.65786 59.0 0.9251 2.00820 1.0400 0.207 2.620
2OH 11 11 1.1024 0.60757 55.1 0.9228 1.99273 1.1800 0.211 2.380
22H 11 11 0.9143 0.60935 66.6 0.7273 2.11695 0.7180 0.177 2.040
23.5H 11 11 0.7845 0.43513 55.5 0.6564 1.98755 0.6800 0.152 1.590
Days
27 & 30 OH 20 20 0.8355 0.27418 32.8 0.7927 1.40162 0.8425 0.429 1.520
Combined
1 H 20 20 0.7128 0.29865 41.9 0.6572 1.51580 0.6775 0.337 1.530
2H 20 20 0.6587 0.21398 32.5 0.6249 1.40321 0.6350 0.326 1.040
4H 20 20 0.7109 0.43544 61.3 0.6061 1.77284 0.6215 0.234 1.970
5H 20 20 0.6862 0.39761 57.9 0.5898 1.75445 0.5405 0.238 1.600
6H 20 20 0.6457 0.46023 71.3 0.5254 1.91808 0.5745 0.212 2.120
7H 20 20 0.7136 0.46484 65.1 0.5686 2.04611 0.6965 0.207 1.730
8H 20 20 0.8298 0.55130 66.4 0.6440 2.14976 0.7915 0.233 1.780
1OH 20 20 0.6910 0.50527 73.1 0.5275 2.17303 0.5420 0.149 1.780
12H 20 20 0.8417 0.65746 78.1 0.6451 2.13366 0.6960 0.218 2.900
14H 20 20 0.9868 0.78422 79.5 0.7701 2.03948 0.8180 0.258 3.450
16H 20 20 0.9948 0.49266 49.5 0.8681 1.75967 0.9970 0.245 2.040
18H 20 20 1.0498 0.56598 53.9 0.8947 1.86048 1.0750 0.207 2.620
2OH 20 20 1.0395 0.56111 54.0 0.8769 1.91021 1.1200 0.211 2.380
22H 20 20 0.8384 0.52628 62.8 0.6873 1.95602 0.7020 0.177 2.040
23.5H 20 20 0.7353 0.37824 51.4 0.6392 1.77529 0.6685 0.152 1.590
Application Site = Abdomen
# Obs.
Day Time n >LOQ Mean SD CV (%) Geo. Mean Geo. SD Median Mm Max Day 25 OH 12 12 0.8559 0.38007 44.4 0.7614 1.72897 0.7580 0.224 1.340
4H 12 12 0.5725 0.33593 58.7 0.4801 1.94032 0.5070 0.109 1.340
8H 12 12 0.6619 0.49938 75.4 0.5231 2.02481 0.4540 0.180 1.810
12H 11 11 0.7678 0.59324 77.3 0.5923 2.15139 0.6440 0.208 2.210 Day 26 OH 11 11 10170 065848 647 08238 204230 10900 0223 2470
4H 11 11 09453 061240 648 07860 190388 07580 0267 2300
8H 11 11 09732 064445 662 07493 227998 09140 0151 1980
12H 11 11 10673 066268 621 08841 197633 08750 0209 2580
Day 27 OH 11 11 09265 051511 556 08158 167838 07240 0432 1960
1H 11 11 06864 028320 413 06332 153213 06280 0333 1200
2H 11 11 06846 034457 503 06064 169019 05580 0275 1270
4H 11 11 09067 066590 734 07424 189613 07080 0338 2570
5H 11 11 08715 069574 798 07018 194180 07360 0286 2750
6H 11 11 08515 060073 705 07041 187712 06780 0283 2340
7H 11 11 09251 085810 928 07189 198763 06800 0304 3350
8H 11 11 08564 052352 611 07264 188449 08360 0173 2210
10H 11 11 09087 047489 523 08157 160445 07660 0468 1900
12H 11 11 09115 039041 428 08482 147127 07630 0498 1820
UH 11 11 09315 049896 536 08403 158290 08160 0388 2260
16H 11 11 10727 042625 397 10035 145818 09040 0613 1960
18H 11 11 10615 035591 335 10055 142014 10800 0606 1620
2OH 11 11 10844 041945 387 10182 144293 09620 0584 1980
22H 11 11 10067 048036 477 09105 159773 08040 0463 1880
235H 11 11 09287 059391 639 08065 169713 07200 0421 2500
Day 28 4H 10 10 06127 025358 414 05715 147709 05975 0284 1220
8H 10 10 06547 035608 544 05802 165843 04790 0332 1350
12H 10 10 08782 045510 518 07665 176318 09055 0366 1670
Day 29 OH 10 10 10294 043246 420 09445 156797 09940 0423 1780
4H 10 10 06672 038443 576 05958 160208 05485 0356 1620
8H 10 10 08180 042471 519 07379 159032 06350 0373 1780
12H 10 10 09772 062645 641 08403 173878 07780 0458 2380
Day 30 OH g 9 06223 035642 573 05340 183375 04960 0170 1220
1H g 9 05937 041692 702 04753 204532 04740 0165 1300
2H 9 9 05682 035033 617 04613 205524 04990 0182 1090
4H 9 9 05613 036307 647 04531 206279 05990 0158 1190
5H 9 9 05039 026008 516 04307 189151 05850 0151 0794
6H 9 9 04732 025628 542 04137 174385 03460 0178 0851
7H 9 9 05576 023738 426 05042 166077 05430 0199 0899
8H 9 9 06087 021507 353 05734 145199 05930 0326 0880
10H 9 9 05918 018376 311 05631 141664 06020 0285 0847
12H 9 9 05992 024044 401 05619 144860 05450 0353 1020
14H 9 9 06353 022602 356 06032 140225 06200 0347 1120
16H 9 9 07680 027706 361 07242 144498 06800 0370 1290
18H 9 9 07886 030936 392 07428 142577 06800 0495 1320
2OH 9 9 06752 018458 273 06532 131491 06320 0435 0971
22H 9 9 06586 027135 412 06128 149041 05530 0365 1190
235H 9 9 06134 032518 530 05450 166356 04150 0282 1210 Days
27&30 OH 20 20 07896 046609 590 06742 1 79574 06340 0170 1960
Combined
1H 20 20 06446 034299 532 05565 1 78054 05870 0165 1300
2H 20 20 06323 034307 543 05362 1 85679 05390 0182 1270
4H 20 20 07513 056565 753 05945 2 02775 06065 0158 2570
5H 20 20 07061 056431 799 05634 1 97759 06785 0151 2750
6H 20 20 06813 050486 741 05543 1 90097 05005 0178 2340
7H 20 20 07597 066818 880 06129 1 86655 06615 0199 3350
8H 20 20 07449 042392 569 06531 1 70461 07465 0173 2210
1OH 20 20 07661 039885 521 06904 1 57175 07060 0285 1900
12H 20 20 07710 036052 468 07048 1 52931 06750 0353 1820
14H 20 20 07983 041881 525 07238 1 54236 06715 0347 2260
16H 20 20 09356 039005 417 08665 1 49115 08085 0370 1960
18H 20 20 09387 035548 379 08774 1 45693 07955 0495 1620
2OH 20 20 09003 038801 431 08338 1 47996 07910 0435 1980
22H 20 20 08501 042899 505 07619 1 60433 07700 0365 1880
235H 20 20 07869 050603 643 06761 1 72350 06775 0282 2500
Application Site = Flank
#Obs
Day Time n >LOQ Mean SD CV(%) Geo Mean Geo SD Median Mm Max
Day25 OH 9 9 06722 029287 436 06120 161551 06290 0238 1170
4H 9 9 07684 052305 681 06275 202705 07370 0159 1980
8H 9 9 10453 073978 708 08723 185081 07130 0376 2780
12H 9 9 11301 057397 508 10344 152769 09720 0565 2530
Day26 OH 10 10 05991 051432 858 04750 192537 04065 0239 1810
4H 10 10 07246 066163 913 05297 221190 03775 0232 2050
8H 10 10 08006 065923 823 05965 224353 05675 0219 2120
12H 10 10 08713 055705 639 06991 211591 07015 0167 1860
Day27 OH 12 12 10206 059848 586 08713 181989 09135 0339 2190
1H 12 12 08854 048531 548 07686 176217 08550 0321 1900
2H 12 12 07239 032666 451 06551 161715 06995 0272 1320
4H 12 12 07117 041155 578 06366 159337 06350 0335 1890
5H 12 12 07970 061097 767 06506 188533 05595 0276 2460
6H 12 12 08569 081012 945 05915 251432 07135 0145 3070
7H 12 12 09963 092756 931 06780 254736 06695 0170 3350
8H 12 12 10207 095022 931 07304 234634 07845 0177 3600
10H 12 12 11392 092575 813 08959 202851 10305 0333 3700
12H 12 12 10202 094429 926 07286 234821 06125 0173 3530
14H 12 12 13253 105047 793 09441 256498 09325 0123 3630
16H 12 12 13274 089040 671 10127 232638 12750 0185 2830
18H 12 12 11423 067794 594 08945 230262 11350 0194 2500 2OH 12 12 1.3704 0.96508 70.4 1.0214 2.41068 1.2950 0.198 3.380
22H 12 12 1.2376 1.10689 89.4 0.9098 2.23945 0.9500 0.339 4.180
23.5H 12 12 1.1897 1.30093 109.4 0.7457 2.70731 0.6040 0.170 4.610
Day 28 4H 12 12 0.9311 1.07976 116.0 0.6766 2.05352 0.5450 0.323 4.230
8H 12 12 0.9149 0.90740 99.2 0.6574 2.30859 0.6595 0.143 3.540
12H 12 12 0.8508 0.60145 70.7 0.7159 1.81436 0.8040 0.274 2.580
Day 29 OH 9 9 0.7540 0.35840 47.5 0.6774 1.64381 0.6460 0.386 1.290
4H 9 9 0.5993 0.24232 40.4 0.5506 1.58457 0.6230 0.224 1.010
8H 9 9 0.6587 0.31488 47.8 0.5870 1.69309 0.5640 0.245 1.090
12H 9 9 0.8814 0.36184 41.1 0.8202 1.50138 0.8640 0.383 1.680
Day 30 OH 11 11 0.9399 0.40036 42.6 0.8191 1.89480 1.0100 0.166 1.380
1H 11 11 0.7815 0.34249 43.8 0.6955 1.73588 0.8460 0.208 1.270
2H 11 11 0.8638 0.37218 43.1 0.7512 1.89862 0.9500 0.162 1.410
4H 11 11 0.7585 0.33664 44.4 0.6662 1.80852 0.8520 0.191 1.280
5H 11 11 0.6801 0.29523 43.4 0.6189 1.59817 0.7060 0.300 1.140
6H 11 11 0.7087 0.34400 48.5 0.6279 1.71641 0.6490 0.256 1.350
7H 11 11 0.8363 0.62511 74.7 0.6834 1.91810 0.6000 0.210 2.470
8H 11 11 0.8677 0.36331 41.9 0.7956 1.56690 0.8140 0.386 1.370
10H 11 11 0.8692 0.36211 41.7 0.8047 1.50878 0.8050 0.435 1.600
12H 11 11 0.8829 0.40916 46.3 0.8109 1.52540 0.7310 0.461 1.860
14H 1 1 11 1.1887 0.52014 43.8 1.0588 1.73139 1.2000 0.332 2.030
16H 11 11 1.0951 0.48695 44.5 0.9871 1.64244 0.9930 0.447 1.750
18H 11 11 1.3349 0.70412 52.7 1.1748 1.71481 1.2700 0.491 2.660
2OH 11 11 1.1201 0.57443 51.3 0.9911 1.70965 1.0400 0.340 2.470
22H 11 11 0.9278 0.48847 52.6 0.8199 1.69467 0.7730 0.334 2.020
23.5H 11 11 1.0127 0.55687 55.0 0.8877 1.73559 1.0000 0.283 2.370
Days
27 & 30 OH 23 23 0.9820 0.50364 51.3 0.8460 1.83111 1.0000 0.166 2.190
Combined
1 H 23 23 0.8357 0.41702 49.9 0.7327 1.73144 0.8460 0.208 1.900
2H 23 23 0.7908 0.34845 44.1 0.6994 1.74072 0.8080 0.162 1.410
4H 23 23 0.7341 0.36982 50.4 0.6506 1.67916 0.7390 0.191 1.890
5H 23 23 0.7411 0.47940 64.7 0.6352 1.73186 0.6050 0.276 2.460
6H 23 23 0.7860 0.62263 79.2 0.6087 2.11154 0.6490 0.145 3.070
7H 23 23 0.9197 0.78389 85.2 0.6806 2.21165 0.6000 0.170 3.350
8H 23 23 0.9475 0.71942 75.9 0.7609 1.96642 0.8140 0.177 3.600
1OH 23 23 1.0100 0.71213 70.5 0.8511 1.77622 0.9110 0.333 3.700
12H 23 23 0.9545 0.72584 76.0 0.7669 1.95351 0.7170 0.173 3.530
14H 23 23 1.2600 0.82437 65.4 0.9973 2.14732 1.1700 0.123 3.630
16H 23 23 1.2163 0.71991 59.2 1.0004 1.98274 1.1900 0.185 2.830
18H 23 23 1.2344 0.68179 55.2 1.0190 2.02726 1.1900 0.194 2.660
2OH 23 23 1.2507 0.79500 63.6 1.0068 2.05398 1.2400 0.198 3.380
22H 23 23 1.0894 0.86377 79.3 0.8656 1.96211 0.7730 0.334 4.180
23.5H 23 23 1.1050 0.99766 90.3 0.8105 2.22842 0.7140 0.170 4.610 Summary statistics for AUC0-t Ss and Cmax ss for unconjugated rotigotine for each patch application site using separated data for Day 27 and Day 30 are given in Table 17
Table 17: Descriptive statistics of parameters of pharmacokinetics for rotigotine under multiple dose in patients with early-stage Parkinson's disease (H = hip, S = shoulder, UA = upper arm, T = thigh, AB = abdomen, F = flank)
Day Parameter Site n Mean SD CV (%) Geo Mean Geo SD Median Mm Max
Day 27 AUC 0-t, ss H 10 24714 121148 490 2 222228844 16080 18704 1127 4538 (ng*h/ml)
S 11 21147 99209 469 19167 16046 17603 751 4351
UA 10 23846 126658 631 20347 19076 20963 513 4650
T 9 18464 100154 542 15994 17917 17649 706 3406
AB 11 21868 99971 457 20228 14849 16608 1372 4582
F 12 25438 174836 687 20817 19421 20727 673 6864
AUC 0-t, ss, H 10 26338 132896 505 23915 1567 23103 1256 5819 normalized
(ng*h*kg/ml/mg)
S 11 23337 75596 317 22555 1444 26241 1066 3541
UA 10 32254 99970 310 30816 1384 29842 1654 4970
T 9 22262 84993 382 20797 1488 22707 1187 3720
AB 11 31661 233860 739 26254 1859 23201 893 9521
F 12 25809 132295 513 23342 1575 21830 1043 5781
Maximum H 10 18159 119253 657 15354 180840 12250 0679 4440
Concentration
(ng/ml)
S 11 13583 057413 423 12418 159520 11900 0431 2580
UA 10 14986 071726 479 13274 174189 14000 0403 2870
T 9 11772 061214 520 10354 173314 11800 0469 2120
AB 11 15598 081231 521 13953 162515 12100 0775 3350
F 12 19218 110854 577 16674 174328 16500 0683 4610 Day Parameter Site n Mean SD CV (%) Geo Mean Geo SD Median Mm Max
Day 27
Maximum Cone H 10 19 784 15 6559 79 1 16478 1 7821 13 943 9 46 61 31 normalized (ng*kg/ml/mg)
S 11 15493 5 0158 32 4 14613 1 4647 15873 612 2237
UA 10 21 552 8 7051 404 20103 1 4770 19225 1116 3901
T 9 14 217 4 9198 34 6 13464 1 4247 14659 769 2315
AB 11 21 413 12 9134 60 3 18110 1 8837 20181 496 5252
F 12 20 022 8 2775 41 3 18697 1 4562 16847 1058 3883
Average H 10 10516 051553 490 09483 160805 07959 0479 1931
Concentration
(ng/ml)
S 11 08999 042217 469 08156 1 60465 07491 0319 1852
UA 10 10147 053897 531 08658 1 90761 08920 0218 1979
T 9 07857 042619 542 06806 1 79171 07510 0300 1449
AB 11 09306 042541 457 08608 1 48493 07067 0584 1950
F 12 10825 074398 687 08858 1 94211 08820 0286 2921
Timeto Maximum H 10 1350 7382 547 1342 1758 1600 00 220
Concentration
(hours)
S 11 1345 7699 572 1565 1456 1800 00 200
UA 10 960 9324 971 1497 1520 900 00 220
T 9 1200 7874 656 1457 1503 1600 00 200
AB 11 1295 8020 619 1182 2124 1600 00 235
F 12 1371 8516 621 1165 2478 1600 00 235
Day
Parameter Site n Mean SD CV (%) Geo Mean Geo SD Median Mm Max
Day 27
Peak-Trough H 10 1143 4318 378 1073 145 1042 61 198
Fluctuation (%)
S 11 996 2106 212 976 124 1029 72 136
UA 10 945 3406 361 893 143 871 51 168
T 9 950 2411 254 920 132 1059 57 124
AB 11 1166 7007 601 1047 156 883 60 314
F 12 1481 3634 245 1441 128 1379 100 200
Half Value H 10 1639 6414 391 1487 1670 1767 49 235
Duration (hour)
S 11 1835 4227 230 1786 1287 1961 117 230
UA 10 1934 3802 197 1898 1230 1983 131 235
T 9 1842 3690 200 1810 1217 1605 147 235
AB 11 1793 6295 351 1505 2339 2045 12 235
F 12 1142 4479 392 1057 1530 1084 45 183
Apparent Dose of H 10 6861 20513 299 6590 13500 6305 412 1033
Rotigotine (mg)
S 11 6474 20421 315 6155 14096 6500 353 968
UA 10 5619 27460 489 4824 19268 5535 106 1010
T 9 6438 29351 456 5912 15345 5130 348 1157
AB 11 6369 24858 390 5773 16789 7090 161 938
F 12 7258 26769 369 6883 13880 6170 483 1352
Day Parameter Site n Mean SD CV (%) Geo Mean Geo SD Median Mm Max
Day 30 AUC 0-t, ss H 10 22 916 13 4155 58 5 19 957 1 7352 19 954 849 54 54 (ng*h/ml)
S 11 26 442 13 8860 52 5 23741 16054 22634 1233 5777
UA 11 22 333 8 9481 40 1 20795 14861 21025 1185 3968
T 11 20 713 11 8144 57 0 17832 17938 18354 737 4616
AB 9 14 776 5 2155 35 3 13964 14308 14797 885 2322
F 11 22 577 8 9371 39 6 20789 15642 25736 914 3998
AUC 0-t, ss, H 10 272 01 119459 43 ! 251 27 1 510 22922 143 0 489 0 normalized
(ng*h*kg/ml/mg)
S 11 239 26 102 668 42 9 21973 1 553 20637 933 4217
UA 11 218 21 50 674 23 2 21244 1 284 21878 1218 2998
T 11 275 09 158 016 574 24830 1 551 23576 1296 7178
AB 9 224 48 49 363 22 0 21975 1 245 23290 1527 3197
F 11 255 07 110 435 43 3 23360 1 561 21891 1183 4391
Maximum H 10 17803 140713 790 14347 194153 13150 0598 5310
Concentration
(ng/ml)
S 11 18044 120853 670 1 5544 1 70345 1 3900 0 874 4810
UA 11 14595 063351 434 1 3509 1 49873 1 2900 0 747 2830
T 11 14849 078230 527 1 3303 1 62641 1 2500 0 555 3450
AB 9 09682 031038 321 0 9190 1 42608 1 0100 0 502 1320
F 11 15509 071145 459 1 3920 1 66366 1 4300 0 583 2660
Day Parameter Site n Mean SD CV (%) Geo. Mean Geo. SD Median Min Max
Day 30
Maximum Cone H 10 20.128 11.2346 55.8 18.063 1.5895 15.754 10.08 47.61 normalized (ng*kg/ml/mg)
S 11 16.303 8.9019 54.6 14.386 1.6858 14.201 5.60 35.11
UA 11 14.249 3.5763 25.1 13.801 1.3154 14.711 7.68 19.46
T 11 20.719 12.0527 58.2 18.523 1.5976 16.694 8.59 53.65
AB 9 14.874 4.0113 27.0 14.462 1.2751 13.548 11.17 23.78
F 11 17.834 9.3068 52.2 15.642 1.7272 16.666 7.25 35.23
Average H 10 0.9752 0.57087 58.5 0.8493 1.73518 0.8491 0.361 2.321
Concentration
(ng/ml)
S 11 1.1252 0.59089 52.5 1.0102 1.60542 0.9631 0.525 2.458
UA 11 0.9503 0.38077 40.1 0.8849 1.48608 0.8947 0.504 1.688
T 11 0.8814 0.50274 57.0 0.7588 1.79383 0.7810 0.314 1.964
AB 9 0.6287 0.22194 35.3 0.5942 1.43075 0.6296 0.377 0.988
F 11 0.9607 0.38030 39.6 0.8846 1.56423 1.0951 0.389 1.701
Time to Maximum H 10 14.75 9.145 62.0 17.28 1.553 18.00 0.0 23.5
Concentration
(hours)
S 11 12.36 6.281 50.8 10.86 1.731 12.00 5.0 22.0
UA 11 15.55 5.087 32.7 14.54 1.525 16.00 5.0 22.0
T 11 13.82 7.872 57.0 16.26 1.366 16.00 0.0 22.0
AB 9 13.44 7.468 55.6 9.54 3.054 16.00 1.0 22.0
F 11 16.41 5.324 32.4 15.43 1.485 18.00 7.0 23.5
Day
Parameter Site n Mean SD CV (%) Geo. Mean Geo. SD Median Min Max
Day 30
Peak-Trough H 10 120.5 45.13 37.4 113.3 1.45 102.4 65 185
Fluctuation (%)
S 11 110.8 30.52 27.5 107.3 1.30 101.6 78 171
UA 11 101.4 24.49 24.2 98.7 1.28 104.6 66 144
T 11 127.6 78.15 61.2 111.7 1.67 90.7 60 312
AB g 100.7 34.78 34.6 95.5 1.41 86.2 59 154
F 11 103.9 44.17 42.5 95.5 1.55 89.8 43 195
Half Value H 10 15.06 6.103 40.5 13.50 1.740 15.43 3.8 23.5
Duration (hour)
S 11 18.34 4.563 24.9 17.72 1.339 20.36 9.6 22.8
UA 11 18.14 3.700 20.4 17.76 1.252 18.46 10.8 23.2
T 11 16.03 7.689 48.0 12.71 2.410 19.52 2.0 23.5
AB θ 18.49 4.616 25.0 17.92 1.317 20.20 10.7 23.5
F 11 16.71 6.323 37.8 15.37 1.584 18.78 5.7 23.5
Apparent Dose of H 10 6.230 2.1042 33.8 5.886 1.4409 6.555 3.36 9.30
Rotigotine (mg)
S 11 8.157 1.9871 24.4 7.948 1.2679 7.480 5.91 11.20
UA 11 7.034 1.5860 22.5 6.875 1.2508 6.920 4.92 10.21
T 11 5.521 1.7372 31.5 5.232 1.4356 5.460 2.55 7.78
AB 9 4.802 1.4404 30.0 4.623 1.3356 4.350 3.22 7.22
F 11 7.555 2.0697 27.4 7.291 1.3270 8.300 4.63 11.19
Day Parameter Site n Mean SD CV (%) Geo. Mean Geo. SD Median Min Max
Days 27 and 30 combined
AUC 0-t, ss H 20 23.815 12.4750 52.4 21.089 1.6552 19.491 8.49 54.54
(ng*h/ml)
S 22 23.794 12.0843 50.8 21.332 1.6073 21.304 7.51 57.77
UA 21 23.053 10.6219 46.1 20.580 1.6754 21.025 5.13 46.50
T 20 19.701 10.8174 54.9 16.980 1.7700 18.002 7.06 46.16
AB 20 18.677 8.7841 47.0 17.121 1.5141 16.233 8.85 45.82
F 23 24.069 13.8303 57.5 20.803 1.7470 23.025 6.73 68.64
AUC 0-t, SS, H 20 267.69 123.066 46.0 245.13 1.522 229.22 125.6 581.9 normalized
(ng*h*kg/ml/mg)
S 22 238.82 87.983 36.8 222.62 1.486 249.31 93.3 421.7
UA 21 267.89 92.907 34.7 253.61 1.403 244.24 121.8 497.0
T 20 251.48 130.002 51.7 229.27 1.521 232.36 118.7 717.8
AB 20 275.15 178.946 65.0 242.34 1.617 232.46 89.3 952.1
F 23 256.64 119.570 46.6 233.51 1.553 218.91 104.3 578.1
Maximum H 20 1.7981 1.26959 70.6 1.4842 1.84629 1.3150 0.598 5.310
Concentration
(ng/ml)
S 22 1.5813 0.95110 60.1 1.3893 1.65227 1.3250 0.431 4.810
UA 21 1.4781 0.65771 44.5 1.3396 1.59938 1.2900 0.403 2.870
T 20 1.3465 0.71031 52.8 1.1884 1.67848 1.2100 0.469 3.450
AB 20 1.2936 0.69212 53.5 1.1563 1.60286 1.0950 0.502 3.350
F 23 1.7444 0.93829 53.8 1.5295 1.69863 1.4300 0.583 4.610
Day Parameter Site n Mean SD CV (%) Geo Mean Geo SD Median Mm Max
Days 27 and 30 combined Maximum Cone H 20 19956 132635 665 17253 16685 15577 946 6131 normalized (ng*kg/ml/mg)
S 22 15898 70630 444 14499 15627 15328 560 3511
UA 21 17727 73798 416 16508 14597 15499 768 3901
T 20 17793 98823 555 16046 15548 15506 769 5365
AB 20 18470 102802 557 16367 16473 14906 496 5252
F 23 18976 86532 456 17168 15894 16666 725 3883
Average H 20 10134 053085 524 08974 165522 08294 0361 2321
Concentration
(ng/ml)
S 22 10125 051423 508 09077 1 60729 09065 0319 2458
UA 21 09810 045199 461 08758 1 67538 08947 0218 1979
T 20 08383 046031 549 07226 1 76997 07660 0300 1964
AB 20 07947 037379 470 07286 1 51410 06908 0377 1950
F 23 10242 058853 575 08853 1 74705 09798 0286 2921
TimetoMaximum H 20 1413 3114 574 1512 1666 1700 00 235
Concentration
(hours)
S 22 1291 6879 533 1280 1653 1500 00 220
UA 21 1271 7830 616 1469 1504 1400 00 220
T 20 1300 7719 594 1550 1417 1600 00 220
AB 20 1318 7576 575 1068 2514 1600 00 235
F 23 1500 7145 476 1340 2010 1600 00 235
Day
Parameter Site n Mean SD CV (%) Geo Mean Geo SD Median Mm Max
Days 27 and 30 combined
Peak-Trough H 20 1174 43 10 36 7 110 3 1 44 102 5 61 198
Fluctuation (%)
S 22 105 2 26 22 24 9 102 3 1 27 102 2 72 171
UA 21 98 1 28 89 29 5 94 1 1 35 93 8 51 168
T 20 112 9 61 12 54 1 1024 1 53 985 57 312
AB 20 1094 56 21 51 4 100 4 1 48 88 0 59 314
F 23 127 0 45 34 35 7 118 4 1 49 123 5 43 200
Half Value H 20 15 73 6 132 39 0 14 17 1 685 15 95 3 8 23 5
Duration (hour)
S 22 18 35 4 292 23 4 17 79 1 305 20 33 9 6 23 0
UA 21 1871 3705 19 8 18 33 1 239 18 64 10 8 23 5
T 20 17 11 6 192 36 2 14 90 1 965 19 23 2 0 23 5
AB 20 18 18 5469 30 1 16 28 1 912 20 33 1 2 23 5
F 23 13 95 5 959 42 7 1264 1 604 1247 45 23 5
Apparent Dose of H 20 6 546 2 0483 31 3 6 228 1 3916 6 455 3 36 10 33
Rotigotine (mg)
S 22 7 315 2 1468 29 3 6 994 1 3721 7 270 3 53 11 20
UA 21 6 360 2 2749 35 8 5 808 1 6512 6 360 1 06 10 21
T 20 5 934 2 3312 39 3 5 528 1 4728 5 245 2 55 11 57
AB 20 5664 2 1830 38 5 5 223 1 5453 5 000 1 61 9 38
F 23 7 400 2 3565 31 8 7 075 1 3521 7 090 4 63 13 52
Table 18 shows the summary statistics for AUC0-t,Ss and Cmax, 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 (AUC0- t,ss,normaiιzed) and maximum plasma concentration (Cmax,normaiιzed) 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
EXAMPLE 5
[0093] A multicenter, randomized, double-blind, placebo-controlled, 2-arm, parallel group clinical trial was performed to evaluate the safety and efficacy of a rotigotine patch in subjects with early stage, idiopathic Parkinson's disease. . The silicone transdermal patches were made in accordance with the teachings of U.S. Patent Application Publication No. US 2003/0026830 at paragraphs 38-42, U.S. Patent Application Publication No. US 2003/0027793 at paragraphs 37-41 and U.S. Patent No. 6,884,434, columns 5-6, Example 2 and comprised the following layers and components:
Patches D, E and F
[0094] 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.
[0095] 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.
[0096] 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.

Claims

WHAT IS CLAIMED IS
1. 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 Cmax is from about 0.14 ng/mL to about 1.54 ng/mL and wherein the mean area under the curve (AUC0-O is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
2. The method of claim 1 , wherein the rotigotine is transdermal^ administered.
3. The method of claim 1 , wherein the Cmax is from about about 0.20 ng/mL to about 1.30 ng/mL.
4. The method of claim 1 , wherein the Cmax is from about 0.30 ng/mL to about 1.20 ng/mL.
5. The method of claim 1 , wherein the Cmax is from about 0.14 ng/mL to about 0.48 ng/mL.
6. The method of claim 1 , wherein the Cmax is from about 0.37 ng/mL to about 0.75 ng/mL.
7. The method of claim 1 , wherein the Cmax is from about 0.84 ng/mL to about 1.54 ng/mL.
8. The method of claim 1 , wherein the Cmax is about 0.31 ng/mL.
9. The method of claim 1 , wherein the Cmax is about 0.56 ng/mL.
10. The method of claim 1 , wherein the Cmax is about 1.19 ng/mL.
11. The method of claim 1 , wherein the AUC0-t is from about 4.0 ng/mL *h to about 30.0 ng/mL *h.
12. The method of claim 1 , wherein the AUC0.t is from about 5.0 ng/mL *h to about 25.0 ng/mL *h.
13. The method of claim 1, wherein the AUC0-t is from about 3.3 ng/mL *h to about 8.9 ng/mL *h.
14. The method of ciaim 1 , wherein the AUC0-4 is from about 7 ng/mL *h to about 15.2 ng/mL *h.
15. The method of claim 1, wherein the AUC0.t is from about 15.2 ng/mL *h to about 32.2 ng/mL *h.
16. The method of claim 1 , wherein the AUC0-I is about 6.1 ng/mL *h.
17. The method of claim 1 , wherein the AUC0-1 is about 11.1 ng/mL *h.
18. The method of claim 1 , wherein the AUC0.t is about 23.7 ng/mL *h.
19. The method of claim 1 , wherein the method provides the plasma concentration effective to alleviate the symptoms of Parkinson's disease regardless of where the rotigotine is administered to the body of the human patient.
20. 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 Cmax 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 (AUC0-t) is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
21. The method of claim 20, wherein the rotigotine is transdermal^ administered.
22. The method of claim 20, wherein the Cmax is from about about 0.20 ng/mL to about 1.30 ng/mL.
23. The method of claim 20, wherein the Cmax is from about 0.30 ng/mL to about 1.20 ng/mL.
24. The method of claim 20, wherein the Cmax is from about 0.14 ng/mL to about 0.48 ng/mL.
25. The method of claim 20, wherein the Cmax is from about 0.37 ng/mL to about 0.75 ng/mL.
26. The method of claim 20, wherein the Cmax is from about 0.84 ng/mL to about 1.54 ng/mL.
27. The method of claim 20, wherein the Cmax is about 0.31 ng/mL.
28. The method of claim 20, wherein the Cmaχ is about 0.56 ng/mL.
29. The method of claim 20, wherein the Cmax is about 1.19 ng/mL.
30. The method of claim 20, wherein the AUCo-t is from about 4.0 ng/mL *h to about 30.0 ng/mL *h.
31. The method of claim 20, wherein the AUC0-t is from about 5.0 ng/mL *h to about 25.0 ng/mL *h.
32. The method of claim 20, wherein the AUC0.t is from about 3.3 ng/mL *h to about 8.9 ng/mL *h.
33. The method of claim 20, wherein the AUC0-1 is from about 7 ng/mL *h to about 15.2 ng/mL *h.
34. The method of claim 20, wherein the AUC0-1 is from about 15.2 ng/mL *h to about 32.2 ng/mL *h.
35. The method of claim 20, wherein the AUC0-1 is about 6.1 ng/mL *h.
36. The method of claim 20, wherein the AUC0-t is about 11.1 ng/mL *h.
37. The method of claim 20, wherein the AUC0-1 is about 23.7 ng/mL *h.
38. The method of claim 20, wherein the method provides the plasma concentration effective to alleviate the symptoms of Parkinson's disease regardless of where the rotigotine is administered to the body of the human patient.
39. 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 Cmax is from about 0.14 ng/mL to about 1.54 ng/mL and wherein the mean area under the curve (AUC0-1) is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
40. The method of claim 39, wherein the Cmax is from about about 0.20 ng/mL to about 1.30 ng/mL.
41. The method of claim 39, wherein the Cmax is from about 0.30 ng/mL to about 1.20 ng/mL.
42. The method of claim 39, wherein the Cmax is from about 0.14 ng/mL to about 0.48 ng/mL.
43. The method of claim 39, wherein the Cmax is from about 0.37 ng/mL to about 0.75 ng/mL.
44. The method of claim 39, wherein the Cmax is from about 0.84 ng/mL to about 1.54 ng/mL.
45. The method of claim 39, wherein the Cmax is about 0.31 ng/mL.
46. The method of claim 39, wherein the Cmax is about 0.56 ng/mL.
47. The method of claim 39, wherein the Cmax is about 1.19 ng/mL.
48. The method of claim 39, wherein the AUC0-t is from about 4.0 ng/mL *h to about 30.0 ng/mL *h.
49. The method of claim 39, wherein the AUC0-t is from about 5.0 ng/mL *h to about 25.0 ng/mL *h.
50. The method of claim 39, wherein the AUC0-t is from about 3.3 ng/mL *h to about 8.9 ng/mL •h.
51. The method of claim 39, wherein the AUC0-t is from about 7 ng/mL *h to about 15.2 ng/mL *h.
52. The method of claim 39, wherein the AUC0.t is from about 15.2 ng/mL *h to about 32.2 ng/mL *h.
53. The method of claim 39, wherein the AUC0-t is about 6.1 ng/mL *h.
54. The method of claim 39, wherein the AUC0.t is about 11.1 ng/mL *h.
55. The method of claim 39, wherein the AUC0-t is about 23.7 ng/mL *h.
56. The method of claim 39, wherein the method provides the plasma concentration effective to alleviate the symptoms of Parkinson's disease regardless of where the rotigotine is administered to the body of the human patient.
57. 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 Cmax is from about 0.14 ng/mL to about 1.54 ng/mL and the AUC0-t is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
58. The method of claim 57, wherein the rotigotine is transdermal^ administered.
59. The method of claim 57, wherein the Cmax is from about about 0.20 ng/mL to about 1.30 ng/mL.
60. The method of claim 57, wherein the Cmax is from about 0.30 ng/mL to about 1.20 ng/mL.
61. The method of claim 57, wherein the Cmax is from about 0.14 ng/mL to about 0.48 ng/mL.
62. The method of claim 57, wherein the Cmax is from about 0.37 ng/mL to about 0.75 ng/mL.
63. The method of claim 57, wherein the Cmax is from about 0.84 ng/mL to about 1.54 ng/mL.
64. The method of claim 57, wherein the Cmax is about 0.31 ng/mL.
65. The method of claim 57, wherein the Cmax is about 0.56 ng/mL.
66. The method of claim 57, wherein the Cmax is about 1.19 ng/mL.
67. The method of claim 57, wherein the AUC0-t is from about 4.0 ng/mL *h to about 30.0 ng/mL *h.
68. The method of claim 57, wherein the AUC0.t is from about 5.0 ng/mL *h to about 25.0 ng/mL *h.
69. The method of claim 57, wherein the AUC0.t is from about 3.3 ng/mL *h to about 8.9 ng/mL •h.
70. The method of claim 57, wherein the AUC0-t is from about 7 ng/mL *h to about 15.2 ng/mL •h.
71. The method of claim 57, wherein the AUC0.t is from about 15.2 ng/mL *h to about 32.2 ng/mL *h.
72. The method of claim 57, wherein the AUC0-t is about 6.1 ng/mL *h.
73. The method of claim 57, wherein the AUC0-4 is about 11.1 ng/mL *h.
74. The method of claim 57, wherein the AUCo-t is about 23.7 ng/mL *h.
75. The method of claim 57, wherein the method provides the plasma concentration effective to alleviate the symptoms of Parkinson's disease regardless of where the rotigotine is administered to the body of the human patient.
76. 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 Cmax is sustained at a level from about 0.14 ng/mL to about 1.54 ng/mL and the mean area under the curve (AUC0-O in the patient is from about 3.3 ng/mL *h to about 32.2 ng/mL *h.
77. The method of claim 76, wherein the Cmax is from about 0.20 ng/mL to about 1.30 ng/mL.
78. The method of claim 76, wherein the Cmax is from about 0.30 ng/mL to about 1.20 ng/mL.
79. The method of claim 76, wherein the Cmax is from about 0.14 ng/mL to about 0.48 ng/mL.
80. The method of claim 76, wherein the Cmax is from about 0.37 ng/mL to about 0.75 ng/mL.
81. The method of claim 76, wherein the Cmax is from about 0.84 ng/mL to about 1.54 ng/mL.
82. The method of claim 76, wherein the Cmax is about 0.31 ng/mL.
83. The method of claim 76, wherein the Cmax is about 0.56 ng/mL.
84. The method of claim 76, wherein the Cmax is about 1.19 ng/mL.
85. The method of claim 76, wherein the AUC0-t is from about 4.0 ng/mL *h to about 30.0 ng/mL •h.
86. The method of claim 76, wherein the AUC0-t is from about 5.0 ng/mL *h to about 25.0 ng/mL *h.
87. The method of claim 76, wherein the AUC0-t is from about 3.3 ng/mL *h to about 8.9 ng/mL *h.
88. The method of claim 76, wherein the AUC0-t is from about 7 ng/mL *h to about 15.2 ng/mL *h.
89. The method of claim 76, wherein the AUC0-t is from about 15.2 ng/mL *h to about 32.2 ng/mL *h.
90. The method of claim 76, wherein the AUC0-t is about 6.1 ng/mL *h.
91. The method of claim 76, wherein the AUC0-t is about 11.1 ng/mL *h.
92. The method of claim 76, wherein the AUC0-1 is about 23.7 ng/mL *h.
93. The method of claim 76, wherein the method provides the plasma concentration effective to alleviate the symptoms of Parkinson's disease regardless of where the rotigotine is administered to the body of the human patient.
94. A method of treating Parkinson's Disease in a human patient comprising a) applying one or more transdermal patches comprising an amount of rotigotine from 4 mg to 20 mg to the 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 patient at an interval providing a plasma concentration effective to alleviate the symptoms of Parkinson's Disease in the patient; and c) repeating step b) as required to sustain the Cmax at a level effective to alleviate the symptoms of Parkinson's Disease in the human patient, wherein the Cmax is sustained at a level from about 0.14 ng/mL to about 1.54 ng/mL.
95. The method of claim 94, wherein the Cmax is from about 0.20 ng/mL to about 1.30 ng/mL.
96. The method of claim 94, wherein the Cmax is from about 0.30 ng/mL to about 1.20 ng/mL.
97. The method of claim 94, wherein the Cmax is from about 0.14 ng/mL to about 0.48 ng/mL.
98. The method of claim 94, wherein the Cmax is from about 0.37 ng/mL to about 0.75 ng/mL.
99. The method of claim 94, wherein the Cmax is from about 0.84 ng/mL to about 1.54 ng/mL.
100. The method of claim 94, wherein the Cmax is about 0.31 ng/mL.
101. The method of claim 94, wherein the Cmax is about 0.56 ng/mL.
102. The method of claim 94, wherein the Cmax is about 1.19 ng/mL.
103. The method of claim 94, wherein the Cmax is sustained at a level effective to alleviate the symptoms of Parkinson's Disease in the human patient for a period from 1 day to 7 days.
104. The method of claim 94, wherein the Cmax is sustained at a level effective to alleviate the symptoms of Parkinson's Disease in the human patient for a period of time is from 1 week to 6 weeks.
105. The method of claim 94, wherein the Cmax is sustained at a level effective to alleviate the symptoms of Parkinson's Disease in the human patient for a period of time is 7 weeks.
106. The method of claim 94, wherein the Cmax is sustained at a level effective to alleviate the symptoms of Parkinson's Disease in the human patient for a period of time is from 8 weeks to 28 weeks.
107. The method of claim 94, wherein the method gives the plasma concentration effective to alleviate the symptoms of Parkinson's Disease regardless of where the patches are applied on the body of the human patient.
108. The method of claim 94, wherein the patch or patches are replaced daily.
109. The method of claim 94, wherein the Cmax is sustained at a level effective to alleviate the symptoms of Parkinson's Disease in the human patient for a period of time from 1 day to 28 weeks.
110. A method for treating Parkinson's Disease in a human patient, comprising administering over a 24 hour period a rotigotine formulation capable of providing a plasma concentration effective to alleviate the symptoms of Parkinson's Disease, wherein the Cmax is from about 0.14 ng/mL to about 1.54 ng/mL and the AUC0-tis from about 3.3 ng/mL *h to about 32.2 ng/mL *h, regardless of where the rotigotine is administered to the body of the human patient.
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