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 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.
• 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.
• L-DOPA levodopa
• 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 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
• Figure 7 Mean (+/-standard deviation) rotigotine plasma concentrations (in ng/mL) during and after single transdermal administration of 4.5mg rotigotine with Patch C.
• 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 .
• 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 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 patch or patches are removed and another patch or patches are applied daily, twice daily, weekly, twice weekly, monthly or twice monthly.
• 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.
• 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.
• 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 .
• Table 6 Parameters of model independent pharmacokinetics of rotigotine during and after single transdermal administration of 18.0mg rotigotine. with 2 x Patch A
• Table 13 Parameters of model independent pharmacokinetics of rotigotine under administration of 4 5mg roligotine with Patch D
• 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)
• 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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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 2005
  • 2005-09-29 JP JP2007534813A patent/JP2008514376A/ja active Pending
  • 2005-09-29 WO PCT/US2005/035257 patent/WO2006039532A2/en not_active Ceased
  • 2005-09-29 EP EP05802679A patent/EP1796610A4/en not_active Withdrawn

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