AU2005242160B2 - Improved transdermal therapeutic system for the treatment of parkinson's disease - Google Patents

Description

08/12 2005 15:40 FAX 61 3 92438333 GRIFFITH HACK 1004

AUSTRALIA

0. Patents Act 1990 O :I 00 COMPLETE SPECIFICATION SSTANDARD PATENT

VD

Ci Applicants: SCHWARZ PHARMA AG and LTS LOHMANN THERAPIE-SYSTEME AG Invention Title: IMPROVED TRANSDERMAL THERAPEUTIC SYSTEM FOR THE TREATMENT OF PARKINSON'S DISEASE The following statement is a full description of this invention, including the best method of perf6rming it known to

US:

S08/12 2005 15:40 FAX 61 3 92438333 GRIFFITH HACK 005 2 o 1 SImproved Transdermal Treatment of Parkinson's Disease The entire disclosure in the complete specifica ion of our O Australian Patent Application No. 2002310805 is 'y this crosso 5 reference incorporated into the present specification.

o Technical Field 'i Cq

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T) The present invention relates to an effective method for V 10 treating or alleviating symptoms of Parkinson's Pisease, and the o use of a Transdermal Therapeutic System (TTS) fdL delivering the C dopamine receptor agonist rotigotine in a sufficient amount and at a sufficient rate to provide therapeutically 'ffective treatment or alleviation of symptoms of Parkinson's disease.

Background Parkinson's disease is believed to be primarily -aused by the degeneration of dopaminergic neurons in the substantia nigra.

This, in effect, results in loss of tonic dopamiie secretion and dopamine-related modulation of neuronal activity.!in the caudate nucleus, and thus in a deficiency of dopamine inlcertain brain regions. The resulting imbalance of the 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, dyskin sia, gait disturbances, and speech disorders. In some patients, dementia may accompany these symptoms. Involvement of thelautonomic nerve system may produce orthostatic hypotension, paroxysmal flushing, problems with thermal regulation, constipation, and loss of bladder and sphincter control. Psychological disdrders such as loss of motivation and depression may also accompany Parkinson's Disease.

H:!\lklM9\kee \SpCio ica2ionB\F5y2l 0.dDoc /122/0S 08/12 2005 15:41 FAX 61 3 92438333 GRIFFITH BACK 1006 -3o

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o Parkinson's Disease is primarily a disease of mLddle age and o beyond, and it affects both men and women equal y. The highest rate of occurrence of Parkinson's Disease is in )the age group OO over 70 years old, where Parkinson's Disease exists in 1.5 to 0 5 2.5% of that population. The mean age at onset is between 58 and 62 years of age, and most patients develop Parkinson's SDisease between the ages of 50 and 79. There arq approximately NO i 800,000 people in the United States alone with Earkinson's Disease.

o Early motor deficits of Parkinson's Disease can be traced to CA incipient degeneration of nigral dopamine-releasing cells. This neuronal degeneration produces a defect in the dopaminergic pathway that connects the substantia nigra to the striatum. As the disease progresses, refractory motor, autonomic, and mental abnormalities may develop, which implies that thbre is progressive degeneration of striatal receptor mechanisms.

The clinical diagnosis of Parkinson's Disease is!based on the presence of characteristic physical signs. 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 agematched controls before symptoms occur. i Treatment of Parkinson's disease has been attempted with, inter alia, L-dopa (levodopa), which still is the gold standard for the therapy of Parkinson's Disease. Levodopa pabses the bloodbrain barrier as a precursor for dopamine and isl then converted into dopamine in the brain. L-dopa improves the 'ymptoms of Parkinson's Disease but may cause severe side efaects. Moreover, the drug tends to lose its effectiveness after tie first two to three years of treatment. After five to six years, only 25% to of patients maintain improvement, N!\kah\keep\pectfrlcat~ioi\pS49210.doc 6/12/05 S08/12 2005 15:41 FAX 61 3 92438333 GRIFFITH HACK 2007 -4 o i 0 Furthermore a major drawback of currently utilized therapies for o) Parkinson's Disease is the eventual manifestation of the "fluctuation syndrome", resulting in "all-or-noAe" conditions OO characterized by alternating "on" periods of mobility with o 5 dyskinesias and "off" periods with hypokinesia dr akinesia.

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Patients who display unpredictable or erratic "dn-off" phenomena with oral anti-Parkinson therapy have a predictable beneficial response to i.v. administration of L-dopa and other dopamine agonists, suggesting that fluctuations in plasma concentrations if) 10 of drug are responsible for the "on-off" phenomena, The Sfrequency of "on-off" fluctuations has also beei improved by continuous infusions of the dopamine receptor agonists apomorphine and lisuride. However, this mode of administration is inconvenient. Therefore, other modes of admiistration providing a more constant plasma level, such as topical administration, are beneficial and have been suggested in the past.

As mentioned above, one treatment approach for Parkinson's disease involves dopamine receptor agonists. Dopamine receptor agonists (sometimes also referred to as dopamin agonists) are substances which, while structurally different from dopamine, bind to different subtypes of dopamine receptors! and trigger an effect which is comparable to that of dopamine..i Due to the reduced side-effects, it is advantageous when the substances selectively bind to a sub-group of dopamine rece tors, i.e. the D2 receptors.

One dopamine receptor agonist which has been use to treat the symptoms of Parkinson's Disease is rotigotine. it has mostly been used in the form of its hydrochloride. Rotiootine is the International Non-Proprietary Name (INN) of the compound 6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl -amino]1naphthalenol having the structure shown below H;\kimh\; P59210.doc B/12/0n 08/12 2005 15:41 FAX 61 3 92438333 GRIFFITH HACK i1008 In i o OH C i oo

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To date, various transdermal therapeutic systemsj (TTS) for the administration of rotigotine have been described. WO 94/07468 discloses a tcansdermal therapeutic system contlining rotigotine hydrochloride as active substance in a two-phase matrix which is essentially formed by a hydrophobic polymer mate ial as the continuous phase and a disperse hydrophilic phask contained therein and mainly containing the drug and hydrated silica. The silica enhances the maximum possible loading of |he TTS with the hydrophilic salt. Moreover, the formulation of WO 94/07468 usually contains additional hydrophobic solvents- permeationpromoting substances, dispersing agents and, in particular, an emulsifier which is required to emulsify the aquious solution of the active principle in the lipophilic polymer phase. A TTS, prepared by using such a system, has been testediin healthy subjects and Parkinson patients. The average drug plasma levels obtained by using this system were around 0.15 ni/ml with a cm patch containing 10 mg rotigotine. This level must be considered as too low to achieve a truly efficacious treatment or alleviation of symptoms related to Parkinson's disease.

Various further transdermal therapeutic systems have been described in WO 99/49852. The TTS used in this patent application comprise 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 H:\kimh\kacp\s pac tic t1ona\Ps9210.doc 0/12/05 08/12 2005 15:41 FAX 61 3 92438333 GRIFFITH HACK a 009 -6 hydrochloride and a protective film which is to be removed before use. The matrix system is composed of a non-aqueous polymer adhesive system, based on acrylate or s licone, with a solubility of rotigotine of at least 5% w/w. S id matrix is essentially free of inorganic silicate particle In Examples 1 and 2 and in Figure 1 of WO 99/49852 two transdirmal therapeutic systems are compared. These are based on acrylate or silicone adhesives, respectively. Figure 1 of WO 99 4985 2 shows that a silicone patch releases about the same amount of active principle through 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 sy tem employed.

Therefore an identical flux rate through human sikin was expected.

It should be noted that the drug content of the silicone patch used in WO 99/49852 was lower than the drug content of the acrylate patch. However, this merely reflects the difference in solubility of the drug in the respective polymeric silicone and acrylate adhesives used in Examples 1 and 2, respectively. The TTS used in both examples contained the drug at about its saturation solubility in the respective adhesive, systems. While the acrylate system is able to dissolve more dru4 than the silicone system, silicone in turn allows for a better release of the drug to skin. As these two effects compensate each other, it has been thought that the acrylate and the silic ne systems as used in WO 99/49852 are about equivalent in the btainable drug plasma levels and, hence, in therapeutic efficacy.

Considering the rather discouraging experiences made with the silicone formulation of WO 94/07568, the acrylate-based TTS of Example 1 of WO 99/49852 has been subjected to cjinical tests (safety and pharmacokinetic studies). The mean s eady flux rate across human skin in vitro of this TTS amounted to 15.3 pg/cmV/h. However, it turned out that the plasma levels obtained using this TTS were still unsatisfactory and too low to allow H:\kiimh\keep\SpeciL cations\PS210.doc 0/12/

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S08/12 2005 15:42 FAX 61 3 92438333 GRIFFITH HACK i 010 7 't o for a really efficacious treatment of Parkinson s Disease. A o mg (20 cm 2 patch only yielded a mean maximum plisma concentration of 0.12 ng/ml, while a 5 cm' patch! containing 00 mg yielded a mean maximum plasma concentration of 0.068 ng/ml.

o 5 Again, such values have to be considered as too jlow to provide a real therapeutic progress in the treatment of Pdrkinson's SDisease. Thus, in summary, both the 20 cm 2 silipone patch of WO 94/07468 and the 20 cm 2 acrylate patch of WO 99/49852 failed to evoke sufficient drug plasma levels to provide a satisfactory n 10 therapeutic effectiveness.

0i In view of these experiences, it has been very Aurprising that a transdermal therapeutic system containing rotigtine in free base form in a silicone matrix could not only piovide unexpectedly high plasma levels of rotigotine but also a significant therapeutic progress in the transdejmal treatment of Parkinson's Disease. In particular, it has been- unexpected that a transdermal therapeutic system having a size f as little as or 20 cm 2 could provide for an effective treatment of Parkinson's Disease in a placebo-controlled clinical study, as indicated by an improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) of 2 or more compared to a placebo treatment. In the context of this application, 'Iplacebo treatment" refers to a treatment with a transde mal therapeutic system of identical qualitative composition and according to the same therapy regimen but where the active ingredient (rotigotine) in the transdermal therapeutic system has been omitted.

It is to be understood that, if any prior art publication is -i referred to herein, such reference does not contitute an admission that the publication forms a part of fjhe common general knowledge in the art, in Australia or any other country.

p\ i :i 8 00 Summary SIn a first aspect, the present invention provides a method Sfor treating Parkinson's Disease in a patient suffering I 5 from such disease by applying a silicone-based transdermal therapeutic system comprising a mixture of at least one high tack and one medium tack amine-resistant silicone sD pressure sensitive adhesive as the main adhesive component C-i having an area of 10 to 40 cm 2 and containing 0.1 to 3.15 c-i 10 mg cm 2 of rotigotine in the free-base form as active V ingredient, wherein said treatment effects an improvement, vis a vis placebo treatment, in the condition of a human Parkinson patient of 2 units or more following administration for at least 7 weeks, when measured according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III.

In a second aspect, the present invention provides use of a composition comprising a mixture of at least one high tack and one medium tack amine-resistant silicone pressure sensitive adhesive and 0.1 to 3.15 mg cm 2 of rotigotine in the free-base form as active ingredient for preparation of a silicone-based transdermal therapeutic system which is to 40 cm 2 in size and effects an improvement, vis A vis placebo treatment, in the condition of a human Parkinson patient of 2 units or more following administration for at least 7 weeks, when measured according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III.

In a third aspect, the present invention provides a transdermal therapeutic system to effect an improvement, vis A vis placebo treatment, in the condition of a human Parkinson patient of 2 units or more following N:\a 1bourna\o.\Patent\5OQO- 5O99\)P$oo04.AU. UUpeCis\A ndmenL.doe 15/12/O0 9 00 administration for at least 7 weeks, when measured 0 according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III, which has a size of 10 to 40 cm 2 Sand contains 0.1 to 3.15 mg/cm 2 rotigotine in free base V 5 form as active ingredient in a matrix mainly comprising a mixture of at least one high tack and one medium tack amine-resistant silicone pressure sensitive adhesives.

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C- In a fourth aspect, the present invention provides a method Cy 10 of preparing a silicone-based transdermal therapeutic Ssystem comprising the steps of: mixing rotigotine in the free-base form in a solvent with a mixture of at least one high tack and one medium tack amine-resistant silicone pressure sensitive adhesive; coating a liner with the mixture obtained at step and removing the solvent by drying; laminating the dried-matrix film obtained at step with a backing foil; and punching patches from the complete laminate.

An aspect of the present application relates to a method for treating Parkinson's Disease in a patient suffering from such disease by applying a silicone-based transdermal therapeutic system comprising at least one amine-resistant silicone pressure sensitive adhesive as the main adhesive component having an area of 10 to 40 cm 2 and containing 0.1 to 3.15 mg cm 2 of rotigotine in the free-base form as active ingredient, wherein said treatment effects an improvement, vis a vis placebo treatment, in the condition of a human Parkinson patient of 2 units or more following administration for at least 7 weeks, when measured N \ft~b~urn.\CaB-\Patent\$000Q 50999\PS0704.AU I\SpPC~l\\. endment o 15/1/08 10 00 according to the Unified Parkinson's Disease Rating Scale 0 (UPDRS) parts II and III.

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SAnother aspect of the present application relates to use of a composition comprising at least one amine-resistant silicone pressure sensitive adhesive and 0.1 to 3.15 mg cm 2 of rotigotine in the free-base form as active NO ingredient for preparation of a silicone-based transdermal C- therapeutic system which is 10 to 40 cm 2 in size and 10 effects an improvement, vis vis placebo treatment, in the Scondition of a human Parkinson patient of 2 units or more following administration for at least 7 weeks, when measured according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III.

Another aspect of the present application relates to a transdermal therapeutic system to effect an improvement, vis d vis placebo treatment, in the condition of a human Parkinson patient of 2 units or more following administration for at least 7 weeks, when measured according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III, which has a size of 10 to 40 cm 2 and contains 0.1 to 3.15 mg/cm 2 rotigotine as active ingredient in a matrix mainly comprising an admixture of at least two amine-resistant silicone pressure sensitive adhesives.

Another aspect of the present application relates to a method of preparing a silicone-based transdermal therapeutic system comprising the steps of: 4 mixing rotigotine in the free-base form in a solvent with at least one amine-resistant silicone pressure sensitive adhesive; N,\1lbourn\C&.t\Pnt5O\50000-O,\PS0104.AU. I\pIcis\l.ndaent..do 15/12/09 10a 00 coating a liner with the mixture obtained at step

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U and removing the solvent by drying; S(c) laminating the dried-matrix film obtained at step with a backing foil; and punching patches from the complete laminate.

Description It should be understood that the term "treatment" in the V' context of this application is meant to designate a Streatment or alleviation of the symptoms of Parkinson's Disease, rather than a real causative treatment of Parkinson's Disease leading to a complete cure.

In the claims and description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

It must be noted that, as used in the subject specification, the singular forms "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "an adhesive component" includes a single adhesive component, as well as two or more adhesives, and so forth.

The silicone-based transdermal therapeutic system contains a mixture of at least one high tack and one medium tack N:\ft boAU.e\fle.\Catentn000ndm.\P5.doc 25/13/G.

10b 00 amine-resistant silicone compound as the main adhesive 0 component. Usually, the silicone compound will be a Spressure sensitive adhesive or a mixture thereof and will form a matrix in which the other components of the TTS are I 5 embedded. Moreover, the adhesives should preferably be pharmaceutically acceptable in a sense that it is biocompatible, non-sensitizing and non-irritating to skin.

NO Particularly advantageous silicone adhesives for use in the Ce present invention should further meet the following 4 10 requirements: Retained adhesive and cohesive properties in the presence Sof moisture or perspiration, under normal temperature variations, good compatibility with rotigotine as well as with the further excipients used in the formulation; in particular, the adhesive should not react with the amino group contained in rotigotine.

It has been shown that pressure sensitive adhesives of the type forming a soluble polycondensed polydimethylsiloxane (PDMS) resin network, wherein the hydroxy endgroups are capped with e.g. trimethylsilyl (TMS) groups, are particularly useful in the practice of the present invention. Preferred adhesives of this kind are the BIO-PSA silicone pressure sensitive adhesives manufactured by Dow Corning, particularly the Q7-4201 and Q7-4301 qualities.

However, other silicone adhesives may likewise be used.

One embodiment of the invention provides a silicone-based transdermal therapeutic system comprising two or more amine-resistant silicone compounds as the main adhesive components. It can be advantageous if such a mixture of silicone adhesives comprises at least one high tack and at N 3\lbAurne\U.eo\Pate\50000-5099\P50704 AU.1\Speci.aeondmon-oc IS/120o8 lOc 00 least one medium tack adhesive to provide for the optimum 0 balance between good adhesion and little cold flux.

Excessive cold flux may result in a too soft patch which Seasily adheres to the package or to patient garments.

Moreover, such a mixture of adhesives seems to be particularly useful for obtaining an efficacious transdermal N aurne\Cams\Paat\SDA.I\pec i aendment..OC 1512208 08/12 2005 15:43 FAX 61 3 92438333GRFIHAC j01 GRIFFITH HACK 16014 therapeutic system. A mixture of the al (medium tack) and Q7-430l (high tack) E pressure sensitive adhesives in about e particularly useful in the practice of In a further preferred embodiment, the transdermai therapeutic system ftirther Several surfactant-like or amphiphilic solubilizers. They should be pharmacaut approved for use in medicamnents. It is solu-bilizers also acts to improve the c transdermal therapeutic system. A parti of such a solubilizer is soluble polyv Polyvinylpyrrolidone is commercially aN trademark Kollidon*' (Bayer AG) other e copolymners of polyvinylpyrrolilone and polyethyleneglycol, polypropyleneglycol esters of glycerol or copolymers of eth The silicone-based transderinal therapeu according to the present invention pref 1 wt% of inorganic silicates, most pref free from inorganic silicates.

The water content in the transdermal t1 7 in the present inventioxi is preferably evaporation of water during preparatior Typically, the water content in a fresh below more preferably 1 wt% or low In a particularly preferred embodiment the transdermal therapeutic system has cm 2 more preferably 20 to 30 cm 2

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that a TTS having a surface area of, se pharmacologically equivalent to and ma CM? patches or four 5 cm 2patches havinc orementi dned Q7-4201 me res-I'stant silicone qual. amodlnts proved to be this inve'ntion.

sji icone-~ba sed includes ija solubilizer.

substancels may be used as ically aqceptable and advantag~ous if the ohesion of the cularly Jreferred example nylpyrroiidone.

ailable, under the camples ida'clude vinyl ac tater glycerol and fatty acid ylene and vinylacetate.

tic syst erably cc erably it mn for use ntains less than is completely Ierapeutiq systems for use low enough so that no of the T]TS is necessary.

ly prepated patch is of the p~esent invention, a surfacd, area of 10 to Lgoes wi hout saying y, 20 cm.2 i s be exch~nged by two rthe sami drug content II11/0 1: \ki~~~uh~teeP~~sP if atn\S21~ 08/12 2005 15:43 FAX 61 3 92438333 GRIFFITH HACK I015 0 12

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0 per cm 2 Thus, the surface areas as indicated in this o application should be understood to refer to the total surface Sof all TTS simultaneously administered to a patient.

00 Providing and applying one or several transdermal therapeutic systems according to the invention has the pharmacological 0 S advantage over oral therapy that the attending physician can titrate the optimum dose for the individual patient relatively 3 quickly and accurately, e.g. by simply increasiig the number or t 10 size of patches given to the patient. Thus, the ioptimum Sindividual dosage can often be determined after a time period of C<1 only about 3 weeks with low side effects.

A preferred content of rotigotine per patch is in the range of 0.1 to 2.0 mg cm 2 Still more preferred are OAk to 1.5 mg 2 rotigotine per cm 2 If a 7 day patch is desired,, higher drug contents will generally be required. A rotigotine content in the range of about 0.4 to 0.5 wt% has been found tobe particularly advantageous in that it provides the optimum usage of the drug contained in the TTS, i.e. there is only very little residual drug content in the TTS after administration. Thie apparent dose administered by using such a TTS usually is 50% Jor more and may be as high as 80-90% of the drug amount originally contained in the TTS.

The fact that the silicone-based transdermal thJrapeutic system described in this invention is able to provide a significant therapeutic effect against symptoms of Parkinsori's Disease even at surface areas of 10 to 30 cm 2 and particularly as little as 10 or 20 cm 2 and at low drug contents of about d.4 to 0.5 mg/cm 2 particularly about 0.45 g/cm 2 must be considered as a further particular benefit provided by the present invention.

1 The transdermal therapeutic system used in the present invention usually is a patch having a continuous adhesive matrix in at least its center portion containing the drug. Hdwever, H!\kimh\kaap\spb[±tications\F59210.doc 0/12/05 il |i 08/12 2005 15:43 FAX 61 3 92438333 GRIFFITH HACK [a016 13 In o transdermal equivalents to such patches are lik6wise comprised o by the present invention, e.g. an embodiment where the drug is Sin an inert but non-adhesive silicone matrix in the center OO portion of the TTS and is surrounded by an adhesive portion

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5 along the patch edges.

This invention relates to a method of treating arkinson's Disease by applying on a patient in need thereof a siliconebased transdermal therapeutic system having an qrea of 10 to cm 2 and containing 0.1 to 3.15 mg cm 2 of rotidotine as active ingredient, the improvement wherein is that the icondition of the patient, measured according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III, is improved, vis 6 vis placebo treatment, by about 2 units or more ove: a time period of at least 7 weeks administration. Maintenance Iof this UPDRS

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score improvement for up to 7 weeks has been shdwn as well.

Thus, improving the UPDRS (parts II+III) score over placebo by at least 2 units following administration for preferably 11 weeks forms a particularly beneficial aspect of 'the present invention.

Unless expressly indicated otherwise, any references to rotigotine in the context of this invention and the claims of this application mean rotigotine in the form of its free base.

In some cases traces or rotigotine hydrochloride may be contained in rotigotine but these traces do typiically not exceed wt%, based on the amount of the free base. More preferably the content of hydrochloride impurities should be less than 2 wt%, even more preEerably less than and most preferably the rotigotine used in the present invention contai's less than 0.1 wt% or no hydrochloride impurities at all.

Extensive clinical trials using the transdermal therapeutic system described herein have shown that it is surprisingly possible to achieve and warrant a constant stimulation of the dopamine receptors of Parkinson patients, resulding in a notable

II

LI; \kixh\kemp\5Pec ificationc\P59210.doc 8/12/05 08/12 2005 15:43 FAX 61 3 92438333 GRIFFITH HACK Ia017 i 14 N improvement in the clinically relevant UPDRS for a time period .1 o of at least 7 weeks. More specifically, clinical studies using a 0 patch according to the preparation example as gaven herein have OO resulted in the following improvements in the FAS UPDRS (part II and III) score following administration for 11 weeks: Patch Size Amount of Improvement in UPDRt p rotigotine over Placebo Treatment (one sided) cm 4.5 mg 2.148 0.0393 cm 2 9.0 mg 3.123 4 0.0063 cm 2 13.5 mg 4.909 0.0000 cm 18.0 mg 5.035 0.0000 The abbreviation FAS stands for "Full Analysis 4et" and thus designates an analysis including all patients wio were included in the study. The UPDRS score and the study design is explained in more detail in the Clinical Trials Example b low. Fig. 1 is a graph illustrating the mean change from base li e in UPDRS (II III) total scores from day 0 to end of treatment in this study.

This figure compares the effects of a treatment' according to the present invention with a placebo treatment. Statistically significant improvements can particularly be observed for patches having an area of 20 cm 2 or more, though'leven the effect of the 10 cm 2 patch must be considered as an improvement, The value indicated as p in the above table represents the one-sided p-value obtained from a statistical evaluation qf the trial data.

While an improvement in the UPDRS scale of 2, cohpared to placebo, may already be called a success, an improvement of 3, 4 or even 5 or more units would even more represedt a therapeutic progress and, as such, form a preferred aspect of the present invention.

Additional tests including pharmacokinetics, do e-activity relationship, compliance, and drug safety confi ed the lU;\kiMh\keeip\SpelIlI iciois\ps9p220.doc /12/0S ,i 08/12 2005 15:44 FAX 61 3 92438333 GRIFFITH HACK ia018 15 I 0 therapeutic usefulness of the silicone-based tr nsdermal 0 therapeutic system used herein.

OO The invention and the best mode for carrying itjout will be explained in more detail in the following non-limiting examples.

0 i 9\ Preparation Example A transdermal therapeutic system using a combination of t 10 silicone-type pressure sensitive adhesives was prepared as o follows.

(-)-5,6,7,B-tetrahydro-6-[propyl[2-2-(-thienyl) thyl]-amino]lnaphthalenol hydrochloride (rotigotine hydrochlqride, 150 g) was added to a solution of 17.05 g NaOH in 218 g ethanol The resulting mixture was stirred for approximately :10 minutes.

Then 23.7 g of sodium phosphate buffer solution (8.35 g Na 2 HPODx2H20 and 16.07 g NaH 2

PO

4 x2H20 in 90.3 g waler) was added.

Insoluble or precipitated solids were separated from the mixture by filtration. The filter was rinsed with 60.4'ig ethanol (96%) to obtain a particle-free ethanolic solution of rotigotine in the form of the free base.

The rotigotine free base solution (346.4 g) in ethanol (35% w/w) was mixed with 36.2 g ethanol The resulting solution was mixed with 109 g of an ethanolic solution containing 25 wt% polyvinylpyrrolidone (KOLLIDON 90F), 0.077 wt% aqueous sodium bisulfite solution (10 0.25 wt% ascorbyl palmitater and 0.63 wt% DL-alpha-tocopherol until homogenous. To the mixture, 817.2 g of an amine resistant high tack siliconj adhesive (BIO-

PSA

0 Q7-4301 mfd. by Dow Corning) (74 wt% soluti6n in heptane), 851.8 g of an amine resistant medium tack silicohe adhesive (BIO-PSA® Q7-4201 mfd. by Dow Corning) (71 wt% sblution in heptane), and 205.8 g petrol ether (heptane) were added, and all components wece stirred until a homogenous dispe sion was obtained.

H;\kcimh\koop\Spcio. tl~nn\P59310Q.doo 08/12 2005 15:44 FAX 61 3 92438333GIFIH AC J01 GRIFFITH HACK [a 019 The dispersion was coated onto a suitable poiyelfter release liner (SCOTCHPAKO 1022) with a suitable doctor )diife and the solvents were continuously removed in a drying ~en at temperatures up to 80 0 C for about 30 min to obtain a drug- Containing adhesive matrix of 50 g/ caigweight. The dried matrix film was laminated with a polyester-type 6acking foil (SCOTChPAK' 1J.09). The individual patches were hunched out of the complete laminate in the desired sizes (eg 10 cm 2 20 c2,

CM

2 and se'aled into pouches under the flow ol nitrogen.

The following table shows the composition in rag/ transderynal therapeutic system according to the invention cont~aining a combination of two silico 20 cm 2 of a pre sent ae-type PSA.

Compsitin CmponntsAmount (mg) Rotigotine Basge 9.00 Polyvinylpyrrolidone 2.00 Silicone BIO-PSA Q7-4301 44.47 Silicone BIO-p1SAO Q7-4201 44.46 Ascorbyl palniitate 0.02 DL-alpha Tocopherol 0.05 Sodium metabisulfite 0.0006 Matrix coating~ weight 50- g9/M_1 Clinical Trials M~ethods: The rotigotine TTS as prepared in the above prep~ration example has been tested in multicenter, placebo-controll d, doubleblind, randomised clinical trials involving more Ithan 300 Parkinson patients, and proven to yield an effecl~ive alleviation of the SYMrttonnLS of Parkinson's Disease in patienis suffering from this disease upon prolonged administration times (11 weeks, of which 4 weeks were a titration period and 7 weeks were the H: \k11nh\ketp\Speci H \~ii~\ke~Xpei :ian\F9210.dar 8/32/05 08/12 2005 15:44 FAX 61 3 92438333 GRIFFITH HACK 2020 17 .i o maintenance period), once daily administration) The patients O were not receiving other dopaminergic medications at that time.

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CO After a 4-7 day open-label placebo run-in period, 329 patients o 5 were randomized to placebo or one of four rotigJtine daily dosages (drug content in patch 4.5 mg, 9.0 mg, 13.5 mg or 18 Smg), and followed for a 4-week dose-titration period, a 7-week Sdose-maintenance period, a 1-week dose de-escaltion period and a 2-week safety follow-up period in a double-blind fashion. The study design (therapy plan) is illustrated in mqre detail in Fig. 2.

The prespecified primary efficacy outcome was a change in the Activities of Daily Living and Motor components ,of the generally accepted Unified Parkinson's Disease Rating Scae (UPDRS II/III) between baseline and the last evaluation on treatment (week 11).

Parts II and III of the UPDRS measure and rate the following clinical parameters in Parkinson patients; II. ACTIVITES OF DAILY LIVING A. Speech 0= Normal, 1= Mildly affected. No difficulty being understood.

2= Moderately affected. Sometimes asked to rpeat statements.

3= Severely affected. Frequently asked to repeat statements.

4= Unintelligible most of the time.

B. Salivation 0= Normal.

1= Slight but definite excess of saliva in mouth; may have nighttime drooling.

M:\kimh\tkeap\spec l tiona\PS9210.doc EB/2/a .1 08/12 2005 15:44 FAX 61 3 92438333GRFIHAC J02 GRIFFITH HACK 121021 18 Moderate--ly excessive saliva; may have mini Marked excess of saliva with some drooling Marked drooling, requires constant tissue nrai. drooling.

)r handkerchief.

C, swallowing 0= 2= 4=

D.

3= 4= N'ormal.

Rare choking.

Occasional choking.

Requires soft food.

Require$ NG tube or gastronomy feeding.

Handwriting Normal.

Slightly slow or small, Moderately slow or small; all words are lejible.

Severely affected; not all words are legible.

The majority of words are not legible.

E Cutting food and handling utensils 1= 3= 4= Normal.

Somewhat slow and clumsy, but no help neede4 Can cut most foods, although clumsy and slop, some help needed.

Food must be cut by someone, but can still feed slowly.

Needs to be fed.

F. Dressing 0= Normal.

H-'kWh\keOP\9PQ.cs LctionaNP59210.dou 0/12/cQ5 08/12 2005 15:45 FAX 61 3 92438333 GIFT AK1J 2 GRIFFITH HACK [a 022 19 1= 2= 3= 4=: G Somewhat slow, but no help needed.

Occasional assistance with buttoning, gett ing arms in sleeves.

Considex:able help required, but can do soml4 things alone.

Helpless.

Hygiene 0= Normal 1= Somewhat, slow, but no help needed.I 2 Needs help to shower or bathe; or very slo care.

in hygienic eeth, combing 3= Requires assistance for washing, brushing t" hair, going to bathroom.

4 Foley catheter or other mechanical aids, Ii. Turning in bed and adjusting bed clothes 0= Normal.

1= 2= 3-; 4= Somewhat slow and clumsy, but no help needeild.

Can turn alone or adjuast sheets, but with gCreat difficulty.

Can initiate, but not turn or adjust sheetsj alone.

Helpless.

I. Falling (unrelated to freezing) 0= 1= 3= 4= None.

Rare falling.

occasionally falls, less than once per day.

ralls an average of once daily.

Falls more than once daily.

II; \ki~h\k:Gp\Specib icatians\M,9210,doc el12/o S08/12 2005 15:45 FAX 61 3 92438333 GRIFFITH HACK 12023 J. Freezing when walking 0= None.

1= Rare freezing when walking; may have start esitation.

2= Occasional freezing when walking.

3= Frequent freezing. Occasionally falls froni freezing.

4= Frequent falls from freezing.

K. Walking 0= 1= 2= 3= 4= Normal.

Mild difficulty. May not swing arms or may tend to drag leg.

Moderate difficulty, but requires little or no assistance.

Severe disturbance of walking, requiring assistance.

Cannot walk at all, even with assistance, Tremor (Symptomatic complaint of tremor in any part of

L.

body.

0= 1= 2= 3= 4= Absent.

Slight and infrequently present.

Moderate; bothersome to patient.

Severe; interferes with many activities.

Marked; interferes with most activities.

M. Sensory complaints related to parkinsonism 0= None.

1= Occasionally has numbness, tingling, or mile 2= Frequently has numbness, tingling, or achinc distressing.

3= Frequent painful sensations.

H: \:iiU\ (p\S cif.

I

aching.

not catli0)n\P59210.doc 8/12/05 08/12 2005 15:45 FAX 61 3 92438333 GRIFFITH HACK []024 -21- 0 0 o ci 4= Excruciating pain, *1 0 00 S 5 III. MOTOR EXAMINATION 0 i N. Speech 0= Normal.

S1= Slight loss of expression, diction and/or vblume.

C 2= Monotone, slurred but understandable; moderitely impaired.

I

3= Marked inpairment, difficult to understand.! 4= Unintelligible.,

I

0. Facial Expression 0= Normal.

1= Minimal hypomimia, could be normal "Poker FAce." 2= Slight but definitely abnormal diminution of facial 'i expression. 3= Moderate hypomimia; lips parted some of thejtime.

4= Masked or fixed facies with severe or complete loss of facial expression; lips parted 4 inch or mote.

i P. Tremor at rest (head, upper and lower extreiities) 0= Absent.

1= Slight and infrequently present.

2= Mild in amplitude and persistent. Or moderdte in amplitude, but only intermittently present.

3= Moderate in amplitude and present most of tle time.

4= Marked in amplitude and present most of the, time, R!\Kth\uef\3pecificatlons\p59210,dor 0/12/03

I

08/12 2005 15:45 FAX 61 3 92438333 GRIFFITH HACK 1025 22 Q. Action or Postural Tremor of hands 0= Absent.

1= Slight; present with action, 2= Moderate in amplitude; present with action 3= Moderate in amplitude with posture holding action.

4= Marked in amplitude; interferes with feedii R, Rigidity (Judged on passive movement of ma: patient relaxed in sitting position. Cogwl ignored).

as well as ig.

or joints with eeling to be mirror or other ieved.

culty.

0= 1= 2= 3= 4=

S.

Absent.

Slight or detectable only when activated by movements.

Mild to moderate.

Marked, but full range of motion easily ach Severe, range of motion achieved with diffi Finger Taps (Patient taps thumb with index ringer in rapid succession.) 0= Normal.

1= Mild slowing and/or reduction in amplitude, 2= Moderately impaired. Definite and early fatiguing.

have occasional arrests in movement.

3= Severely impaired. Frequent hesitation in Initiating movements or arrests in ongoing movement.

4= Can barely perform the task.

May T. Hand Movements (Patient opens and closes har succession.) Il;\kih\keop\Specil ds in rapid .cations\P5210.doc 8/12/D5 08/12 2005 15:46 FAX 61 3 92438333 GRIFFITH HACK I1026 23 0= Normal.

1= Mild slowing and/or reduction in amplitude.

2= Moderately impaired. Definite and early fz have occasional arrests in movement.

3- Severely impaired. Frequent hesitation in, movements or arrests in ongoing movement.

4= Can barely perform the task.

.tiguing. May jinitiating U. Rapid Alternating Movements of Hands (Prona movements of hands, vertically and horizont large an amplitude as possible, both hands tion-supination ally, with as simultaneously.) 0= 1= 2= 3= Normal.

Mild slowing and/or reduction in amplitude.

Moderately impaired. Definite and early fatiguing.

have occasional arrests in movement.

Severely impaired. Frequent hesitation in initiati] movements or arrests in ongoing movement.

Can barely perform the task.

May ng V. Leg Ability (Patient taps heel on the ground in rapid succession picking up entire leg. Amplitude should be at least 3 inches.) 0= Normal.

1= Mild slowing and/or reduction in amplitude.

2- Moderately impaired. Definite and early fatiguing.

have occasional arrests in movement.

3= Severely impaired. Frequent hesitation in initiating movements or arrests in ongoing movement.

4= Can barely perform the task.

May

'I

If RI\kLiil\apspCI1~ Ira~os9pO1o 0 0 f12/OS0 08/12 2005 15:46 FAX 61 3 92438333 GRIFFITH HACK 027 24 W. Arising from Chair (Patient attempts to ri straightbacked chair, with arms folded acrit 0= Normal.

1= Slow; or may need more than one attempt.

2= Pushes self up from arms of seat.

3= Tends to fall back and may have to try more but can get up without help, 4= Unable to arise without help.

X. Posture 0= Normal erect.

1= Not quite o.

§e from a

I

nss chest.) 'than one time, i ould be normal rmal; can be be moderately I Q jyniy stoopea posture; for older person.

2= Moderately stooped posture, definitely abno slightly leaning to one side.

3= Severely stooped posture with kyphosis; can leaning to one side.

4= Marked flexion with extreme abnormality of Posture.

Y. Gait 0= Normal.

1= Walks slowly, may shuffle with short steps,' festination (hastening steps) or propulsion 2= Walks with difficulty, but requires little assistance; may have some festination, short propulsion.

3= Severe disturbance of gait, requiring assist 4- Cannot walk at all, even with assistance.

U:\kimh\ kqp\Sbeci but no r no steps, or ance.

atiorna\P59210 .dac B/12/05 08/12 2005 15:46 FAX 61 3 92438333 GRIFFITH HACK @1028 25 0, 0

OO

0 Z. Postural Stability (Response to sudden, st: displacement produced by pull on shoulders erect with eyes open and feet slightly apaj prepared,) song posterior while patient Patient is 0= Normal.

1= Retropulsion, but recovers unaided.

2= Absence of postural response; would fall ii not caught by examiner, 3= Very unstable, tends to lose balance spontaneously.

4= Unable to stand without assistance.

I:

AA. Body Bradykinesia and Hypokinesia (Combinin slowness, hesitancy, decreased armswing, small amplitpde, and poverty of movement in general.) 0= None.

1= Minimal slowness, giving movement a delib te character; could be normal for some persons. Possibly reduced amplitude. i 2= Mild degree of slowness and poverty of movement which is definitely abnormal, Alternatively, some reduced amplitude. 1 3= Moderate slowness, poverty or small amplitude of movement.

4= Marked slowness, poverty or small amplitude!of movement.

The total UPDRS score is determined from the individual scores as follows: First, a baseline value is determined for each patient participating in the study. This is done by summkng up the individual scores of the UPDRS part II and III parameters at day 0, i.e. before treatment. Any determinations of the UPDRS score in the course of treatment will then be compared jo this H;\kimh\kep\speei .catoin\P59210.doc B/12/D5 08/12 2005 15:46 FAX 61 3 92438333 GRIFFITH HACK 029 -26 o o baseline value and changes relative to baseline lvalue are O recorded. Finally the mean improvement in UPDRS iI+III at Day 77 0(week 11) relative to baseline will be determined by averaging O over all trial subjects. The resulting value is designated as o 5 the FAS (Full Analysis Set) Randomized Mean Change from Baseline Value in Total UPDRS Score (II III) and is plotted as the y- Saxis in Figure 1. The term "randomized" refers t the fact that the patients were randomized to the different pre-defined doses in advance.

S o Patients suffering from Parkinson's Disease are known to Cl experience a relatively strong placebo effect, i e. even a placebo treatment improves the UPDRS score of Parkinson patients to some extent. It is therefore important to compare any effects of drug treatment with the level of UPDRS improvement attained by a placebo treatment of the same length. The final evaluation of improvement is therefore made relative to the effect of a placebo treatment of the same duration.

Results: There was a significant, dose-related improvemen in UPDRS II/III scores between baseline and week 11 when 4pplying the TTS according to the present invention, particularly for the 13.5, and 18 mg groups, compared to placebo. Thi result is apparent from Figure 1 and the following table: H,\kimh\ee\SPecis4ratons\Pss2a1Odoc 0/12/05 08/12 2005 15:47 FAX 61 3 92438333 GIFT AKII3 GRIFFITH RACK [a 030 27 Patch Size Amount off Improvement in Meansr p rotigotine Total UPDRS 11±111 over (one Placebo Treatment sided) at week 11 c)Cm 4.5 mg -2,148 0.0393 2 0 m 2 9.0 mg -3.123 q1 0.0063 cm' 13.5 mg-4.909 1 0.0000 cm18.0 rag -5.035 1 0.0000 Rotigotine, when administered using the inventive TTS, was generally well, tolerated. Application site skint reactions were generally mild and occurred with placebo patches," but were more common among subjects randomized to the higher dc~sage groups.

There were no differences among the groups regaraing vital signs, laboratory tests and ECGs.

Conclusions: The above results show for the first t'ixre in a placebocontrolled study that a dopaminie agonist (rotigotie) administered transdermally and once daily by a soecific TTS, produces clinical improvement with satisfactory t olerability and safety in patients with early Parkinson's Diseas.- Such a result could neither be obtained with the ~crylic transdermal therapeutic system of WO 99/49852 no. with the silicone transderma. therapeutic system of WO 94/107468. Before this background, this result must be viewed as pakticularly surprising and beneficial for Parkinson patients.! ait1 O118\P5922u. dOC a/1;,/05

Claims (20)

1. A method for treating Parkinson's Disease in a patient suffering from such disease by applying a silicone- based transdermal therapeutic system comprising a mixture of at least one high tack and one medium tack amine- resistant silicone pressure sensitive adhesive as the main adhesive component having an area of 10 to 40 cm 2 and containing 0.1 to 3.15 mg cm 2 of rotigotine in the free- base form as active ingredient, wherein said treatment effects an improvement, vis vis placebo treatment, in the condition of a human Parkinson patient of 2 units or more following administration for at least 7 weeks, when measured according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III.

2. The method according to claim 1 wherein the silicone-based transdermal therapeutic system comprises more than two amine-resistant silicone pressure sensitive adhesives as the main adhesive components.

3. The method according to claim 1 or 2 wherein the silicone-based transdermal therapeutic system further comprises a solubilizer.

4. The method according to claim 3 wherein the solubilizer is polyvinylpyrrolidone. The method according to any one of the preceding claims wherein the silicone-based transdermal therapeutic system comprises less than 1 wt% of inorganic silicates.

6. The method according to claim 5 wherein the N; \He I ,rne \Case.\ Paent-\50oo- 50999\P50104 AU. 1 9peC1\.enAeGdnt.dW 15/12/0, 29 00 silicone-based transdermal therapeutic system is free from 0 inorganic silicates. (N

7. The method according to any one of the preceding I 5 claims wherein the silicone-based transdermal therapeutic system has an area of 10 to 30 cm 2

8. The method according to any one of the preceding Cg claims wherein the silicone-based transdermal therapeutic 10 system comprises 0.1 to 1.5 mg cm 2 of rotigotine. In

9. The method according to claim 1 wherein the silicone-based transdermal therapeutic system is a patch having an area of 10 to 30 cm 2 and a content of rotigotine of 0.4 to 0.5 mg/cm 2 in an adhesive silicone-based matrix. Use of a composition comprising a mixture of at least one high tack and one medium tack amine-resistant silicone pressure sensitive adhesive and 0.1 to 3.15 mg cm 2 of rotigotine in the free-base form as active ingredient for preparation of a silicone-based transdermal therapeutic system which is 10 to 40 cm 2 in size and effects an improvement, vis d vis placebo treatment, in the condition of a human Parkinson patient of 2 units or more following administration for at least 7 weeks, when measured according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III.

11. The use according to claim 10 wherein the silicone-based transdermal therapeutic system further comprises a solubilizer.

12. The use according to claim 11 wherein the N.\Melbcum \Cale\Patent\0000-999\P$0 S 15/12108 30 00 solubilizer is polyvinylpyrrolidone. 0 13. The use according to any one of claims 10-12 Swherein the silicone-based transdermal therapeutic system V' 5 comprises less than 1 wt% of inorganic silicates.

14. The use according to claim 13 wherein the IO silicone-based transdermal therapeutic system is free from inorganic silicates. c- The use according to any one of claims 10-14 wherein the silicone-based transdermal therapeutic system has an area of 10 to 30 cm 2

16. The use according to any one of claims 10-15 wherein the silicone-based transdermal therapeutic system comprises 0.1 to 1.5 mg cm 2 of rotigotine.

17. The use according to claim 10 wherein the silicone-based transdermal therapeutic system is a patch having an area of 10 to 30 cm 2 and a content of rotigotine of 0.4 to 0.5 mg/cm 2 in an adhesive silicone-based matrix.

18. A transdermal therapeutic system to effect an improvement, vis vis placebo treatment, in the condition of a human Parkinson patient of 2 units or more following administration for at least 7 weeks, when measured according to the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III, which has a size of 10 to 40 cm 2 and contains 0.1 to 3.15 mg/cm 2 rotigotine in free base form as active ingredient in a matrix mainly comprising a mixture of at least one high tack and one medium tack amine-resistant silicone pressure sensitive adhesives. rl\Pst.. \51000050999\P0704.AU.I\- 15/12/04 31 00

19. The transdermal therapeutic system according to Sclaim 18 further comprising less than 1 wt% of inorganic silicates. The transdermal therapeutic system according to 9\ claim 18 or 19 further comprising a solubilizer. C r 10 21. The transdermal therapeutic system of claim wherein the solubilizer is polyvinylpyrrolidone.

22. A method of preparing a silicone-based transdermal therapeutic system comprising the steps of: mixing rotigotine in the free-base form in a solvent with a mixture of at least one high tack and one medium tack amine-resistant silicone pressure sensitive adhesive; coating a liner with the mixture obtained at step and removing the solvent by drying; laminating the dried-matrix film obtained at step with a backing foil; and punching patches from the complete laminate.

23. The method of claim 22 further comprising the step of admixing a solubilizer at step

24. The method according to claim 23 wherein the solubilizer is polyvinylpyrrolidone. A method for treating Parkinson's Disease in a patient suffering from such disease by applying a silicone- based transdermal therapeutic system substantially as N:\Mlborne\Casel\Ptent\0000-0999NP0704.U 1s0/3/o 32 herein described with reference to any one of the Examples and/or accompanying Figures.

26. Use of a composition comprising a mixture of at least one high tack and one medium tack amine-resistant silicone pressure sensitive adhesive and rotigotine in the free-base form substantially as herein described with reference to any one of the Examples and/or accompanying Figures.

27. A method of preparing a silicone-based transdermal therapeutic system substantially as herein described with reference to any one of the Examples and/or accompanying Figures. N:\.Mlbourne\Caes\Patenc\50000- 50999\P5004 .AU. \Specli\Aendmens .doc 11/02/09