WO2012084969A1 - Adhesive composition containing rotigotine and transdermal therapeutic system comprising the adhesive composition - Google Patents

Adhesive composition containing rotigotine and transdermal therapeutic system comprising the adhesive composition Download PDF

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Publication number
WO2012084969A1
WO2012084969A1 PCT/EP2011/073435 EP2011073435W WO2012084969A1 WO 2012084969 A1 WO2012084969 A1 WO 2012084969A1 EP 2011073435 W EP2011073435 W EP 2011073435W WO 2012084969 A1 WO2012084969 A1 WO 2012084969A1
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WO
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Prior art keywords
preferably
weight
adhesive composition
adhesive
rotigotine
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PCT/EP2011/073435
Other languages
French (fr)
Inventor
Jörg NINK
Michael Helfrich
Michael SEDLMAYR
Sigrid Grundsteiner
Original Assignee
Hexal Ag
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Priority to EP10015958 priority Critical
Priority to EP10015958.1 priority
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Publication of WO2012084969A1 publication Critical patent/WO2012084969A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703Transdermal 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
    • A61K9/7038Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings

Abstract

The present invention relates to an adhesive composition containing a pressure sensitive adhesive (PSA) selected from the group consisting of a styrenic polymer, a polyisobutylene, or mixtures thereof, rotigotine or a pharmaceutically acceptable salt thereof as the active !"ingredient, and at least one crosslinked polyvinyl pyrrolidone or at least one copolymer of vinyl pyrrolidone and vinyl acetate, or a mixture thereof. Moreover, the present invention relates to a transdermal therapeutic system (TTS) for the transdermal administration of rotigotine which comprises the adhesive composition. Further the present invention relates to a method for producing such a TTS and to a pouch comprising the TTS. In particular, the invention relates to the use of a transdermal therapeutic system for the purpose to treat or alleviate dopamine-related disorders such as Parkinson's Disease.

Description

Adhesive Composition containing Rotigotine and Transdermal Therapeutic System comprising the Adhesive Composition

The present invention relates to an adhesive composition containing as an active ingredient rotigotine, and to a transdermal therapeutic system (TTS) for the transdermal administration of rotigotine which comprises the adhesive composition. Further the present invention relates to a method for producing such a TTS and to a pouch comprising the TTS. In particular, the invention relates to the use of a transdermal therapeutic system for the purposes to treat or alleviate dopamine-related disorders such as Parkinson's Disease.

General remarks:

Rotigotine ((-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-l-naphthol) is a non- ergolinic D1/D2/D3 dopamine agonist which has a receptor profile similar to dopamine but a receptor affinity higher than dopamine. It is known to be effective in treating patients suffering from Parkinson's Disease, Parkinson's plus syndrome, depression and the restless- legs syndrome. Rotigotine is also effective in treating and preventing dopaminergic neuron loss. This is known for example from WO 2009/068520 A2 and EP 1 033 978 B l being incorporated herein by reference.

Transdermal delivery systems and more specifically transdermal therapeutic systems which are also referred to herein as TTS, such as transdermal patches, have been proven to be advantageous in the administration and delivery of pharmaceutically active agents, such as rotigotine. One of the reasons for this is that transdermal delivery systems avoid hepatic metabolization of the pharmaceutically active agent, which is frequently observed upon oral administration of a pharmaceutically active agent. As a consequence, upon administration of a pharmaceutically active agent through a transdermal delivery system the liver is relieved and gastrointestinal side effects are avoided. Additionally, compared to a non-transdermal administration, usually less of the pharmaceutically active agent is required so as to have the same effect. Furthermore, transdermal delivery systems provide a more constant blood level of the pharmaceutically active agent as there is a constant supply of active ingredient from the patch through the skin during wear of the patch. Finally, transdermal delivery systems increase patients' compliance due to their easy and convenient application. Common transdermal delivery systems have the disadvantage that they often do not provide sufficient adhesive power or strength to remain attached to a patient's skin for the period of time needed for administration of the drug, which can be from one to seven days. Thus, a need exists for alternative pressure sensitive adhesive polymers for use in transdermal applications.

Commercially available classes of adhesives for use in skin contact applications such as TTS are acrylic polymers, polyisobutylene polymers (PIB) and silicone polymers. However, styrenic polymers have not yet been intensively used due to a widely-held prejudice that copolymers with high styrene content make the polymer difficult to tackify (Istvan Benedek; Pressure-Sensitive Adhesives and Applications, 2nd edition, 2004).

For the administration of rotigotine various transdermal therapeutic systems have been described in the prior art. WO 2004/012721 A2 discloses the use of hotmelt adhesives which may contain plasticizers in preparing the matrix of the TTS. A preferred hot melt adhesive therein is a silicone pressure sensitive adhesive. However, the use of a hotmelt process for preparing the matrix has several drawbacks such as its strict temperature conditions which seriously impede the incorporation of thermolabile and/or oxidation sensitive compounds into the matrix.

EP 1 033 978 Bl discloses a TTS containing rotigotine wherein the adhesive is based on acrylate or silicone. However, the TTS provides for an inferior and non-satisfying stability as shown by the presence of rotigotine crystals on the surface of the TTS after some time of storage, probably based on the low solubility of rotigotine in the adhesive matrix material. Moreover, the adhesive strength on the patient's skin is insufficient.

US 2010/086582 Al discloses a transdermal delivery device comprising an adhesive matrix layer containing amorphous rotigotine in a supersaturated concentration. EP 2 177 217 Al discloses rotigotine containing compositions comprising an acrylic pressure sensitive adhesive and a silicone pressure sensitive adhesive together with water soluble polyvinyl pyrrolidone in specific ratios. WO 2004/069231 Al discloses transdermal therapeutic systems having improved adhesion to the skin. Several active ingredients and pressure sensitive adhesives are described.

WO 2011/076879 Al relates to transdermal therapeutic systems comprising rotigotine, a silicone pressure sensitive adhesive and PVP in specific ratios.

The combination of a low stability (e.g. as shown by the presence of rotigotine crystals on the surface of the patch) and an insufficient adhesive strength on the patient's skin over time thus makes it extremely difficult to provide a rotigotine transdermal system such as a transdermal patch releasing an appropriate and reliable amount of the drug to the patient for the longest possible period.

Thus, a need exists for a transdermal rotigotine system which releases an effective amount of drug in a patient in need of a treatment or alleviation of dopamine-related disorders such as Parkinson's Disease and which is effective in providing a reliable and constant drug level in the patient.

Object of the invention: Thus, it is the object of the present invention to provide an adhesive composition and a transdermal therapeutic system (TTS) containing the adhesive composition which solve the afore-mentioned problems. In particular, it is the object of the present invention to provide an adhesive composition and a transdermal system containing the adhesive composition which has a high adhesive strength against patient's skin, which is stable and maintains the active ingredient in solution in the adhesive matrix, i.e. shows no appearance of crystals of the active ingredient on the surface of the TTS, and which is effective in providing a constant drug level in the patient. Moreover, it is an object to increase the skin permeation rate of the active ingredient in order to improve systemic availability and, consequently, the effectiveness and safety of the TTS.

Description of the drawings:

Figure 1 shows the increased rotigotine in vitro flux of the TTS in Examples 1 and 2.

Figure 2 shows the increased rotigotine in vitro flux of the TTS in Example 4. Figure 3 shows the increased rotigotine in vitro flux of the TTS in Example 5.

Figure 4 shows the improved peel strength according to the invention (Example 5) as compared to the silicone containing patches (Neupro patch) and to acrylate containing patches.

Description of the invention:

The inventors have surprisingly found that an adhesive composition for a TTS comprising a styrenic polymer and/or polyisobutylene, rotigotine or a pharmaceutically acceptable salt thereof, and at least one specific vinyl pyrrolidone (co)polymer, as well as a TTS containing the adhesive composition solve the above problems.

A TTS containing the said adhesive composition is particularly useful for providing a constant and high blood plasma level of rotigotine and continuous drug delivery for one day or more (> 24 h), preferably three days or more (>72 h), more preferably for four days or more (about 96 h), and most preferably for seven days or more (about 168 h), while at the same time providing optimum adhesive strength and greatest comfort to the patient for the entire period of use. Moreover, the TTS does not show any crystals of rotigotine on its surface upon storage under various temperature/time conditions and, thus, provides for a high (chemical) stability and safety.

The above-mentioned objects have thus been surprisingly solved in the present invention by the provision of an adhesive composition comprising

i. a pressure sensitive adhesive (PSA) selected from the group consisting of a styrenic polymer, a polyisobutylene, or mixtures thereof,

ii. rotigotine or a pharmaceutically acceptable salt thereof,

iii. at least one crosslinked polyvinyl pyrrolidone or at least one copolymer of vinyl pyrrolidone and vinyl acetate, or a mixture thereof. The present invention further relates to a transdermal therapeutic system comprising

a) at least one adhesive layer made of the adhesive composition as described above, and

b) optionally, a backing layer,

c) further optionally, a release liner, and d) further optionally, a coverpatch being either integrated in or separated from the transdermal therapeutic system.

In a preferred embodiment the transdermal therapeutic system comprises at least one additional adhesive layer which more preferably is free of rotigotine.

The present invention further relates to method of producing a transdermal therapeutic system comprising a backing layer, at least one adhesive layer and a release liner, comprising the steps of

1) preparing a solution comprising

i) rotigotine or a pharmaceutically acceptable salt thereof, ii) at least one crosslinked polyvinyl pyrrolidone or at least one copolymer of vinyl pyrrolidone and vinyl acetate, or a mixture thereof,

iii) a pressure sensitive adhesive (PSA) selected from the group consisting of a styrenic polymer, a polyisobutylene, or mixtures thereof, iv) solvent, and

v) optionally, one or more of a penetration and/or permeation enhancer, tackifier, solubilizer, liquid diluent, antioxidant, filler, oxygen or humidity absorber, crystallisation inhibitor, emollient, anti-irritant, opacifier, or mixtures thereof,

2) coating the solution on the release liner or on the backing layer,

3) drying the coating to form the at least one adhesive layer, and

4) laminating the at least one adhesive layer with the backing layer or the release liner.

In a preferred embodiment of the invention the solution is coated onto the release liner, and the obtained adhesive layer is laminated with the backing layer.

The invention further relates to a TTS, which is obtainable by the method of the present invention. Finally, the present invention relates to a pouch comprising the transdermal therapeutic system of the present invention, together with an inlay. The inlay preferably contains an oxygen or humidity absorber, antioxidant, or a mixture thereof. The TTS of the present invention is particularly useful for treating a patient suffering from dopamine-related disorders such as Parkinson's Disease.

Detailed description of the invention: The present invention provides an adhesive composition (also referred to herein below as the drug containing adhesive composition) suitable and intended to prepare the adhesive matrix of a TTS as well as the TTS itself for the transdermal delivery of the drug rotigotine. The TTS of the invention typically is a multi-layered system comprising at least one drug containing adhesive layer. The drug containing adhesive layer (matrix) comprises or consists of a drug containing adhesive composition comprising rotigotine or a rotigotine analogue such as a pharmaceutically acceptable salt thereof as active ingredient. The drug containing adhesive composition further comprises as an adhesive component one or more styrenic polymer(s) and/or one or more polyisobutylene(s), and as a permeation enhancer a crosslinked polyvinyl pyrrolidone and/or a copolymer of vinyl pyrrolidone (VP) and vinyl acetate (VA).

Rotigotine:

Rotigotine relates to a compound represented by the following formula:

Figure imgf000007_0001
which has the IUPAC nomenclature of (-)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]- amino]-l-naphthol). The term "rotigotine" in the context of the present invention comprises rotigotine and analogues thereof such as a pharmaceutically acceptable rotigotine salt or rotigotine in its basic form. In preferred embodiments, the drug used in the transdermal system of the present invention is rotigotine in the basic form (rotigotine base). Pharmaceutically acceptable rotigotine salts include, but are not limited to, salts such as the hydrochloride, hydrobromide, sulfate, phosphate, heminaphthalene-l,5-disulfonate, tartrate and tosylate. Moreover, the term "rotigotine" is intended to cover both the amorphous form and the crystal forms of the drug, the latter including all polymorphic crystal forms such as polymorphic forms I and II as described in WO 2009/068520, particularly as shown in the powder X-ray diffractograms in Figures 1 and 4 therein. This document is incorporated in its entirety herein by reference. Characteristic X-ray powder diffraction peaks (°2Θ) of form I are at 10.83, 12.68, 15.32, 16.66, and 20.23, and of form II are at 12.04, 13.68, 17.72, and 19.01, as measured with a Cu- Ka irradiation (1.54060 A). Preferably rotigotine is present as rotigotine base. Rotigotine can be contained in the drug containing adhesive composition of the present invention in an amount of 1 to 30 % by weight, preferably in an amount of 5 to 20 % by weight, more preferably in an amount of 7 to 15 % by weight, based on the total weight of the adhesive composition. An amount of below 1 % by weight of rotigotine is usually not sufficient to effectively treat or alleviate dopamine-related disorders whereas an amount of above 30 % may increase the risk of undesirable side effects due to the high concentration of the drug in the adhesive layer.

Pressure sensitive adhesive (PSA)

The pressure sensitive adhesive (PSA) contained in the composition of the present invention is selected from the group consisting of a styrenic polymer, a polyisobutylene, or any kind of mixtures thereof. Thus, the PSA according to the present invention may be one or more styrenic polymer(s), or one or more polyisobutylene(s), or a mixture of one or more styrenic polymer(s) and one or more polyisobutylene(s). Preferably the pressure sensitive adhesive has a dynamic viscosity at 160°C of more than 100 Pa.s (determined as described in US RE 36754). More preferably, the dynamic viscosity at 160 °C is not more than 180 Pa.s, even more preferably not more than 150 Pa.s. Within this range the PSA shows particularly improved physical properties such as a decreased cold flow and an increased adhesive strength.

The amount of PSA in the adhesive composition preferably ranges from 40 to 98 % by weight, more preferably from 50 to 90 % by weight, even more preferably from 55 to 86 % by weight, most preferably from 60 to 86 % by weight, based upon the total weight of the composition.

In case a mixture of the styrenic polymer(s) and polyisobutylene(s) is used the mixing ratio (weight basis) ranges from 1 :20 to 20: 1, preferably from 1 : 10 to 10: 1, more preferably from 1 :5 to 5: 1, and most preferably from 1 :2 to 2: 1. According to the present invention also 1 : 1 mixtures of the styrenic polymer and polyisobutylene are preferably comprised.

The styrenic polymer and/or polyisobutylene pressure sensitive adhesives as used in the adhesive composition according to the present invention provide for improved adhesive strength or adhesive power of a TTS containing the adhesive composition on the skin of a patient as compared to other adhesives such as silicone or acrylate adhesives.

1. Styrenic polymer:

The drug containing adhesive composition may comprise an adhesive in the form of a styrenic polymer or of a mixture of two, three or more different styrenic polymers. Preferably, the styrenic polymer is a styrenic copolymer, most preferably a block copolymer. The styrenic polymer such as the styrenic copolymer can be a linear, random, graft or block polymer. Preferred block copolymers are di- and triblock copolymers, such as A-B, A-B-A and A-B-C block copolymers.

In a preferred embodiment, the block copolymers of the invention have a weight average molecular weight of from 100 to 10,000,000, preferably from 1,000 to 1,000,000, more preferably from 2,000 to 200,000, and most preferably from 10,000 to 150,000, as measured by gel permeation chromatography.

In a preferred embodiment of the invention the styrenic copolymer is an A-B-A triblock copolymer. More preferably, the A-B-A copolymer comprises at least one styrenic polymer block A, preferably polystyrene, and at least one polymer block B obtained from monomers selected from ethylene, propylene, isoprene, butylene, butadiene or mixtures thereof.

The A-block may further comprise from 1 to 95 wt. %, preferably from 5 to 50 wt. %, based on the total weight of the A-blocks of the styrene copolymer, of homopolymers or copolymers of vinyl monomers such as vinyl arenes, vinyl pyridines, vinyl halides and vinyl carboxylates. Monovinyl aromatic hydrocarbons include particularly those of the benzene series such as styrene, vinyl toluene, vinyl xylene, ethyl vinyl benzene as well as dicyclic monovinyl compounds such as vinyl naphthalene and the like. Other polymer blocks, which may be contained in the A-block of the styrene copolymer, may be derived from alpha olefins, alkylene oxides, acetals, and urethanes. Styrene is preferred.

The polymer block B can be obtained from isoprene, butadiene or mixtures thereof. Moreover, when the polymer block B is obtained from one of these monomers, the polymer block B can be completely or partially hydrogenated and preferably more than 50 % of the unsaturated, hydrogenizable bondings are hydrogenated.

In a preferred embodiment the end-block portion (i.e., the "A-block") of the styrenic copolymer has a glass transition temperature Tg which is higher than the glass transition temperature of the mid-block portion (i.e., the "B-block"). Preferably, the glass transition temperature Tg of the A-block is from 0 to 200 °C, more preferably from 20 to 150 °C, most preferably from 30 to 120 °C. Glass transition measurement is achieved by ISO 11357-1, -2, -3. In a further preferred embodiment, the B-block of the styrenic copolymer has a glass transition temperature Tg less than about room temperature. Preferably, the Tg is in the range of -30 to 20 °C, preferably from -25 °C to 10 °C, as measured by ISO 11357-1, -2, -3.

The A- and B- blocks can be contained in the styrenic copolymer in a ratio of 5 : 95 to 95 : 5, preferably 10 : 90 to 40 : 60.

In an even more preferred embodiment, the A-B-A triblock copolymer is selected from styrene-ethylene-styrene (SES), styrene-butadiene-styrene (SBS), styrene-isoprene-styrene (SIS), styrene-ethylene/butylene-styrene (S-EB-S), styrene-ethylene/butylene/propylene- styrene (S-EBP-S), styrene-isoprene/butadiene-styrene (S-IB-S), or mixtures thereof. In this description the hyphen "-" is used for separating the A- from the B-blocks, whereas a slash "/" is used for separating individual monomers in case the B-block is obtained from more than one monomer.

For the A-B-A triblock copolymer, the polymer block B can be completely or partially hydrogenated and preferably more than 50 % of the unsaturated, hydrogenizable bondings are hydrogenated. The drug containing adhesive composition may further comprise from 1 to 95 wt.%, preferably from 5 to 55 wt.%, based on the total amount of the styrenic polymers contained in the drug containing adhesive composition, of a styrenic A-B diblock copolymer. In this embodiment, blocks A and B may be defined as above for the styrenic triblock copolymer. The styrenic diblock copolymer is preferably selected from styrene-ethylene (SE), styrene- butadiene (SB), styrene-isoprene (SI), styrene-ethylene/butadiene-styrene (SE-BS), styrene- ethylene/propylene (S-EP), or mixtures thereof.

For the A-B diblock copolymer, the polymer block B can be completely or partially hydrogenated and preferably more than 50 % of the unsaturated, hydrogenizable bondings are hydrogenated.

Preferably, the styrenic copolymer does not comprise any acrylic units. The styrenic polymer according to the present invention may be prepared by copolymerizing styrenic monomers (such as styrene monomers and derivatives thereof) and other commonly known co- monomers in an established manner, wherein the co-monomers preferably are no acrylic monomers, in particular no acrylic acid monomers, acrylate monomers, and derivatives thereof. In other words, the group of suitable co-monomers preferably is free of acrylic acid and acrylate monomers and derivatives thereof. In a preferred embodiment, the styrenic polymer of the invention has a weight average molecular weight of from 1,000 to 10,000,000, preferably from 5,000 to 2,000,000, most preferably from 10,000 to 500,000, as measured by gel permeation chromatography. It is preferred that the adhesive composition additionally comprises up to 20, preferably 3 to 8, parts by weight of a high molecular weight (i.e., viscosity of 1,000 to 1,000,000 cps as measured at 25 °C. at 20 % in toluene) diblock polymer of the general A-B configuration. In this diblock copolymer, the A- and B-blocks are generally as described above. While the adhesive composition preferably comprises a diblock polymer, the diblock may be replaced entirely or in part with another high molecular weight polymer such as polyisobutylene and/or polyisoprene. The high molecular weight polymer may be used in amounts of 1 to 15 wt.%, preferably 2 to 10 wt.% based on the total weight of the drug containing adhesive composition.

In a preferred embodiment the styrenic polymer comprises a hydrogenated styrene- isoprene/butadiene-styrene block copolymer (S-IB-S) and a hydrogenated styrene-isoprene block copolymer (SI). The styrenic polymer adhesive preferably comprises a tackifier as described in more detail below.

2. Polyisobutylene (PIBV The drug containing adhesive composition may comprise an adhesive in the form of a polyisobutylene or of a mixture of two, three or more different polyisobutylenes. The polyisobutylenes preferably are homopolymers. According to the present invention it is particularly preferred to employ mixtures of polyisobutylenes having a different molecular weight. These mixtures include mixtures of high molecular weight (HMW) PIB and low molecular weight (LMW) PIB. Such mixtures are known from the prior art, such as from WO 91/16085 Al being incorporated herein by reference. The weight average molecular weight of the HMW PIB preferably ranges from 500,000 to 2, 100,000, more preferably from 700,000 to 1,800,000, even more preferably from 990,000 to 1,600,000. The weight average molecular weight of the LMW PIB preferably ranges from 1,000 to 450,000, more preferably from 15,000 to 100,000, even more preferably from 35,000 to 50,000. The weight average molecular weight is measured by gel permeation chromatography. The weight ratio of HMW PIB to LMW PIB in the adhesive preferably is within a range of from 5-40:95-60, more preferably from 10- 25 :90-75, even more preferably from 10-20:90-80. The polyisobutylene adhesive preferably comprises a tackifier as described in more detail below. A preferred tackifier for PIB is a polybutene oil and/or a high Tg, low molecular weight aliphatic resin. Suitable polyisobutylene materials are commercially available from Henkel (such as Durotak® 87-608A, having a dynamic viscosity at 160°C of 143.5 Pa.s) or from Exxon Chemical under the trade name VISTANEX™.

Crosslinked polyvinyl pyrrolidone/Copolymer of vinyl pyrrolidone and vinyl acetate:

The adhesive composition contains as a further mandatory component a crosslinked polyvinyl pyrrolidone or a copolymer of vinyl pyrrolidone and vinyl acetate, or a mixture thereof.

Crosslinked polyvinyl pyrrolidones which may be used in the drug containing adhesive composition of the transdermal therapeutic system according to the present invention are insoluble polyvinyl pyrrolidones e.g. as commercially available under the trademark Kollidon®. The following terms are used as synonyms for the crosslinked polyvinyl pyrrolidones as used according to the present invention: crospovidone, crospovidonum, insoluble polyvinyl pyrrolidone, and crosslinked PVP. Insoluble polyvinyl pyrrolidones are generally prepared by popcorn polymerization of N- vinyl pyrrolidone which yields a crosslinked polymer. The process uses either an alkali hydroxide at temperatures over 100°C , which yields some bifunctional monomer, or a small percentage of bifunctional monomer in water to initiate crosslinking of the polymer. This process is generally known in the prior art. As the crosslinked polyvinyl pyrrolidones are completely insoluble in solvents, it is not possible to determine their molecular weight or the K-value. Therefore, the product differentiation is done mainly by the particle size distribution as measured e.g. in an air jet screen after 5 minutes at 20 mbar. A further characterizing feature of the crosslinked polyvinyl pyrrolidones is the specific surface area determined according to DIN 66131-132.

The following products are particularly preferred according to the present invention: Kollidon® CL, Kollidon® CL-F, Kollidon® CL-SF, and Kollidon® CL-M. Particularly preferred is Kollidon® CL-M. Copolymers of vinyl pyrrolidone (VP) and vinyl acetate (VA) which may be used in the drug containing adhesive composition of the transdermal therapeutic system according to the present invention are also commercially available under the trademark Kollidon®. The following terms are used as synonyms for the VP VA copolymers as used according to the present invention: copovidone, copovidonum, copolyvidone, copovidon. These copolymers are generally prepared by free-radical polymerization of N- vinyl pyrrolidone and vinyl acetate in isopropanol. This process is generally known in the prior art.

The copolymers as mentioned above usually have a weight average molecular weight Mw of 45,000 to 70,000, more preferably from 50,000 to 65,000, as measured by the light scattering method.

The molecular weight of the VP VA copolymers is usually expressed as the K-value. The copolymers used herein preferably have a K-value of 20 to 30, preferably from 25 to 30, most preferably around 28.

Kollidon® VA 64 being a copolymer of 6 parts of vinyl pyrrolidone and 4 parts vinyl acetate is particularly preferred according to the present invention. The crosslinked polyvinyl pyrrolidone or the copolymer of vinyl pyrrolidone and vinyl acetate is preferably present in the polyisobutylene containing adhesive composition of the invention in an amount of 1 to 30 % by weight, preferably from 10 to 25 % by weight and most preferably from 15 to 20 % by weight, based upon the total weight of the composition. The crosslinked polyvinyl pyrrolidone or the copolymer of vinyl pyrrolidone and vinyl acetate is preferably present in the styrenic polymer containing adhesive composition of the invention in an amount of 1 to 30 % by weight, preferably from 2 to 20 % by weight and most preferably from 5 to 10 % by weight, based upon the total weight of the composition. In case a mixture of the crosslinked polyvinyl pyrrolidone and the copolymer of vinyl pyrrolidone and vinyl acetate is used the mixing ratio (weight basis) ranges from 1 :20 to 20: 1, preferably from 1 : 10 to 10: 1, more preferably from 1 :5 to 5: 1, and most preferably from 1 :2 to 2: 1. According to the present invention also 1 : 1 mixtures of the crosslinked polyvinyl pyrrolidone and the copolymer of vinyl pyrrolidone and vinyl acetate are preferably comprised.

The inventors have surprisingly found that the crosslinked polyvinyl pyrrolidone and/or the copolymer of vinyl pyrrolidone and vinyl acetate distinctly increases the skin permeation rate of rotigotine after application of a TTS containing the adhesive composition according to the present invention. "Increase in skin permeation" means that the rate at which the active ingredient, i.e. rotigotine, passes through the skin including the Stratum corneum, the epidermis and the dermis is increased. In this way the active ingredient becomes systemically available. Thus, the systemic availability of rotigotine is improved according to the present invention.

It was further surprisingly found that the increase of skin permeation is very significant when using the crosslinked polyvinyl pyrrolidone (e.g. Kollidon® CL-M) in an amount of 15 to 25 % by weight, preferably of 18 to 22 % by weight, particularly together with a PIB adhesive. Moreover, it was surprisingly found that the increase of skin permeation is very significant when using the copolymer of vinyl pyrrolidone and vinyl acetate (e.g. Kollidon® VA 64) in an amount of 20 to 30 % by weight, preferably of 25 to 30 % by weight, particularly together with a styrenic polymer adhesive. Furthermore, it was surprisingly found that the increase of skin permeation is also very significant when using the crosslinked polyvinyl pyrrolidone (e.g. Kollidon® CL-M) in an amount of 5 to 10 % by weight, preferably of 5 to 8 % by weight, particularly together with a styrenic polymer adhesive.

Additives:

The adhesive composition according to the present invention may further comprise optional components (additives/excipients) selected from penetration and/or permeation enhancers, tackifiers, solubilizers, liquid diluents, antioxidants, or fillers, or mixtures thereof. 1. Penetration/permeation enhancers:

The drug containing adhesive composition of the subject invention may further comprise one or more penetration and/or permeation enhancer(s). Since the skin presents a substantial barrier to ingress of foreign substances into the body, the art has recognized that the barrier to the transdermal delivery of an active ingredient through the skin can be overcome or reduced by incorporating excipients into the carrier that enhance the rate at which the active ingredient, i.e., the drug, passes through the skin. "Penetration" means entering of the active ingredient into the outer layers of the skin, i.e. the Stratum corneum. The term "enhancement" or "penetration enhancement" means an increase in the permeability of the Stratum corneum to a drug. On the other hand, "permeation" as mentioned above is the passing of the drug through the skin in total including the epidermis and the dermis. Both "penetration enhancers" and "permeation enhancers" eventually increase the rate at which the drug penetrates through the membrane and accelerate drug delivery. The terms "penetration/permeation enhancer" relates to a substance or mixture of substances.

The additional penetration/permeation enhancers of the present invention include but are not limited to penetration/permeation enhancers selected from alkyl methyl sulfoxides, preferably decylmethyl sulfoxide, dimethyl sulfoxide; saturated fatty acids such as adipinic acid, caproic acid, caprylic acid, capric acid, myristic acid, lauric acid, stearic acid, palmitic acid, and alkyl esters thereof such as adipinic acid monoethylester; unsaturated fatty acids such as oleic acid, linoleic acid, linolenic acid, palmitoleic acid, and alkyl esters thereof, preferably oleyl oleate; saturated fatty alcohols such as myristyl alcohol, lauryl alcohol, stearyl alcohol, palmityl alcohol and cetyl alcohol; esters of saturated fatty alcohols such as lauryl lactate; unsaturated fatty alcohols such as oleyl alcohol, palmitoleyl alcohol, elaidyl alcohol, linoleyl alcohol and linolenyl alcohol; azocyclo-alkan-2-ones, preferably l-dodecylazacycloheptan-2-one; pyrrolidones such as 2-pyrrolidone, alkyl-2-pyrrolidone and N-methylpyrrolidone; glycols such as propylene glycol, polyethylene glycols, glycerol, dipropylene glycol, tripropylene glycol, diethylene glycol and triethylene glycol; alcohols, preferably ethanol, isopropyl alcohol, cyclohexanol; diethyltoluamide; tetrahydrofurfuryl alcohol; dimethyl formamide; dimethyl acetamide; 2,2,2-trichloroethanol; 2,2,2-trifluoroethanol; urea; salicylic acid; ethylene glycol monomethyl ether; Ν,Ν-dialkylhydroxylamine; 1,2-isopropylidene glycerol; Ν,Ν-dialkylnicotinamide; alkylaminooxide; hyaluronidase; isopropyl myristate; saccharose monooleate; lecithins; non-ionic surfactants; cholic acid; (medium chain) triglycerides such as caprylic/capric acid triglycerides (e.g. tradename Myritol 318); and derivatives thereof.

Preferred penetration/permeation enhancers are alkylic fatty acid esters of saturated and/or unsaturated fatty acids, each containing from 8-18 carbon atoms or long chain (C10 to C30) aliphatic alcohols. Particularly preferred is octyldodecanol, most preferred 2-octyldodecanol. The additional penetration/permeation enhancer is contained in the drug containing adhesive composition in an amount of 1 to 15 % by weight, preferably 3 to 10 % by weight, more preferably 3 to 7 % by weight, based upon the total weight of the drug containing adhesive composition.

2. Liquid diluent:

The drug containing adhesive composition may further comprise one or more of a liquid diluent. The liquid diluent may have the function of a plasticizer for reducing the glass transition temperature (Tg) of the adhesive polymers in particular of the mid-block polymer (B-block), if present. For example, these components may associate with the B-blocks described above by swelling it, which generally results in a change, preferably in a decrease in the Tg thereof. In a preferred embodiment, the liquid diluent is an oil component such as mineral oil, preferably paraffinic mineral oil, naphthenic mineral oil, aromatic mineral oil, synthetic liquid oligomers of polybutene, polypropene and polyterpene, isoparaffin oil, paraffin oil, or mixtures thereof. Most preferably, the liquid diluent is white petroleum mineral oil. In the context of the present invention the term mineral oil such as white mineral oil also includes a technical grade mineral oil. Thus, the mineral oil may include small amounts of other chemicals. In a preferred embodiment, the purity of the mineral oil of the present invention is more than 90 %, preferably more then 95 %, even more preferably more than 98 %, most preferably more than 99 %, based on the total weight of the mineral oil. A mineral oil of the present invention can be a mixture of liquid hydrocarbons. Mineral oils are generally obtained by refining crude petroleum oil. A mineral oil can comprise saturated hydrocarbons such as alkanes or unsaturated hydrocarbons such as alkenes or aromatic hydrocarbons. Preferably, the mineral oil comprises saturated hydrocarbons such as alkanes having 10 to 50, preferably 20 to 40 carbon atoms. Hydrocarbons include linear, branched or cyclic hydrocarbons.

A mineral oil of the present invention can have one or more of the physical properties such as a kinematic viscosity at 100 °C of 2 to 50 mm2/s, preferably 5 to 30 mm2/s as measured with a glass capillary viscometer, a specific gravity of 0.8 to 0.95, preferably of 0.82 to 0.9 and a boiling point of 200 to 400 °C, preferably of 250 to 350 °C

The liquid diluent is generally contained in the adhesive composition in an amount of less than 60 wt.%, preferably 15 to 50 % by weight, based on the total amount of the drug containing adhesive composition.

3. Tackifier: The drug containing adhesive composition may further comprise one or more of a tackifier. Such tackifiers increase the adhesiveness of the adhesive layer.

Tackifiers which may be used in the drug containing adhesive composition according to the present invention include but are not limited to any compatible resins or mixtures thereof such as (1) natural or modified rosins, such as gum rosin, wood rosin, tall-oil rosin, distilled rosin, hydrogenated rosin, dimerized rosin, and polymerized rosin; (2) glycerol and pentaerythritol esters of natural or modified rosins, such as the glycerol ester of pale, wood rosin, the glycerol ester of hydrogenated rosin, the glycerol ester of polymerized rosin, the pentaerythritol ester of hydrogenated rosin, and the phenolic-modified pentaerythritol ester of rosin; (3) copolymers and terpolymers of natural terpenes, e.g., styrene/terpene and alpha methyl styrene/terpene; (4) polyterpene resins having a softening point, as determined by ASTM method E28,58T, of 80 to 150 °C; the latter polyterpene resins generally resulting from the polymerization of terpene hydrocarbons, such as the bicyclic monoterpene known as pinene, in the presence of Friedel-Crafts catalysts at moderately low temperatures; also included are the hydrogenated polyterpene resins; (5) phenolic modified terpene resins and hydrogenated derivatives thereof, for example the resin product resulting from the condensation, in an acidic medium, of a bicyclic terpene and phenol; (6) aliphatic petroleum hydrocarbon resins having a Ball and Ring softening point of 70 to 135 °C; the latter resins resulting from the polymerization of monomers consisting of primarily of olefins and diolefins; also included are the hydrogenated aliphatic petroleum hydrocarbon resins; (7) alicyclic petroleum hydrocarbon resins and the hydrogenated derivatives thereof; (8) aliphatic/aromatic or cycloaliphatic/aromatic copolymers and their hydrogenated derivatives; and (9) styrene resins such as styrene-alpha-m ethyl styrene resin; or mixtures thereof. Preferred tackifiers include but are not limited to tackifiers selected from polybutenes; polysiloxanes; elastomeric and polymeric resins; terpene-based esters such as from β-pines; aromatic, aliphatic and alkylaromatic resins; melamine formaldehyde resins; phenolic resins; hydroabietyl alcohol; synthetic resins; wood resins, preferably collophonium resin; or mixtures thereof.

In a further preferred embodiment, the tackifier is a resin, preferably selected from hydrogenated collophonium resin, styrene resin, hydrogenated petroleum hydrocarbon resin or a mixture thereof. The most preferred tackifier is a synthetic resin or wood resin such as collophonium ester, which can be hydrogenated. Hydrogenated collophonium resin is commercially available under the trademark Foral®.

The one or more tackifier(s) are preferably contained in the drug containing adhesive composition in an amount of 10 to 70 % by weight, preferably 25 to 65 % by weight, more preferably 40 to 55 % by weight, based upon the total weight of the drug containing adhesive composition.

4. Solubilizer: The drug containing adhesive composition may thus comprise constituents such as solubilizers. Typically, the function of the solubilizer is such that it acts as a crystallization inhibitor and/or that it increases the mechanical stability of the transdermal therapeutic system. Such solubilizers further increase the solubility of the pharmaceutically active agent in the drug containing adhesive composition.

The solubilizer might be present in the drug containing adhesive composition in an amount of 1 to 30 % by weight, preferably 3 to 15 % by weight, more preferably 5 to 15 % by weight based upon the total weight of the composition. Solubilizers which may be used in the drug containing adhesive composition of the transdermal therapeutic system according to the present invention include but are not limited to soluble polyvinyl pyrrolidones as commercially available under the trademark Kollidon®. A soluble polyvinyl pyrrolidone is generally obtained by radical polymerization of N-vinyl pyrrolidone. Soluble polyvinyl pyrrolidone is also known as povidon(e), povidonum, polyvidone, poly(l-vinyl-2-pyrrolidone) and PVP (such as Kollidon 90 F).

The soluble polyvinyl pyrrolidones as mentioned above are non-crosslinked polyvinyl pyrrolidone homopolymers having a weight average molecular weight Mw of 1,000 to 3,000,000, more preferably from 100,000 to 2,000,000, most preferably from 1,000,000 to 1,500,000 as measured by gel permeation chromatography.

The molecular weight of polyvinyl pyrrolidone (povidone) is usually expressed as the K- value. The polyvinyl pyrrolidone used herein preferably has a K-value of 10 to 100, most preferably from 80 to 95.

Further examples of such solubilizers include, but are not limited to, cyclodextrins and cyclodextrin derivatives such as substituted cyclodextrins; 2-(2-ethoxyethoxy)ethanol, urea, methyl 2-methylprop-2-enoate, neohesperidine, alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, octyldecanol, octyldodecanol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol; hydroxypropyl methylcellulose and other cellulose derivatives; ethers of polyethylene glycols (PEG) having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides such as 2- pyrrolidone, 2-piperidone, s-caprolactam, N-alkylpyrrolidone, N-hydroxyalkyl pyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinyl pyrrolidone (such as Kollidon 90 F); esters, such as ethyl propionate, tributyl citrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ- valerolactone and isomers thereof, p-butyrolactone and isomers thereof; and other solubilizers known in the art, such as Eudragit® E100, dimethyl acetamide, dimethyl isosorbide, N- methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water. Mixtures of solubilizers are also within the scope of the invention.

Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, glycofurol, diethylene glycol monoethyl ether, propylene glycol, and dimethyl isosorbide.

Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, polyethylene glycol, glycofurol, and propylene glycol.

5. Fillers:

The drug containing adhesive composition may also further comprise fillers. Fillers which may be used in the drug containing adhesive composition according to the present invention include but are not limited to silicon dioxide, metal oxides such as titanium dioxide or zinc dioxide, talc, silicates such as magnesium silicate or aluminium silicate, stearates, such as zinc stearate, or mixtures thereof. Fillers may be contained in the drug containing adhesive composition in an amount from 0 to 30 wt.%, preferably from 5 to 20 % by weight, based on the total weight of the drug containing adhesive composition.

6. Antioxidants:

The drug containing adhesive composition may further comprise one or more of an antioxidant which may be selected from a-tocopherol, sodium metabi sulfite, and ascorbylpalmitate. Further suitable antioxidants are hindered phenols such as 1,3,5-trimethyl 2,4,6-tris (3,5-di-tert-butyl-4-hydroxybenzyl) benzene; butylhydroxy toluene; pentaerythrityl tetrakis-3(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate; pentaerythrityl-3(3,5-di(l, 1- dimethylethyl)-4-hydroxyphenyl)-propionate (Irganox 1010FF); 4,4'-methylenebis (2,6-tert- butylphenol); 4,4'-thiobis (6-tert-butyl-o-cresol); 2,6-di-tert-butylphenol; 6-(4-hydroxy- phenoxy)-2,4-bis(n-octylthio)-l,2,5-triazine; di-n-octadecyl 3,5-di-tert-butyl-4-hydroxy- benzyl phosphonate; tris(2,4-di-tert-butylphenyl)phosphite (Irgafos 168); 2-(n-octylthio)ethyl 3,5-di-tert-butyl-4-hydroxybenzoate; and sorbitol hexa[3-(3,5-di-tert-butyl-4-hydroxyphenyl)- propionate], or mixtures thereof. Preferred antioxidants are a-tocopherol, sodium metabi sulfite, ascorbylpalmitate, and mixtures thereof.

The one or more antioxidants are typically comprised in the drug containing adhesive composition in an amount up to 5 wt.%, preferably from 0.001 to 2 % by weight more preferably from 0.01 to 0.1 % by weight, based on the total weight of the drug containing adhesive composition.

Further optional ingredients which may be present in the composition of the present invention are oxygen or humidity absorbers, crystallisation inhibitors, emollients, anti -irritants, opacifiers, as well as other components that are commonly formulated as additives into a drug containing adhesive composition. These components are generally known to the skilled person. Transdermal therapeutic systems (TTS):

A transdermal therapeutic system according to the present invention typically comprises a backing layer, at least one adhesive layer (also referred herein as drug containing adhesive layer) and a release liner. The at least one drug containing adhesive layer(s) is formed from the drug containing adhesive composition described above and thus comprises or consists of the drug containing adhesive composition. In a preferred embodiment, the drug containing adhesive layer consists of the drug containing adhesive composition. The transdermal therapeutic systems of the present invention are often referred to as matrix-controlled transdermal therapeutic systems or matrix TTS.

The TTS of the present invention typically comprises a backing layer, which usually is impermeable for the pharmaceutically active agent. The TTS of the present invention may further comprise one or more additional drug containing adhesive layers. The TTS may further comprise one or more further adhesive layers, which do not contain an active ingredient, i.e. rotigotine at all. All embodiments described above for the drug containing adhesive composition also apply for adhesive compositions, which are used for forming the further adhesive layer(s). The weight percentages are then to be based on the composition containing all ingredients except the drug, i.e. rotigotine. The adhesive layer(s) thus may form one or more separate layers or be part of the drug containing layer(s). On the side, which is opposite to the backing layer the TTS generally comprises a release liner such as a peelable release liner.

Preferably, the drug containing adhesive layer is, on one side, affixed to the backing layer, and, on another side, to the release liner thus providing for a multi-layered design. Backing layer:

The backing layer is typically impermeable to the drug or other excipients. The backing layer is thus generally made of a material that is impermeable to the pharmaceutically active agent and other excipients of the adhesive (matrix) layer. The backing layer serves as a protective cover for the matrix layer and provides a support function. The backing layer can be formed so that it is essentially the same size as the matrix layer containing the pharmaceutically active agent. The backing layer can be of any appropriate thickness that will provide the desired protective and support functions. A suitable thickness is from about 5 μιη to about 300 μπι. More specifically, the thickness is less than about 150 μπι, yet more specifically, it is less than about 100 μπι, and most specifically, the thickness is less than about 50 μπι. The thickness is further preferably more than 5 μπι, more preferably more than 10 μπι. Examples of materials suitable for making the backing layer are films of acrylate, acrylonitrile-butadiene-styrene, acrylonitrile (methyl methacrylate) copolymer, acrylonitrile copolymer, ethylene ethyl acrylate, ethylene methyl acrylate, ethylene vinyl acetate, ethylene vinyl acetate copolymer, ethylene vinyl alcohol polymer, ionomers, nylon (polyamide), nylon (polyamide) copolymer, polybutylene, polycarbonate, polyester, polyethylene terephthalate (PET), thermoplastic polyester copolymer, polyethylene copolymer (high density), polyethylene (high-molecular-weight, high density), polyethylene (intermediate-molecular weight, high density), polyethylene (linear, low density), polyethylene (low density), polyethylene (medium density), polyethylene oxide, polyimide, polypropylene, polypropylene (coated), polypropylene (oriented), polystyrene, polyurethane, polyvinyl acetate, polyvinyl chloride, polyvinylidene chloride and/or styrene-acrylonitrile. It is within the present invention that such films may be metallised or pigmented.

Preferred materials for the manufacture of the backing layer are polyurethane, ethylene vinyl alcohol polymer and polyester, most preferably polyethylene terephthalate (PET).

In a preferred embodiment the backing layer has a tensile strength in the longitudinal and in the cross direction of 100 to 500 N/mm2, preferably of 200 to 300 N/mm2, most preferably of 220 to 280 N/mm2 as measured by ISO 527-1 and 527-3 using test piece type 2, test speed 100%/min; 23 °C, 50 % rel. humidity. In a further preferred embodiment the backing layer has an elongation at break in the longitudinal direction of 100 to 200 %, preferably of 105 to 150 %, and in the cross direction of 100 to 120 %, most preferably of about 100 % as measured by ISO 527-1 and 527-3 using test piece type 2, test speed 100%/min; 23 °C, 50 % rel. humidity.

In a further preferred embodiment the backing layer has an elasticity modulus in the longitudinal and in the cross direction of 2,000 to 10,000 N/mm2, preferably of 4,000 to 6,000 N/mm2 as measured by ISO 527-1 and 527-3 using test piece type 2, test speed 100%/min; 23 °C, 50 % rel. humidity.

Moreover, the backing layer preferably provides gas barrier properties as determined with a layer of 12 μιη thickness. For air the gas barrier is preferably 20 to 100, more preferably of 40 to 80 cm3/m2*d*bar as measured by DIN 53380 at 23 °C, 0 % rel. humidity. For oxygen the gas barrier is preferably 50 to 150, more preferably of 80 to 130 cm3/m2*d*bar as measured by DIN 53380 at 23 °C, 50 % rel. humidity. For water vapour the gas barrier is preferably 5 to 150, more preferably of 10 to 250 g/m2*d as measured by DIN 53122 at 23 °C, 85 % rel. humidity. For nitrogen the gas barrier is preferably 10 to 100, more preferably of 20 to 45 cm3/m2*d*bar as measured by DIN 53380 at 23 °C, 0 % rel. humidity. For carbon dioxide the gas barrier is preferably 100 to 5000, more preferably of 250 to 750 cm3/m2*d*bar as measured by DIN 53380 at 23 °C, 0 % rel. humidity.

Release liner: The release liner, which preferably is a peelable release liner, is to protect the adhesive, which mediates the attachment of the transdermal therapeutic system to the subject or patient to which the TTS is applied. The release liner is thus to be removed from the transdermal delivery system prior to the application to the subject. Release liners can be formed of polyester, polyethylene, polypropylene, polysiloxane, e.g. with a fluorosiliconized coating, polyacrylate, ethylene vinyl acetate, polyurethane, polyisobutene or paper. Preferably the paper is coated with silicone and/or polyethylene. In an embodiment, a foil consisting of polyethylene terephthalate (PET) is used, whereby, preferably, one side of such foil is siliconized. Typically, the thickness of such release liner is from 50 to 120 μπι, preferably from 60 to 100 μιη. Also a combination of any of the above materials may be used in the preparation of the release liner. The release liner preferably also comprises an adhesive, which may be one as defined herein. Moreover, the release liner can be made from the same material as the backing layer. In this embodiment the features described above for the backing layer equally apply for the release liner.

Coverpatch:

In a further embodiment of the invention the TTS additionally comprises a coverpatch being either integrated in or separated from the TTS. It has the function to additionally fix the TTS on the subject to which it is applied. The coverpatch can be made from the same material as the backing layer or release liner. In this embodiment the features described above for the backing layer/release liner equally apply for the coverpatch. In order to properly fix the coverpatch (and consequently also the TTS per se) adhesive materials generally known in the prior art can be employed.

Pouch:

The TTS of the present invention may be packed in a pouch (also named as sachet) generally known in the prior art. Preferably, the pouch contains an inlay for accommodating various additives such as oxygen or humidity absorbers, antioxidants, or mixtures thereof. More preferably, all additives necessary to improve the stability of the TTS, such as oxygen or humidity absorbers, antioxidants, etc., are contained in the inlay only, i.e. separate from the drug containing adhesive composition, in order to avoid any contact with the skin of the patient after having applied the TTS. This embodiment of the invention is particularly suitable for patients having skin sensitive against the additives mentioned. Manufacture:

The TTS according to the present invention is prepared using the solvent process rather than a hotmelt process. The solvent process has several advantages such as its gentle temperature conditions which allow the incorporation of even thermolabile and/or oxidation sensitive compounds into the adhesive matrix. Moreover, the various components of the adhesive composition having different characteristics (such as solubility) may be solved in suitable solvents before mixing which allows the preparation of the adhesive composition in a highly flexible manner. Moreover, it also allows a crystal-free preparation as the components (in particular the drug) is solved in a suitable solvent before mixing it with the other components.

Thus, the TTS may be manufactured by preparing a solution or dispersion of the ingredients as described above, coating the solution or dispersion on the release liner, drying the coating to form the adhesive layer, and then optionally laminating the adhesive layer with a backing layer. The features as described above for the transdermal therapeutic system and the drug containing adhesive composition also apply for the manufacture of a TTS according to the present invention.

In the method of manufacture according to the present invention, the drug containing adhesive composition forming the drug containing adhesive layer is generally prepared in a first step by mixing a pressure sensitive adhesive (PSA) selected from the group consisting of a styrenic polymer, polyisobutylene, or mixtures thereof, rotigotine or a pharmaceutically acceptable salt thereof, and at least one crosslinked polyvinylpyrrolidone or at least one copolymer of vinylpyrrolidone and vinyl acetate, or a mixture thereof, optionally together with further additives in an appropriate solvent or solvent mixture. The ingredients are mixed, for example by mechanically stirring the mixture. Stirring is preferably achieved until the active ingredient is completely solved and the mixture has become homogeneous under visual inspection.

Suitable solvents include, but are not limited to, organic solvents such as ethanol, ethyl acetate, 2-propanol, heptane, hexane, isopropyl alcohol, methanol, toluene, 2,4-pentandion and mixtures thereof. The drug containing solution or dispersion (in the following abbreviated as solution/dispersion) is typically mixed at a temperature between 20 °C and 25 °C. Homogenization can be achieved by using a stirrer. In a further embodiment rotigotine and at least one crosslinked polyvinyl pyrrolidone or at least one copolymer of vinyl pyrrolidone and vinyl acetate, or a mixture thereof, are added to a suitable solvent and mixed to form a first solution/dispersion. Optional excipients such as antioxidants are then added to the first solution/dispersion. A second solution/ dispersion comprising the adhesive polymer is then added to the first solution/dispersion. The thus obtained mixture of the first and second solution/dispersion is then further homogenized until the adhesive polymer and preferably all ingredients are solved to form a solution.

The solution or dispersion is then preferably coated on a release liner. Preferably, the solution/dispersion is applied to a siliconized side of a release liner. Such a release liner e.g. consists of a transparent foil such as a PET-foil as explained above. The coating is dried to remove the solvent partially or completely, preferably the solvent is removed completely, and to form the drug containing adhesive layer. In a further embodiment, in a first step the release liner or the backing layer is first coated with one or more adhesive layers being free of active ingredient, i.e. rotigotine. In a second step the backing layer or release liner (i.e. the one not being used in the first step) is coated with one or more adhesive layers according to the present invention containing the active ingredient, i.e. rotigotine. Subsequently the coated layers of the first and second steps are combined by lamination. The transdermal patches are subsequently punched from the thus obtained layered product.

In a still further embodiment, the release liner is first coated with one or more adhesive layers, which do not contain an active ingredient, wherein the one or more adhesive layers are then coated with the drug containing adhesive layer of the invention.

The dried adhesive layer(s) are then supplied with a backing layer on the side, which is opposite to the release liner. Alternatively, the drug containing homogenous solution is applied to a film, which acts as a backing layer e.g. a PET film such as Hostaphan® RN 19 is used as the backing layer, preferably a drug impermeable backing layer. The thus one-side coated backing layer is then usually dried as described above. Upon drying, the drug containing adhesive layer is formed from the drug containing adhesive composition. The dried adhesive layer is then supplied with a release liner. The transdermal patches are subsequently punched from the thus obtained layered product.

The invention thus further refers to the transdermal therapeutic system obtainable by the above described methods of manufacture. All preferred embodiments and features as described above for the transdermal therapeutic system of the present invention thus also apply for the methods of manufacture of the TTS as described herein and the TTS obtainable by these methods. The TTS of the present invention preferably is 1 to 200 cm2 in size, more preferably 5 to 70 cm2. The coating weight of the drug containing adhesive layer per unit area is typically between 30 and 150 g/m2, preferably between 40 and 100 g/m2, most preferably 50 to 80 g/m2. In a preferred embodiment, the transdermal therapeutic system comprises an adhesive layer containing an amount of rotigotine sufficient to maintain a constant release of the rotigotine or rotigotine analogue through the skin of a patient for the entire period of use of the TTS.

The transdermal therapeutic system of the invention provides delivery of rotigotine to a patient in need of the active ingredient. On administration over skin the TTS generally exhibits a steady state drug flux of 0.1 to 20 g/cm2/h, preferably 2 to 15 g/cm2/h and more preferably 5 to 10 g/cm2/h.

Preferably, the flux remains constant for period of at least 24 h, more preferably for at least 72 h, most preferably for at least 96 h. In addition, the rotigotine flux generally should remain constant up to 120 h, more preferably for up to 144 h, most preferably up to 168 h. It is particularly preferred that the transdermal rotigotine flux is between 0.8 to 10 μg/cm2/h for at least 72 h. Rotigotine is preferably released to the patient to achieve a constant blood plasma level for the entire period of administration, which generally is more then 24 hours, preferably more then 72h. The TTS of the invention may be used to achieve a constant blood plasma level of rotigotine up to 4 days, preferably up to 7 days.

The transdermal therapeutic system is used for treating dopamine-related disorders such Parkinson's Disease. The invention will be described further in the following examples, which are included for purposes of illustrating the invention and are not intended, in any way, to be limiting of the scope of invention. EXAMPLES

Example 1: Manufacture of a transdermal therapeutic system

The components as indicated in the following table were used:

Figure imgf000029_0001

In a stirred vessel, rotigotine and crospovidone were dissolved in a mixture of ethanol, ethyl acetate, and n-heptane as solvents. Subsequently the antioxidants (alpha tocopherol, sodium metabisulfite and ascorbylpalmitate) and then the PSA (PIB- Durotak®) were added. The mixture was stirred for about 1 h and controlled visually, whether all solids were solved. The solution was then coated on a transparent polyester foil, which served as a release liner. The solvents were removed by drying with heated air, which was streamed over the wet coating. The adhesive coating was then covered with a polyester foil (PET) of a thickness of 15 μπι. An area of 10 cm2 was then punched out by appropriate cutting tools. The edges between distinct systems were removed. Subsequently it was packed into pouches with a separate enclosed drying agent.

Stability: The stability was determined by visual inspection based on the amount of rotigotine crystals in the matrix of the TTS after different storage times and temperatures. The results are summarized in the table below. Storage time Storage conditions Crystals in the matrix [%]

0 months 2 - 8 °C, refrigerator 0

3 months 5 °C / 65 % relative humidity 0

3 months 25°C/ 60 % relative humidity 0

3 months 40 °C/ 75 °C relative humidity 0

4 months 40 °C/75 °C relative humidity 0

6 months 5 °C / 65 % relative humidity 0

6 months 25°C/ 60 % relative humidity 0

The TTS according to the invention does not show any rotigotine crystals in the matrix giving evidence for the improved stability.

Example 2:

The same procedure as in Example 1 was carried out, however, the amount of crospovidone (Kollidon CL-M) was varied to 0 % by weight (comparative), 15 % by weight and 25 % by weight, while at the same time amending the amount of PSA so as to adapt the composition to 100 % by weight.

Example 3:

The components as indicated in the following table were used:

Figure imgf000030_0001
In a stirred vessel, rotigotine, crospovidone and octyldodecanol are dissolved in ethanol, ethyl acetate, and n-heptane as solvents. Further steps are as described in Example 1.

Stability:

The stability was determined as in Example 1 by visual inspection based on the amount of rotigotine crystals in the matrix of the TTS after different storage times and temperatures. The results are summarized in the table below.

Figure imgf000031_0001

The TTS according to the invention does not show any rotigotine crystals in the matrix giving evidence for the improved stability.

Example 4:

The components as indicated in the following table were used:

Figure imgf000031_0002
In a stirred vessel, rotigotine and Kollidon VA 64 are dissolved in ethanol, ethyl acetate, and n-heptane as solvents. Further steps are as described in Example 1.

Stability:

The stability was determined as in Example 1 by visual inspection based on the amount of rotigotine crystals in the matrix of the TTS after different storage times and temperatures. The results are summarized in the table below.

Figure imgf000032_0001

The TTS according to the invention does not show any rotigotine crystals in the matrix giving evidence for the improved stability.

The same procedure as described above was carried out except that 0% by weight of Kollidon VA 64 was used (comparative), while at the same time amending the amount of PSA so as to adapt the composition to 100 % by weight.

Example 5: The components as indicated in the following table were used:

Figure imgf000032_0002

The procedure was carried out as described in Example 1. The same procedure as described above was carried out, however, the amount of crospovidone (Kollidon CL-M) was varied to 0 % by weight (comparative), while at the same time amending the amount of PSA so as to adapt the composition to 100 % by weight.

Example 6: Evaluation of rotigotine skin permeation

The in vitro skin permeation of rotigotine through skin (human or pig split skin) was evaluated using the TTS as prepared in any one of Examples 1, 2, 4, and 5.

The flux was determined by using a two-compartment diffusion cell with a section of human or pig epidermis mounted between the cell halves. A TTS was adhered to one side of the skin and a drug-receiving medium was placed on the receptor-side of the cell. The apparatus was placed in a water bath maintained at 32±1 °C. Samples of the receptor medium were collected over a period of 48 hours for HPLC analysis of drug concentration.

It can be seen by Figure 1 (Examples 1 and 2) that the TTS according to the invention with PIB as PSA increased rotigotine in vitro skin flux compared to the reference TTS containing no crosslinked polyvinyl pyrrolidone (crospovidone). Moreover, it becomes evident that the highest flux values are achieved when using 20 % by weight of crosslinked polyvinyl pyrrolidone.

Moreover, it can be seen by Figure 2 (Example 4) that the TTS according to the invention with styrenic polymer as PSA increased rotigotine in vitro skin flux compared to the reference TTS containing no polyvinyl pyrrolidone (Kollidon VA 64).

Finally, it can be seen by Figure 3 (Example 5) that the TTS according to the invention with styrenic polymer as PSA increased rotigotine in vitro skin flux compared to the reference TTS containing no crosslinked polyvinyl pyrrolidone (crospovidone). Example 7: Peel adhesion test

A peel adhesion test was carried out with the TTS of Example 5 using the PSTC test method as described in Test Methods of Pressure Sensitive Tapes, 14th ed. Northbrook, IL: Pressure Sensitive Tape Council; 2004, pages 101.1-101.10.

As reference materials a Neupro patch (commercially available from Schwarz Pharma/UCB; indicated herein after as "state of the art") using a silicone adhesive and a soluble PVP, and two patches containing an acrylate adhesive and crosslinked PVP (5 % and 20 % by weight of Kollidon CL-M, respectively) were used. The two acrylate patches apart from the acrylate PSA instead of the styrenic rubber contained the same adhesive composition as Example 5.

It can be seen by Figure 4 that the TTS according to the invention (Example 5) provides for an increased peel force/peel strength as compared to the silicone containing patches (Neupro patch) and to acrylate containing patches.

In summary, the invention provides a transdermal system having one or more of the benefits of

(1) a long lasting (one day or more) and continuous release of active ingredient, (2) increased skin permeability,

(3) good tolerability by the skin over the entire period of use,

(4) high stability in storage (no rotigotine crystals in the matrix),

(5) good comfort even after the entire period of use,

(6) inexpensive production with a highly reproducibly quality,

(7) the dosage can be adjusted by simply varying the size of the skin-contact area, (8) high mechanical stability due to the homogeneous structure of the system, and (9) high peel force/strength.

Claims

Claims
1. An adhesive composition comprising
i. a pressure sensitive adhesive (PSA) selected from at least one styrenic polymer, or at least one polyisobutylene, or mixtures thereof,
ii. rotigotine or a pharmaceutically acceptable salt thereof,
iii. at least one crosslinked polyvinyl pyrrolidone or at least one copolymer of vinyl pyrrolidone and vinyl acetate, or a mixture thereof.
2. The adhesive composition according to claim 1, wherein the pressure sensitive adhesive has a dynamic viscosity at 160°C of more than 100 Pa.s.
3. The adhesive composition according to claim 1 and/or claim 2, wherein the weight average molecular weight of the styrenic polymer is from 1,000 to 10,000,000, preferably from 5,000 to 2,000,000, most preferably from 10,000 to 500,000, and/or the weight average molecular weight of polyisobutylene is from 1,000 to 2, 100,000, more preferably from 15,000 to 1,800,000, even more preferably from 35,000 to 1,600,000, as measured by gel permeation chromatography.
4. The adhesive composition according to any one of claims 1 to 3, wherein the crosslinked polyvinyl pyrrolidone is selected from Kollidon® CL, Kollidon® CL-F, Kollidon® CL-SF, and Kollidon® CL-M, and/or the copolymer of vinyl pyrrolidone and vinyl acetate is Kollidon® VA 64.
5. The adhesive composition according to any one of claims 1 to 4, comprising rotigotine or a pharmaceutically acceptable salt thereof in an amount of 1 to 30 % by weight, based upon the total weight of the composition.
6. The adhesive composition according to any one of claims 1 to 5, comprising the crosslinked polyvinyl pyrrolidone and/or the copolymer of vinyl pyrrolidone and vinyl acetate in an amount of 1 to 30 % by weight, based upon the total weight of the composition.
7. The adhesive composition according to any one of claims 1 to 5, comprising the pressure sensitive adhesive in an amount of from 40 to 98% by weight, based upon the total weight of the composition.
8. The adhesive composition according to any one of claims 1 to 7, further comprising a penetration and/or permeation enhancer, tackifier, solubilizer, liquid diluent, antioxidant, filler, oxygen or humidity absorber, crystallisation inhibitor, emollient, anti-irritant, opacifier, or mixtures thereof.
9. The adhesive composition according to any one of claims 1 to 8, which consists of the pressure sensitive adhesive in an amount of from 40 to 98% by weight, rotigotine or a pharmaceutically acceptable salt thereof in an amount of 1 to 30 % by weight, the crosslinked polyvinyl pyrrolidone and/or the copolymer of vinyl pyrrolidone and vinyl acetate in an amount of in total 1 to 30 % by weight, and preferably of one or more antioxidants in an amount of from 0.001 to 2% by weight and additional penetration and/or permeation enhancer in an amount of from 1 to 15% by weight, each based upon the total weight of the composition.
10. A transdermal therapeutic system comprising
a) at least one adhesive layer made of the adhesive composition as defined in any one of claims 1 to 9, and
b) optionally, a backing layer,
c) further optionally, a release liner, and
d) further optionally, a coverpatch being either integrated in or separated from the transdermal therapeutic system.
11. The transdermal therapeutic system according to claim 10, comprising at least one additional adhesive layer.
12. A method of producing a transdermal therapeutic system comprising a backing layer, at least one adhesive layer and a release liner, comprising the steps of
1) preparing a solution comprising i) rotigotine or a pharmaceutically acceptable salt thereof, ii) at least one crosslinked polyvinyl pyrrolidone or at least one copolymer of vinyl pyrrolidone and vinyl acetate, or a mixture thereof,
iii) a pressure sensitive adhesive (PSA) selected from at least one styrenic polymer, or at least one polyisobutylene, or mixtures thereof, iv) solvent, and
v) optionally, one or more of a penetration and/or permeation enhancer, tackifier, solubilizer, liquid diluent, antioxidant, filler, oxygen or humidity absorber, crystallisation inhibitor, emollient, anti-irritant, opacifier, or mixtures thereof,
2) coating the solution on the release liner or on the backing layer,
3) drying the coating to form the at least one adhesive layer, and
4) laminating the at least one adhesive layer with the release liner or the backing layer.
13. The method according to claim 12, wherein the solution is coated onto the release liner, and the obtained adhesive layer is laminated with the backing layer.
14. A transdermal therapeutic system obtainable by the method of claim 12 or 13.
15. A pouch comprising the transdermal therapeutic system according to any one of claims 9, 10 or 14 and an inlay, which inlay preferably contains an oxygen or humidity absorber, antioxidant, or a mixture thereof.
PCT/EP2011/073435 2010-12-22 2011-12-20 Adhesive composition containing rotigotine and transdermal therapeutic system comprising the adhesive composition WO2012084969A1 (en)

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WO2015177204A1 (en) * 2014-05-20 2015-11-26 Lts Lohmann Therapie-Systeme Ag Transdermal delivery system containing rotigotine
WO2015177209A1 (en) * 2014-05-20 2015-11-26 Lts Lohmann Therapie-Systeme Ag Method for adjusting the release of active agent in a transdermal delivery system
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US10179096B2 (en) 2001-05-01 2019-01-15 Corium International, Inc. Hydrogel compositions for tooth whitening
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US10300025B2 (en) 2016-07-27 2019-05-28 Corium, Inc. Donepezil transdermal delivery system
US10307379B2 (en) 2016-07-27 2019-06-04 Corium, Inc. Donepezil transdermal delivery system
WO2018143384A1 (en) * 2017-02-03 2018-08-09 コスメディ製薬株式会社 Rotigotine-containing percutaneous absorption type patch

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