EP3697394A1

EP3697394A1 - Transdermal delivery system containing a dopamine agonist

Info

Publication number: EP3697394A1
Application number: EP18792907.0A
Authority: EP
Inventors: Stefanie RODLER; Sonja GRASSER
Original assignee: AMW GmbH
Current assignee: AMW GmbH
Priority date: 2017-10-20
Filing date: 2018-10-19
Publication date: 2020-08-26
Also published as: US20210145761A1; WO2019077116A1; DE102017124627A1

Abstract

The invention relates to a transdermal delivery system (TDS) comprising at least one dopamine agonist, said at least one dopamine agonist being in a matrix containing at least one polymer from the class of polybutylenes. The invention further relates to a process for manufacturing the TDS of the invention as well as to the use of the TDS of the invention.

Description

Transdermal delivery system containing a dopamine agonist

The present invention relates to a transdermal delivery system (TDS) comprising at least one dopamine agonist, wherein the at least one dopamine agonist is present in a matrix which contains at least one polymer from the class of polybutylenes. Furthermore, the present invention relates to a method for producing the TDS according to the invention and to the use of the TDS according to the invention.

Dopamine agonists are drugs that can produce similar effects in the organism as the body's own neurotransmitter dopamine, mainly by stimulating dopamine receptors. Dopamine agonists are structurally in the class of ergoline and the non-ergoline dopamine agonist or in accordance with its binding affinity in the class of D _1/5 - divided and D _2/3/4 agonists. They are used for the treatment of, for example, Parkinson's disease, amenorrhea, acromegaly, as an emetic, for breastfeeding in lactation and as a sexual enhancer.

So far, the active ingredient L-DOPA (L-3,4-DihydroxyjDhenylalanine), a natural precursor of dopamine, is considered the gold standard for the treatment of diseases where an increase in dopamine levels is beneficial. However, during treatment with L-DOPA, side effects such as, for example, disorders of the course of motion occur.

Dopamine agonists are able to completely replace the active ingredient L-DOPA in earlier disease stages and to relieve the side effects of L-DOPA by adjunctive therapy in later stages of the disease. However, dopamine agonists, in turn, may cause severe side effects, possibly due to the drug being given a pulsatile route (Samuel et al., Mov. Disord., 2015), which may cause the drug concentration in the blood plasma to vary greatly. Thus, most oral dopamine dopamine agonists are at least partially metabolized or retained during the first passage through the digestive tract and the liver (first-pass effect). As a result, only a fraction of the orally taken active ingredient generally reaches the site of action in active form. Furthermore, most dopamine agonists have low plasma half-lives, so that initially high plasma drug concentrations can decrease after a short time. For the above reasons, the development of a safe and effective pharmaceutical dosage form by means of which controlled amounts of the drug can be administered is of importance.

Transdermal delivery systems are a useful alternative for the administration of dopamine agonists, as agents can be controlled by this mode of delivery and delivered within the appropriate therapeutic dose. Transdermal delivery systems (syn: transdermal therapeutic systems, TTS) are generally flexible, adhesive formulations for the controlled delivery of one or more active ingredients for application to the skin. The active ingredient can be resorbed from the TDS over the skin over a period of about one day to about seven days, and directly into the bloodstream without substantial metabolism. Frequently, a therapy takes place over months or years.

The prerequisite for a successful systemic delivery of the active substance with the aid of transdermal delivery systems is the highest possible drug release rate of the TDS. The drug delivery rate depends essentially on the concentration of the drug in the matrix of the transdermal delivery system and on the physicochemical properties of the drug.

In order to achieve an increased drug release rate, the saturation solubility exceeding active ingredient concentrations are often dissolved in the active ingredient-containing matrix of the TDS. However, because of the high concentration of drug in the drug matrix, such drug-supersaturated systems often tend to crystallize during storage (Stefano et al., 1997, Variankaval et al., 1999, Lipp et al., 1999, Kim & Choi). However, crystallization of the drug lowers its thermodynamic activity and, consequently, the drug release rate and is therefore usually limited by the addition of solubilizers.

However, it is known that solubilizing agents can undesirably stress the organism, for example by allergic reactions and / or skin irritations. Furthermore, the addition of solubilizers may result in a decrease in the bond strength of the transdermal delivery system.

However, the transdermal delivery systems described in the prior art either have a complex structure and require a variety of different Adjuvants to produce TDS at high drug delivery rates or by far missed the required therapeutic drug dose.

WO 02/015903 A2 discloses a rotigotine-containing depot form with which, after administration to the patient, a plasma level therapeutically relevant for at least 24 hours can be achieved.

It is therefore the object of the present invention to provide a transdermal delivery system containing at least one dopamine agonist, wherein the TDS comprises a drug-containing matrix which contains at least one polymer from the class of polybutylenes and shows an efficient drug release rate and a good storage stability ,

This object is achieved by a TDS with a drug-containing matrix, which contains at least one polymer from the class of polybutylenes according to claim 1, and by a method for producing the TDS according to the invention according to claim 1 1. Furthermore, the object is achieved by a composition according to the invention for use according to claim 14.

The present invention therefore relates to a transdermal delivery system comprising

(i) at least one dopamine agonist in at least one matrix,

(ii) a drug-impermeable backing layer, and

(iii) an optional application-side protective film, wherein the matrix containing the at least one dopamine agonist comprises at least one polymer from the class of polybutylenes, in particular polyisobutylenes.

Inventive transdermal delivery systems according to claim 1 advantageously have a good storage stability, in particular with regard to a possible crystallization, and at the same time a controlled and good drug delivery rate.

In its simplest embodiment, the transdermal therapeutic systems according to the invention comprise a back layer and at least one dopamine agonist in at least one matrix which comprises at least one polymer from the class of polybutylenes, in particular the polyisobutylenes. The matrix layer is arranged horizontally in the TDS and serves to attach the TTS to the skin.

The side of the TDS, generally intended for application to a skin or in contact with the skin, is referred to as the application side. For this purpose, the application side can be designed to be pressure-sensitive over the whole area, for example by the pressure-sensitive matrix containing dopamine agonist itself.

Optionally, a TDS according to the invention may contain a protective layer which is applied to the dopamine agonist-containing matrix and is removed before application of the TTS.

As mentioned above, the at least one dopamine agonist is advantageously contained in a matrix which contains at least one polymer from the class of polybutylenes. In the following, the term dopamine agonist-containing matrix which contains at least one polymer from the class of polybutylenes is to be equated with a polybutylene based at least one dopamine agonist-containing matrix. The term polybutylene (PB) is to be equated with polybutene. In particular, a polybutylene may comprise a polymer which at least partially contains one or more isobutylenes or polyisobutylenes (PIB) and / or is completely replaced by one or more polyisobutylene / s.

According to the invention, the at least one dopamine agonist is contained in a matrix based on polybutylene, in particular based on polyisobutylene. A matrix based on polybutylene, in particular based on polyisobutylene, is to be understood as meaning a matrix layer which, based on all substances contained in the matrix, in particular active ingredients and any adjuvants present, has a total content of polybutylene or polyisobutylene which preferably at least 25 wt .-%, particularly preferably at least 35 wt .-%, in particular at least 45 wt .-%, particularly preferably at least 50 wt .-%, is. In principle, the preferred level of adhesive may be up to about 95% by weight, but it is particularly preferred that the level of adhesive be no more than about 80% by weight. The total content of polybutylene comprises the content of all polybutylene polymers or polyisobutylene polymers in the dopamine agonist-containing matrix.

The transdermal therapeutic systems according to the invention are suitable for administration of basically all dopamine agonists such as, for example, dihydrexidine, cabergoline, Dihydroergocryptine, terguride, dinapsoline, dinoxyline, etilevodopa, melevodopa, ibopamine, pergolide, lisuride, quinagolide, rotigotine, bromocriptine, apomorphine, pramipexole, ropinirole, propylnorapomorphine, sumanirol, piribedil and roxindole.

The transdermal therapeutic system according to the invention thereby delivers the dopamine agonist from the active ingredient-containing matrix based on polybutylene to or into the skin, wherein a substantial part of the active ingredient is absorbed systemically.

The present invention thus also relates to the medical and / or veterinary use of the patch according to the invention (hereinafter the TTS is also referred to as patch) for the delivery of dopamine agonists, in particular D ₂ agonists, to or through the skin of a human or animal body.

Furthermore, the present invention relates to a method for producing a TDS according to the invention, the method comprising the following steps:

(i) providing at least one dopamine agonist-containing matrix containing at least one polymer from the class of polybutylenes, in particular polyisobutylenes,

(ii) optionally applying the at least one dopamine agonist-containing matrix to a film to obtain a laminate having a dopamine agonist-containing matrix,

(iii) optionally drying the laminate comprising the at least one dopamine agonist-containing matrix,

(iv) optionally punching transdermal delivery systems to obtain sheeted drug cores,

(v) optionally packaging transdermal delivery systems.

In this case, provision is both an on-site production and a delivery of a dopamine agonist-containing matrix which comprises at least one polymer from the class of polybutylenes, in particular polyisobutylenes. In this case, a dopamine agonist-containing matrix, which comprises at least one polymer from the class of polybutylenes, may already be provided with a protective film covering the application side of the dopamine agonist-containing matrix, which remains on the latter during production or optionally in one or more production steps can be replaced by an alternative protective film. According to a preferred method, the at least one dopamine agonist-containing matrix can be applied to a film to obtain a laminate. In this case, a laminate can be understood as meaning a material or a product which consists of two or more layers glued together in a flat manner. These layers may consist of the same or different materials, but preferably of different materials.

Finally, the present invention comprises a transdermal therapeutic system obtainable by a method as described above.

Further particularly advantageous refinements and developments of the invention will become apparent from the dependent claims and the following description, wherein the claims of a particular category can also be developed according to the dependent claims of another category and features of different embodiments can be combined to form new embodiments.

According to a preferred embodiment, the TTS contains in the at least one matrix comprising a polymer from the class of polybutylenes, in particular polyisobutylenes, a dopamine agonist from the class of D ₂ agonists or ergot alkaloids or their derivatives, particularly preferably from the class of D. ₂ - agonists, in particular of rotigotine, pramipexole and / or ropinirole, particularly preferably of rotigotine.

The at least one dopamine agonist may be present in various forms in the matrix, depending on which form gives the optimal release property of the active ingredient from the TDS or the matrix. Dopamine agonists may generally be in the form of free base or acid, esters or other pharmacologically acceptable derivatives or as components of molecular complexes. The at least one dopamine agonist, in particular rotigotine, is preferably present in the form of the free base.

Advantageously, the amount of the dopamine agonist, preferably the D ₂ agonist, in particular rotigotine, in the system is at least about 0.3% by weight, preferably at least about 3% by weight, more preferably at least about 4.5 Wt .-%, in particular of at least about 7 wt .-%, vary. at the most however, the content of the dopamine agonist, preferably of the D ₂ agonist, in particular of rotigotine, is preferably up to about 50% by weight, more preferably up to about 15% by weight, in particular up to about 12.5% by weight .-%, particularly preferably up to about 9 wt .-%,

The amount of absolute drug contained in the patch generally determines the length of time in which continuous delivery of the drug into or onto the organism is maintained. Therefore, the highest possible loading of the polybutylene-based matrix with dopamine agonists is desirable when the application time of a patch is long, i. H. several days to a week. However, a transdermal therapeutic system according to the invention is preferably used for an application period of one to four days, in particular for an application period of one to three days, particularly preferably of one to two days.

In principle, a suitable basis weight of the dopamine agonist-containing matrix based on polybutylene is in a range customary for transdermal therapeutic systems. Inasmuch as a preferred transdermal therapeutic system is provided for an application period of about one day, a preferred basis weight of at least one dopamine agonist-containing matrix based on polybutylene is at least about 10 mg / 10 cm ² , more preferably at least about 20 mg / 10 cm ² , especially at least about 30 mg / 10 cm ² , more preferably at least about 40 mg / 10 cm ² . At most, a preferred basis weight is up to about 100 mg / 10 cm ² , more preferably up to about 80 mg / 10 cm ² , especially up to about 75 mg / 10 cm ² , most preferably up to about 70 mg / 10 cm ² .

Insofar as an advantageous transdermal therapeutic system is to be used for more than one day, a preferred basis weight may also be above about 100 mg / 10 cm ² . For example, a preferred transdermal therapeutic system with an application period of about two days may have a basis weight of up to about 400 mg / 10 cm ² , more preferably up to about 300 mg / 10 cm ² , especially up to about 200 mg / 10 cm ² , have. An advantageous transdermal therapeutic system having a gestation period of about three days preferably has a basis weight of at least about 150 mg / 10 cm ² , more preferably at least about 200 mg / 10 cm ² , especially at least about 300 mg / 10 cm ² , At most, a transdermal therapeutic system having a gestation period of about three days has a basis weight of preferably up to about 500 mg / 10 cm ² , more preferably up to about 400 mg / 10 cm ² .

The abovementioned transdermal therapeutic systems can in principle comprise both one or more matrix layers, which in each case contain or contain at least one polymer from the class of polybutylenes or polyisobutylenes.

Insofar as transdermal therapeutic systems consist of two or more matrices based on polybutylene or polyisobutylene, only one matrix layer can have at least one dopamine agonist or the at least one dopamine agonist active substance can also be present in further matrix layers. Further, said polybutylene-based matrices may have a different composition from each other. In principle, all combinations of dopamine agonists with affinity for all classes of dopamine receptors are possible.

For example, a first matrix layer of the TDS may contain a dopamine D ₂ agonist and a second or further matrix layer of the TDS may contain a dopamine drug agonist. Examples of dopamine Dr agonists are dihydrexidine, cabergoline, dihydroergocryptine, terguride, dinapsoline, dinoxyline, etilevodopa, melevodopa, ibopamine, pergolide and lisuride. Examples of dopamine D ₂ agonists are quinagolide, rotigotine, bromocriptine, cabergoline, apomorphine, pramipexole, ropinirole, propylnorapomorphine, sumanirole, pergolide, piribedil, dihydroergocryptine and lisuride. Of course, combinations of dopamine agonists with affinity for the other dopamine receptor classes are possible. For example, the class of dopamine D ₃ agonists includes pramipexole, ropinirole, propylnorapomorphine, pergolide, piribedil and lisuride. Examples of dopamine D ₄ agonists are, for example, roxindole and lisuride. Examples of dopamine D ₅ agonists are dihydrexidine and again lisuride. However, according to a particularly preferred embodiment, the TDS comprises only dopamine agonists with affinity for the same class determined by the receptor affinity, in particular to dopamine D ₂ receptors, particularly preferably rotigotine.

Finally, an application-side matrix can be designed to be free from active substance or can also have one or more dopamine agonists; however, an application-side matrix preferably has a dopamine agonist.

The at least one dopamine agonist-containing matrix based on polybutylene or polyisobutylene or else a further optional active ingredient-containing or active ingredient-free layer of the TTS can finally contain additional materials that are common for transdermal therapeutic systems. To mention here are especially polymers that are used in the production of transdermal systems and physiologically harmless, such. As styrene-butadiene copolymers and / or styrene-butadiene-styrene copolymers, polybutenes or polyisobutylenes, homo- and copolymers of (meth) acrylates, polyvinyl ethers, polyisoprene rubbers and silicones. Among the (meth) acrylate copolymers, there can be mentioned, for example, the copolymers of alkyl acrylates and / or alkyl methacrylates and other unsaturated monomers, such as acrylic acid, methacrylic acid, acrylamide, dimethylacrylamide,

Dimethylaminoethylacrylamide, acrylonitrile and / or vinyl acetate.

According to a particularly preferred embodiment, the at least one dopamine agonist-containing matrix based on polybutylene, in particular based on polyisobutylene, comprises a further polymer which is selected from the class of the styrene-butadiene (SB) copolymers and / or the styrene-butadiene -styrene (SBS) copolymers. Such a SB or SBS copolymer can be purchased, for example, from Henkel (Germany).

According to an advantageous embodiment, the copolymer of the class of styrene-butadiene and / or styrene-butadiene-styrene has pressure-sensitive adhesive properties, which advantageously ensures a good bonding of the at least one dopamine agonist-containing matrix with the back layer of the transdermal system, so that in particular shear forces which can occur on the skin during the period of application of the transdermal system, or even in the case of moisture, for example due to shower water or condensation, a robust composite back layer and drug-containing matrix is ensured, but without adversely affecting the adhesive properties of the transdermal system on the skin.

According to a very particularly preferred embodiment, the at least one dopamine agonist-containing matrix based on polybutylene, in particular based on polyisobutylene, comprises at least one styrene-butadiene and / or styrene-butadiene-styrene copolymer, wherein the dopamine agonist is selected from a dopamine D ₂ agonist, preferably from quinagolide, rotigotine, bromocriptine, cabergoline, apomorphine, pramipexole, ropinirole, propylnorapomorphine, sumanirol, pergolide, piribedil, dihydroergocryptine and / or lisuride, especially from rotigotine.

If a particularly preferred embodiment comprises a polymer from the class of styrene-butadiene and / or styrene-butadiene-styrene copolymers, then a preferred ratio of the at least one polybutylene or polyisobutylene and the at least one styrene-butadiene and / or Styrene-butadiene-styrene copolymers at least about 1 to about 1, more preferably at least about 2 to about 1, more preferably about 2.3 to about 1. At most, a preferred ratio of the at least one polybutylene or polyisobutylene and the at least one styrene-butadiene and / or styrene-butadiene-styrene copolymer is up to about 6 to about 1, more preferably up to about 5 to about 1, in particular at up to about 4 to about 1. The ratio refers to the total content (wt .-%) of one or more polymers from the class of polybutylenes or polyisobutylenes to the total content (wt .-%) of one or more polymers from the class of styrene-butadiene and / or styrene Butadiene-styrene copolymers in the dried matrix.

In principle, the molecular weight of the at least one polybutylene of a TDS according to the invention with at least one dopamine agonist-containing matrix can vary within a wide range. However, the molecular weight of the at least one polybutylene or polyisobutylene is preferably at least about 20,000 g / mol, more preferably at least about 45,000 g / mol, in particular at least about 60,000 g / mol. Preferably, the molecular weight of the at least one polybutylene or polyisobutylene is up to about 100,000 g / mol, more preferably up to about 85,000 g / mol, in particular up to about 75,000 g / mol. A polybutylene polymer or polyisobutylene polymer having these properties is also referred to below as "medium molecular weight polybutylene polymer". According to a preferred embodiment, however, the at least one matrix based on polybutylene, in particular based on polyisobutylene, comprises at least two polymers from the class of polybutylenes or polyisobutylenes. In this case, a first of the at least two polybutylenes is particularly preferably a medium-molecular weight polybutylene polymer or polyisobutylene polymer.

Insofar as the at least one matrix contains a second polymer based on polybutylene, this second polybutylene or polyisobutylene preferably has a molecular weight of at least about 500,000 g / mol, in particular of at least about 800,000 g / mol. At most, a preferred molecular weight of a second polymer based on polybutylene or polyisobutylene is up to about 3,500,000 g / mol, in particular up to about 1,200,000 g / mol. A polybutylene polymer or polyisobutylene polymer having these properties is also referred to below as "high molecular weight polybutylene polymer".

According to a particularly preferred embodiment, a first polybutylene or polyisobutylene polymer of an advantageous TDS has a preferred molecular weight of at least about 60,000 g / mol and / or at most about 75,000 g / mol and / or a second polybutylene or polyisobutylene a preferred molecular weight of at least about 800,000 g / mol and / or of at most about 1,200,000 g / mol.

A ratio of the at least two polybutylene or polyisobutylene polymers may in principle vary within a wide range. In the following, the ratio of the at least two polybutylene or polyisobutylene polymers refers to the ratio of the proportion (wt .-%) of a first polybutylene or polyisobutylene polymer to the proportion (wt .-%) of a second polybutylene or Polyisobutylene polymer in the dried matrix. However, the ratio of a first polybutylene or polyisobutylene polymer and a second polybutylene or polyisobutylene polymer is preferably at most about 9 to about 0.1, more preferably at most about 7 to about 0.5, in particular at most about 6 to about 1.

Finally, an active ingredient-containing matrix may also comprise more than two polybutylenes, for example three polybutylenes.

The matrix of a TDS may also contain one or more solubilizing agents which advantageously have good solubility of the dopamine agonist in the matrix enable. Solubilizers may be selected from the group of hydrophilic polymers, such as polyvinylpyrrolidone (PVP), copolymers of vinylpyrrolidone and vinyl acetate, polyethylene glycol, polypropylene glycol, copolymers of ethylene and vinyl acetate and glycerol and its esters. Particularly preferred solubilizers include a vinylpyrrolidone-vinyl acetate copolymer and / or PVP and can be described, for example, under the name Kollidon VA 64 or Kollidon CLIN /! be acquired by the company BASF (Germany).

The content of a solubilizer, preferably a vinylpyrrolidone-vinyl acetate copolymer and / or a PVP, in the advantageous TDS is preferably in the range from 1 to 10% by weight, particularly preferably in the range from 1 to 5% by weight. ,

Preferably, the content of a vinylpyrrolidone-vinyl acetate copolymer is at least about 4 wt%, more preferably about 6 wt%. At the most, the content of a vinylpyrrolidone-vinyl acetate copolymer is up to about 8% by weight. The content of a PVP is preferably at least about 1% by weight, more preferably about 2% by weight. At most, the content of a PVP is preferably up to about 4% by weight, in particular up to about 3% by weight.

It has been shown that the delivery of the at least one dopamine agonist to or into the skin can be improved if an absorption promoter from the group of isopropyl esters, for example from esterifications of propanol with carboxylic acids consisting of 8-20 carbon atoms, is a constituent of the matrix of an advantageous TDS is. Isopropyl myristate, which can be obtained, for example, from Merck (Germany), is suitable as a particularly preferred absorption promoter.

The content of an absorption mediator, in particular isopropyl myristate, in the advantageous TDS is preferably at least about 4% by weight, more preferably at least about 6% by weight, especially at least about 7% by weight, most preferably at least about 7.8 wt .-%. At most, a preferred content of an absorption mediator, especially isopropyl myristate, is up to about 12% by weight, more preferably up to about 10% by weight, especially up to about 9% by weight, especially preferably up to about 8.2% by weight.

The release rate of the dopamine agonist can be advantageously increased by adding an optional cosolvent selected from the group of aliphatic Alcohols. Preferably, such an aliphatic alcohol is selected from the group of linear aliphatic alcohols, preferably having a chain length between 10 and 14 carbon atoms. The number of OH groups can vary fundamentally between 1 and the number of carbon atoms. The preferred aliphatic alcohol is n-dodecanol, but particularly preferred is 1-dodecanol, which can be purchased, for example, under the name Selectophore ™ from Sigma-Aldrich (Germany).

The content of the aliphatic alcohol, preferably of n-dodecanol, in particular of 1-dodecanol, in the advantageous TDS is preferably at least about 4% by weight, more preferably at least about 6% by weight, in particular at least about 7 Wt .-%, particularly preferably at least about 7.8 wt .-%. At most, a preferred level of an aliphatic alcohol, especially n-dodecanol, is up to about 12% by weight, more preferably up to about 10% by weight, especially up to about 9% by weight, most preferably at up to about 8.2% by weight.

Advantageously, a content of one or more of the preferred cosolvents and / or absorption mediator (s) causes a controlled and sustained release of active ingredient from the preferred transdermal therapeutic system, more preferably from a transdermal therapeutic system comprising a dopamine agonist from the class of D ₂ agonists and the ergot alkaloid derivatives, more preferably from the class of D ₂ agonists, in particular from rotigotine, pramipexole and / or ropinirole, particularly preferably from rotigotine.

An advantageous composition of a dopamine agonist-containing matrix based on polybutylene, in particular based on polyisobutylene

(i) 0.3 to 50% by weight of a D ₂ agonist,

(ii) from 15 to 80% by weight of the medium molecular weight or of the high molecular weight polybutylene, preferably of the medium molecular weight polybutylene or polyisobutylene,

(iii) 2 to 10% by weight of vinylpyrrolidone-vinyl acetate copolymer,

(iv) optionally 4 to 12% by weight of isopropyl myristate, and

(V) optionally 4 to 12 wt .-% n-dodecanol.

Preferably, a composition comprises a dopamine agonist-containing polybutylene-based matrix

From 3 to 15% by weight of rotigotine, in particular from 4.5 to 12.5% by weight of rotigotine,

3 to 65 wt .-% of the medium molecular weight polybutylene or polyisobutylene,

5 to 35 wt .-% of high molecular weight polybutylene or polyisobutylene,

From 4 to 8% by weight of vinylpyrrolidone-vinyl acetate copolymer,

From 6 to 10% by weight of isopropyl myristate, and

optionally 6 to 10% by weight of 1-dodecanol.

The components of a dopamine agonist-containing matrix based on polybutylene are particularly preferably selected from

(i) 6 to 10% by weight of rotigotine,

(ii) from 35 to 63% by weight of the medium molecular weight polybutylene or polyisobutylene,

(iii) from 5 to 1% by weight of the high molecular weight polybutylene or polyisobutylene,

(iv) 5 to 8% by weight of vinylpyrrolidone-vinyl acetate copolymer,

(v) 1 to 3% by weight of PVP

(vi) 7 to 9% by weight of isopropyl myristate, and

(vii) 7 to 9% by weight of 1-dodecanol. In particular, the components of a dopamine agonist-containing polybutylene-based matrix are selected from

6 to 10% by weight of rotigotine,

35 to 63 wt .-% of the medium molecular weight polybutylene or polyisobutylene, 5 to 1 1 wt .-% of high molecular weight polybutylene or polyisobutylene, 10 to 25 wt .-% of a SB and / or SBS copolymer,

From 5 to 8% by weight of vinylpyrrolidone-vinyl acetate copolymer,

From 1 to 4% by weight of PVP,

7 to 9 wt .-% isopropyl myristate, and

7 to 9% by weight of 1-dodecanol.

More preferably, the components of a dopamine agonist-containing polybutylene-based matrix are selected from

6 to 10% by weight of rotigotine,

35 to 63 wt .-% of the medium molecular weight polybutylene or polyisobutylene, 5 to 1 1 wt .-% of high molecular weight polybutylene or polyisobutylene, 15 to 25 wt .-% of a SB and / or SBS copolymer,

From 5 to 8% by weight of vinylpyrrolidone-vinyl acetate copolymer,

From 1 to 3% by weight of PVP,

7 to 9 wt .-% isopropyl myristate, and

7 to 9% by weight of 1-dodecanol.

In particular, a preferred level of rotigotine is at least about 7 to at most about 9 weight percent, a content of a first polybutylene polymer or polyisobutylene polymer is preferably up to about 60 weight percent, more preferably about 57 weight percent. -%, and a preferred content of a second polybutylene polymer or polyisobutylene polymer at least about 8 wt .-%, in particular about 10% by weight. In this case, the first polybutylene or polyisobutylene polymer particularly preferably has a molecular weight in the range from about 60,000 g / mol to about 75,000 g / mol and the second polybutylene or polyisobutylene polymer has a molecular weight in the range from about 800,000 g / mol to about 1,200,000 g / mol. If a preferred embodiment of an advantageous TDS comprises an SB and / or SBS copolymer, a preferred content of a first polybutylene polymer or polyisobutylene polymer is preferably up to about 45% by weight, in particular up to about 40% by weight .-%, and a preferred content of a second polybutylene polymer or polyisobutylene polymer at least about 5 wt .-%, in particular about 7% by weight. The preferred content of a SB and / or SBS copolymer is at least about 10% by weight, preferably at least about 15% by weight, especially about 20% by weight. At most, a preferred level of SB and / or SBS copolymer is up to about 30% by weight, more preferably up to about 25% by weight.

Furthermore, TDS may comprise a control membrane. In TDS, which have only one dopamine agonist-containing matrix layer, the control membrane can be laminated onto the application-side matrix. In order to obtain the pressure-sensitive adhesive properties of the TDS, an application-side, dopamine agonist-containing or drug-free matrix is additionally applied to the control membrane in this case.

In particular, a control membrane is based on a polymer selected from the group of polyolefins, olefin copolymers, polyesters, co-polyesters, polyamides, co-polyamides, polyurethanes and the like. As examples of suitable materials can be mentioned polyesters and of these in particular polyethylene terephthalates and polycarbonates, polyolefins such. As polyethylenes, polypropylenes or polybutylenes, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides, co-polymers such as acrylonitrile-butadiene-styrene terpolymers, or ethylene-vinyl acetate copolymers. A preferred control membrane comprises a polypropylene and can be purchased, for example, under the name Celgard from the company Azelis (Germany).

Insofar as the TDS according to the invention has more than one matrix, the basis weight of a first or further matrix is particularly preferably at least about 15 mg / 10 cm ² , in particular at least about 30 mg / 10 cm ² , particularly preferably at least about 40 mg / 10 cm ² . At most, a particularly preferred basis weight of a first or further matrix is up to about 70 mg / 10 cm ² , in particular up to about 60 mg / 10 cm ² , particularly preferably up to about 50 mg / 10 cm ² . However, in this case a first or further matrix does not have to have the same basis weight, but rather a first matrix may have a weight per unit area of at least about 30 mg / 10 cm ² and / or at most about 50 mg / 10 cm ² and a further matrix a basis weight of, for example at least about 10 mg / 10 cm ² and / or at most about 35 mg / 10 cm ² . Insofar as an advantageous transdermal therapeutic system is provided for an application period of about one day, a preferred basis weight of a first matrix is at least about 10 mg / 10 cm ² , in particular about 15 mg / 10 cm ² . A basis weight of a second matrix is at most about 45 mg / 10 cm ² , in particular about 35 mg / 10 cm ² .

A coordination of the basis weights to the total layer thickness or the total basis weight of the TDS according to the invention seems to make sense when a first initial release of an active substance from an application layer having an active substance content is to be coordinated with a second sustained release drug from a matrix layer facing the back layer. Also, when selecting the basis weight, the influence on the wearing properties of the TDS must be considered.

To prevent migration of drug from the polybutylene-based matrix, a preferred transdermal delivery system advantageously has an occlusive backing layer. As backing layers of a TDS according to the invention are usually so-called backing foils of for example polyester with a thickness of preferably at least about 5 μηι, more preferably of at least about 7.5 μηι, in particular of at least about 10 μηι, more preferably of at least about 12 μηι used. At most, such a backing sheet has a preferred thickness of up to about 200 μηι, more preferably of up to about 150 μηι, in particular of up to about 100 μηι, more preferably of up to about 50 μηι, most preferably of up to about 30 μηι , on. Such backing sheets are flexible and may optionally surround the edges of the matrix layer, i. around the side surfaces of the drug-containing matrix pointing in lateral directions and cover them.

Preferably, a backing layer, in particular an occlusive backing layer, is based on a polymer selected from the group consisting of polyolefins, olefin copolymers, polyesters, co-polyesters, polyamides, co-polyamides, polyurethanes and the like. As examples of suitable materials, polyesters and the like in particular polyethylene terephthalates (PET) and polycarbonates may be mentioned, polyolefins such. As polyethylenes, polypropylenes or polybutylenes, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides, co-polymers such as acrylonitrile-butadiene-styrene terpolymers, or ethylene-vinyl acetate copolymers. A preferred material of a backing layer is selected from a polyester, more preferably from a polyethylene terephthalate. Such a backing layer can be purchased, for example, under the name Hostaphan MN 15 DMF from Mitsubishi Polyester Film GmbH (Germany).

Also, a backing layer of a TDS according to the invention may comprise a cover layer or an overtape, which protrudes laterally beyond the edges of the polybutylene-based matrix containing at least one dopamine agonist and thus may allow an improved adhesion of the TDS according to the invention to the skin. A preferred cover layer or a preferred overtape is formed occlusively.

The overtape may further be formed in multiple layers. In particular, an overtape comprises an active ingredient-free adhesive layer and an overtape film, wherein an overtape film preferably comprises a polymer selected from the group of polyolefins, olefin copolymers, polyesters, co-polyesters, polyamides, co-polyamides, polyurethanes and the like. As examples of suitable materials, polyesters and of these, in particular polyethylene terephthalates, as well as polycarbonates, polyolefins, such as. As polyethylenes, polypropylenes or polybutylenes, polyethylene oxides, polyurethanes, polystyrenes, polyamides, polyimides, polyvinyl acetates, polyvinyl chlorides, polyvinylidene chlorides, co-polymers such as acrylonitrile-butadiene-styrene terpolymers, or ethylene-vinyl acetate copolymers may be mentioned. A preferred material of an overtape is selected from a polyester, more preferably from a polyethylene terephthalate.

In one embodiment of the TTS according to the invention, the dopamine agonist-containing matrix based on polybutylene or a dopamine agonist-containing or drug-free application layer can be covered with a peelable protective film referred to in the jargon as a release liner, as mentioned above. When the TTS is stored, this effectively protects the active substance-containing matrix or the application layer from mechanical influences and / or undesired admission of air. Preventing unwanted air entry causes decomposition of in the matrix contained Dopaminagonisten, in particular of oxygen-sensitive dopamine agonists, prevented and thus improves the storage or long-term stability of the patch. For application of the patch is then removed before attaching the system on the skin first, the protective film of the plaster. For better gripping and thereby to facilitate detachment of the protective film, the protective film protrudes over advantageous patches over the edge of the remaining plaster.

Inventive embodiments of a transdermal therapeutic system comprise, as mentioned, an active substance matrix based on polybutylene or polyisobutylene and containing at least one dopamine agonist. According to a preferred embodiment, the dopamine agonist is dispersed in the form of a solution in the matrix-forming polymer or the polybutylene-based or polyisobutylene-based polymer mixture.

For the purposes of the present invention, a solution is understood as meaning a mixture of a solvent and a solvate, it being possible for the solvate to be molecularly disperse, that is to say it may have a particle size of less than 1 nm. Furthermore, a solution can also colloidally disperse dissolved particles having a size in the range of 1 nm to 1 μηη and / or coarsely disperse dissolved particles having a size of about 1 μηη.

Advantageously, therefore, the above-mentioned components required for the preparation of the dopamine agonist-containing matrix are stirred into a suitable solvent by the process according to the invention. The coating composition prepared in this way is coated onto a release liner and dried to remove the solvent (s) used. Insofar as a matrix of a particularly preferred embodiment comprises one or more of the abovementioned SB and / or SBS copolymers, at least one of the copolymers is admixed as a further constituent to obtain a coating composition.

Drying as explained above can be carried out, for example, at a preferred temperature of at least about 40 ° C., more preferably of at least about 60 ° C., in particular of at least about 70 ° C. The drying may preferably over a period of up to several hours, more preferably over a period of up to about 30 minutes, in particular over a period of up to about 15 minutes, more preferably over a period of up to about 5 minutes, for example about 1 to about 3, or about 4 or about 5 minutes. However, at most, a preferred temperature is up to about 130 ° C, more preferably up to about 100 ° C, especially up to about 95 ° C.

Advantageously, a drying or even a temperature control of the active substance-containing matrix and / or the laminate and / or the transdermal delivery systems and / or the packaged transdermal delivery systems over a preferred period of at least a few minutes, more preferably at least about 30 minutes, in particular at least about 8 hours. At most, drying or tempering takes place for a preferred period of time of up to one week, more preferably of up to three days, in particular of up to 48 hours, particularly preferably of about 24 hours. Tempering is understood as meaning a heating of the active ingredient-containing matrix and / or the laminate and / or the punched transdermal therapeutic systems and / or the packaged transdermal therapeutic systems to a moderately warm, well-tuned temperature at which the active substance-containing matrix or The active ingredient itself does not change adversely, for example, undergoes no significant physico-chemical change and / or crystallization of the active ingredient is brought about.

Such a procedure advantageously makes possible a complete solution of the dopamine agonist (s), in particular of rotigotine, and prevents the formation of nuclei, whereby recrystallisation of the active ingredient can be prevented or at least delayed. Furthermore, the water content of a dried drug-containing matrix based on polybutylene or polyisobutylene can be set to the lowest possible value. Preferred TDSs therefore have a water content of up to about 2% by weight, preferably of up to about 1% by weight, more preferably of up to about 0.75% by weight, in particular of up to about 0.5% by weight .-%, particularly preferably up to about 0.2 wt .-%, on.

In addition, a preferred method according to the invention may take into account the use of a pre-dried packaging material, in particular a bag, in which the TDS are packaged, which may be further provided with moisture-absorbing materials.

Thus, a preferred packaged transdermal delivery system may include a desiccant which is loosely or firmly attached in the packaging means, preferably in a pouch, a desiccant, more preferably based on a desiccant Thermoplastics, in particular based on polyethylene. Such a desiccant or moisture-absorbing material is available, for example, under the name Activ-Film ™ from CSP Technologies and can be introduced into the bag in a packaging step, whereby the moisture content, in particular the water content, in the environment of the packaged TDS during storage in addition can be reduced. An active ingredient-containing matrix based on polybutylene or polyisobutylene thus exhibits a low water content of up to about 2% by weight, preferably of up to about 1% by weight, particularly preferably of, even after a longer storage period of several months or years at about 0.75 weight percent, more preferably up to about 0.5 weight percent, most preferably up to about 0.2 weight percent, whereby recrystallization of the drug in the matrix can be prevented ,

In order to keep the moisture content, in particular the water content, in the dried active substance-containing matrix of the TDS according to the invention as low as possible, according to a preferred method in the production of the laminate, a backing layer and / or a protective film with moisture-absorbing material properties, such as, for example, with materials comprising a silica Gel formulation, to be used.

According to a further embodiment, flat active substance cores, for. Example, drug-containing matrix cores, before or after application to a protective film of the laminate with a drug-containing matrix on polybutylene-based or polyisobutylene basis punched and subjected to the further manufacturing process of the invention. An active substance core here is to be understood as meaning a planar dopamine agonist-containing matrix which advantageously comprises a backing layer or a protective film on its rear side and / or on its application side and which is cut from the above-mentioned active substance-containing laminate with the aid of a cutting tool, in particular a punching tool , in particular stamped, is. Particular preference is given to laminating active substance cores of a laminate comprising the polybutylene-based active substance-containing matrix and a protective film.

Dopamine agonists are generally used for the treatment of Parkinson's disease, amenorrhea, acromegaly, hyperprolactinemia, as emetics, for breastfeeding in lactation and as a sexual enhancer. The present invention preferably comprises a transdermal therapeutic system for use in the treatment Parkinson's disease, restless leg syndrome, amenorrhea, acromegaly, and hyperprolactinemia. Particular preference is given to a treatment in particular of Parkinson's disease and restless leg syndrome.

Further features of the invention will become apparent from the following description of exemplary embodiments in conjunction with the claims and the figures. It should be noted that the invention is not limited to the embodiments of the described embodiments, but is determined by the scope of the appended claims. In particular, the individual features in embodiments according to the invention can be realized in a different combination than in the examples given below. In the following explanation of some embodiments of the invention, reference is made to the accompanying figures. Show it:

FIG. 1 shows a diagram for the in vitro permeation of rotigotine base (g / cm ² ) from a transdermal therapeutic system according to the invention according to Example 1 through naked mouse skin. Skin permeation was carried out over a period of 24 hours (hrs.).

FIG. 2 shows a diagram for the in vitro permeation of rotigotine base (g / cm ² ) from a transdermal therapeutic system according to the invention according to Example 2 through naked mouse skin. Skin permeation was carried out over a period of 24 hours (hrs.).

Examples

The following describes the preparation of transdermal therapeutic systems according to the present invention as well as the skin permeation of the active substance performed therewith. example 1

Composition of the TDS according to the invention (based on the dried matrix):

Rotigotine base: 9% by weight

PI B adhesive (DT 87-6908): 67% by weight

Vinylpyrrolidone-vinyl acetate copolymer

(Kollidon VA 64): 6% by weight

PVP (Kollidon CL-M): 2% by weight

Isopropyl myristate: 8% by weight

1 -dodecanol: 8% by weight

The Löslichkeitsverbesserer, the vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA 64, BASF Germany, Ludwigshafen) was dissolved in ethanol and the polyvinylpyrrolidone (Kollidon CL-M, BTC Europe GmbH, Germany) was stirred. Rotigotine (Olon, Italy) was dissolved in tetrahydrofuran (THF, VWR, Germany), isopropyl myristate (AppliChem, Germany) and 1-dodecanol (Sasol, Germany) added and then homogenized. In another vessel PIB adhesive (DT 87-6908, Henkel, Germany, mixing ratio medium to high molecular weight: 85 wt .-% to 15 wt .-%) and THF was submitted and added the previously prepared mixture and homogenized. Subsequently, the coating composition was coated on a one-side siliconized PE film (Primeliner PET 75μηι 1 S, Loparex, Netherlands), dried at 60 ° C for 15 min and with a PETP film (Hostaphan MN 15 DMF, Mitsubishi Polyester Films, Germany ) laminated. The resulting basis weight in the dried state was 50 mg / 10 cm ² .

Example 2

Composition of the TDS according to the invention (based on the dried matrix):

Rotigotine base: 9% by weight

PI B adhesive (DT 87-6908): 46.9% by weight

SB adhesive (DT 87-691 1): 20.1% by weight

Vinylpyrrolidone-vinyl acetate copolymer

(Kollidon VA 64): 6% by weight

PVP (Kollidon CL-M): 2% by weight

Isopropyl myristate: 8% by weight

1 -dodecanol: 8% by weight

The Löslichkeitsverbesserer, the vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA 64, BASF Germany, Ludwigshafen) was dissolved in ethanol and the polyvinylpyrrolidone (Kollidon CL-M, BTC Europe GmbH, Germany) was stirred. Rotigotine (Olon, Italy) was dissolved in tetrahydrofuran (THF, VWR, Germany), isopropyl myristate (AppliChem, Germany) and 1-dodecanol (Sasol, Germany) added and then homogenized. In another vessel were PIB (DT 87-6908, Henkel, Germany, mixing ratio medium to high molecular weight: 85 wt .-% to 15 wt .-%) and SB adhesive (DT-87-691 1, Henkel, Germany ) and THF and mixed, then added the previously prepared mixture and homogenized. Subsequently, the coating composition was coated on a one-side siliconized PE film (Primeliner PET 75μηι 1 S, Loparex, Netherlands), dried at 60 ° C for 15 min and with a PETP film (Hostaphan MN 15 DMF, Mitsubishi Polyester Films, Germany ) laminated. The resulting basis weight in the dried state was 50 mg / 10 cm ² .

Carrying out an in vitro skin permeation of the TDS according to Example 1 and 2:

In vitro skin permeation was performed using modified Franz cells in which the donor and acceptor chambers are vertically separated by a mouse skin (naked mouse skin, Harlan Laboratories, The Netherlands). For the preparation of the donor side, the skin was moistened with acceptor medium (phosphate buffer 50 mM, pH 6) and applied to the opening of the Franz cell (opening area 0.98 cm ² ). The TDS according to Example 1 or Example 2 was punched out in each case in a size of 0.98 cm ² and glued centrally on the skin.

A magnetic stir bar was placed in the acceptor medium filled acceptor chamber. The cells were sealed and fixed on a heatable magnetic stir plate (32 ° C). Using an automated device, samples were taken at defined times and then analyzed for their rotigotine content by HPLC. The permeated amounts of rotigotine are shown in FIG. 1 and FIG.

Claims

claims

1 . Transdermal delivery system comprising

(i) at least one dopamine agonist in at least one matrix,

(ii) a drug-impermeable backing layer, and

(iii) an optional application-side protective film,

wherein the matrix containing the at least one dopamine agonist comprises at least one polymer from the class of polybutylenes, in particular polyisobutylenes.

2. Transdermal delivery system according to claim 1, characterized in that the Dopaminagonist is selected from rotigotine.

The transdermal delivery system of any of claims 1 or 2, wherein the dopamine agonist-containing matrix further comprises a polymer of the class of styrene-butadiene copolymers and / or styrene-butadiene-styrene copolymers.

4. Transdermal delivery system according to one of the preceding claims, wherein the at least one polybutylene, in particular a polyisobutylene, a molecular weight of at least about 20,000 g / mol, preferably of at least about 60,000 g / mol, and / or of at most about 100,000 g / mol, preferably of at most about 75,000 g / mol.

5. Transdermal delivery system according to one of the preceding claims, wherein a second polybutylene, in particular a polyisobutylene, a molecular weight of at least about 500,000 g / mol, preferably of at least about 800,000 g / mol, and / or of at most about 3,500,000 g / mol , preferably of at most about 1,200,000 g / mol.

6. Transdermal delivery system according to one of the preceding claims, wherein a first polybutylene, in particular a polyisobutylene, a molecular weight of at least about 60,000 g / mol and / or at most about 75,000 g / mol, and / or a second polybutylene, in particular a polyisobutylene, has a molecular weight of at least about 800,000 g / mol and / or at most about 1,200,000 g / mol.

7. Transdermal delivery system according to one of the preceding claims, wherein the ratio of the weight fractions of a first polybutylene, in particular a polyisobutylene, and a second polybutylene, in particular a polyisobutylene, up to about 9 to about 0.1, more preferably up to about 7 to about 0.5, especially up to about 6 to about 1.

8. Transdermal delivery system according to one of the preceding claims, wherein the transdermal delivery system comprises at least one active substance-containing matrix, preferably at least two matrices, of which at least one matrix contains at least one active substance.

9. Transdermal delivery system according to one of the preceding claims, wherein the at least one matrix contains a polyvinylpyrrolidone.

10. Transdermal delivery system according to one of the preceding claims, wherein the at least one matrix contains an isopropyl myristate.

1 1. Transdermal delivery system according to one of the preceding claims, wherein the at least one matrix 1 dodecanol comprises.

12. Transdermal delivery system according to one of the preceding claims, wherein the at least one matrix comprises a copolymer of vinylpyrrolidone and vinyl acetate.

13. A method for producing a transdermal delivery system according to one of the preceding claims, comprising the steps

(v) optionally packaging transdermal delivery systems.

14. A transdermal delivery system according to any one of claims 1-12, wherein the transdermal delivery system is obtainable by a method according to claim 13.

15. Transdermal delivery system according to one of the preceding claims, wherein the transdermal delivery system is packaged in a bag containing a desiccant, preferably a desiccant based on a thermoplastic, especially based on polyethylene.

16. Transdermal delivery system according to one of the preceding claims for medical, veterinary or cosmetic use.

17. Transdermal delivery system according to one of the preceding claims for use in the treatment of Parkinson's disease and / or restless leg syndrome.