HK1083459A - Improved transdermal delivery system for the administration of rotigotine - Google Patents

Description

Improved transdermal delivery system for administration of rotigotine

Technical Field

The present invention relates to an improved transdermal drug delivery system for Rotigotine (Rotigotine). Furthermore, the present invention relates to methods of treatment using transdermal drug delivery systems.

Technical Field

To date, various Transdermal Delivery Systems (TDS) for the administration of rotigotine have been described. WO94/07568 discloses TDS comprising rotigotine hydrochloride as active substance in a biphasic matrix, which is mainly composed of a hydrophobic polymeric material as a continuous phase and a dispersed hydrophilic phase contained therein, wherein the dispersed phase mainly comprises a drug and silica hydrate. The silica is said to increase the maximum possible loading of TDS with hydrophilic salts. In addition, the formulations of WO94/07568 usually contain additional hydrophobic solvents, permeation enhancing substances, dispersants and emulsifiers which serve, inter alia, to emulsify aqueous solutions of the active ingredients in the lipophilic polymer phase. TDS prepared using this system has been tested in healthy subjects and parkinson's disease patients. However, satisfactory blood levels are not obtained.

More TDS have been disclosed in WO 99/49852. The TDS used in this patent application comprises a backing layer (inert to the matrix components), a self-adhesive matrix layer containing an effective amount of rotigotine hydrochloride or rotigotine, which contains a substantial mass (> 5% w/w) of rotigotine hydrochloride, and a protective film which is removed before use.

The matrix system consists of a non-aqueous polymeric adhesive system (based on acrylates or silicones) wherein rotigotine has a solubility of at least 5% w/w. The matrix is substantially free of inorganic silicate particles. However, even the TDS described in WO99/49852 presents some problems with the achievable flux rate of a drug through human skin.

In TDS according to WO94/07568 and many related applications, passive diffusion membranes are used.

However, since the skin is considered to be a very powerful barrier for most drugs, membrane-controlled systems of this type are more or less limited in the implementation of transdermal delivery of active substances exhibiting very high skin permeability. Furthermore, similar to contact delivery over several days, it is to meet specific requirements on the kinetics of drug release.

The object of the present invention is to control (i.e. direct/manipulate) the transport of rotigotine from the drug reservoir to and through the skin, thereby increasing the flux of rotigotine through the TDS/skin interface.

It is a further object and aspect of the invention to provide suitable compositions and methods of preparation of a polymer matrix in TDS that enhances the delivery of rotigotine to and through the skin by:

(i) prevents back diffusion of drug moieties ionized in the skin according to their pKa values from the skin tissue to the TDS,

(ii) continuous delivery of active compounds through the stratum corneum is provided not only via generally more lipophilic pathways (e.g., intercellular) but also through hydrophilic pores (e.g., eccrine sweat glands).

Summary of The Invention

These objects are achieved by providing a TDS comprising a backing layer inert to the components of the matrix, a self-adhesive matrix comprising rotigotine and a protective foil or sheet to be removed before use, characterized in that

The self-adhesive matrix comprises a solid or semi-solid semi-permeable polymer

(1) Wherein rotigotine in free base form has been incorporated,

(2) which is saturated with rotigotine and comprises said rotigotine in a plurality of micro-reservoirs in a matrix,

(3) which is highly permeable to the free base of rotigotine,

(4) which is impermeable to the protonated form of rotigotine,

(5) wherein the maximum diameter of the micro-reservoirs is less than the thickness of the substrate.

Brief Description of Drawings

Figure 1 shows the effect of the protonation of rotigotine in a semipermeable matrix on drug absorption.

Figure 2 shows the effect of the size distribution of the microreservoirs in the semipermeable matrix on the absorption of the drug.

Figure 3 shows the effect of a reduction in the amount of protonated form of rotigotine in the semipermeable matrix and a reduction in the size of the microreservoirs on drug absorption.

Fig. 4 shows a microscope image of a conventional TDS.

Fig. 5 shows an image of a microscope image of a TDS according to the invention.

Figure 6 shows the effect of a reduction in the amount of protonated form of rotigotine in a semipermeable matrix and a reduction in the size of the microreservoirs on the skin permeation of the drug in vitro.

Fig. 7 shows a comparison of the in vitro skin permeation of rotigotine with TDS of the invention and TDS based on acrylates.

Detailed Description

The present invention provides a TDS for rotigotine which is capable of providing a highly steady state flux rate of rotigotine across the TDS/skin interface.

It has surprisingly been found that the drug release profile of TDS with a silicone based adhesive matrix comprising rotigotine is achieved by:

(1) minimizing the amount of rotigotine present in protonated form (salt form);

(2) rotigotine is incorporated into a plurality of microreservoirs within a self-adhesive matrix comprising a solid or semi-solid semi-permeable polymer,

and is significantly enhanced.

The effect of the above measures on the in vivo rotigotine drug release profile is shown in figures 1, 2 and 3. For the samples according to the invention, the relative drug absorption in vivo is highest; increasing the size of the micro-reservoir and/or the amount of drug salt remaining in the TDS results in a slower initial drug release.

The present invention has been completed based on the above findings.

When TDS (according to the invention) is used, a high degree of transfer of rotigotine from the silicone matrix into the outermost skin layer can be achieved. Thus, plasma values of rotigotine sufficient to reasonably expect effective treatment with these drugs with fewer side effects may be provided.

The drug comprised in the TDS according to the invention is 5, 6, 7, 8-tetrahydro-6- [ propyl- [2- (2-thienyl) ethyl ] amino ] -1-naphthol (INN: rotigotine). Rotigotine is a dopamine D2 receptor antagonist which can be used, for example, in the treatment of parkinson's disease.

It is to be understood that the term "treatment" in the context of this application refers to the treatment or alleviation of the symptoms of a disease. Treatment may be therapeutic or prophylactic.

It will be appreciated by those skilled in the art that rotigotine exists in a number of isomeric forms. It is to be understood that any single isomer or mixture of different isomers may be used in the TDS according to the invention. Thus, mixtures of the S-or R-enantiomers or racemates or any other enantiomers of rotigotine may be used.

The multitude of microreservoirs distributed in the self-adhesive matrix of the TDS according to the invention comprises at least part of rotigotine. This is not to be excluded and normally even means: a specific fraction of rotigotine is dispersed in the solid or semi-solid semi-permeable polymer of the matrix at its saturation concentration.

In the present description, "microreservoir" is understood to mean a granular, spatially and functionally separate compartment containing the pure drug or drug dispersed in a self-adhesive (polymeric) matrixA mixture of a drug and a crystallization inhibitor. The self-adhesive matrix preferably comprises 10³～10⁹Micro storage pool/cm²Surface, particularly preferably 10⁶～10⁹Micro storage pool/cm²

Rotigotine is incorporated in the self-adhesive matrix in its free base form. This does not completely exclude the presence of certain residual salt forms of rotigotine in the final TDS. However, the amount of rotigotine in salt form contained in the self-adhesive matrix of the final TDS should preferably be below 5%, more preferably below 2%, especially below 1% (w/w).

Rotigotine cannot be released by the self-adhesive matrix if it is present in its protonated (salt) form in the self-adhesive matrix. Thus, the amount of rotigotine in salt form can be determined by performing a drug dissolution test according to the Paddle over Disk method described in the United States pharmacopoeia (United States Pharmacopeia/New formulation (USP25/NF20), Chapter 724 "drug Release", United States Pharmacopeial Convention, Inc., Rockville, MD 20852, USA (2002)) using the following conditions: dissolving the matrix: 900ml of phosphate buffer pH 4.5; adjusting the temperature to 32 +/-0.5 ℃; rotating speed of a stirring paddle: 50 rpm; the sampling time is respectively as follows: 0.5, 1, 2 and 3 hours. The increase in the eluted rotigotine concentration can be used to calculate the amount of unprotonated rotigotine in the matrix.

The amount of rotigotine in salt form can be reduced by reducing the water content of the mixture comprising the drug and the organic solvent. In a particularly preferred embodiment of the invention, the water content is preferably reduced to less than 0.4% by mass (w/w), more preferably less than 0.1% by mass, during the preparation.

A further step of isolating the free base form of rotigotine in solid form may be carried out before the TDS is prepared, which may be carried out in order to reduce the amount of the salt form of rotigotine. If the free base of rotigotine is prepared in situ during the preparation of the TDS by neutralisation of an acid addition salt, a specific residue of the ionised drug form will remain in the polymer matrix (typically > 5% (w/w), up to about 10%). Thus, the in situ preparation of the free base form is generally not suitable for the practice of the present invention.

The maximum diameter of the microreservoir is less than the thickness of the substrate, preferably up to 70% of the thickness of the substrate, particularly preferably 5 to 60% of the thickness of the substrate. For example, a substrate having a thickness of 50 μm preferably has a maximum diameter of the micro-reservoir corresponding to at most 35 μm. The term "maximum diameter" is to be understood as the maximum diameter of the microreservoir in one axis (x-, y-or z-axis). In the case of a sphere diameter, the maximum diameter corresponds to the diameter of the micro reservoir, as will be apparent to the skilled person. However, in the case of microreservoirs that are not spherical (i.e., of different geometries), there can be large differences in the x-, y-and z-axes.

The maximum diameter of the micro-reservoirs in the cross-sectional direction of the matrix (i.e. between the release surface and the backing layer) is smaller than the thickness of the matrix, so that direct contact between the skin and the rotigotine-containing alkaline micro-reservoirs is avoided, even if not prevented at all. Since the skin has a slightly acidic pH, direct contact of the skin with the microreservoirs within the matrix leads to protonation of rotigotine, thereby reducing the semipermeability of the matrix.

In a particularly preferred embodiment of the invention, the average diameter of the microreservoir cells comprising rotigotine distributed in the matrix is 1 to 40%, more preferably 1 to 20% of the thickness of the drug-loaded self-adhesive matrix. For example, the average diameter of the micro-reservoir corresponding to a substrate having a thickness of 50 μm is preferably 0.5 to 20 μm. The term "average diameter" refers to the average of the x, y, z-average diameters of all the microreservoirs. The target particle size can be adjusted by the solids content and the viscosity of the drug-containing coating.

The maximum and average diameter of the microreservoirs and the number of microreservoirs per surface area of the self-adhesive matrix can be determined as follows: the maximum and average diameter of the microreservoirs and the number of microreservoirs per surface area of the self-adhesive matrix can be determined as follows: the release liner was removed from the TDS and the free adhesive surface was examined by optical microscopy (Leica microscope, model DM/RBE equipped with a Basler A113C camera). Detection was carried out by the accompanying polarized light analysis using a microscope at a magnification of 200 ×. Image analysis was performed using the software Nikon Lucia _ Di, version 4.21, resulting in the average and maximum diameters for each sample.

The TDS of the invention is of the "matrix" type. In the matrix TDS, a drug is dispersed in a polymer layer. The matric TDS in its simplest form comprises a one-phase (monolayer) matrix. Which comprises a backing layer, a self-adhesive matrix containing the active agent and a protective foil or sheet which is removed before use.

More complex forms include multi-layer matrices, wherein the drug may be contained in one or more non-adhesive matrices. The TDS of the invention is preferably a one-phase (monolayer) matrix system.

The solid or semi-solid semipermeable polymer of the self-adhesive matrix must satisfy the following conditions:

1. has sufficient solubility and permeability for rotigotine in its free base form.

2. Has impermeability to the protonated form of rotigotine.

In a particularly preferred embodiment of the invention, the self-adhesive matrix is free of particles capable of absorbing the salt of rotigotine at the TDS/skin interface. Examples of particles capable of absorbing salts of rotigotine at the TDS/skin interface include silica. The particles capable of absorbing the salt of rotigotine at the TDS/skin interface may act as a diffusion barrier to the free base form of the drug and may result in the formation of channels that produce a self-adhesive matrix partially permeable to the protonated form of rotigotine. The described embodiments are therefore not advantageous for the implementation of the present invention.

The self-adhesive matrix of TDS of the present invention comprises a solid or semi-solid semi-permeable polymer. The polymer is typically a Pressure Sensitive Adhesive (PSA) or a mixture of said adhesives. The pressure sensitive adhesive forms a matrix into which the active ingredient and other components of the TDS are incorporated.

The adhesive used in the present invention is preferably pharmaceutically acceptable in the sense that it is biocompatible, non-allergenic and non-irritating to the skin. Particularly advantageous binders for use in the present invention should further meet the following conditions:

1. in the presence of moisture or perspiration, its adhesive and co-adhesive properties are maintained over a normal range of temperature variation,

2. has excellent compatibility with rotigotine, and other excipients used in the formulation.

Although different types of pressure sensitive adhesives may be used in the present invention, it is preferable to use a lipophilic adhesive having both low absorption of drugs and water. It is particularly preferred that the solubility parameter of the binder is lower than the solubility parameter of rotigotine. The preferred pressure sensitive adhesive for the TDS of the present invention is a silicone type pressure sensitive adhesive. A particularly preferred pressure sensitive adhesive for the TDS of the present invention is a Polydimethylsiloxane (PDMS)/resin network type adhesive that forms a soluble poly condensation in which the hydroxyl groups are terminated, for example, with Trimethylsilyl (TMS). Such adhesives are preferably BIO-PSA silicone pressure sensitive adhesives produced by Dow Corning, particularly products having the qualities Q7-4201 and Q7-4301. However, other silicone adhesives may also be used.

In another and particularly preferred aspect, two or more silicone adhesives are used as the primary adhesive component. It is advantageous if the mixture of silicone adhesives comprises a mixture of a high-tack silicone pressure sensitive adhesive comprising a polysiloxane and a resin and a medium-tack silicone type pressure sensitive adhesive comprising a polysiloxane and a resin.

Viscosity refers to the property of an adhesive to form a bond with the surface of another material upon brief contact under light Pressure (see, e.g., "Pressure Sensitive Tack of adhesive using an introduced Probe Machine", ASTM D2979-71 (1982); H.F. Hammond in D.Satas "Handbook of Pressure Sensitive adhesives technology" (1989), second edition, fourth edition, Van Nostrand Reinhold, New York, p. 38).

The medium viscosity of the silicon pressure sensitive adhesive means that direct bonding to the surface of another material is weaker than that of the high viscosity silicon adhesive. The average resin/polymer ratio for medium viscosity adhesive groups is about 60/40, while the average resin/polymer ratio for high viscosity adhesive groups is about 55/45. It is known to those skilled in The art that both tape casting and rheological properties are significantly affected by The resin/polymer ratio (K.L. Ulman and R.P.sweet "The Correlation of tape properties and Rheology" (1998), Information broadcasting, Dow Corning Corp., USA).

The mixture comprising high and medium viscosity silicone-based pressure sensitive adhesives comprising polysiloxanes and resins is beneficial, providing an optimal balance between good adhesion and minimal cold flow. Excessive cold flow can cause the patch to be too soft, making it prone to sticking to the package or the patient's clothing. Moreover, the mixture appears to be particularly suitable for obtaining higher plasma levels. Mixtures of the above Q7-4201 (medium viscosity) and Q7-4301 (high viscosity) are particularly suitable as substrates for the TDS according to the invention.

In another preferred embodiment, the TDS further comprises a crystallization inhibitor. Certain surfactants or amphoteric substances can be used as crystallization inhibitors. They should be pharmaceutically acceptable and have been approved for use in medicine. A particularly preferred example of such a crystallisation inhibitor is soluble polyvinylpyrrolidone, which is commercially available, for example under the trade name Kollidon * (Bayer AG). Other suitable crystallization inhibitors include copolymers of polyvinylpyrrolidone and vinyl acetate, polyethylene glycol, polypropylene glycol, fatty acid esters of glycerol and glycerin, or copolymers of ethylene and vinyl acetate.

The device of the present invention also includes a backing layer that is inert to the matrix component. The backing layer is a thin film that is impermeable to the active compound. The film may comprise polyester, polyamide, polyethylene, polypropylene, polyurethane, polyvinyl chloride, or combinations thereof. These films may or may not be coated with aluminum film or aluminum plating. The back layer may have a thickness of 10 to 100 μm, preferably 15 to 40 μm.

The TDS of the invention also comprises a protective foil or sheet which will be removed immediately before use, i.e. immediately before the TDS will contact the skin. The protective foil or sheet may comprise polyester, polyethylene or polypropylene, which may or may not be coated with aluminium film or aluminium plating or with a fluoropolymer. Typically, the protective foil or sheet has a thickness of 50 to 150 μm. To facilitate removal of the protective foil or sheet when applying TDS, the protective foil or sheet may comprise a separate protective foil or sheet with overlapping edges, similar to the type used for most conventional pastes.

In a preferred embodiment of the present invention, the base area of the TDS is 5 to 50cm²Especially 10-30 cm². Having a width of 20cm²The surface area of the device is pharmacologically equivalent to per cm²Has the same drug content/cm²Two of 10cm²Devices or four 5cm²It is self-evident that the device may be interchanged therewith. Thus, the surface area is herein understood to mean the total surface area of all devices applied to a patient at the same time.

Providing and administering one or several TDS according to the invention has a pharmacological advantage over oral treatment in that the attending physician can relatively quickly and accurately escalate the dose, e.g. by simply increasing the number or size of devices administered to the patient to obtain an optimal dose for the individual patient. Thus, the optimal individual dose can usually be determined only after about three weeks with low side effects.

The preferable content of rotigotine in the TDS is 0.1-2.0 mg/cm². More preferably 0.20 to 1.0mg/cm². Higher drug levels are generally required if a 7 day patch is required.

The device used in the present invention is preferably a patch having a continuous adhesive matrix containing the drug at least in a central portion thereof. However, the invention also includes transdermal equivalents of the patch, such as embodiments where the drug is in an inert but adhesive-free matrix in the central portion of the device and surrounded by adhesive portions along the edges.

The TDS according to the present invention is prepared by a manufacturing method comprising preparing rotigotine loaded adhesive, coating, drying or cooling and laminating to obtain a bulk product, making the laminate into a patch by cutting, and packaging.

The invention and its best mode are described in more detail by the following non-limiting examples.

Inventive example 1 (very Low salt content, Small micro reservoir)

252.6g rotigotine free base was dissolved in 587.8g ethanol 100% w/w and mixed with 222.2g ethanol solution containing 25% w/w polyvinylpyrrolidone (Kollidon F90), 0.11% w/w aqueous sodium bisulfite (10% w/w), 0.25% ascorbyl palmitate and 0.62% DL-alpha-tocopherol. To the homogeneous mixture was added 1692.8g of BIO-PSA Q74301 (73% w/w), 1691.6g of BIO-PSA Q74201 (73% w/w) and 416.3g of petroleum ether, and then all the components were stirred for at least 1 hour to obtain a homogeneous dispersion.

To prepare the patch matrix, the dispersion is coated on a suitable release liner (e.g. Scotchpak1022) and the solvent is continuously removed in a drying oven at temperatures up to 80 ℃ to give a coating weight of 50g/m²The drug-containing adhesive matrix of (1). The dried substrate film was laminated with a polyester type backing film siliconized on the inside and coated with an aluminum plating on the opposite side.

Individual patches were punched out of the complete laminate and then sealed in a bag under nitrogen.

Rotigotine contained in the matrix was released quantitatively after 3 hours of drug dissolution test using the above conditions according to the "tablet over Disk" method described by USP. The results show that the TDS obtained was completely free of rotigotine hydrochloride.

The average size of the micro-storage pools in TDS is about 10 μm, and the typical size is 5-35 μm. Microscopic imaging of the resulting TDS is shown in fig. 5.

COMPARATIVE EXAMPLE 1 (high salt content, small micro-reservoir)

2400g of rotigotine hydrochloride were added to a solution of 272.8g of NaOH in 3488g of ethanol (96%). The resulting mixture was stirred for about 10 minutes. 379.2g of sodium phosphate buffer (27.6g Na) was then added₂HPO₄×2H₂O and 53.2g NaH₂PO₄×2H₂O dissolved in 298.5g of water). Insoluble or precipitated solids were separated from the mixture by filtration. The filter was rinsed with 964g ethanol (96%) to obtain a particle-free ethanol solution of rotigotine substantially in the form of the free base.

A solution of rotigotine in ethanol (30% w/w) (6150g) was mixed with 407g ethanol (96%). Mixing the obtained solution with a solution containing 25 wt.% polyvinylpyrrolidone (Kollidon)^*90F) 0.11 wt.% aqueous sodium bisulfite (10% wt.%), 0.25 wt.% ascorbyl palmitate and 0.62 wt.% DL-alpha-tocopherol in 1738.8g ethanol were mixed until homogenized. To this mixture 13240g of amine resistant high viscosity silicone adhesive (BIO-PSA) was added^*Q7-4301, manufactured by Dow Corning) (73 wt.% heptane solution), 13420g of an amine-resistant medium-viscosity silicone adhesive (BIO-PSA)^*Q7-4201, manufactured by Dow Corning) (72 wt.% solution in heptane), and 3073g petroleum ether, all components then being stirred until a homogeneous dispersion is obtained.

The dispersion is applied to a suitable polyester release liner (e.g., SCOTCHPAK) using a suitable medical knife^*1022) And the solvent was continuously removed in a drying oven (temperature up to 80 ℃ C., about 30 minutes) to give a coating weight of 50g/m²The drug-containing adhesive matrix of (1). Mixing the dried matrix film with polyester backing film (SCOTCHPAK)^*1109) And (6) laminating. Punching out the desired size (e.g. 10 cm) from the complete laminate²、20cm²、30cm²) Then the bag was sealed under nitrogen.

Only about 95% of the rotigotine contained in the matrix was released after 3 hours of drug dissolution testing using the above conditions according to the "tablet over Disk" method described by USP. Thus, the resulting TDS contained approximately 5% (w/w) protonated rotigotine.

The average size of the micro-storage pool in TDS is about 15 μm, and the average size is generally 10-20 μm.

COMPARATIVE EXAMPLE 2 (high salt content, Large micro-reservoir)

150g rotigotine hydrochloride was added to a solution of 17.05g NaOH in 218g ethanol (96%). The resulting mixture was stirred for about 10 minutes. Then 23.7g of sodium phosphate buffer (8.35g Na) was added₂HPO₄×2H₂O and 16.07g NaH₂PO₄×2H₂O dissolved in 90.3g of water). Insoluble or precipitated solids were separated from the mixture by filtration. The filter was rinsed with 60.4g ethanol (96%) to obtain a particle-free ethanol solution of rotigotine substantially in the form of the free base.

A solution of rotigotine in ethanol (35% w/w) (346.4g) was mixed with 36.2g ethanol (96%). Mixing the obtained solution with a solution containing 25 wt.% polyvinylpyrrolidone (KOLLIDON)^*90F) 0.077 wt.% aqueous sodium bisulfite (10% wt.%), 0.25 wt.% ascorbyl palmitate and 0.63 wt.% DL-alpha-tocopherol in 109g ethanol were mixed until homogenized. 817.2g of an amine-resistant high-viscosity silicone adhesive (BIO-PSA) were added to the mixture^*Q7-4301, manufactured by Dow Corning) (74 wt.% heptane solution), 851.8g amine-resistant medium viscosity silicone adhesive (BIO-PSA)^*Q7-4201, manufactured by Dow Corning) (71 wt.% solution in heptane), and 205.8g petroleum ether (heptane), all components were then stirred until a homogeneous dispersion was obtained.

The dispersion was applied to a suitable polyester release liner (SCOTCHPAK) using a suitable medical knife^*1022) And the solvent was continuously removed in a drying oven (temperature up to 80 ℃ C., about 30 minutes) to give a coating weight of 50g/m²The drug-containing adhesive matrix of (1). Mixing the dried matrix film with polyester backing film (SCOTCHPAK)^*1109) And (6) laminating. Punching out the desired size (e.g. 10 cm) from the complete laminate²、20cm²、30cm²) Then the bag was sealed under nitrogen.

Due to the presence of large micro reservoirs in the matrix of TDS, rotigotine salts can be dissolved by direct contact with the dissolution medium. It is therefore not possible to determine the amount of the protonated form of rotigotine. This suggests that the maximum diameter of the micro-reservoirs is greater than the thickness of the substrate.

The average size of the micro-storage pools in TDS is about 50 μm, and the average size is 20-90 μm. Microscopic imaging of the resulting TDS is shown in fig. 4.

Following a similar procedure to that of comparative example 1 to release rotigotine from rotigotine hydrochloride, it can be concluded that the resulting TDS also contained 5% (w/w) of the protonated form of rotigotine.

COMPARATIVE EXAMPLE 3 (acrylate-type preparation)

A mixture of 50.0g rotigotine hydrochloride and 28.6g sodium trisilicate in 95g methyl ethyl ketone was stirred at room temperature for 48 hours. Subsequently, 17.9g oleyl alcohol, 128.6g of an acrylic-type adhesive solution (51.4% w/w in ethyl acetate; trade name: Durotak) was added^*387 2287 obtained from NATIONAL STARCH& CHEMICAL)，33.0g EUDRAGIT^*E100 (obtained from ROEHM PHARMA) (50% w/w in ethyl acetate) and 45.0g of ethyl acetate, and the resulting mixture was then mechanically homogenized.

The dispersion is applied to a siliconized liner (e.g. Hostaphan)^*RN 100) and evaporating the solvent at 50 ℃ for more than 30 minutes, whereby a weight of 60g/m is obtained²The substrate of (1). The dried matrix film is coated with a suitable polyester foil (Hostaphan)^*RN 15) lamination. Punching out of the resulting laminate to a desired size (e.g. 20 cm)²) Then the bag was sealed under nitrogen.

Example 2

In vivo drug absorption test

To monitor the uptake of rotigotine by human skin, the following tests were performed. Tests were carried out on TDS obtained from example 1 and comparative examples 1 and 2.

Time profiles of plasma concentrations at different test times were determined in pharmacokinetic experiments involving (a)14 healthy men (TDS of comparative examples 2 and 3) or (B)30 healthy men (TDS of example 1 and comparative example 1), respectively. The experiments were performed as either (B) two-way or (a) three-way crossover designs with open single-dose randomization.

The individual concentration of rotigotine was determined by liquid chromatography and mass spectrometry. The lower limit of quantitation (LOQ) was 10 pg/ml.

Drug absorption was calculated from the Plasma concentration data according to the Wagner-Nelson method (Malcom Rowland, Thomas N.Tozer (Eds.) "Estimation of absorption Kinetics from Plasma concentration data" in Clinical pharmaceuticals, pp 480-483, Williams & Wilkins, 1995), with an absorption rate after 48 hours of 100%; patch application time was 24 hours.

A comparison of flux through human skin for the different TDSs tested is shown in figures 1, 2 and 3.

In fig. 1, the rotigotine absorption obtained from the salt-free sample (∘) of example 1 and the rotigotine absorption obtained from the sample containing about 5% (w/w) rotigotine hydrochloride (●) of comparative example 1 were compared. The comparison in figure 1 clearly shows that the absorption of the drug after application of the patch depends on the residual salt content in the semipermeable matrix and can be significantly improved by reducing the amount of the protonated form of rotigotine present in the matrix.

FIG. 2 shows the effect of the size distribution of the micro reservoirs distributed in a semipermeable matrix by comparing the samples obtained from comparative example 1 with a mean micro reservoir size of about 15 μm and typical sizes of 10 to 20 μm (●) with the samples obtained from comparative example 2 with a mean micro reservoir size of about 50 μm and typical sizes of 20 to 90 μm (. tangle-solidup.). From this comparison, it can be deduced that decreasing the size of the matrix micro-reservoirs can significantly increase flux through human skin.

FIG. 3 shows a comparison between the TDS of example 1 (. smallcircle.) and of comparative example 2 (. tangle-solidup.). This comparison clearly shows that flux through human skin can be significantly enhanced by reducing the salt content and reducing the size of the micro-reservoir.

Example 3

In vitro diffusion assay for transdermal drug delivery systems

The test was performed using a sandwich of a supporting separator membrane, skin and TDS adjacent. The active substance diffusing from the TDS through the skin and/or the membrane is dissolved in the absorption liquid passing continuously under the membrane; collecting the absorption liquid in a test tube in a flow collector; fractions were then analyzed for rotigotine content. The flux of the active substance through the skin is calculated by correcting the influence of the separator membrane.

The diffusion cell described by Tanojo et al (Tanojo et al, "New design of a flow through polymerization cells for in vitro polymerization assays" Journal of Controlled Release (1997), 45, 41-47) was used in order to carry out the experiments.

The flask containing the absorption solution and assembled diffusion cell was placed in a temperature controlled water bath (32.0 + -0.5 deg.C). The absorption solution was continuously pumped from the flask through the PTFE tube by a peristaltic pump, through a diffusion cell where diffusion occurred, and then transferred through the PTFE tube to a test tube placed in a flow collector.

A circular knife was used to punch the required number of discs from the TDS. Human epidermis (used to refer to skin) with a thickness of 200-300 μm cut from fresh donor skin (4 ℃, stored for 36 hours) with a skin-remover was spread on a laboratory film in a petri dish. And punching the required number of wafers by using an annular cutter. A piece of membrane was placed in the center of each cell surface. A skin disk was spread on the membrane on the surface of the well with forceps. Discs of TDS were applied to each well and the wells were then assembled. The test was then carried out in a similar manner to that described by Tanojo et al, supra.

The tubes containing the recovered fractions were then weighed and the content of each tube was analyzed by HPLC.

This experiment was performed on TDS obtained from example 1 and comparative examples 2 and 3.

Fig. 6 shows in vitro skin permeation profiles of TDS of example 1(●) compared to TDS of comparative example 2(∘).

Figure 7 shows in vitro skin permeation profiles of TDS of example 1(●) compared to acrylate TDS of comparative example 3(∘).

It is clear from the data obtained that the flux through human skin can be significantly improved by controlling the size of the micro reservoirs in the TDS while providing a semipermeable matrix which is highly permeable to the free base of rotigotine and impermeable to its protonated form.

Claims (7)

1. A Transdermal Delivery System (TDS) comprising a backing layer inert to the components of the matrix, a self-adhesive matrix comprising rotigotine and a protective foil or sheet to be removed before use, characterised in that

The self-adhesive matrix comprises a solid or semi-solid semi-permeable polymer

(1) Wherein rotigotine in free base form has been incorporated,

(2) which is saturated with rotigotine and comprises said rotigotine in a plurality of micro-reservoirs in a matrix,

(3) which is highly permeable to the free base of rotigotine,

(4) which is impermeable to the protonated form of rotigotine,

(5) wherein the maximum diameter of the micro-reservoirs is less than the thickness of the substrate.

2. TDS according to claim 1, characterized in that the average diameter of the micro reservoirs is 0.5 to 20 μm.

3. TDS according to claim 1 or 2, characterized in that the self-adhesive matrix is free of particles capable of absorbing salts of rotigotine at the TDS/skin interface.

4. TDS according to any of the claims 1-3, characterized in that the polymer matrix comprises a pressure sensitive adhesive of the silicone type.

5. TDS according to any of the claims 1-4, characterized in that the polymer matrix comprises two or more pressure sensitive adhesives of the silicone type as main adhesive components.

6. The TDS according to claim 5, wherein the silicone-based pressure sensitive adhesive is a mixture of a high viscosity silicone-based pressure sensitive adhesive comprising polysiloxane and resin and a medium viscosity silicone-based pressure sensitive adhesive comprising polysiloxane and resin.

7. Method of treating a patient suffering from a rotigotine treatable disease by administering a TDS according to any of claims 1 to 6 to the skin of the patient.