Transdermal therapeutic system of lumarizine

Abstract

The present invention relates to a transdermal therapeutic system for the administration of the active ingredient lumefanorum comprising a backing layer and at least one active ingredient-containing layer, which comprises the active ingredient in free base or salt form embedded in a polymeric matrix, wherein the polymeric matrix comprises a polymer selected from (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer and mixtures thereof. The transdermal therapeutic system can further comprise an adhesive layer, a film layer and a release liner.

Description

Technical Field

[0001] This invention relates to a transdermal therapeutic system for administering lumateperone. Background Technology

[0002] Lumepirolone, namely 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-but-1-one, also known as "ITI-007", is a potent 5-HT 2A The receptor ligand exhibits strong affinity for the dopamine (DA)-D2 receptor and the serotonin transporter (SERT). Lumepiride has the following structure:

[0003]

[0004] Lumepiride free base

[0005] Lumepiride, its analogues, its salts, as well as treatments containing such compounds and methods for preparing such compounds have been disclosed in a number of patent applications, including, for example, WO 2020 / 047241 A1 and other patent documents mentioned in paragraph

[0003] of WO 2020 / 047241A1 (hereinafter referred to as WO'241).

[0006] This drug was approved in the United States in December 2019 for the treatment of schizophrenia and in December 2021 for the treatment of type I and type II bipolar depression. The commercial formulation of rumepiride is marketed under the brand name Caplyta®. This product is permitted for administration only as a once-daily oral capsule, with each capsule containing 10.5 mg, 21 mg, or 42 mg of rumepiride. The active ingredient is used in its tosylate form, where each capsule contains 60 mg (30 mg or 15 mg) of rumepiride free base, equivalent to 42 mg (21 mg or 10.5 mg).

[0007] Lumepiride has a very low oral bioavailability of only about 4.4% due to its strong first-pass metabolism in the liver. This makes the development of alternative dosage forms extremely necessary.

[0008] Transdermal therapy systems (TDS) are well-known alternatives to other dosage forms, especially oral dosage forms. TDS typically offer several advantages, including, for example, higher bioavailability through transdermal delivery, which allows for a reduction in the amount of drug in the formulation; better patient compliance with multi-day patches instead of once-daily oral administration; avoidance of first-pass effects; reduced fluctuations in plasma levels; and so on.

[0009] WO'241 describes a transdermal therapeutic system for lumepone. The TDS according to WO'241 contains lumepone (in free base or salt form), an adhesive polymer, and optional other excipients, including penetration enhancers and antioxidants. Penetration enhancers, and certain combinations thereof, are used to enhance penetration and in vivo drug delivery. Antioxidants are said to improve the chemical stability of the formulation by preventing oxidative chemical degradation of the active ingredient.

[0010] Aside from permeability (achieved through certain permeation enhancers and combinations thereof) and chemical stability (short-term), WO'241 failed to address some other properties required for transdermal therapeutic systems.

[0011] While WO'241 generally discloses the use of acrylate adhesives, silicone adhesives, and mixtures thereof, WO'241 does not contain any suggestion of using other polymer adhesives.

[0012] For example, WO'241 completely fails to address the need for high adhesion. Achieving high adhesion is essential for providing patches that can be used for one day, especially if they are expected to last for several days.

[0013] Furthermore, WO'241 does not address the need for providing physically stable transdermal therapeutic systems, namely, inhibiting the crystallization of active ingredients during storage. Crystallization of active ingredients from TDS is problematic because, in addition to adverse effects on therapeutic efficacy and matrix appearance, it can also negatively impact in vitro drug release, adhesive strength, tack, and shear properties of the TDS.

[0014] Although the pharmaceutical formulations disclosed in WO'241 are chemically stable under short-term storage at room temperature (i.e., up to two months), WO'241 does not address the need for chemical stability of the system under long-term and accelerated conditions for longer periods (i.e., months).

[0015] Furthermore, WO'241 did not address the relationship between drug loading and matrix weight. This is an important aspect to consider when achieving sustained penetration over several days.

[0016] Finally, the use of penetration enhancers appears necessary for achieving sufficient penetration in the WO'241 system, but is often accompanied by drawbacks such as skin irritation. They also complicate the preparation of transdermal therapeutic systems because they are volatile upon drying, efflux into the lipophilic matrix, and adversely affect adhesion and cohesion. From a regulatory perspective, enhancers make development more difficult and expensive because they must be quantified, controlled, and their effects on in vivo performance must be demonstrated. Specific requirements for enhancers are outlined in "Guideline on excipients in the dossier for application for marketing authorization of a medicinal product" (EMEA / CPMP / CVMP / QWP / 396951 / 2006). Given these drawbacks of using penetration enhancers, it would be desirable to provide a rumeperone transdermal therapeutic system with good penetration properties without the use of enhancers.

[0017] In conclusion, further or improved Lumepiride transdermal therapy systems are still needed.

[0018] Therefore, the object of the present invention is to provide a physically and chemically stable lumepiderm transdermal therapeutic system that exhibits sufficiently high and substantially constant permeability, as well as high adhesion over a preferred number of days (e.g., at least 2 or 3 days), allowing the transdermal therapeutic system to be used as a multi-day patch. Ideally, such a transdermal therapeutic system does not require the use of a penetration enhancer. Summary of the Invention

[0019] The present invention attempts to achieve this objective through the following aspects.

[0020] In a first aspect, the present invention provides a transdermal therapeutic system for administering the active ingredient lumepirox ...

[0021] a) Backing layer, and

[0022] b) At least one layer containing an active ingredient, which comprises the active ingredient in the form of a free base or salt embedded in a polymer matrix.

[0023] Its features are:

[0024] The polymer matrix comprises polymers selected from the following: (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer and mixtures thereof.

[0025] It has been found that the transdermal therapy system of the present invention has sufficiently high and substantially constant permeability, preferably without the need for the use of a permeability enhancer.

[0026] As used herein, "constant permeability" refers to a permeation rate (expressed as the amount of permeation per unit time and per unit surface area) that does not change significantly over extended time intervals, resulting in a substantially linear cumulative permeation curve. However, a so-called lag time may occur, particularly in the initial stages, during which permeation does not exhibit a constant permeation rate. Furthermore, the permeation rate may decrease at very late time points due to very strong release from the system. Permeability can be determined in ways known to those skilled in the art, such as the NovoCell Schönbach in vitro permeability test performed according to OECD (2004) Test Guideline 428 "Skin absorption: In vitro Method & Series on testing and assessment", No. 28 "Guidance document for the conduct of skin absorption studies".

[0027] Furthermore, it has been found that the transdermal therapeutic system of the present invention has high adhesion suitable for at least one day (e.g., 2 or 3 days), which makes the transdermal therapeutic system of the present invention usable as a multi-day patch.

[0028] Furthermore, the transdermal therapy system of the present invention is physically and chemically stable during storage.

[0029] In a second aspect, the present invention provides a transdermal treatment system according to the first aspect, wherein the system further comprises:

[0030] c) An adhesive layer on top of the layer containing the active pharmaceutical ingredient.

[0031] The adhesive layer comprises at least one adhesive polymer.

[0032] The adhesive layer initially does not contain any active ingredients, and

[0033] The adhesive layer mentioned above is the skin contact layer of the system.

[0034] "Initially free of active ingredients" means that the adhesive layer does not contain any active ingredients before it comes into contact with the layer containing active ingredients. Once laminated, a certain amount of active ingredients diffuses from the layer containing active ingredients into the adhesive layer.

[0035] It has been found that by using an adhesive layer in the transdermal therapeutic system according to the second aspect of the invention, the time period of constant permeation can be extended, for example, by 1 or 2 days, or from 2 days to 3 days. Furthermore, the adhesiveness of the transdermal therapeutic system can be increased. Compared to systems without an adhesive layer, this extends the usable time of the transdermal therapeutic system, for example, by 1 or 2 days.

[0036] In a third aspect, the present invention provides a transdermal therapeutic system according to the second aspect, wherein the system further comprises:

[0037] d) The film layer between the layer containing the active ingredient and the adhesive layer,

[0038] The membrane layer comprises a membrane polymer that can permeate the active ingredient and control the release of the active ingredient.

[0039] It has been found that by using a membrane layer between the active ingredient layer and the adhesive layer according to the third aspect, the time period of constant permeation can be extended, for example, by 1 to 3 days, compared with systems that do not contain a membrane layer.

[0040] In another aspect, the present invention provides a method for preparing a transdermal therapeutic system according to the present invention, comprising the following steps:

[0041] (a) Preparation of a layer composition containing an active ingredient,

[0042] (b) Apply the composition prepared in step (a) onto the release liner (i).

[0043] (c) The components prepared in drying step (b), and

[0044] (d) Laminating the backing layer onto the active ingredient layer of the component prepared in step (c);

[0045] Optionally, in addition to steps (a)-(d), the following steps are also included:

[0046] (e) Preparation of the adhesive layer composition,

[0047] (f) Apply the composition prepared in step (e) onto the release liner (ii).

[0048] (g) The components prepared in drying step (f),

[0049] (h) Remove the release liner (i) from the components prepared in step (d).

[0050] (i) Press the active ingredient-containing layer prepared in step (h) onto the adhesive layer of the component prepared in step (g), or vice versa;

[0051] Alternatively, in addition to steps (a)-(d), the following steps may also be included:

[0052] (j) Laminating a membrane layer suitable for controlling the release of the active ingredient onto the active ingredient-containing layer of the component prepared according to step (h),

[0053] (k) Perform steps (e) through (g),

[0054] (l) Laminate the adhesive layer of the component prepared in step (k) onto the film layer of the component prepared in step (j), or vice versa.

[0055] In another respect, the present invention relates to the use of polymers selected from the following: (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer and mixtures thereof, for stabilizing lumepiroline free base in a transdermal therapeutic system or reducing the degradation of lumepiroline free base in a transdermal therapeutic system, preferably the transdermal therapeutic system of the present invention.

[0056] In another aspect, the present invention relates to the use of antioxidants, preferably ascorbic acid or tocopherol, in a transdermal therapeutic system according to the invention to reduce, preferably inhibit, the formation of N-nitrosamines in the system.

[0057] On the other hand, a transdermal therapeutic system according to the invention is provided for the treatment of a method for diseases selected from: major depressive disorder (MDD) and associated mixed features, bipolar I or II, and schizophrenia.

[0058] In another aspect of the invention, rumepiride is provided for the treatment of a disease selected from major depressive disorder (MDD) and its associated mixed features, bipolar I or II, and schizophrenia, wherein rumepiride is administered via the patient’s skin in the form of a free base or salt through the transdermal treatment system of the invention.

[0059] The above aspects should be understood as being freely combinable unless otherwise stated. Attached Figure Description

[0060] Figure 1 This is a cross-sectional view of the TDS according to various aspects of the present invention. Figure 1 -A's TDS includes a backing layer, an active ingredient-containing layer, and a release liner according to the first aspect of the invention. Figure 1 -B's TDS includes a backing layer, a first layer containing an active ingredient, a second layer containing an active ingredient, and a release liner, which is also according to a first aspect of the invention. According to Figure 1-C's TDS includes a backing layer, an active ingredient-containing layer, an adhesive layer, and a release liner according to a second aspect of the invention. Figure 1 -D's TDS includes a backing layer, an active ingredient layer, a film layer, an adhesive layer, and a release liner according to the third aspect of the invention.

[0061] Figure 2-5 Adhesive strength measured for various samples prepared in Examples 1.1 to 1.4 after storage at 40 °C / 75% RH is shown, compared with prior art patches Neupro® (a 1-day patch containing rotigotine and BIO-PSA Q7-4301 & 4201), FNT (a 3-day patch containing fentanyl and Duro-Tak® 87-4098), and FTA (a 3-day patch containing fentanyl and Duro-Tak® 387-2510). Figure 6 The adhesive strength of the various samples prepared in Example 1.2 is shown with and without the reinforcing agent.

[0062] Figure 7-10 The adhesion of the various samples prepared in Examples 1.1 to 1.4 is shown after storage at 40 °C / 75% RH, compared to the prior art patch Neupro®. Figure 11 The adhesion of the various samples prepared in Example 1.2 is shown with and without the reinforcing agent.

[0063] Figure 12-15 The separation force required to remove the release liner after storage at 40 °C / 75% RH, compared to prior art patch FTA, is shown. This separation force was measured for various samples prepared in Examples 1.1 to 1.4. Figure 16 The separation force required to remove the release liner from the various samples prepared in Example 1.2 is shown, with and without the reinforcing agent.

[0064] Figure 17-20 The cumulative permeation of lumepirocin [µg / cm³] of various samples prepared in Examples 1.1 to 1.4 is shown on a human skin model (HSE) over a period of 96 hours. 2 ].

[0065] Figure 21 The cumulative permeation of lumepirocin on a human skin model (HSE) over 96 hours is shown in µg / cm³ for various samples prepared in Example 1.2. 2 ].

[0066] Figure 22 The chemical stability of the samples prepared in Examples 1.1 and 1.3 after storage at 40°C / 75% RH for 6 months is shown.

[0067] Figure 23 The chemical stability of the sample prepared in Example 1.2 after storage at 40 °C / 75% RH for 6 months is shown. Invention Details

[0069] The invention will be described in further detail below. Unless otherwise stated, the description of the various features applies to all aspects of the invention and can be freely combined.

[0070] definition

[0071] The transdermal therapy system ("TDS") of the present invention may also be referred to as a patch. The TDS of the present invention is intended to be applied to the skin of patients in need, namely patients requiring lumepirox treatment.

[0072] In this invention, the "active ingredient" is lumepirozoline, specifically 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalo-8-yl)-but-1-one. The active ingredient is used in the TDS of this invention in either free base form or salt form. "Salt form" means a pharmaceutically acceptable salt form, wherein the salt form can be amorphous or polymorphic. The salt form of lumepirozoline may be selected from toluenesulfonate, oxalate, cyclosulfonate, 4-aminosalicylic acid salt, or hydrochloride salt forms, wherein toluenesulfonate is the preferred salt form. However, in this invention, the free base form of lumepirozoline is preferred. This applies to all aspects and embodiments of the invention.

[0073] A "polymer matrix" is a solid or semi-solid composition having a three-dimensional structure, comprising one or a mixture of polymers. In this invention, the polymer matrix comprises an acrylate polymer or copolymer containing free hydroxyl groups. The polymer matrix is ​​also referred to as a polymer backbone because the three-dimensional backbone structure is typically provided by a polymer or a mixture of polymers. Preferably, the active ingredient is uniformly distributed within the polymer matrix.

[0074] As described herein, the term "a" refers to one or more elements. For example, the term "an acrylate polymer" refers to one or more acrylate polymers.

[0075] Unless otherwise stated, percentages refer to weight percentages, abbreviated as "wt.-%". Unless otherwise stated, weight percentages are given relative to dried products, such as dried layers containing active ingredients or dried adhesive layers.

[0076] In the TDS according to the invention, the active ingredient is chemically sufficiently stable. "Sufficiently stable" means that after storage at 40°C and 75% relative humidity (RH) for one month, the total amount of degradation products of the active ingredient preferably does not exceed about 1 wt%, more preferably not more than about 0.5 wt%, based on the desired content of the active ingredient in the system. Preferably, after storage at 40°C and 75% relative humidity for three months, the total amount of degradation products is less than about 2 wt%, more preferably less than about 0.6 wt%. Even more preferably, after storage at 40°C and 75% relative humidity for six months, the total amount of degradation products is less than about 4 wt%, more preferably less than 3 wt%. Information regarding degradation products in "wt.-%" always refers to the amount of active ingredient in the formulation unless otherwise stated.

[0077] In the TDS according to the invention, the active ingredient is also physically stable. "Physically stable" means that crystallization of the active ingredient is inhibited during storage at room temperature for at least 12 months, or at 40°C and 75% relative humidity for at least 6 months, preferably 12 months. Preferably, "physically stable" also means that the stability of adhesive strength, tack, and release force is substantially maintained during storage at room temperature for at least 12 months, or at 40°C and 75% relative humidity for at least 6 months, preferably 12 months. The term "substantially maintained" means a change of no more than ±10%, no more than ±5%, or no more than ±2.5%.

[0078] The application period of the TDS according to the present invention is at least one day, preferably at least two days, for example two to three days, more preferably at least three days, for example three to four days.

[0079] While penetration enhancers can be used in the TDS of the present invention (i.e., in the layers and / or adhesive layers containing the active ingredient), it is preferred that the TDS of the present invention does not contain penetration enhancers. In particular, the TDS of the present invention does not contain the penetration enhancers used in WO'241, including fatty acid esters (e.g., lauryl lactate, isopropyl myristate, oleic acid ester, methyl laurate, isopropyl palmitate, ethyl oleate), fatty alcohols (dodecyl alcohol, octyldecyl alcohol, lauryl alcohol, alcohols (e.g., propylene glycol), amine oxides (e.g., dimethyl dodecylamine oxide, myristamine oxide), carboxylic acids (e.g., α-hydroxy acids, such as lactic acid), decanoates (e.g., methyl decanoate, propylene glycol didecanoate / dioctanoate) and combinations thereof, such as lauryl lactate / propylene glycol.

[0080] TDS structure

[0081] The TDS of the present invention comprises multiple layers.

[0082] The backing layer is located on the back of the TDS.

[0083] The layer containing the active ingredient is located on the skin-facing side of the backing layer (after application of the TDS). In a first aspect of the invention, the layer containing the active ingredient is a skin contact layer protected by a release liner during storage. Therefore, the first aspect of the invention relates to a TDS comprising the following layers in the following order (see...). Figure 1 -A):

[0084] 1. Backing layer

[0085] 2. The first layer containing active ingredients

[0086] 3. Release liner.

[0087] In one embodiment, the TDS of the present invention comprises two laminated layers containing active ingredients. In this case, the TDS according to the first aspect of the present invention comprises the following layers, in the following order ( Figure 1 -B):

[0088] 1. Backing layer

[0089] 2. The first layer containing active ingredients

[0090] 3. The second layer containing active ingredients

[0091] 4. Release liner.

[0092] In a second aspect of the invention, an adhesive layer is deposited on a layer containing active ingredients that faces the human skin during use. In this second aspect, the adhesive layer is a skin contact layer protected by a release liner during storage. Therefore, the second aspect of the invention relates to a TDS comprising the following layers in the following order ( Figure 1 -C):

[0093] 1. Backing layer

[0094] 2. Layer containing active ingredients

[0095] 3. Adhesive layer

[0096] 4. Release liner.

[0097] In a third aspect of the invention, the TDS comprises a film layer deposited between a layer containing an active ingredient and an adhesive layer. Therefore, the third aspect of the invention relates to a TDS comprising the following layers, in the following order ( Figure 1 -D):

[0098] 1. Backing layer

[0099] 2. Layer containing active ingredients

[0100] 3. Membrane layer

[0101] 4. Adhesive layer

[0102] 5. Release liner

[0103] Prior to the use of TDS, release liner is deposited on the active ingredient layer (first side) and the adhesive layers (second and third sides), respectively, and these layers are protected before the use of TDS. The release liner is removed before the use of TDS.

[0104] In one embodiment, the area of ​​the backing layer of the TDS according to the present invention corresponds at least to the area of ​​the layer or adhesive layer containing the active ingredient.

[0105] Layer containing active ingredients

[0106] The TDS according to the present invention comprises at least one layer containing an active ingredient. Generally, this means that the TDS of the present invention contains one layer containing an active ingredient. However, the TDS of the present invention may also contain two layers containing active ingredients, particularly when the weight of the layers containing active ingredients exceeds 100 g / m³. 2 In this case, two layers containing the active ingredient can be used instead of one. These two layers are typically identical in composition and size and are laminated together to achieve 100 g / m². 2 Weights of 100 to 150 g / m³ and above 2 For example, if the target is 130 g / m³ 2 Based on the substrate weight, a substrate weight of 75g / m² can be used per layer. 2 It has two layers containing active ingredients.

[0107] The active ingredient layer of the TDS according to the present invention contains lumepirozol, an active ingredient in the form of a free base or salt embedded in a polymer matrix.

[0108] Preferably, the active ingredient layer of the TDS according to the present invention contains 5 to 20% by weight, more preferably 10 to 15% by weight, and particularly preferably 11 to 13% by weight of the active ingredient lumepirozol.

[0109] Preferably, the active ingredient layer of the TDS according to the invention contains 65 to 95% by weight, more preferably 70 to 90% by weight or 75 to 85% by weight, and particularly preferably 80 to 85% by weight of a polymer matrix.

[0110] The polymer matrix comprises polymers selected from the following: (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer, and mixtures thereof.

[0111] (1) Polyisobutylene

[0112] Polyisobutylene (PIB), also known as polyisobutylene, is commercially available.

[0113] Examples of polyisobutylenes (also known as polyisobutylenes) suitable for use in this invention include commercial products Duro-Tak® 87-6900, Duro-Tak® 87-626A, and Duro-Tak® 87-625A, or mixtures thereof. In one embodiment, the polymer matrix contains only one type of polyisobutylene. In a preferred embodiment, the polymer matrix contains a mixture of two or more types of polyisobutylenes. In one embodiment, the polymer matrix contains at least two types of polyisobutylenes. In one embodiment, the polymer matrix contains two types of polyisobutylenes, PIB A and PIB B, in a weight ratio of PIB A:PIB B of 1:10 to 10:1, or 1.3 to 3:1.

[0114] Preferred examples of polyisobutylene suitable as the adhesive polymer in the TDS adhesive layer of this invention are products Duro-Tak® 87-626A and Duro-Tak® 87-6900. These products are preferably used in a 1:1 mixture. The two products have different molecular weights.

[0115] It has been further discovered that the adhesive strength of polyisobutylene-based layers containing active ingredients can be improved by adding polybutene (a plasticizer), such as products Indopol® H-1900 and H-18000. Indopol® H-1900 has an average molecular weight M... N Approximately 2,500 g / mol of polybutene. Indopol® H-18000 has an average molecular weight M N Approximately 6,000 g / mol of polybutene. Average molecular weight M N "It is the number-average molar mass, which can be determined according to American standards ASTM D3536-91 or ASTM D5296-05. Polyisobutylene and polybutene are preferably used in a weight ratio of 4:1 to 1:2, more preferably 3:1 to 1:2. For example, polyisobutylene and polybutene may be present in a weight ratio of about 1:1."

[0116] It has been found in this invention that sufficiently high penetration can be achieved when using polymer matrices based on (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer, and mixtures thereof, resulting in sufficiently high flux to achieve sufficiently small patch size. This can be achieved without the use of skin penetration enhancers. Furthermore, (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer, and mixtures thereof exhibit promisingly high adhesion (adhesive strength and tack) compared to commercially available one-day and three-day patches. Regarding chemical stability, the four polymers show adequate or even good stability to the free base of the active ingredient lumepirolen in the active ingredient layer compared to prior art acrylate polymers.

[0117] (2) Styrene-butadiene-styrene copolymer

[0118] Styrene-butadiene-styrene copolymers, also known as styrene-based rubber polymers, are also suitable as polymer matrix polymers. Preferably, the copolymer is a block copolymer.

[0119] Examples of suitable silicone adhesives include Duro-Tak® 87-6911 (containing a petroleum-based hydrocarbon resin) and Duro-Tak® 87-6173 (containing a resin derived from hydrogenated rosin glycerol esters). In a particularly preferred embodiment, the styrene-butadiene-styrene copolymer is the product Duro-Tak® 87-6911, which is a mixture of styrene-butadiene-styrene and styrene-butadiene block copolymers with a tackifier (resin) composed of a petroleum-based hydrocarbon resin.

[0120] (3) Silicone-acrylate hybrid polymer

[0121] The silicone-acrylate hybrid polymer comprises polymerizable hybrid species, including co-polymerizable silicone subspecies and acrylate subspecies. Therefore, the silicone-acrylate hybrid polymer comprises a silicone domain and an acrylate domain. Preferably, the silicone-acrylate hybrid polymer is a silicone-acrylate hybrid pressure-sensitive adhesive.

[0122] Preferably, the weight ratio of silicone to acrylate in the silicone-acrylate hybrid polymer is 5:95 to 95:5, or 20:80 to 80:20, more preferably 40:60 to 60:40, and most preferably the ratio of silicone to acrylate is about 50:50.

[0123] Examples of suitable silicone-acrylate hybrid polymers include BIO-PSA 7-6302 (high tack; in ethyl acetate) and BIO-PSA 7-6102 (low tack; in ethyl acetate), as well as BIO-PSA 7-6301 (high tack; in n-heptane) and BIO-PSA 7-6101 (low tack; in n-heptane), and Duro-Tak® SH 87-500.

[0124] Silicone-acrylate hybrid polymers are preferred, using ethyl acetate as a solvent, in which the active ingredient in its free base form is soluble. Such commercially available products typically contain between 30% and 70% solids.

[0125] (4) Styrene-isoprene-styrene copolymer

[0126] Styrene-isoprene-styrene copolymer is a preferred block copolymer.

[0127] Examples of styrene-isoprene-styrene copolymers include, for example, SIS 5002, SIS 5229, and styrene, isoprene, and styrene block copolymers from JSR Corporation of Japan.

[0128] In one embodiment, the layer containing the active ingredient consists of the active ingredient and a polymer matrix.

[0129] In addition to the active ingredient and the matrix polymer, the layer containing the active ingredient may optionally include other excipients known in the art. Preferably, these other excipients are selected from antioxidants, penetration enhancers, plasticizers, thickeners, crystallization inhibitors, and substances that enhance cohesion. Furthermore, substances that trigger the in-situ release of lumepiroline free base when the active ingredient is used in salt form may be added.

[0130] The excipients used in the active ingredient layer are typically up to 75% by weight, for example, 0.05 to 75 wt.-%, 0.1 to 70 wt.-%, 0.5 to 65 wt.-%, 1 to 60 wt.-%, 1 to 55 wt.-%, 1 to 50 wt.-%, 1 to 45 wt.-%, 2 to 40 wt.-%, 2.5 to 35 wt.-%, 2.5 to 10 wt.-%, 5 to 10 wt.-%, or 10 to 15 wt.-%, based on the total weight of the (dry) active ingredient layer.

[0131] Antioxidants suitable for the active ingredient-containing layer of the system of the present invention include tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), N,N'-bis[3-propionamide]Irganox®, tris(2,4-di-tert-butylphenyl) phosphite Irgafos®, ascorbic acid, ascorbyl palmitate, and combinations thereof. Antioxidants are typically present in the active ingredient-containing layer in an amount of 0.05 to 2% by weight, preferably 0.05 to 1.75% by weight, more preferably 0.05 to 1.5% by weight, and even more preferably 0.05 to 1.1% by weight, based on the total weight of the active ingredient-containing layer. Tocopherol and / or ascorbyl palmitate are preferred antioxidants used in the active ingredient-containing layer. The role of antioxidants is to improve the chemical stability of the active ingredient during TDS storage by preventing oxidative chemical degradation. They can also help inhibit the formation of N-nitrosamines in pharmaceutical products.

[0132] The inventors have also discovered that the use of antioxidants in the TDS of the present invention, particularly in the active ingredient-containing layer of the TDS of the present invention, advantageously reduces, and preferably inhibits, the degradation of the active ingredient, especially the formation of N-nitrosamines during storage of the transdermal therapeutic system. Those skilled in the art understand the term N-nitrosamine and which compounds it refers to. N-nitrosamines are carcinogenic compounds and are only permitted in very small amounts by regulatory agencies in pharmaceuticals including transdermal therapeutic systems. N-nitrosamines can form in active ingredients having secondary or tertiary amine functional groups (such as lumepirolenone) under certain conditions that promote nitrosamine formation (e.g., high temperatures during finished product storage). The inventors have found that antioxidants, particularly ascorbic acid and tocopherol, reduce, and preferably prevent, the formation of N-nitrosamines in the TDS of the present invention by stabilizing the active ingredient (especially during storage).

[0133] Plasticizers (softeners) suitable for the active ingredient layer include polybutene, fatty acid esters such as decanoyl and octanoyl glycerides or mixtures thereof (such as product Miglyol® 812), and hydrocarbon mixtures such as paraffin. The plasticizer is typically present in the active ingredient layer in an amount of 1 to 5% by weight, for example 2.5% by weight, based on the total weight of the (dry) active ingredient layer. In one embodiment, the TDS of the present invention is plasticizer-free. In one embodiment, the active ingredient layer contains 1 to 60% by weight of plasticizer. Particularly when the polymer matrix contains polyisobutylene, it is preferred that the active ingredient layer contains 1 to 60% by weight, or 20 to 50% by weight, of plasticizer.

[0134] The penetration enhancers suitable for use in this invention include those disclosed in WO'241, namely fatty acid esters (e.g., lauryl lactate, isopropyl myristate, oleic acid ester, methyl laurate, isopropyl palmitate, ethyl oleate), fatty alcohols (dodecyl alcohol, octyldecyl alcohol, lauryl alcohol, alcohols (e.g., propylene glycol), amine oxides (e.g., dimethyl dodecylamine oxide, myristamine oxide), carboxylic acids (e.g., α-hydroxy acids, such as lactic acid), decanoates (e.g., methyl decanoate, propylene glycol didecanoate / dioctanoate), and combinations thereof, such as lauryl lactate / propylene glycol. The penetration enhancer or combination of penetration enhancers is typically present in the layer containing the active ingredient in an amount of 1 to 10% by weight, based on the total weight of the layer containing the active ingredient. However, in this invention, it is preferred that the layer containing the active ingredient does not contain the penetration enhancer. Particularly preferred is that the layer containing the active ingredient does not contain the penetration enhancers used in the transdermal therapeutic systems disclosed in WO'241.

[0135] Materials suitable for enhancing the cohesiveness of layers containing active ingredients include cationic copolymers of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, such as Eudragit® E100, Plastoid® B (butyl methacrylate and methyl methacrylate copolymer), polyvinylpyrrolidone, and polyvinyl acetate.

[0136] Materials suitable for enhancing the cohesiveness of layers containing active ingredients also include cationic crosslinking agents containing cationic aluminum (such as aluminum acetylacetonate) or titanium (such as butoxytitanium).

[0137] Crystallization inhibitors prevent the crystallization of active ingredients in layers containing active ingredients. Suitable crystallization inhibitors for layers containing active ingredients include polyvinylpyrrolidone (PVP), polyvinyl acetate, and cellulose derivatives.

[0138] In addition, the layer containing the active ingredient may contain a tackifier. The tackifier is preferably selected from resins containing hydrogenated rosin glycerol esters, petroleum-based hydrocarbon resins, polybutene, alicyclic hydrogenated hydrocarbon resins (Arkon® P-100), and mixtures thereof. The tackifier content in the active ingredient layer can be from 0 to 80% by weight, preferably 25 to 75% by weight, particularly 40 to 70% by weight, for example about 50% by weight, based on the total dry weight of the active ingredient layer in each case.

[0139] If the active ingredient, lumepirozon, is used in salt form, such as as a toluenesulfonate, the layer containing the active ingredient may include substances that further trigger the in-situ release of the free lumepirozon base. These substances include inorganic or organic bases, such as alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides, oxides, and diisopropanolamines.

[0140] Particularly preferred are layers containing active ingredients comprising styrene-butadiene-styrene copolymer and petroleum-based hydrocarbon resin (e.g., Duro-Tak® 87-6911). In even more preferred embodiments, the weight ratio of styrene-butadiene-styrene copolymer to petroleum-based hydrocarbon resin is 1:5 to 5:1, 1:3 to 3:1, or 1:2.5 to 2.5:1.

[0141] The layers containing active ingredients are particularly preferred to include silicone-acrylate hybrid polymers and alicyclic hydrogenated hydrocarbon resins.

[0142] Particularly preferred is that the layer containing the active ingredient comprises polyisobutylene and polybutene. In even more preferred embodiments, the weight ratio of polyisobutylene to polybutene is 1:5 to 5:1, 1:3 to 3:1, or 1:2.5 to 2.5:1.

[0143] The absolute amount of active ingredient in the active ingredient layer of the TDS according to the present invention depends on various factors, particularly the size of the TDS to be used, the matrix weight, and the concentration of the active ingredient in the active ingredient layer. Exemplary amounts of the active ingredient lumepirozoline (free base equivalent) used are in the range of 2 to 43.2 mg, for example 2 to 28.8 mg, 2 to 27 mg, 2 to 18 mg, 4.5 to 12.5 mg, 6.75 to 18.75 mg, 7.2 to 20 mg, 10.8 to 30 mg, 8 to 11 mg, 12 to 16.5 mg, or 12.8 to 17.6 mg, 29.2 to 26.4 mg. If a salt form of lumepirozoline is used, adjustments need to be made based on the difference in molar weight between the free base and salt forms of lumepirozoline.

[0144] The size of the layer containing the active ingredient is typically between 4 and 40 cm. 2 Within the specified range. In one embodiment, the size of the layer containing the active ingredient is no greater than 36 cm. 2 Preferably no larger than 25 cm 2 More preferably, not larger than 22 cm 2 The optimal size is no larger than 20 cm. 2 For example, 18, 16, 14, 12, 10, 8, or 6 cm 2 .

[0145] The weight of the dried layer containing the active ingredient ("matrix weight") is preferably between 20 and 100 g / m³. 2 More preferably, it is within the range of 30 to 90 g / m 2 Within the range, 40 to 80 g / m is still preferred. 2 Within the range. For a one-day patch, the weight is typically 40 to 50 g / m². 2 Within the range. For 1-2 day patches, the weight is typically 40-60 g / m².2 Within the range. For 2-3 day patches, the weight is typically 50-70 g / m². 2 Within the range. For 3- to 4-day patches, the weight is typically 65 to 80 g / m². 2 Within the range.

[0146] Consider the following exemplary combinations of transdermal therapy system size, drug loading, and matrix weight (where API = active pharmaceutical ingredient = lumepirozol free base):

[0147] 4 cm 2 TDS, 10% API (2 mg), 50 g / m 2

[0148] 9 cm 2 TDS, 10% API (4.5 mg), 50 g / m 2

[0149] 16 cm 2 TDS, 10% API (8 mg), 50 g / m 2

[0150] 20 cm 2 TDS, 10% API (10 mg), 50 g / m 2

[0151] 22 cm 2 TDS, 10% API (11 mg), 50 g / m 2

[0152] 25 cm 2 TDS, 10% API (12.5 mg), 50 g / m 2

[0153] 36 cm 2 TDS, 10% API (18 mg), 50 g / m 2

[0154] 4 cm 2 TDS, 15% API (3 mg), 50 g / m 2

[0155] 9 cm 2 TDS, 15% API (6.75 mg), 50 g / m 2

[0156] 16 cm 2TDS,15% API (12 mg),50 g / m 2

[0157] 20 cm 2 TDS,15% API (15 mg),50 g / m 2

[0158] 22 cm 2 TDS,15% API (16.5 mg),50 g / m 2

[0159] 25 cm 2 TDS,15% API (18.75 mg),50 g / m 2

[0160] 36 cm 2 TDS,15% API (27 mg),50 g / m 2

[0161] 4 cm 2 TDS,10% API (3.2 mg),80 g / m 2

[0162] 9 cm 2 TDS,10% API (7.2 mg),80 g / m 2

[0163] 16 cm 2 TDS,10% API (12.8 mg),80 g / m 2

[0164] 20 cm 2 TDS,10% API (16 mg),80 g / m 2

[0165] 22 cm 2 TDS,10% API (17.6 mg),80 g / m 2

[0166] 25 cm 2 TDS,10% API (20 mg),80 g / m 2

[0167] 36 cm 2 TDS,10% API (28.8 mg),80 g / m 2

[0168] 4 cm 2 TDS, 15% API (4.8 mg), 80 g / m 2

[0169] 9 cm 2 TDS, 15% API (10.8 mg), 80 g / m 2

[0170] 16 cm 2 TDS, 15% API (19.2 mg), 80 g / m 2

[0171] 20 cm 2 TDS, 15% API (24 mg), 80 g / m 2

[0172] 22 cm 2 TDS, 15% API (26.4 mg), 80 g / m 2

[0173] 25 cm 2 TDS, 15% API (30 mg), 80 g / m 2

[0174] 36 cm 2 TDS, 15% API (43.2 mg), 80 g / m 2 .

[0175] Adhesion layer

[0176] In a preferred embodiment of the invention, the transdermal therapeutic system further includes an adhesive layer. In this embodiment, the adhesive layer is the skin contact layer of the system. The function of the adhesive layer is to increase the adhesiveness of the system. Furthermore, the adhesive layer prolongs the penetration duration, i.e., extends the usable time of the transdermal system.

[0177] The adhesive layer contains an adhesive polymer and is initially free of the active ingredient lumepirolen. As mentioned above, "initially free" means that the adhesive layer does not contain the active ingredient during preparation, and therefore does not contain the active ingredient before lamination with the layer containing the active ingredient. When TDS is manufactured by laminating the layer containing the active ingredient with the adhesive layer, a certain amount of the active ingredient diffuses into the initially free adhesive layer. The adhesive layer then is no longer free of the active ingredient. This is normal and does not affect the performance of the TDS.

[0178] The adhesive polymer used in the adhesive layer is preferably selected from acrylate polymers and copolymers, styrene-butadiene-styrene (SBS) copolymers and polyisobutylene, and mixtures thereof.

[0179] In a preferred embodiment, homopolymers, copolymers, and block copolymers of polyacrylates based on acrylates and / or methacrylates can be used as adhesive polymers. As monomers for preparing suitable polyacrylates, particularly suitable monomers include n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate, tert-butyl acrylate, sec-butyl acrylate, tert-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate, isopropyl methacrylate, and mixtures of these monomers. These monomers are esters of acrylic acid or methacrylate, and they have linear, branched, or cyclic aliphatic C1-C12 substituents without other free functional groups. Vinyl acetate can also be used as a comonomer to prepare polyacrylates with at least one of these monomers.

[0180] In a more preferred embodiment, the acrylate polymer and copolymer used as the adhesive polymer contains free hydroxyl groups. Examples include products Duro-Tak® 87-2516 and 387-2516, which are acrylate-vinyl acetate copolymers containing free hydroxyl groups.

[0181] In another preferred embodiment, the acrylate polymer and copolymer used as the adhesive polymer contains free carboxylic acid groups. Examples include products Duro-Tak® 87-2051 and 387-2051, which are acrylate-vinyl acetate copolymers containing free carboxylic acid groups.

[0182] In another preferred embodiment, the adhesive polymer is a styrene-butadiene-styrene copolymer. In a particularly preferred embodiment, the styrene-butadiene-styrene copolymer is product Duro-Tak® 87-6911, which is a mixture of styrene-butadiene-styrene and styrene-butadiene block copolymers with a tackifier (resin) composed of a petroleum-based hydrocarbon resin.

[0183] It has been further discovered that the adhesive strength of polyisobutylene-based adhesive layers can be improved by adding polybutene (which is also an adhesive polymer), such as products Indopol® H-1900 and H-18000. Indopol® H-1900 has an average molecular weight M... N Approximately 2,500 g / mol of polybutene. Indopol® H-18000 has an average molecular weight M NApproximately 6,000 g / mol of polybutene. Average molecular weight M N "It is the number-average molar mass, which can be determined according to American standards ASTM D3536-91 or ASTM D5296-05. Polyisobutylene and polybutene are preferably used in a weight ratio of 4:1 to 1:2, more preferably 3:1 to 1:2. For example, polyisobutylene and polybutene may be present in a weight ratio of about 1:1."

[0184] Preferably, the adhesive layer of the TDS according to the present invention contains 80 to 100% by weight of at least one adhesive polymer, such as 85 to 100% by weight, 90 to 100% by weight, 95 to 100% by weight or 97.5 to 100% by weight, based on the total weight of the adhesive layer.

[0185] The adhesive layer preferably consists of at least one adhesive polymer. Optionally, it further comprises one or more excipients selected from adhesive enhancers, plasticizers, cohesive agents, and antioxidants, which are typically present in amounts up to 20% by weight, such as 15% by weight, 10% by weight, 5% by weight, or 2.5% by weight, based on the total weight of the adhesive layer.

[0186] Adhesion enhancers increase the adhesive strength of adhesive layers. Surprisingly, it has been found that adding small amounts, such as 2% by weight of Miglyol® 812, can increase the adhesive strength of adhesive layers based on acrylate polymers and copolymers, based on the total weight of the adhesive layer. Miglyol® 812 is typically used as a plasticizer (softener) rather than as an adhesion enhancer.

[0187] The weight of the (dry) adhesive layer is typically between 10 and 50 g / m². 2 Within the range, preferably 20 to 40 g / m 2 Within a range, for example, 30 g / m 2 .

[0188] membrane

[0189] In a third aspect of the invention, a membrane layer is used between a layer containing an active ingredient and an adhesive layer, wherein the membrane layer comprises a membrane polymer that allows the active ingredient to permeate and controls the release of the active ingredient. The membrane layer allows for a constant permeation time that can be extended to several days. However, simultaneously, permeation is reduced compared to TDS without the membrane layer.

[0190] Preferably, the membrane polymer is composed of a polyolefin, such as polypropylene (PP) (e.g., Celgard® 2400) or polyethylene (PE) (e.g., CoTran). TM 9719 or CoTran TM9720), or polyethylene (EVA) with a vinyl acetate ratio, such as 4.5 to 19% vinyl acetate (e.g., CoTran). TM 9707; CoTran TM 9702; CoTran TM 9728). In addition, membranes can have porosity up to 90% (e.g., Solupor® 10P05A, Celgard® 2400).

[0191] Porous membranes or dense membranes can be used.

[0192] Porous membranes can have a porosity as high as approximately 90%. Examples of preferred porous membranes include:

[0193] Solupor® 10P05A (Polyethylene, Porosity: 83%, Thickness: 60 μm)

[0194] Celgard® 2400 (Polypropylene, Porosity: 41%, Thickness: 25 μm)

[0195] Typically, the membrane thickness is between 0.01 and 0.15 mm. The preferred membrane thickness is 0.020 to 0.080 mm.

[0196] According to the invention, a dense film composed primarily of polyethylene with a thickness of about 40 to 50 μm is particularly preferred (e.g., CoTran). TM 9719), which extends the constant permeation time to 3 days; or a porous membrane composed of polypropylene with a thickness of about 20 to 40 μm (e.g., Celgard® 2400), which extends the constant permeation time to three days, but on the other hand maintains a sufficiently high permeation to allow for a smaller patch size, such as about 36 or preferably 20 cm. 2 Or smaller.

[0197] Backing layer

[0198] The TDS of this invention includes a backing layer. Typically, the backing layer of the TDS according to this invention is closed, meaning it is the outermost layer furthest from the skin contact layer in the cross-section of the finished TDS. The backing layer is an inert layer, substantially free of active ingredients and substantially impermeable to active ingredients.

[0199] In a preferred embodiment, such a backing layer is composed of polyolefins, particularly polyethylene or polyester, and polyurethane. It is also preferable to use layers comprising several different polymers arranged on top of each other. Suitable materials include polyolefins, cellophane, cellulose acetate, ethyl cellulose, vinyl acetate-vinyl chloride copolymers with plasticizers, ethylene-vinyl acetate copolymers, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidene chloride, ethylene-methacrylate copolymers, optionally coated paper, textile fabrics, aluminum foil, and polymer-metal composites. Polyester foils, such as polyethylene terephthalate foil, for example, the product Hostaphan... TM MN 19 is a particularly preferred choice.

[0200] Particularly preferred are composite foils of yellowish-brown colored polyethylene, thermoplastic resin, and aluminum vapor-deposited polyester, such as the product Scotchpack. TM 9738 or coated metallized Hueck PET foil. Polymer-metal composites, such as the product Scotchpack. TM 9738 or coated metallized Hueck PET foil protects the active ingredients from light-induced degradation, especially during storage. If the composition of the backing layer sufficiently inhibits light-induced degradation through, for example, the pigments or excipients in the varnish or outer layer, polymer-nonmetallic composites, such as Scotchpak, can also contribute. TM 9723 or coated Hueck PET foil can also be used.

[0201] As is common in the prior art, the thickness of the back layer can be, for example, from 10 μm to 100 μm, such as about 40 μm (nominal thickness). This ensures the flexibility and wearing comfort of the transdermal therapy system of the present invention.

[0202] Release liner

[0203] In a preferred embodiment of the invention, the skin contact layer of the TDS, i.e., the layer containing the active ingredient (first aspect) or the adhesive layer (second and third aspects), is protected by a release liner. The release liner is deposited on the skin contact layer and is removed when the TDS is used.

[0204] Preferably, the release liner is made of a polymeric material that can be optionally metallized. Examples of preferred materials include polyurethane, polyvinyl acetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, and paper that can be surface-coated with the corresponding polymer. The release liner can be coated, for example, with fluoropolymers or non-fluoropolymers, silicone or fluorosilicone coated on one or both sides, with silicone-coated release liners being particularly suitable for polyacrylate-based layers. Particularly preferred are coated polyester foils, such as the commercially available single-sided silicone-coated Primeliner. TM 75 or 100 μm and Perlasic LF 75 μm (Loparex, Netherlands and Perlen Converting AG, Switzerland) and silicone-coated polyethylene terephthalate (PET) (e.g., Loparex Primeliner) TM 78HL), or single-sided fluoropolymer coated products, such as Scotchpak TM 1022 (3M Drug delivery). Other suitable products include Scotchpak. TM 9744 and Scotchpak TM 9709.

[0205] Method for preparing TDS of the present invention

[0206] Another aspect of the present invention is to provide a method for producing the TDS of the present invention. The method includes the following steps:

[0207] (a) Preparation of a layer composition containing an active ingredient,

[0208] (b) Apply the composition prepared in step (a) onto the release liner (i).

[0209] (c) The components prepared in drying step (b), and

[0210] (d) Laminating the backing layer onto the active ingredient layer of the component prepared in step (c);

[0211] Optionally, in addition to steps (a)-(d), the following steps are also included:

[0212] (e) Preparation of the adhesive layer composition,

[0213] (f) Apply the composition prepared in step (e) onto the release liner (ii).

[0214] (g) The components prepared in drying step (f),

[0215] (h) Remove the release liner (i) from the components prepared in step (d).

[0216] (i) Press the active ingredient-containing layer prepared in step (h) onto the adhesive layer of the component prepared in step (g), or vice versa;

[0217] Alternatively, in addition to steps (a)-(d), the following steps may also be included:

[0218] (j) Laminating a membrane layer suitable for controlling the release of the active ingredient onto the active ingredient-containing layer of the component prepared according to step (h),

[0219] (k) Perform steps (e) through (g),

[0220] (l) Laminate the adhesive layer of the component prepared in step (k) onto the film layer of the component prepared in step (j), or vice versa.

[0221] Generally, the expressions "layer composition containing active ingredient," "adhesive layer composition," and "film composition" mean that they contain the same components as described above for "layer containing active ingredient," "adhesive layer," and "film layer." Furthermore, they may contain suitable organic solvents, such as heptane or ethyl acetate, but other organic solvents or solvent mixtures known to those skilled in the art are also possible. It is preferred to use volatile organic solvents or solvent mixtures to prepare the compositions.

[0222] The preparation of the TDS of the present invention can begin by dispersing or dissolving (unless the polymer is already dissolved) the components of the layer containing the active ingredient (i.e., the active ingredient and the polymer or copolymer forming the matrix, or a mixture thereof) separately in a suitable organic solvent (as described above), such as heptane or ethyl acetate, or other organic solvents or solvent mixtures known to those skilled in the art. Volatile organic solvents or solvent mixtures are preferred. Optionally, other excipients as described with respect to the layer containing the active ingredient are added. Typically, the polymer or copolymer forming the matrix, or a mixture thereof, is already present in the solvent. Here, according to the present invention, the polymer and / or copolymer as defined above with respect to the TDS according to the present invention are used. The preferred embodiments of the polymer matrix described above are accordingly applicable to the method according to the present invention.

[0223] The mixture is then applied as a uniform layer onto the release liner (i) and dried.

[0224] In the next step, a backing layer is applied onto the layer containing the active ingredient.

[0225] In a separate step, the adhesive layer is prepared by optionally dispersing the polymer mixture (dissolved in an organic solvent) that forms the contact adhesive, together with other excipients as described with respect to the adhesive layer, in a suitable organic solvent such as heptane or ethyl acetate, although other organic solvents or solvent mixtures known to those skilled in the art may also be used. Volatile organic solvents or solvent mixtures are preferred. The mixture is then applied to the release liner (ii) and allowed to dry. The preferred embodiments described above with respect to the adhesive layer are accordingly applicable to the preparation method according to the invention.

[0226] The components obtained in these two process steps are then laminated together, i.e., the adhesive layer is applied directly to the layer containing the active ingredient after the release liner (i) is removed. In embodiments using a membrane layer that controls the release of the active ingredient, the adhesive layer is laminated onto the membrane, or vice versa.

[0227] If a film is to be applied to control the release of the active ingredient, it can be applied to the side of the layer containing the active ingredient after the active ingredient layer has dried and the release liner (i) has been removed. An adhesive layer is then laminated onto the film layer, or vice versa. Subsequently, sheets of the desired size can be punched out of the finished laminate and packaged.

[0228] In each process step, the organic solvents required to dissolve or disperse the components are removed by using a drying step of the product with elevated temperature (optionally partial vacuum).

[0229] The method for preparing a transdermal therapeutic system according to the present invention is further illustrated in the examples.

[0230] Other aspects and implementation methods

[0231] Preferably, the TDS of the present invention does not use a penetration enhancer. Particularly preferred is that the TDS of the present invention does not contain the penetration enhancers used in the transdermal therapy systems disclosed in WO'241.

[0232] The size of the TDS in this invention is not particularly limited, but is generally between 4 and 40 cm. 2 Within the specified range. In one embodiment, the size of the TDS of the present invention is no greater than 36 cm. 2 Preferably no larger than 25 cm 2 More preferably, not larger than 22 cm 2 The optimal size is no larger than 20cm. 2 For example, 18, 16, 14, 12, 10, 8, 6 cm 2 .

[0233] The preferred daily transdermal delivery of the active ingredient lumepirox is at least about 1.5 mg / day, and preferably about 1.8 mg / day. This is equivalent to a daily oral dose of 60 mg lumepirox tosylate, which is equivalent to 42 mg of lumepirox free base, taking into account the low oral bioavailability of Caplyta® at approximately 4.4%.

[0234] Consistent with this, the flux is preferably at least 3.75 µg / cm³. 2 *h. For a preferred size of 20 cm 2 The patch results in a daily dose of at least 1.5 mg / day. This flux is preferably achieved without utilizing the penetration enhancer in the TDS.

[0235] The TDS according to the present invention has an application period of at least one day, preferably at least two days, and more preferably at least three days. The TDS according to the first aspect of the present invention is preferably suitable for an application period of two to three days, more preferably three to four days. The TDS according to the second aspect of the present invention is preferably suitable for an application period of two to three days, more preferably three to four days. The TDS according to the third aspect of the present invention is preferably suitable for an application period of two to three days, more preferably three to four days.

[0236] Preferably, the TDS according to the invention has a constant permeation curve over several days. Here, the permeation is constant for at least 24 hours (1 day), preferably at least 48 hours (2 days), and more preferably at least 72 hours (3 days).

[0237] According to the first aspect of the invention, the TDS has a constant permeation curve, preferably over a period of 2 days, more preferably 3 days.

[0238] On the other hand, the present invention relates to the use of (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer and mixtures thereof for stabilizing lumepimeline free base in a transdermal therapeutic system, or for reducing, preferably preventing, the degradation of lumepimeline free base in a transdermal therapeutic system, preferably for a period of at least 6 months, more preferably for a period of at least 12 months at room temperature. The transdermal therapeutic system is preferably a TDS as defined in all aspects and embodiments of the present invention.

[0239] In another aspect of the invention, the transdermal therapeutic system of the invention is used for the treatment of a method for diseases selected from: major depressive disorder (MDD) and its associated mixed features, bipolar I or II, and schizophrenia.

[0240] In another aspect of the invention, rumepiride is used to treat a disease selected from major depressive disorder (MDD) and its associated mixed features, bipolar I or II, and schizophrenia, wherein rumepiride is administered via the skin in the form of a free base or a salt using the transdermal treatment system of the invention. Detailed Implementation Plan

[0241] In one specific embodiment, the TDS of the present invention comprises (according to the first aspect of the present invention):

[0242] a. A backing layer, preferably a polyester foil;

[0243] b. The active ingredient layer comprises a polymer matrix containing 10 to 15% by weight, preferably 15% by weight, of the active ingredient lumepirozol (preferably in its free base form) and a mixture of two polyisobutylenes (such as products Duro-Tak® 87-626A and 87-6900); the active ingredient layer preferably contains 0.05-2% by weight of the antioxidant tocopherol, ascorbyl palmitate, or a combination thereof to improve the chemical stability of the active ingredient; the active ingredient layer optionally contains 15-45% by weight of polybutene; and the active ingredient layer optionally contains a crystallization inhibitor (such as PVP VA 64); for obtaining a 3-day patch, the matrix weight is preferably 65-80 g / m². 2 ;

[0244] c. Release liner, preferably silicone-coated polyester foil.

[0245] In another specific embodiment, the TDS of the present invention comprises (according to the first aspect of the present invention):

[0246] a. A backing layer, preferably a polyester foil;

[0247] b. The active ingredient layer comprises a polymer matrix containing 10 to 15% by weight, preferably 15% by weight, of the active ingredient lumepirozon (preferably in its free base form) and a styrene-butadiene-styrene polymer, preferably containing a petroleum-based hydrocarbon resin (as contained in product Duro-Tak® 87-6911); the active ingredient layer may contain a crystallization inhibitor (such as PVP); the active ingredient layer may contain a penetration enhancer (such as oleic acid ester) to increase the system's permeability—however, it is preferred not to add a penetration enhancer; for a 3-4 day patch, the matrix weight is preferably 65-80 g / m². 2 ;

[0248] c. Release liner, preferably fluorosilicone-coated or non-fluorinated polyester foil.

[0249] In another specific embodiment, the TDS of the present invention comprises (according to the first aspect of the present invention):

[0250] a. A backing layer, preferably a polyester foil;

[0251] b. A layer containing the active ingredient, comprising a polymer matrix containing 10 to 15% by weight, preferably 15% by weight, of the active ingredient lumepirozon (preferably in its free base form) and a silicone-acrylate hybrid polymer (such as BIO-PSA7-6302) or a mixture of a low-to-high tack silicone-acrylate hybrid polymer (such as BIO-PSA 7-6302) and a high-tack silicone-acrylate hybrid polymer (such as BIO-PSA 7-6102), preferably in a weight ratio of 60-80:40-20; the layer containing the active ingredient preferably contains 0.05-2% by weight of the antioxidant tocopherol, ascorbyl palmitate, or a combination thereof, to improve the chemical stability of the active ingredient; for obtaining a 3-day patch, the matrix weight is preferably 65-80 g / m². 2 ;

[0252] c. Release liner, preferably a fluoropolymer-coated or fluorosilicone-coated, or non-perfluorinated or non-polyfluorinated polyester foil.

[0253] In another specific embodiment, the TDS of the present invention comprises (according to the first aspect of the present invention):

[0254] a. A backing layer, preferably a polyester foil;

[0255] b. A layer containing active ingredients, comprising a polymer matrix containing 10 to 15% by weight, preferably 15% by weight, of the active ingredient lumepirozon (preferably in its free base form) and a styrene-isoprene-styrene polymer and an alicyclic hydrogenated hydrocarbon resin, preferably in a weight ratio of about 1:1; the layer containing active ingredients preferably contains 0.05-2% by weight of the antioxidant tocopherol, ascorbate palmitate, or a combination thereof, to improve the chemical stability of the active ingredient; for obtaining a 3-day patch, the matrix weight is preferably 70-80 g / m². 2 ;

[0256] c. Release liner, preferably a fluoropolymer-coated or fluorosilicone-coated, or non-perfluorinated or non-polyfluorinated polyester foil.

[0257] In another specific embodiment, the TDS of the present invention includes (in accordance with the second aspect of the present invention):

[0258] a. The backing layer as defined above;

[0259] b. The layer containing active ingredients as defined above;

[0260] c. An adhesive layer comprising a polyacrylate adhesive having free hydroxyl groups (such as Duro-Tak® 387-2516), preferably with the addition of a small amount, for example, 2% by weight of a mixture of decanoyl and octanoyl glycerides (such as Miglyol® 812) to increase the adhesion of the layer; or comprising a styrene-butadiene-styrene (SBS) copolymer adhesive, preferably further comprising a petroleum-based hydrocarbon resin (such as that contained in product Duro-Tak® 87-6911); or comprising a mixture of one or more polyisobutylenes (such as products Duro-Tak® 87-626A and Duro-Tak® 87-6900, in a ratio of 1:1 or 3:2) and one or more polybutenes (such as products Indopol H-1900 and Indopol H-18000, in a ratio of 1:1 or 3:2), wherein the polyisobutylene / polybutene ratio is 1:1; for obtaining a 3 to 4-day patch, the weight of the adhesive layer is preferably about 30 g / m². 2 ;

[0261] d. Release liner as defined above.

[0262] In another specific embodiment, the TDS of the present invention comprises (according to the third aspect of the present invention):

[0263] a. The backing layer as defined above;

[0264] b. The layer containing active ingredients as defined above;

[0265] c. A film layer composed of dense polyethylene (such as the product Cotran) TM 9719), or composed of porous polypropylene (such as product Celgard). TM 2400);

[0266] d. An adhesive layer as defined above;

[0267] e. Release liner as defined above.

[0268] Example

[0269] Example 1: Single-layer formulation (first aspect of the invention)

[0270] a) Preparation

[0271] Example 1.1: Polyisobutylene polymer matrix

[0272] Samples 1–7

[0273] A layer containing the active ingredient lumepirolen free base, polyisobutylene (Duro-Tak® 87-626A, Duro-Tak® 87-625A, Duro-Tak® 87-6900 and mixtures thereof), and optional other excipients (Indopol H-1900, Indopol H-18000, PVP, oleic acid esters), is coated onto a protective film (Primeliner). TM 78HL). Remove the solvent in an oven. Then apply the active layer to the backing layer (Hostaphan). TM MN 19 Med or Scotchpak TM 9738) Lamination. The resulting laminates are shown in Table 1.

[0274] Example 1.2: Styrene-butadiene-styrene (SBS) copolymer matrix

[0275] Sample 8-26

[0276] A layer containing the active ingredient lumepirolen free base, a resin-containing styrene-butadiene-styrene copolymer adhesive (Duro-Tak® 87-6911 or Duro-Tak® 87-6173), and optional other excipients (PVP K90, oleic acid ester, isopropyl myristate, lauryl lactate, 1-dodecanool, oleic acid, DEET, Trancutol®, Miglyol® 812, Span® 60) is coated onto a protective film (Primeliner). TM 78HL). Remove the solvent in a drying oven. Then coat the active layer with the backing layer (Hostaphan). TM MN 19 Med or Scotchpak TM 9738) Lamination. The resulting laminates are shown in Table 1.

[0277] Example 1.3: Silicone-acrylate hybrid polymer matrix

[0278] Samples 27-30

[0279] A layer containing the active ingredient lumepirolen free base and a silicone-acrylate hybrid polymer (BIO-PSA 7-6302, BIO-PSA 7-6102, BIO-PSA 7-6301 or BIO-PSA 7-6101) is coated onto a protective film (Scotchpak). TM 9709) was applied. The solvent was removed in a drying oven. Then the active layer was bonded to the backing layer (Scotchpak). TM9738) Lamination. The resulting laminates are shown in Table 1.

[0280] Example 1.4: Styrene-isoprene-styrene (SIS) copolymer matrix

[0281] Samples 31-33

[0282] A layer containing the active ingredient lumepirozon free base, styrene-isoprene-styrene copolymer, alicyclic hydrogenated hydrocarbon resin (Arkon® P-100), and optional other excipients (tocopherol or paraffin) is coated onto a protective film (Primeliner). TM 78HL). Remove the solvent in a drying oven. Then coat the active layer with the backing layer (Scotchpak). TM 9738) Lamination. The resulting laminates are shown in Table 1 below.

[0283] Table 1

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290] b) Crystallization and Phase Systems

[0291] After storage at 40°C / 75% RH, the crystallization and two-phase system presence of some samples prepared in Examples 1.1-1.4 were analyzed. The results are shown in Table 2 below.

[0292] Table 2

[0293]

[0294] rt = room temperature; RH = relative humidity

[0295] c) Adhesion strength

[0296] The adhesive strength of some transdermal therapeutic systems prepared in Examples 1.1-1.4 was measured after storage at 40°C / 75% RH for 0, 1, 3 and 6 months.

[0297] Adhesive strength can be measured as the force required to peel a sample from a suitable carrier at a specific angle and defined speed. To determine adhesive strength, a TDS (Total Displacement of Dimensions) of a defined size (e.g., 10 cm) is stamped out. 2 ), and adjust at 23±1℃ and 50±5% RH. Use a conductive strip (e.g., 10 cm). 2 The TDS (with its release liner removed) is applied to the test plate (e.g., steel), and then pressed between two glass plates with a 2 kg weight for, for example, 1 minute. The test plate is horizontally fixed in a tensile testing machine (e.g., Texture Analyzer plus from Stable Micro Systems), and the liner is clamped, causing the TDS to peel off at a 90° angle. Measurements are typically taken at a specified speed of 300 ± 30 mm / min at 23 ± 1 °C and 50 ± 5% RH. The average value [N / 25 mm], normalized to a sample width of 25 mm, is the adhesive strength measured over a distance.

[0298] The results are shown in Figure 2-6 .

[0299] from Figure 2-6 It can be seen that the TDS containing lumepirozon free base and (1) polyisobutylene polymers (Duro-Tak® 87-625A, Duro-Tak® 87-626A, Duro-Tak® 87-6900 and mixtures thereof), (2) styrene-butadiene-styrene copolymers (Duro-Tak® 87-6911), (3) silicone-acrylate hybrid polymers (BIO-PSA 7-6302 or BIO-PSA7-6102) or (4) styrene-isoprene-styrene copolymers have higher adhesive strength than 1-day patch Neupro® and 3-day patch FNT and FTA.

[0300] In particular, from Figure 2 It can be seen that significantly higher adhesive strength can be achieved using polybutene (whether Indopol H-1900 or H-18000, alone or in combination). All formulations measured were storage-stable in terms of adhesive strength. Surprisingly, the use of 7.5% concentration of oleic acid ester showed a sharp decrease in adhesive strength. Therefore, the use of oleic acid ester is not preferred.

[0301] from Figure 3It can be seen that TDS containing petroleum-based hydrocarbon resin SBS (Duro-Tak® 87-6911) exhibits significantly higher adhesive strength than 1-day patch Neupro® and 3-day patches FNT and FTA. The use of hydrogenated glycerol ester resin (Duro-Tak® 87-6173) reduces the adhesive strength of TDS. Furthermore, the use of PVP also reduces adhesive strength.

[0302] from Figure 4 It can be seen that, in particular, the high-viscosity silicone-acrylate hybrid polymers in ethyl acetate (BIO-PSA7-6302 and BIO-PSA 7-6102) exhibit significantly higher adhesive strength than the 1-day patch Neupro® and the 3-day patches FNT and FTA. The silicone-acrylate hybrid polymers in heptane (BIO-PSA 7-6301 and BIO-PSA 7-6101) did not exhibit significantly higher adhesive strength than the 1-day patch Neupro® and the 3-day patches FNT and FTA.

[0303] from Figure 5 It can be seen that all styrene-isoprene-styrene copolymers exhibit significantly higher adhesive strength than the 1-day patch Neupro® and the 3-day patches FNT and FTA. Furthermore, increasing the ratio of alicyclic hydrogenated hydrocarbon resin to SIS copolymer or using viscous paraffin oil can improve the initial adhesive strength (at 0 months). However, for batch 115 LUMTDS containing a large amount of alicyclic hydrogenated hydrocarbon resin or batch 117 LUMTDS containing a corresponding amount of viscous paraffin oil, the adhesive strength decreased after storage (only after 1 month). Therefore, in the absence of excessive paraffin oil, the optimal ratio of alicyclic hydrogenated hydrocarbon resin to SIS copolymer is approximately 1:1.

[0304] from Figure 6 As can be seen, SBS containing petroleum-based hydrocarbon resins (Duro-Tak® 87-6911) without other excipients such as skin penetration enhancers like oleic acid ester, isopropyl myristate, lauryl lactate, 1-dodecyl alcohol, oleic acid, DEET, Trancutol®, or matrix softener Miglyol® 812 or emulsifier Span® 60 exhibits slightly or significantly higher adhesive strength compared to products using such additional excipients. The use of oleic acid or oleic acid ester reduces adhesive strength, while Span® 60 drastically reduces it. The use of skin penetration enhancers, especially emulsifiers, can have significant disadvantages to adhesion in certain situations.

[0305] During storage at 40°C / 75% RH for 6 months, the adhesive strength did not decrease significantly except for batches 115 and 117LUMTDS.

[0306] d) Adhesion

[0307] After storage at 40°C / 75% RH for 0, 1, 3, and 6 months, the adhesion of some transdermal therapeutic systems prepared in Examples 1.1–1.4 was measured.

[0308] Adhesion force can be determined as the maximum force required to completely separate a stainless steel sample from the TDS adhesive layer. To determine adhesion force, the patch or laminate is conditioned at 23±1°C and 50±5% RH, and then fixed to a perforated carrier plate with its release liner removed and the adhesive matrix exposed. The plate is fixed in a tensile testing machine (e.g., Texture Analyserplus from Stable Micro Systems). Typically at 23±1°C and 50±5% RH, the test sample is pressed against the top of the sample and peeled off after a typically defined contact time of 2 seconds. A series of measurements should be completed within 30 minutes after the release liner is removed from the first sample. The maximum force (adhesion force; [N]) required to separate the bond between the sample and the adhesive layer is determined.

[0309] The results are shown in Figure 7-11 .

[0310] from Figure 7-11 It can be seen that the TDS of the 1-day patch Neupro® containing lumepirozon free base and (1) polyisobutylene polymers (Duro-Tak® 87-625A, Duro-Tak® 87-626A, Duro-Tak® 87-6900 and mixtures thereof), (2) styrene-butadiene-styrene copolymers (Duro-Tak® 87-6911), (3) silicone-acrylate hybrid polymers (BIO-PSA 7-6302 or BIO-PSA7-6102) or (4) styrene-isoprene-styrene copolymers has a higher or similarly higher tack than the 1-day patch Neupro®.

[0311] In particular, from Figure 7 It can be seen that significantly higher tack strength can be achieved using polybutene (whether Indopol H-1900 or H-18000, alone or in combination). All formulations measured were storage-stable in terms of tack strength. Surprisingly, the use of 7.5% oleic acid ester showed a sharp decrease in tack strength. Therefore, the use of oleic acid ester is not preferred.

[0312] from Figure 8It can be seen that the TDS containing SBS (Duro-Tak® 87-6911) with petroleum-based hydrocarbon resin has significantly higher tack than the 1-day patch Neupro®. The use of hydrogenated glycerol ester resin (Duro-Tak® 87-6173) reduces the tack of the TDS and leads to a decrease in tack during storage (batch 032 LUMTDS). Furthermore, the use of PVP reduces tack.

[0313] from Figure 9 It can be seen that, in particular, the high-adhesion silicone-acrylate hybrid polymers in ethyl acetate (BIO-PSA 7-6302 and BIO-PSA 7-6102) exhibited higher adhesion than the 1-day patch Neupro®. The silicone-acrylate hybrid polymers in heptane (BIO-PSA 7-6301 and BIO-PSA 7-6101) did not exhibit higher adhesion than the 1-day patch Neupro®.

[0314] from Figure 10 It can be seen that the combination of lumepone free base and styrene-isoprene-styrene copolymer exhibits significantly higher tack than the 1-day patch Neupro®. However, for batch 115 LUMTDS containing a large amount of alicyclic hydrogenated hydrocarbon resin or batch 117 LUMTDS containing a corresponding amount of viscous paraffin oil, the tack decreased after storage (only after 1 month). Therefore, in the absence of excessive paraffin oil, the optimal ratio of alicyclic hydrated hydrocarbon resin to SIS copolymer is approximately 1:1.

[0315] from Figure 11 It can be seen that TDS using SBS (Duro-Tak® 87-6911) containing petroleum-based hydrocarbon resins, without other excipients such as skin penetration enhancers like oleic acid esters, isopropyl myristate, lauryl lactate, 1-dodecyl alcohol, oleic acid, DEET, Trancutol®, or matrix softeners like Miglyol® 812, or emulsifiers like Span® 60, exhibits slightly or significantly higher tack compared to using such additional excipients. The use of oleic acid or oleic acid esters reduces tack, while Span® 60 drastically reduces it. The use of skin penetration enhancers, especially emulsifiers, can have a significant negative impact on adhesion in certain situations.

[0316] During a 6-month storage period at 40°C / 75% RH, the adhesion did not decrease significantly except for 032, 115, and 117 LUMTDS.

[0317] e) Separation force

[0318] After being stored at 40°C / 75% RH for 0, 1, 3 and 6 months, the separation force of some transdermal therapy systems prepared in Examples 1.1-1.4, i.e. the force required to remove the release liner from the transdermal therapy system, was measured.

[0319] Separation force can be measured as the force required to peel a sample from its release liner at a specific angle and velocity. For measurement, a TDS of defined dimensions (e.g., 10 cm⁻¹) is stamped out. 2 The sample is conditioned at 23±1℃ and 50±5% RH. A guide strip in the form of a pad is cut out. The guide strip (the same width as the TDS) is attached to the TDS. The TDS is then secured to the instrument slide with the release liner facing down using double-sided tape. The slide is inserted into a tensile testing machine (e.g., Texture Analyser plusfrom Stable Micro Systems) and the TDS is peeled at a 90° angle. The speed is typically 300±30 mm / min, and the test is usually performed at 23±1℃ and 50±5% RH. The average force [N / 25 mm] measured at the separation distance, normalized to a sample width of 25 mm, is the separation force.

[0320] The results are shown in Figure 12-16 .

[0321] from Figure 12-16 It can be seen that the combination of lumepirone free base with (1) polyisobutylene polymers (Duro-Tak® 87-625A, Duro-Tak® 87-626A, Duro-Tak® 87-6900 and mixtures thereof), (2) styrene-butadiene-styrene copolymers (Duro-Tak® 87-6911 or Duro-Tak® 87-6173), (3) silicone-acrylate hybrid polymers (BIO-PSA 7-6302, BIO-PSA 7-6102, BIO-PSA 7-6301 or BIO-PSA 7-6101) or (4) styrene-isoprene-styrene copolymers results in low separation power, and there is no significant increase in separation power during 6 months of storage at 40°C / 75% RH when using silicone polyester release liner.

[0322] f) Infiltration

[0323] aa) Explanation

[0324] To achieve a small patch size, the cumulative penetration over 24 hours must be sufficiently high. Approximately 1.8 mg of rumepiride must be delivered transdermally daily at a bioavailability of approximately 4.4%.

[0325] To achieve approximately 20 cm 2The patch size must meet a minimum requirement of 3.75 μg / cm². 2 *h flux (3.75 μg / cm) 2 *hx 20 cm 2 x 24 = 1,800 μg / 24 h = 1.8 mg / 24 h).

[0326] For 1 cm 2 Theoretically, 90 μg must be delivered per skin per day per unit area. After 3 days, the cumulative permeation per square centimeter is 270 μg, and after 4 days it is 360 μg.

[0327] Ideally, this flux is achieved without the use of a permeation enhancer.

[0328] Infiltration on human skin model (HSE)

[0329] The permeation of selected samples prepared in Examples 1.1-1.3 on human skin models was measured to determine the cumulative permeation of rumeperone per square centimeter over a period of up to 96 hours.

[0330] In vitro skin absorption studies were conducted using the NovoCell Schönbach skin absorption system in accordance with OECD (2004) test guideline 428 "Skin absorption: In vitro method & series on testing and assessment", No. 28 "Guidance document for the conduct of skin absorption studies".

[0331] The measuring cell was maintained at 32±1℃ throughout the measurement process. The measuring cell consists of a donor chamber and a recipient chamber, which are separated by a 1.05 cm... 2 The effective penetration area is separated from the human skin epidermis by thermal separation, which lies on a cellulose membrane. The matrix of the test patch (approximately 1.2 cm) 2 The sample (of a specific size) adheres to the stratum corneum with the surface to be released facing the receptor chamber. The measuring cell contains a total volume of 15 mL and is filled with phosphate buffer at pH 4.5. At defined time points (e.g., 1, 2, 3, 6, 9, 12, 24, 36, 48, 72, and 96 hours), aliquots are removed from the receptor chamber as samples, and the concentration of lumepirolen is determined using RP-HPLC. The aliquots are immediately replaced with fresh buffer. Uniform temperature and lumepirolen concentration are ensured by an integrated magnetic stirring system in the receptor chamber.

[0332] RP-HPLC analysis was performed and sample concentrations were calculated. Stationary phase: C18 (e.g., 50 × 3 mm, 5 μm particle size, 30 °C oven temperature). Mobile phase: 10 mM phosphate buffer (pH 2.5) / methanol; 55 / 45 (v / v), flow rate 0.7 mL / min. Injection volume: 10 µL, detection wavelength: 229 nm, lumepiroline retention time: approximately 3–4 min, run time: 5 min (isoclinic). Evaluation was performed using single-point calibration with external standard solutions. Cumulative release [%] was calculated based on the concentrations measured in the sample solutions.

[0333] Subsequently, the cumulative permeability at each time point was calculated, and a curve was plotted relative to time. Then, the steady-state flux [µg / cm³] can be calculated. 2 / h).

[0334] The results are as follows Figure 17-20 As shown.

[0335] The samples exhibit the following penetration effects on the human skin model (HSE) from high to low, as shown in Figures 17-20:

[0336] for Figure 17 :

[0337] 15% Lumepiride, 42.5% Duro-Tak® 87-6626A, 42.5% Duro-Tak® 87-6900(018LUMTDS) >

[0338] 15% Lumepirone, 22.5% Duro-Tak® 87-6626A, 22.5% Duro-Tak® 87-6900, 40% Indopol H-18000 (020LUMTDS)

[0339] for Figure 18 :

[0340] 15% Lumepiride, 82.5% Duro-Tak® 87-6911, 2.5% PVP (031LUMTDS) >

[0341] 15% Lumepiride, 85% Duro-Tak® 87-6911 (016LUMTDS) >

[0342] 15% Lumepiride, 85% Duro-Tak® 87-6173 (032LUMTDS).

[0343] for Figure 19 :

[0344] 15% Lumepiride, 85% BIO-PSA 7-6302

[0345] for Figure 20 :

[0346] 15% Lumepiride, 7.5% Paraffin Oil, 23.25% SIS Block Copolymer, 54.25% Arkon® P-100 >

[0347] 15% Lumepiride, 0.15% Tocopherol, 25.46% SIS Block Copolymer, 59.39% Arkon® P-100 >

[0348] 15% Lumepiride, 0.05% Tocopherol, 42.48% SIS Block Copolymer, 42.48% Arkon® P-100.

[0349] Figure 17-20 The dotted line in the middle represents 20 cm. 2 The theoretical amount of lumepirolen required for the matrix. Most samples contained lumepirolen that met this requirement, except for sample 032 LUMTDS, which resulted in a lower amount of lumepirolen permeation (up to 96 hours).

[0350] No accelerator is needed to achieve 20 cm 2 The permeability requirements of the matrix.

[0351] These patches (15% drug load, 50 mg / cm²) 2 The penetration of the patch is constant over 2-3 days.

[0352] Optimization of drug concentration and matrix weight (cc)

[0353] To optimize matrix weight, the permeation of selected samples prepared in Example 1.2 with different drug concentrations and matrix weights was compared on a human skin model (HSE). The results are as follows: Figure 21 As shown.

[0354] like Figure 21 As shown, the penetration effect of the samples on the human skin model (HSE) from high to low is as follows:

[0355] 15% Lumepiride, 85% Duro-Tak® 87-6173, 80 g / m 2 (063LUMTDS) >

[0356] 15% Lumepiride, 85% Duro-Tak® 87-6173, 65 g / m 2 (063LUMTDS) >

[0357] 15% Lumepiride, 85% Duro-Tak® 87-6173, 50 g / m2 (052LUMTDS) >

[0358] 10% Lumepiride, 90% Duro-Tak® 87-6173, 80 g / m 2 (064LUMTDS) >

[0359] 10% Lumepiride, 90% Duro-Tak® 87-6173, 65 g / m 2 (064LUMTDS) >

[0360] 10% Lumepiride, 90% Duro-Tak® 87-6173, 50 g / m 2 (064LUMTDS)

[0361] Figure 21 The dotted line in the middle represents 20 cm. 2 The theoretical amount of lumepirocin required for the matrix. All samples in the studies met this requirement, but the duration of constant skin penetration varied depending on the drug concentration used and the weight of the matrix.

[0362] Preferred formulations contain 15% lumepirozoline and 65-80 g / m³. 2 Samples weighing the matrix can achieve high permeability and constant permeability for about 3 days.

[0363] g) Chemical stability

[0364] The samples in Table 3 below were prepared according to the procedure described in a).

[0365] Table 3

[0366]

[0367]

[0368] Degradation product formation was monitored for 6 months at 40℃ / 75% RH. Results are as follows: Figure 22-23 As shown.

[0369] Surprisingly, the use of silicone-acrylate hybrid polymers resulted in moderate to high levels of degradation products, while the use of polyisobutylene, with or without polybutene, resulted in moderate levels of degradation products (see [link to article]). Figure 22 ).

[0370] from Figure 23It can be seen that the polymer matrix containing SBS and petroleum-based hydrocarbon resins leads to a significant reduction in the formation of degradation products (see 057 LUMTDS), resulting in a low amount of degradation products. In contrast, the polymer matrix containing SBS and hydrogenated rosin glycerol ester resins leads to a less significant reduction in the formation of degradation products (see 052 LUMTDS), resulting in a moderate amount of degradation products.

[0371] Example 2: A bilayer formulation with an adhesive layer (Second aspect of the invention)

[0372] a) Preparation

[0373] An active ingredient layer (active matrix layer) containing the active ingredient lumepirozon free base, styrene-butadiene-styrene copolymer (Duro-Tak® 87-6911), and optional other excipients is coated onto the intermediate release liner (Primeliner). TM 78HL). Remove the solvent in a drying oven. Then coat the layer containing the active ingredient with an aluminum-coated Scotchpak layer as a backing layer. TM 9738 PET film lamination, and storage for further processing (e.g., batch 077LUMTDS).

[0374] Individually, an adhesive layer initially free of the active ingredient lumepirolen free base and containing an adhesive polymer and optional other excipients is coated onto the release liner (Primeliner). TM 78HL). Remove the solvent in a drying oven.

[0375] Remove the intermediate release liner of the active ingredient layer and laminate the initially non-active ingredient adhesive layer with the active matrix layer to form a layered system consisting of: a backing layer, an active ingredient matrix layer, an initially drug-free adhesive layer, and a release liner (protective film) (e.g., batch 077_099LUMTDS).

[0376] The resulting laminates are shown in items 1 and 2 of Table 4 below.

[0377] Example 3: A bilayer formulation having an adhesive layer and a drug-permeable membrane (third aspect of the invention)

[0378] a) Preparation

[0379] A layer containing the active ingredient lumepirozon free base, styrene-butadiene-styrene copolymer (Duro-Tak® 87-6911), and optional other excipients (the dried active ingredient layer) is coated onto the intermediate release liner (Primeliner). TM 78HL). Remove the solvent in a drying oven. Then coat the layer containing the active ingredient with an aluminized PET film (Scotchpak) as a backing layer.TM 9738) Lamination, and storage for further processing.

[0380] Separately, a layer without active ingredients (adhesive layer after drying) is coated onto the release liner (Primeliner). TM 78HL). Remove the solvent in a drying oven. Then laminate the adhesive layer to the drug-permeable membrane layer.

[0381] The intermediate release liner of the active ingredient layer is removed, and the exposed active ingredient layer is laminated to the membrane side of the adhesive layer to form a layered system comprising: a backing layer, an active ingredient matrix layer, a drug-permeable membrane, an initially drug-free adhesive layer, and a release liner.

[0382] The resulting laminate is shown in item 3 of Table 4 below.

[0383] Table 4

[0384]

[0385] Table 4 – Continued

[0386]

Claims

1. A transdermal therapy system for administering the active ingredient lumepirox ... a) Backing layer, and b) At least one layer containing an active ingredient, which comprises the active ingredient in the form of a free base or salt embedded in a polymer matrix. Its features are: The polymer matrix comprises polymers selected from the following: (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer, and mixtures thereof.

2. The transdermal therapy system of claim 1, comprising the active ingredient lumepirox in the form of a free base.

3. The transdermal therapy system according to claim 1 or 2, characterized in that... The layer containing the active ingredient contains 5 to 20 wt% lumepirozol, based on the total weight of the layer containing the active ingredient.

4. The transdermal therapy system according to any one of the preceding claims, Its features The layer containing the active ingredient further comprises one or more pharmaceutically acceptable excipients selected from the following: antioxidants, penetration enhancers, plasticizers, thickeners, crystallization inhibitors, and cohesive agents.

5. A transdermal therapy system according to any one of the preceding claims, Its features The layer containing the active ingredient further includes a substance that triggers the in-situ release of lumepone free base when the active pharmaceutical ingredient is used in salt form.

6. The transdermal therapy system according to any one of the preceding claims, characterized in that... The layer containing the active ingredient is the skin contact layer of the system.

7. The transdermal therapy system according to any one of the preceding claims, characterized in that... It further includes: c) The adhesion layer above the layer containing the active pharmaceutical ingredient. The adhesive layer comprises at least one adhesive polymer. The adhesive layer initially does not contain the active ingredient. And the adhesive layer mentioned therein is the skin contact layer of the system.

8. The transdermal therapy system according to claim 7, characterized in that... At least one adhesive polymer of the adhesive layer is selected from acrylate polymers and / or copolymers, styrene-butadiene-styrene (SBS) copolymers, polyisobutylene, and mixtures of polyisobutylene and polybutene, and is preferably selected from polyacrylates and styrene-butadiene-styrene (SBS) copolymers having free hydroxyl groups.

9. The transdermal therapy system according to claim 7 or 8, characterized in that... The adhesive layer consists of at least one adhesive polymer or further comprises one or more pharmaceutically acceptable excipients selected from the following: reinforcing agents, plasticizers, cohesive agents, and antioxidants.

10. The transdermal therapy system according to any one of claims 7 to 9, characterized in that... It further includes: d) The film layer between the layer containing the active ingredient and the adhesive layer, The membrane layer comprises a membrane polymer that can permeate the active ingredient and control the release of the active ingredient.

11. The transdermal therapy system according to claim 10, characterized in that... The membrane polymer is a polyolefin selected from the following: polypropylene, polyethylene, and vinyl acetate.

12. A transdermal therapy system according to any one of the preceding claims, characterized in that... It further includes: e) Release liner, used to protect the skin contact layer before the system is used.

13. A transdermal therapy system according to any one of the preceding claims, characterized in that... The permeation is constant for at least 48 hours, preferably at least 72 hours; and / or the flux is at least 3.75 µg / cm³. 2 *h; and / or a daily delivery dose of at least 1.5 mg / day, preferably 1.8 mg / day; and / or a transdermal therapy system with a size of 4 to 40 cm. 2 Within the range.

14. A transdermal therapy system according to any one of the preceding claims, Its features It does not contain penetration enhancers.

15. A method for preparing a transdermal therapeutic system according to any one of the preceding claims, comprising the following steps: (a) Preparation of a layer composition containing an active ingredient, (b) Apply the composition prepared in step (a) onto the release liner (i). (c) The components prepared in drying step (b), and (d) Laminating the backing layer onto the active ingredient layer of the component prepared in step (c); Optionally, in addition to steps (a)-(d), the following steps are also included: (e) Preparation of the adhesive layer composition, (f) Apply the composition prepared in step (e) onto the release liner (ii). (g) The components prepared in drying step (f), (h) Remove the release liner (i) from the components prepared in step (d). (i) Press the active ingredient-containing layer prepared in step (h) onto the adhesive layer of the component prepared in step (g), or vice versa; Alternatively, in addition to steps (a)-(d), the following steps may also be included: (j) Laminating a membrane layer suitable for controlling the release of the active ingredient onto the active ingredient-containing layer of the component prepared according to step (h), (k) Perform steps (e) through (g), (l) Laminate the adhesive layer of the component prepared in step (k) onto the film layer of the component prepared in step (j), or vice versa.

16. Use of polymers selected from the following: (1) polyisobutylene, (2) styrene-butadiene-styrene copolymer, (3) silicone-acrylate hybrid polymer, (4) styrene-isoprene-styrene copolymer, and mixtures thereof, for stabilizing or reducing the decomposition of lumepiroline free base in a transdermal therapeutic system, preferably in a transdermal therapeutic system as defined in any one of claims 1 to 14.

17. Use of an antioxidant, preferably ascorbic acid or tocopherol, in a transdermal therapeutic system as defined in any one of claims 1 to 14, for reducing, preferably inhibiting, the formation of N-nitrosamines in the system.

18. A transdermal therapy system according to any one of claims 1 to 14, wherein the method of treating a disease selected from: major depressive disorder (MDD) and associated mixed features, bipolar I or II and schizophrenia.

19. A method of treating diseases selected from major depressive disorder (MDD) and associated mixed features, bipolar I or II and schizophrenia, wherein rumepiride is administered via the patient’s skin in the form of a free alkali or salt through a transdermal treatment system as defined in any one of claims 1 to 14.

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