DE102010026879A1 - Transdermal system, useful for indicating and preventing multiple sclerosis, immunomodulator including quinolines or isoxazoles, metabolite forming groups, skin protective layer, a reservoir and a carrier impermeable to active substance - Google Patents

Abstract

Transdermal system comprises: at least one immunomodulator as an active substance including quinolines, isoxazoles, fumaric acid derivatives, sphingosine-1-phosphatase-receptor-modulators or their salts; metabolite forming groups; a skin protective layer impermeable to the active substance; an active substance reservoir; and a carrier impermeable to the active substance for the reservoir. ACTIVITY : Neuroprotective; Anti-inflammatory; Gastrointestinal-Gen. MECHANISM OF ACTION : Sphingosine-1-phosphatase-receptor-modulator.

Description

State of the art

The number of patients with multiple sclerosis in Germany alone is estimated at around 120,000.

All previous multiple sclerosis preventive base therapy medicines are only parenterally invasive. However, clinical trials are currently underway for the oral effective delivery of drugs of various chemical classes, including drugs for the preventive basic therapy of multiple sclerosis; see. Lancet, 317 (2008): 2085-2092 , Many patients may welcome alternatives to previous medications, which must be administered either subcutaneously (such as interferons or glatiramer) or intravenously (such as mitoxantrone or natalizumab), and may also desire better compliance than with an oral drug.

Reference should also be made to this WO 2008/021 368 in which "Compositions and Methods for Neuroprotection" are described, and on WO 2007/014943 in which a "Therapy for Neurological Diseases" is disclosed.

• – Polman C. et al., Treatment with laquinimod reduces development of active MRI lesions in relapsing MS, Neurology 64, March 2005, 987-991
• – Tuvessin H. et al., Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunmodulator, Drug metabolism and Disposition 33: 866–872, 2005

For example, laquinimod represents a further development of the immunomodulator Roquinimex / Linomide, which was tested in the 1990s and was not used clinically due to cardiovascular events in Phase III ( Pharmaceutical newspaper, Govi-Verlag, issue 41/2006 ). Laquinimod is described as an immunomodulator in multiple sclerosis in

• - Polman C. et al., Treatment with laquinimod reduces development of active MRI lesions in relapsing MS, Neurology 64, March 2005, 987-991
• - Tuvessin H. et al., Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator, Drug metabolism and Disposition 33: 866-872, 2005

In addition, phase II clinical trials of laquinimod in Crohn's disease patients in Teva USA, see ClinicalTrials.gov , z. NCT00737932.

invention

Object of the present invention is to provide a trandermal system for the indication of multiple sclerosis and Crohn's disease. The system is to be used for multiple sclerosis for preventive basic therapy as monotherapy or adjunctive therapy.

• – mindestens einem Immunmodulator als Wirkstoff, insbesondere mindestens einem Wirkstoff aus der durch Chinoline, Isoxazole, Sphingosin-1-Phosphatase-Rezeptor-Modulatoren, Fumarsäureester, deren Metabolite und Salze gebildeten Gruppe, und mit
• – einer wirkstoffundurchlässigen Abziehschutzschicht,
• – einem Wirkstoff-Reservoir und
• – einem wirkstoffundurchlässigen Träger für das Wirkstoff-Reservoir.

The object underlying the invention is achieved by a transdermal system with

• - At least one immunomodulator as an active ingredient, in particular at least one active ingredient from the group formed by quinolines, isoxazoles, sphingosine 1-phosphatase receptor modulators, fumaric acid esters, their metabolites and salts, and with
• An active substance-impermeable peel-off protective layer,
• - a drug reservoir and
• - A drug-impermeable carrier for the drug reservoir.

Quinolines and quinoline derivatives are described, for example, in DE 69 911 415 T2 and EP 1 511 732 B1 described.

The transdermal system may be characterized as quinoline by 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydro-quinoline-3-carboxamide (laquinimod), the active also may be present as alkali metal salt, in particular as sodium salt. The active ingredient is used for example in EP 1 937 642 A2 and WO 2007/146 248 described.

In particular, the transdermal system may be characterized by 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide as the sole active ingredient.

Further, the transdermal system may be characterized by 2- [hydroxy - [[4- (trifluoromethyl) phenyl] amino] methylidene] -3-oxo-butanenitrile as the isoxazole or isoxazole metabolite, respectively.

In particular, the transdermal system may be characterized by 2- [hydroxy - [[4- (trifluoromethyl) phenyl] amino] methylidene] -3-oxo-butanenitrile as the sole active ingredient.

The transdermal system may have an active ingredient content corresponding to human skin permeation in vitro ranging from 0.5 μg (micrograms) / (hr and system) to 3 mg / (hr and system), and more particularly 1 μg (micrograms) / (hr and system ) to 2 mg / (h and system).

Furthermore, the transdermal system may have an active ingredient content of 1 to 50% by weight (based on the weight of the reservoir or a matrix forming or being included in the reservoir).

The drug reservoir of the transdermal system may comprise or consist of a matrix with or of one or more acrylate hydrocarbon pressure sensitive graft copolymers, and in particular acrylate rubber graft copolymers (acrylate rubber hybrid polymers).

The polymer (s) may be solvent or dispersant for the drug (s).

Thus, in the transdermal therapeutic system of the present invention, the drug reservoir or matrix can be an acrylate- [poly (ethylene-butylene)] graft copolymer, acrylate- [poly (ethylene-propylene)] graft copolymer or acrylate- [Poly (ethylene-butylene-propylene)] graft copolymers as acrylate hydrocarbon graft copolymer include or consist of.

Acrylate hydrocarbon graft copolymers or acrylate rubber graft copolymers are known, for example US 5,625,005 . US 6 642 298 . US Pat. No. 6,670,417 such as US 2020/0 068 515 A1 ,

• – ein durch Hydroxylgruppen funktionalisiertes Acrylat-polymeres als Pfropfgrundlage des aufgepfropften Kohlenwasserstoffs des Pfropf-copolymeren und/oder
• – ein Poly-(ethylen-butylen)-Macromeres als aufgepfropfter Kohlenwasserstoff, insbesondere eines Mw von etwa 4000 bus 7200 (Gewichtsmittel),

vorgesehen sein.Thus, in the inventive transdermal therapeutic system for the drug reservoir

• A hydroxyl-functionalized acrylate polymer as the grafting base of the grafted hydrocarbon of the graft copolymer and / or
• A poly (ethylene-butylene) -macromer as a grafted hydrocarbon, in particular a Mw of about 4000 bus 7200 (weight average),

be provided.

• – das Poly-(ethylen-butylen)-Macromere endständige Acryl- oder Acrylatgruppen aufweisen und/oder
• – die Hydroxylgruppen des Acrylat-polymeren vernetzt sein, insbesondere durch Aluminium-tris-acetylacetonat.

Further, in the transdermal therapeutic system of the invention for the drug reservoir

• The poly (ethylene-butylene) macromers have terminal acrylic or acrylate groups and / or
• - The hydroxyl groups of the acrylate polymer crosslinked, in particular by aluminum tris-acetylacetonate.

Crosslinking of matrices with the aid of hydroxyl groups is described, for example, in US Pat WO 03/018 075 A2 or US 2010/0 068 515 A1 described. The disclosure of this prior art is incorporated by reference.

Examples of acrylate-hydrocarbon graft copolymers to be used according to the invention are an acrylate polymer having functional hydroxyl groups as graft base with grafted ethylene-butylene macromer having terminal methacrylate groups (weight average Mw of macromolecular weight about 4000 to 7200), in particular an acrylate-hydrocarbon graft copolymer (hybrid adhesive) according to US 2010/0 068 515 A1 Example 2 Sample B (weight average Mw of macromolecular weight about 4000 to 7200).

Further, in the transdermal therapeutic system of the present invention, the acrylate-hydrocarbon graft copolymer may be modified with a natural or synthetic hydrocarbon-based tackifier. Examples of adhesives describe, inter alia EP 0 836 506 B1 (eg [0016]), WO 95/018603 A (eg pages 30-31) and US 2010/0 068 515 A1 (e.g., [0038] to [0039]). The disclosure of this prior art is incorporated by reference.

The active substance reservoir may have a content of at least one stabilizer, in particular at least one stabilizer, of the group formed by antioxidant and crystallization inhibitor (s).

Examples of crystallization inhibitors are polyvinylpyrrolidone having various molecular weight ranges.

Examples of antioxidants are hydrogen sulfites such as Na-hydrogen sulfite, ascorbic acid, ascorbic acid esters, butylhydroxy-toluene, butylhydroxy-anisole, tocopherol (s) and chelating agents such as citric acid and ethylenediamine-tetraacetic acid (EDTA).

Furthermore, the active ingredient reservoir may have a content of at least one cohesion promoter (eg polysiloxanes). The cohesion can be promoted both by the degree of polymerization and by crosslinkers which attack free functional groups of polymers forming the reservoir.

Furthermore, the active substance reservoir may have a content of at least one adhesion promoter (for example resins, oils and / or fillers). The bond strength can be adjusted by providing combinations of different polymers for the reservoir.

Furthermore, the active ingredient reservoir may have a content of at least one permeation enhancer. For permeation enhancers that increase the distribution and / or diffusion of an active ingredient, reference may be made to the following documents, the disclosure of which is incorporated herein by reference. Ghosh et al. in Pharm. Tech., 17 (1993) (3): 72-98 and 17 (1993) (4): 62-89 and 17 (1993) (5): 68-76 ; Pfister et al. in Pharm. Tech., 14 (1990) (9): 132-140 ; Aungst, Skin Permeation Enhancers for Improved Transdermal Drug Delivery, in: High Performance Biomaterial, A Comprehensive Guide to Medical and Pharmaceutical Applications, Scycher Ed., (1991): 527-538 ,

Examples of permeation enhancers are ethyl alcohol, isopropyl alcohol, octylphenol, polyethylene glycol octylphenyl ether, polyethylene glycol, in particular PEG 400, propylene glycol, N-decylmethyl sulfoxide, fatty acid esters, in particular isopropyl myristate, methyl laurate, glycerol mono-oleate and propylene glycol monooleate, and N-methylpyrrolidone.

Another example of a permeation enhancer is aloe vera extracts and aloe vera gels; see. approximately US 6,455,066 and commercial products of, for example, Florida Food Products, Inc. (Eustis, Florida, USA), Tri-K Industries (Emerson, NJ, USA), Active Organics (Dallas, Texas, USA), and Maruzen Pharmaceuticals (Morristown, NJ, USA).

The extractant in Aloe vera extracts may be natural vegetable oils or hydrogenated vegetable oils. Example of a vegetable oil is soybean oil.

Another example of a permeation enhancer is dodecanol (lauryl alcohol), preferably in an amount of 0 to 20% by weight (based on the weight of the reservoir or a matrix that forms or is comprised by the reservoir).

Furthermore, the active ingredient reservoir may be provided with a content of at least one monounsaturated fatty acid and / or at least one polyunsaturated fatty acid, in particular from the group formed by oleic acid, linolenic acid and mixtures thereof.

Finally, the active substance reservoir may have a content of at least one light stabilizer (for example benzotriazoles and / or hydroxyphenyltriazines) for the system, in particular the active substance reservoir and preferably the active substance (s).

The transdermal system with the matrix may be provided with a lamination of the group formed by polyester film, nonwoven, plastic foam and fabric as a carrier.

Finally, the matrix transdermal system may have a reservoir weight / system area ratio of from 15 to 200 g / m ^2, and more preferably from 30 to 150 g / m ² . Further, the system may have an area of a range of 5 to 50 cm ^2, and more preferably 10 to 35 cm ² .

With the transdermal system should or can be achieved a continuous drug release over 1 to 7 days, in particular from 0.05 to 2.5 mg / (day and system) and preferably from 0.1 to 1.2 mg / ( Day and system).

Finally, the transdermal system should or can offer properties such as good skin compatibility with good wearing comfort and sufficient adhesive power, reliable effectiveness, high storage stability, convenient application to the skin and satisfactory compliance.

The invention will be explained in more detail by examples and a figure.

example 1

Laquinimod was dissolved in dimethylacetamide and 5% by weight of aloe vera extract was added. To the obtained mixture, an acrylate polymer having hydroxyl functional groups as a graft base with grafted ethylene-butylene macromer having methacrylate end groups (weight average Mw of macromolecular weight about 4000) was added, followed by mixing to homogeneity. The weight ratio of the active ingredient to the polymer was 1:50. Thereafter, the resulting mixture was spread on a polyester film to a weight of 50 g / m ² . The solvent was removed by drying at 80 ° C for 20 minutes. Thereafter, an aluminized polyester film was laminated.

Example 2

Laquinimod was dissolved in dimethylacetamide and 5% by weight of aloe vera extract was added. To the resulting mixture, an acrylate-hydrocarbon graft copolymer (hybrid adhesive) was used according to US 2010/0 068 515 A1 Example 2 Sample B (weight average Mw of macromolecular weight about 4000) was added, followed by mixing to homogeneity. The weight ratio of the active ingredient to the polymer was 1:50. Thereafter, the resulting mixture was spread on a polyester film to a weight of 50 g / m ² . The solvent was removed by drying at 80 ° C for 20 minutes. Thereafter, an aluminized polyester film was laminated.

Examples 3 to 5 (a to c) and Working Examples 1 to 2 (d to e)

Laquinimod, as an example of immunomodulators, was dissolved in various solvents until a saturated solution was formed. From these solutions, after filtration, the concentration of laquinimod was measured by HPLC. a), b) and c) also served as donor media for in vitro mouse skin permeation. The saturation concentrations are at a) and b) at about 0.35%, which is very low. Solvent / solvent mixture Mean value (n = 2) a) ethanol / dodecanol (9.5: 0.5) 0.35% b) ethanol / oleic acid (8.5: 1.5) 0.34% c) propylene glycol / water (8: 2) 0.11% d) water <0.01% e) HEPES buffer pH 7.2 0.30%

For in vitro skin permeation, see the figure. parameter EtOH / dodecanol 9.5 / 0.5 EtOH / oleic acid 8.5 / 1.5 PG / water 8/2 Middle max. Flux [μg / (cm ² .h)] 86 12 1.5 Mean permeated amount after 20 h in μg / cm ² 963 (Individual values) 295.61 2

At a daily dose of 0.3 mg orally and assuming that BV is high and that the mouse: human skin ratio is 3: 1, one would aim for a matrix patch of 10 cm ² size

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 2008/021368 [0003]
• WO 2007/014943 [0003]
• DE 69911415 T2 [0008]
• EP 1511732 B1 [0008]
• EP 1937642 A2 [0009]
• WO 2007/146248 [0009]
• US 5625005 [0018]
• US 6642298 [0018]
• US 6670417 [0018]
• US 2020/0068515 A1 [0018]
• WO 03/018075 A2 [0021]
• US 2010/0068515 A1 [0021, 0022, 0023, 0042]
• EP 0836506 B1 [0023]
• WO 95/018603 A [0023]
• US 6455066 [0031]

Cited non-patent literature

• Lancet, 317 (2008): 2085-2092 [0002]
• Pharmazeutische Zeitung, Govi-Verlag, issue 41/2006 [0004]
• Polman C. et al., Treatment with laquinimod Reduces Development of Active MRI Lesions in Relapsing MS, Neurology 64, March 2005, 987-991 [0004]
• Tuvessin H. et al., Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator, Drug metabolism and disposition 33: 866-872, 2005 [0004]
• ClinicalTrials.gov [0005]
• Ghosh et al. in Pharm. Tech., 17 (1993) (3): 72-98 and 17 (1993) (4): 62-89 and 17 (1993) (5): 68-76 [0029]
• Pfister et al. in Pharm. Tech., 14 (1990) (9): 132-140 [0029]
• Aungst, Skin Permeation Enhancers for Improved Transdermal Drug Delivery, in: High Performance Biomaterial, A Comprehensive Guide to Medical and Pharmaceutical Applications, Scycher Ed., (1991): 527-538 [0029]

Claims (21)

Transdermal system with at least one immunomodulator as active ingredient, in particular at least one active ingredient from the group formed by quinolines, isoxazoles, fumaric acid derivatives, sphingosine 1-phosphatase receptor modulators or their salts and metabolites, and with An active substance-impermeable peel-off protective layer, - a drug reservoir and - A drug-impermeable carrier for the drug reservoir. Transdermal system according to claim 1 with 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide as quinoline. Transdermal system according to claim 2 with 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide as the sole active ingredient. Transdermal system according to claim 1 with 2- [hydroxy - [[4- (trifluoromethyl) phenyl] amino] methylidene] -3-oxo-butanenitrile as isoxazole or isoxazole metabolite. Transdermal system according to claim 4 with 2- [hydroxy - [[4- (trifluoromethyl) phenyl] amino] methylidene] -3-oxo-butanenitrile as the sole active ingredient. Transdermal system according to at least one of the preceding claims having an active substance content corresponding to a human skin permeation in vitro of a range from 0.5 μg (micrograms) / (h and system) to 3 mg / (h and system) and in particular from 1 μg (micrograms ) / (h and system) to 0.5 mg / (h and system). Transdermal system according to at least one of the preceding claims, in particular according to at least one of claims 1 to 5 with an active ingredient content of 1 to 50 wt .-% (based on the weight of the reservoir or a matrix which forms the reservoir or is covered thereof). Transdermal system according to at least one of the preceding claims, wherein the active substance reservoir comprises or consists of a matrix with or consisting of one or more acrylate-hydrocarbon graft-type pressure-sensitive copolymers and in particular acrylate-rubber graft copolymers (acrylate-rubber hybrid polymers) , The transdermal system of claim 8, wherein the polymer (s) is (are) solvent or dispersant for the drug (s). Transdermal therapeutic system according to claim 8 and / or 9, wherein the drug reservoir or matrix comprises or consists of an acrylate- [poly (ethylene-butylene)] graft copolymer as acrylate-hydrocarbon graft copolymer. Transdermal therapeutic system according to claim 8 and / or 9 and / or 10 with A hydroxyl-functionalized acrylate polymer as the grafting base of the grafted hydrocarbon of the graft copolymer and / or A poly (ethylene-butylene) -macromer as a grafted hydrocarbon, in particular a Mw of about 4000 to 7200 (weight average). Transdermal therapeutic system according to claim 8 and / or 9 and / or 10 and / or 11, in which The poly (ethylene-butylene) macromer has terminal acrylic or acrylate groups and / or - The hydroxyl groups of the acrylate polymer are crosslinked, in particular by aluminum tris-acetylacetonate. The transdermal therapeutic system of any one of claims 8 to 12, wherein the acrylate-hydrocarbon graft copolymer is modified with a natural or synthetic hydrocarbon-based tackifier. Transdermal system according to at least one of the preceding claims with an active substance reservoir containing at least one stabilizer, in particular at least one stabilizer from the group formed by antioxidant and crystallization inhibitor (s). Transdermal system according to at least one of the preceding claims with an active substance reservoir containing at least one cohesion promoter, in particular polyvinylpyrrolidone. Transdermal system according to at least one of the preceding claims with an active substance reservoir containing at least one adhesive force promoter. Transdermal system according to at least one of the preceding claims with a drug reservoir containing at least one permeation enhancer, in particular dodecanol (lauryl alcohol), preferably in an amount of 0 to 20 wt .-% (based on the weight of the reservoir or a matrix that forms or is included in the reservoir). Transdermal system according to at least one of the preceding claims, characterized by an active substance reservoir containing at least one monounsaturated fatty acid and / or at least one polyunsaturated fatty acid, in particular from the group formed by oleic acid, linolenic acid and mixtures thereof. Transdermal system according to at least one of the preceding claims with an active substance reservoir containing at least one light stabilizer for the system, in particular the reservoir and preferably the active agent (s). Transdermal system according to at least one of the preceding claims with a lamination of the group formed by polyester film, non-woven, plastic foam and fabric as a carrier. Transdermal system according to at least one of the preceding claims, having a matrix with a matrix weight / system area ratio of a range of 15 to 200 g / m ² and in particular 30 to 150 g / m ² , the system having an area of a range of 5 to 50 cm ² and in particular 10 to 35 cm ² .

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