DE102010048788A1 - Transdermal system, useful e.g. as monotherapy for indicating e.g. multiple sclerosis, comprises immunomodulator as active agent and active agent-impermeable removable protective coating, adhesive layer and active agent permeable membrane - Google Patents

Abstract

Transdermal system comprises: at least one immunomodulator as active agent including quinoline, isoxazole or fumaric acid; and (a) an active agent-impermeable removable protective coating, an adhesive layer, at least one active agent permeable membrane on the side, which faces away from the protective coating, a semipermeable active agent reservoir, which blocks the remaining impermeable active agent, or (b) active agent-impermeable removable protective coating, a matrix as an active agent reservoir, and an active agent-impermeable carrier for the active agent reservoir. Transdermal system comprises: at least one immunomodulator as active agent including quinoline, isoxazole, fumaric acid, sphingosine-1-phosphate receptor modulator or their salts and metabolites; and (a) an active agent-impermeable removable protective coating, an adhesive layer, at least one active agent permeable membrane on the side, which faces away from the protective coating, a semipermeable active agent reservoir, which blocks the remaining impermeable active agent, or (b) active agent-impermeable removable protective coating, a matrix as an active agent reservoir, and an active agent-impermeable carrier for the active agent reservoir. ACTIVITY : Neuroprotective; Antiinflammatory; Gastrointestinal-Gen. Test details are described but no results given. MECHANISM OF ACTION : None given.

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.

For example, Laquinimod represents a further development of the immunomodulator Roquinimex / Linomide, which was tested in the 1990s and was not used for further clinical use due to cardiovascular events in Phase III (Pharmazeutische Zeitung, 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

There are also Phase II clinical trials of laquinimod in Crohn's disease patients in Teva USA, see ClinicalTrials.gov, e.g. 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,
• – einer Haftklebeschicht und
• – einer zumindest wirkstoffpermeablen Membran, die auf der Seite, die der Abziehschutzschicht abgewandt ist,
• – ein im übrigen wirkstoffundurchlässiges Wirkstoff-Reservoir semipermeabel verschließt.

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 pressure-sensitive adhesive layer and
• An at least drug-permeable membrane which is disposed on the side facing away from the peel-off protective layer,
• - An otherwise drug-impermeable drug reservoir semipermeable closes.

In this embodiment, the active substance reservoir can be a closed pocket, in particular a pocket closed by a membrane, from which the at least one active substance can only escape via the membrane.

• – 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,
• – einer Matrix als Wirkstoff-Reservoir und
• – einem wirkstoffundurchlässigen Träger für das Wirkstoff-Reservoir.

The object underlying the invention is further 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 matrix as an active substance reservoir and
• - A drug-impermeable carrier for the drug reservoir.

Quinoline or 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 in vitro skin permeation ranging from 0.5 μg (micrograms) / (hr and system) to 3 mg / (hr and system), and more particularly 1 μg (micrograms) / (hrs and s) System) to 2 mg / (h and system).

Further, the transdermal system may have an active ingredient content of 1 to 50% by weight (based on the weight of the contents of the membraneized reservoir or matrix).

The matrix of the transdermal system may be formed from or with one or more pressure-sensitive polymers or from one or more gellable polymers.

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

The matrix can be formed from or with at least one polymer from the group formed by simple or branched polyacrylates, polyvinyl acetates, silicones, natural rubbers, synthetic rubbers, block copolymers, polyisobutylenes, oligomeric polyethylene oxides and combinations thereof.

Examples of polyacrylates are polymethyl acrylate, polybutyl acrylate and poly-2-ethylhexyl acrylate.

Styrene-isoprene-styrene, styrene-butadiene-styrene and styrene-ethylene / butadiene-styrene are examples of block copolymers.

The gellable polymer may be a hydrogel, e.g. B. tragacanth, starch, methyl cellulose, poly (acrylic acid) and / or Mg-Al phyllosilicates act.

The membraneed reservoir may be filled with a hydrophilic gel.

Furthermore, the membrane-provided reservoir may have a content of at least one thickener, in particular hydroxymethylcellulose.

Further, the membraneized reservoir may have an ethanol content of 5 to 45 weight percent (based on the weight of the reservoir contents).

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 contents of the membraneized reservoir or matrix).

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 .

The transdermal membrane-encapsulated reservoir system may have an area of a range of 0.5 to 5 cm ^2, and more preferably about 1 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 resulting mixture was added styrene-butadiene-styrene block polymer (e.g., DuroTak 87-611A) 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 2 to 4 (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 the assumption that the BV is high, and that the ratio mouse: human skin is 3: 1, one would aim for a reservoir patch with a size of 1 cm ² , or a matrix patch with a size of 10 cm ² .

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 [0010]
• EP 1511732 B1 [0010]
• EP 1937642 A2 [0011]
• WO 2007/146248 [0011]
• US 6455066 [0033]

Cited non-patent literature

• Lancet, 317 (2008): 2085-2092 [0002]
• 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]
• Ghosh et al. in Pharm. Tech., 17 (1993) (3): 72-98 and 17 (1993) (4): 62-89 and 17 (1993) (5): 68-76 [0031]
• Pfister et al. in Pharm. Tech., 14 (1990) (9): 132-140 [0031]
• 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 [0031]

Claims (23)

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, fumaric acid derivatives, sphingosine 1-phosphatase receptor modulators or their salts and metabolites, and with (A) An active substance-impermeable peel-off protective layer, - a pressure-sensitive adhesive layer and An at least drug-permeable membrane which is disposed on the side facing away from the peel-off protective layer, - An otherwise drug-impermeable drug reservoir semipermeable closes, or with (B) An active substance-impermeable peel-off protective layer, - a matrix as an active substance 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 contents of the reservoir according to claim 1 (a) or the matrix according to claim 1 (b)). Transdermal system comprising a matrix according to claim 1 (b) and at least one of the preceding claims, wherein the matrix is formed from or with one or more pressure-sensitive polymers or from one or more gellable polymers. The transdermal system of claim 8, wherein the polymer (s) is (are) solvent or dispersant for the drug (s). Transdermal system according to claim 8 and / or 9, wherein the matrix is formed from or with at least one polymer from the group formed by polyacrylates, silicones, block copolymers, polyisobutylenes and mixtures thereof. Transdermal system according to claim 10 with styrene-butadiene-styrene as block copolymer. Transdermal system with a reservoir according to claim 1 (a) and according to at least one of the preceding claims 1 to 7, wherein the reservoir is filled with a hydrophilic gel. Transdermal system with a reservoir according to claim 1 (a) and according to at least one of the preceding claims 1 to 7 and 12 containing at least one thickening agent, in particular hydroxymethylcellulose. A transdermal system comprising a reservoir according to claim 1 (a) and at least one of the preceding claims 1 to 7 and 12 to 13 containing from 5 to 45% by weight of ethanol (based on the weight of the reservoir contents). 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 contents of the reservoir according to Claim 1 (a) or the matrix according to claim 1 (b)). 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 with a matrix according to claim 1 (b) and 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 comprising a matrix according to Claim 1 (b) and at least one of the preceding claims having a matrix according to Claim 1 (b) 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 more preferably 10 to 35 cm ² . Transdermal system with a reservoir according to claim 1 (a) and according to at least one of the preceding claims, having an area of a range of 0.5 to 5 cm ² , preferably 0.5 to 30 cm ² and in particular about 1 cm ² .

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