DE102010026883A1 - Transdermal system useful e.g. for indication of breast cancer with progesterone-receptor positive status, comprises e.g. aromatase inhibitor, active substance puller protection layer, active substance reservoir - Google Patents

Abstract

Transdermal system comprises: at least one aromatase inhibitor as an active substance, preferably at least one active substance from non-steroidal and steroidal aromatase inhibitors and group formed from their derivatives; an active substance puller protection layer; an active substance reservoir; an optionally active substance permeable membrane; and a carrier for an active substance reservoir or an optional membrane.

Description

State of the art

It is already known, for adjuvant treatment in breast cancer with estrogen or progesterone-receptor-positive status or with unknown hormone receptor status (stage I and II) to use aromatase inhibitors in postmenopausal women (including technical information of Arimidex ^®; Aromatase inhibitors for the endocrine adjuvant treatment of breast cancer, The Lancet, 359 (2002) (June 22) ). Aromatase inhibitors represent the newest therapy class for this indication.

The mechanism of action of aromatase inhibitors is to suppress the conversion of the hormone androstenedione to estrone and other estrogens. A distinction is made between steroidal aromatase inhibitors (such as formestan and exemestane) and non-steroidal aromatase inhibitors (such as letrozole and anastrozole). The usual dosage form of the aromatase inhibitor is the oral tablet.

Aromatase inhibitors belong to the state of the art. For example Microparticles with Anastrozole as Anticancer Drug Carriers from Zidan & Habib in AAPS Pharm. Sci. Tech., 7 (2006) (3): Article 61 as well as pellets with formestan for the treatment of tumor diseases in DE 10 2005 031 780 A1 described. Reference is also made to Sipe et al. in Fertility and Sterility, 86 (6) (2006): 1676-1681 comparing anastrozole and clomiphene citrate in an "ovulation induction protocol using gonadotropins" as well as on Buzdar et al. in Cancer, 95 (9) (2002): 2006-2016 that give "anastrozole, letrozole, and exemestane" to the new generation of aromatase inhibitors.

Besides, it is off WO 02/17928 A2 a Transdermal Therapeutic System (TTS) having a backing layer which is impermeable to the drug, a drug reservoir containing exemestane, formestan, anastrozole or letrozole as an aromatase inhibitor, an adhesive layer and a removable protective layer. The drug reservoir and the adhesive layer may be identical. The reservoir may be formed as a matrix for the polyacrylates, poly (meth) acrylates, polyacrylic acid, cellulose derivatives, isobutylene, ethylene-vinyl acetate, natural and synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block copolymers, acrylonitrile Butadiene rubber, butyl rubber, neoprene rubber or hot melt adhesive and silicone-based pressure-sensitive adhesives. Suitable permeation enhancers are substances from the groups of fatty alcohols, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, fatty alcohol esters and fatty acid esters, in particular sorbitan monolaurate or esters of long-chain fatty acids with methyl, ethyl or isopropyl alcohol, or esters proposed by fatty alcohols with acetic acid or lactic acid. Furthermore, it is off WO 97/06 788 A1 a transdermal therapeutic patch with vorozole known as an aromatase inhibitor. This system may comprise an active-substance-impermeable backing layer, a pressure-sensitive adhesive as drug reservoir, for example based on poly (isobutylene) or poly (acrylate) and a peelable protective layer (cf. 3 ). The permeation enhancers mentioned are fatty acids, monoglyceride esters of fatty acids, C8-18-alkyl saccharides, C8-18-acylcarnitines and C1-14-alkylmethylsulfoxides. Besides, it is off CN 1 927 190 A1 (See EPODOC European Patent Office, The Hague NL; XP002 510 618; or espacenet database) for a transdermal therapeutic pilaster containing letrozole as an aromatase inhibitor and having a matrix, a backing layer, and a protective layer. Finally is off WO 2009/007 334 A2 a transdermal therapeutic system (TTS) with a drug-impermeable backing layer, an adhesive layer containing an adhesive and as an active ingredient anastrozole (optionally as a hydrate, solvate or salt), and a stripping layer known. This prior art provides an adhesive from the group of acrylates, methacrylates or acrylate methacrylates, silicones, polystyrenes, polyisobutylenes, celluloses or cellulose derivatives, in particular a silicone-based adhesive. Furthermore, permeation enhancers which are selected from the group of the alcohols, N-alkylpyrrolidones, 2-alkylpyrrolidones, N-alkyl-azacycloheptanones, polyoxyethylene sorbitan esters or sorbitan esters, in particular aliphatic alcohols and dodecanol, can be provided as a further component. When using a silicone matrix, the presence of a permeation enhancer should be detrimental to long-term drug administration.

invention

The object of the present invention is to provide a trandermal system for the indication breast cancer with estrogen or progesterone receptor positive status or with unknown hormone receptor status in postmenopausal women. This is designed to circumvent the frequent to very common side effects associated with oral administration, such as nausea, diarrhea and vomiting, and increase compliance.

• – mindestens einem Aromatasehemmer als Wirkstoff, insbesondere mindestens einem Wirkstoff aus der durch nicht-steroidale und steroidale Aromatasehemmer oder deren Derivate gebildeten Gruppe,
• – einer wirkstoffundurchlässigen Abziehschutzschicht,
• – einem Wirkstoff-Reservoir,
• – einer fakultativen wirkstoffdurchlässigen Membran und
• – einem Träger für das Wirkstoff-Reservoir oder die fakultative Membran.

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

• At least one aromatase inhibitor as active substance, in particular at least one active substance from the group formed by non-steroidal and steroidal aromatase inhibitors or their derivatives,
• An active substance-impermeable peel-off protective layer,
• - a drug reservoir,
• - an optional drug-permeable membrane and
• A carrier for the drug reservoir or the optional membrane.

Aromatase inhibitors are used, for example, in EP 0 296 749 and US 4,935,437 described.

The transdermal system may be characterized by a non-steroidal aromatase inhibitor, especially formestane and / or exemestane.

Furthermore, the transdermal system may be characterized by a steroidal aromatase inhibitor, in particular letrozole and / or anastrozole.

The aromatase inhibitor may be present as a derivative, especially as an aromatase inhibitor salt or aromatase inhibitor ester.

The transdermal system may have an active substance content corresponding to a human skin permeation in vitro ranging from 5 μg (micrograms) / (h and system) to 10 mg / (h and system) and in particular 10 μg (micrograms) / (h and system) to 5 mg / (h and system).

Furthermore, the transdermal system may have an active ingredient content of from 0.5 to 75% by weight and preferably from 1 to 50% by weight (based on the reservoir).

The reservoir of the transdermal system may comprise or be formed from a matrix with or from 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 may 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 bis 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 to 7200 (weight average),

be provided.

• – das Poly-(ehylen-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 2010/0068 515 A1 (e.g., [0038] to [0039]). The disclosure of this prior art is incorporated by reference.

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

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).

Examples of crystallization inhibitors are copovidones and povidone, which may have different molecular weight ranges.

Examples of solubilizers can be found in the group formed by 1,2-propanediol, dimethylacetamide and N-methylpyrrolidone.

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

Furthermore, the 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, dodecanol, octylphenol, polyethylene glycol octylphenyl ether, oleic acid, caprylic acid, polyethylene glycol, in particular PEG 400, propylene glycol, N-decylmethyl sulfoxide, fatty acid esters, especially isopropyl myristate, methyl laurate, glycerol monooleate 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.

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

The transdermal system can be provided with a lamination of the group formed by polyester film, nonwoven, plastic foam and fabric as a carrier. The carrier of the transdermal system should be drug-impermeable.

Finally, the transdermal system may comprise a reservoir ratio weight / system area of a region of 15 to 200 g / m ² and in particular 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, 2, 3, 4, 5, 6 or up to 7 days, in particular from 0.3 to 3 mg / (day and system) and preferably from 0 , 5 to 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 below with reference to examples and figures, where all figures are expressed in percent on a weight basis.

Example 1 and working examples 1 to 6

In seven examples (Example 1: Ch.-B. 005, working examples 1 to 6: Ch.-B. 001 to 004, 008 and 019) various acrylate adhesives of different composition, a block copolymer and an acrylate hydrocarbon Graft copolymer (adhesive) is charged with anastrozole. The individual formulations can be found in the following table. In the mouse skin permeation experiments, it has been discovered that in vitro mouse skin permeation from an acrylate-hydrocarbon graft copolymer is considerably higher than from the various acrylate polymers or acrylate copolymers, regardless of their functional groups. Also, from pure rubber polymer (polyisobutylene), mouse skin permeation is low compared to the results obtained for acrylates ( 1 ).
Abbreviations: A = anastrozole, MW = mean, PSA = pressure sensitive adhesive, KW = hydrocarbon, PIB = polyisobutylene; in the acrylate copolymer Ch.-B. 001, the comonomer is not isobutylene) mouse skin permeations in vitro CH B. Anastrozole (%) PSA 001 5 Acrylate copolymer without functional groups 002 5 Methyl acrylate with OH groups 003 5 Acrylate-vinyl acetate copolymer with OH groups 004 5 Acrylate polymer with COOH groups 005 5 KW acrylate copolymer 019 5 PIB 008 5 Styrene copolymer

Examples 2 to 3 and working examples 7 to 9

Anastrozole is dissolved in the solvent and the respective adjuvant is added. The crystallization inhibitor is also dissolved in the solvent and added. The resulting mixture is added to PSA (Examples 2 to 3: Ch.-B. 005 and 063; Working Examples 7 to 9: Ch.-B. 008 and 064 to 065), followed by mixing to visible homogeneity becomes. Thereafter, a laminate is produced from the active ingredient adhesive composition with a basis weight of 40 to 60 g / m ² . CH B. active substance excipient crystallization inhibitor PSA 063 Anastrozole 5% Isopropyl myristate 5% Copovidone 5% KW acrylate copolymer 065 Anastrozole 5% Isopropyl myristate 5% Copovidone 5% Styrene copolymer 064 Anastrozole 5% Dodecanol 2% Copovidone 5% Styrene copolymer 005 Anastrozole 5% - - KW acrylate copolymer 008 Anastrozole 5% - - Styrene copolymer

2 can be seen that Ch.-B 063 and 065 are comparable in terms of permeation achieved, the bond strength of Ch.-B. However, 063 with acrylate-HC copolymer is clearly superior.

Example 4 to 5

For these examples, as the acrylate-hydrocarbon graft copolymer (hybrid adhesive), an acrylate polymer having hydroxyl functional groups as graft base having grafted ethylene-butylene macromer having methacrylate end groups (weight average Mw of macromolecular weight about 4000) was used. used, wherein the graft copolymer was crosslinked in Example 5. Incidentally, reference may be made to Example 3 (Ch.-B. 063).

Example 6

For this example, 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) is used. Incidentally, reference may be made to Example 3 (Ch.-B. 063).

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

• DE 102005031780 A1 [0003]
• WO 02/17928 A2 [0004]
• WO 97/06788 A1 [0004]
• CN 1927190 A1 [0004]
• WO 2009/007334 A2 [0004]
• EP 0296749 [0007]
• US 4935437 [0007]
• US 5625005 [0016]
• US 6642298 [0016]
• US 6670417 [0016]
• US 2020/0068515 Al [0016]
• WO 03/018075 A2 [0019]
• US 2010/0068515 A1 [0019, 0020, 0021, 0042]
• EP 0836506 B1 [0021]
• WO 95/018603 A [0021]
• US 6455066 [0030]

Cited non-patent literature

• Aromatase inhibitors for the endocrine adjuvant treatment of breast cancer, The Lancet, 359 (2002) (June 22) [0001]
• Microparticles with Anastrozole as Anticancer Drug Carriers from Zidan & Habib in AAPS Pharm. Sci. Tech., 7 (2006) (3): Article 61 [0003]
• Sipe et al. in Fertility and Sterility, 86 (6) (2006): 1676-1681 [0003]
• Buzdar et al. in Cancer, 95 (9) (2002): 2006-2016 [0003]
• Ghosh et al. in Pharm. Tech., 17 (1993) (3): 72-98 and 17 (1993) (4): 62-89 and 17 (1993) (5): 68-76 [0028]
• Pfister et al. in Pharm. Tech., 14 (1990) (9): 132-140 [0028]
• 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 [0028]

Claims (25)

Transdermal system with At least one aromatase inhibitor as active ingredient, in particular at least one active ingredient from the group formed by non-steroidal and steroidal aromatase inhibitors or their derivatives, An active substance-impermeable peel-off protective layer, - a drug reservoir, - an optional drug-permeable membrane and A carrier for the drug reservoir or the optional membrane. Transdermal system according to claim 1 with formestane as active ingredient. Transdermal system according to claim 1 with exemestane as active ingredient. Transdermal system according to claim 1 with letrozole as active ingredient. Transdermal system according to claim 1 with anastrozole as active ingredient. Transdermal system according to one of the preceding claims, having at least one aromatase inhibitor derivative of the group formed by aromatase inhibitor salts and aromatase inhibitor esters. 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 of 5 μg (micrograms) / (h and system) to 10 mg / (h and system) and in particular of 10 μg (micrograms) / (h and system) to 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 6 with an active ingredient content of 0.5 to 75 wt .-% and preferably 1 to 50 wt .-% (based on the reservoir). The transdermal system according to at least one of the preceding claims, wherein the drug reservoir comprises or is formed from a matrix of or with one or more acrylate hydrocarbon pressure sensitive graft copolymers and in particular acrylate rubber graft copolymers (acrylate rubber hybrid polymers) is. The transdermal system of claim 9, wherein the polymer (s) is (are) solvent or dispersant for the drug (s). The transdermal therapeutic system of claim 9 and / or 10, wherein the drug reservoir or matrix comprises or consists of an acrylate [poly (ethylene butylene)] graft copolymer as an acrylate hydrocarbon graft copolymer. Transdermal therapeutic system according to claim 9 and / or 10 and / or 11 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 9 and / or 10 and / or 11 and / or 12, 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 9 to 13, 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 a reservoir containing at least one stabilizer, in particular at least one stabilizer from the group formed by antioxidant, crystallization inhibitor (s) and solubilizer. The transdermal system of claim 15, wherein the antioxidant is an agent selected from the group consisting of hydrogen sulfites, ascorbic acid, ascorbic acid esters, butylhydroxytoluene, butylhydroxyanisole, tocopherol (s), and chelating agents. Transdermal system according to claim 15 and / or 16, wherein the crystallization inhibitor is a copovidone. Transdermal system according to claim 15, 16 and / or 17 with at least one solubilizer of the group formed by 1,2-propanediol, dimethylacetamide and N-methylpyrrolidone. Transdermal system according to at least one of the preceding claims with a reservoir containing at least one cohesion promoter, preferably at least one polysiloxane. Transdermal system according to at least one of the preceding claims with a reservoir containing at least one adhesion promoter, preferably at least one resin of natural origin or natural resin. Transdermal system according to at least one of the preceding claims with a reservoir containing at least one permeation enhancer. Transdermal system according to at least one of the preceding claims with a reservoir containing at least one light stabilizer for the system, in particular for the reservoir and preferably the active ingredient (s), preferably with at least one light stabilizer from benzotriazole (e) and Hydroxyphenyltriazine (e) formed group. 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 with a reservoir 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 . Transdermal system according to at least one of the preceding claims with a drug release for 1, 2, 3, 4, 5, 6 or 7 days, preferably with a drug release of 0.3 to 3 mg and in particular 0.5 to 2 mg / (day and System).

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