WO2002017928A2 - Transdermal therapeutic system for releasing exemestane - Google Patents
Transdermal therapeutic system for releasing exemestane Download PDFInfo
- Publication number
- WO2002017928A2 WO2002017928A2 PCT/EP2001/009530 EP0109530W WO0217928A2 WO 2002017928 A2 WO2002017928 A2 WO 2002017928A2 EP 0109530 W EP0109530 W EP 0109530W WO 0217928 A2 WO0217928 A2 WO 0217928A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- active substance
- transdermal therapeutic
- therapeutic system
- exemestane
- matrix
- Prior art date
Links
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 title claims abstract description 31
- 229960000255 exemestane Drugs 0.000 title claims abstract description 31
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 30
- 239000013543 active substance Substances 0.000 claims abstract description 66
- 239000010410 layer Substances 0.000 claims abstract description 39
- 239000003886 aromatase inhibitor Substances 0.000 claims abstract description 9
- 239000011241 protective layer Substances 0.000 claims abstract description 7
- 229940046844 aromatase inhibitors Drugs 0.000 claims abstract description 4
- 239000011505 plaster Substances 0.000 claims abstract description 4
- 239000011159 matrix material Substances 0.000 claims description 34
- 239000004480 active ingredient Substances 0.000 claims description 20
- -1 polyoxyethylene Polymers 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 17
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 9
- 239000004014 plasticizer Substances 0.000 claims description 8
- 239000000853 adhesive Substances 0.000 claims description 7
- 230000001070 adhesive effect Effects 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims description 6
- 229920002678 cellulose Chemical class 0.000 claims description 6
- 239000001913 cellulose Chemical class 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 5
- 229940122815 Aromatase inhibitor Drugs 0.000 claims description 5
- 239000004831 Hot glue Substances 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 229920005601 base polymer Polymers 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 5
- 229920003023 plastic Polymers 0.000 claims description 5
- 235000013772 propylene glycol Nutrition 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 150000001735 carboxylic acids Chemical class 0.000 claims description 4
- 239000002657 fibrous material Substances 0.000 claims description 4
- 239000004033 plastic Substances 0.000 claims description 4
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 4
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 3
- 229920000459 Nitrile rubber Polymers 0.000 claims description 3
- 229920002125 Sokalan® Chemical class 0.000 claims description 3
- 229920001400 block copolymer Polymers 0.000 claims description 3
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 claims description 3
- 229920005549 butyl rubber Polymers 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 239000005038 ethylene vinyl acetate Substances 0.000 claims description 3
- 150000002191 fatty alcohols Chemical class 0.000 claims description 3
- 229920003052 natural elastomer Polymers 0.000 claims description 3
- 229920001194 natural rubber Polymers 0.000 claims description 3
- 229920001084 poly(chloroprene) Polymers 0.000 claims description 3
- 229920000058 polyacrylate Polymers 0.000 claims description 3
- 239000004584 polyacrylic acid Chemical class 0.000 claims description 3
- 229920001296 polysiloxane Polymers 0.000 claims description 3
- 229920003048 styrene butadiene rubber Polymers 0.000 claims description 3
- 229920003051 synthetic elastomer Polymers 0.000 claims description 3
- 229920003002 synthetic resin Polymers 0.000 claims description 3
- 239000000057 synthetic resin Substances 0.000 claims description 3
- 239000005061 synthetic rubber Substances 0.000 claims description 3
- VTDOEFXTVHCAAM-UHFFFAOYSA-N 4-methylpent-3-ene-1,2,3-triol Chemical compound CC(C)=C(O)C(O)CO VTDOEFXTVHCAAM-UHFFFAOYSA-N 0.000 claims description 2
- 229920000742 Cotton Polymers 0.000 claims description 2
- MMOXZBCLCQITDF-UHFFFAOYSA-N N,N-diethyl-m-toluamide Chemical compound CCN(CC)C(=O)C1=CC=CC(C)=C1 MMOXZBCLCQITDF-UHFFFAOYSA-N 0.000 claims description 2
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical class CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 claims description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 2
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 2
- 229960001673 diethyltoluamide Drugs 0.000 claims description 2
- 239000004744 fabric Substances 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 229960003881 letrozole Drugs 0.000 claims description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- 229920000193 polymethacrylate Polymers 0.000 claims description 2
- 239000003755 preservative agent Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 150000005846 sugar alcohols Polymers 0.000 claims description 2
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 claims description 2
- 229920002994 synthetic fiber Polymers 0.000 claims 2
- 229920006397 acrylic thermoplastic Polymers 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical class CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 claims 1
- 239000012790 adhesive layer Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229920000139 polyethylene terephthalate Polymers 0.000 description 3
- 239000005020 polyethylene terephthalate Substances 0.000 description 3
- 244000299507 Gossypium hirsutum Species 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 229960004421 formestane Drugs 0.000 description 2
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000013464 silicone adhesive Substances 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LPMBTLLQQJBUOO-KTKRTIGZSA-N (z)-n,n-bis(2-hydroxyethyl)octadec-9-enamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)N(CCO)CCO LPMBTLLQQJBUOO-KTKRTIGZSA-N 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000088 plastic resin Substances 0.000 description 1
- 229920001707 polybutylene terephthalate Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000004381 surface treatment Methods 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- 238000007740 vapor deposition Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
Definitions
- Transdermal therapeutic system for the delivery of exemestane.
- the present invention relates to transdermal therapeutic systems with the active substance exemestane or another active substance from the group of the aromatase inhibitors, which enable the administration of this active substance through the skin.
- the invention further includes the use of such systems for therapeutic treatment.
- Exemestane is the first oral steroidal aromatase inhibitor to appear on the market after intravenous formestane. It is indicated for the treatment of advanced breast cancer in women with natural or induced postmenopause after progression under anti-estrogen treatment.
- exemestane When administered orally, exemestane undergoes a pronounced and rapid metabolism during the first intestine-liver passage ("first pass") and has a short plasma half-life.
- TTS Transdermal therapeutic systems
- TTS consist of a drug-impermeable backing layer (also called a backing layer), a drug-containing reservoir layer and a pressure-sensitive adhesive layer for attachment to the skin.
- the latter layer can also be identical to the drug-containing layer.
- TTS usually point a backing which is also impermeable to the active ingredient and which is to be removed before the application.
- other components may be present, such as. B. a control membrane limiting the active ingredient be.
- the drug-containing reservoir layer mostly consists of polymeric basic substances; it can also contain various auxiliaries or additives.
- the object of the present invention was to provide a dosage form for the active substance exemestane, the use of which avoids the disadvantages associated with the oral administration of exemestane, as described above.
- Such a dosage form enables a sufficiently high active substance flux in vivo and can be produced inexpensively by means of common manufacturing processes.
- the invention thus relates to TTS in plaster form for the administration of the active substance exemestane and / or another aromatase heater, which have an active substance-impermeable backing layer, an associated active substance reservoir containing the active substance exemestane, a skin-side pressure-sensitive adhesive layer and a protective layer which is removable before application and has an active substance-impermeable protective layer.
- the TTS according to the invention enable a constant release of the active substance exemestane to and through the skin over a prolonged application period, which makes this active substance systemically available. That way the relatively rapid elimination of exemestane can be compensated for by constant supply from the drug reservoir of the TTS, and the therapeutic value of drug administration is increased. This is due to the fact that, in the case of transdermal administration, the metabolism of the active substance is prevented during the first intestinal-liver passage ("Fir . St-Pass" effect) and the plasma half-life is thus increased. It also avoids the problems of potentially low peroral availability or insufficient enteral absorption or gastrointestinal intolerance.
- active ingredients from the aromatase inhibitor group are also suitable, preferably formestane, anasatrozole and letrozole. These active substances can be contained in the active substance reservoir either individually or in combination.
- the TTS according to the invention can be produced both in the form of matrix systems and in the form of bag reservoir or membrane systems.
- matrix systems includes not only those systems in which the active ingredient is dissolved in a layered synthetic resin or plastic matrix and is released therefrom, but also those in which the active ingredient is based on fiber material, such as. B. cotton fabric or cotton fleece is adsorbed. This fiber material can be embedded in a plastic or synthetic resin matrix.
- the active substance reservoir of the TTS according to the invention can also contain various auxiliaries or additives, for example from the group of solvents, solubilizers, plasticizers, permeation improvers, pH regulators, antioxidants and preservatives.
- the preparation of the TTS according to the invention can be carried out by coarsely, colloidally or molecularly dispersing exemestane in a solution of matrix base polymers and coating the mixture on a suitable base, for example a thermoplastic film provided with a silicone layer.
- a suitable base for example a thermoplastic film provided with a silicone layer.
- the active substance-containing matrix layer is covered with another film, which represents the later back layer of the TTS.
- TTS is produced from such a laminate by punching flat structures in the desired geometric shape and size.
- Suitable base polymers for the active substance matrix and the pressure-sensitive adhesive layer are polyacrylates, poly (meth) acrylates, polyacrylic acid, cellulose derivatives, in particular methyl and ethyl celluloses, isobutylene, ethylene-vinyl acetate, natural and synthetic rubbers such as styrene-diene copolymers, styrene -Butadiene block copolymers, isoprene block copolymers, acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber, and hot melt adhesive. Silicone-based adhesives can also be used. Suitable mixtures of the polymers mentioned can also advantageously be used.
- hot melt adhesive includes all adhesives that are not melted by solvents but by melting when high temperatures, for example in the range of 60-200 ° C, can be liquefied.
- hot melt adhesive z.
- a particularly preferred embodiment of the invention is characterized in that the active substance exemestane is present in the TTS in combination with a solubilizer, preferably in the dissolved state; a mixture of different solubilizers can also be used.
- solubilizers are polyhydric alcohols such as 1,2-propanediol, the various butanediols, glycerol, polyethylene glycol 400, tetrahydrofurfuryl alcohol, diethylene glycol monoethyl ether, diethyl toluamide and monoisopropylidene glycerol.
- 1,2-Propanediol is particularly preferably used.
- 1,2-propanediol can also promote performance. It has proven to be advantageous that the proportion of the solubilizer (s) is between 1 and 50% by weight, preferably between 5 and 35% by weight, based on the total TTS in the final state after production.
- Suitable permeation-promoting substances are, in particular, substances from the groups of fatty alcohols, fatty acids, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, fatty alcohol esters and fatty acid esters, in particular sorbitan onolaurate or esters of long-chain fatty acids with methyl, ethyl or isopropyl alcohol, or esters of fatty alcohols with acetic acid or lactic acid. Substances such as oleic acid diethanolamine are also suitable. Polyoxylauryl ethers (Brij ® ) are particularly preferably used.
- the active substance matrix of the TTS according to the invention can also have a two or more layers, ie. H. it can consist of two or more matrix layers.
- the different matrix layers can differ in terms of their composition or the concentration of the constituents contained therein.
- the different matrix layers can have a different polymer composition or consist of different pressure sensitive adhesives.
- the individual matrix layers can contain different concentrations of active ingredient or additives such as permeation-promoting agents, solubilizers and plasticizers. Depending on the intended application, the concentrations of these ingredients, in particular the
- Active ingredient concentration in these layers are adjusted so that they become smaller or larger from the inner layer to the layer on the skin side, depending on whether a particular long-term effect or a particularly strong initial effect is desired.
- customary plasticizers are added to the active substance matrix, or individual layers of this matrix, in a concentration of up to 30% by weight, particularly preferably in a concentration of 5-20% by weight, based in each case on the active substance matrix.
- Preferred plasticizers are those from the group of hydrocarbons, alcohols, carboxylic acids, derivatives of carboxylic acids, ethers, esters and amines.
- the drug reservoir on the delivery side can also be provided with a control membrane which has a limited permeability for the drug and controls the delivery of the drug to the skin.
- the pressure-sensitive adhesive attachment of the TTS according to the invention to the skin can be carried out in various ways.
- the active substance-containing matrix can itself consist of a pressure-sensitive adhesive and thus establish the connection to the skin, or a separate pressure-sensitive adhesive layer is attached, which takes over this function.
- a separate pressure-sensitive adhesive layer is attached, which takes over this function.
- the invention further comprises embodiments in which the active substance reservoir containing exemestane is designed as a bag-shaped reservoir which is filled with a flowable, highly viscous, semi-solid or gel-like matrix which contains the active substance.
- the active substance reservoir containing exemestane is designed as a bag-shaped reservoir which is filled with a flowable, highly viscous, semi-solid or gel-like matrix which contains the active substance.
- it can be a polymer matrix, in particular a plastic matrix or a solution thereof. It is particularly advantageous if the active substance reservoir contains a gel former.
- a drug-permeable membrane can control the drug release. Suitable materials for the production of the bag wall or the control membrane are known to the person skilled in the art.
- the TTS according to the invention also have a backing layer which is impermeable to the active substance and a removable protective layer or release film which is likewise impermeable to the active substance.
- Particularly suitable materials for the backing layer are polyesters, which are characterized by particular strength, such as. B. polyethylene terephthalate and polybutylene terephthalate, but also almost any other skin-compatible plastics, such as polyvinyl chloride, ethylene-vinyl acetate copolymers, polyvinyl acetate, polyethylene, polypropylene, polyurethanes, cellulose derivatives and many others.
- the backing layer can be provided with an additional layer, e.g. B.
- removable protective layer as for the backing layer, provided that they can be treated by a suitable surface treatment, such as. B. siliconization, is equipped removable.
- a suitable surface treatment such as. B. siliconization
- other removable protective layers such as e.g. B. treated with polytetrafluoroethylene
- Paper or Cellophan ® (cellulose hydrate) can be used.
- TTS according to the invention with the active ingredient exemestane are advantageously suitable for the treatment of advanced breast cancer in women with natural or induced postmenopause after progression under anti-estrogen treatment.
- the active substance reservoir contains exemestane in combination with at least one further pharmaceutical active substance; it is preferably a drug with a tumor-inhibiting effect.
- the invention is illustrated by the following example.
- the TTS according to the invention can be produced, for example, as follows:
- exemestane and 20 g of a suitable permeation-promoting substance are dissolved in 200 g of 1,2-propanediol.
- This solution is introduced into a silicone adhesive (No. 4301; Dow Corning, USA) using a suitable stirring apparatus and dispersed, so that the most homogeneous liquid-liquid dispersion possible.
- This dispersion is homogeneously applied to a carrier film, e.g. B. from polyethylene terephthalate coated.
- the solvent of the silicone adhesive and any portions of the propanediol are then removed by controlled drying. Controlled drying means that the coated laminate has a very specific drying temperature,
- Drying speed or drying time is suspended in order to adjust the intended content of volatile substances (e.g. solubilizers).
- volatile substances e.g. solubilizers.
- the laminate obtained in this way is then laminated with a further film of polyethylene terephthalate.
- TTS are punched out with a certain area and packed in a suitable packaging.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Transdermales therapeutisches System zur Abgabe von Exemestan.Transdermal therapeutic system for the delivery of exemestane.
Die vorliegende Erfindung betrifft transdermale therapeutische Systeme mit dem Wirkstoff Exemestan oder einem anderen Wirkstoff aus der Gruppe der Aromatase-Hemmer, welche die Verabreichung dieses Wirkstoffs über die Haut ermöglichen. Die Erfindung umfaßt ferner die Verwendung derartiger Sy- steme zur therapeutischen Behandlung.The present invention relates to transdermal therapeutic systems with the active substance exemestane or another active substance from the group of the aromatase inhibitors, which enable the administration of this active substance through the skin. The invention further includes the use of such systems for therapeutic treatment.
Exemestan ist nach dem intravenös zu applizierenden For- mestan der erste orale steroidale Aromatase-Hem er, der auf den Markt kommt. Er ist angezeigt für die Behandlung des fortgeschrittenen Mamakarzinoms bei Frauen mit natürlicher oder induzierter Postmenopause nach Progression unter Anti- östrogen-Behandlung.Exemestane is the first oral steroidal aromatase inhibitor to appear on the market after intravenous formestane. It is indicated for the treatment of advanced breast cancer in women with natural or induced postmenopause after progression under anti-estrogen treatment.
Die orale Applikation von Exemestan ist allerdings mit ei- ner Reihe von Nachteilen verbunden, die durch die Pharmako- kinetik bedingt sind. Exemestan unterliegt bei oraler Gabe einer ausgeprägten und raschen Metabolisierung während der ersten Darm-Leber-Passage ("first pass") und besitzt eine geringe Plasmahalbwertszeit.Oral application of exemestane is associated with a number of disadvantages which are due to the pharmacokinetics. When administered orally, exemestane undergoes a pronounced and rapid metabolism during the first intestine-liver passage ("first pass") and has a short plasma half-life.
Transdermale therapeutische Systeme (TTS) sind Darreichungsformen, die auf die Haut appliziert werden und einen Wirkstoff an die Haut abgeben, wobei dieser Wirkstoff dadurch systemisch verfügbar gemacht wird. TTS bestehen nach dem Stand der Technik aus einer arznei- stoffundurchlässigen Trägerschicht (auch Rückschicht genannt) , einer arzneistoffhaltigen Reservoirschicht sowie einer Haftklebeschicht zur Befestigung auf der Haut. Die letztgenannte Schicht kann auch mit der arzneistoffhaltigen Schicht identisch sein. Außerdem weisen TTS in der Regel eine vor der Applikation zu entfernende, ebenfalls wirkstoffundurchlassige Rückschiσht auf. Zusätzlich können noch andere Komponenten vorhanden sein, wie z. B. eine die Wirkstoffabg be begrenzende Steuermembran. Die arzneistoffhal- tige Reservoirschicht besteht meist aus polymeren Grundsubstanzen; sie kann ferner verschiedene Hilfs- oder Zusatzstoffe enthalten.Transdermal therapeutic systems (TTS) are dosage forms that are applied to the skin and release an active ingredient to the skin, whereby this active ingredient is made systemically available. According to the state of the art, TTS consist of a drug-impermeable backing layer (also called a backing layer), a drug-containing reservoir layer and a pressure-sensitive adhesive layer for attachment to the skin. The latter layer can also be identical to the drug-containing layer. In addition, TTS usually point a backing which is also impermeable to the active ingredient and which is to be removed before the application. In addition, other components may be present, such as. B. a control membrane limiting the active ingredient be. The drug-containing reservoir layer mostly consists of polymeric basic substances; it can also contain various auxiliaries or additives.
Aufgabe der vorliegenden Erfindung war es, eine Darrei- chungsform für den Wirkstoff Exemestan bereitzustellen, bei deren Anwendung die Nachteile vermieden werden, die mit der oralen Verabreichung von Exemestan einher gehen, wie oben beschrieben.The object of the present invention was to provide a dosage form for the active substance exemestane, the use of which avoids the disadvantages associated with the oral administration of exemestane, as described above.
Des weiteren ist zu fordern, daß eine solche Darreichungs- form einen genügend hohen Wirkstoff-Flux in vivo ermöglicht und mittels gängiger Herstellungsverfahren kostengünstig produziert werden kann.Furthermore, it has to be demanded that such a dosage form enables a sufficiently high active substance flux in vivo and can be produced inexpensively by means of common manufacturing processes.
Überraschenderweise wird diese Aufgabe gelöst durch ein transdermales therapeutisches System in Pflasterform gemäß Anspruch 1, sowie durch die in den Unteransprüchen beschriebenen besonderen Ausführungsformen.Surprisingly, this object is achieved by a transdermal therapeutic system in plaster form according to claim 1, and by the special embodiments described in the subclaims.
Gegenstand der Erfindung sind folglich TTS in Pflasterform zur Verabreichung des Wirkstoffs Exemestan oder/und eines anderen Aromatasehe mers, welche eine wirkstoffundurchlassige Rückschicht, ein damit verbundenes, den Wirkstoff Exemestan enthaltendes Wirkstoffreservoir, eine hautseitige haftklebende Schicht und eine vor der Applikation ablösbare wirkstoffundurchlässige Schutzschicht aufweisen.The invention thus relates to TTS in plaster form for the administration of the active substance exemestane and / or another aromatase heater, which have an active substance-impermeable backing layer, an associated active substance reservoir containing the active substance exemestane, a skin-side pressure-sensitive adhesive layer and a protective layer which is removable before application and has an active substance-impermeable protective layer.
Die erfindungsgemäßen TTS ermöglichen über einen verlängerten Applikations-Zeitraum eine konstante Abgabe des Wirkstoffs Exemestan an und durch die Haut, wodurch dieser Wirkstoff systemisch verfügbar wird. Auf diese Weise kann die relativ rasche Elimination von Exemestan durch ständiges Nachliefern aus dem Wirkstoffreservoir des TTS kompensiert werden, und der therapeutische Wert der Arzneistoffverabreichung wird erhöht. Dies beruht darauf, daß bei der transdermalen Verabreichung die Metabolisierung des Wirkstoffs während der ersten Darm-Leber-Passage ("Fir.st-Pass"- Effekt) verhindert wird und damit die Plasmahalbwertszeit erhöht wird. Außerdem werden auf diese Weise die Probleme einer ögli- cherweise geringen peroralen Verfügbarkeit oder einer unzureichenden enteralen Absorption oder gastrointestinalen Intoleranz umgangen.The TTS according to the invention enable a constant release of the active substance exemestane to and through the skin over a prolonged application period, which makes this active substance systemically available. That way the relatively rapid elimination of exemestane can be compensated for by constant supply from the drug reservoir of the TTS, and the therapeutic value of drug administration is increased. This is due to the fact that, in the case of transdermal administration, the metabolism of the active substance is prevented during the first intestinal-liver passage ("Fir . St-Pass" effect) and the plasma half-life is thus increased. It also avoids the problems of potentially low peroral availability or insufficient enteral absorption or gastrointestinal intolerance.
Neben Exemestan kommen auch andere Wirkstoffe aus der Grup- pe der Aromatasehemmer in Frage, vorzugsweise Formestan, Anasatrozol und Letrozol. Diese Wirkstoffe können entweder einzeln oder in Kombination im Wirkstoffreservoir enthalten sein.In addition to exemestane, other active ingredients from the aromatase inhibitor group are also suitable, preferably formestane, anasatrozole and letrozole. These active substances can be contained in the active substance reservoir either individually or in combination.
Die erfindungsgemäßen TTS können sowohl in Form von Matrix- Systemen als auch in Form von Beutel-Reservoir- bzw. Me - bransyste en hergestellt werden.The TTS according to the invention can be produced both in the form of matrix systems and in the form of bag reservoir or membrane systems.
Der Begriff "Matrixsysteine" schließt nicht nur solche Systeme ein, bei denen der Wirkstoff in einer schiσhtförmigen Kunstharz- oder Kunststoffmatrix gelöst ist und aus dieser abgegeben wird, sondern auch solche, in denen der Wirkstoff an Fasermaterial, wie z. B. Baumwollgewebe oder Baumwollvlies adsorbiert ist. Dieses Fasermaterial kann in einer Kunststoff- oder Kunstharzmatrix eingebettet sein.The term "matrix systems" includes not only those systems in which the active ingredient is dissolved in a layered synthetic resin or plastic matrix and is released therefrom, but also those in which the active ingredient is based on fiber material, such as. B. cotton fabric or cotton fleece is adsorbed. This fiber material can be embedded in a plastic or synthetic resin matrix.
Grundsätzlich können für die Herstellung des Wirkstoffreservoirs bzw. der Wirkstoffmatrix eine Vielzahl von Polymeren, Harzen und Zusatzstoffen eingesetzt werden, sofern die mit der Haut in Berührung kommenden Stoffe hautverträglich sind Und solange die damit hergestellte Formulierung in der Lage ist, den Wirkstoff Exemestan an die Haut abzugeben.In principle, a large number of polymers, resins and additives can be used for the production of the active substance reservoir or the active substance matrix, provided that the substances that come into contact with the skin are compatible with the skin And as long as the formulation produced with it is able to deliver the active ingredient exemestane to the skin.
Das Wirkstoffreservoir der erfindungsgemäßen TTS kann fer- ner verschiedene Hilfs- oder Zusatzstoffe enthalten, beispielsweise aus der Gruppe der Lösemittel, Lösungsvermittler, Weichmacher, Permeationsverbesserer, pH-Regulatoren, Antioxidantien und Konservierungmittel.The active substance reservoir of the TTS according to the invention can also contain various auxiliaries or additives, for example from the group of solvents, solubilizers, plasticizers, permeation improvers, pH regulators, antioxidants and preservatives.
Bei der Herstellung der erfindungsgemäßen TTS kann im einfachsten Fall so vorgegangen werden, daß Exemestan in einer Lösung von Matrix-Grundpolymeren grob, kolloidal oder molekular dispergiert wird und die Mischung auf eine geeignete Unterlage, beispielsweise eine mit einer Silikonschicht versehene thermoplastische Folie, beschichtet wird. NachIn the simplest case, the preparation of the TTS according to the invention can be carried out by coarsely, colloidally or molecularly dispersing exemestane in a solution of matrix base polymers and coating the mixture on a suitable base, for example a thermoplastic film provided with a silicone layer. To
Trocknen und Abdampfen der Lösemittelanteile wird die wirk- stoffhaltige Matrixschicht mit einer weiteren Folie abgedeckt, welche die spätere Rückschicht des TTS darstellt. Durch Stanzen flächiger Gebilde in der gewünschten geo e- trischen Form und Größe werden aus einem solchen Laminat TTS hergestellt.Drying and evaporation of the solvent content, the active substance-containing matrix layer is covered with another film, which represents the later back layer of the TTS. TTS is produced from such a laminate by punching flat structures in the desired geometric shape and size.
Geeignete Grundpolymere für die Wirkstoffmatrix und die haftklebende Schicht sind Polyacrylate, Poly(meth)acrylate, Polyacrylsäure, Cellulose-Derivate, insbesondere Methyl- und Ethylcellulosen, Isobutylen, Ethylen-Vinylacetat, natürliche und synthetische Kautschuke wie Styrol-Dien-Copo- lymere, Styrol-Butadien-Blockcopolymere, Isopren-Blockcopo- ly ere, Acrylnitril-Butadien-Kautschuk, Butylkautschuk oder Neoprenkautschuk, sowie Heißsch elzkleber. Als Haftkleber kommen auch solche auf Silikonbasis in Betracht. Mit Vorteil können auch geeignete Mischungen der genannten Polymere zum Einsatz kommen. Unter den Begriff "Heißschmelzkleber" fallen alle Kleber, die nicht durch Lösemittel, sondern durch Schmelzen bei er- höhten Temperaturen, beispielsweise im Bereich von 60-200 °C, verflüssigt werden. Als Heißschmelzkleber eignen sich z. B. Mischungen aus Estern des hydrierten Kolophoniums mit Cellulosederivaten.Suitable base polymers for the active substance matrix and the pressure-sensitive adhesive layer are polyacrylates, poly (meth) acrylates, polyacrylic acid, cellulose derivatives, in particular methyl and ethyl celluloses, isobutylene, ethylene-vinyl acetate, natural and synthetic rubbers such as styrene-diene copolymers, styrene -Butadiene block copolymers, isoprene block copolymers, acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber, and hot melt adhesive. Silicone-based adhesives can also be used. Suitable mixtures of the polymers mentioned can also advantageously be used. The term "hot melt adhesive" includes all adhesives that are not melted by solvents but by melting when high temperatures, for example in the range of 60-200 ° C, can be liquefied. As hot melt adhesive z. B. Mixtures of esters of hydrogenated rosin with cellulose derivatives.
Neben den genannten Polymeren können auch weitere, dem Fachmann bekannte Polymere als Grundpolymere für die Herstellung der Matrix oder der Haftklebesσhiσht verwendet werden, vorausgesetzt, diese sind mit dem Wirkstoff Exemestan kompatibel.In addition to the polymers mentioned, other polymers known to those skilled in the art can also be used as base polymers for the production of the matrix or the PSA, provided these are compatible with the active substance exemestane.
Eine besonders bevorzugte Ausführungsform der Erfindung ist dadurch gekennzeichnet, daß der Wirkstoff Exemestan im TTS in Kombination mit einem Lösungsvermittler, vorzugsweise im gelösten Zustand vorliegt; auch eine Mischung verschiedener Lösungsvermittler kann verwendet werden.A particularly preferred embodiment of the invention is characterized in that the active substance exemestane is present in the TTS in combination with a solubilizer, preferably in the dissolved state; a mixture of different solubilizers can also be used.
Beispiele für bevorzugte Lösungsvermittler sind mehrwertige Alkohole wie 1,2-Propandiol, die verschiedenen Butandiole, Glycerin, Polyethylenglykol 400, Tetrahydrofurfurylalkohol, Diethylenglykolmonoethylether, Diethyltoluamid und Monoiso- propyliden-glycerin. Besonders bevorzugt wird 1,2-Propan- diol verwendet. Einige der genannten Lösungs ermittler, wie z. B. auch das 1,2-Propandiol, können zusätzlich auch per- eationsfördernd wirken. Als vorteilhaft hat sich herausgestellt, daß der Anteil des/der Lösungsvermittler zwischen 1 und 50 Gew.-%, vorzugsweise zwischen 5 und 35 Gew.-% beträgt, bezogen auf das gesamte TTS im Endzustand nach der Herstellung.Examples of preferred solubilizers are polyhydric alcohols such as 1,2-propanediol, the various butanediols, glycerol, polyethylene glycol 400, tetrahydrofurfuryl alcohol, diethylene glycol monoethyl ether, diethyl toluamide and monoisopropylidene glycerol. 1,2-Propanediol is particularly preferably used. Some of the solution investigators mentioned, such as. For example, 1,2-propanediol can also promote performance. It has proven to be advantageous that the proportion of the solubilizer (s) is between 1 and 50% by weight, preferably between 5 and 35% by weight, based on the total TTS in the final state after production.
Um einen hohen Wirkstoff-Flux durch die Haut zu erreichen, hat es sich insbesondere bei Matrix-Systemen als besonders vorteilhaft erwiesen, wenn der Matrix ein oder mehrere per- meation fördernde Stoffe zugesetzt werden, und zwar in einem Mengenanteil von 0,1 bis 25 Gew.-%, vorzugsweise von 1 bis 10 Gew.-Ss, jeweils bezogen auf das Gesamtgewicht der Wirkstoffmatrix. Als permeationsfördernde Stoffe eignen sich vor allem Stoffe aus den Gruppen der Fettalkohole, Fettsäuren, Polyoxy- ethylenfettalkoholether, Polyoxyethylenfettsäureester, Fettalkoholester und Fettsäureester, insbesondere Sorbitan- onolaurat oder Ester von langkettigen Fettsäuren mit Methyl-, Ethyl- oder Isopropylalkohol, oder Ester von Fettalkoholen mit Essigsäure oder Milchsäure. Auch Stoffe wie Öl- säurediethanolamin kommen in Betracht. Besonders bevorzugt werden Polyoxylaurylether (Brij®) eingesetzt.In order to achieve a high flux of active ingredients through the skin, it has proven particularly advantageous, particularly in the case of matrix systems, if one or more substances which promote permeation are added to the matrix, in a proportion of 0.1 to 25 % By weight, preferably from 1 to 10% by weight, in each case based on the total weight of the active substance matrix. Suitable permeation-promoting substances are, in particular, substances from the groups of fatty alcohols, fatty acids, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, fatty alcohol esters and fatty acid esters, in particular sorbitan onolaurate or esters of long-chain fatty acids with methyl, ethyl or isopropyl alcohol, or esters of fatty alcohols with acetic acid or lactic acid. Substances such as oleic acid diethanolamine are also suitable. Polyoxylauryl ethers (Brij ® ) are particularly preferably used.
Die Wirkstoffmatrix der erfindungsgemäßen TTS kann gemäß einer besonderen Ausführungsform auch einen zwei- oder mehrschichtigen Aufbau aufweisen, d. h. sie kann aus zwei oder mehreren Matrixschichten bestehen. Dabei können sich die verschiedenen Matrixschichten hinsichtlich ihrer Zusammensetzung oder der Konzentration der darin enthaltenen Bestandteile unterscheiden. Beispielsweise können die verschiedenen Matrixschichten eine unterschiedliche Polymerzusammensetzung aufweisen oder aus unterschiedlichen Haftkle- bern bestehen. Ferner können die einzelnen Matrixschichten unterschiedliche Konzentrationen an Wirkstoff oder Zusatzstoffen wie permeationsfördernden Mitteln, Lösungsvermittlern und Weichmachern enthalten. In Abhängigkeit von dem beabsichtigten Anwendungszweck können beispielsweise die Konzentrationen dieser Inhaltssto fe, insbesondere dieAccording to a particular embodiment, the active substance matrix of the TTS according to the invention can also have a two or more layers, ie. H. it can consist of two or more matrix layers. The different matrix layers can differ in terms of their composition or the concentration of the constituents contained therein. For example, the different matrix layers can have a different polymer composition or consist of different pressure sensitive adhesives. Furthermore, the individual matrix layers can contain different concentrations of active ingredient or additives such as permeation-promoting agents, solubilizers and plasticizers. Depending on the intended application, the concentrations of these ingredients, in particular the
Wirkstoffkonzentration, in diesen Schichten so eingestellt werden, daß sie von der inneren Schicht zu der hautseitig gelegenen Schicht kleiner oder größer werden, je nachdem, ob eine besondere Langzeitwirkung oder eine besonders star- ke Initialwirkung angestrebt wird.Active ingredient concentration in these layers are adjusted so that they become smaller or larger from the inner layer to the layer on the skin side, depending on whether a particular long-term effect or a particularly strong initial effect is desired.
Bei weiteren Ausführungsformen der erfindungsgemäßen TTS ist vorgesehen, daß der Wirkstoffmatrix, oder einzelnen Schichten dieser Matrix, übliche Weichmacher in einer Kon- zentration von bis zu 30 Gew.-% zugesetzt werden, besonders bevorzugt in einer Konzentration von 5-20 Gew.-Ss, jeweils bezogen auf die Wirkstoffmatrix.In further embodiments of the TTS according to the invention, it is provided that customary plasticizers are added to the active substance matrix, or individual layers of this matrix, in a concentration of up to 30% by weight, particularly preferably in a concentration of 5-20% by weight, based in each case on the active substance matrix.
Als Weichmacher können bevorzugt solche aus der Gruppe der Kohlenwasserstoffe, Alkohole, Carbonsäuren, Derivate von Carbonsäuren, Ether, Ester und Amine verwendet werden.Preferred plasticizers are those from the group of hydrocarbons, alcohols, carboxylic acids, derivatives of carboxylic acids, ethers, esters and amines.
Um eine hohe Freisetzungsrate zu erzielen, wird bevorzugt, eine möglichst hohe Wirkstoffkonzentration in der/den Wirkstoffhaltigen Schicht (en) vorzusehen, wobei allerdings zu beachten ist, daß zu hohe Wirkstoffkonzentrationen die physikalische Stabilität der Wirkstoffmatrix beeinträchtigen können. Bei den erfindungsgemäßen TTS werden deshalb Wirk- stoffkonzentrationen im Bereich von 0,1 bis 50 Gew.-%, bevorzugt im Bereich von 1 bis 10 Gew.-% angewandt, jeweils bezogen auf die Gesamtmasse der wirkstoffhaltigen Schicht (en) .In order to achieve a high release rate, it is preferred to provide the highest possible active substance concentration in the active substance-containing layer (s), although it should be noted that excessive active substance concentrations can impair the physical stability of the active substance matrix. Active ingredient concentrations in the range from 0.1 to 50% by weight, preferably in the range from 1 to 10% by weight, are therefore used in the TTS according to the invention, in each case based on the total mass of the active ingredient-containing layer (s).
Um eine Steuerung der Wirkstofffreisetzung zu ermöglichen - sofern dies nicht durch andere Mechanismen bewirkt wird -, kann das Wirkstoffreservoir auf der Abgabeseite auch mit einer Steuermembran versehen werden, welche eine begrenzte Durchlässigkeit für den Wirkstoff aufweist und die Abgabe des Wirkstoffs an die Haut steuert.In order to enable control of the drug release - unless this is caused by other mechanisms - the drug reservoir on the delivery side can also be provided with a control membrane which has a limited permeability for the drug and controls the delivery of the drug to the skin.
Die haftklebende Befestigung der erfindungsgemäßen TTS auf der Haut kann auf verschiedene Arten erfolgen. Beispielsweise kann die wirkstoffhaltige Matrix selbst aus einem Haftkleber bestehen und so die Verbindung zur Haut bewirken, oder es ist eine separate haftklebende Schicht ange- bracht, welche diese Funktion übernimmt. Insbesondere bei Systemen, welche - wie vorstehend beschrieben - mit einer hautseitigen, nicht klebenden Steuermembran ausgestattet sind, ist es vorteilhaft, die Befestigung auf der Haut durch einen Klebstoffrand zu bewirken, der die Membranflä- ehe, über welche der Wirkstoff an die Haut abgegeben wird, umgibt, jedoch nicht berührt; d. h. der Klebstoffrand steht mit der Steuermembran in keiner Verbindung.The pressure-sensitive adhesive attachment of the TTS according to the invention to the skin can be carried out in various ways. For example, the active substance-containing matrix can itself consist of a pressure-sensitive adhesive and thus establish the connection to the skin, or a separate pressure-sensitive adhesive layer is attached, which takes over this function. In particular in systems which, as described above, are equipped with a non-adhesive control membrane on the skin side, it is advantageous to effect attachment to the skin by means of an adhesive edge which covers the membrane surface via which the active ingredient is released to the skin . surrounds but not touched; ie the adhesive edge is not connected to the control membrane.
Die Erfindung umfaßt ferner Ausführungsformen, bei denen das Exemestan enthaltende Wirkstoffreservoir als beuteiförmiges Reservoir gestaltet ist, welches mit einer fließfähigen, hochviskosen, halbfesten oder gel-artigen Matrix gefüllt ist, die den Wirkstoff enthält. Beispielsweise kann es sich dabei um eine Polymermatrix, insbesondere um eine Kunststoffmatrix oder eine Lösung davon handeln. Besonders vorteilhaft ist es, wenn das Wirkstoffreservoir einen Gelbildner enthält .The invention further comprises embodiments in which the active substance reservoir containing exemestane is designed as a bag-shaped reservoir which is filled with a flowable, highly viscous, semi-solid or gel-like matrix which contains the active substance. For example, it can be a polymer matrix, in particular a plastic matrix or a solution thereof. It is particularly advantageous if the active substance reservoir contains a gel former.
Die der Haut abgewandte Beutelrückseite muß dabei wirk- stoffundurchlässig, die der Haut zugewandte Seite (Abgabe- seite) wirkstoffdurchlässig sein. Falls erforderlich, kann eine wirkstoffdurσhlässige Membran die Steuerung der Wirkstofffreisetzung übernehmen. Geeignete Materialien für die Herstellung der Beutelwand bzw. der Steuermembran sind dem Fachmann bekannt.The back of the bag facing away from the skin must be impermeable to the active ingredient, and the side facing the skin (delivery side) must be permeable to the active ingredient. If necessary, a drug-permeable membrane can control the drug release. Suitable materials for the production of the bag wall or the control membrane are known to the person skilled in the art.
Die erfindungsgemäßen TTS weisen neben dem Wirkstoffreservoir außerdem eine wirkstoffundurchlässige Rüσkschicht sowie eine ebenfalls wirkstoffundurchlässige ablösbare Schutzschicht oder Abziehfolie auf. Als Materialien für die Rückschicht eignen sich vor allem Polyester, die sich durch besondere Festigkeit auszeichnen, wie z. B. Polyethylenterephthalat und Polybutylenterephtha- lat, darüber hinaus aber nahezu beliebige andere hautverträgliche Kunststoffe, wie Polyvinylchlorid, Ethylen-Vinyl- acetat-Copolymere, Polyvinylacetat, Polyethylen, Polypropylen, Polyurethane, Cellulosederivate und viele andere mehr. Im Einzelfall kann die Rückschicht mit einer zusätzlichen Auflage versehen werden, z. B. durch Bedampfung mit Metallen, insbesondere Aluminium. Für die ablösbare Schutzschicht können grundsätzlich dieselben Materialien verwendet werden wie für die Rückschicht, vorausgesetzt, daß sie durch eine geeignete Oberflächenbehandlung, wie z. B. Silikonisierung, ablösbar aus- gerüstet ist. Es können aber auch andere ablösbare Schutzschichten wie z. B. mit Polytetrafluorethylen behandeltesIn addition to the active substance reservoir, the TTS according to the invention also have a backing layer which is impermeable to the active substance and a removable protective layer or release film which is likewise impermeable to the active substance. Particularly suitable materials for the backing layer are polyesters, which are characterized by particular strength, such as. B. polyethylene terephthalate and polybutylene terephthalate, but also almost any other skin-compatible plastics, such as polyvinyl chloride, ethylene-vinyl acetate copolymers, polyvinyl acetate, polyethylene, polypropylene, polyurethanes, cellulose derivatives and many others. In individual cases, the backing layer can be provided with an additional layer, e.g. B. by vapor deposition with metals, especially aluminum. In principle, the same materials can be used for the removable protective layer as for the backing layer, provided that they can be treated by a suitable surface treatment, such as. B. siliconization, is equipped removable. However, other removable protective layers such as e.g. B. treated with polytetrafluoroethylene
Papier oder Cellophan® (Cellulosehydrat) verwendet werden.Paper or Cellophan ® (cellulose hydrate) can be used.
Die erfindungsgemäßen TTS mit dem Wirkstoff Exemestan eig- nen sich in vorteilhafter Weise zur Behandlung des fortgeschrittenen Mammakarzinoms bei Frauen mit natürlicher oder induzierter Postmenopause nach Progression unter Antiöstro- gen-Behandlung.The TTS according to the invention with the active ingredient exemestane are advantageously suitable for the treatment of advanced breast cancer in women with natural or induced postmenopause after progression under anti-estrogen treatment.
Gemäß einer weiteren Ausführungsform der Erfindung ist vorgesehen, daß das Wirkstoffreservoir Exemestan in Kombination mit mindestens einem weiteren pharmazeutischen Wirkstoff enthält; vorzugsweise handelt es sich dabei um einen Arzneistoff mit tumorhemmender Wirkung.According to a further embodiment of the invention, it is provided that the active substance reservoir contains exemestane in combination with at least one further pharmaceutical active substance; it is preferably a drug with a tumor-inhibiting effect.
Die Erfindung wird durch nachfolgendes Beispiel erläutert.The invention is illustrated by the following example.
Beispielexample
Die erfindungsgemäßen TTS können beispielsweise wie folgt hergestellt werden:The TTS according to the invention can be produced, for example, as follows:
Es werden 50 g Exemestan sowie 20 g eines geeigneten per- meationsfordernden Stoffes (z. B. Brij®30) in 200 g 1,2- Propandiol gelöst. Diese Lösung wird mit einer geeigneten Rührapparatur in einen Silikonkleber (Nr. 4301; Fa. Dow Corning, USA) gegeben und dispergiert, so daß eine möglichst homogene Flüssig-Flüssig-Dispersion entsteht. Diese Dispersion wird mit einer geeigneten Vorrichtung homogen auf eine Trägerfolie, z. B. aus Polyethylenterephthalat be- schichtet. Anschließend wird durch eine kontrollierte Trocknung das Lösungsmittel des Silikonklebers sowie etwaige Anteile des Propandiols entfernt. Kontrollierte Trocknung bedeutet, daß das beschichtete La- minat einer ganz bestimmten Trocknungstemperatur,50 g of exemestane and 20 g of a suitable permeation-promoting substance (eg Brij ® 30) are dissolved in 200 g of 1,2-propanediol. This solution is introduced into a silicone adhesive (No. 4301; Dow Corning, USA) using a suitable stirring apparatus and dispersed, so that the most homogeneous liquid-liquid dispersion possible. This dispersion is homogeneously applied to a carrier film, e.g. B. from polyethylene terephthalate coated. The solvent of the silicone adhesive and any portions of the propanediol are then removed by controlled drying. Controlled drying means that the coated laminate has a very specific drying temperature,
Trocknungsgeschwindigkeit oder Trocknungszeit ausgesetzt wird, um den beabsichtigten Gehalt von flüchtigen Substanzen (z. B. Lösungsvermittler) einzustellen. Das so erhaltene Laminat wird anschließend mit einer weite- ren Folie aus Polyethylenterephthalat zukaschiert. Zuletzt werden TTS mit einer bestimmten Fläche ausgestanzt und in ein geeignetes Packmittel verpackt. Drying speed or drying time is suspended in order to adjust the intended content of volatile substances (e.g. solubilizers). The laminate obtained in this way is then laminated with a further film of polyethylene terephthalate. Finally, TTS are punched out with a certain area and packed in a suitable packaging.
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2000142411 DE10042411A1 (en) | 2000-08-30 | 2000-08-30 | Transdermal therapeutic system for the delivery of exemestane |
| DE10042411.2 | 2000-08-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2002017928A2 true WO2002017928A2 (en) | 2002-03-07 |
| WO2002017928A3 WO2002017928A3 (en) | 2002-06-27 |
Family
ID=7654181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2001/009530 WO2002017928A2 (en) | 2000-08-30 | 2001-08-18 | Transdermal therapeutic system for releasing exemestane |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE10042411A1 (en) |
| WO (1) | WO2002017928A2 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009007334A3 (en) * | 2007-07-10 | 2009-03-12 | Christian Braetter | Transdermal therapeutic systems which contain the substance anastrozole |
| DE102010046464A1 (en) | 2009-03-19 | 2011-04-21 | Amw Gmbh | Transdermal system, useful for indicating breast cancer in postmenopausal women, comprises aromatase inhibitor, drug-impermeable skin protective layer, reservoir, optional drug-permeable membrane and a carrier for reservoir or membrane |
| DE102010026883A1 (en) | 2010-03-11 | 2011-12-15 | Amw Gmbh | 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 |
| US9775908B2 (en) | 2007-07-10 | 2017-10-03 | Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag | Pharmaceutical preparations containing highly volatile silicones |
| US10045935B2 (en) | 2012-07-31 | 2018-08-14 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
| EP3725301A1 (en) * | 2019-04-18 | 2020-10-21 | AMW GmbH | Transdermal delivery system with aromatase inhibitor in supersaturated matrix |
| EP3725300A1 (en) * | 2019-04-18 | 2020-10-21 | AMW GmbH | Transdermal delivery system with aromatase inhibitor |
| US11154535B2 (en) | 2012-07-31 | 2021-10-26 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102019201430A1 (en) | 2019-02-05 | 2020-08-06 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system (TTS) with transport medium |
| DE102019201431A1 (en) | 2019-02-05 | 2020-08-06 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system (TTS) with solids reservoir |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9207437D0 (en) * | 1992-04-03 | 1992-05-20 | Orion Yhtymae Oy | Topical administration of toremifene and its metabolites |
| GB9212833D0 (en) * | 1992-06-17 | 1992-07-29 | Glaxo Group Ltd | Chemical compounds |
| WO1997006788A1 (en) * | 1995-08-14 | 1997-02-27 | Janssen Pharmaceutica N.V. | Transdermal administration of vorozole |
| US5567831A (en) * | 1995-08-16 | 1996-10-22 | Duguesne University Of The Holy Ghost | Non-steroidal sulfatase inhibitor compounds and their method of use |
| AUPN814496A0 (en) * | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
| EP0943333A1 (en) * | 1998-03-18 | 1999-09-22 | S.W. Patentverwertungs GmbH | Medicament for the prevention and/or treatment of breast cancer comprising an inhibitor of estrogen synthesis |
| US6638727B1 (en) * | 1999-01-26 | 2003-10-28 | Cytyc Health Corporation | Methods for identifying treating or monitoring asymptomatic patients for risk reduction or therapeutic treatment of breast cancer |
-
2000
- 2000-08-30 DE DE2000142411 patent/DE10042411A1/en not_active Withdrawn
-
2001
- 2001-08-18 WO PCT/EP2001/009530 patent/WO2002017928A2/en active Application Filing
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009007334A3 (en) * | 2007-07-10 | 2009-03-12 | Christian Braetter | Transdermal therapeutic systems which contain the substance anastrozole |
| US9775908B2 (en) | 2007-07-10 | 2017-10-03 | Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag | Pharmaceutical preparations containing highly volatile silicones |
| DE102010046464A1 (en) | 2009-03-19 | 2011-04-21 | Amw Gmbh | Transdermal system, useful for indicating breast cancer in postmenopausal women, comprises aromatase inhibitor, drug-impermeable skin protective layer, reservoir, optional drug-permeable membrane and a carrier for reservoir or membrane |
| DE102010026883A1 (en) | 2010-03-11 | 2011-12-15 | Amw Gmbh | 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 |
| US10045935B2 (en) | 2012-07-31 | 2018-08-14 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
| US11154535B2 (en) | 2012-07-31 | 2021-10-26 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
| EP3725301A1 (en) * | 2019-04-18 | 2020-10-21 | AMW GmbH | Transdermal delivery system with aromatase inhibitor in supersaturated matrix |
| EP3725300A1 (en) * | 2019-04-18 | 2020-10-21 | AMW GmbH | Transdermal delivery system with aromatase inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002017928A3 (en) | 2002-06-27 |
| DE10042411A1 (en) | 2002-03-28 |
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