EP1509210A1 - Pflaster, enthaltend fentanylum - Google Patents
Pflaster, enthaltend fentanylumInfo
- Publication number
- EP1509210A1 EP1509210A1 EP03755897A EP03755897A EP1509210A1 EP 1509210 A1 EP1509210 A1 EP 1509210A1 EP 03755897 A EP03755897 A EP 03755897A EP 03755897 A EP03755897 A EP 03755897A EP 1509210 A1 EP1509210 A1 EP 1509210A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acrylate
- therapeutic system
- transdermal therapeutic
- adhesive matrix
- acrylate copolymer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960002428 fentanyl Drugs 0.000 title claims abstract description 37
- 239000011505 plaster Substances 0.000 title description 3
- 230000001070 adhesive effect Effects 0.000 claims abstract description 42
- 239000000853 adhesive Substances 0.000 claims abstract description 39
- 239000011159 matrix material Substances 0.000 claims abstract description 26
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 20
- 229920001577 copolymer Polymers 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical group OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 claims description 14
- 239000010410 layer Substances 0.000 claims description 14
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical group CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 9
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 230000035515 penetration Effects 0.000 claims description 8
- 239000003431 cross linking reagent Substances 0.000 claims description 7
- 229920000728 polyester Polymers 0.000 claims description 5
- 239000011241 protective layer Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000004132 cross linking Methods 0.000 claims description 3
- -1 polypropylene Polymers 0.000 claims description 3
- 150000003609 titanium compounds Chemical class 0.000 claims description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims 8
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 claims 4
- 239000004743 Polypropylene Substances 0.000 claims 2
- 229920001155 polypropylene Polymers 0.000 claims 2
- 239000004744 fabric Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000011247 coating layer Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 16
- 210000003491 skin Anatomy 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- 239000013543 active substance Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 229920006378 biaxially oriented polypropylene Polymers 0.000 description 7
- 239000011127 biaxially oriented polypropylene Substances 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 229920006267 polyester film Polymers 0.000 description 7
- 239000004971 Cross linker Substances 0.000 description 6
- 239000003522 acrylic cement Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000008591 skin barrier function Effects 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940100640 transdermal system Drugs 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 230000036765 blood level Effects 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000004814 polyurethane Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000012790 adhesive layer Substances 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 229920002367 Polyisobutene Polymers 0.000 description 1
- 208000034804 Product quality issues Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- AWGZKFQMWZYCHF-UHFFFAOYSA-N n-octylprop-2-enamide Chemical compound CCCCCCCCNC(=O)C=C AWGZKFQMWZYCHF-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
Definitions
- the invention relates to a transdermal therapeutic system with a cover layer, an adhesive matrix containing fentanyl as the active ingredient and with a removable protective layer.
- Fentanylum (fentanyl, fentanil) was patented in 1984 using a transdermal patch (US 45 88 580). Since then, it has proven its worth in the therapy of severe and / or chronic pain conditions, particularly postoperatively, as well as in cancer patients. Side effects in this class of opioids include fentanyl, nausea, circulatory problems, constipation or pruritus and life-threatening respiratory depression, which requires slow and continuous supply to the body. Due to the poor oral bioavailability of ⁇ 10%, oral prolonged-release forms (prolonged-release tablets) cannot be used.
- transdermal patch Applied transdermally, the first pass effect is avoided in the liver
- the absorption of the substance through the skin is good and long-lasting, uniform blood levels can be achieved in this way if a suitable transdermal formulation can be developed.
- the application of fentanyl from a transdermal patch is an ever growing market share in the treatment of severe pain.
- a transdermal system such as Durogesic TM
- the fentanyl released from the formulation penetrates the skin barrier in order to enter the systemic bloodstream through the subcutaneous blood flow and from there to develop centrally the analgesic effect by means of a reaction at the opiate receptors in the brain.
- a skin depot due to the high lipophilicity of the opioid analogue, there is an accumulation in the adipose tissue, which in turn can be released into the circulation at a later point in time - this is called a skin depot.
- the penetration of drugs through the skin is largely determined by the physicochemical properties of the substance.
- the octa- nol / water distribution coefficient and the molecular size play a role here (Potts RO, Guy RH in: Gurny R, Teubner A; Dermal and transdermal drug delivery, Wiss. Verlagsges. Stuttgart (1993)). Since the patient prefers to use an effective patch in a size as inconspicuous and small as possible, there is also a desire to increase the penetration rate in this case, although there are actually only two options if the skin is not “microinjected” , Micro lesions or the application of external energy sources (e.g. iontophoresis or the like): 1. Facilitation of diffusion by adding penetration accelerators or applying electrical voltage (iontophoresis)
- Alcohols, fatty acids, fatty alcohols, simple and polyhydric alcohols, lauro- ' capram and surfactants are used as penetration accelerators. However, many of these substances act by disrupting the skin's barrier function and can therefore be classified as more or less irritating to the skin. Nevertheless, numerous systems are described in patent specifications (cf. WO 89 10 108, WO 9956782, WO 9932153 etc.).
- the use of systems in which the active ingredient is present in supersaturated form is more compatible.
- the maximum flux of a substance through the skin is usually limited by its solubility in the cornea (stratum corneum), which is the main barrier to penetration.
- This saturation concentration will occur when the active substance in the vehicle, for example in the matrix of the transdermal system, is also present in a concentration that corresponds to the solubility in the vehicle.
- One way to further increase this so-called maximum thermodynamic activity is to incorporate the drug in a concentration that exceeds the solubility in the vehicle. This is possible, for example, by incorporating fentanyl into acrylate copolymers (WO 20024386).
- the setting of the supersaturation must be so sensitive that the supersaturations are as high as possible, but also as stable as necessary, since supersaturated systems are known to be metastable and, after storage, re-crystallized to a saturated state. s. This then has the disadvantage that, due to the crystallization, these systems lead to product complaints due to a lack of aspect as well as a lack of tack. Close contact between the transdermal system and the skin is also necessary in order to obtain an effective amount of fentanyl in the target area of the blood circulation.
- fentanyl is one of the few drugs that, due to the physicochemical properties of the substance, permeate very well through the skin barrier and like to migrate and accumulate in polymers. Since the therapeutic range of fentanyl is small and there is also an addictive potential as with all opioids, another wish is to incorporate as little substance as possible but as much as necessary in the development of a transdermal fentanyl patch so that a therapeutic blood level spans several Days can be maintained.
- the object of the present invention is to develop an improved transdermal therapeutic system of the type mentioned in the introduction.
- an acrylate copolymer adhesive matrix is used which is free from penetration accelerators, the adhesive matrix being selected from the following group:
- Adhesives without functional groups were found to be sufficiently stable, but adhesives with a low proportion of hydroxyethyl acrylate (Durotak 387-2510) are clearly superior in terms of thermodynamic activity at the same concentration, which is reflected by better in vitro permeation rates exceded human skin in Franzzellen.
- the wearing properties are achieved by crosslinking the basic Durotak.
- Durotak 387-2510, 387-2516 There are many other ways of influencing the cohesion and adhesive properties of these adhesives from National Starch & Chemical (Durotak 387-2510, 387-2516), for example by means of titanium crosslinking agents, or by adding solids such as Aerosil or talc, which are found in others Systems have led to success (P 2000 04447), or by adding other polymers such as silicone, resins, polyisobutylenes (WO 9902141, WO 9300058), but if only the Durotak 387-2510 adhesive mentioned above is used, the use of polybutyl titanate leads to the best result, which was surprising.
- titanium crosslinker requires some skills on the part of the expert. Depending on the source of supply of the polybutyl titanate, it may have to be incorporated differently.
- the crosslinker from Aldrich (Germany), for example, can simply be added to the active substance-containing adhesive composition in one go after dissolving it in a little ethanol. If the same procedure is used with crosslinkers from Synetix (Vertec TM, UK), brown particles form in the laminate after a few weeks. Therefore you have to pre-dissolve this crosslinker in heptane, then add ethanol to the mixture (mixing ratio 60:40) so that a 3% crosslinker solution results. This is slowly added to the active substance-containing adhesive mass with vigorous stirring. Only then will a perfect matrix be obtained even after storage.
- Another possibility of reducing the softening effect of fentanyl on the basic adhesive used is to adjust it by adding a "harder” adhesive, characterized by a proportion of vinyl acetate in the acrylate copolymer. This was successfully achieved by adding an adhesive without functional groups such as Durotak 87-4098.
- the ratio of 2-hydroxyethyl acrylate to vinyl acetate is no longer 1: 0.4 to 1: 5, but 1: 5.2 or 1: 6 and thus no longer has the positive properties of the high thermodynamic activity and the associated high in vitro release and in vitro skin permeation as in the adhesive mixture according to the invention in which the ratio of hydroxyethyl acrylate to vinyl acetate according to the invention is 1: 0, 4 to 1: 5.
- the following table provides an overview of the values obtained for those formulations that were tested:
- the carriers of the matrix play an important role in the wearing properties. Since the transdermal system in the strongest dosage of 100 ⁇ g fentanyl per hour delivery rate already reaches a size of at least 40 cm 2 , which is considerable, a certain flexibility is advantageous for the comfort.
- the protective film should not be too thin (at least 36 ⁇ m layer thickness, preferably 100 ⁇ m layer thickness), so that the larger systems of 30 cm 2 and more are still easy to handle by the patient.
- the dermal therapeutic systems according to the invention are preferably such that they consist of a cover layer impermeable to the active substance, an adhesive layer containing the active substance adhering to the cover layer and a removable protective layer.
- TDS This simplest form of a TDS can be produced in the manner known to the person skilled in the art by mixing a solution of the adhesive or adhesive mixture in a low-boiling solvent with the active ingredient, applying the mixture evenly to a removable protective layer, removing the solvent quantitatively by heating, and that product obtained is covered with a carrier.
- the applied active substance-containing adhesive layer has a thickness of 20 to 500 ⁇ m.
- Example 1 According to the Invention:
- the active substance-containing adhesive mass is homogenized by stirring for one hour and then spread with a doctor blade on a siliconized, 100 ⁇ m thick polyester film (FL 2000 100 ⁇ 1-S, Loparex BV, NL-Apeldoorn) in a wet layer thickness of 310 ⁇ m. After drying (10 min. At 70 ° C and 5 min at 100 ° C), the clear and homogeneous laminate is laminated with a polyester film (Hostaphan RN15, Mitsubishi, D-Frankfurt). A patch of size 10 cm 2 contains 5.5 mg fentanyl with a matrix weight of 55.0 g / m 2 .
- a patch of size 10 cm 2 contains 5.5 mg fentanyl with a matrix weight of 55.0 g / m 2 .
- a patch of size 10 cm 2 contains 5.5 mg fentanyl with a matrix weight of 55.0 g / m 2 .
- Example 2 The formulation corresponded to Example 1 according to the invention, with the exception that instead of a polyester film (Hoestphan RN15, Mitsubishi, D-Frankfurt), a BOPP film was used (Trespaphan NAA 40 ⁇ m, Trespaphan, D-Frankfurt).
- Each patch size 10 cm 2 tested contained 5.5 mg fentanyl with a matrix weight of 55.0 g / m 2 .
- the comparative product was called Durogesic TM 25 ⁇ g membrane patch.
- the results of the kinetics are summarized in the table:
- the graph in Figure 1 shows the course of the blood levels of both products.
- the drying conditions reported in the examples were those used on a laboratory scale to make the patches. When manufacturing on a larger scale, the conditions may vary. So the product is e.g. conveyed in a pilot plant in a drying tunnel with 4 drying zones at a speed of 2m / min, the individual zones have temperatures of 40 ° C, 60 ° C, 90 ° C and 120 ° C. In the case of production on a production scale, there may be other conditions which must be determined in the scale-up tests.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE20321052U DE20321052U1 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend Fentanylum |
EP07018343.9A EP1894563B2 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend Fentanylum |
EP10011331.5A EP2438912B1 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend Fentanylum |
DE20321153U DE20321153U1 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend Fentanylum |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10223835 | 2002-05-28 | ||
DE10223835A DE10223835A1 (de) | 2002-05-28 | 2002-05-28 | Pflaster, enthaltend Fentanylum |
US42855602P | 2002-11-22 | 2002-11-22 | |
US428556P | 2002-11-22 | ||
PCT/DE2003/001635 WO2003101433A1 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend fentanylum |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10011331.5A Division EP2438912B1 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend Fentanylum |
EP07018343.9A Division EP1894563B2 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend Fentanylum |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1509210A1 true EP1509210A1 (de) | 2005-03-02 |
Family
ID=29713116
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07018343.9A Expired - Lifetime EP1894563B2 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend Fentanylum |
EP03755897A Ceased EP1509210A1 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend fentanylum |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07018343.9A Expired - Lifetime EP1894563B2 (de) | 2002-05-28 | 2003-05-20 | Pflaster, enthaltend Fentanylum |
Country Status (9)
Country | Link |
---|---|
US (2) | US20060039960A1 (de) |
EP (2) | EP1894563B2 (de) |
CN (1) | CN1655772B (de) |
AT (2) | AT10109U3 (de) |
AU (1) | AU2003243896B2 (de) |
CA (1) | CA2487123C (de) |
DE (1) | DE20321052U1 (de) |
MX (1) | MXPA04011759A (de) |
WO (1) | WO2003101433A1 (de) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2001292781A1 (en) | 2000-09-19 | 2002-04-02 | National Starch And Chemical Investment Holding Corporation | Acryl adhesive useful in transdermal drug delivery systems |
CN1320008C (zh) * | 2005-03-24 | 2007-06-06 | 上海交通大学 | 包含酯基部分带羧基基团的丙烯酸酯的组合物 |
CN1320006C (zh) * | 2005-03-24 | 2007-06-06 | 上海交通大学 | 包含酯基部分带酯基基团的丙烯酸酯的组合物 |
CN1320005C (zh) * | 2005-03-24 | 2007-06-06 | 上海交通大学 | 包含酯基部分带烷烃基的丙烯酸酯的组合物 |
CN1326894C (zh) * | 2005-03-24 | 2007-07-18 | 上海交通大学 | 包含酯基部分带烷氧基的丙烯酸酯的组合物 |
CN1320009C (zh) * | 2005-03-24 | 2007-06-06 | 上海交通大学 | 包含酯基部分带羟基基团的丙烯酸酯的组合物 |
WO2007023791A1 (ja) * | 2005-08-22 | 2007-03-01 | Hisamitsu Pharmaceutical Co., Inc. | 外用剤 |
KR101170705B1 (ko) * | 2005-09-23 | 2012-08-07 | 헨켈 아게 운트 코. 카게아아 | 아크릴 폴리머계 접착제 |
DE102007020799A1 (de) * | 2007-05-03 | 2008-11-06 | Novosis Ag | Transdermales therapeutisches System mit Remifentanil |
KR20090101579A (ko) * | 2008-03-24 | 2009-09-29 | 조선대학교산학협력단 | 펜타닐을 함유한 경피 흡수제 |
TWI541246B (zh) | 2008-12-08 | 2016-07-11 | 歐陸斯迪公司 | 二氫羥戊甲嗎啡 |
CN101780057B (zh) * | 2009-01-21 | 2012-09-05 | 考司美德制药株式会社 | 经皮吸收贴剂 |
GB201309654D0 (en) | 2013-05-30 | 2013-07-17 | Euro Celtique Sa | Method |
EP3233081B1 (de) | 2014-12-19 | 2021-09-22 | Kindeva Drug Delivery L.P. | Transdermale arzneimittelverabreichungsvorrichtung enthaltend fentanyl |
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EP0622075A1 (de) | 1993-04-27 | 1994-11-02 | Hercon Laboratories Corporation | Transdermale Verabreichung aktiver Arzneistoffe |
EP0887075A2 (de) | 1997-06-26 | 1998-12-30 | Bertek, Inc. | Klebstoffmasse zur transdermalen Verabreichung von stark weichmachenden Wirkstoffen |
WO2002026217A2 (en) | 2000-09-29 | 2002-04-04 | 3M Innovative Properties Company | Composition for the transdermal delivery of fentanyl |
WO2003018075A2 (de) | 2001-08-24 | 2003-03-06 | Lts Lohmann Therapie-Systeme Ag | Transdermales therapeutisches system mit fentanyl bzw. verwandten substanzen |
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US3321451A (en) * | 1965-07-02 | 1967-05-23 | Johnson & Johnson | Adhesive compositions |
US4185051A (en) * | 1977-12-22 | 1980-01-22 | Monsanto Company | Pressure sensitive adhesive compositions containing a polymetaloxane |
US4588580B2 (en) * | 1984-07-23 | 1999-02-16 | Alaz Corp | Transdermal administration of fentanyl and device therefor |
US4906463A (en) | 1986-12-22 | 1990-03-06 | Cygnus Research Corporation | Transdermal drug-delivery composition |
US5474783A (en) | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
CA2039586A1 (en) * | 1990-05-02 | 1991-11-03 | Marian R. Appelt | Crosslinked pressure-sensitive adhesives tolerant of alcohol-based excipients used in transdermal delivery devices and method of preparing same |
DE59203307D1 (de) * | 1991-06-10 | 1995-09-21 | Lohmann Therapie Syst Lts | Nitroglycerin-pflaster und verfahren zu seiner herstellung. |
EP0686958B1 (de) * | 1994-06-06 | 2003-10-29 | Canon Kabushiki Kaisha | Gleichstromkompensation für Anzeige mit Zeilensprung |
GB9714650D0 (en) | 1997-07-11 | 1997-09-17 | Strakan Ltd | Block copolymer |
AU1728099A (en) | 1997-12-22 | 1999-07-12 | Alza Corporation | Monoglyceride and ethyl palmitate permeation enhancer compositions |
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JP2000004447A (ja) | 1998-06-16 | 2000-01-07 | Mitsubishi Electric Corp | 受像管装置 |
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-
2003
- 2003-05-20 EP EP07018343.9A patent/EP1894563B2/de not_active Expired - Lifetime
- 2003-05-20 US US10/515,608 patent/US20060039960A1/en not_active Abandoned
- 2003-05-20 CN CN038119986A patent/CN1655772B/zh not_active Expired - Lifetime
- 2003-05-20 CA CA2487123A patent/CA2487123C/en not_active Expired - Lifetime
- 2003-05-20 AU AU2003243896A patent/AU2003243896B2/en not_active Ceased
- 2003-05-20 MX MXPA04011759A patent/MXPA04011759A/es unknown
- 2003-05-20 WO PCT/DE2003/001635 patent/WO2003101433A1/de not_active Application Discontinuation
- 2003-05-20 EP EP03755897A patent/EP1509210A1/de not_active Ceased
- 2003-05-20 DE DE20321052U patent/DE20321052U1/de not_active Ceased
-
2008
- 2008-03-28 AT AT0019108U patent/AT10109U3/de not_active IP Right Cessation
- 2008-03-28 AT AT0019008U patent/AT10108U3/de not_active IP Right Cessation
-
2016
- 2016-02-17 US US15/045,267 patent/US20160158161A1/en not_active Abandoned
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EP0622075A1 (de) | 1993-04-27 | 1994-11-02 | Hercon Laboratories Corporation | Transdermale Verabreichung aktiver Arzneistoffe |
EP0887075A2 (de) | 1997-06-26 | 1998-12-30 | Bertek, Inc. | Klebstoffmasse zur transdermalen Verabreichung von stark weichmachenden Wirkstoffen |
WO2002026217A2 (en) | 2000-09-29 | 2002-04-04 | 3M Innovative Properties Company | Composition for the transdermal delivery of fentanyl |
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See also references of WO03101433A1 |
Also Published As
Publication number | Publication date |
---|---|
EP1894563B2 (de) | 2022-04-27 |
US20160158161A1 (en) | 2016-06-09 |
AT10109U3 (de) | 2009-07-15 |
US20060039960A1 (en) | 2006-02-23 |
AU2003243896B2 (en) | 2008-07-03 |
AT10108U2 (de) | 2008-09-15 |
CN1655772A (zh) | 2005-08-17 |
WO2003101433A1 (de) | 2003-12-11 |
AU2003243896A1 (en) | 2003-12-19 |
EP1894563A1 (de) | 2008-03-05 |
EP1894563B1 (de) | 2010-10-27 |
CA2487123A1 (en) | 2003-12-11 |
MXPA04011759A (es) | 2005-07-27 |
AT10109U2 (de) | 2008-09-15 |
CA2487123C (en) | 2011-10-18 |
DE20321052U1 (de) | 2005-09-22 |
AT10108U3 (de) | 2009-07-15 |
CN1655772B (zh) | 2010-05-26 |
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