CA2336712C - Transdermal plaster containing at least one active ingredient which influences blood serum lipid levels - Google Patents
Transdermal plaster containing at least one active ingredient which influences blood serum lipid levels Download PDFInfo
- Publication number
- CA2336712C CA2336712C CA002336712A CA2336712A CA2336712C CA 2336712 C CA2336712 C CA 2336712C CA 002336712 A CA002336712 A CA 002336712A CA 2336712 A CA2336712 A CA 2336712A CA 2336712 C CA2336712 C CA 2336712C
- Authority
- CA
- Canada
- Prior art keywords
- preparation according
- self
- active substance
- adhesive
- substance
- 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.)
- Expired - Lifetime
Links
- 150000002632 lipids Chemical class 0.000 title claims description 7
- 239000004480 active ingredient Substances 0.000 title 1
- 239000011505 plaster Substances 0.000 title 1
- 210000002966 serum Anatomy 0.000 title 1
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- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 239000000853 adhesive Substances 0.000 claims abstract description 18
- 239000011159 matrix material Substances 0.000 claims abstract description 7
- 230000001322 lipid blood level Effects 0.000 claims abstract description 5
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 5
- -1 N-substituted-o-toluidines Chemical class 0.000 claims description 23
- 239000000126 substance Substances 0.000 claims description 20
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- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 claims description 8
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 7
- 229960004844 lovastatin Drugs 0.000 claims description 7
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- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- KNDHRUPPBXRELB-UHFFFAOYSA-M [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium;chloride Chemical compound [Cl-].C1=CC(CC)=CC=C1C(C)CCC1=CC=C([N+](C)(C)C)C=C1 KNDHRUPPBXRELB-UHFFFAOYSA-M 0.000 description 1
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- 206010000496 acne Diseases 0.000 description 1
- 150000001346 alkyl aryl ethers Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
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- 150000001412 amines Chemical class 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000002682 anti-psoriatic effect Effects 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229940030999 antipsoriatics Drugs 0.000 description 1
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
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- 229920001400 block copolymer Polymers 0.000 description 1
- FACXGONDLDSNOE-UHFFFAOYSA-N buta-1,3-diene;styrene Chemical compound C=CC=C.C=CC1=CC=CC=C1.C=CC1=CC=CC=C1 FACXGONDLDSNOE-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 235000019480 chamomile oil Nutrition 0.000 description 1
- 239000010628 chamomile oil Substances 0.000 description 1
- 235000020974 cholesterol intake Nutrition 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 229960001678 colestyramine Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 229960001767 dextrothyroxine Drugs 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000013325 dietary fiber Nutrition 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- BXOUVIIITJXIKB-UHFFFAOYSA-N ethene;styrene Chemical group C=C.C=CC1=CC=CC=C1 BXOUVIIITJXIKB-UHFFFAOYSA-N 0.000 description 1
- MEGHWIAOTJPCHQ-UHFFFAOYSA-N ethenyl butanoate Chemical compound CCCC(=O)OC=C MEGHWIAOTJPCHQ-UHFFFAOYSA-N 0.000 description 1
- UIWXSTHGICQLQT-UHFFFAOYSA-N ethenyl propanoate Chemical compound CCC(=O)OC=C UIWXSTHGICQLQT-UHFFFAOYSA-N 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- XXRVYAFBUDSLJX-UHFFFAOYSA-N etofibrate Chemical compound C=1C=CN=CC=1C(=O)OCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 XXRVYAFBUDSLJX-UHFFFAOYSA-N 0.000 description 1
- 229960003501 etofibrate Drugs 0.000 description 1
- 229950009036 etofylline clofibrate Drugs 0.000 description 1
- KYAKGJDISSNVPZ-UHFFFAOYSA-N etofylline clofibrate Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KYAKGJDISSNVPZ-UHFFFAOYSA-N 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920006270 hydrocarbon resin Polymers 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical class 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical class CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 235000021281 monounsaturated fatty acids Nutrition 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960004738 nicotinyl alcohol Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000005011 phenolic resin Substances 0.000 description 1
- 229920001515 polyalkylene glycol Chemical class 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 229920001083 polybutene Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920005996 polystyrene-poly(ethylene-butylene)-polystyrene Polymers 0.000 description 1
- 150000003097 polyterpenes Chemical class 0.000 description 1
- 229920001289 polyvinyl ether Polymers 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- HJWLCRVIBGQPNF-UHFFFAOYSA-N prop-2-enylbenzene Chemical compound C=CCC1=CC=CC=C1 HJWLCRVIBGQPNF-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 1
- 235000015500 sitosterol Nutrition 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Child & Adolescent Psychology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A preparation containing at least one active substance having an influence on the lipid blood levels of an organism is characterized in that it is present in the form of a transdermal therapeutic patch containing the active substance in a self-adhesive matrix layer which can be covered at the side facing away from the skin with an active substance--impermeable backing layer
Description
The invention relates to a preparation containing at least one active substance which has an influence on the levels of lipids in the blood of an organism.
This active substance is a member of a group of active substances which intervene in the lipid metabolism of the organism and which are used for treating diseases related thereto.
Said substances are preferably inhibitors of hydroxymethyl-glutaryl-CoA reductase (HIMG-CoA reductase).
Systemic lipid metabolism disturbances, especially so-called hyperlipoproteinemias, are of great significance in the pathogenesis of arteriosclerotic vascular diseases and of their consequences, such as cardiac infarction, apoplectic insultus and occlusive arterial diseases. In the USA and Europe about 15 percent of adults have an increased risk of suffering cardiovascular incidents because of increased lipid levels in the blood. A sensible starting point for prophylaxis, therapy and the treatment of consequences consists in lowering increased plasma lipid levels.
Basis for any treatment of hyperlipoproteinemia is an appropriate diet. A normalization of weight, appropriate diet composition, a proportion of fat <30% of the total number of calories, a sufficient dietary fibre intake, and a reduced cholesterol intake, especially <300 mg per.day, must be ensured. Furthermore it is advisable to increase the intake of unsaturated - above all monounsaturated - fatty acids, since these improve the metabolisation of lipoproteins.
If by dietary measures alone it is not possible to achieve a sufficient normalisation of the lipid blood level and if this means a higher risk of atherosclerosis, lipid-lowering medicaments are indicated in addition. By treatment with lipid-lowering medicaments a marked reduction of these diseases can be achieved. Current studies, e.g. LCAS -Lipoprotein and Coronary Arterosclerosis Study; LIPID - Long-term Intervention with Pravastatin in Ischemic Disease; CARE
- The Cholesterol and Recurrent Events Trial, were able to show that drug therapy for prevention of arteriosclerotic vascular diseases is effective even where the lipid blood levels prior to treatment are only slightly increased or even within the normal range.
Long-term success of bypass operations is often restricted by atherosclerosis in the bypasses. The progression of athero-sclerosis can be reduced by consistent lowering of the blood LDL level. It was possible to show that post-operative treatment with lovastatin keeps bypasses open longer and thereby leads to an improved prognosis of bypass operations.
Lipid-lowering medicaatents can be classified into substances lowering the triglyceride as well as the cholesterol blood levels, and substances which first of all lower the cholesterol blood level. Among the substances belonging to the first substance group are, for example, aryloxyalcane carboxylic acids, e.g. clofibrate, etofibrate, etofylline clofibrate, bezafibrate, fenofibrate, gemfibrozil, nicotinic acid, nicotinyl alcohol and acipimox. Examples for substances influencing mainly the cholesterol blood level are: anion exchange resins such as colestyramine or colestipol;
inhibitors of hydroxymethylglutaryl-CoA reductase, HIMG-CoA
reductase, inhibitors such as lovastatin, simvastatin, mevastatin, pravastatin, fluvastatin, cerivastatin or atorvastatin, probucol, dextrothyroxine and sitosterol.
These substances inhibit hydroxymethylglutaryl-CoA reductase - an early stage of cholesterol synthesis. These inhibitors are the most potent substances for treatment of hypercholesterolemia.
This active substance is a member of a group of active substances which intervene in the lipid metabolism of the organism and which are used for treating diseases related thereto.
Said substances are preferably inhibitors of hydroxymethyl-glutaryl-CoA reductase (HIMG-CoA reductase).
Systemic lipid metabolism disturbances, especially so-called hyperlipoproteinemias, are of great significance in the pathogenesis of arteriosclerotic vascular diseases and of their consequences, such as cardiac infarction, apoplectic insultus and occlusive arterial diseases. In the USA and Europe about 15 percent of adults have an increased risk of suffering cardiovascular incidents because of increased lipid levels in the blood. A sensible starting point for prophylaxis, therapy and the treatment of consequences consists in lowering increased plasma lipid levels.
Basis for any treatment of hyperlipoproteinemia is an appropriate diet. A normalization of weight, appropriate diet composition, a proportion of fat <30% of the total number of calories, a sufficient dietary fibre intake, and a reduced cholesterol intake, especially <300 mg per.day, must be ensured. Furthermore it is advisable to increase the intake of unsaturated - above all monounsaturated - fatty acids, since these improve the metabolisation of lipoproteins.
If by dietary measures alone it is not possible to achieve a sufficient normalisation of the lipid blood level and if this means a higher risk of atherosclerosis, lipid-lowering medicaments are indicated in addition. By treatment with lipid-lowering medicaments a marked reduction of these diseases can be achieved. Current studies, e.g. LCAS -Lipoprotein and Coronary Arterosclerosis Study; LIPID - Long-term Intervention with Pravastatin in Ischemic Disease; CARE
- The Cholesterol and Recurrent Events Trial, were able to show that drug therapy for prevention of arteriosclerotic vascular diseases is effective even where the lipid blood levels prior to treatment are only slightly increased or even within the normal range.
Long-term success of bypass operations is often restricted by atherosclerosis in the bypasses. The progression of athero-sclerosis can be reduced by consistent lowering of the blood LDL level. It was possible to show that post-operative treatment with lovastatin keeps bypasses open longer and thereby leads to an improved prognosis of bypass operations.
Lipid-lowering medicaatents can be classified into substances lowering the triglyceride as well as the cholesterol blood levels, and substances which first of all lower the cholesterol blood level. Among the substances belonging to the first substance group are, for example, aryloxyalcane carboxylic acids, e.g. clofibrate, etofibrate, etofylline clofibrate, bezafibrate, fenofibrate, gemfibrozil, nicotinic acid, nicotinyl alcohol and acipimox. Examples for substances influencing mainly the cholesterol blood level are: anion exchange resins such as colestyramine or colestipol;
inhibitors of hydroxymethylglutaryl-CoA reductase, HIMG-CoA
reductase, inhibitors such as lovastatin, simvastatin, mevastatin, pravastatin, fluvastatin, cerivastatin or atorvastatin, probucol, dextrothyroxine and sitosterol.
These substances inhibit hydroxymethylglutaryl-CoA reductase - an early stage of cholesterol synthesis. These inhibitors are the most potent substances for treatment of hypercholesterolemia.
Commercial administration forms are currently tablets and capsules with a dosage of 5 to 40 mg. The active substances are administered either in their active form, i.e. as the sodium salt of the hydroxy acid (e.g. pravastatin) or as a prodrug, i.e in their lactone form (e.g. lovastatin). After oral treatment, however, only about 30% of the dose applied are absorbed from the gastrointestinal tract. The active substance portion absorbed is then subject to a considerable first pass effect. Absolute bioavailability ranges from 10 to 30%. The average elimination half-time of the active substance form lies within the range of 1- 2 hours;
exception: atorvastatin with 14 h.
Preparations containing HMG-CoA reductase inhibitors and intended for topical application are prior art. Substances of this class can be employed for the therapy of skin diseases.
Here, the HMG-CoA reductase inhibitors serve as anti-psoriatics, for example as anti-aging agents for the skin, or for the treatment of acne. The active compound here is incorporated in a classical administration form such as gel, ointment or cream. A non-therapeutic use consists in employing the substance class described herein for raising the percutaneous absorption rate of substances which can normally only insufficiently be absorbed.
Descriptions of systems considering a transdermal application of this class of substances are more scarce.
US 5,629,014 describes a system suitable, inter alia, for controlled release of lovastatin to the skin or mucous membranes. The system comprises a microcellular polyester or polyether foam serving as active substance reservoir. Since this foam is not adhesive itself, an additional means is necessary for fixing the foam on the surface of application.
This foam-like system turns out to be relatively thick and inflexible. Application by the patient is thus not very practicable since the system, being exposed because of its height, is prone to being removed unintentionally and does not yield to movements of the body.
A transdermal application of lipid-lowering agents, indicated as the overall group, is mentioned in DE 36 34 016 C2. This system is characterized in that the component responsible for adhesion is present separately from the non-adhesive active substance reservoir.
Starting from the above-mentioned prior art, the invention has the object of providing a preparation containing at least one active substance which has an influence on the lipid blood levels of an organism, by which preparation it is possible to achieve a release of the therapeutically active substance which takes place at a constantly low rate over prolonged periods of time and which can be accurately dosed, and which preparation, in particular, guarantees absolute bioavaxlability of the substance while affording a user-friendly mode of application, and with the said preparation serving as active substance reservoir.
To achieve this object, it is proposed by the invention that the said preparation be present in the form of a tranadermal therapeutic patch (TTS) containing the active substance in a self-adhesive matrix layer which on the side facing away from the skin can be covered with an active substance-impermeable backing layer.
The transdermal therapeutic application system according to the invention ensures an extremely efficient drug therapy wherein the release of the active substance remains virtually constant over a long period and can be accurately controlled, with the absolute bioavailability of the substance being significantly increased.
2tSBr2lz.1 Further embodiments are provided according to the subclaims.
In particular, the self-adhesive mass is characterized in that it contains at least one hydroxymethylglutaryl-CoA
reductase-inhibiting active substance, and that it contains structural elements of a beta-hydroxycarboxylic acid (I) or a tetrahydro-4-hydroxy-6-oxo-2H-pyrans (ii). The active substance may be present in the form of its salt or in the form of an ester.
Ho (I) HO (II) OH
For the inventive patch a self-adhesive mass based on polyacrylate, silicone, ethylene vinyl acetate, rubber, rubber-like synthetic homo-, co- or block polymers, or of a hot-melt adhesive or the like may be used.
Masses based on polyacrylate are characterized in that acrylic acid and/or alkyl acrylic acid, especially methacrylic acid or its derivatives, especially the alkyl esters, are used for their production. Among the alkyl esters of acrylic acid and/or methacrylic acid those are preferred which have 1 to 18 carbon atoms in the alkyl residue, especially methyl, ethyl, n-butyl, isobutyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, isooctyl, 2-ethylhexyl, n-decyl, isodecyl, n-dodecyl and stearyl acrylate or methacrylate. Apart from these, further comonomers can participate in the structure of the polymer/copolymer. Examples are acrylic and/or methacrylic amide, hydroxyalkyl esters and polyalkylene glycol esters of acrylic and/or methacrylic acid, nitrogen-containing monomers of acrylic and/or methacrylic acid or the salts thereof, ethylene, vinyl acetate, vinyl propionate, vinyl butyrate, vinylpyrrolidone, vinyl chloride, vinyl toluene, acrylonitril or styrene.
Masses based on silicone are characterized in that they have a large free volume, a low gas transition temperature, high flexibility and high gas permeability, are biocompatible, have a low surface tension and good wettability, are thermostable as well as chemically inert, and have good tackiness, adhesion and cohesion. Typically, silicone-based masses contain a polycondensate, comprising a low-viscous polydimethyl siloxane and a silicate resin, characterized by a three-dimensional network. To increase the so-called amine resistance, it is possible for the terminal hydroxyl group of the polydimethyl siloxane to be condensed with trimethyl siloxane.
Examples for rubber-like synthetic homo-, co- or block polymers which may be employed according to the invention are polyisobutylene, polyisoprene, polystyrene, styrene-butadiene-styrene copolymers, styrene-isoprene-styrene copolymers, styrene-ethylene/propylene-styrene copolymers, styrene-ethylene/butylene-styrene copolymers, polyvinyl ethers, polyurethane, polybutadiene, styrene-butadiene copolymers, styrene-isoprene copolymers or.styrene-isoprene-butylene block copolymers.
Furthermore, a backing layer may be contained which is connected with the self-adhesive mass. This backing layer may be impermeable to the active substance and have occlusive character. Any materials may be used which are employed in common preparations. Examples for such materials are cellulose acetate, ethyl cellulose, polyethylene tereph-thalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene, polyamide or aluminium.
The composition may further comprise: tackifiers, penetration enhancers, agents for alleviating skin irritations, metal ions such as aluminium or titanium, and for increasing cohesion: plasticizers, paraffins, cyclic hydrocarbons or vegetable oils.
As agents increasing tack, colophony resins, polyterpene resins, petroleum resins, coumarone-indene resins, terpene phenol resins, hydrocarbon resins or liquid polybutene resins may be used.
Examples for agents enhancing the penetration of the active substance are: pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glykol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers, propylene glycol fatty acid derivatives, glycerol fatty acid esters, polysorbates, poloxamers, dialkyl sulfoxides, urea and urea derivatives, glycerol, native oils, laurocaprames, phospholipides, amides, amino acids, N,N-dimethyl formamide, N-methyl formamide, acetonides, calcium thioglycolate, propylene glycol, polyethylene glycol, alkyl sulfate, sodium lauryl sulfate, tetrahydrofurfuryl alcohol, N,N-diethyl-m-toluamide, anticholinergics, macrocyclic compounds or polar solvents such as isosorbitol and panthenol.
The preparation according to the present invention may also contain agents for alleviating skin irritations, such as bisabolol, chamomile oil, allantoin, glycerol or dipanthenol The invention will be explained in the following by means of examples:
B}CAMPLE 1 626 g of a solution of a self-adhesive polymer based on silicone (e.g. BIO PSATM X7-4301, 70k-wt. in n-heptane) and 48 g of 2-pyrrolidone (with 7.ovastatin) were mixed and, with the aid of a doctor knife, applied as a film of 600 m thi.cknes$ onto a fluoropolymerized polyester film (e.g.
scotchpack 1022). The moist film was dried for 30 minutes at 50 C and subsequently laminated with a polyester film (e.g. HoetaphanTh' RN 15). The weight per unit area of an adhesive film prepared in this manner was about 300 g/m'.
From the laminate, TTSs of the desired size were punched out by means of a suitable punch, and in vitro permeation through isolated cow udder skin waa measured. The flow rate was on average 0.3 g/cm'/h over a period of 72 hours.
459.2 g of a solution of a self-adhesive polymer based on silicone (e.g. BIO PSATM X7-4301, 70*-wt. in n-heptane) and 6.6 g of ethyl oleate (with lovastatin) were mixed and, with the aid of a doctor knife, applied as a film of 600 m thickness onto a fluoropolymerized polyester film (e.g.
Scotchpa]ci 1022). The moist film was dried for 30 minutes at so C and subsequently laminated with a polyester film (e.g. HostaphaziTN RN 15) . The weight per unit area of an adhesive film prepared in this manner was about 300 g/m~.
From the laminate, TTSs of the dssired size were punched out by means of a suitable punch, and in vitro permeation through isolated cow udder skin was measured. over a period of 72 hours the incorporated active substance diffused almost quantitatively through the cow udder skin, 23585276.1 EXAMPLE 3.
85.34 g of a self-adhesive, carboxyl group-containing polyacrylate (e.g. Durotak 387-2052, 48.1%-wt. in a mixture of ethyl.acetate-, n-heptane, 2-propanol and ethanol), 85.34 g of a hydrophile acrylate adhesive mixture (e.g.
PlastoidTM E 35 H, 60%-wt. in ethyl acetate), 12.5 g ethyl acetate as well as 8.4 g of 2-pyrrolidone (with lovastatin) were mixed and, with the aid of a doctor.knife, applied as a film of 400 pm thickness to a siliconized polyester film (e.g. Hostaphan RN100). The moist film was dried for 30 minutes at-50 C and subsequently laminated with a polyester film (e.g. Hostaphan RN 15). The weight per unit area of an adhesive film prepared in this manner was about 130 g/m2.
exception: atorvastatin with 14 h.
Preparations containing HMG-CoA reductase inhibitors and intended for topical application are prior art. Substances of this class can be employed for the therapy of skin diseases.
Here, the HMG-CoA reductase inhibitors serve as anti-psoriatics, for example as anti-aging agents for the skin, or for the treatment of acne. The active compound here is incorporated in a classical administration form such as gel, ointment or cream. A non-therapeutic use consists in employing the substance class described herein for raising the percutaneous absorption rate of substances which can normally only insufficiently be absorbed.
Descriptions of systems considering a transdermal application of this class of substances are more scarce.
US 5,629,014 describes a system suitable, inter alia, for controlled release of lovastatin to the skin or mucous membranes. The system comprises a microcellular polyester or polyether foam serving as active substance reservoir. Since this foam is not adhesive itself, an additional means is necessary for fixing the foam on the surface of application.
This foam-like system turns out to be relatively thick and inflexible. Application by the patient is thus not very practicable since the system, being exposed because of its height, is prone to being removed unintentionally and does not yield to movements of the body.
A transdermal application of lipid-lowering agents, indicated as the overall group, is mentioned in DE 36 34 016 C2. This system is characterized in that the component responsible for adhesion is present separately from the non-adhesive active substance reservoir.
Starting from the above-mentioned prior art, the invention has the object of providing a preparation containing at least one active substance which has an influence on the lipid blood levels of an organism, by which preparation it is possible to achieve a release of the therapeutically active substance which takes place at a constantly low rate over prolonged periods of time and which can be accurately dosed, and which preparation, in particular, guarantees absolute bioavaxlability of the substance while affording a user-friendly mode of application, and with the said preparation serving as active substance reservoir.
To achieve this object, it is proposed by the invention that the said preparation be present in the form of a tranadermal therapeutic patch (TTS) containing the active substance in a self-adhesive matrix layer which on the side facing away from the skin can be covered with an active substance-impermeable backing layer.
The transdermal therapeutic application system according to the invention ensures an extremely efficient drug therapy wherein the release of the active substance remains virtually constant over a long period and can be accurately controlled, with the absolute bioavailability of the substance being significantly increased.
2tSBr2lz.1 Further embodiments are provided according to the subclaims.
In particular, the self-adhesive mass is characterized in that it contains at least one hydroxymethylglutaryl-CoA
reductase-inhibiting active substance, and that it contains structural elements of a beta-hydroxycarboxylic acid (I) or a tetrahydro-4-hydroxy-6-oxo-2H-pyrans (ii). The active substance may be present in the form of its salt or in the form of an ester.
Ho (I) HO (II) OH
For the inventive patch a self-adhesive mass based on polyacrylate, silicone, ethylene vinyl acetate, rubber, rubber-like synthetic homo-, co- or block polymers, or of a hot-melt adhesive or the like may be used.
Masses based on polyacrylate are characterized in that acrylic acid and/or alkyl acrylic acid, especially methacrylic acid or its derivatives, especially the alkyl esters, are used for their production. Among the alkyl esters of acrylic acid and/or methacrylic acid those are preferred which have 1 to 18 carbon atoms in the alkyl residue, especially methyl, ethyl, n-butyl, isobutyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, isooctyl, 2-ethylhexyl, n-decyl, isodecyl, n-dodecyl and stearyl acrylate or methacrylate. Apart from these, further comonomers can participate in the structure of the polymer/copolymer. Examples are acrylic and/or methacrylic amide, hydroxyalkyl esters and polyalkylene glycol esters of acrylic and/or methacrylic acid, nitrogen-containing monomers of acrylic and/or methacrylic acid or the salts thereof, ethylene, vinyl acetate, vinyl propionate, vinyl butyrate, vinylpyrrolidone, vinyl chloride, vinyl toluene, acrylonitril or styrene.
Masses based on silicone are characterized in that they have a large free volume, a low gas transition temperature, high flexibility and high gas permeability, are biocompatible, have a low surface tension and good wettability, are thermostable as well as chemically inert, and have good tackiness, adhesion and cohesion. Typically, silicone-based masses contain a polycondensate, comprising a low-viscous polydimethyl siloxane and a silicate resin, characterized by a three-dimensional network. To increase the so-called amine resistance, it is possible for the terminal hydroxyl group of the polydimethyl siloxane to be condensed with trimethyl siloxane.
Examples for rubber-like synthetic homo-, co- or block polymers which may be employed according to the invention are polyisobutylene, polyisoprene, polystyrene, styrene-butadiene-styrene copolymers, styrene-isoprene-styrene copolymers, styrene-ethylene/propylene-styrene copolymers, styrene-ethylene/butylene-styrene copolymers, polyvinyl ethers, polyurethane, polybutadiene, styrene-butadiene copolymers, styrene-isoprene copolymers or.styrene-isoprene-butylene block copolymers.
Furthermore, a backing layer may be contained which is connected with the self-adhesive mass. This backing layer may be impermeable to the active substance and have occlusive character. Any materials may be used which are employed in common preparations. Examples for such materials are cellulose acetate, ethyl cellulose, polyethylene tereph-thalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene, polyamide or aluminium.
The composition may further comprise: tackifiers, penetration enhancers, agents for alleviating skin irritations, metal ions such as aluminium or titanium, and for increasing cohesion: plasticizers, paraffins, cyclic hydrocarbons or vegetable oils.
As agents increasing tack, colophony resins, polyterpene resins, petroleum resins, coumarone-indene resins, terpene phenol resins, hydrocarbon resins or liquid polybutene resins may be used.
Examples for agents enhancing the penetration of the active substance are: pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glykol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers, propylene glycol fatty acid derivatives, glycerol fatty acid esters, polysorbates, poloxamers, dialkyl sulfoxides, urea and urea derivatives, glycerol, native oils, laurocaprames, phospholipides, amides, amino acids, N,N-dimethyl formamide, N-methyl formamide, acetonides, calcium thioglycolate, propylene glycol, polyethylene glycol, alkyl sulfate, sodium lauryl sulfate, tetrahydrofurfuryl alcohol, N,N-diethyl-m-toluamide, anticholinergics, macrocyclic compounds or polar solvents such as isosorbitol and panthenol.
The preparation according to the present invention may also contain agents for alleviating skin irritations, such as bisabolol, chamomile oil, allantoin, glycerol or dipanthenol The invention will be explained in the following by means of examples:
B}CAMPLE 1 626 g of a solution of a self-adhesive polymer based on silicone (e.g. BIO PSATM X7-4301, 70k-wt. in n-heptane) and 48 g of 2-pyrrolidone (with 7.ovastatin) were mixed and, with the aid of a doctor knife, applied as a film of 600 m thi.cknes$ onto a fluoropolymerized polyester film (e.g.
scotchpack 1022). The moist film was dried for 30 minutes at 50 C and subsequently laminated with a polyester film (e.g. HoetaphanTh' RN 15). The weight per unit area of an adhesive film prepared in this manner was about 300 g/m'.
From the laminate, TTSs of the desired size were punched out by means of a suitable punch, and in vitro permeation through isolated cow udder skin waa measured. The flow rate was on average 0.3 g/cm'/h over a period of 72 hours.
459.2 g of a solution of a self-adhesive polymer based on silicone (e.g. BIO PSATM X7-4301, 70*-wt. in n-heptane) and 6.6 g of ethyl oleate (with lovastatin) were mixed and, with the aid of a doctor knife, applied as a film of 600 m thickness onto a fluoropolymerized polyester film (e.g.
Scotchpa]ci 1022). The moist film was dried for 30 minutes at so C and subsequently laminated with a polyester film (e.g. HostaphaziTN RN 15) . The weight per unit area of an adhesive film prepared in this manner was about 300 g/m~.
From the laminate, TTSs of the dssired size were punched out by means of a suitable punch, and in vitro permeation through isolated cow udder skin was measured. over a period of 72 hours the incorporated active substance diffused almost quantitatively through the cow udder skin, 23585276.1 EXAMPLE 3.
85.34 g of a self-adhesive, carboxyl group-containing polyacrylate (e.g. Durotak 387-2052, 48.1%-wt. in a mixture of ethyl.acetate-, n-heptane, 2-propanol and ethanol), 85.34 g of a hydrophile acrylate adhesive mixture (e.g.
PlastoidTM E 35 H, 60%-wt. in ethyl acetate), 12.5 g ethyl acetate as well as 8.4 g of 2-pyrrolidone (with lovastatin) were mixed and, with the aid of a doctor.knife, applied as a film of 400 pm thickness to a siliconized polyester film (e.g. Hostaphan RN100). The moist film was dried for 30 minutes at-50 C and subsequently laminated with a polyester film (e.g. Hostaphan RN 15). The weight per unit area of an adhesive film prepared in this manner was about 130 g/m2.
Claims (16)
1. A preparation in the form of a transdermal therapeutic system containing at least one active substance having an influence on the lipid blood levels of an organism and at least one auxiliary substance enhancing the permeation of the active substance through the skin in a self-adhesive matrix layer, characterized in that the active substance is contained in a self-adhesive matrix layer, and that said active substance is selected from the group of active substances inhibiting hydroxymethylglutaryl-CoA reductase, and wherein the said auxiliary substance is not an N-substituted-o-toluidines.
2. The preparation according to claim 1, wherein the auxiliary substance is selected from the group consisting of pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glycol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers, propylene glycol fatty acid derivatives, glycerol fatty acid esters, polysorbates, poloxamers, dialkyl sulfoxides, urea and urea derivatives, glycerol, native oils, laurocaprames, phospholipides, amides, amino acids, N,N-dimethyl formamide, N-methyl formamide, acetonides, calcium thioglycolate, propylene glycol, polyethylene glycol, alkyl sulfate, sodium lauryl sulfate, tetrahydrofurfuryl alcohol, macrocyclic compounds and polar solvents.
3. The preparation according to claim 1, characterized in that the active substance inhibiting hydroxymethylglutaryl-CoA
reductase contains the structural features of a beta-hydroxcarboxylic acid or a tetrahydro-4-hydroxy-6-oxo-2H-pyrans in its molecule.
reductase contains the structural features of a beta-hydroxcarboxylic acid or a tetrahydro-4-hydroxy-6-oxo-2H-pyrans in its molecule.
4. The preparation according to claim 1 or 2, characterized in that the active substance inhibiting hydroxymethylglutaryl-CoA reductase is present in the form of a salt or in the form of an ester.
5. The preparation according to any one of claims 1 to 3, characterized in that the active substance inhibiting hydroxymethylglutaryl-CoA reductase is lovastatin, simvastatin, mevastatin, pravastatin, fluvastatin, atorvastatin, eptastatin or cerivastatin.
6. The preparation according to any one of claims 1 to 4, characterized in that the self-adhesive layer of the matrix contains at least one homo-, co- or block polymer.
7. The preparation according to any one of claims 1 to 5, characterized in that the self-adhesive matrix layer is a mass based on polyacrylate, silicone, polyisobutylene, polyisoprene, polystyrene, ethylene vinyl acetate, rubber or similar synthetic homo-, co- or block polymers.
8. The preparation according to any one of claims 1 to 6, characterized in that the self-adhesive mass is a hot-melt adhesive.
9. The preparation according to any one of claims 1 to 7, characterized in that the self-adhesive mass contains an auxiliary substance which increases tack.
10. The preparation according to any one of claims 1 to 8, characterized in that the self-adhesive mass contains at least one plasticizer.
11. The preparation according to any one of claims 1 to 9, characterized in that the self-adhesive mass contains at least one auxiliary substance alleviating skin irritations.
12. The preparation according to any one of claims 1 to 10, characterized in that the self-adhesive mass contains at least one substance having an influence on cohesion.
13. The preparation according to claim 1, wherein the side of the self-adhesive matrix layer facing away from the skin is covered with an active substance-impermeable backing layer.
14. The preparation according to claim 2, characterized in that the polar solvent is panthenol.
15. The use of the preparation according to any one of claims 1 to 11 for producing a means for lowering increased plasma lipid levels.
16. The use according to claim 15, for producing the means for lowering increased plasma lipid levels in case of systemic lipid metabolism disturbances, so called hyperlipoproteinemias, vascular diseases, cardiac infarctions and occlusive arterial diseases.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19830732A DE19830732B4 (en) | 1998-07-09 | 1998-07-09 | Composition containing at least one substance influencing blood lipid levels and its use |
| DE19830732.2 | 1998-07-09 | ||
| PCT/EP1999/004757 WO2000002541A1 (en) | 1998-07-09 | 1999-07-07 | Transdermal plaster containing at least one active ingredient which influences blood serum lipid levels |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2336712A1 CA2336712A1 (en) | 2000-01-20 |
| CA2336712C true CA2336712C (en) | 2008-09-09 |
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|---|---|---|---|
| CA002336712A Expired - Lifetime CA2336712C (en) | 1998-07-09 | 1999-07-07 | Transdermal plaster containing at least one active ingredient which influences blood serum lipid levels |
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| EP (1) | EP1094797B1 (en) |
| JP (1) | JP2002520272A (en) |
| KR (1) | KR100549848B1 (en) |
| CN (1) | CN1309377C (en) |
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| CA (1) | CA2336712C (en) |
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| RU (1) | RU2227023C2 (en) |
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| TW (1) | TWI237572B (en) |
| WO (1) | WO2000002541A1 (en) |
| ZA (1) | ZA200100171B (en) |
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| PL189890B1 (en) * | 1999-09-14 | 2005-10-31 | Kazmierski Jan Zaklad Prod Usl | Preparation for protecting plants against diseases |
| WO2004026297A1 (en) * | 2002-09-20 | 2004-04-01 | Kowa Co., Ltd. | Preparation for external use |
| EP1578421A4 (en) * | 2003-01-02 | 2009-04-22 | Femmepharma Holding Co Inc | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
| US9173836B2 (en) | 2003-01-02 | 2015-11-03 | FemmeParma Holding Company, Inc. | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
| RU2261705C1 (en) * | 2004-01-29 | 2005-10-10 | Медведев Илья Николаевич | Method for treatment of thrombocytopathy at metablic syndrome |
| US20070166360A1 (en) * | 2004-03-31 | 2007-07-19 | Kowa Co., Ltd. | External preparation |
| JP4986411B2 (en) * | 2004-06-01 | 2012-07-25 | 久光製薬株式会社 | Patch |
| EP1611882B1 (en) | 2004-06-01 | 2010-04-07 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive patch |
| US20050281868A1 (en) * | 2004-06-21 | 2005-12-22 | Fairfield Clinical Trials, Llc | Transdermal delivery system for statin combination therapy |
| JP4824963B2 (en) * | 2004-08-12 | 2011-11-30 | 日東電工株式会社 | Patch and patch preparation |
| DE102004062182B4 (en) * | 2004-12-20 | 2007-06-06 | Bayer Schering Pharma Ag | Transdermal patch with progesterone A-specific ligands (PRASL) as active ingredient |
| EP1996118A4 (en) * | 2006-03-07 | 2013-03-06 | Osteoscreen Ip Llc | Hmg co-a reductase inhibitor enhancement of bone and cartilage |
| KR100817274B1 (en) * | 2006-08-21 | 2008-03-27 | 삼성전기주식회사 | Light emitting diode package and manufacturing method thereof |
| RU2392929C2 (en) * | 2007-06-20 | 2010-06-27 | Общество С Ограниченной Ответственностью "Гамаветфарм" | Agent stimulating hemopoietic stem cell emission in blood flow |
| WO2018115535A1 (en) | 2016-12-19 | 2018-06-28 | Nutritape, S.L. | Energising patch for sportspeople |
| CN113573794B (en) * | 2019-03-12 | 2023-06-16 | 康宁股份有限公司 | Ceramic honeycomb body with skin |
| TWI803052B (en) * | 2021-11-12 | 2023-05-21 | 佛教慈濟醫療財團法人 | Transdermal delivery device, methods of using and making the same |
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| DE3634016A1 (en) * | 1986-04-17 | 1987-10-29 | Lohmann Gmbh & Co Kg | AREA-BASED THERAPEUTIC SYSTEM, METHOD FOR THE PRODUCTION THEREOF AND ITS USE |
| US5503844A (en) * | 1993-05-18 | 1996-04-02 | Mli Acquisition Corp. Ii | Foam laminate transdermal patch |
| FR2719220A1 (en) * | 1994-04-29 | 1995-11-03 | Lafon Labor | New galenic form for transdermal administration. |
| JP3184534B2 (en) * | 1994-10-05 | 2001-07-09 | 久光製薬株式会社 | Medicinal compound comprising N-substituted-o-toluidine derivative and transdermal preparation |
| DE19541260A1 (en) * | 1995-11-06 | 1997-05-07 | Lohmann Therapie Syst Lts | Therapeutic preparation for transdermal application of active ingredients through the skin |
| WO1999024032A1 (en) * | 1997-11-10 | 1999-05-20 | Novo Nordisk A/S | Transdermal delivery of 3,4-diarylchromans |
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1998
- 1998-07-09 DE DE19830732A patent/DE19830732B4/en not_active Expired - Lifetime
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1999
- 1999-07-06 TW TW088111470A patent/TWI237572B/en not_active IP Right Cessation
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- 1999-07-07 DE DE59910758T patent/DE59910758D1/en not_active Expired - Lifetime
- 1999-07-07 EP EP99936490A patent/EP1094797B1/en not_active Expired - Lifetime
- 1999-07-07 MX MXPA01000126A patent/MXPA01000126A/en active IP Right Grant
- 1999-07-07 AT AT99936490T patent/ATE278395T1/en not_active IP Right Cessation
- 1999-07-07 RU RU2001102046/15A patent/RU2227023C2/en active
- 1999-07-07 TR TR2001/00021T patent/TR200100021T2/en unknown
- 1999-07-07 CZ CZ20010093A patent/CZ300976B6/en unknown
- 1999-07-07 IL IL14066799A patent/IL140667A0/en active IP Right Grant
- 1999-07-07 AR ARP990103304A patent/AR019902A1/en active IP Right Grant
- 1999-07-07 WO PCT/EP1999/004757 patent/WO2000002541A1/en not_active Ceased
- 1999-07-07 BR BR9911941-2A patent/BR9911941A/en not_active Application Discontinuation
- 1999-07-07 JP JP2000558801A patent/JP2002520272A/en active Pending
- 1999-07-07 NZ NZ509215A patent/NZ509215A/en not_active IP Right Cessation
- 1999-07-07 PL PL345510A patent/PL194983B1/en unknown
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- 1999-07-07 ES ES99936490T patent/ES2230872T3/en not_active Expired - Lifetime
- 1999-07-07 KR KR1020017000286A patent/KR100549848B1/en not_active Expired - Lifetime
- 1999-07-07 HU HU0102718A patent/HU226614B1/en unknown
- 1999-07-07 CA CA002336712A patent/CA2336712C/en not_active Expired - Lifetime
-
2001
- 2001-01-01 IL IL140667A patent/IL140667A/en not_active IP Right Cessation
- 2001-01-08 ZA ZA200100171A patent/ZA200100171B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL140667A (en) | 2007-05-15 |
| HU226614B1 (en) | 2009-04-28 |
| CZ200193A3 (en) | 2001-05-16 |
| CN1309377C (en) | 2007-04-11 |
| KR20010079513A (en) | 2001-08-22 |
| BR9911941A (en) | 2001-03-27 |
| ZA200100171B (en) | 2001-08-10 |
| IL140667A0 (en) | 2002-02-10 |
| DE19830732B4 (en) | 2008-11-13 |
| TR200100021T2 (en) | 2001-05-21 |
| ATE278395T1 (en) | 2004-10-15 |
| EP1094797A1 (en) | 2001-05-02 |
| WO2000002541A1 (en) | 2000-01-20 |
| CA2336712A1 (en) | 2000-01-20 |
| HUP0102718A3 (en) | 2002-12-28 |
| CN1308525A (en) | 2001-08-15 |
| HUP0102718A2 (en) | 2002-03-28 |
| PL194983B1 (en) | 2007-07-31 |
| EP1094797B1 (en) | 2004-10-06 |
| MXPA01000126A (en) | 2002-06-04 |
| AU770573B2 (en) | 2004-02-26 |
| JP2002520272A (en) | 2002-07-09 |
| AR019902A1 (en) | 2002-03-20 |
| DE59910758D1 (en) | 2004-11-11 |
| PL345510A1 (en) | 2001-12-17 |
| AU5157499A (en) | 2000-02-01 |
| CZ300976B6 (en) | 2009-09-30 |
| ES2230872T3 (en) | 2005-05-01 |
| DE19830732A1 (en) | 2000-01-13 |
| KR100549848B1 (en) | 2006-02-06 |
| RU2227023C2 (en) | 2004-04-20 |
| NZ509215A (en) | 2003-04-29 |
| TWI237572B (en) | 2005-08-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20190708 |