IL92678A - Transdermal therapeutical system comprising norpseudoephedrine as active component - Google Patents
Transdermal therapeutical system comprising norpseudoephedrine as active componentInfo
- Publication number
- IL92678A IL92678A IL9267889A IL9267889A IL92678A IL 92678 A IL92678 A IL 92678A IL 9267889 A IL9267889 A IL 9267889A IL 9267889 A IL9267889 A IL 9267889A IL 92678 A IL92678 A IL 92678A
- Authority
- IL
- Israel
- Prior art keywords
- therapeutical system
- transdermal therapeutical
- polymeric material
- transdermal
- material comprises
- Prior art date
Links
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 29
- DLNKOYKMWOXYQA-IONNQARKSA-N cathine Chemical compound C[C@H](N)[C@@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-IONNQARKSA-N 0.000 title claims abstract description 17
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960003609 cathine Drugs 0.000 title claims abstract description 16
- 239000013543 active substance Substances 0.000 claims abstract description 25
- 239000010410 layer Substances 0.000 claims abstract description 22
- 239000011241 protective layer Substances 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims description 12
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 11
- 229920000642 polymer Polymers 0.000 claims description 11
- 230000000390 anti-adipogenic effect Effects 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 claims description 7
- 229920001577 copolymer Polymers 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 6
- 125000005908 glyceryl ester group Chemical group 0.000 claims description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 3
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 3
- 229920001400 block copolymer Polymers 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 150000003626 triacylglycerols Chemical class 0.000 claims description 3
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims description 2
- XTJFFFGAUHQWII-UHFFFAOYSA-N Dibutyl adipate Chemical compound CCCCOC(=O)CCCCC(=O)OCCCC XTJFFFGAUHQWII-UHFFFAOYSA-N 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 2
- 229920002367 Polyisobutene Polymers 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 239000013522 chelant Substances 0.000 claims description 2
- 239000008240 homogeneous mixture Substances 0.000 claims description 2
- 150000002734 metacrylic acid derivatives Chemical class 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 229920000346 polystyrene-polyisoprene block-polystyrene Polymers 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims 2
- 150000001298 alcohols Chemical group 0.000 claims 1
- 125000005397 methacrylic acid ester group Chemical group 0.000 claims 1
- 229920003048 styrene butadiene rubber Polymers 0.000 claims 1
- 239000000853 adhesive Substances 0.000 abstract description 4
- 230000001070 adhesive effect Effects 0.000 abstract description 4
- 239000002861 polymer material Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000011159 matrix material Substances 0.000 description 8
- 239000011888 foil Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000036765 blood level Effects 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 210000004051 gastric juice Anatomy 0.000 description 4
- 239000011505 plaster Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- -1 polyethylene Polymers 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 239000002313 adhesive film Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 235000019864 coconut oil Nutrition 0.000 description 2
- 239000003240 coconut oil Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 229960002179 ephedrine Drugs 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 229940057917 medium chain triglycerides Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical group C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 150000007854 aminals Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000004913 chyme Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229940058401 polytetrafluoroethylene Drugs 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 239000004753 textile 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
- 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
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention relates to a transdermal therapeutic system for applying an active substance to the skin and consisting of a backing layer impermeable to the active substance, a reservoir layer and, if appropriate, a detachable protective layer, the reservoir layer being adhesive and containing 10-90% by weight of polymer material, 0-30% by weight of softener and 0.1-20% by weight of a norpseudoephedrine.
Description
Transdermal therapeutical system comprising norpseudoephedrine as active component LTS LOHMANN Therapie-Systeme GmbH & Co. KG C. 79356 D E S C R I P T I O N The present invention relates to a transdermal therapeutical system comprising norpseudoephedrine as active component.
The amphetamines, the chemical group many of the antiadi-pogenics belong to, were discovered as early as in the nineteen thirties, however were prescribed only as remedy against fatigue. Even later, it was recognized that these pharmaceuticals had another therapeutically useful effect -they reduce the sensation of hunger. It was achieved by systematic synthesis of the pharmaceutical to develop substances which emphasize the reduction of the feeling of hunger, while neglecting the stimulating component. Nevertheless, the following aspects have to be considered in the application of such antiadipogenics : - They must not be combined with certain other medicines ( neither with alcohol ) - Drug habituation and drug addiction have to be observed - Intravenous injections are to be avoided due to the danger of induction of blood level peaks.
Legislation as well as the pharmaceutical industry take into account these facts, on the one hand in that liquid drugs are sold only on prescription while the solid ones are OTC--pharmaceuticals, and, on the other hand, in that due to the development of orally adminstrable controlled release drugs the dosage of the antiadipogenics may be reduced, the blood levels, however, may be kept constant. Since, nowadays, the medical profession is of the opinion that the administration form contributes to the addiction to a substance ( a constant blood level is by far more favourable as the rapid change of blood level peaks with overdose and intervals with under-supply), it is obvious to develop controlled release drugs which create an even better constant concentration level than the oral ones are able to provide. Since, although the common oral forms of controlled release drugs are a masterly achievement of galenic technology, which under in-vitro-con-ditions, i.e. in artificial gastric or intestinal juices, create optimum release, they cannot guarantee constant blood levels, since the resorption of drug substance from the gastrointestinal tract is considerably influenced by the evacuation time of the stomach which is retarded by the ingestion of food as a function of the volume and the composition of the nourishment. Furthermore, pH-value shifs in the stomach occur during the ingestion and the diffusion effective gradients decrease due to mixing of the gastric juice with the chyme. The significance of the pH-value conditions within the stomach for the gastral resorption is underlined by tests in which the gastric juice was alkalized. It was proved in aminal tests that after alkalization of the stomach content with NaHCC>3 to pH : 8.0, the resorption from the stomach was reduced in the case of weak acids corresponding to the pKa-value and increased in the case of weak bases. Since amphetamines are bases of medium strength (pKa-value D-norpseudoephedrine : 8.9), the effect of the pH-value depending resorption is not distinctive, but it should not be neglected at all.
The use of so-called therapeutical systems is suitable for the creation of an active substance concentration which is as constant as possible; said therapeutical systems are defined as a drug containing device or administration form, respectively, which continuously releases a drug or several drugs at a predefined rate over a predetermined period of time onto a defined place of application (cf. Heilmann, "Therapeutische Systeme", 4th edition, Enke publishers, Stuttgart 1984 , page 26). An oral therapeutical system, e.g., as described in EP 0 237 159 , however, is no solution to the problem described, since bases of medium strength better dissolve in acidic gastric juice than in neutral gastric juice. Thus the release becomes pH-value dependent.
In US-PS 4 , 292 , 301 the transdermal release of ephedrine from a non-adhesive polymeric matrix has been described, however, the ephedrine exhibits only a weak efficiency as antiadipogenic .
EP 0 261 042 describes transdermal therapeutic systems which exhibit a pressure-sensitive adhesive fixation means for fixing the therapeutic system to the skin. According to the description, line 38 , column 4 , the reservoir maxtrix may be pressure-sensitive adhesive, but according to column 4 , line 54 et seq. preferred non-pressure-sensitive adhesive matrix materials are also proposed for use in a nicotine patch, such as polymerides consisting of poly (meth) aerylate , polyvinylpyr- rolidine, etc. Furhtermore, EP 0 62 1 402 does not contain any hint to a transdermal therapeutic system comprising norpseudoephedrine as active component.
The assessment regarding inventive step of the present invention must also be seen against the backgroung of physiological problems to be overcome by the application of norpseudoephedrine. As stated above, the administration of an antiadipogenic through the skin via a pressure-sensitive adhesive reservoir layer has as yet not been succesfully carried out, whereby daily dosages must be applied which can, or rather could, generally not be attained in acceptable amounts by transdermal systems (EP 0 374 725 , page 2 , lines 53 and 54 ) . Apparently in order to overcome these problems for a transdermal therapeutic system EP 0 1 95 634 describes a solution completely different o' that of the present invention: as active substance, a substance bound to an ion exchange resin was proposed and further, in order to influence the release rate, a salt which is related to the active substance was proposed for the dermal composition. The interaction of skin and pharmacological substance in this system is influenced, according to page 3, line 11 and following lines, by th&cutaneous moisture. The matrix proposed in EP 0 195 643 is not pressure-sensitive adhesive, but instead the gel-like mass is present in a flat tray, which according to page 5, line 20 of the description is fixed to the patient* body, e.g. with an adhesive plastic tape. This kind of fixation entails great disadvantages compared to a pressure-sensitive adhesive transdermal application layer, since the intimate connection between the skin and the active substance-releasing matrix is missing This is also the case where the tray containing the active substance has a protruding rim coated with adhesive.
However, EP 0 195 643 differs from the present invention not only with regard to the embodiments of the system; rather, pseude-oephedrine and norpseudoephedrine , while being chemically similar, are nethertheless different pharmaceuticals. The minor alteration in the chemical structure leads to a lasting change in the physical solubility and melting properties, which are of essential importance for the penetration through the skin by diffusion.
In view of the aforementioned problems involved in the application of acceptably high dosages of norpseudoephedrine by transdermal systems, an independent concept had to be developed which could not have been derived from the two abovementioned references. On the contrary, the solution described in EP 0 195 643 teaches away from the present invention.
EP 0 305 756 describes a transdermal therapeutic system, wherein the active substance distribution means and the active substance control means are provided by a reservoir matrix comprising active substance depots embedded therein' (see page 3, lines 37 to 40), as contrasted. to the system according to the invention in which the ac tive substance is homogeneously mixed with the components of the pressure-sensitive reservoir layer.' Thus it is the object of the present invention to provide norpseudoephedrine as antiadipogenic or an agent, respectively, in a form with which a by far improved, constant active substance level in contrast to the oral form of controlled release drugs is achieved, in order to overcome the disadvantages of the prior art.
According to the present invention this object is surprisingly achieved by a transdermal therapeutical system which releases an antiadipogenic to the skin via a backing layer being impermeable to active substances, a reservoir layer, and optionally a removable protective layer, and which is characterized in that the reservoir layer is pressure-sensitive adhesive and comprises 10-90%-wt polymeric material, 0-30%-wt softener, and 0.1-20%-wt norpseudoephedrine, whereby the active substance is present in homogenous mixture with the components of the pressure-sensitive adhesive reservoir layer.
This solution is surprising all the more, since norpseudoephedrine has to be applied in daily dosages, and this normally cannot be achieved in acceptable ranges by transdermal therapeutical systems. 4 In this connection, the backing layer which is impermeable to active substances may consist of flexible or non-flexible material. Substances suitable for the production are polymeric foils or metal foils, such as aluminium foils which can be used alone or coated with a polymeric substrate. Textile fabrics may be used as well, if the components of the reservoir, due to their physical properties, cannot penetrate through the fabrics. In a preferred embodiment the backing layer is a nonwoven fabric from a foil vapourized with aluminium.
The reservoir layer consists of a polymeric matrix and the active substance, whereby the polymeric matrix guarantees the coherence of the system. The matrix consists of a basic polymer and optionally of common additives. The selection of the basic polymer depends on the chemical and physical properties of the active substance used. Examples for polymers are rubber, rubber-like synthetic homopolymers, copolymers or block polymers, polyacrylic acid esters and their copolymers, polyurethanes, and silicones. In principle all polymers are suitable which are used in the production of pressure-sensitive adhesives and which are physiologically acceptable. It is particularly preferred to use those polymers consisting of block copolymers on the basis of styrene and 1,3-dienes, polyisobutylenes, polymers of acrylate and/or methacrylate. In particular, linear styrene-isoprene block copolymers are used from the group of block copolymers on the basis of styrene and 1,3-dienes.
Acrylate-copolymers of 2-ethylhexylacrylate, vinyl acetate, and acrylic acid with or without titane chelate ester are preferred as polymers on acrylate basis. Copolymers on the basis of dimethylaminoethyl methacrylates and neutral meth- 5 acrylic acid esters are preferred as methacrylates . As esters of hydrogenated colophonium its methyl and glyceryl esters are particularly preferred.
The kind of possible additive depends on the polymer used and the active substance: According to their function they can be divided into softeners, tackifiers, stabilizers, carriers, diffusion and penetration regulating additives or fillers. Suitable physiologically acceptable substances are known to the man skilled in the art. The reservoir layer has such a self-adhesiveness that a constant contact to the skin is guaranteed.
Examples for suitable softeners are diesters of dicarboxylic acids, such as di-n-butyl adipate and triglycerides, particularly medium chain triglycerides of the caprylic/capric acid of coconut oil. Further examples for suitable softeners are glycerol, propanediol (1,2) etc.
The removable protective layer, which is in contact with the reservoir layer and is removed prior to application, for example consists of the same materials as are used for the production of the backing layer, provided that they are rendered removable, for example by way of a silicone treatment. Further detachable protective layers, e.g., are poly-tetrafluoroethylene, treated paper, cellophane, polyvinyl chloride, etc. If the laminate according to the present invention is cut into suitable sizes (plasters) prior to applying the protective layer, the dimensions of the protective layer to be applied may have overlapping ends, so that they may be removed from the plaster more easily.
According to the present invention, norpseudoephedrine is used as antiadipogenic, since it exhibits the lowest ten- 6 dency to dependence of all antladipogenlcs.
The transdermal therapeutical system according to the present invention is produced in. that the active substance together with the components of the pressure-sensitive reservoir layer, optionally in solution, are homogeneously admixed and coated onto the backing layer which is impermeable to the active substance, then optionally the solvent or solvents is/are removed. Subsequently, the adhesive layer is provided with a suitable protective layer.
The invention is illustrated but not limited by the following examples: Preparation - Example 1: 4.3 g n-heptane and 15.7 g butanone are mixed. 4.0 g nor-pseudoephedrine, free base, is dissolved therein. After complete dissolution of the active substance there is added by portions 23.5 g of a glyceryl ester of completely hydro-genated colophonium, 15.5 g of a linear styrene-butadiene--styrene block copolymer, 3.9 g methyl ester of hydrogenated colophonium and 3.1 g triglycerides of the caprylic/capric acid of coconut oil ("medium chain triglycerides" DAB 8 (= The German Pharmacopeia, 1978). Under elimination of light it is stirred up to complete dissolution (approximately 8 hours) and the solution obtained is coated onto a aluminized and siliconized polyethylene foil with a 300 m coating knife.
After removal of the solvent by drying at 50 eC in the drying channel for 25 minutes, the adhesive film is covered with a polyester foil of 15μ. Sizes of 16cm2 and 50cm2, respectively, are punched with an adequate cutting tool and the edges are separated off. The diagram of the in-vitro-release is 7 shown in figure 1. It shows the controlled active substance release from a 16 cm2 plaster in physiological saline.
Furthermore", a healthy volunteer wore a 50 cm2 plaster for 12 hours, which contains 52 mg norpseudoephedrine, free base, having an area weight of 130 g/m2. After removal of the system the residual content was determined at approximately 17 mg, so that approximately 35 mg/50 cm2 have been diffused through human skin within 12 hours.
Thus, the therapeutically required value has been surpassed.
Preparation - Example 2: 25 g butanone and 15 g ethylacetate are mixed. 10.0 g norpseudoephedrine, free base, is dissolved therein. After complete dissolution of the active substance there is added by portions 17.5 g of a glyceryl ester of completely hydro-genated colophonium and 22.5 g of a linear styrene-butadiene--styrene block copolymer. Under elimination of light it is stirred up to complete dissolution ( approximately 8 hours ) and the solution obtained is coated onto a aluminized and siliconized polyethylene foil (thickness: 100 μπι) with a 350μπι coating knife.
After removal of the solvent by drying at 50 "C in the drying channel for 25 minutes, the adhesive film is covered with a polyethylene foil (thickness: 15ym). Sizes of 16cm2 are punched with an adequate cutting tool and the edges are separated off. The diagram of the in-vitro-release is shown in figure 2. It shows the controlled release of the active substance from a 16 cm2 plaster in physiological saline.
Furthermore, the in-vitro penetration was determined with excised mice skin. It amounts to 9.8 mg/16 cm2 x 24 h and thus lies in the range of example 1 without the addition of 8 a softener.
Claims (14)
1. A transdermal therapeutical system for the administration of an antiadipogenic to the skin via a backing layer being impermeable to the active substance, a reservoir layer, and optionally a removable protective layer, characterized in that the reservoir layer is pressure-sensitive adhesive and comprises 10-90%-wt polymeric material, 0-30 %-wt softener and 0.1-20%-wt norpseudoephedrine, whereby the active substance is present in homogenous mixture with the components of the pressure-sensitive adhesive reservoir layer.
2. The transdermal therapeutical system according to claim 1, characterized in that the polymeric material is selected from the group consisting of block copolymers on the basis of styrene and 1,3-dienes, polyisobutylenes, polymers on the basis of acrylate and/or methacrylate, and esters of hydro- genated colophonium.
3. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises linear styrene-isoprene block copolymer.
4. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises linear styrene-butadiene block copolymer.
5. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises self-crosslinking acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid, and titane chelate ester.
6. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises non-self-crosslinking acrylate copolymers of 2-ethylhexyl acrylate, vinyl acetate, and acrylic acid.
7. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises as polymer on the basis of methacrylates a copolymer of dimethylaminoethyl methacrylate and neutral methacrylic acid esters.
8. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises as ester of the hydrogenated colophonium the methylester thereof.
9. The transdermal therapeutical system according to claim 2, characterized in that the polymeric material comprises as ester of the hydrogenated colophonium the glyceryl ester thereof.
10. The transdermal therapeutical system according to claim 1, characterized in that the softeners are selected from the group consisting of vicinal alcohols and esters.
11. The transdermal therapeutical system according to claim 10, characterized in that it comprises propanediol-1, 2 as softener.
12. The transdermal therapeutical system according to claim 10, characterized in that it comprises di-n-butyl adipate as softener.
13. The transdermal therapeutical system according to claim 10, characterized in that it comprises triglycerides as softener.
14. The transdermal therapeutical system according to claim 10, characterized in that it comprises glycerol as softener. For ihe Λ ppl'xants AND PARTNERS
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3843237A DE3843237A1 (en) | 1988-12-22 | 1988-12-22 | TRANSDERMAL THERAPEUTIC SYSTEM WITH AN ANTIADIPOSITUM AS AN ACTIVE INGREDIENT |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL92678A0 IL92678A0 (en) | 1990-09-17 |
| IL92678A true IL92678A (en) | 1994-06-24 |
Family
ID=6369853
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL9267889A IL92678A (en) | 1988-12-22 | 1989-12-13 | Transdermal therapeutical system comprising norpseudoephedrine as active component |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP0374725B1 (en) |
| JP (1) | JP2602108B2 (en) |
| KR (1) | KR950015055B1 (en) |
| AT (1) | ATE93147T1 (en) |
| AU (1) | AU614208B2 (en) |
| CA (1) | CA2006425C (en) |
| CS (1) | CS275356B2 (en) |
| DD (1) | DD290581A5 (en) |
| DE (2) | DE3843237A1 (en) |
| DK (1) | DK651089A (en) |
| ES (1) | ES2045369T3 (en) |
| FI (1) | FI95772C (en) |
| HU (1) | HU203280B (en) |
| IE (1) | IE63878B1 (en) |
| IL (1) | IL92678A (en) |
| MY (1) | MY105074A (en) |
| NO (1) | NO178784C (en) |
| NZ (1) | NZ231909A (en) |
| PH (1) | PH25854A (en) |
| PL (1) | PL163292B1 (en) |
| PT (1) | PT92650B (en) |
| YU (1) | YU47075B (en) |
| ZA (1) | ZA899879B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3939376C1 (en) * | 1989-11-29 | 1991-05-08 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg, 5450 Neuwied, De | |
| DE4342893C2 (en) * | 1993-12-16 | 1999-09-23 | Lohmann Gmbh & Co Kg | Reversible adhesive, residue-free removable pressure sensitive adhesive, process for its production and use as re-adhesive pressure sensitive adhesive articles |
| US6719997B2 (en) | 2000-06-30 | 2004-04-13 | Dermatrends, Inc. | Transdermal administration of pharmacologically active amines using hydroxide-releasing agents as permeation enhancers |
| US6602912B2 (en) | 2000-06-30 | 2003-08-05 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
| US6673363B2 (en) | 1999-12-16 | 2004-01-06 | Dermatrends, Inc. | Transdermal and topical administration of local anesthetic agents using basic enhancers |
| CA2395289A1 (en) * | 1999-12-16 | 2001-06-21 | Dermatrends, Inc. | Transdermal administration of phenylpropanolamine |
| KR100956865B1 (en) * | 2009-08-10 | 2010-05-11 | 주식회사 라이트론 | Slide pressure packing type linear lighting apparatus |
| US20190298661A1 (en) * | 2016-10-31 | 2019-10-03 | The Corporation Of Mercer University | Transdermal Delivery of Phenethylamine Monoamine Releasers |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4291015A (en) * | 1979-08-14 | 1981-09-22 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing a vasodilator |
| JPS57116011A (en) * | 1981-01-08 | 1982-07-19 | Nitto Electric Ind Co Ltd | Pharmaceutical preparation |
| JPS60185713A (en) * | 1984-03-05 | 1985-09-21 | Nitto Electric Ind Co Ltd | Percutaneous preparation and its production |
| ATE42901T1 (en) * | 1984-03-05 | 1989-05-15 | Nitto Denko Corp | ADHESIVE MEDICATION FOR PERCUTANEOUS ABSORPTION. |
| US4692462A (en) * | 1985-03-18 | 1987-09-08 | Menley & James Laboratories, Ltd. | Compositions and method of controlling transdermal penetration of topical and systemic agents |
| DE3629304A1 (en) * | 1986-08-28 | 1988-03-24 | Lohmann Gmbh & Co Kg | TRANSDERMAL THERAPEUTIC SYSTEM, ITS USE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3743945A1 (en) * | 1987-09-01 | 1989-03-09 | Lohmann Gmbh & Co Kg | DEVICE FOR DELIVERING SUBSTANCES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE |
-
1988
- 1988-12-22 DE DE3843237A patent/DE3843237A1/en active Granted
-
1989
- 1989-12-13 IL IL9267889A patent/IL92678A/en not_active IP Right Cessation
- 1989-12-14 ES ES89123091T patent/ES2045369T3/en not_active Expired - Lifetime
- 1989-12-14 EP EP89123091A patent/EP0374725B1/en not_active Expired - Lifetime
- 1989-12-14 DE DE8989123091T patent/DE58905320D1/en not_active Expired - Fee Related
- 1989-12-14 AT AT89123091T patent/ATE93147T1/en not_active IP Right Cessation
- 1989-12-14 MY MYPI89001760A patent/MY105074A/en unknown
- 1989-12-18 AU AU46843/89A patent/AU614208B2/en not_active Ceased
- 1989-12-19 IE IE407789A patent/IE63878B1/en not_active IP Right Cessation
- 1989-12-19 YU YU240589A patent/YU47075B/en unknown
- 1989-12-19 CS CS897193A patent/CS275356B2/en unknown
- 1989-12-19 FI FI896097A patent/FI95772C/en not_active IP Right Cessation
- 1989-12-20 NZ NZ231909A patent/NZ231909A/en unknown
- 1989-12-20 DK DK651089A patent/DK651089A/en not_active Application Discontinuation
- 1989-12-20 PH PH39752A patent/PH25854A/en unknown
- 1989-12-21 ZA ZA899879A patent/ZA899879B/en unknown
- 1989-12-21 DD DD89336084A patent/DD290581A5/en not_active IP Right Cessation
- 1989-12-21 CA CA002006425A patent/CA2006425C/en not_active Expired - Fee Related
- 1989-12-21 PT PT92650A patent/PT92650B/en not_active IP Right Cessation
- 1989-12-21 HU HU896721A patent/HU203280B/en not_active IP Right Cessation
- 1989-12-21 NO NO895173A patent/NO178784C/en unknown
- 1989-12-22 PL PL89282948A patent/PL163292B1/en unknown
- 1989-12-22 KR KR1019890019229A patent/KR950015055B1/en not_active IP Right Cessation
- 1989-12-22 JP JP1331442A patent/JP2602108B2/en not_active Expired - Lifetime
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU784779B2 (en) | Ultraviolet-shielding adhesive preparation | |
| US5240711A (en) | Transdermal therapeutic system comprising as active component buprenorphine | |
| KR950015061B1 (en) | Transdermal therapeutic system containing buprenorphine as a active component | |
| TW577760B (en) | Transdermal patch with non-steroid antirheumatic agents having an acid group | |
| IL108235A (en) | Transdermal therapeutic system containing galanthamine | |
| ES2230872T3 (en) | TRANSDERMAL PATCH THAT CONTAINS AT LEAST AN ACTIVE PRINCIPLE THAT INFLUENCES THE LEVELS OF LIPIDS IN BLOOD. | |
| CA2006425C (en) | Transdermal therapeutical system comprising norpseudoephedrine as active component | |
| JP3170304B2 (en) | Eperisone or tolperisone transdermal preparation | |
| US5705186A (en) | Pharmaceutical composition for the systemic transdermal administration having the active substance morphine-6-glucuronide | |
| JPH08310946A (en) | Percutaneous absorbable pharmaceutical preparation | |
| JPH07103016B2 (en) | Patch and method for producing the same | |
| JPH07116025B2 (en) | Patch | |
| KR100552649B1 (en) | Pelbinac-containing anti-inflammatory analgesic plaster | |
| US5965155A (en) | Transdermal therapeutic system with pentylene tetrazol as active substance | |
| WO2003097022A1 (en) | Matrix type patch containing bronchodilators | |
| KR20020037616A (en) | Transdermal ketorolac formulation for increasing transdermal absorption of ketorolac | |
| WO2004019892A2 (en) | Drug delivery system for treating urinary incontinence | |
| KR20010005871A (en) | Base composition for percutaneous absorption and percutaneously absorbable preparation containing the base compositon |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| KB | Patent renewed | ||
| RH | Patent void |