SI9400023A - Transdermally administered system containing acetylsalicylic acid for thrombosis theraphy and cancer prophilaxys - Google Patents
Transdermally administered system containing acetylsalicylic acid for thrombosis theraphy and cancer prophilaxys Download PDFInfo
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Abstract
Izum se nanaša na transdermalni sistem za proti raku, ki vsebuje kot dejavno snov acetilsalicilno dajanje za antitrombotsko terapijo oz. za profilakso kislino in/ali njene farmacevtsko sprejemljive soli.The invention relates to a transdermal anticancer system containing acetylsalicylic as the active substance administration for antithrombotic therapy. for the prophylaxis of the acid and / or its pharmaceutically acceptable salts.
Description
Transdermalni sistem dajanja, vsebujoč acetilsalicilno kislino za anititrombotsko terapijo in profilakso proti rakuTransdermal administration system containing acetylsalicylic acid for antithrombotic therapy and anti-cancer prophylaxis
Področje, v katero spada izumFIELD OF THE INVENTION
Področje, v katero spada izum, je transdermalni sistem za antitrombotsko terapijo in profilakso proti raku, ki vsebuje acetil.....The field of the invention is the transdermal system for antithrombotic therapy and prophylaxis against cancer containing acetyl .....
salicilno kislino.salicylic acid.
Tehnični problem in stanje tehnikeTechnical problem and state of the art
Učinek acetilsalicilne kisline (A55) na preprečevanje agregacije trombocitov in njeno delovanje pri preprečevanju srčne tromboze sta bila opisana v poznih 60. letih. V sledečem času je biloThe effect of acetylsalicylic acid (A55) on preventing platelet aggregation and its action in preventing cardiac thrombosis was described in the late 1960s. In the next time it was
ODVETN I K i t izvedeno večje število kliničnih študij, pri katerih so dajali oralno ASS pri sledečih indikacijah:There have been a number of clinical studies conducted that have given oral ASS in the following indications:
~ preprečevanje prvega srčnega infarkta,~ prevention of the first heart attack,
- preprečevanje ponovnega infarkta, ~ obravnava nestabilne angine pectoris,- prevention of re-infarction, ~ treats unstable angina pectoris,
- profilaksa tromboze po uporabi protez ožilja oz. umetnih srčnih zaklopk, ~ profilaksa tromboze perifernega arterijskega ožilja in- prophylaxis of thrombosis after the use of vascular or dental prostheses. artificial heart valves, ~ prophylaxis of peripheral arterial thrombosis and
- profilaksa tromboze cerebralne nezadostne prekrvavitve.- prophylaxis of thrombosis of cerebral insufficient blood flow.
če v sledečem uporabljamo izraz antitrombotska terapija, so obsežene v bistvu te indikacije.if the term antithrombotic therapy is used in the following, these indications are substantially widespread.
Rezultati teh terapevtskih študij na pacientih so bili v zadnjem času strnjeni (V.Fuster et al., Aspirin in the prevention of coronary disease, New Eng. J.Med. 321, 183-185 (1989) in R.The results of these therapeutic studies in patients have recently been condensed (V.Fuster et al., Aspirin in the prevention of coronary disease, New Eng. J.Med. 321, 183-185 (1989) and R.
Zichner et al., K optimalnemu doziranju acetiIsalici1 ne kisline. Med. Klin. 84, 43-51 (1989)).Zichner et al., Towards optimal dosing of acetic acid. Med. Wedge. 84, 43-51 (1989).
Acetilsalicilna kislina se v medicinski praksi pogosto uporablja kot nestereoidalna, vnetje zadržujoča, analgetska in antipiretska dejavna snov. ASS vpliva na funkcijo trombocitov in preprečuje trombozo z nereverzibilnim zaviranjem sinteze Tromboksana A2 (M.Buchanan et. al. Aspirin inhibits platelet function independ.....Acetylsalicylic acid is often used in medical practice as a non-stereoidal, inflammatory, analgesic and antipyretic active substance. ASS affects platelet function and prevents thrombosis by non-reversible inhibition of thromboxane A2 synthesis (M.Buchanan et al. Aspirin inhibits platelet function independ .....
ent of cyclooxygenase Thrombosis Res. 25, 363-373 (1982)).ent of cyclooxygenase Thrombosis Res. 25, 363-373 (1982).
Po oralnem dajanju se ASS hitro absorbira. Biološki čas polovične vrednosti v telesnem obtoku je vendar zelo kratek, traja samo 15-20 min (M.Rowland et al., Kinetics of acetylsalicylic acid disposition in man, Nature 215, 413-414 (1967)). Pri normalnih odraslih se ASS hitro hidrolizira že v želodčnem črevesnem traktu v salicilno kislino (G. Levy, Clinical pharmacokinetics of aspirin, Pediatrics 62, 867-872 (1978)).After oral administration, ASS is rapidly absorbed. The biological half-life in body circulation is however very short, lasting only 15-20 min (M.Rowland et al., Kinetics of acetylsalicylic acid disposition in man, Nature 215, 413-414 (1967)). In normal adults, ASS is rapidly hydrolyzed already in the intestinal tract to salicylic acid (G. Levy, Clinical pharmacokinetics of aspirin, Pediatrics 62, 867-872 (1978)).
Moramo se pa vendar držati tega, da je ASS sama aktivna pri zaviranju funkcije tormbocitov in ne hidrolizni produkt salicilne kisline (W.Horsch, Die Salicylate, Pharmazie 34, 585-604 (1979)).However, it must be borne in mind that ASS is itself active in inhibiting platelet function rather than the hydrolysis product of salicylic acid (W. Horsch, Die Salicylate, Pharmazie 34, 585-604 (1979)).
Acetilsalicilno kislino (ASS) tekoče jemlje zlasti v ZDA širok krog prebivalstva. Po objavi Thuna et al., Aspirin Use and Reduced Risk of Fatal Colon Cancer, New Engl. J.Med. 325, 1593-1596 (1991) zmanjša ASS smrtnost zaradi raka debelega črevesa na približno polovico, če se je jemalo ASS tekoče In sicer na najmanj 16 dni mesečno. Raziskava se je razširila na več kot 660.000 oseb, ki so jemali ASS vsaj eno leto in so živeli v vseh državah ZDA, v okraju Columbia in v Portoriku, čeprav se je nanašalo samo na uporabo ASS, ne da bi bili podani nadaljnji podatki o vrsti dajanja in o dozi, moramo vendar izhajati iz tega, da se je ASS jemala oralno in da za učinek odgovorna snov ni bil hidrolizni produkt salicilne kisline, marveč ASS sam na sebi .Acetylsalicylic acid (ASS) is widely used in the United States especially by a wide population. Following the publication of Thuna et al., Aspirin Use and Reduced Risk of Fatal Colon Cancer, New Engl. J.Med. 325, 1593-1596 (1991) reduced ASS mortality from colon cancer to about half if ASS was taken fluidly at a minimum of 16 days per month. The survey spread to more than 660,000 people who have taken ASS for at least one year and have lived in all U.S. states, Columbia and Puerto Rico, although it only covered ASS use without providing further information on the type administration and dose, however, it must be assumed that ASS was taken orally and that the responsible substance was not the hydrolysis product of salicylic acid, but ASS itself.
Pri antitrombotski terapiji se prakticira skoraj izključno oralno dajanje; nasprotno so bili znani pri vnetje zadržujočih, analgetskih in antipiretskih indikacijah poizkusi, da se dejavno snov aplicira tudi preko kože. Tako se omenja ASS v US-PS 3, 598, 122 kot možna antipiretska dejavna snov v membransko krmiljenem transdermalnem terapevtskem sistemu.Oral administration is practiced almost exclusively with antithrombotic therapy; conversely, inflammatory retention, analgesic and antipyretic indications have been known to try to apply the active substance via the skin. Thus, reference is made to ASS in US-PS 3, 598, 122 as a possible antipyretic active substance in a membrane-controlled transdermal therapeutic system.
FR-M 1757 opisuje dermalno topično uporabo emulzije olja v vodi, ki vsebuje 5% ASS proti akutni bolečini. FR-A 2 297 612 obsega sredstva za vtiranje in mazila, ki vsebujejo ASS kot analgetsko sredstvo.FR-M 1757 describes a dermal topical application of an oil-in-water emulsion containing 5% ASS against acute pain. FR-A 2 297 612 comprises rubbing agents and ointments containing ASS as an analgesic agent.
ASS se kombinira s kortikosteroidi v US-PS 4, 012, 508 za topično uporabo pri dermatoloških indikacijah. US-PS 4, 219, 548 opisuje topično uporabo ASS za zadrževanje vnetja. ASS vsebujoči gel se topično aplicira v EP-A 0 055 635 pri vnetje zadržujočih, analgetskih in antipiretskih indikacijah. Predmet US-PS 4,460,368 je priprava za transdermalno aplikacijo ASS iz vodnega sistema za doseganje vnetje zadržujočih in analgetskih učinkov. V US-PS 4,665,063 se topično aplicira ASS iz etanolske raztopine proti dermatološkim motnjam. Stopnjevanje stopnje penetracije ASS pri transdermalni uporabi se doseže v US-PS 4,640,689 z električnim tokom.ASS is combined with corticosteroids in US-PS 4, 012, 508 for topical use in dermatological indications. US-PS 4, 219, 548 describes the topical use of ASS to contain inflammation. The ASS containing gel is topically applied to EP-A 0 055 635 for inflammatory retention, analgesic and antipyretic indications. The subject of US-PS 4,460,368 is the preparation for transdermal application of ASS from an aqueous system to achieve inflammatory retention and analgesic effects. In US-PS 4,665,063, ASS from ethanol solution is topically applied for dermatological disorders. The ASS penetration rate of transdermal administration is achieved in US-PS 4,640,689 with electrical current.
Tudi dodatek primernih penetracijo pospešujočih snovi po EP-A 162 239 vodi pri transdermalni uporabi do izboljšane penetracije ASS skozi kožo. Po JP-OS 61 167 615 se aplicira ASS s pomočjo filma na kožo. US-PS 4, 810, 699 opisuje kombinacijo ASS z drugimi dejavnimi snovmi za transdermalno obdelavo vnetij, bolečine in vročice.Also, the addition of suitable penetration enhancers according to EP-A 162 239 leads, in transdermal administration, to improved penetration of ASS through the skin. According to JP-OS 61 167 615 ASS is applied using a film to the skin. US-PS 4, 810, 699 describes the combination of ASS with other active agents for transdermal treatment of inflammation, pain and fever.
Specialni penetracijski pospeševalci za transdermalno aplikacijo ASS kot bolečinsko sredstvo so vsebina JP--PS 1 203 336. Nadaljnje snovi te vrste za ASS pri transdermalni aplikaciji za zadrževanje vnetja se najdejo v JP-PS 1, 242, 521. Za skladiščenje stabilne raztopine ASS za topično aplikacijo s ciljem zadrževanja vnetja in lajšanja bolečin so končno predmet US-PS 4, 975, 269.Special penetration enhancers for transdermal ASS application as pain agent are JP-PS 1 203 336. Further substances of this type for ASS in transdermal inflammatory restraint application are found in JP-PS 1, 242, 521. For the storage of a stable ASS solution for topical application aimed at holding back inflammation and relieving pain are finally subject to US-PS 4, 975, 269.
Iz opisanega stanja tehnike ni mogoče povzeti niti ni mogoče iz tega izpeljati, da se upošteva uporaba transdermalnega sistema, ki bi vseboval ASS in/ali njene farmacevtsko sprejemljive soli za preprečevanje trombocitne agregacije pri ljudeh in/ali za profi.....The described state of the art cannot be summarized or derived from the use of a transdermal system containing ASS and / or its pharmaceutically acceptable salts for the prevention of platelet aggregation in humans and / or for profi .....
lakso proti raku.anti-cancer laxative.
Mnoge formulacije in sestava vsebujejo vodo ali hidrofilna topila, ki pospešujejo hidrolizo ASS v salicilno kislino. Ker le-ta ne razvija antitrombotskega delovanja, kot je bilo že zgoraj razloženo, nasprotno pa kaže z ASS primerljiv vnetje zavirajoč in analgetski učinek, je razumljivo, da ni bila v podrobnosti raziskana razgradnja ASS v omenjenih aplikacijskih sistemih.Many formulations and compositions contain water or hydrophilic solvents that promote the hydrolysis of ASS to salicylic acid. Since it does not develop antithrombotic activity, as explained above, and, on the contrary, exhibits a comparable inflammatory inhibitory and analgesic effect with ASS, it is understandable that the breakdown of ASS in the aforementioned application systems has not been investigated in detail.
Opis rešitve tehničnega problemaDescription of solution to a technical problem
Zato je bila naloga tega izuma pripraviti za aplikacijo ASS In/ali njenih farmacevtsko sprejemljivih soli za antitrombotsko terapijo in/ali za profilakso proti raku sistem dajanja, ki se izogne pomanjkljivostim oralne aplikacije in dovoljuje ciljno doziranje nespremenjene dejavne snovi.Therefore, it has been an object of the present invention to provide, for the administration of ASS In / or its pharmaceutically acceptable salts for antithrombotic therapy and / or for cancer prophylaxis, a delivery system that avoids the disadvantages of oral administration and permits targeted dosing of the unchanged active substance.
Rešitev te naloge obstoja presenetljivo v tem, da se uporabi za dajanje acetilsalicilne kisline in/ali njenih farmacevtsko spre.....The solution to this task is surprising in that it is used to administer acetylsalicylic acid and / or its pharmaceutically acceptable components.
jemljivih soli za antitrombotsko terapijo in/ali za profilakso proti raku transdermalni sistem prednostno takšen, ki vsebuje acetilsalicilno kislino oz. soli v matriki, ki bistveno zatre hidrolizo acetilsalicilne kisline oz. je ne dovoli. Z drugimi besedami je sistem prednostno prost snovi, ki povzročajo pod pogoji vskladiščenja oz. med uporabo odcepitev acetilne skupine.salts for antithrombotic therapy and / or for cancer prophylaxis, preferably a transdermal system containing acetylsalicylic acid or. salts in the matrix that substantially suppress the hydrolysis of acetylsalicylic acid or. Don't let her. In other words, the system is preferably free from substances which, under storage and / or storage conditions. while using acetyl group cleavages.
Transdermalni sistem za dajanje nudi pri antitrombotski terapiji sledeče prednosti:The transdermal delivery system offers the following benefits in antithrombotic therapy:
1. ASS se daje v svoji farmakološko aktivni obliki direktno v telesni obtok, s čemer se prepreči presnova snovi v gastrointestinalnem traktu.1. ASS is administered, in its pharmacologically active form, directly into the body, thereby preventing the metabolism of the substance in the gastrointestinal tract.
2. Reduciranje gastrointestinalnih stranskih učinkov.2. Reduction of gastrointestinal side effects.
3. Konstantni terapevtski učinek z zmanjšanimi dajanji ASS.3. Constant therapeutic effect with reduced ASS administration.
4. Zmanjšano tveganje čezmernega doziranja.4. Reduced risk of overdosage.
5. Ambulantna obravnava pacientov brez potrebe nadzora.5. Outpatient treatment of patients without the need for supervision.
6. Zboljšana terapevtska zvestoba pacientov.6. Improved therapeutic loyalty of patients.
Vsebina ASS v takšni enoti dajanja leži na splošno pri 5 do 500, prednostno 30 do 200 mg oz. odgovarjajoči količini farmacevtsko sprejemljive soli. Pri tem uporabljive soli ASS so vse netoksične, farmakološko učinkujoče soli kot so litijeve, natrijeve, kalijeve, magnezijeve in kalcijeve soli ali soli ASS z bazičnimi organskimi spojinami kot lisin, arglnin ali cetrimoni.....The content of ASS in such a unit of administration generally ranges from 5 to 500, preferably 30 to 200 mg, or. the appropriate amount of pharmaceutically acceptable salt. Useful ASS salts are all non-toxic, pharmacologically effective salts such as lithium, sodium, potassium, magnesium and calcium salts or ASS salts with basic organic compounds such as lysine, argline or cetrimones .....
jev bromid (heksadeciltrimetilamonijev bromid). Hitrost in izmera transdermalnega prehoda ASS v telo zavisi naravno od količine, vrste spojine (prosta kislina ali sol) in eventualno tudi od prisotnosti pomožnih snovi kot penetracijskih pospeševalcev. Smotrno nastavimo sistem tako, da se vzpostavi vrednost krvne ravni ASS med 0,1 in 1,0 pg/ml. Za praktično uporabo se vskladi vsebina smotrno glede na vrsto indikacije, telesno težo (otroci oz. odrasli), permeabilnost matrike oz. membrane obliža in permeacijo skozi kožo.bromide (hexadecyltrimethylammonium bromide). The rate and measurement of the transdermal passage of ASS into the body depends naturally on the amount, type of compound (free acid or salt) and possibly also on the presence of excipients as penetration enhancers. It is advisable to adjust the system to establish an ASS blood level between 0.1 and 1.0 pg / ml. For practical use, the content is adjusted according to the type of indication, body weight (children or adults), matrix permeability, or patch membranes and permeation through the skin.
Pri antitrombotski terapiji in pri profilaksi proti raku terapevtsko dejavna količina ASS in/ali soli ASS v krvi odgovarja vrednostim krvne ravni ASS med o,l in 1,0 pg/ml. čeprav se ASS po oralnem dajanju hitro absorbira, je zaradi hidrolize ASS v šali.....For antithrombotic therapy and for prophylaxis against cancer, the therapeutically active amount of ASS and / or ASS salts in the blood corresponds to blood ASS values between o, l and 1.0 pg / ml. although ASS is rapidly absorbed after oral administration, ASS hydrolysis is a joke .....
cilno kislino ta vrsta dajanja neugodna, zlasti če upoštevamo kratki biološki čas polovične vrednosti in dejstvo, da se želi za profilakso čim bolj konstantno dajanje. S transdermalno obravnavo, predlagano z izumom, dobimo nasprotno precej konstantne in ponovljive vrednosti krvne ravni ASS, ki so pri antitrombotski terapiji zlasti učinkovite in primerne za profilakso proti raku. Transdermalni sistem dajanja po izumu zagotavlja konstantno in ponovljivo krvno raven ASS, ki je učinkovita pri antitrombotski terapiji.target acid, this type of administration is disadvantageous, especially considering the short biological half-life and the fact that prophylaxis is desired as constant as possible. The transdermal treatment of the invention, in contrast, results in fairly constant and reproducible ASS blood levels that are particularly effective and suitable for cancer prophylaxis in antithrombotic therapy. The transdermal delivery system of the invention provides a constant and reproducible ASS blood level that is effective in antithrombotic therapy.
Pod profilakso proti raku se npr. razume profilakso proti raku s tvorbo bule, npr. v želodčno črevesnem traktu, kot je rak debelega črevesa.Under cancer prophylaxis, for example. understands anti-cancer prophylaxis by bula formation, e.g. in the gastrointestinal tract, such as colon cancer.
Transdermalni sistem dajanja ASS in/ali soli ASS po izumu se lahko realizira na mnogovrstne načine, tako npr. kot zlasti oprijemno lepljivi obliž, kot film, kot spray, krema, mazilo ali podobno.The transdermal delivery system of ASS and / or ASS salts according to the invention can be realized in a variety of ways, e.g. such as a particularly adhesive adhesive patch, as a film such as spray, cream, ointment or the like.
Prednostna je oblika dajanja oprijemno lepljivega obliža, ki obsega nepropustni hrbtni sloj, z njim povezani rezervoar dejavne snovi iz polimerne matrike, pri odsotnosti drugih krmilnih mehanizmov membrano za krmiljenje oddaje dejavne snovi, napravo oprijemnega lepljenja za pritrditev sistema na kožo in po potrebi varovalni sloj, ki ga lahko zopet odstranimo pred uporabo. Pri vseh oblikah moramo paziti na to, da je matrika, ki tvori rezervoar dejavne snovi, tako izbrana, da izostane hidroliza ASS ali je vsaj močno zadrževana. Hidrofobna nastavitev matrike vodi pri tem hitreje do cilja kot hidrofilna.A preferred form of administration is a adhesive adhesive patch comprising an impermeable back layer, an associated reservoir of active substance of a polymeric matrix, in the absence of other control mechanisms, a membrane for controlling the release of the active substance, a adhesive adhesive device for securing the system to the skin, and, if necessary, a protective layer. which can be removed again before use. In all forms, care must be taken to ensure that the matrix forming the reservoir of the active substance is chosen so as to avoid ASS hydrolysis or at least is strongly retained. Hydrophobic array setup leads to a faster target than hydrophilic.
Za zadrževanje oz. preprečevanje hidrolize lahko dodamo snovi kot so sredstva za aciliranje, prednostno sredstvo za acetiliranje, zlasti acetanhidrid, npr. v količini 0,01 do 3, prednostno 0,1 do 2 masna % glede na acetilsalicilno kislino.To hold or. to prevent hydrolysis, substances such as acylating agents, preferably acetylating agents, in particular acetanhydride, e.g. in an amount of 0.01 to 3, preferably 0.1 to 2% by weight with respect to acetylsalicylic acid.
Kot po izumu uporabni transdermalni oprijemno lepljivi obliži so vsi obliži, ki so strokovnjaku znani iz stanja tehnike. Lahko seAs used according to the invention, transdermal adhesive adhesive patches are all patches known to the person skilled in the art. We can
- 9 prirede dalekosežno dvema temeljnima krmilnima principoma: krmiljenje z difuzijo matrike in krmiljenje z membrano, pri čemer ima samo slednja sproščanje dejavne snovi ničelnega reda. Obliž s krmiljenjem z difuzijo matrike je npr. opisan v DE-PS 33 15 272. Sestavljen je iz neprepustnega hrbtnega sloja, iz z njim povezanega rezervoarja iz polimerne matrike, ki vsebuje dejavno snov v koncentraciji iznad koncentracije nasičenosti, iz oprijemno lepljivega sloja, povezanega z rezervoarjem in za dejavno snov prepustnega in iz varovalnega sloja, ki prekriva oprijemno.....- 9 delivers far-reaching two fundamental control principles: matrix diffusion control and membrane control, with only the latter having zero order active substance release. The matrix diffusion control patch is e.g. described in DE-PS 33 15 272. It consists of an impermeable backing layer, an associated polymer matrix reservoir containing an active substance at a concentration above the saturation concentration, a adhesive adhesive layer bound to the reservoir and an active substance permeable and of a protective layer covering the adhesive .....
lepljivi sloj ter se za uporabo zopet odstrani, npr. iz silikonizirane folije iz poliestra, zlasti polietilentereftalata. če je rezervoarna matrika že sama oprijemno-lepljiva, lahko opustimo dodatni oprijemno-lepljivi sloj. So pa možni tudi sistemi z manjšo kot je koncentracija nasičenosti.adhesive layer and again removed for use, e.g. made of siliconized polyester film, in particular polyethylene terephthalate. if the reservoir matrix is already adhesive-adhesive itself, the additional adhesive-adhesive layer can be omitted. Systems with less than saturation concentration are also possible.
Za obliže z membranskim krmiljenjem se navaja patentne spise US 3,742,951, 3,797,494, 3,996,934 in 4,031,894. Ti obliži obstoje principialno iz hrbtnega sloja (pr. folije iz poliestra kot je polietilentereftalat, ki se lahko aluminizira, ali iz aluminizirane folije iz umetne smole,kot je polipropilen, nylon, polika.....For membrane-controlled patches, U.S. Patent Nos. 3,742,951, 3,797,494, 3,996,934 and 4,031,894 are indicated. These patches exist, in principle, from the back layer (e.g. polyester film such as aluminizable polyethylene terephthalate or aluminized resin film such as polypropylene, nylon, shelf .....
prolaktam, ki predstavlja eno od površin, iz membrane, iz lepilnega sloja, propustnega za dejavno snov, ki predstavlja drugo površino in končno iz rezervoarja, ki vsebuje dejavno snov med obema slojema, ki tvorita površini. Alternativno k temu lahko vsebuje dejavno snov tudi množica mikrokapsul, ki so razdeljene znotraj prepustnega lepljivega sloja. V vsakem primeru se kontinuarno oddaja dejavna snov iz rezervoarja ali iz mikrokapsul skozi membrano v lepljivem sloju, prepustnem za dejavno snov, ki je v dotiku s kožo obravnavanega. V primeru mikrokapsul učinkuje material kapsul tudi kot membrana. Za membrane in za mikrokapsule primerne snovi so opisane npr. v LJS-PS 3,996,934.prolactam representing one of the surfaces, from the membrane, from the adhesive layer permeable to the active substance representing the other surface and finally from the reservoir containing the active substance between the two layers forming the surfaces. Alternatively, the active substance may also comprise a plurality of microcapsules distributed within a permeable adhesive layer. In each case, the active substance is continuously emitted from the reservoir or microcapsules through a membrane in a sticky layer permeable to the active substance in contact with the skin under consideration. In the case of microcapsules, the capsule material also acts as a membrane. For membranes and microcapsules, suitable substances are described e.g. in LJS-PS 3,996,934.
Dopolnilno k temu je potrebno še navesti, da je možno krmiljenje tudi s pomočjo električnega toka, pri čemer predstavlja prehod dejavne snovi skozi kožo korak, ki določa hitrost. Takšni postopki so označeni kot elektroozmoza, iontoforeza ali elektrofore···' za.In addition, it must be stated that the control is also possible by means of an electric current, the passage of the active substance through the skin being a step that determines the speed. Such procedures are referred to as electroosmosis, iontophoresis, or electrophoresis.
Obliži kakršnekoli vrste lahko vsebujejo v slučaju potrebe poleg matrike, ki tvori rezervoar, in dejavne snovi, k čemur štejejo tudi kombinacije ASS in njenih soli, tudi različne vrste dodatnih snovi, da bi dosegli željeno sliko lastnosti. Zlasti naj bodo omenjene takšne dodatne snovi, ki pospešujejo permeacijo ASS in/ali njenih farmacevtsko sprejemljivih soli skozi kožo.. Natančno naštevanje dodatnih snovi ni potrebno za strokovnjaka na tem področju, vendar naj bodo kot primer omenjeni glicerin, 1,2.....Patches of any kind may contain, in the case of need, in addition to the matrix forming the reservoir, as well as the active substances, including combinations of ASS and its salts, various types of additional substances, in order to obtain the desired image of the properties. In particular, such additional substances that promote the permeation of ASS and / or its pharmaceutically acceptable salts through the skin should be mentioned. Precise listing of additional substances is not necessary for a person skilled in the art, but for example glycerin, 1,2 .... .
propandiol, eter monometila oz. monoetila etilenglikola, 2oktildodekanol, laurat, palmitat, stearat ali oleat sorbitola, Cg-CjO - etoksilirani gliceridi oljne kisline, nižji alkilni (Cj do ¢3)- estri laurinske kisline, kot propilenglikolmonolaurat, laurinska, kaprinska, oljna kislina itd. Količina znaša na splošno od 0 do 20, prednostno od 0,5 do 10 masnih % glede na celotne sestavne dele matrike. Zavisi od vrste matrike, permeabilnosti matrike oz. membrane obliža, topilne zmožnosti penetra.....propanediol, monomethyl ether ethylene glycol monoethyl, 2octyldodecanol, laurate, palmitate, stearate or oleate of sorbitol, Cg-CjO - ethoxylated butyric acid glycerides, lower alkyl (Cj to ¢ 3) - lauric acid esters such as propylene glycol monolaurate, lauric, capric acid The amount is generally from 0 to 20, preferably from 0.5 to 10% by weight, based on the total components of the matrix. It depends on the type of array, the permeability of the array, or. patch membranes, penetration capability .....
oljskega pospeševalca za dejavno snov in permeacije skozi kožo.an oil accelerator for the active substance and permeation through the skin.
Izum bomo obrazložili s sledečimi primeri:The invention will be explained by the following examples:
PrimerExample
1. Enoslojni sistem na osnovi akrilata1. A single layer acrylic based system
K 100 g raztopine akrilatnega lepila (npr. DurotakR 280-2516 National Starch and Chemical) z vsebnostjo čvrste snovi 42 masnih % se doda 5g dioktilcikloheksana, 8 g acetilsalicilne kisline in 40 mg acetanhidrida in raztopina se homogenizira z mešanjem.To 100 g of acrylate adhesive solution (eg Durotak R 280-2516 National Starch and Chemical) with a solids content of 42% by weight, 5 g of dioctylcyclohexane, 8 g of acetylsalicylic acid and 40 mg of acetanhydride are added and the solution is homogenized by stirring.
Raztopina se nato nanese 300 pm debelo na silikonizirano, 100 pm debelo poliestersko folijo. Ta folija prevzame pri končanem sistemu funkcijo ponovno odstranijivega varovalnega sloja ter se mora pred uporabo odstraniti. Vlažni film se suši 20 min pri 50°C in ima nato ploskovno težo 100 g/m2.The solution is then applied 300 µm thick to a siliconized, 100 µm thick polyester film. This foil assumes the function of a removable protective layer on the finished system and must be removed before use. The wet film is dried at 50 ° C for 20 min and then has a surface weight of 100 g / m 2 .
Nato se posušeni film z 12 pm debelo poliestersko folijo kašira. Iz laminata se štancajo gotovi obliži.Then the dried film with 12 pm thick polyester film is lined. Finished patches are stamped from the laminate.
2. Večslojni sistem2. A multilayer system
Gotovi sistem je sestavljen iz ponovno odstranijivega varovalnega sloja, iz premaza za lepljenje na kožo, iz nelepljivega rezei— voarja, iz hrbtnega sloja, nepropustnega za dejavno snov in iz temeljnega premaza, ki dobro lepi, ki se nahaja med rezervoarnim slojem in hrbtnim slojem in ima nalogo, da zasidra nelepljivi rezervoar na hrbtnem sloju.The finished system consists of a removable protective layer, a skin adhesive coating, a non-sticky rezei-voar, an active-impermeable back layer and a good-adhesive primer between the reservoir layer and the back layer, and it is tasked to anchor the non-stick tank on the back layer.
A. Izdelava premaza za lepljenje na kožoA. Production of a coating for adhesion to the skin
- 100 g blokpolimera iz polistirola In poliizoprena (npr. CarflexR TR - 1107, firma Shell),- 100 g of block polymers of polystyrene and polyisoprene (eg Carflex R TR - 1107, Shell company),
- 175 g glicerinskega estra iz delno hidriranega kolofonija in175 g glycerin ester of partially hydrated rosin and
- 50 g dioktilcikloheksana se raztopi v 500 g n-heptana in nato doda 15 g acetilsalicilne kisline in 150 mg acetanhidrida. Masa se z mešanjem homogenizira in nato premaže 100 pm debelo na silikonizirano poliestersko folijo, ki služi pri gotovem produktu kot ponovno odstranljiv varovalni sloj. Vlažni film se suši 20 min pri 50°C in ima nato ploščinsko težo 25 g/m^.- 50 g of dioctylcyclohexane is dissolved in 500 g of n-heptane and then 15 g of acetylsalicylic acid and 150 mg of acetanhydride are added. The mass is homogenized by stirring and then coated 100 µm thick on siliconized polyester film, which serves as a removable protective layer on the finished product. The wet film is dried for 20 min at 50 ° C and then has a surface weight of 25 g / m ^.
B. Izdelava rezervoarnega premazaB. Production of reservoir coating
- 100 g blokpolimera iz polistirola in poliizoprena (npr. Čari™ flexR TR-1107, firme Shell) in- 100 g of polystyrene and polyisoprene block polymers (eg charms ™ flex R TR-1107 by Shell), and
- 20 g dioktilcikloheksana se raztopi v 120 g n-heptana.- 20 g of dioctylcyclohexane is dissolved in 120 g of n-heptane.
Nato se doda 40 g acetilsalicilne kisline in 40 mg acetanhidrida in masa se homogenizira z mešanjem. Masa se premaže 300 pm debelo na debelejšo kot ponovno odstranljivi zaščitni sloj silikonizirano poliestersko folijo in sušeno 20 min pri 5O0C. Posušeni rezei— voarni film ima ploščinsko težo 100 g/m2.Then 40 g of acetylsalicylic acid and 40 mg of acetanhydride are added and the mass is homogenized by stirring. The mass of the coated 300 pm thick at the thickest as a removable protective layer of a siliconized polyester film and dried for 20 min at 5O 0 C. The dried rezei- voarni film has a weight of 100 g / m2.
C. Izdelava temeljnega premazaC. Coating
- 100 g blokpolimera iz polistirola in poliizoprena (npr. ČariflexR TR-1107 firme Shell),- 100 g of polystyrene and polyisoprene block polymers (eg Shell Chariflex R TR-1107),
- 175 g glicerinovega estra parcialno hidriranega kolofonija in175 g of glycerin ester of partially hydrated rosin and
- 50 g dioktilcikloheksana se raztopi v 500 g n-heptana in 100 pm debelo premaže analogno z- 50 g of dioctylcyclohexane are dissolved in 500 g of n-heptane and 100 pm thick coated analogously to
B na debelejšo kot ponovno odstranljivi zaščitni sloj silikonizi.....B thicker than the removable silicone protective layer .....
rano poliestersko folijo in sušeno 20 min pri 50°C. Posušeni film ima ploščinsko težo 25 g/m2.wound polyester film and dried at 50 ° C for 20 min. The dried film has a surface weight of 25 g / m 2 .
D. Sestava celotnega sistema in štancanje posameznih obliževD. Composition of the whole system and punching of individual patches
Pod B proizvedeni rezervoarni premaz se nakašira na premaz A za lepljenje na kožo in nato odstrani pod B imenovano močneje silikonizirano folijo. Nato se nanese na enak način temeljni premaz C in po odstranitvi pod C imenovane močneje silikonizirane folije se nakašira 12 pm debela poliesterska folija.Under B, the reservoir coating produced is tacked onto Coating A for adhesion to the skin and then removed under B called stronger silicone foil. The primer C is then applied in the same way, and after removal of the more strongly siliconized foil under the name of C, a 12 pm thick polyester film is coated.
Izgotovljeni obliži se izštancajo iz celotnega laminata.The resulting patches are extruded from the entire laminate.
3. Membranski sistem3. Membrane system
Laminat sposoben za vroče pečatenje, iz fleksibilne poliesterske folije in iz folije iz kopolimera polietilen/vinilacetata se pečati odgovarjajoče izmeram in oblikam kasnejših obližev na 50 pm debele membrane iz kopolimera polietilena/vinilacetata z vsebnostjo 19% vi nilacetata, da nastane neke vrste ploska vrečica. Pečatni šiv naj ima širino 4 mm. Preden se vrečica brez vrzeli pečati, se napolni s tekočo pripravo iz silikonskega olja z 10% acetilsalicilne kisline in 0,05% acetanhidrida.Hot seal laminate, made of flexible polyester film and of polyethylene / vinyl acetate film copolymer, is sealed according to the dimensions and shapes of later patches on a 50 pm thick membrane of polyethylene / vinyl acetate copolymer containing 19% vi nyl acetate to form a sort of flat. The seam should be 4 mm wide. Before filling the bag without a gap, it is filled with a liquid silicone oil preparation with 10% acetylsalicylic acid and 0.05% acetanhydride.
Membranska stran vrečic se sedaj nakašira na premaz za lepljenje na kožo na silikonski bazi, ki je na primerni, abhezivno opremi.....The diaphragm side of the bags is now attached to a silicone-based adhesive coating on the skin that is suitable, abrasive, .....
jeni foliji. Ta folija je identična s ponovno odstrani jivim zaščitnim slojem.yen foil. This foil is identical to the removable protective layer.
Gotovi sistemi se tako izštancajo, da ostane vrečica na 3 mm debelem pečatnem robu.The finished systems are so thin that the bag remains on the 3 mm thick sealing edge.
Claims (9)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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SI9400023A SI9400023B (en) | 1994-01-21 | 1994-01-21 | Transdermally administered system containing acetylsalicylic acid for thrombosis theraphy and cancer prophilaxys |
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Application Number | Priority Date | Filing Date | Title |
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SI9400023A SI9400023B (en) | 1994-01-21 | 1994-01-21 | Transdermally administered system containing acetylsalicylic acid for thrombosis theraphy and cancer prophilaxys |
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SI9400023A true SI9400023A (en) | 1995-08-31 |
SI9400023B SI9400023B (en) | 2000-06-30 |
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SI9400023A SI9400023B (en) | 1994-01-21 | 1994-01-21 | Transdermally administered system containing acetylsalicylic acid for thrombosis theraphy and cancer prophilaxys |
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