HRP930662A2 - Process for the production of a transdermal therapeutic system gradually releasing an active substance - Google Patents
Process for the production of a transdermal therapeutic system gradually releasing an active substance Download PDFInfo
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- HRP930662A2 HRP930662A2 HR930662A HRP930662A HRP930662A2 HR P930662 A2 HRP930662 A2 HR P930662A2 HR 930662 A HR930662 A HR 930662A HR P930662 A HRP930662 A HR P930662A HR P930662 A2 HRP930662 A2 HR P930662A2
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- 239000013543 active substance Substances 0.000 title claims description 94
- 238000000034 method Methods 0.000 title claims description 13
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- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 5
- 239000012790 adhesive layer Substances 0.000 description 5
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- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 5
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- 102220536557 Transcription factor NF-E4_A45D_mutation Human genes 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000003152 motion sickness Diseases 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
- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 1
- 229940124641 pain reliever Drugs 0.000 description 1
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Classifications
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- 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
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Anesthesiology (AREA)
- Medical Informatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Media Introduction/Drainage Providing Device (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Adhesives Or Adhesive Processes (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- External Artificial Organs (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
Grana tehnike u koju spada izum The technical branch to which the invention belongs
Izum spada u granu tekućih potreba, a sekundarno u oblast prerade, a specifično u oblast izrade oblika lijeka za terapijsku primjenu na koži. Simboli međunarodne klasifikacije patenata su: A61L 15/03, A61L 15/06, A61F 13/02, A61M 37/00, B32B 7/02, B32B 7/06, B01J 4/00, A61J 3/00, A45D 34/00 i A24F 47/00. The invention belongs to the branch of current needs, and secondarily to the field of processing, and specifically to the field of making forms of medicine for therapeutic application on the skin. International patent classification symbols are: A61L 15/03, A61L 15/06, A61F 13/02, A61M 37/00, B32B 7/02, B32B 7/06, B01J 4/00, A61J 3/00, A45D 34/00. and A24F 47/00.
Tehnički problem Technical problem
Tehnički problem je kako dobiti transdermalni terapijski sustav s potpunim otpuštanjem aktivne tvari za lokalno i sustavno davanje aktivne tvari na koži, što se postiže time, da se sustav pomoću ljepljivog sloja nanosi na kožu, a sam sustav se sastoji od spremnika aktivne tvari u kome je predviđena opna koja omogućuje da se aktivna tvar kontrolirano otpušta kroz kožu. The technical problem is how to obtain a transdermal therapeutic system with complete release of the active substance for local and systemic administration of the active substance on the skin, which is achieved by applying the system to the skin using an adhesive layer, and the system itself consists of a container of the active substance in which provided membrane that allows the active substance to be released in a controlled manner through the skin.
Stanje tehnike State of the art
Transdermalni terapijski sustavi su pri svemu tome osvojili svoje stalno mjesto u liječenju najrazličitijih bolesti. Njihova glavna prednost je u tome, što uz zaobilaženje primarnog prolaza jetre, koje se obavezno događa pri oralno danim aktivnim tvarima, aktivna tvar poslije prolaza kroz kožu dolazi direktno sustavno do djelovanja i što se odgovarajućim umetanjem sustava mogu postići vrlo konstantne razine plazme. Ovo je naročito važno kod aktivnih tvari koje imaju kratko poluvrijeme vrijednosti i stoga čine potrebnim konstantno dovođenje aktivne tvari. Budući da se sustav primjenjuje izvana, može se bez promjene vrlo dugo - kod nekih sustava koji se mogu dobiti u trgovini čak do jednog tjedna - na ovaj način ispuniti svoju funkciju njemu namijenjenu. Despite all this, transdermal therapeutic systems have won their permanent place in the treatment of a wide variety of diseases. Their main advantage is that in addition to bypassing the primary passage of the liver, which necessarily occurs with orally administered active substances, the active substance after passing through the skin takes effect directly in the system and that with appropriate insertion of the system, very constant plasma levels can be achieved. This is especially important with active substances that have a short half-life and therefore require a constant supply of the active substance. Since the system is applied externally, it can perform its intended function without change for a very long time - with some systems that can be obtained in the store even up to a week - in this way.
Ovo je pomoću oralnih sustava apsolutno nemoguće, budući da su oni aktivnošću probave najduže poslije jednog dana napustili organizam. Takvi transdermalni sustavi se obično sastoje od zadnjeg sloja nepropusnog za aktivnu tvar, spremnika za aktivnu tvar, naprave za pričvršćivanje za učvršćivanje sustava za kožu i odstranjive zaštitne folije za stranu sustava prema koži. Izvođenje naprave za pričvršćivanje koje se pretpostavlja sastoji se u tome, što je ono na strani sustava prema koži bar djelomično izrađeno samoljepljivo. Spremnik može u takvim sustavima imati oblik vreće, koja sadrži tekuću ili otopivu aktivnu tvar ili biti više proizvod u oblik folije, koji sadrži aktivnu tvar u pripravku koji sadrži polimer. This is absolutely impossible with oral systems, since they have left the body after one day at most due to the activity of digestion. Such transdermal systems typically consist of a back layer impermeable to the active substance, a reservoir for the active substance, an attachment device for securing the system to the skin, and a removable protective film for the skin side of the system. The design of the fixing device that is assumed consists in the fact that the one on the side of the system towards the skin is at least partially made self-adhesive. In such systems, the container can have the form of a bag, which contains a liquid or soluble active substance, or be more of a product in the form of a foil, which contains an active substance in a preparation containing a polymer.
Posljednje spomenuti sustavi se nazivaju također i matriksni sustavi i sva slijedeće izvođenja odnose se na sustave ove vrste. Ako se spremmik takvog matriksnog sustava sastoji iz jednog homogenog sloja i između strane spremnika okrenutoj koži poslije primjene i same kože se ne nalaze daljnji slojevi koji reguliraju otpuštanje aktivne tvari, tada sustav regulira odavanje aktivne tvari, ako je matriks prezasićen aktivnom tvari prema jednadžbi jedan odnosno ako ovo nije slučaj prema jednadžbi dva. The last mentioned systems are also called matrix systems and all the following implementations refer to systems of this type. If the preparation of such a matrix system consists of one homogeneous layer and between the side of the container facing the skin after application and the skin itself there are no further layers that regulate the release of the active substance, then the system regulates the release of the active substance, if the matrix is oversaturated with the active substance according to equation one or if this is not the case according to equation two.
Q=(DDR x [CDR - CSDR] x CSDR x t) jednadžba 1 Q=(DDR x [CDR - CSDR] x CSDR x t) equation 1
Q=2 x CDR x (DDR xt/3,14) jednadžba 2 Q=2 x CDR x (DDR xt/3.14) equation 2
Q: za vrijeme t oslobođena količine aktivne tvari Q: amount of active substance released during time t
t: vrijeme t: time
DDR: koeficijent difuzije aktivne tvari u matriksu DDR: diffusion coefficient of the active substance in the matrix
CDR: koncentracija aktivne tvari u spremniku CDR: concentration of the active substance in the container
CSDR: otopivost zasićenja aktivne tvari u spremniku CSDR: saturation solubility of the active substance in the container
Budući je Q direktno proporcionalno kvadratnom korijenu iz vremena, ove jednadžbe se nazivaju također i zakon korijena. Odavanje aktivne tvari kod ovih sustava nije konstantno i brzo opada s vremenom. Ako je poželjno konstantnije odavanje aktivne tvari, ovo se može postići primjenom tzv. regulacione opne. Takav sustav se sastoji iz zadnjeg sloja, spremnika aktivne tvari, regulacione opne, sloja ljepila za prijanjanje za pričvršćivanje sustava na kožu i ponovo odstranjivanje zaštitne folije. Since Q is directly proportional to the square root of time, these equations are also called the root law. The release of the active substance in these systems is not constant and rapidly decreases over time. If a more constant release of the active substance is desired, this can be achieved by applying the so-called regulation membranes. Such a system consists of the last layer, the container of the active substance, the regulating membrane, the adhesive layer for attaching the system to the skin and removing the protective film again.
Q=Co x e-D/l x t jednadžba 3 Q=Co x e-D/l x t equation 3
Co = početna koncentracija aktivne tvari Co = initial concentration of the active substance
D = koeficijent difuzije aktivne tvari u opni D = diffusion coefficient of the active substance in the membrane
l = debljina opne l = membrane thickness
Ali kod nekih grupa aktivnih tvari mogu konstantni odnosi otpuštanja i konstantni nivoi plazme biti prije nepoželjni. U te spadaju na primjer sredstva koja utječu na krvni tlak i na krvotok, sredstva za umirenje i spavanje, psihofarmaka, sredstva protiv bolova aktivne tvari protiv angine pectoris, antihistaminici, i tvari koje olakšavaju odvikavanje od zavisnosti kao na primjer nikotin. Kod ovih supstanci je od prednosti, ako bi se mogle dostići razine plazme koje su prilagođene potrebama. But with some groups of active substances, constant release rates and constant plasma levels may be rather undesirable. These include, for example, agents that affect blood pressure and blood flow, sedatives and sleep aids, psychopharmaceuticals, pain relievers, active substances against angina pectoris, antihistamines, and substances that facilitate withdrawal from addiction, such as nicotine. With these substances, it would be advantageous if plasma levels could be reached that are adapted to the needs.
Neke aktivne tvari se uostalom ne uzimaju stalno već samo po potrebi u po mogućnosti vrlo velikim vremenskim razmacima. Takva supstanca, koja je već kao transdermalni sustav na tržištu je na primjer skopolamin protiv tegoba putovanja. After all, some active substances are not taken all the time, but only when needed, preferably at very long intervals. Such a substance, which is already on the market as a transdermal system, is for example scopolamine against travel sickness.
Druge aktivne tvari, za koje se može zamisliti takva povremena primjena su na primjer sredstva protiv bolova, psihofarmaka, sredstva za umirenje, sredstva za spavanje ili sredstva za obuzdavanje apetita. Pri transdermalnoj primjeni takvih supstanci mora transdermalni sustav pri tom izazvati u toku vremenskog perioda primjene promjenjljiv protok kroz kožu, pri čemu se početna doza brine za brzo nastupanje djelovanja i doza primanja za dovoljno dugu konstantnost ili unaprijed programirano opadanje razine plazme. Other active substances for which such occasional use is conceivable are, for example, painkillers, psychopharmaceuticals, sedatives, sleeping aids or appetite suppressants. During the transdermal application of such substances, the transdermal system must cause a variable flow through the skin during the time period of application, whereby the initial dose ensures a quick onset of action and the receiving dose for a sufficiently long constancy or a pre-programmed decrease in the plasma level.
Transdermalni terapijski sustav za rješenje ovog problema je već opisan u EP-A 0 227 252. Tamo se aktivna tvar stavlja u dodir u spremniku samo sa toliko ubrzivača prodiranja, da se ubrzano prodiranje održava samo u tijeku definirane faze primjene. Ovdje je manjkavo što se za svaku aktivnu tvar mora naći pogodan ubrzivač prodiranja. A transdermal therapeutic system for the solution of this problem is already described in EP-A 0 227 252. There, the active substance is brought into contact in the container with only so much penetration accelerator, that the accelerated penetration is maintained only during the defined application phase. The disadvantage here is that a suitable penetration accelerator must be found for each active substance.
Drugo rješenje problema predlaže se u DE-OS 36 42 931. Tamo su predviđene najmanje dvije komore flastera jedna od druge odvojene i koje leže jedna pored druge sa različitim koncentracijama aktivne tvari, tako da u prvoj fazi primjene oslobađanja aktivne tvari i svih komora predstavlja visoku početnu dozu, dok poslije pražnjenja komora sa nižom koncentracijom aktivne tvari pridonose oslobađanju samo još komore s višom koncentracijom aktivne tvari i time izazivaju nižu dozu primanja. Ovaj sustav je već po konstrukciji komora skup i zahtijeva naročite mjere u pogledu različitih prilagođavanja koncentracije u komorama. Another solution to the problem is proposed in DE-OS 36 42 931. There are provided at least two patch chambers separated from each other and lying next to each other with different concentrations of the active substance, so that in the first phase of application the release of the active substance and all chambers represents a high the initial dose, while after emptying the chambers with a lower concentration of the active substance, they contribute to the release of only more chambers with a higher concentration of the active substance and thus cause a lower receiving dose. This system is already expensive due to the construction of the chambers and requires special measures regarding different adjustments of the concentration in the chambers.
Opis rješenja tehničkog problema s primjerima izvođenja i popisom i kratkim opisom slika nacrta Description of the solution to the technical problem with implementation examples and a list and brief description of the blueprint images
Izum se odnosi na postupak za izradu transdermalnog sustava s postupnim odavanjem aktivne tvari i na njegovu primjenu za lokalno ili sustavno dermalno davanje aktivne tvari u humanoj ili veterinarskoj medicini ili kozmetici. The invention relates to a process for the production of a transdermal system with gradual release of an active substance and to its application for local or systemic dermal administration of an active substance in human or veterinary medicine or cosmetics.
Stoga je zadatak izuma da stavi na raspolaganje flaster kao terapijski sustav za davanje aktivne tvari na koži sa stupnjevitim otpuštanjem aktivne tvari, koji izbjegava obavezno prisustvo ubrzivača prodiranja, pruža nad dosadašnjim stanjem tehnike dodatne mogućnosti da se regulira otpuštanje aktivne tvari i može se izraditi na jednostavan način. Therefore, the task of the invention is to make available a patch as a therapeutic system for administering an active substance to the skin with a gradual release of the active substance, which avoids the obligatory presence of penetration accelerators, provides additional possibilities over the current state of the art to regulate the release of the active substance, and can be made in a simple way.
Zadatak se prema izumu na iznenađujući način rješava tako, što spremnik koji sadrži aktivne tvari sadrži paralelno prema površini oslobađanja najmanju opnu, koja je u svom površinskom dimenzioniranju manja od površine oslobađanja. According to the invention, the task is solved in a surprising way by the fact that the container containing the active substances contains, parallel to the release surface, the smallest membrane, which in its surface dimensions is smaller than the release surface.
Predmet izuma je prema tome postupak za izradu transdermalnog sustava za regulirano, postupno davanje aktivnih tvari na kožu s višom početnom dozom i nižom dozom primanja, koji se sastoji do zadnje strane nepropusne za aktivnu tvar otklonjene od kože, spremnika aktivne tvari, koji paralelno prema površini oslobađanja sadži bar opnu, uređaja za učvršćivanje koji se lijepi za sustav na koži i u danom slučaju odvojivog zaštitnog sloja koji pokriva površine sustava prema koži, pri čemu je paralelno prema površini oslobađanja spremnika aktivne tvari postavljena opna ili integrirana u spremnik ili se pripija na spremnik prema strani kože, i površina opne je manja od površine oslobađanja spremnika aktivne tvari. The subject of the invention is therefore a procedure for creating a transdermal system for the regulated, gradual administration of active substances to the skin with a higher initial dose and a lower receiving dose, which consists up to the last side impermeable to the active substance removed from the skin, a container of the active substance, which is parallel to the surface of the release of the soot, at least a membrane, a fastening device that sticks to the system on the skin and, in a given case, a detachable protective layer that covers the surfaces of the system to the skin, whereby a membrane is placed parallel to the release surface of the container of the active substance, or integrated into the container or attached to the container according to side of the skin, and the membrane surface is smaller than the release surface of the active substance container.
Pod opnom se podrazumijeva, u vezi s ovim, u obliku površine savitljiv proizvod, čija propustljivost za sastojke spremnika aktivne tvari kože može biti također i nula. Pod pojmom opna spada dakle također i na primjer tanka metalne folija. Uobičajena debljina takve membrane rijetko prelazi 50 μ, ali u specijalnim slučejavima nisu isključene također i deblje opne. In this connection, membrane means a flexible product in the form of a surface, the permeability of which to the components of the skin's active substance container can also be zero. The term membrane therefore also includes, for example, thin metal foils. The usual thickness of such a membrane rarely exceeds 50 μ, but in special cases thicker membranes are not excluded.
Obično su debljine opne od 20 do 100 μ. Usually, the thickness of the membrane is from 20 to 100 μ.
Opna može biti ili integrirana u spremnik odnosno biti umetnuta ili pripijena na spremnik na strani prema koži. The membrane can be either integrated into the container or inserted or attached to the container on the side towards the skin.
Prema jednom obliku izvođenja je opna za oslobađanje određene aktivne tvari ili određenih aktivnih tvari nepropusna. Prema jednom daljem obliku izvođenja je membrana za aktivnu tvar ili aktivne tvari ograničeno propusna. Prema izumu mogu se kombinirati također i dvije memebrane-opne, koje imaju razkličitu propustljivost tvari određenih za otpuštanje, od kojih bar jedna ima manju površinu od površine oslobađanja sustava. Za ovaj slučaj je pogodno da je opna, koja je po površini, manja od površine oslobađanja sustava, nepropusna za tvar određenu za otpuštanje ili tvari određene za lučenje i da je integrirana u spremnik. According to one embodiment, the membrane for releasing a certain active substance or certain active substances is impermeable. According to a further embodiment, the membrane is limitedly permeable to the active substance or active substances. According to the invention, two membranes can also be combined, which have different permeability of substances intended for release, at least one of which has a smaller surface area than the release surface of the system. For this case, it is convenient that the membrane, which is smaller in surface area than the release surface of the system, is impermeable to the substance designated for release or substances designated for secretion and that it is integrated into the container.
Aktivna tvar ili aktivne tvari mogu u spremniku biti prisutne ili u koncentraciji koja ne prelazi koncentraciju zasićenja. Sam se spremnik može opet sastojati iz raznih slojeva različitog sastava. The active substance or active substances can be present in the container or in a concentration that does not exceed the saturation concentration. The container itself can again consist of various layers of different composition.
Za sve komponente jednog takvog sustava principijelno mogu se primijeniti i isti materijali, koji su opisani za uobičajene sustave. Ovi materijali su stručnjaku poznati. For all components of such a system, in principle, the same materials described for common systems can be used. These materials are known to the expert.
Zadnji sloj može se sastojati od savitljivog ili nesavitljivog materijala i biti izrađen jedno ili višeslojno. Supstance, koje se mogu primijeniti za njegovu izradu su polimerne supstance, kao na primjer polietilen, polipropilen, poletilentereftalat, poliuretan ili poliamid. Kao daljnji materijal mogu se primijeniti također i metalne folije kao na primjer aluminijske folije, sama ili s polimernom podlogom obložene. Mogu se primijeniti tekstilni ravni proizvodi, ako sastojci spremnika ovaj ne mogu preko plinske faze napustiti na osnovu njihovih fizikalnih podataka. The back layer can consist of flexible or non-flexible material and be made in one or more layers. Substances that can be used for its production are polymeric substances, such as polyethylene, polypropylene, polyethylene terephthalate, polyurethane or polyamide. As a further material, metal foils, such as aluminum foils, alone or coated with a polymer substrate, can also be used. Flat textile products can be used, if the contents of the container cannot leave it through the gas phase based on their physical data.
Za odstranjivu zaštitnu foliju u principu mogu se primijeniti isti materijali, ali oni moraju biti dodatno abhezivno opremljeni. Abhezivno opremanje može se postići specijalnim silikoniziranjem. Spremnik odnosno slojevi spremnika sastoje se iz polimernog matriksa i aktivne tvari ili aktivnih tvari, pri čemu polimerni matriks posjeduje takvu vlastitu ljepljivost, da je zajamčena povezanost pri višeslojnoj izgradnji. In principle, the same materials can be used for the removable protective film, but they must be additionally equipped with adhesive. Adhesive equipment can be achieved by special siliconization. The container or the layers of the container consist of a polymer matrix and an active substance or active substances, whereby the polymer matrix has such an inherent adhesiveness that it guarantees connection during multi-layer construction.
Polimerni materijal matriksa može na primjer biti izrađen na polimerima kao kaučuku, kaučuku sličnim sintetskim homo-, ko- ili blok polimerima, esetrima poliakrilne kiseline i njenim kopolimerima, poliuretanima, kopolimerima etilena i polisilikonima. Načelno dolaze u obzir svi polimeri koji se upotrebljavaju pri izradi ljepila i fiziološki su nesumljivi. Mogu se primijeniti još dodaci, čija priroda zavisi od upotrijebljenog polimera i od aktivne ili aktivnih tvari. Prema njihovoj funkciji mogu se podijeliti u omekšivače, stvaraoce ljepljivosti, posrednike resorpcije, stabilizatore ili punioce. Fiziološki nesumljive supstance koje ovdje dolaze u obzir poznate su stručnjaku. The polymer matrix material can for example be made on polymers such as rubber, rubber-like synthetic homo-, co- or block polymers, polyacrylic acid esters and its copolymers, polyurethanes, ethylene copolymers and polysilicones. In principle, all polymers that are used in the production of glue come into consideration and are physiologically unsuspected. Other additives can be applied, the nature of which depends on the polymer used and on the active substance(s). According to their function, they can be divided into softeners, tackifiers, resorption mediators, stabilizers or fillers. Physiologically unsuspected substances that come into consideration here are known to the expert.
Za opne se mogu upotrijebiti svi fiziološki nesumljivi materijali u obliku folija, koji imaju za svrhu primjene odgovarajuću propustljivost za aktivnu tvar ili aktivne tvari odnosno pomoćne tvari. Naročito su pogodne opne na bazi polietilena, poliamida, etilenvinilacetatnih kopolimera i polisiloksana. All physiologically unsuspicious materials in the form of foils can be used for membranes, which have for the purpose of application an appropriate permeability for the active substance or active substances or auxiliary substances. Membranes based on polyethylene, polyamide, ethylene vinyl acetate copolymers and polysiloxane are particularly suitable.
Izum se u slijedećem objašnjava pobliže na osnovu slike. Pri tome pokazuje: In the following, the invention is explained in more detail on the basis of the figure. It shows:
Slika 1 presjek kroz sustav s regulacionom opnom prema stanju tehnike, Figure 1 section through a system with a regulation membrane according to the state of the art,
Slika 2 oblik izvođenja sustava prema izumu, Fig. 2, the embodiment of the system according to the invention,
Slika 3 pokazuje drugi izgled matriksa iz slike 2 s opnom integriranom u matriks, Figure 3 shows another view of the matrix from Figure 2 with the membrane integrated into the matrix,
Slika 4 različiti oblici izvođenja opne, Fig. 4 different forms of performing the membrane,
Slika 5a presjek kroz oblik izvođenja izuma, koji ima kombinaciju nepropusne opne s opnom veće propustljivosti, Figure 5a is a section through an embodiment of the invention, which has a combination of an impermeable membrane with a membrane of higher permeability,
Slika 5b izgled odozgo na oblik izvođenja slike 5a Figure 5b is a top view of the embodiment of Figure 5a
Slika 6 u grafičkom predstavljanju ponašanje oslobađanja oblika izvođenja s nepropusnom opnom za aktivnu tvar integriranu u spremnik oblika, kako je on predstavljen na slici 4, pri čemu je kumulirana oslobođena količina aktivne tvari predstavljena kao funkcija vremena, Figure 6 graphically represents the form release behavior of an impermeable membrane embodiment for the active substance integrated in the form container, as presented in Figure 4, where the cumulative released amount of the active substance is represented as a function of time,
Slika 7 ponašanje oslobađanja istog sustava kao na slici 6, ali predstavljenu u grafičkom predstavljanju odnosa otpuštanja aktivne tvari po sustavu i satu kao funkcija vremena, Figure 7 shows the behavior of the release of the same system as in Figure 6, but presented in a graphical representation of the relationship of the release of the active substance per system and hour as a function of time,
Slika 8 u grafičkom predstavljanju ponašanja oslobađanja sustava prema izumu s ograničenom propusnom opnom za aktivnu tvar, pri čemu je kumulativno oslobađanje aktivne tvari predstavljeno preko vremena, Figure 8 in a graphical representation of the release behavior of the system according to the invention with a limited permeability membrane for the active substance, wherein the cumulative release of the active substance is represented over time,
Slika 9 u grafičkom predstavljanju količine otpuštanja istog sustava kao na slici 8 po sustavu i satu kao funkcija vremena. Figure 9 is a graphical representation of the release amount of the same system as in Figure 8 per system and hour as a function of time.
Na slici 1 opisani sustav se sastoji iz zadnjeg sloja 11, spremnika 12 aktivne tvari, regulacione opne 13, ljepljivog sloja 14 za pričvršćivanje sustava na kožu i ponovo odvojive zaštitne folije 15. The system described in Figure 1 consists of the last layer 11, the container 12 of the active substance, the regulating membrane 13, the adhesive layer 14 for attaching the system to the skin and the removable protective film 15.
U nekim slučajevima ima ljepljivi sloj 14 istu formulaciju kao spremnik 12, tako da je u principu opna integrirana u spremnik i stoga se može spremnik zamisliti izrađen iz dva dijela. In some cases, the adhesive layer 14 has the same formulation as the container 12, so that in principle the membrane is integrated into the container and therefore the container can be imagined to be made of two parts.
Membranom se postiže, kada je aktivna tvar u spremniku prisutna u prezasićenoj koncentraciji, oslobađanje prema kinetici 0. reda, tj. konstantno oslobađanje u tijeku vremenskog razdoblja, i kad je aktivna tvar prisutna ispod ove koncentracije oslobađanja prema kinetici 1. reda prema jednadžbi 3. The membrane achieves, when the active substance in the container is present in a supersaturated concentration, release according to the 0th order kinetics, i.e. constant release during the time period, and when the active substance is present below this concentration, release according to the 1st order kinetics according to equation 3.
Na slici 2 je prikazana principijelna izgradnja sustava prema izumu. Sastoji se iz zadnjeg sloja 21, spremnika 22, opne 23, samoljepljivog namaza 24 za kožu i ponovo odstranjive zaštitne folije 25. Figure 2 shows the principle construction of the system according to the invention. It consists of the last layer 21, container 22, membrane 23, self-adhesive skin coating 24 and removable protective film 25.
Opna 23 je manja od površine spremnika, budući u sredini ima ostavljen otvor kružnog oblika. Diaphragm 23 is smaller than the surface of the tank, since it has a circular opening in the middle.
Na slici 3 je opna 31 integrirana u spremnik 32, koji se tako dijeli u dvije polovine 33 i 34. Ako je formulacija spremnika samoljepljiva, tada prirodno može samoljepljivi namaz 24 za kožu iz Slike 2 otpasti. Uvjetovano time, da je površina opne uvijek manja od ukupne površine spremnika, imaju na površini spremnika nepokrivenoj opnom i koža, odnosno spremnik i ljepljivi sloj odnosno oba dijela spremnika direktan međusobni kontakt. In Figure 3, the membrane 31 is integrated into the container 32, which is thus divided into two halves 33 and 34. If the formulation of the container is self-adhesive, then naturally the self-adhesive skin spread 24 of Figure 2 may fall off. Provided that the surface of the membrane is always smaller than the total surface of the container, the skin, or the container and the adhesive layer, or both parts of the container, have direct mutual contact on the surface of the container not covered by the membrane.
Slika 4 pokazuje neke primjere za geometrijsko oblikovanje takve opne prema izumu, gdje su opne ili iscrtkane površine ili neiscrtane površine. Figure 4 shows some examples for the geometric design of such a membrane according to the invention, where the membranes are either drawn surfaces or non-drawn surfaces.
Oblici izvođenja prema izumu prema Slikama 3 i 4 su naročito pogodni za sustave za samo jednu opnu nepropusnu za aktivnu tvar, na primjer kako je izvedeno na Slici 4.1 i prema Slici 3 integrirano u spremnik. The embodiments according to the invention according to Figures 3 and 4 are particularly suitable for systems for only one membrane impermeable to the active substance, for example as performed in Figure 4.1 and according to Figure 3 integrated into the container.
Ovaj se sustav najprije ponaša kao uobičajeni matriksni sustav, tj. po cijeloj površini oslobađanja se aktivna tvar luči po tzv. zakonu korijena-t. Kada je pak dio spremnika, koji se nalazi ispod površine opne toliko ispražnjen, da je zona osiromašenja dostigla opnu, drastično se mijenja njeno ponašanje u usporedbi s uobičajenim matriksnim sustavom. This system first behaves like a normal matrix system, i.e. the active substance is secreted over the entire release surface by the so-called to the root-t law. When the part of the tank, which is located below the surface of the membrane, is so emptied that the depletion zone has reached the membrane, its behavior changes drastically compared to the usual matrix system.
Na površini koja odgovara u svojoj veličini opni povlači se vrlo brzo odavanje aktivne tvari, dok se na dijelu površine ne pokrivenim opnom zadržava nesmanjeno oslobađanje prema zakonu korijena-t, dotle dok zona osiromašenja dostigne zadnji sloj. Dodatna početna doza potječe dakle od površine koja leži ispod opne. Promjenama apsolutnih veličina površine spremnika i odnosa između površine opne i ukupne površine spremnika može se utjecati u širokim granicama na veličinu početne doze i doze primanja. On the surface that corresponds in its size to the membrane, the release of the active substance is withdrawn very quickly, while on the part of the surface not covered by the membrane, the release remains undiminished according to the law of the root-t, until the depletion zone reaches the last layer. The additional initial dose therefore originates from the surface that lies below the membrane. By changing the absolute sizes of the container surface and the relationship between the membrane surface and the total container surface, the size of the initial dose and the receiving dose can be influenced within wide limits.
Takvo ponašanje oslobađanja prirodno se može postići i tako, što se spremniku daje geometrija stupnjevitog oblika. Ali ovo ima nedostatak, što se takav sustav može teže izraditi i što na osnovu plastične sposobnosti oblikovanja uobičajenih formulacija spremnika takav sustav ne zadržava svoj izgled stupnjevitog oblika. Such release behavior can naturally be achieved by giving the tank a stepped geometry. But this has the disadvantage that such a system can be more difficult to manufacture and that, based on the plastic formability of common container formulations, such a system does not retain its stepped appearance.
Naročito je pogodno izvođenje 4.5, budući da velikim brojem rupa koje se nalaze u opni ne nastaju problemi postavljanja. Promjenom odnosa površine opne prema ukupnoj površini i izbor opni različite propustljivosti za aktivnu tvar, može se, kako se u slijedećem pokazuje, u širokim granicama utjecati na ponašanje oslobađanja sustava. Naročito je moguće davanje vrlo visokih početnih doza. Design 4.5 is particularly suitable, since the large number of holes in the membrane do not cause installation problems. By changing the ratio of the membrane surface to the total surface and choosing membranes with different permeability for the active substance, it is possible, as shown in the following, to influence the release behavior of the system within wide limits. In particular, it is possible to administer very high initial doses.
Slike 5a i 5b pokazuju u presjeku i u izgledu odozgo oblik izvođenja prema izumu, koji ima kombinaciju dviju različitih opni. Figures 5a and 5b show in section and in top view an embodiment according to the invention, which has a combination of two different membranes.
Naročito je oštroumna npr. kombinacija opne propustljivosti "0" s opnom veće propustljivosti. Takav sustav je pokazan na slici 5a. Sastoji se iz nepropusnog zadnjeg sloja 51, spremnika 52, opne s propustljivošću 0 za aktivnu tvar ili aktivne tvari 53, opne s propustljivošću većom od 0 za aktivnu ili aktivne tvari i ponovo odstanjivanje zaštitnog sloja 55. The combination of membrane permeability "0" with membrane of higher permeability, for example, is particularly clever. Such a system is shown in Figure 5a. It consists of an impermeable back layer 51, a container 52, a membrane with a permeability of 0 for the active substance or substances 53, a membrane with a permeability greater than 0 for the active substance or active substances, and again a separation of the protective layer 55.
Obje opne su još jednom pokazane na Slici 5b u izgledu odozgo. Opna s propustljivošću 0 mora prirodno po površini biti manja od površine ukupnog otpuštanja sustava i tako ograničava maksimalno otpuštanje aktivne tvari na dijelu površine ukupnog otpuštanja koji odgovara njenoj veličini, budući a udio aktivne tvari koji leži preko nje kroz nju ne može proći. Both membranes are once again shown in Figure 5b in top view. The membrane with a permeability of 0 must naturally be smaller in surface area than the surface of the total release of the system and thus limits the maximum release of the active substance on the part of the surface of the total release that corresponds to its size, since the part of the active substance lying over it cannot pass through it.
Opna s propustljivošću većom od 0 vodi na dijelu površine ukupnog otpuštanja koje njoj odgovara do otpuštanja aktivne tvari prema kinetici nultog ili prvog reda. A membrane with a permeability greater than 0 leads to the release of the active substance according to zero or first order kinetics on the part of the surface of the total release that corresponds to it.
Obje opne ne moraju unutar sustava obvezno ležati u istoj ravnini. Njihov točan položaj upravlja se prema svakim zahtjevima i dodatno sredstvo treba postići željeno ponašanje oslobađanja. Ako opna s propustljivošću 0 je bliže površini oslobađanja, može druga opna, a da se ne mijenja ponašanje oslobađanja, površinski biti isto toliko velika kao površina ukupnog otpuštanja, budući ona iznad nepropusne opne ne izaziva nikakvo djelovanje. Both diaphragms do not necessarily have to lie in the same plane within the system. Their exact position is controlled according to each requirement and an additional means should achieve the desired release behavior. If a membrane with a permeability of 0 is closer to the release surface, the other membrane, without changing the release behavior, can have a surface area as large as the total release surface, since the one above the impermeable membrane does not cause any action.
Na Slikama 6 i 7 je pokazano ponašanje oslobađanja takvih sustava s nepropusnom membranom-opnom za aktivnu tvar na primjeru skopolaminskog flastera. Za sve u slijedećem opisane uzorke vrijedi, da sadržaj aktivne tvari iznosi 450 μg/cm2 i površinska težina samoljepljivog spremnika 12,5 mg/cm2. Figures 6 and 7 show the release behavior of such systems with an impermeable membrane-membrane for the active substance on the example of a scopolamine patch. For all the samples described below, the content of the active substance is 450 μg/cm2 and the surface weight of the self-adhesive container is 12.5 mg/cm2.
Na Slici 6 je prikazan kumulirana oslobođena količina skopolamina kao funkcija vremena. Figure 6 shows the cumulative released amount of scopolamine as a function of time.
Krivulja I odgovara normalnom 2 cm2 velikom sustavu bez opne i služi kao usporedba. Curve I corresponds to a normal 2 cm2 large system without membrane and serves as a comparison.
Krivulja II odgovara 3 cm2 velikom sustavu, u čijem je spremniku integrirana nepropusna opna. Opna ima površinu od 1 cm2 i dijelu spremnik u sloj s težinom površine od 10,4 mg/cm2 i sloj s težinom površine od 2,1 mg/cm2. Curve II corresponds to a 3 cm2 large system, in the tank of which an impermeable membrane is integrated. The membrane has an area of 1 cm2 and divides the container into a layer with an area weight of 10.4 mg/cm2 and a layer with an area weight of 2.1 mg/cm2.
Krivulja III odgovara sustavu s ukupnom površinom od 4 cm2 i površinom opne od 2 cm2. Curve III corresponds to a system with a total area of 4 cm2 and a membrane area of 2 cm2.
Može se jasno uočiti ukupno više otpuštanja aktivne tvari sustava s opnom. Da se ovo povišeno otpuštanje aktivne tvari ograničava svakako samo na početnu fazu oslobađanja, može se bolje razaznati na Slici 7, kod koje količina otpuštanja po sustavu i satu navedena kao funkcija vremena tj. protoka. A total higher release of the active substance of the membrane system can be clearly observed. That this increased release of the active substance is certainly limited only to the initial release phase can be better seen in Figure 7, where the amount of release per system and hour is listed as a function of time, i.e. flow.
Ovaj sustav je također naročito dobro pogodan, kada se želi kombinirati relativno visoke početne doze sa ne bezuvjetno konstantnom dozom primanja. This system is also particularly well suited, when one wants to combine relatively high initial doses with a not unconditionally constant receiving dose.
Slike 8 i 9 pokazuju oblik izvođenja prema izumu s ograničeno propusnom opnom za aktivnu tvar na primjeru skopolaminskog flastera i pod istim uvjetima kao što je opisano kod slika 6 i 7. Kumulativno oslobađanje je predstavljeno na Slici 8 i protok na Slici 9. Krivulja I odnosno protok I odgovara 2 cm2 velikom sustavu, koji sadrži opnu iste veličine, /usporedba/krivulja II odnosno protok II odgovaraju 2,5 cm2 velikom sustavu sa 2 cm2 velikom opnom i krivulja III odnosno protok III odgovaraju 3 cm2 velikom sustavu sa 2 cm2 velikom opnom. Figures 8 and 9 show an embodiment according to the invention with a limited permeability membrane for the active substance on the example of a scopolamine patch and under the same conditions as described in Figures 6 and 7. Cumulative release is presented in Figure 8 and flow in Figure 9. Curve I, respectively flow I corresponds to a 2 cm2 large system, which contains a membrane of the same size, /comparison/curve II i.e. flow II corresponds to a 2.5 cm2 large system with a 2 cm2 large membrane and curve III i.e. flow III corresponds to a 3 cm2 large system with a 2 cm2 large membrane .
Također i sustav prema krivulji I i protoku I može otpuštati izvjesnu početnu dozu. Ova početna doza odgovara oslobađanju po zakonu korijena-t prema jednadžbi 1 i 2, koje se odigrava, dok zona osiromašenja aktivne tvari nije dostigla opnu. Also, the system according to curve I and flow rate I can release a certain initial dose. This initial dose corresponds to the release according to the root-t law according to equations 1 and 2, which takes place until the depletion zone of the active substance has reached the membrane.
Oba sustava s opnom, koji su površinski manji od površine oslobađanja sustava izum čine očiglednim, pokazuju pak, kako se jednostavno ova početna doza može povisiti. U ovom slučaju slijedi poslije početne doze konstantna doza primanja, čija visina zavisi od propustiljvosti opne i površine opne. Both membrane systems, which are smaller in surface area than the release surface of the system that makes the invention obvious, show how simply this initial dose can be increased. In this case, the initial dose is followed by a constant receiving dose, the height of which depends on the permeability of the membrane and the surface of the membrane.
Izrada sistema prema izumu koji su primjenjeni na Slikama 6 do 9 / uzorak /. Creation of the system according to the invention that is applied in Figures 6 to 9 / sample /.
230 g ljepila od poliakrilne smole / 50% u etil acetatu / 230 g of polyacrylic resin glue / 50% in ethyl acetate /
6 g skopolamin baze 6 g of scopolamine base
10 g Cetiol-a S 10 g of Cetiol S
50 g metanola 50 g of methanol
se stavi zajedno i smjesu homogenizira. Sa ovom smjesom se na 100 / u debelu silikoniziranu polietilensku foliju nanese 400 μ / film I / i 100 μ debeli / film II / i filmovi se suše na 50°C 15 minuta. Film I imao jeposlije sušenja površinsku težinu od 103 g/m2 i film II površinsku težinu od 21 g/m2. is put together and the mixture is homogenized. With this mixture, 400 μ / film I / and 100 μ thick / film II / are applied to 100 / thick siliconized polyethylene foil and the films are dried at 50°C for 15 minutes. After drying, film I had a surface weight of 103 g/m2 and film II a surface weight of 21 g/m2.
Na film II je nalijepljena kaširanjem opna sa kružnim otvorima odgovarajuće veličine i na to ponov film I. Silikonizirana poliesterska folija filma I je skinuta i zamijenjena 15 μ debelom nesilikoniziranom folijom. Film II was laminated with a membrane with circular openings of the appropriate size, and again film I. The siliconized polyester film of film I was removed and replaced with a 15 μ thick non-siliconized film.
Poslije toga su pojedinačni uzorci tako izrezivani, da se dobila ukupna odgovarajuća površina a da je otvor centralno ležao. After that, the individual samples were cut in such a way that the total corresponding surface was obtained and that the opening lay centrally.
Izvođenje oslobađanja in vitro In vitro release performance
Oslobađanje je izvedeno na 32°C po metodi Paddle-over-disk pomoću 50 ml fiziološke otopine kuhinjske soli. Za uzimanje uzorka je kompletno izmjenjena cjelokupna sredina oslobađanja i sadržaj mjeren HPLC metodom. The release was performed at 32°C by the Paddle-over-disk method using 50 ml of physiological saline solution. For taking the sample, the entire medium of release and the content measured by the HPLC method were completely changed.
Navod o najboljem načinu za privrednu upotrebu prijavljenog izuma Statement on the best way for commercial use of the reported invention
Najbolji način za privrednu upotrebu prijavljenog izuma, koji je prijavitelju bio poznat u vrijeme podnošenja ove patentne prijave jest da se izum primjenjuje na način iznijet u opisu, a sa konstrukcijom kakva je prikazana na crtežima. The best way for the commercial use of the reported invention, which was known to the applicant at the time of filing this patent application, is to apply the invention in the manner stated in the description, with the construction as shown in the drawings.
Claims (8)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3908431A DE3908431A1 (en) | 1989-03-15 | 1989-03-15 | TRANSDERMAL SYSTEM WITH STAGE SUBSTANCE DELIVERY AND USE FOR LOCAL OR SYSTEMIC DISPENSER |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP930662A2 true HRP930662A2 (en) | 1994-10-31 |
Family
ID=6376396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR930662A HRP930662A2 (en) | 1989-03-15 | 1993-04-01 | Process for the production of a transdermal therapeutic system gradually releasing an active substance |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0387693B1 (en) |
| JP (1) | JPH0693921B2 (en) |
| KR (1) | KR960005148B1 (en) |
| AT (1) | ATE143276T1 (en) |
| AU (1) | AU625402B2 (en) |
| CA (1) | CA2012123C (en) |
| CZ (1) | CZ284770B6 (en) |
| DD (1) | DD292383A5 (en) |
| DE (2) | DE3908431A1 (en) |
| DK (1) | DK0387693T3 (en) |
| ES (1) | ES2095216T3 (en) |
| FI (1) | FI901290A0 (en) |
| GR (1) | GR3022033T3 (en) |
| HR (1) | HRP930662A2 (en) |
| HU (1) | HU206991B (en) |
| IL (1) | IL93678A (en) |
| MY (1) | MY107420A (en) |
| NO (1) | NO300087B1 (en) |
| NZ (1) | NZ232895A (en) |
| PH (1) | PH26276A (en) |
| PL (1) | PL162693B1 (en) |
| PT (1) | PT93430B (en) |
| SI (1) | SI9010493B (en) |
| SK (1) | SK279357B6 (en) |
| YU (1) | YU48228B (en) |
| ZA (1) | ZA901941B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4341444C2 (en) * | 1993-12-04 | 1996-03-14 | Lohmann Therapie Syst Lts | Active substance-containing plaster and process for its production |
| WO1996008270A2 (en) * | 1994-09-13 | 1996-03-21 | Magainin Pharmaceuticals Inc. | Method for inhibiting sexually transmitted diseases using magaining antimicrobials or squalamine compounds |
| US5714162A (en) * | 1994-09-16 | 1998-02-03 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Scopolamine patch |
| DE4438989C2 (en) * | 1994-09-16 | 1999-02-25 | Lohmann Therapie Syst Lts | Scopolamine patches |
| DE19705138A1 (en) * | 1997-02-11 | 1998-08-13 | Lohmann Therapie Syst Lts | Stretchy transdermal therapeutic system |
| DE19733981A1 (en) * | 1997-08-06 | 1999-02-11 | Lohmann Therapie Syst Lts | Transdermal therapeutic system (TTS) for the delivery of active ingredient through the skin to an organism and method for application to the skin |
| DE19738643C2 (en) | 1997-09-04 | 2001-10-04 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with the active ingredient scopolamine base and process for its preparation |
| DE10056014A1 (en) * | 2000-11-11 | 2002-05-16 | Beiersdorf Ag | Laminated plaster with active substance, used as transdermal therapeutic system, has impermeable barrier layer on side away from skin and separable carrier layer with adhesive on side towards skin |
| DE10056012A1 (en) * | 2000-11-11 | 2002-05-16 | Beiersdorf Ag | Carrier material for medical applications, preferably for transdermal therapeutic system, has aluminum film between carrier and self-adhesive coating |
| DE102004020463A1 (en) * | 2004-04-26 | 2005-11-10 | Grünenthal GmbH | Drug delivery system consisting of a drug-containing patch and at least one Wirkstoffabgaberegulierungsmittel |
| ES2698049T3 (en) | 2011-04-04 | 2019-01-30 | Procter & Gamble | Article for home care |
| US9540602B2 (en) | 2011-08-15 | 2017-01-10 | The Procter & Gamble Company | Conformable personal care articles |
| US8795695B2 (en) | 2011-08-15 | 2014-08-05 | The Procter & Gamble Company | Personal care methods |
| CA2915920C (en) | 2013-06-27 | 2018-07-03 | The Procter & Gamble Company | Personal care articles |
| DE102018216244A1 (en) | 2018-09-24 | 2020-03-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system with barrier layer |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5755157A (en) * | 1980-09-19 | 1982-04-01 | Nitto Electric Ind Co | Drug member having transcataneous absorbing property |
| IE53703B1 (en) * | 1982-12-13 | 1989-01-18 | Elan Corp Plc | Drug delivery device |
| US4698062A (en) * | 1985-10-30 | 1987-10-06 | Alza Corporation | Medical device for pulsatile transdermal delivery of biologically active agents |
| US4666441A (en) * | 1985-12-17 | 1987-05-19 | Ciba-Geigy Corporation | Multicompartmentalized transdermal patches |
| DE3634016A1 (en) * | 1986-04-17 | 1987-10-29 | Lohmann Gmbh & Co Kg | AREA-BASED THERAPEUTIC SYSTEM, METHOD FOR THE PRODUCTION THEREOF AND ITS USE |
| ATE71287T1 (en) * | 1986-06-13 | 1992-01-15 | Alza Corp | ACTIVATION OF A TRANSDERMAL DRUG DELIVERY SYSTEM BY MOISTURE. |
| US4781924A (en) * | 1987-11-09 | 1988-11-01 | Alza Corporation | Transdermal drug delivery device |
-
1989
- 1989-03-15 DE DE3908431A patent/DE3908431A1/en active Granted
-
1990
- 1990-03-07 PH PH40155A patent/PH26276A/en unknown
- 1990-03-07 AU AU50765/90A patent/AU625402B2/en not_active Ceased
- 1990-03-07 MY MYPI90000358A patent/MY107420A/en unknown
- 1990-03-08 IL IL9367890A patent/IL93678A/en not_active IP Right Cessation
- 1990-03-08 ES ES90104406T patent/ES2095216T3/en not_active Expired - Lifetime
- 1990-03-08 SK SK1136-90A patent/SK279357B6/en unknown
- 1990-03-08 DK DK90104406.5T patent/DK0387693T3/en active
- 1990-03-08 AT AT90104406T patent/ATE143276T1/en not_active IP Right Cessation
- 1990-03-08 DE DE59010514T patent/DE59010514D1/en not_active Expired - Fee Related
- 1990-03-08 EP EP90104406A patent/EP0387693B1/en not_active Expired - Lifetime
- 1990-03-08 CZ CS901136A patent/CZ284770B6/en unknown
- 1990-03-09 NO NO901128A patent/NO300087B1/en not_active IP Right Cessation
- 1990-03-12 JP JP2058241A patent/JPH0693921B2/en not_active Expired - Fee Related
- 1990-03-13 HU HU901422A patent/HU206991B/en not_active IP Right Cessation
- 1990-03-13 NZ NZ232895A patent/NZ232895A/en unknown
- 1990-03-13 DD DD90338650A patent/DD292383A5/en unknown
- 1990-03-14 ZA ZA901941A patent/ZA901941B/en unknown
- 1990-03-14 KR KR1019900003563A patent/KR960005148B1/en not_active IP Right Cessation
- 1990-03-14 SI SI9010493A patent/SI9010493B/en unknown
- 1990-03-14 PL PL28430190A patent/PL162693B1/en unknown
- 1990-03-14 CA CA002012123A patent/CA2012123C/en not_active Expired - Fee Related
- 1990-03-14 YU YU49390A patent/YU48228B/en unknown
- 1990-03-14 PT PT93430A patent/PT93430B/en not_active IP Right Cessation
- 1990-03-15 FI FI901290A patent/FI901290A0/en not_active Application Discontinuation
-
1993
- 1993-04-01 HR HR930662A patent/HRP930662A2/en not_active Application Discontinuation
-
1996
- 1996-12-13 GR GR960403458T patent/GR3022033T3/en unknown
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