CS277375B6 - Matrix for percutaneous application of glycerol trinitrate by transdermal therapeutic system - Google Patents
Matrix for percutaneous application of glycerol trinitrate by transdermal therapeutic system Download PDFInfo
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- CS277375B6 CS277375B6 CS911408A CS140891A CS277375B6 CS 277375 B6 CS277375 B6 CS 277375B6 CS 911408 A CS911408 A CS 911408A CS 140891 A CS140891 A CS 140891A CS 277375 B6 CS277375 B6 CS 277375B6
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- matrix
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- glycerol trinitrate
- transdermal therapeutic
- release
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- 239000011159 matrix material Substances 0.000 title claims description 30
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 title claims description 19
- 230000001225 therapeutic effect Effects 0.000 title claims description 17
- 229920001577 copolymer Polymers 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 229920000249 biocompatible polymer Polymers 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 description 30
- 229940079593 drug Drugs 0.000 description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 3
- 239000002131 composite material Substances 0.000 description 2
- 238000013267 controlled drug release Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 241000283707 Capra Species 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical class CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- NNKAHFKLYXCFDQ-UHFFFAOYSA-N [diethoxy(triethoxysilyloxy)silyl] diethyl triethoxysilyl silicate Chemical compound CCO[Si](OCC)(OCC)O[Si](OCC)(OCC)O[Si](OCC)(OCC)O[Si](OCC)(OCC)OCC NNKAHFKLYXCFDQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- AYOHIQLKSOJJQH-UHFFFAOYSA-N dibutyltin Chemical compound CCCC[Sn]CCCC AYOHIQLKSOJJQH-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
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Description
Matrica pre perkutánnu aplikáciu glyceroltrinitrátu transdermálnym terapeutickým systémemMatrix for percutaneous administration of glycerol trinitrate by transdermal therapeutic system
Oblast technikyField of technology
Vynález sa týká matrice pre perkutánnu aplikáciu glyceroltrimetrátu transdermálnym terapeutickým systémom.The invention relates to a matrix for the percutaneous administration of glycerol trimeter by a transdermal therapeutic system.
Doterajší stav technikyPrior art
Na liečenie róznych foriem ischemickej choroby srdca sa ako jedny z najdlhšie používaných liečiv používajú organické nitráty polyhydrických alkoholov, z nich predovšetkým glyceroltrinitrát. Glyceroltrinitrát sa po perorálnom podaní z gastrointestinálneho traktu rýchlo absorbuje, ale pre jeho značné aktívny metabolizmus je jeho biologická dostupnost velmi nízká (Cossum, P.A., Roberts, M.S.. Eur.J.Clin.Pharmacol. 29, 169/1985).Organic nitrates of polyhydric alcohols, especially glycerol trinitrate, are used as one of the longest used drugs for the treatment of various forms of ischemic heart disease. Glycerol trinitrate is rapidly absorbed from the gastrointestinal tract after oral administration, but its bioavailability is very low due to its extensive active metabolism (Cossum, P.A., Roberts, M.S., Eur.J.Clin.Pharmacol. 29, 169/1985).
Niektoré nevýhody perorálneho podania glyceroltrimitrátu, predovšetkým jeho first -pass effect, je možné odstranit jeho perkutánnou aplikáciou, pričom sa dosiahne tiež predlženého účinku liečiva. Na transdermálne podanie glyceroltrinitrátu sa používajú masti a krémy (Fung, H.L. : Z.Kardiol. 74 Suppl. 4,4 /1985). Nezaručujú však rovnoměrné uvolňovanie liečiva, problematické je tiež vymedzenie plochy, na ktorú sa aplikujú a tiež hrúbka vrstvy nanesená na kožu móže značné kolísat. Preto sa na transdermálnu aplikáciu glyceroltrinitrátu vyvinuli transdermálne terapeutické systémy umožňujúce kontinuálnu perkutánnu aplikáciu liečiva, ktoré sa z nich uvolňuje stanovenou rýchlostou a absorbuje v krvnom oběhu (Good,W.R.: Drug Dev. Ind.Pharm. 9, 674 /1983/, Berner,B.: J.Pharm. Sci. 74, 718 /1985/). Dlhodobý účinok liečiva umožňuje znížit potrebnú frekvenciu aplíkácie přípravku, čo má priamy vztah k tzv. patients compliance (HeoIman, K.: Dtsch. Apoth. Ztg. 123, 1145 /1983/). Výhodou je tiež skutočnost, že transdermálne terapeutické systémy sú schopné uvolňovat liečivo stálou rýchlostou podlá kinetiky nultého poriadku (Pirottr, B., Jaminet, F.:J.Pharm. Belg. 39, 125 /1984/; čs. autorské osvedčenie č. 261 105). Preto sa transdermálna aplikácia glyceroltrinitrátu pomocou transdermálnych terapeutických systémov sa zařadila medzi mimoriadne cenný spósob podania tohto liečiva.Some disadvantages of oral administration of glycerol trimitrate, in particular its first-pass effect, can be eliminated by its percutaneous administration, while also achieving a prolonged drug effect. Ointments and creams are used for transdermal administration of glycerol trinitrate (Fung, H.L.: Z. Cardiol. 74 Suppl. 4.4 / 1985). However, they do not guarantee an even release of the drug, it is also problematic to define the area to which they are applied and also the thickness of the layer applied to the skin can vary considerably. Therefore, for the transdermal administration of glycerol trinitrate, transdermal therapeutic systems have been developed that allow continuous percutaneous administration of a drug that is released from them at a predetermined rate and absorbed into the bloodstream (Good, WR: Drug Dev. Ind. Pharm. 9, 674 (1983), Berner, B .: J. Pharm. Sci. 74, 718 (1985)). The long-term effect of the drug makes it possible to reduce the required frequency of application of the preparation, which is directly related to the so-called patient compliance (HeoIman, K .: Dtsch. Apoth. Ztg. 123, 1145 (1983)). Another advantage is the fact that transdermal therapeutic systems are able to release the drug at a constant rate according to zero order kinetics (Pirottr, B., Jaminet, F.:J.Pharm. Belg. 39, 125 (1984); Czech Author's Certificate No. 261 105). Therefore, transdermal administration of glycerol trinitrate using transdermal therapeutic systems has become one of the most valuable routes of administration for this drug.
Je známy celý rad patentových spisov týkajúcich sa transdermálnych terapeutických systémov, ktoré móžu byt rozličného typu (Eur.Pat.Appl. EP 113.562; Eur.Pat.Appl. EP 250.125; Ger.Offen. De 3.319.469; Ger.Offen. DE 3.629.304; Eur.Pat.Appl. EP 328.806). V klinickej praxi sa používá viacero hromadné vyrábaných transdermálnych terapeutických systémov, zaručujúcich riadené uvolňovanie glyceroltrinitrátu v priebehu 24 hod.A number of patents are known for transdermal therapeutic systems, which can be of various types (Eur.Pat.Appl. EP 113.562; Eur.Pat.Appl. EP 250.125; Ger.Offen. De 3.319.469; Ger.Offen. DE 3,629,304; Eur.Pat.Appl EP 328,806). In clinical practice, several mass-produced transdermal therapeutic systems are used, ensuring controlled release of glycerol trinitrate within 24 hours.
Bežne sa transdermálne terapeutické systémy delia do skupiny systémov membránových, matricových, připadne zmiešaných (Lippold, B.H.. Pharm.Ind.49, 1295/1987/; Banakar, U.V.. Pharmazie 45, 121/1990/). Súčasná tendencia však upřednostňuje matricové transdermálne terapeutické systémy, ktorých přípravu je možné lepšie štandarizovat (Belg.Pat. 899.444).Conventionally, transdermal therapeutic systems are divided into a group of membrane, matrix, or mixed systems (Lippold, B.H. Pharm. Ind. 49, 1295 (1987); Banakar, U.. Pharmazie 45, 121 (1990)). However, the current trend is to favor matrix transdermal therapeutic systems, the preparation of which can be better standardized (Belg. Pat. 899,444).
US patentový spis 3.742.951 popisuje trojvrstevný matricový systém pre transdermálne podanie vazodilatačných látok. Skládá sa z ochrannéj vrstvy, matrice, ktorá riadi uvolňovanie liečiva a z lepívej vrstvy, ktorou sa transdermálny terapeutický systém upevní na kozu . .U.S. Pat. No. 3,742,951 discloses a three-layer matrix system for transdermal delivery of vasodilators. It consists of a protective layer, a matrix that controls drug release, and an adhesive layer that secures the transdermal therapeutic system to the goat. .
Matrica pre transdermálny terapeutický systém je tvořená biokompatibilným polymérom, ktorý má vyhovujúce mechanické vlastnosti a dostatočnú tvarovaciu schopnost. Samotná matrica však nie je schopná riadit uvoíňovanie glyceroltrinitrátu. Kladeného uvolňovania je možné dosiahnut modifikováním jej zloženia, například použitím pomocných látok ako kompozitných súčastí matrice.The matrix for the transdermal therapeutic system is formed of a biocompatible polymer that has satisfactory mechanical properties and sufficient molding ability. However, the matrix alone is not able to control the release of glycerol trinitrate. Sustained release can be achieved by modifying its composition, for example by using excipients as composite matrix components.
Podstata vynálezuThe essence of the invention
Matrica pre perkutálnu aplikáciu glyceroltrinitrátu transdermálnym terapeutickým systémem podlá vynálezu pozostáva z nosiča a samotného glyceroltrinitrátu a jej podstata spočívá v tom, že glyceroltrinitrát adsorbovaný na laktózu pozostáva z mikropeliet o strednej velkosti častíc od 100 do 900 um obalených disperziou kopolymérov esterov kyseliny akrylovej a metakrylovej v množstve 10 až 50 % hmot.The matrix for percutaneous administration of glycerol trinitrate by the transdermal therapeutic system according to the invention consists of a carrier and glycerol trinitrate itself and consists in that glycerol trinitrate adsorbed on lactose consists of micropellets with a mean particle size of 100 to 900 μm coated with a dispersion of copolymers 10 to 50 wt.
Středná velkost častíc mikropeliet sa pohybuje od 100 um do 900 um. .The average particle size of the micropellets ranges from 100 μm to 900 μm. .
Mikropelety sa s výhodou pripravia fluidnou technológiou umožňujúcou přípravu peliet s homogénnou disperziou (Baluch,J., Rak,J., Ďucková,K.; Farm.obzor. 55, 539 (1986)).The micropellets are preferably prepared by fluid technology enabling the preparation of pellets with a homogeneous dispersion (Baluch, J., Rak, J., Duckova, K .; Farm.obzor. 55, 539 (1986)).
V priebehu uvolňovania dochádza pri styku matrice s hydrofílnym akceptorovým médiom k napučiavaniu polymérneho filmu mikropeliet, k úpravě procesu uvolňovania, výsledkom čoho je riadené uvolňovanie liečiva. Potvrdili to výsledky skúšok uvolňovania glyceroltrinitrátu z matric podlá vynálezu, zistenej in vitro metodou za použitia modifikovaného prístroja podia Keshary a spol. (Keshary,P.R., Huang,Y.C., Chien,Y.W.: Drug.Develop.Ind.Pharm. 11, 1213 (1985) ). Množstvo liečiva uvolněného do fosforečnanového tlmivého roztoku s pH 7,4 sa v intervaloch 1 až 24 hod. stanovilo spektrofotometricky. Výsledky uvolňovania liečiva sa hodnotili pomocou Tornquistovej hyperbolickéj funkcie (Kučera,J., Heinrich,J., Ducková,K.. Pharmazie 45, 635 (1990)), najma na základe regresného parametra T (h) (čas, za ktorý sa uvolní polovica z kumulatívneho množstva liečiva v čase t = oo).During release, upon contact of the matrix with the hydrophilic acceptor medium, the polymer film of the micropellets swells, modifying the release process, resulting in controlled drug release. This was confirmed by the results of glycerol trinitrate release assays from the matrices of the invention, determined in vitro by a modified apparatus according to Keshara et al. (Keshary, P.R., Huang, Y.C., Chien, Y.W .: Drug.Develop.Ind.Pharm. 11, 1213 (1985)). The amount of drug released into the phosphate buffer pH 7.4 was determined spectrophotometrically at intervals of 1 to 24 hours. Drug release results were evaluated using the Tornquist hyperbolic function (Kučera, J., Heinrich, J., Ducková, K., Pharmazie 45, 635 (1990)), mainly on the basis of the regression parameter T (h) (time taken to release half of the cumulative amount of drug at time t = oo).
Na základe získaných výsledkov sa skutočne ukázalo, že k riadenému uvolňovaniu liečiva dochádza vtedy, ak sa použije glyceroltrinitrát vo forme mikropeliet obalených makromolekulovou látkou zo skupiny derivátou kyseliny metakrylovej.Indeed, the results obtained show that controlled drug release occurs when glycerol trinitrate is used in the form of micropellets coated with a macromolecular methacrylic acid derivative.
Výhodou matric podlá vynálezu je skutečnost, že rýchlost uvolňovania možno riadit množstvom filmotvornej látky použitej pri fluidnom obalovaní, teda úpravou hrůbky obalu mikropeliet. So stúpajúcou hmotnostou obalu sa rýchlost uvolňovania liečiva ustáli a jeho uvolňovací profil sa blíži kinetike nultého poriadku. Svedčia o tom vypočítané hodnoty regresného parametra T, ktoré sa pohybovali od 3,48 (h) do 7,5 (h). Množstvo liečiva uvolněného z matric sa pohybovalo od 418 μg/cm2/24 h do 915 μg/cm2/24 h v závislosti od koncentrácie liečiva a hrůbky obalu mikropeliet, čo sú mnozstvá přijatelné i z hladiska terapeutického. Představuje to od·'47 % do 70 % uvolněného liečiva, čo je koncentrácia dostatočná k tomu, aby v matrici ostalo množstvo liečiva postačujúce k zachovaniu koncentračného spádu potřebného na stále rovnoměrné uvolňovanie liečiva.An advantage of the matrices according to the invention is the fact that the release rate can be controlled by the amount of film-forming substance used in the fluid coating, i.e. by adjusting the coating thickness of the micropellets. As the weight of the package increases, the rate of drug release has stabilized and its release profile approaches zero order kinetics. This is evidenced by the calculated values of the regression parameter T, which ranged from 3.48 (h) to 7.5 (h). The amount of drug released from the matrix is varied from 418 mcg / cm 2/24 h to 915 micrograms / cm2 / 24 h, depending on the drug concentration and the coating thickness micropellets, which are acceptable from the standpoint amount of therapeutic. This represents from 47% to 70% of the drug released, which is a concentration sufficient to leave enough drug in the matrix to maintain the concentration gradient required for steady drug release.
Z dosiahnutých výsledkov uvolňovania teda vyplývá, že matrica podlá vynálezu, ktorá obsahuje liečivo vo forme mikropeliet je schopná ho uvolňoval: stálou rýchlostou. Matricu tak možno využit na formuláciu transdermálneho terapeutického, systému umožňujúceho kontinuálnu perkutánnu aplikáciu liečiva s jeho absorpciou v krvnom oběhu. Výhodou v porovnaní s doslal používanými transdermálnymi terapeutickými systémami je velmi jednoduchá příprava matrice vzhladom na použité suroviny aj výrobné zariadenia. Rozhodujúcim momentom je pri tom možnost riadenia rýchlosti uvolňovania jednoduchou technologickou úpravou liečiva- změnou hmotnosti obalu mikropeliet. Celkové množstvo aplikovaného liečiva je teda štruktúrou matrice, ale najma technologickou úpravou samotného liečiva. Výhodou je aj skutočnost, že matrica obsahuje iba mikropelety liečiva a žiadne pomocné látky.Thus, the release results obtained show that the matrix according to the invention, which contains the drug in the form of micropellets, is able to release it: at a constant rate. The matrix can thus be used to formulate a transdermal therapeutic system enabling continuous percutaneous administration of the drug with its absorption into the bloodstream. The advantage compared to previously used transdermal therapeutic systems is the very simple preparation of the matrix with respect to the raw materials used and the production equipment. The decisive moment is the possibility of controlling the release rate by a simple technological modification of the drug - by changing the weight of the micropellet package. The total amount of drug applied is thus the structure of the matrix, but especially the technological modification of the drug itself. Another advantage is that the matrix contains only drug micropellets and no excipients.
Příklady uskutočňovania vynálezuExamples of embodiments of the invention
Příklad 1Example 1
Matrica sa připraví vulkanizáciou nosiča, kterým je a, aj - dihydroxypolydimetylsiloxan-silikónový kaučuk typu Lukoprén N, viskozity 2.000 mPa.s približnej molekulovéj hmotnosti 40.000 g/mol po zmiešaní s mikropeletami liečiva (glyceroltrinitrát adsorbovaný na laktózu) o strednej velkosti častíc 100 μη, ktorých obal je tvořený 20 % hmot. filmotvornej látky, ktorou je kopolymér esterov kyseliny akrylovej a metakrylovej. Mikropelety sa pridajú v takom množstve, aby celkový obsah glyceroltrinitrátu v matrici bol 5 mg. Disperzia Lukoprénu N s mikropeletami liečiva po přidaní sietovadla 3 % hmot, dekaetoxytetrasiloxanu a katalyzátore 1 % hmot, dibutylcín dilauranu sa naleje do formy, kde sa v priebehu 24 hodin zosieůuje. Zložený vulkanizát sa připraví vo forme asi 0,6 mm tenkých doštičiek, z ktorých sa vykrojí matrica. Z matrice sa uvolnilo 915 μg/cm2/24 h liečiva. .The matrix is prepared by vulcanizing a support which is α, α-dihydroxypolydimethylsiloxane-silicone rubber of the Lukopren N type, viscosity 2,000 mPa.s with an approximate molecular weight of 40,000 g / mol after mixing with drug micropellets (glycerol trinitrate adsorbed on lactose) of medium size, whose packaging consists of 20% by weight. a film-forming agent which is a copolymer of acrylic and methacrylic acid esters. The micropellets are added in such an amount that the total glycerol trinitrate content of the matrix is 5 mg. A dispersion of Lukoprene N with drug micropellets after the addition of a 3% by weight crosslinker, decaethoxytetrasiloxane and a 1% by weight catalyst, dibutyltin dilaurane is poured into a mold where it crosslinks within 24 hours. The composite vulcanizate is prepared in the form of about 0.6 mm thin plates from which the matrix is cut. From the matrix is released 915 micrograms / cm2 / 24 h drug. .
Příklad 2Example 2
Postup přípravy matrice ako v příklade 1, použijú sa však mikropelety, ktorých obal je tvořený 30 % hmot, filmotvornej látky (kopolymér esterov kyseliny akrylovej a metakrylovej). Z matrice sa uvolnilo 852 μg/cm2/24 h liečiva. 'However, the matrix preparation procedure as in Example 1 uses micropellets, the coating of which consists of 30% by weight, of a film-forming substance (copolymer of acrylic and methacrylic acid esters). From the matrix is released 852 micrograms / cm2 / 24 h drug. '
Příklad 3Example 3
Postup přípravy matrice ako v příklade 1, použijú sa však mikropelety, ktorých obal je tvořený 40 % hmot, filmotvornej látky (kopolymér esterov kyseliny akrylovej a metakrylovej). Z matrice sa uvolnilo 655 μg/cm2/24 h liečiva.However, the matrix preparation procedure as in Example 1 uses micropellets, the coating of which consists of 40% by weight, of a film-forming substance (copolymer of acrylic and methacrylic acid esters). From the matrix is released 655 micrograms / cm2 / 24 h drug.
Příklad 4Example 4
Postup přípravy matrice ako v příklade 1, použijú sa však mikropelety, ktorých obal je tvořený 50 % hmot, filmotvornej látky (kopolymér esterov kyseliny akrylovéj a metakrylovej). Z matrice sa uvolnilo 615 μg/cm2/24 h liečiva.However, the process for preparing the matrix as in Example 1 uses micropellets, the coating of which consists of 50% by weight, of a film-forming substance (copolymer of acrylic and methacrylic acid esters). From the matrix is released 615 micrograms / cm2 / 24 h drug.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS911408A CZ140891A3 (en) | 1991-05-14 | 1991-05-14 | matrix for percutaneous application of glycerol trinitrate by transdermal therapeutic system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS911408A CZ140891A3 (en) | 1991-05-14 | 1991-05-14 | matrix for percutaneous application of glycerol trinitrate by transdermal therapeutic system |
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| Publication Number | Publication Date |
|---|---|
| CS277375B6 true CS277375B6 (en) | 1993-01-13 |
| CZ140891A3 CZ140891A3 (en) | 1993-01-13 |
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| Country | Link |
|---|---|
| CZ (1) | CZ140891A3 (en) |
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1991
- 1991-05-14 CZ CS911408A patent/CZ140891A3/en unknown
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| Publication number | Publication date |
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| CZ140891A3 (en) | 1993-01-13 |
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