Pharmaceutical Sustained-release Excipients

01 Cellulose ether

Cellulose e ka aroloa ka li-ether tse le 'ngoe le li-ether tse tsoakiloeng ho latela mofuta oa li-substitute. Ho na le mofuta o le mong feela oa sebaka sa ether e le 'ngoe, e kang methyl cellulose (MC), ethyl cellulose (EC), hydroxyl Propyl cellulose (HPC), joalo-joalo; ho ka ba le li-substituents tse peli kapa ho feta ho ether e tsoakiloeng, e sebelisoang hangata ke hydroxypropyl methyl cellulose (HPMC), ethyl methyl cellulose (EMC), joalo-joalo. Li-excipients tse sebelisoang ha ho etsoa litokisetso tsa lithethefatsi tse hlahisoang ke pulse li emeloa ke ether e tsoakiloeng HPMC, single ether HPC, le EC, tse atisang ho sebelisoa e le li-disintegrants, mahlahana a ho ruruha, li-retarders le lisebelisoa tsa ho roala filimi.

1.1 Hydroxypropylmethylcellulose (HPMC)

Ka lebaka la likarolo tse fapaneng tsa ho fetola lihlopha tsa methoxy le hydroxypropyl, HPMC ka kakaretso e arotsoe ka mefuta e meraro linaheng tse ling: K, E le F. Har'a tsona, letoto la K le na le lebelo le potlakileng la hydration 'me le loketse e le lisebelisoa tsa skeleton bakeng sa ts'ehetso le ho laoloa. tokollo litokisetso. Hape ke moemeli oa ho lokolla pelo. E 'ngoe ea lijari tsa lithethefatsi tse sebelisoang ka ho fetisisa litokisetsong tsa meriana. HPMC ke ether e qhibilihang ka metsing e seng ionic cellulose, phofo e tšoeu, e sa latsoeheng, e sa nkheng ebile e se chefo, 'me e ntšoa ntle le phetoho leha e le efe 'meleng oa motho. Ha e le hantle ha e qhibilihe metsing a chesang a fetang 60°C mme e ka ruruha feela; ha li-derivatives tsa eona tse nang le li-viscosity tse fapaneng li tsoakane ka likarolo tse fapaneng, kamano ea linear e ntle, 'me gel e entsoeng e ka laola ka katleho ho ata ha metsi le ho lokolloa ha lithethefatsi.

HPMC ke e 'ngoe ea lisebelisoa tsa polymer tse sebelisoang hangata tse ipapisitseng le ho ruruha kapa khoholeho ea mobu e laoloang ke mokhoa oa tokollo ea lithethefatsi tsamaisong ea pulse release. Ho lokolloa ha lithethefatsi tsa ho ruruha ke ho lokisetsa metsoako e sebetsang ea meriana ka matlapa kapa li-pellets, ebe ho roala ka mekhahlelo e mengata, lesela le ka ntle ke lesela la polymer le ke keng la qhibiliha empa le kenngoa ka metsi, lesela le ka hare ke polymer e nang le bokhoni ba ho ruruha, ha mokelikeli o kenella ka hare. lera le ka hare, ho ruruha ho tla hlahisa khatello, 'me ka mor'a nako e itseng, sethethefatsi se tla ruruha' me se laoloe ho lokolla lithethefatsi; ha sethethefatsi se lokollang khoholeho se le ka har'a sephutheloana sa lithethefatsi tsa mantlha. Ho roala ka li-polymers tse sa keneng metsi kapa tsa khoholeho ea mobu, ho lokisa botenya ba ho roala ho laola nako ea ho lokolloa ha lithethefatsi.

Bafuputsi ba bang ba entse lipatlisiso ka litšobotsi tsa tokollo le katoloso ea matlapa a thehiloeng ho hydrophilic HPMC, mme ba fumane hore sekhahla sa tokollo se lieha ho feta makhetlo a 5 ho feta matlapa a tloaelehileng mme se na le keketseho e kholo.

Ho ntse ho e-na le mofuputsi oa ho sebelisa pseudoephedrine hydrochloride e le moriana oa mohlala, ho sebelisa mokhoa o omileng oa ho roala, ho lokisa lesela le nang le HPMC ea li-viscosities tse fapaneng, ho lokisa ho lokolloa ha meriana. Liphetho tsa liteko tsa vivo li bonts'itse hore tlas'a botenya bo ts'oanang, HPMC e nang le viscosity e tlase e ka fihla tlhorong ea 5h, ha HPMC e nang le viscosity e phahameng e fihletse tlhoro ea mahloriso hoo e ka bang 10h. Sena se fana ka maikutlo a hore ha HPMC e sebelisoa e le thepa ea ho roala, viscosity ea eona e na le phello e kholo boitšoarong ba ho lokolloa ha lithethefatsi.

Bafuputsi ba sebelisitse verapamil hydrochloride e le sethethefatsi sa mohlala ho lokisa matlapa a mabeli a likarolo tse tharo, 'me ba etsa lipatlisiso ka litekanyetso tse fapaneng tsa HPMC K4M (15%, 20%, 25%, 30%, 35%, w/w; 4M. e bua ka phello ea viscosity (4000 centipoise) ka nako ea nako Liphetho li bontša hore ka keketseho ea palo ea HPMC K4M, nako ea nako e behiloe lihora tse 4 ho isa ho tse 5, kahoo HPMC K4M dikahare li ikemiseditse ho ba 25%. Sena se bontša hore HPMC e ka lieha ho lokolloa ha moriana oa mantlha ka ho thibela lithethefatsi ho kopana le mokelikeli le ho phetha karolo ea ho lokolloa ho laoloang.

1.2 Hydroxypropylcellulose (HPC)

HPC e ka aroloa ka karolo e tlase ea hydroxypropyl cellulose (L-HPC) le hydroxypropyl cellulose e phahameng (H-HPC). L-HPC ke phofo e seng ea ionic, e tšoeu kapa e bosoeu, ha e na monko ebile ha e latsoehe, 'me e na le lintho tse tsoang ho cellulose tse mahareng tse se nang chefo tse se nang kotsi 'meleng oa motho. Hobane L-HPC e na le sebaka se seholo sa holim'a metsi le porosity, e khona ho monya metsi ka potlako le ho ruruha, 'me sekhahla sa eona sa ho ata ha metsi ke 500-700%. E kene ka har'a mali, kahoo e ka khothalletsa ho lokolloa ha lithethefatsi ka har'a letlapa la li-multi-layer le pellet core, le ho ntlafatsa haholo phello ea phekolo.

Ka matlapa kapa li-pellets, ho eketsa L-HPC ho thusa mokokotlo oa letlapa (kapa pellet core) ho atoloha ho hlahisa matla a ka hare, a senyang lesela la ho roala ebe o ntša lithethefatsi ka pulse. Bafuputsi ba ile ba sebelisa sulpiride hydrochloride, metoclopramide hydrochloride, diclofenac sodium, le nilvadipine e le lithethefatsi tsa mohlala, le hydroxypropyl cellulose (L-HPC) e tlaase e nkeloang sebaka e le moemeli ea senyang. Liteko li bontšitse hore botenya ba lera la ho ruruha le khetholla boholo ba likaroloana. nako ea morao.

Bafuputsi ba sebelisitse lithethefatsi tsa antihypertensive e le ntho ea boithuto. Tekong ena, L-HPC e ne e le teng ka har'a matlapa le li-capsules, e le hore li monye metsi ebe li senya ho lokolla lithethefatsi kapele.

Bafuputsi ba ile ba sebelisa li-pellets tsa terbutaline sulfate e le lithethefatsi tsa mohlala, 'me liphetho tsa liteko tsa pele li bontšitse hore ho sebelisa L-HPC e le thepa ea lera le ka hare la ho roala le ho eketsa SDS e loketseng lera la ho roala ka hare ho ka finyella phello e lebelletsoeng ea ho lokolloa ha pulse.

1.3 Ethyl cellulose (EC) le ho hasana ha eona ka metsi (ECD)

EC ke cellulose alkyl ether e se nang ionic, e nang le metsi a se nang metsi, e nang le litšobotsi tsa ho hanyetsa lik'hemik'hale, ho hanyetsa letsoai, ho hanyetsa alkali le botsitso ba mocheso, 'me e na le mefuta e mengata ea viscosity (boima ba molek'hule) le ts'ebetso e ntle ea liaparo , e ka theha ho roala lera ka toughness e ntle 'me ha ho bonolo ho apara, e leng se etsang hore ho pharaletseng sebelisoa ka lithethefatsi tsitsitseng le ho laoloa ho lokolloa filimi barbotage.

ECD ke tsamaiso e sa tšoaneng eo ethyl cellulose e fanyehang ka har'a dispersant (metsi) ka mokhoa oa likaroloana tse nyenyane tsa colloidal 'me e na le botsitso bo botle ba' mele. Polima e qhibilihang ka metsing e sebetsang e le ntho e etsang pore e sebelisetsoa ho lokisa sekhahla sa ho lokolloa ha ECD ho finyella litlhoko tsa tokollo e tsitsitseng ea lithethefatsi bakeng sa litokisetso tsa tokollo e tsitsitseng.

EC ke sesebelisoa se loketseng ho lokisoa ha li-capsules tse sa qhibilihang ka metsing. Bafuputsi ba sebelisitse dichloromethane / absolute ethanol / ethyl acetate (4 / 0.8 / 0.2) e le solvent le EC (45cp) ho lokisetsa 11.5% (w / v) tharollo ea EC , ho lokisa 'mele oa EC capsule, le ho lokisa capsule ea EC e sa phekoleheng. ho fihlella ditlhoko tsa phepelo ya molomo. Bafuputsi ba sebelisitse theophylline e le sethethefatsi sa mohlala ho ithuta ka nts'etsopele ea tsamaiso ea methapo e mengata e koahetsoeng ka ethyl cellulose aqueous dispersion. Liphetho li bontšitse hore mofuta oa Aquacoat® ho ECD o ne o fokola 'me o le bonolo ho robeha, ho netefatsa hore moriana o ka lokolloa ka sekhahla.

Ntle le moo, bafuputsi ba ile ba ithuta ka li-pellets tse laoloang ke pulse tse lokiselitsoeng ka ethyl cellulose aqueous disspersion joalo ka lera la ho koaela kantle. Ha phaello ea boima ba lesela la ho roala ka ntle e ne e le 13%, ho lokolloa ha lithethefatsi ho ile ha finyelloa ka nako ea lihora tse 5 le nako ea 1.5 h. Ho feta 80% ea phello ea pulse release.

02 Resin ea Acrylic

Acrylic resin ke mofuta oa motsoako oa polymer o entsoeng ka copolymerization ea acrylic acid le methacrylic acid kapa li-ester tsa tsona ka tekanyo e itseng. Resin ea acrylic e sebelisoang ka tloaelo ke Eudragit e le lebitso la eona la khoebo, e nang le thepa e ntle ea ho etsa lifilimi 'me e na le mefuta e fapaneng e kang gastric-soluble E mofuta, enteric-soluble L, mofuta oa S, le RL le RS e sa qhibiliheng metsing. Hobane Eudragit e na le melemo ea ts'ebetso e ntle ea ho etsa lifilimi le tšebelisano e ntle har'a mefuta e fapaneng, e 'nile ea sebelisoa haholo ho koahela lifilimi, litokisetso tsa matrix, microspheres le mekhoa e meng ea ho ntša pulse.

Bafuputsi ba sebelisitse nitrendipine e le sethethefatsi sa mohlala le Eudragit E-100 e le mothusi oa bohlokoa ho lokisa li-pellets tse utloang pH, le ho lekola bioavailability ea tsona ho lintja tse phetseng hantle. Liphetho tsa phuputso li fumane hore sebopeho sa mahlakore a mararo sa Eudragit E-100 se nolofalletsa hore e lokolloe ka potlako nakong ea metsotso e 30 tlas'a maemo a acidic. Ha li-pellets li le pH 1.2, nako ea nako ke lihora tse 2, pH 6.4, nako ea nako ke lihora tse 2, 'me ho pH 7.8, nako ea nako ke lihora tse 3, e ka khonang ho hlokomela tsamaiso e laoloang ea tokollo ka har'a pampiri ea mala.

Bafuputsi ba ile ba etsa likarolelano tsa 9: 1, 8: 2, 7: 3 le 6: 4 ho thepa ea ho etsa lifilimi Eudragit RS le Eudragit RL ka ho latellana, 'me ba fumana hore nako e ne e le 10h ha karolelano e ne e le 9: 1. , 'me nako ea nako e ne e le 10h ha karo-karolelano e ne e le 8:2. Nako ea nako ke 7h ho 2, nako ea 7: 3 ke 5h, le nako ea 6: 4 ke 2h; bakeng sa porogens Eudragit L100 le Eudragit S100, Eudragit L100 e ka finyella sepheo sa pulse ea nako ea 5h ea nako sebakeng sa pH5-7; 20%, 40% le 50% ea tharollo ea ho roala, ho fumanoe hore tharollo ea ho roala e nang le 40% EudragitL100 e ka finyella tlhokahalo ea nako ea nako; maemo a ka holimo a ka finyella sepheo sa nako ea nako ea 5.1 h ho pH 6.5 le nako ea ho lokolloa ha pulse lihora tse 3 .

03 Polyvinylpyrrolidones (PVP)

PVP ke motsoako oa polymer o qhibilihang ka metsi o sa tsoeng ka metsing o entsoeng ka polymerized ho tloha N-vinylpyrrolidone (NVP). E arotsoe ka lihlopha tse 'nè ho ea ka karolelano ea boima ba limolek'hule. Hangata e hlalosoa ka boleng ba K. Ha ho na le viscosity e kholo, ho ba le matla a ho khomarela. PVP gel (phofo) e na le phello e matla ea adsorption ho lithethefatsi tse ngata. Ka mor'a ho kena ka mpeng kapa maling, ka lebaka la thepa ea eona e phahameng haholo ea ho ruruha, moriana o lokolloa butle-butle. E ka sebelisoa e le moemeli ea molemo ka ho fetisisa oa tokollo ho PDDS.

Letlapa la Verapamil pulse osmotic ke pompo ea pompo ea osmotic e nang le likarolo tse tharo, karolo e ka hare e entsoe ka hydrophilic polymer PVP e le "push layer", 'me ntho ea hydrophilic e etsa gel ea hydrophilic ha e kopana le metsi, e thibelang ho lokolloa ha lithethefatsi, e fumana nako le ho feta. e sutumetsa Lera le ruruha ka matla ha le kopana le metsi, le sutumelletsa moriana ka ntle ho lesoba la ho lokolloa, 'me mochine oa khatello ea osmotic ke senotlolo sa katleho ea tlhahiso.

Bafuputsi ba sebelisitse matlapa a laoloang a verapamil hydrochloride e le lithethefatsi tsa mohlala, 'me ba sebelisa PVP S630 le PVP K90 ka li-viscosity tse fapaneng e le lisebelisoa tsa ho roala tse laoloang. Ha phaello ea boima ba filimi e le 8%, nako ea nako (tlag) ea ho fihla in vitro ho lokolloa ke lihora tsa 3-4, 'me tekanyo ea ho lokolloa (Rt) ke 20-26 mg / h.

04 Hydrogel

4.1. Alginic acid

Alginic acid ke phofo e tšoeu kapa e bobebe e mosehla, ha e na monko ebile ha e latsoehe, selulose ea tlhaho e sa qhibiliheng metsing. Ts'ebetso e bonolo ea sol-gel le biocompatibility e ntle ea alginic acid e loketse ho etsa li-microcapsules tse lokollang kapa tse kenyang lithethefatsi, liprotheine le lisele - mofuta o mocha oa litekanyetso ho PDDS lilemong tsa morao tjena.

Bafuputsi ba sebelisitse dextran e le sethethefatsi sa mohlala le gel ea alginate ea calcium e le sesebelisoa sa lithethefatsi ho etsa litokisetso tsa ho otla ha pelo. Results Sethethefatsi se nang le boima bo phahameng ba limolek'hule se bonts'itse ho lokolloa ha nako-lag-pulse, 'me nako ea nako e ka fetoloa ke botenya ba filimi ea ho roala.

Bafuputsi ba sebelisitse sodium alginate-chitosan ho etsa li-microcapsules ka ho sebelisana ha electrostatic. Liteko li bonts'a hore li-microcapsules li na le karabelo e ntle ea pH, ho lokolloa ha li-zero ho pH = 12, le ho lokolloa ha pulse ho pH = 6.8. Foromo ea S curve ea ho lokolla, e ka sebelisoa e le sebopeho sa pH-responsive pulsatile formulation.

4.2. Polyacrylamide (PAM) le lihlahisoa tsa eona

PAM le lihlahisoa tsa eona ke li-polymers tse phahameng tsa molek'hule tse qhibilihang ka metsing, tse sebelisoang haholo tsamaisong ea pulse release. Hydrogel e sa utloeng mocheso e ka atoloha ka mokhoa o fetohang le ho atoloha (ho honyela) ka ho fetoha ha mocheso o kantle, ho baka phetoho ea ho kenella, ka hona Ho fihlela sepheo sa ho laola ho lokolloa ha lithethefatsi.

E ithutoang ka ho fetisisa ke N-isopropylacrylamide (NIPAAm) hydrogel, e nang le ntlha e qhibilihisang haholo (LCST) ea 32.°C. Ha mocheso o phahame ho feta LCST, gel e fokotseha, 'me mokelikeli mohahong oa marang-rang o hatelloa, o lokolla tekanyo e kholo ea Meriana e nang le tharollo ea metsi; ha mocheso o le tlase ho feta LCST, gel e ka ruruha hape, 'me kutloisiso ea mocheso ea gel ea NPAAm e ka sebelisoa ho fetola boitšoaro ba ho ruruha, boholo ba gel, sebōpeho, joalo-joalo ho finyella mocheso o nepahetseng oa "on-off" oa ho lokolloa ha lithethefatsi le Sekhahla sa tokollo ea lithethefatsi thermosensitive hydrogel pulsatile controlled tokollo formulation.

Bafuputsi ba ile ba sebelisa motsoako oa hydrogel e nang le mocheso (N-isopropylacrylamide) le likaroloana tsa tetroxide ea tšepe ea superferric e le thepa. Sebopeho sa marang-rang sa hydrogel se fetoloa, kahoo se potlakisa ho lokolloa ha lithethefatsi le ho fumana phello ea ho lokolloa ha pulse.

05 mekhahlelo e meng

Ntle le ts'ebeliso e atileng ea lisebelisoa tsa setso tsa polymer joalo ka HPMC, CMS-Na, PVP, Eudragit, le Surlease, lisebelisoa tse ling tse ncha tse tsamaisang joalo ka leseli, motlakase, matla a khoheli, maqhubu a ultrasonic le nanofibers li 'nile tsa ntlafatsoa khafetsa. Ka mohlala, liposome tsa sonic-sensitive liposome li sebelisoa e le sejari sa lithethefatsi ke bafuputsi, 'me ho eketsoa ha maqhubu a ultrasonic ho ka etsa hore ho be le khase e nyenyane ho sonic-sensitive liposome move, e le hore moriana o ka lokolloa kapele. Li-electrospun nanofibers li ile tsa sebelisoa ke bafuputsi ba TPPS le ChroB ho theha mohlala oa sebopeho sa mekhahlelo e mene, 'me ho lokolloa ha pulse ho ka etsoa ka mokhoa o ts'oanang oa tikoloho ea vivo e nang le 500.μg/ml protease, 50mM hydrochloric acid, pH8.6.