I-Pharmaceutical Sustained-release Excipients

01 Cellulose ether

I-Cellulose ingahlukaniswa ngama-ether awodwa kanye nama-ether axubile ngokuya ngohlobo lwama-substitute. Kukhona uhlobo olulodwa kuphela lwe-substitute ku-ether eyodwa, njenge-methyl cellulose (MC), i-ethyl cellulose (EC), i-hydroxyl Propyl cellulose (HPC), njll.; kungaba khona izinto ezimbili noma ngaphezulu esikhundleni se-ether exubile, evame ukusetshenziswa i-hydroxypropyl methyl cellulose (HPMC), i-ethyl methyl cellulose (EMC), njll. Izinto ezisizayo ezisetshenziswa ekulungiseni izidakamizwa ezikhishwa ukushaya kwenhliziyo zimelelwe i-ether exubile i-HPMC, i-ether eyodwa HPC, ne-EC, evamise ukusetshenziswa njengama-disintegrants, ama-ejenti okuvuvukala, ama-retarders, nezinto zokumboza ifilimu.

1.1 Hydroxypropylmethylcellulose (HPMC)

Ngenxa yamazinga ahlukene okushintshanisa amaqembu e-methoxy ne-hydroxypropyl, i-HPMC imvamisa ihlukaniswe yaba izinhlobo ezintathu phesheya: i-K, E no-F. Phakathi kwazo, uchungechunge lwe-K lunesivinini esisheshayo sokukhipha amanzi futhi lufaneleka njengohlaka lwamathambo ukuze luzinze futhi lulawuleke. ukukhululwa amalungiselelo. Futhi iyi-ejenti yokukhululwa kwe-pulse. Enye yezinkampani ezithwala izidakamizwa ezisetshenziswa kakhulu emalungiselelweni emithi. I-HPMC iyi-ether engeyona ionic cellulose encibilikayo emanzini, impushana emhlophe, ayinambitheki, ayinaphunga futhi ayinabuthi, futhi ikhishwa ngaphandle koshintsho emzimbeni womuntu. Ayincibiliki emanzini ashisayo angaphezu kuka-60°C futhi ingavuvukala kuphela; lapho okuphuma kuyo okunama-viscosities ahlukene kuxutshwe ngezilinganiso ezihlukene, ubudlelwano bomugqa buhle, futhi ijeli elakhiwe lingalawula ngempumelelo ukusakazeka kwamanzi nokukhululwa kwezidakamizwa.

I-HPMC ingenye yezinto ezisetshenziswa kakhulu ze-polymer ezisuselwe ekuvuvukeni noma ekulimaleni okulawulwa ukuguguleka kwezidakamizwa kuhlelo lokukhululwa kwe-pulse. Ukukhishwa kwezidakamizwa ezivuvukalayo ukulungisa izithako zemithi ezisebenzayo zibe amaphilisi noma ama-pellets, bese kuba ungqimba olunezingqimba eziningi, ungqimba lwangaphandle luyi-polymer engancibiliki emanzini kodwa ingena emanzini, ungqimba lwangaphakathi luyi-polymer enekhono lokuvuvukala, lapho uketshezi lungena ngaphakathi. ungqimba lwangaphakathi, ukuvuvukala kuzodala ingcindezi, futhi ngemva kwesikhathi esithile, umuthi uzovuvukala futhi ulawulwe ukuze ukhulule umuthi; ngenkathi isidakamizwa esikhipha ukuguguleka sidlula iphakethe lesidakamizwa esiwumongo. Ukumbozwa ngama-polymer angancibiliki emanzini noma agugulekayo, ukulungisa ukujiya kokunamathela ukuze kulawulwe isikhathi sokukhululwa kwezidakamizwa.

Abanye abacwaningi baphenye ukukhishwa kanye nezici zokunweba zamathebulethi asuselwa ku-hydrophilic HPMC, futhi bathola ukuthi izinga lokukhishwa lihamba kancane izikhathi ezi-5 kunalelo lamathebulethi ajwayelekile futhi linokwanda okukhulu.

Kusenomcwaningi osebenzisa i-pseudoephedrine hydrochloride njengomuthi oyimodeli, asebenzise indlela yokugcoba eyomile, alungise ungqimba lwejazi nge-HPMC yama-viscosities ahlukene, alungise ukukhululwa komuthi. Imiphumela yokuhlolwa kwe-vivo ibonise ukuthi ngaphansi kobukhulu obufanayo, i-HPMC ye-viscosity ephansi ingafinyelela ukuhlushwa okuphezulu ngo-5h, kuyilapho i-HPMC ye-viscosity ephezulu ifinyelele ekugxilweni okuphezulu cishe ngamahora angu-10. Lokhu kuphakamisa ukuthi uma i-HPMC isetshenziswa njengento yokunameka, i-viscosity yayo inomthelela obaluleke kakhulu ekuziphatheni kokukhishwa kwezidakamizwa.

Abacwaningi basebenzise i-verapamil hydrochloride njengomuthi oyimodeli ukuze balungise amaphilisi enkomishi ye-double-pulse three-layer core cup, futhi baphenya imithamo ehlukene ye-HPMC K4M (15%, 20%, 25%, 30%, 35%, w/w; 4M. ibhekisela kumphumela we-viscosity (i-4000 centipoise) ekubambeni kwesikhathi Imiphumela ibonisa ukuthi ngokunyuka kwenani le-HPMC K4M, i-lag yesikhathi isethwe ku-4 kuya ku-5 amahora, ngakho-ke i-HPMC K4M okuqukethwe kunqunywa ukuthi kungama-25%. Lokhu kukhombisa ukuthi i-HPMC ingabambezela ukukhishwa komuthi owumgogodla ngokuvimbela umuthi ukuthi ungahlangani noketshezi futhi idlale indima ekukhululweni okulawulwayo.

1.2 I-Hydroxypropylcellulose (HPC)

I-HPC ingahlukaniswa ibe yi-hydroxypropyl cellulose (L-HPC) efakwe endaweni ephansi ne-high-substituted hydroxypropyl cellulose (H-HPC). I-L-HPC iyimpushana engeyona i-ionic, emhlophe noma emhlophe, ayinaphunga futhi ayinambitheki, futhi iphakathi kokuphuma kwe-cellulose okungeyona ubuthi angenabungozi emzimbeni womuntu. Ngenxa yokuthi i-L-HPC inendawo enkulu kanye ne-porosity, ikwazi ukumunca ngokushesha amanzi futhi ikhukhumale, futhi izinga layo lokunwetshwa kwamanzi lingama-500-700%. Ngena egazini, ngakho-ke ingakhuthaza ukukhululwa kwesidakamizwa kuthebhulethi enezingqimba eziningi kanye ne-pellet core, futhi ithuthukise kakhulu umphumela wokwelapha.

Kumaphilisi noma ama-pellets, ukwengeza i-L-HPC kusiza i-tablet core (noma i-pellet core) ukuthi inwebe ukuze ikhiqize amandla angaphakathi, aphula ungqimba olunamathelayo futhi ikhiphe umuthi ngokushaya kwenhliziyo. Abacwaningi basebenzisa i-sulpiride hydrochloride, i-metoclopramide hydrochloride, i-diclofenac sodium, ne-nilvadipine njengezidakamizwa eziyimodeli, kanye ne-low-substituted hydroxypropyl cellulose (L-HPC) njenge-ejenti ehlakazayo. Ukuhlolwa kwabonisa ukuthi ukushuba kongqimba oluvuvukalayo kunquma usayizi wezinhlayiyana. isikhathi sokuhamba.

Abacwaningi basebenzisa izidakamizwa ze-antihypertensive njengento yocwaningo. Ocwaningweni, i-L-HPC yayikhona kumaphilisi namaphilisi, ukuze amunce amanzi abese eguguleka ukuze akhulule umuthi ngokushesha.

Abacwaningi basebenzise i-terbutaline sulfate pellets njengesidakamizwa esiyimodeli, futhi imiphumela yokuhlola yokuqala ibonise ukuthi ukusebenzisa i-L-HPC njengempahla yesendlalelo sangaphakathi sokumboza kanye nokwengeza i-SDS efanelekile kungqimba lwangaphakathi lokumboza kungafinyelela umphumela wokukhishwa kwe-pulse olindelekile.

1.3 I-Ethyl cellulose (EC) kanye ne-aqueous dispersion (ECD) yayo

I-EC iyi-non-ionic, i-alkyl ether ye-cellulose engancibiliki emanzini, enezici zokumelana namakhemikhali, ukumelana nosawoti, ukumelana ne-alkali nokuqina kokushisa, futhi inezinhlobonhlobo ze-viscosity (isisindo samangqamuzana) nokusebenza okuhle kwezingubo, ingakha ungqimba olunamathelayo olunokuqina okuhle futhi akulula ukulugqoka, okwenza lusetshenziswe kabanzi emugqeni wefilimu wokukhululwa okuqhubekayo nokulawulwayo.

I-ECD iwuhlelo oluhlukile lapho i-ethyl cellulose imiswa ku-dispersant (amanzi) ngesimo sezinhlayiya ezincane ze-colloidal futhi inokusimama okuhle ngokomzimba. I-polymer encibilika emanzini esebenza njenge-ejenti eyenza izimbotshana isetshenziselwa ukulungisa izinga lokukhululwa kwe-ECD ukuze ihlangabezane nezimfuneko zokukhululwa kwezidakamizwa okuqhubekayo ukuze kulungiselelwe ukukhishwa okuqhubekayo.

I-EC iyinto efanelekile yokulungiswa kwama-capsules angancibiliki emanzini. Abacwaningi basebenzise i-dichloromethane/absolute ethanol/ethyl acetate (4/0.8/0.2) njenge-solvent kanye ne-EC (45cp) ukuze balungiselele isisombululo se-EC esingu-11.5% (w/v) , ukulungisa umzimba we-capsule we-EC, nokulungisa i-capsule ye-EC engaphenduki. ukuhlangabezana nezidingo zokukhululwa kwe-oral pulse. Abacwaningi basebenzise i-theophylline njengesidakamizwa esiyimodeli sokutadisha ukuthuthukiswa kwesistimu ye-pulse ye-multiphase ehlanganiswe ne-ethyl cellulose dispersion aqueous. Imiphumela yabonisa ukuthi uhlobo lwe-Aquacoat® ku-ECD lwaluntekenteke futhi kulula ukuphuka, luqinisekisa ukuthi umuthi ungakhishwa ngokushaya kwenhliziyo.

Ngaphezu kwalokho, abacwaningi bafunde ama-pellets okukhululwa alawulwa yi-pulse alungiswe nge-ethyl cellulose aqueous dispersion njengongqimba olungaphandle lokumboza. Lapho ukuzuza kwesisindo sesendlalelo sokumboza sangaphandle kwaba ngu-13%, ukukhululwa kwezidakamizwa okuhlanganisiwe kwafinyelelwa ngokusikeka kwesikhathi samahora angu-5 kanye nokusikeka kwesikhathi esingamahora angu-1.5. Ngaphezu kwama-80% womphumela wokukhishwa kwe-pulse.

02 I-Acrylic resin

I-Acrylic resin iwuhlobo lwenhlanganisela ye-polymer eyakhiwe yi-copolymerization ye-acrylic acid ne-methacrylic acid noma ama-esters awo ngengxenye ethile. I-acrylic resin evame ukusetshenziswa yi-Eudragit njengegama layo lokuhweba, elinezinto ezinhle zokwenza ifilimu futhi linezinhlobo ezahlukene ezifana nohlobo lwe-E oluncibilika esiswini, u-L, uhlobo lwe-S, kanye ne-RL ne-RS enganyibiliki emanzini. Ngenxa yokuthi i-Eudragit inezinzuzo zokusebenza okuhle kakhulu kokwenza ifilimu nokuhambisana okuhle phakathi kwamamodeli ahlukahlukene, iye yasetshenziswa kabanzi ekuhlanganiseni ifilimu, amalungiselelo e-matrix, ama-microspheres nezinye izinhlelo zokukhishwa kwe-pulse.

Abacwaningi basebenzise i-nitrendipine njengesidakamizwa esiyimodeli kanye ne-Eudragit E-100 njengesihlanganisi esibalulekile sokulungisa ama-pellets azwela i-pH, futhi bahlola ukutholakala kwabo kwe-bioavailability ezinjeni ezinempilo. Imiphumela yocwaningo ithole ukuthi ukwakheka kwe-Eudragit E-100 enezinhlangothi ezintathu kwenza ukuthi ikhishwe ngokushesha kungakapheli imizuzu engama-30 ngaphansi kwezimo ezine-acidic. Uma ama-pellets eku-pH 1.2, isikhathi sokulala amahora angu-2, ku-pH 6.4, isikhathi sokulala amahora angu-2, futhi ku-pH 7.8, isikhathi samahora angama-3, esingabona ukuphathwa kokukhululwa okulawulwayo emgudwini wamathumbu.

Abacwaningi benze izilinganiso zika-9:1, 8:2, 7:3 kanye no-6:4 ezintweni zokwakha ifilimu i-Eudragit RS kanye ne-Eudragit RL ngokulandelana, futhi bathola ukuthi isikhathi salo sasingu-10h lapho isilinganiso sasingu-9:1. , futhi isikhathi sasingu-10h lapho isilinganiso singu-8:2. Isikhathi singu-7h ngo-2, isikhathi esingu-7:3 ngu-5h, kanti isikhathi esingu-6:4 ngu-2h; kuma-porogens i-Eudragit L100 ne-Eudragit S100, i-Eudragit L100 ingakwazi ukufeza injongo ye-pulse ye-5h isikhathi lag endaweni ye-pH5-7; I-20%, i-40% kanye ne-50% yesisombululo sokumboza, kwatholakala ukuthi isisombululo sokumboza esiqukethe i-40% i-EudragitL100 singahlangabezana nemfuneko ye-lag yesikhathi; lezi zimo ezingenhla zingafinyelela injongo yokusikeka kwesikhathi okungu-5.1 h ku-pH 6.5 kanye nesikhathi sokukhululwa kweshayela samahora angu-3.

03 I-Polyvinylpyrrolidones (PVP)

I-PVP iyinhlanganisela ye-polymer engeyona i-ionic emanzini e-polymerized kusuka ku-N-vinylpyrrolidone (NVP). Ihlukaniswe ngamamaki amane ngokwesilinganiso sesisindo samangqamuzana. Ngokuvamile kuvezwa inani lika-K. I-viscosity enkulu, i-adhesion iqina. Ijeli ye-PVP (impuphu) inomphumela oqinile wokukhangisa emithini eminingi. Ngemva kokungena esiswini noma egazini, ngenxa yokuvuvukala kwayo okuphezulu kakhulu, umuthi ukhishwa kancane kancane. Ingasetshenziswa njenge-ejenti yokukhululwa eqhubekayo enhle kakhulu ku-PDDS.

Ithebhulethi ye-Verapamil pulse osmotic iyiphampu ye-osmotic enezingqimba ezintathu, ungqimba lwangaphakathi lwenziwe nge-hydrophilic polymer PVP njengongqimba oluphushayo, futhi into eyi-hydrophilic yakha ijeli eyi-hydrophilic lapho ihlangana namanzi, ebambezela ukukhululwa kwezidakamizwa, ithola ukunensa kwesikhathi, futhi iphusha Ungqimba lukhukhumala kakhulu lapho luhlangana namanzi, lusunduza umuthi ngaphandle kwembobo yokukhulula, futhi i-osmotic pressure propellant iyisihluthulelo sempumelelo yokwakheka.

Abacwaningi basebenzise amaphilisi akhishwayo e-verapamil hydrochloride njengezidakamizwa eziyimodeli, futhi basebenzisa i-PVP S630 ne-PVP K90 enama-viscosity ahlukene njengezinto zokumboza ezikhishwayo ezilawulwayo. Uma inzuzo yesisindo sefilimu ingu-8%, isikhathi (i-lag) sokufinyelela ukukhululwa kwe-in vitro amahora angu-3-4, futhi isilinganiso sokukhululwa (Rt) singu-20-26 mg/h.

04 I-Hydrogel

4.1. I-Alginic acid

I-Alginic acid iyimpushana emhlophe noma ephuzi ekhanyayo, ayinaphunga futhi ayinambitheki, i-cellulose yemvelo engancibiliki emanzini. Inqubo ye-sol-gel emnene kanye ne-biocompatibility enhle ye-alginic acid kulungele ukwenza ama-microcapsules akhulula noma ashumeke izidakamizwa, amaprotheni namaseli - ifomu elisha lomthamo ku-PDDS eminyakeni yamuva.

Abacwaningi basebenzisa i-dextran njengesidakamizwa esiyimodeli kanye nejeli ye-calcium alginate njengesithwali sezidakamizwa ukwenza ukulungiswa kwenhliziyo. Imiphumela Umuthi onesisindo samangqamuzana aphezulu ubonise ukukhululwa kwe-time-lag-pulse, futhi ukubambezeleka kwesikhathi kungase kulungiswe ukushuba kwefilimu enamathelayo.

Abacwaningi basebenzisa i-sodium alginate-chitosan ukwakha ama-microcapsules ngokusebenzisa ukuxhumana kwe-electrostatic. Ukuhlola kubonisa ukuthi ama-microcapsules anokusabela okuhle kwe-pH, ukukhululwa kwe-oda elinguziro ku-pH=12, kanye nokukhululwa kwe-pulse ku-pH=6.8. I-release curve Form S, ingasetshenziswa njengendlela yokwenza i-pH esabelayo ye-pulsatile.

4.2. I-Polyacrylamide (PAM) kanye nokuphuma kwayo

I-PAM kanye nokuphuma kwayo ama-polymer aphezulu e-molecular ancibilika emanzini, asetshenziswa kakhulu ohlelweni lokukhishwa kwe-pulse. I-hydrogel ezwela ukushisa inganwebeka ngokuhlehlayo futhi inwebe (inciphe) ngokushintsha kwezinga lokushisa langaphandle, ibangele ushintsho ekungeneni, ngaleyo ndlela Ukufeza inhloso yokulawula ukukhululwa kwezidakamizwa.

Okucwaningwe kakhulu yi-N-isopropylacrylamide (NIPAAm) hydrogel, enephuzu lokuncibilika elibucayi (LCST) lama-32°C. Uma izinga lokushisa liphakeme kune-LCST, ijeli iyancipha, futhi i-solvent esakhiweni senethiwekhi iyakhanywa, ikhiphe inani elikhulu lesisombululo samanzi esine-Drug; lapho izinga lokushisa liphansi kune-LCST, ijeli ingakhukhumala kabusha, futhi ukuzwela kwezinga lokushisa kwejeli ye-NPAAm ingasetshenziswa ukulungisa ukuziphatha kokuvuvukala, usayizi wejeli, ukuma, njll. Isilinganiso sokukhishwa kwezidakamizwa i-thermosensitive hydrogel pulsatile controlled release formulation.

Abacwaningi basebenzise inhlanganisela ye-hydrogel ezwela ukushisa (N-isopropylacrylamide) kanye nezinhlayiya ze-superferric iron tetroxide njengento. Isakhiwo senethiwekhi ye-hydrogel siyashintshwa, ngaleyo ndlela sisheshise ukukhululwa kwezidakamizwa futhi sithole umphumela wokukhululwa kwe-pulse.

05 ezinye izigaba

Ngaphezu kokusetshenziswa kabanzi kwezinto ze-polymer zendabuko ezifana ne-HPMC, i-CMS-Na, i-PVP, i-Eudragit, ne-Surlease, ezinye izinto ezintsha zokuthwala ezifana nokukhanya, ugesi, amandla kazibuthe, amagagasi e-ultrasonic, nama-nanofibers athuthukiswe ngokuqhubekayo. Isibonelo, i-sonic-sensitive liposome isetshenziswa abacwaningi njengomthwali wezidakamizwa, futhi ukungezwa kwamagagasi e-ultrasonic kungenza inani elincane legesi ekuhambeni kwe-sonic-sensitive liposome, ukuze umuthi ukhululwe ngokushesha. Ama-electrospun nanofibers asetshenziswe abacwaningi ku-TPPS naku-ChroB ukuze baklame imodeli yesakhiwo sezendlalelo ezine, futhi ukukhululwa kwe-pulse kungase kubonakale endaweni elingisiwe ye-vivo equkethe i-500.μg/ml protease, 50mM hydrochloric acid, pH8.6.