Pharmaceutical Sustained-release Excipients

01 iSelulosi ether

I-Cellulose inokohlulwa ibe yi-ether enye kunye ne-ethers edibeneyo ngokohlobo lwababambeli. Kukho uhlobo olulodwa lwe-substituent kwi-ether enye, njenge-methyl cellulose (MC), i-ethyl cellulose (EC), i-hydroxyl Propyl cellulose (HPC), njl.; kunokubakho iindawo ezimbini okanye ngaphezulu kwi-ether edibeneyo, esetyenziswa ngokuqhelekileyo yi-hydroxypropyl methyl cellulose (HPMC), i-ethyl methyl cellulose (EMC), njl. I-excipients ezisetyenziswe kumalungiselelo eziyobisi ezikhupha i-pulse zimelwe yi-ether edibeneyo ye-HPMC, i-ether eyodwa ye-HPC, kunye ne-EC, ehlala isetyenziswa njenge-disintegrants, i-ejenti zokudumba, i-retarders, kunye nezixhobo zokugquma ifilimu.

1.I-Hydroxypropylmethylcellulose (HPMC)

Ngenxa yamanqanaba ahlukeneyo okutshintshwa kwamaqela e-methoxy kunye ne-hydroxypropyl, i-HPMC yohlulwe ngokubanzi ibe ziindidi ezintathu kumazwe aphesheya: i-K, i-E kunye ne-F. Phakathi kwazo, uthotho lwe-K lunesantya esikhawulezayo sokugalela amanzi kwaye lufanelekile njengesixhobo samathambo ukuze sigcinwe kwaye silawuleke. ukukhululwa kwamalungiselelo. Ikwayi-agent yokukhupha i-pulse. Enye yezona zithwali zeziyobisi ezisetyenziswa ngokuqhelekileyo kumalungiselelo amayeza. I-HPMC yi-ether ye-cellulose e-soluble e-soluble e-ionic, umgubo omhlophe, ongenancasa, ongenavumba kwaye awunayo ityhefu, kwaye ukhutshwa ngaphandle kotshintsho emzimbeni womntu. Ayinyibiliki kumanzi ashushu angaphezu kwama-60°C kwaye unokudumba kuphela; xa i-derivatives yayo ene-viscosities eyahlukeneyo ixutywe kwimilinganiselo eyahlukeneyo, ubudlelwane bomgca bulungile, kwaye ijeli eyenziweyo inokulawula ngokufanelekileyo ukusasazwa kwamanzi kunye nokukhululwa kweziyobisi.

I-HPMC yenye yezinto ezisetyenziswa ngokuqhelekileyo zepolymer esekwe ekudumbeni okanye kukhukuliseko olulawulwayo lokukhupha ichiza kwindlela yokukhupha ipulse. Ukukhutshwa kwechiza lokudumba kukulungiselela izithako ezisebenzayo zamayeza kwiipilisi okanye iipellets, kwaye emva koko i-multi-layer coating, umaleko wangaphandle nguManzi-ayinyibilikiyo kodwa amanzi angenako ukugquma i-polymer, umaleko wangaphakathi uyipolymer enekhono lokudumba, xa ulwelo lungena ngaphakathi. umaleko wangaphakathi, ukudumba kuya kuvelisa uxinzelelo, kwaye emva kwexesha elithile, iyeza liya kudumba kwaye lilawulwe ukukhulula iyeza; ngelixa ichiza lokukhupha ukhukuliseko lidlula kwiphakheji yeziyobisi ezingundoqo. Ukwambathisa ngamanzi-ayinyibilikiyo okanye ukhukuliseko iipolymers, ukulungelelanisa ukutyeba yokwambathisa ukulawula ixesha ukukhululwa ichiza.

Abanye abaphandi baye baphanda ukukhutshwa kunye neempawu zokwandisa iipilisi ezisekwe kwi-hydrophilic HPMC, kwaye bafumanisa ukuba izinga lokukhululwa liphindwe ka-5 licotha kunelo lamacwecwe aqhelekileyo kwaye linokwanda okukhulu.

Usenomphandi ukuba asebenzise i-pseudoephedrine hydrochloride njengeyeza eliyimodeli, amkele indlela yokwaleka eyomileyo, alungiselele umaleko wedyasi kunye ne-HPMC yee-viscosities ezahlukeneyo, ukulungelelanisa ukukhutshwa kweyeza. Iziphumo zovavanyo lwe-vivo zibonise ukuba phantsi kobunzima obufanayo, i-HPMC ye-viscosity ephantsi inokufikelela kwi-concentration ye-5h, ngelixa i-HPMC ephezulu ye-viscosity ifikelele kwi-concentration ye-peak malunga ne-10h. Oku kuphakamisa ukuba xa i-HPMC isetyenziswa njengento yokugquma, i-viscosity yayo inefuthe elibalulekileyo ekuziphatheni kokukhululwa kweziyobisi.

Abaphandi basebenzise i-verapamil hydrochloride njengechiza eliyimodeli yokulungisa iipilisi eziphindwe kabini ze-tablet ezintathu-layer core cup tablet, kwaye baphanda ngeedosi ezahlukeneyo ze-HPMC K4M (15%, 20%, 25%, 30%, 35%, w/w; 4M ibhekisela kwimpembelelo ye-viscosity (i-4000 centipoise) kwi-lag yexesha Iziphumo zibonisa ukuba ngokunyuka kwenani le-HPMC K4M, ixesha le-lag libekwe kwi-4 ukuya kwiiyure ze-5, ngoko ke i-HPMC K4M umxholo uzimisele ukuba yi-25%. Oku kubonisa ukuba i-HPMC inokulibazisa ukukhutshwa kwechiza eliphambili ngokuthintela ichiza ekudibaneni nolwelo kwaye idlale indima ekukhululweni okulawulwayo.

1.2 iHydroxypropylcellulose (HPC)

I-HPC inokwahlulwa ibe yi-low-substituted hydroxypropyl cellulose (L-HPC) kunye ne-high-substituted hydroxypropyl cellulose (H-HPC). I-L-HPC i-non-ionic, imhlophe okanye i-off-white powder, ayinavumba kwaye ayinancasa, kwaye iphakathi I-non-toxic cellulose derivatives engenabungozi emzimbeni womntu. Ngenxa yokuba i-L-HPC inommandla omkhulu kunye ne-porosity, inokukhawuleza ukufunxa amanzi kunye nokudumba, kwaye izinga layo lokunyuswa kwamanzi li-500-700%. Ukungena egazini, ngoko kunokukhuthaza ukukhululwa kweyeza kwi-tablet ye-multi-layer kunye ne-pellet core, kwaye iphucule kakhulu isiphumo sonyango.

Kwiipilisi okanye iipelisi, ukongeza i-L-HPC inceda i-tablet core (okanye i-pellet core) ukuba ikhulise ukuvelisa amandla angaphakathi, aphule i-coating layer kwaye ikhuphe iyeza kwi-pulse. Abaphandi basebenzisa i-sulpiride hydrochloride, i-metoclopramide hydrochloride, i-diclofenac sodium, kunye ne-nilvadipine njengeziyobisi zemodeli, kunye ne-low-substituted hydroxypropyl cellulose (L-HPC) njenge-agent edibeneyo. Iimvavanyo zibonise ukuba ubukhulu bomgca wokudumba bumisela ubungakanani bamasuntswana. ixesha lokuhamba.

Abaphandi basebenzise iziyobisi ze-antihypertensive njengento efundwayo. Kuvavanyo, i-L-HPC yayikhona kwiipilisi kunye nee-capsules, ukuze zifunxe amanzi kwaye zikhukulise ukukhulula iyeza ngokukhawuleza.

Abaphandi basebenzise iipellets ze-terbutaline sulfate njengeyeza lemodeli, kwaye iziphumo zovavanyo lwangaphambili zibonise ukuba ukusebenzisa i-L-HPC njengempahla ye-coating yangaphakathi kunye nokongeza i-SDS efanelekileyo kwi-coat layer yangaphakathi inokufezekisa umphumo olindelekileyo wokukhululwa kwe-pulse.

1.I-3 Ethyl cellulose (EC) kunye ne-aqueous dispersion (ECD)

I-EC i-non-ionic, i-alkyl ether ye-cellulose engenamanzi, eneempawu zokumelana nemichiza, ukuxhathisa ityuwa, ukuxhathisa kwe-alkali kunye nokuzinza kobushushu, kwaye inoluhlu olubanzi lwe-viscosity (ubunzima be-molecular) kunye nokusebenza kakuhle kwempahla , inokwenza umaleko wokugquma ngokuqina okuhle kwaye akukho lula ukuwunxiba, nto leyo eyenza ukuba isetyenziswe ngokubanzi kwiziyobisi ezizinzileyo kunye nokulawulwa kokukhutshwa kwefilimu.

I-ECD yinkqubo ye-heterogeneous apho i-ethyl cellulose inqunyanyiswa kwi-dispersant (amanzi) ngendlela yamasuntswana amancinci e-colloidal kwaye inozinzo oluhle lomzimba. I-polymer e-soluble yamanzi esebenza njenge-pore-forming agent isetyenziselwa ukulungelelanisa izinga lokukhululwa kwe-ECD ukuhlangabezana neemfuno zokukhutshwa kweziyobisi okuqhubekayo ukulungiselela ukukhutshwa okuzinzileyo.

I-EC yinto efanelekileyo yokulungiswa kwee-capsules ezingenakunyibilika emanzini. Abaphandi basebenzise i-dichloromethane / i-ethanol epheleleyo / i-ethyl acetate (4 / 0.8 / 0.2) njenge-solvent kunye ne-EC (45cp) ukulungiselela i-11.5% (w / v) isisombululo se-EC, ukulungiselela umzimba we-capsule we-EC, kwaye ulungiselele i-capsule ye-EC engavumelekanga ukuhlangabezana neemfuno zokukhululwa kwepulse ngomlomo. Abaphandi basebenzise i-theophylline njengeyeza elingumzekelo wokufunda ukuphuhliswa kwenkqubo ye-pulse ye-multiphase ehlanganiswe ne-ethyl cellulose yokusasazeka kwamanzi. Iziphumo zabonisa ukuba udidi lwe-Aquacoat® kwi-ECD lwaluethe-ethe kwaye kulula ukuqhawuka, luqinisekisa ukuba ichiza linokukhutshwa ngomnxeba.

Ukongeza, abaphandi bafunde iipellets ezilawulwa yi-pulse ezilungiselelwe nge-ethyl cellulose yokusasazeka kwamanzi njengomaleko wokugquma wangaphandle. Xa inzuzo yobunzima bomgangatho wangaphandle wengubo yayiyi-13%, ukukhutshwa kweziyobisi okuqokelelweyo kwaphunyezwa kunye nexesha le-5 h kunye nexesha le-1.5 h. Ngaphezulu kwe-80% yesiphumo sokukhululwa kwe-pulse.

02 I-Acrylic resin

I-Acrylic resin luhlobo lwekhompawundi ye-polymer eyenziwe yi-copolymerization ye-acrylic acid kunye ne-methacrylic acid okanye i-esters yazo ngokomlinganiselo othile. I-resin ye-acrylic esetyenziswa ngokuqhelekileyo yi-Eudragit njengegama layo lokurhweba, elineempawu ezintle zokwenza ifilimu kwaye ineentlobo ezahlukeneyo ezifana ne-gastric-soluble E type, i-enteric-soluble L, uhlobo lwe-S, kunye ne-RL engenamanzi kunye ne-RS. Ngenxa yokuba i-Eudragit ineengenelo zokwenziwa kwefilimu okugqwesileyo kunye nokuhambelana okuhle phakathi kweemodeli ezahlukeneyo, isetyenziswe ngokubanzi ekugqumeni ifilimu, amalungiselelo e-matrix, ii-microspheres kunye nezinye iinkqubo zokukhupha ipulse.

Abaphandi basebenzise i-nitrendipine njengemodeli yeziyobisi kunye ne-Eudragit E-100 njengento ebalulekileyo yokulungiselela iipellets ezithintekayo ze-pH, kwaye bavavanya i-bioavailability yabo kwizinja eziphilileyo. Iziphumo zophononongo zifumanise ukuba ulwakhiwo olunamacala amathathu e-Eudragit E-100 lwenza ukuba lukhutshwe ngokukhawuleza ngaphakathi kwemizuzu engama-30 phantsi kweemeko ezineasidi. Xa iipellet zikwi-pH 1.2, ixesha le-2 iiyure, kwi-pH 6.4, ixesha le-pH 2 iiyure, kunye ne-pH 7.8, ixesha lokuhamba liyi-3 iiyure, ezinokuqonda ukulawulwa kokukhululwa okulawulwayo kwi-intestinal tract.

Abaphandi baye baqhuba umlinganiselo we-9: 1, 8: 2, 7: 3 kunye ne-6: 4 kwizinto zokwenza ifilimu u-Eudragit RS kunye no-Eudragit RL ngokulandelelana, kwaye bafumanisa ukuba ixesha lexesha laliyi-10h xa umlinganiselo wawuyi-9: 1. , kwaye ixesha lag liyi-10h xa umlinganiselo wawuyi-8:2. Ixesha le-7h ngo-2, ixesha le-7: 3 ngu-5h, kunye nexesha le-6: 4 ngu-2h; kwi-porogens i-Eudragit L100 kunye ne-Eudragit S100, i-Eudragit L100 inokufezekisa injongo ye-pulse ye-5h yexesha lag kwindawo ye-pH5-7; I-20%, i-40% kunye ne-50% yesisombululo sokugubungela, kwafunyaniswa ukuba isisombululo se-coating esiqulethe i-40% ye-EudragitL100 sinokuhlangabezana nemfuneko yexesha; iimeko ezingentla zingakwazi ukufezekisa injongo yexesha le-5.1 h kwi-pH 6.5 kunye nexesha lokukhululwa kwe-pulse iiyure ze-3.

03 IiPolyvinylpyrrolidones (PVP)

I-PVP yi-non-ionic water-soluble polymer compound eyenziwe nge-polymerized ukusuka kwi-N-vinylpyrrolidone (NVP). Yahlulahlulwe yaba ngamabakala amane ngokomlinganiselo wobunzima bemolekyuli. Idla ngokubonakaliswa ngexabiso lika-K. Inkulu i-viscosity, i-adhesion yomelele. Ijeli ye-PVP (powder) inefuthe elinamandla le-adsorption kumachiza amaninzi. Emva kokungena esiswini okanye egazini, ngenxa yepropathi yayo ephezulu kakhulu yokudumba, ichiza likhutshwa kancinci. Ingasetyenziswa njengearhente yokukhululwa ezinzileyo ebalaseleyo kwiPDDS.

I-Verapamil pulse osmotic tablet yimpompo ye-osmotic yepilisi enemigangatho emithathu, umaleko wangaphakathi wenziwa nge-hydrophilic polymer PVP njengomgangatho wokutyhala, kwaye i-hydrophilic substance yenza ijeli ye-hydrophilic xa idibana namanzi, ebambezela ukukhutshwa kweziyobisi, ifumana ixesha lokuyeka, kwaye ityhala Umaleko udumba ngamandla xa udibana namanzi, ukutyhala iyeza liphume kumngxunya wokukhulula, kwaye i-osmotic pressure propellant isitshixo kwimpumelelo yokwenziwa.

Abaphandi basebenzise i-verapamil hydrochloride iipilisi ezilawulwayo zokukhutshwa njengeziyobisi zemodeli, kwaye basebenzisa i-PVP S630 kunye ne-PVP K90 enee-viscosities ezahlukeneyo njengezinto zokugqoka ezilawulwayo. Xa ubunzima befilimu bufumana i-8%, ixesha le-lag (i-tlag) yokufikelela kwi-vitro ukukhululwa yi-3-4 iiyure, kunye ne-avareji yokukhululwa (Rt) yi-20-26 mg / h.

04 I-Hydrogel

4.1. Alginic acid

Iasidi yeAlginic ngumgubo omhlophe okanye otyheli okhanyayo, awunavumba kwaye awunancasa, iselulosi yendalo enganyibilikiyo emanzini. Inkqubo epholileyo ye-sol-gel kunye ne-biocompatibility efanelekileyo ye-alginic acid ifanelekile ukwenza i-microcapsules ekhupha okanye ifake iziyobisi, iiprotheni kunye neeseli - ifom yedosi entsha kwi-PDDS kwiminyaka yamuva.

Abaphandi basebenzise i-dextran njengeyeza lomzekelo kunye ne-calcium alginate gel njengomphathi weziyobisi ukwenza ukulungiswa kwe-pulse. Iziphumo Ichiza elinobunzima obuphezulu bemolekyuli libonise ukukhululwa kwexesha-lag-pulse, kunye nexesha elishiyekileyo linokulungiswa bubunzima befilimu yokwambathisa.

Abaphandi basebenzise i-sodium alginate-chitosan ukwenza i-microcapsules ngokusebenzisa i-electrostatic interaction. Iimvavanyo zibonisa ukuba i-microcapsules ine-pH efanelekileyo yokuphendula, ukukhutshwa kwe-zero-odolo kwi-pH = 12, kunye nokukhululwa kwe-pulse kwi-pH = 6.8. I-Curve curve Form S, ingasetyenziswa njenge-pH-responsive pulsatile formulation.

4.2. I-Polyacrylamide (PAM) kunye ne-derivatives yayo

I-PAM kunye ne-derivatives yayo yi-polymers ye-molecular high-soluble yamanzi, esetyenziswa kakhulu kwinkqubo yokukhululwa kwe-pulse. I-hydrogel enobushushu obunobushushu inokubuyisela umva kwaye ikhulise (iyancipha) kunye nokutshintsha kweqondo lokushisa langaphandle, okubangela utshintsho kwi-permeability, ngaloo ndlela Ukufezekisa injongo yokulawula ukukhutshwa kweziyobisi.

Eyona nto ifundwe kakhulu yi-N-isopropylacrylamide (NIPAAm) i-hydrogel, enendawo enyibilikayo ebalulekileyo (LCST) ye-32°C. Xa iqondo lobushushu liphezulu kune-LCST, ijeli iyancipha, kwaye i-solvent kwisakhiwo sothungelwano iyakhanywa, ikhuphe isixa esikhulu se-Drug-containing aqueous solution; xa iqondo lobushushu lisezantsi kune-LCST, ijeli inokuphinda idumbe, kwaye ubushushu bobushushu bejeli ye-NPAAm ingasetyenziselwa ukulungelelanisa indlela yokuziphatha yokudumba, ubungakanani bejeli, imilo, njl. Ireyithi yokukhutshwa kweziyobisi i-thermosensitive hydrogel pulsatile elawulwayo ekukhululweni ukubunjwa.

Abaphandi basebenzise i-composite ye-hydrogel-sensitive hydrogel (N-isopropylacrylamide) kunye ne-superferric iron tetroxide particles njengento. Isakhiwo sothungelwano se-hydrogel sitshintshwe, ngaloo ndlela sikhawuleza ukukhutshwa kweziyobisi kunye nokufumana umphumo wokukhululwa kwe-pulse.

05 ezinye iindidi

Ukongeza kusetyenziso olubanzi lwezixhobo zepolymer zemveli ezifana ne-HPMC, i-CMS-Na, i-PVP, i-Eudragit, kunye ne-Surlease, ezinye izinto ezintsha zokuthwala ezifana nokukhanya, umbane, imimandla yamagnetic, amaza e-ultrasonic, kunye ne-nanofibers ziye zaphuhliswa ngokuqhubekayo. Ngokomzekelo, i-sonic-sensitive liposome isetyenziswe njengomphathi weziyobisi ngabaphandi, kwaye ukongezwa kwamaza e-ultrasonic kunokwenza ixabiso elincinci legesi kwi-sonic-sensitive liposome move, ukwenzela ukuba iyeza likhutshwe ngokukhawuleza. I-electrospun nanofibers isetyenziswe ngabaphandi kwi-TPPS kunye ne-ChroB ukuyila imodeli yesakhiwo esine-layer ezine, kwaye ukukhutshwa kwe-pulse kunokufezekiswa kwindawo efanisiweyo ye-vivo equkethe i-500.μg/ml protease, 50mM hydrochloric acid, pH8.6.