Razvoj osmozno nadzorovanega sistema sproščanja v vodi lahko topnega nadomestka učinkovine

Lukić, Stefan (author), Dreu, Rok (mentor)

Farmacevtske oblike s podaljšanim sproščanjem lahko za razliko od oblik s takojšnjim spro- ščanjem vzdržujejo terapevtsko koncentracijo učinkovine v plazmi daljši čas. Manjše nihanje koncentracije učinkovine povzroči manj neželenih učinkov, zmanjša potrebo po večkratnem odmerjanju in s tem poveča pacientovo adherenco. Ker je pri modelu ničtega reda sproščanje neodvisno od koncentracije učinkovine in poteka s konstantno hitrostjo, je model ničtega reda pri farmacevtskih oblikah s podaljšanim sproščanjem najbolj zaželen. Sproščanje s kinetiko ničtega reda, ki je neodvisno od pogojev okolja, lahko dosežemo pri osmotskih sistemih. Naš cilj v tej magistrski nalogi je bil izdelati osmotsko črpalko z osemurnim sproščanjem lahko topnega tartrazina s kinetiko ničtega reda. Za izdelavo »push-pull« osmotske črpalke smo upo- rabili materiale proizvajalca Colorcon(R). Uporabili smo POLYOX(TM) Coagulant LEO in NaCl kot osmogen v »push« plasti, POLYOX(TM) N-80 NF LEO in tartrazin v »pull« plasti ter Opadry(R) CA za oblogo. Osmotsko črpalko smo izdelali s stiskanjem dvoplastne tablete na table- tirki, oblaganjem v perforiranem oblagalnem bobnu in mehanskim vrtanjem dostavne odprtine. Preizkus sproščanja smo izvedli na napravi z recipročnimi cilindri (naprava USP III). Sprošča- nje je potekalo v mediju s pH 1 prvi dve uri sproščanja in nato še šest ur v mediju s pH 6,8. S tem smo simulirali prehod iz želodca v tanko črevo. V magistrski nalogi preučujemo vpliv sestave »push-pull« osmotske črpalke na kinetiko spro- ščanja lahko topnega tartrazina kot nadomestka učinkovine. Preverjali smo vpliv razmerja med »pull« in »push« plastjo (2 : 1,3, 2 : 1,6 in 2 : 2), vpliv deleža NaCl v »push« plasti (35 % in 45 %) in vpliv debeline polprepustne membrane (8 mg/cm2, 10 mg/cm2 in 12 mg/cm2) na sprošča- nje tartrazina. Preverjali smo tudi vpliv spremembe pH medija na kinetiko sproščanja. Ugotovili smo, da ima na naklon kinetike sproščanja tartrazina največji vpliv debelina obloge. Hitrost sproščanja je z debelino obloge v obratnem sorazmerju. Pri večji vsebnosti NaCl v »push« plasti smo opazili nižjo hitrost sproščanja. Pri večjem deležu »push« plasti smo opazili večjo hitrost sproščanja, a je bil vpliv manjši od vpliva debeline membrane. Dejavniki, ki vpli- vajo na sproščanje iz »push-pull« osmotske črpalke (velikost dostavne odprtine, vrsta in delež osmotske snovi, tip in debelina membrane), morajo biti med sabo uravnoteženi za doseganje želene kinetike sproščanja. Sprememba pH medija med sproščanjem na kinetiko sproščanja tartrazina ni imela bistvenega vpliva.

• Language: Slovenian
• Keywords: “Push-Pull” osmotska črpalka, dvoplastna tableta, filmsko oblaganje tablet, prirejeno sproščanje, podaljšano sproščanje, tartrazin
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2021
• PID: 20.500.12556/RUL-132306
• Publication date in RUL: 21.10.2021

Secondary language

• Language: English
• Title: Development of an osmotically controlled system for release of a freely water-soluble drug surrogate

Abstract

Sustained release dosage forms have the ability of maintaining the desired therapeutic plasma drug concentration over longer periods of time. Lower fluctuations in plasma drug concentra- tion cause less side effects, lower the need for redosing and increase the patient's adherence. Zero order release model provides drug release independent of drug concentration. Drug release takes place at a constant rate, thus making it the desired release model for sustained release dosage forms. Osmotic drug release systems can achieve zero order release kinetics independ- ent of release media characteristics. The objective of this thesis was to develop a push-pull osmotic pump that can deliver a dose of tartrazine in eight hours with zero order release kinetics. Materials from the manufacturer Colorcon (R) were used for producing the osmotic pump. POLYOX(TM) Coagulant LEO and NaCl were used to form the push layer of the osmotic pump. POLYOX(TM) N-80 NF LEO and tartrazine were used for forming the pull layer. Opadry(R) CA was used for coating and forming the sem- ipermeable membrane. The osmotic pump was formed by compressing a bilayer tablet on the tablet press and spray coating it in a perforated drum. Delivery orifice was formed by mechanical drilling. Dissolution testing was conducted on a reciprocating cylinder dissolution apparatus (USP III). Release me- dium with pH of 1 was used for the first two hours of dissolution, followed by six hour disso- lution in medium with pH 6.8, simulating the passage from stomach to the small intestine. This thesis focused on evaluating the impact of push-pull osmotic pump composition on release kinetics of tartrazine. The impact of the ratio of push and pull layer (2:1.3, 2:1.6 and 2:2), NaCl content in the push layer (35 % and 45 %) and the impact of the thickness of the semipermeable membrane (8 mg/cm2, 10 mg/cm2 and 12 mg/cm2) on the release kinetics of tartrazine were evaluated. Furthermore, the impact of media pH on the release kinetics was evaluated. Membrane thickness had the greatest impact on the release rate of tartrazine. The release rate of tartrazine was inversely proportional to membrane thickness. Higher the amount of NaCl in the push layer, slower the release rate of tartrazine. Higher amount of push layer in the tablet resulted in faster release rate of tartrazine, but the impact was smaller than the impact of mem- brane thickness. Change of media pH during release did not affect the release kinetics of tartra- zine.

• Keywords: Push-Pull osmotic pump, bi-layer tablet, film coating, modified release, pro- longed release, tartrazine