Razvoj hidrofilnih nanovlaken s karvedilolom in polimernim zaviralcem obarjanja

Murnc, Katja (author), Kocbek, Petra (mentor), Potrč, Tanja (comentor)

Razvoj potencialnih novih učinkovin, ki izkazujejo velik farmakološki potencial, a so slabo vodotopne, je izzval farmacevtsko tehnologijo k razvoju novih pristopov, s katerimi bi povečali njihovo topnost in s tem morda tudi biološko uporabnost. Nanovlakna veliko obetajo kot dostavni sistem, s katerim lahko potencialno dosežemo prenasičenje v gastrointestinalnem traktu. V okviru našega raziskovalnega dela smo z elektrostatskim sukanjem izdelali hidrofilna polimerna nanovlakna z vgrajenim karvedilolom. Poleg osnovnih polimerov poloksamera 407 in polietilenoksida ter zdravilne učinkovine karvedilola smo v nanovlakna vgradili še potencialni zaviralec obarjanja, in sicer hidroksipropilmetil celulozo ali Soluplus. Pri izdelavi nanovlaken s hidroksipropilmetil celulozo je bilo potrebnih nekaj sprememb že ustaljenega postopka izdelave nanovlaken, kot sta uporaba manj koncentriranega etanola za pripravo polimerne raztopine ter povečanje razdalje med konico igle in zbiralom. S testom sproščanja smo ovrednotili sproščanje karvedilola iz nanovlaken ter ugotovili, da se učinkovina iz vseh formulacij sprosti takoj, razen iz nanovlaken z Methocelom K4M. S testom topnosti smo vrednotili uspešnost posameznega polimernega zaviralca obarjanja pri vzdrževanju stanja prenasičenja. Nanovlakna s Pharmacoatom 606 in Pharmacoatom 615 niso bistveno podaljšala trajanja stanja prenasičenja karvedilola v primerjavi z nanovlakni brez zaviralca obarjanja. Na drugi strani je Soluplus, vgrajen v nanovlakna, povečal topnost karvedilola in podaljšal stanje prenasičenja karvedilola po sprostitvi iz nanovlaken. To priča o dobrih solubilizacijskih lastnostih Soluplusa in njegovi učinkovitosti v vlogi zaviralca obarjanja. Predhodno raztapljanje polimernih zaviralcev obarjanja v mediju za raztapljanje nanovlaken brez vgrajenega zaviralca obarjanja ni podaljšalo trajanja stanja prenasičenja karvedilola, razen v primeru, ko smo predhodno raztopili Soluplus tako, da je bilo masno razmerje s karvedilolom 1:1. Ugotovili smo tudi, da nanovlakna bistveno povečajo topnost in podaljšajo trajanje stanja prenasičenja karvedilola v primerjavi s polimernim filmom, še bolj pa v primerjavi s fizikalno zmesjo enake sestave. S tem smo dokazali, da je poleg sestave formulacije pri povečanju topnosti pomembna tudi farmacevtska oblika, v katero je vgrajena zdravilna učinkovina. Amorfnosti karvedilola v nanovlaknih z diferenčno kalorimetrijo nismo uspeli potrditi.

• Language: Slovenian
• Keywords: Prenasičenje, zaviralec obarjanja, karvedilol, topnost, elektrostatsko sukanje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-111157
• Publication date in RUL: 25.09.2019

Secondary language

• Language: English
• Title: Development of hydrophilic nanofibers with carvedilol and a polymeric precipitation inhibitor

Abstract

The development of potential new active substances that exhibit high pharmacological potential but are poorly water soluble has challenged pharmaceutical technology to develop new approaches that would increase their solubility and, thus, their bioavailability. Nanofibers as a delivery system that can potentially lead to supersaturation in the gastrointestinal tract are very promising. In scope of our research, we have used electrospinning to produce hydrophilic polymer nanofibers with incorporated carvedilol. In addition to the main polymers, namely poloxamer 407 and polyethylene oxide, and the active substance carvedilol, we incorporated in nanofibers also a potential precipitation inhibitor hydroxypropyl methylcellulose or Soluplus. The manufacture of nanofibers with hydroxypropyl methylcellulose required some adjustments, such as less concentrated ethanol for preparation of a polymer solution and increased distance between the needle tip and the collector. We evaluated the carvedilol release from nanofibers by the drug release test, which has shown immediate drug release from all formulations, except nanofibers with Methocel K4M. We evaluated the effectiveness of individual polymeric precipitation inhibitor to maintain the supersaturation state with the solubility test. The nanofibers with Pharmacoat 606 and Pharmacoat 615 did not significantly extend the duration of carvedilol supersaturation state compared to the nanofibers without the precipitation inhibitor. On the other hand, Soluplus incorporated in nanofibers increased the solubility of carvedilol and prolonged the duration of carvedilol supersaturation after its release from the nanofibers. This proved good solubilizing properties of Soluplus and its efficacy as precipitation inhibitor. Pre-dissolution of the polymeric precipitation inhibitors in dissolution medium did not extend the duration of the carvedilol supersaturation state, when released from nanofibers without incorporated precipitation inhibitor, except in case of pre-dissolved Soluplus in a weight ratio of 1: 1 with carvedilol. We have also revealed that nanofibers significantly increase the solubility and prolong the duration of carvedilol supersaturation compared to the polymer film, and even more when compared to the physical mixture with the same composition. This is how we proved that the dosage form is also important in addition to the formulation composition in increasing the drug solubility. However, amorphous state of carvedilol in nanofibers could not be confirmed by differential scanning calorimetry.

• Keywords: Supersaturation, percipitation inhibitor, carvedilol, solubility, electrospinning