doctoral thesis
Jelena Mandić (Author), Alenka Zvonar (Mentor), Franc Vrečer (Co-mentor)

Abstract

Topnost zdravilne učinkovine v vodi je eden od najpomembnejših parametrov, ki zagotavlja njeno absorpcijo in terapevtski učinek. Samo-mikroemulgirajoči sistemi (SMES) spadajo med t.i. na lipidih osnovane dostavne sisteme, s katerimi lahko povečamo topnost in biološko uporabnost vgrajene učinkovine po peroralni aplikaciji. Po dispergiranju v vodnem mediju pod vplivom peristaltičnega gibanja gastrointestinalnega trakta spontano tvorijo mikroemulzije tipa olje v vodi. Majhna velikost kapljic mikroemulzije je povezana z večjo biološko uporabnostjo. Pretvorba v trdno farmacevtsko obliko je zaželena zaradi povečanja stabilnosti, lažjega rokovanja in večje kompliance pacientov. Na tržišču so SMES na voljo samo v obliki tekoče formulacije, polnjene v mehke ali trdne želatinske kapsule, zato v zadnjih letih poteka intenziven razvoj na področju pretvorbe SMES v trdno farmacevtsko obliko (solidifikacije SMES). V uvodu disertacije smo naredili literaturni pregled različnih tehnologij solidifikacije SMES za proizvodnjo samo-emulgirajočih praškov, granul, pelet in tablet. Pri pretvorbi SMES v trdno obliko je zelo pomemen pravilen izbor pomožnih snovi in ustrezna nastavitev procesnih parametrov, da ohranimo samo-emulgirajoče lastnosti dostavnega sistema in pridobimo produkt, ki je primeren za nadaljnje polnjenje v kapsule ali stiskanje v tablete. Namen disertacije je bil raziskati tehnologije za solidifikacijo SMES, ki imajo velik potencial v industrijski farmaciji. Proučiti smo želeli, katere tehnologije omogočajo proizvodnjo trdnih SMES z visoko vsebnostjo zdravilne učinkovine, ohranjenimi samo-mikroemulgirajočimi lastnostmi in izboljšano hitrostjo ter obsegom sproščanja slabo vodotopne zdravilne učinkovine. V prvem delu disertacije (Poglavje 1) smo se osredotočili na razvoj in vrednotenje SMES z izboljšano topnostjo karvedilola, ki smo ga izbrali kot modelno slabo vodotopno zdravilno učinkovino. Nadalje smo SMES s karvedilolom pretvorili v trdne pelete s tehnologijo oblaganja pelet v zvrtinčenih plasteh, do sedaj slabo raziskano metodo za solidifikacijo SMES. Procesne spremenljivke smo ustrezno prilagodili, da smo dosegli velik izkoristek procesa in majhno aglomeracijo pelet med samim procesom oblaganja. Oblaganje pelet smo izvedli v modificirani vrtinčnoslojni napravi z generatorjem vrtinčastega toka zraka, ki se je izkazala za boljšo od običajne Wursterjeve komore. Dodatek polimera kot veziva v disperzijo za oblaganje je omogočil, da se je SMES ujel v peletno oblogo, z dodatkom laktoze pa smo dosegli višjo vsebnost SMES s karvedilolom, preprečila je tudi lepljenje pelet med rokovanjem in skladiščenjem. Trdni produkt je izkazoval samo-mikroemulgirajoče lastnosti in hitro sproščanje zdravilne učinkovine, kar kaže da je tehnologija oblaganja pelet v zvrtinčenih plasteh perspektivna metoda za pripravo samo-mikroemulgirajočih pelet z ustrezno vsebnostjo zdravilne učinkovine in z izboljšanim raztapljanjem slabo vodotopne zdravilne učinkovine. V Poglavju 2 je opisana do sedaj še praktično neraziskana metoda solidifikacije SMES, in sicer granuliranje v zvrtinčenih plasteh, ki smo jo uporabili za proizvodnjo samo-mikroemulgirajočih granul Jelena Mandić, Doctoral thesis 5 s karvedilolom. Pokazali smo, da lahko z optimizacijo formulacijskih in procesnih spremenljivk dosežemo ustrezno aglomeracijo, visoko vsebnost zdravilne učinkovine in ustrezne lastnosti produkta. Dosegli smo visoko vsebnost zdravilne učinkovine (64 mg karvedilola na gram produkta), sproščanje karvedilola pa je bilo hitro in popolno, primerljivo s tekočo formulacijo in boljše od kristaliničnega karvedilola. Po drugi strani so imeli produkti z višjo vsebnostjo karvedilola slabše pretočne lastnosti, zato je potreben kompromis med visoko vsebnostjo zdravilne učinkovine na eni strani in sprejemljivimi pretočnimi lastnostmi na drugi strani. V nadaljevanju smo kot prvi objavili študijo izdelave tablet iz samo-mikroemulgirajočih granulatov, ki smo jih proizvedli s tehnologijo granuliranja v zvrtinčenih plasteh. Kljub visoki vsebnosti SMES v granulatu smo z optimalno izbiro pomožnih snovi za tabletno zmes in z ustrezno silo stiskanja uspeli izdelati tablete z ohranjenimi samo-mikroemulgirajočimi lastnostmi in hitrim sproščanjem karvedilola. Poglavje 3 opisuje proces solidifikacije SMES s karvedilolom s tehnologijo sušenja z razprševanjem, pri čemer smo uporabili različne porozne nosilce na osnovi silicijevega oksida z namenom doseči dovolj visoko vsebnost SMES v produktu (do 67 % m/m), da bi lahko najvišji odmerek karvedilola (25 mg) vgradili v eno odmerno enoto (kapsulo). Procesne parametre smo prilagodili z namenom doseganja visokega izkoristka, vendar pa je na izkoristek vplival tudi izbor nosilca in čas mešanja disperzije za razprševanje pred samim začetkom procesa sušenja z razprševanjem, kar pripisujemo penetraciji SMES globlje v pore nosilca, ko sta nosilec in disperzija SMES dlje časa v stiku. Samo-mikroemulgirajoče lastnosti so se po solidifikaciji ohranile, zdravilna učinkovina pa je ostala molekularno dispergirana v produktu, kar je omogočilo njeno hitro sproščanje. Ugotovili smo tudi, da izbira nosilca in razmerje med SMES in nosilcem v trdnem produktu vplivata na njegove lastnosti (vsebnost zdravilne učinkovine, samo-mikroemulgirajoče lastnosti ter hitrost in obseg sproščanja zdravilne učinkovine). Na izbranih formulacijah trdnih SMES, ki smo jih pripravili z metodo sušenja z razprševanjem, z granulacijo v zvrtinčenih plasteh in za primerjavo tudi z metodo direktne adsorpcije, smo izvedli stabilnostno študijo, kjer smo opazili zmanjšanje vsebnosti karvedilola. Z novo razvito LC-MS metodo (tekočinska kromatografija, sklopljena z masno spektroskopijo) smo raziskali prisotnost razgradnih produktov oz. sorodnih substanc. Identificirali smo amide, ki nastanejo, ko prosta aminska skupina karvedilola z nukleofilnimi lastnostmi reagira z maščobnimi kislinami, ki so kot nečistote prisotne v oljnih komponentah SMES. Dodatno smo pri trdnih SMES, ki smo jih proizvedli z metodo sušenja z razprševanjem in z metodo direktne adsorpcije, opazili zmanjšanje vsebnosti karvedilola, ki ga ni bilo mogoče razložiti zgolj s tvorbo sorodnih substanc. Z namenom preprečevanja penetracije SMES globlje v pore nosilca, ki je lahko povezana z deloma ireverzibilno adsorpcijo SMES, smo raziskali možnost predhodne deaktivacije površine nosilcev z delno zapolnitvijo njegovih por s SMES brez učinkovine oz. s HPMC, vendar s tem nismo uspeli povečati relativne vsebnosti karvedilola. Domnevamo, da sta se SMES oz. HPMC, s katerima smo želeli zapolniti globje pore nosilca, naložila prednostno na njegovo površino. V zadnjem poglavju (Poglavje 4) smo v obliki strnjenega pregleda za vse uporabljene solidifikacijske metode predstavili vpliv procesnih in formulacijskih spremenjljivk na izkoristek procesa in na lastnosti proizvedenih trdnih SMES. Produkte vseh treh solidifikacijskih metod smo tudi primerjali z vidika najpomebnejših lastnosti produkta. Z raziskavo smo pokazali, da ima nastavitev procesnih parametrov velik vpliv na izkoristek procesa pri vseh treh solidifikacijskih metodah, saj smo z ustrezno prilagoditvijo procesnih parametrov zmanjšali lepljenje in aglomeracijo produktov. Formulacijske spremenljivke so imele različen vpliv na lastnosti produkta, odvisno od uporabljene solidifikacijske metode. Pokazali smo, da uporabljene solidifikacijske metode, ki so sicer še slabo raziskane, a imajo velik potencial v farmacevtski industriji, omogočajo izdelavo trdnih SMES z visoko vsebnostjo zdravilne učinkovine, ohranjenimi samo-mikroemulgirajočimi lastnostmi in hitrim sproščanjem zdravilne učinkovine.

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Language: English
Year of publishing:
Typology: 2.08 - Doctoral Dissertation
Organization: UL FFA - Faculty of Pharmacy
Publisher: [J. Mandić]
UDC: 544.351.3:661.12:615.015(043.3)
COBISS: 47871747 Link will open in a new window
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Secondary language: Slovenian
Secondary title: Študij industrijsko aplikativnih tehnoloških pristopov razvoja trdnih samo-mikroemulgirajočih sistemov s karvedilolom
Secondary abstract: Aqueous solubility of the drug is one of the most important parameters for ensuring its absorption and therapeutic effect. Self-microemulsifying drug delivery systems (SMEDDS) are lipid formulations that improve solubility and oral bioavailability of the incorporated drugs. After redispersion in aqueous media under the influence of the gastrointestinal motility, they spontaneously form O/W microemulsions. Small droplet size has been linked with higher oral bioavailabilty. Solid dosage form is preferred due to improved stability, handling and patient compliance. SMEDDS are available on the market only in the form of the liquid SMEDDS filled into soft or hard gelatine capsules, therefore solidification of SMEDDS has been extensively investigated in the recent years. A review of different solidification techniques for production of self-emulsifying powders, granules, pellets and tablets is presented in the introduction of the thesis. Solidification requires the correct selection of excipients and setting of process parameters in order to preserve the self-emulsifying ability of the system and to obtain product suitable for further processing, i.e. filling into capsules or compression into tablets, which represents a major challenge. The aim of our research was investigation of SMEDDS% solidification techniques with large potential in pharmaceutical industry for production of solid SMEDDS (s-SMEDDS) with high drug loading, preserved self-microemulsifying (SME) properties and improved release rate and extent of poorly water soluble drug. The first part of the thesis (Chapter 1) is focused on the development and evaluation of liquid SMEDDS with improved solubility of a model poorly water soluble drug carvedilol (CARV). Further on, fluid-bed coating technology (FBC), yet poorly investigated technique for solidification of SMEDDS, was employed for transformation of CARV-SMEDDS into solid pellets. Process variables were adjusted to obtain high process yield and low pellet agglomeration. Coating process was conducted in the modified, swirl-flow based fluid bed coating device, which was proved superior over the conventional Wurster fluid bed. Addition of polymer as a binder into the coating dispersion enabled entrapping of SMEDDS in the coating layer and addition of lactose enabled higher drug loading and prevented sticking of the pellets during handling and storage. Self-microemulsifying properties as well as fast drug release were preserved in the solid products, indicating the potential of FBC as a method for production of solid SME pellets with adequate drug loading capacity and enhanced release of a poorly water-soluble drug. In Chapter 2 fluid-bed granulation (FBG), a scarcely explored SMEDDS% solidification technique, is investigated as a method for production of CARV-loaded self-microemulsifying granules. Jelena Mandić, Doctoral thesis 2 It was shown that formulation variables (type of solid carrier, optimization of granulation dispersion) and fluid-bed granulation process variables can be optimized in order to achieve suitable agglomeration process, high drug loading and appropriate product characteristics. High drug loading (64 mg CARV per g of product) was obtained and drug release from granulates was fast and complete, comparable to liquid SMEDDS and superior to crystalline carvedilol. However, products with higher drug loading had inferior flow properties, therefore a compromise has to be made. Further on, first ever published production of tablets from SME granulates, obtained with FBG, was made. Despite high content of liquid SMEDDS in entering granulate it was successfully compressed into tablets, which exhibited preserved SME properties and fast CARV release, due to the optimal excipient selection of compression mixture and compression force. In Chapter 3 solidification of CARV-SMEDDS with spray drying (SD) was conducted, using various porous silica-based carriers for achieving high SMEDDS loading (up to 67 % m/m), which can enable delivering highest dosage of CARV (25 mg) in a single dosage form (capsule). Process parameters were adjusted for obtaining high process yield, however it was also influenced by the choice of the carrier and the mixing time of dispersion before spray drying, which was attributed to more extensive absorption/adsorption of SMEDDS in the pores, when time of contact between dispersion of SMEDDS and porous carrier was longer. Products exhibited preserved self-microemulsifying properties, which, along with the presence of CARV in a molecularly dispersed form, enabled fast drug release. However, characteristics of the products (drug loading, self-microemulsifying properties and drug release rate and extent) were affected by choice of the carrier and SMEDDS:carrier ratio in solid SMEDDS. Selected s-SMEDDS, obtained with spray drying, fluid bed granulation and for comparison also direct adsorption technique, were submitted to the stability study, where decrease in content of CARV was observed. Presence of degradation products was investigated with the newly developed LC-MS method. Degradation products were characterised as amides of CARV and fatty acids present in the oil components of SMEDDS, because CARV reacted with free amine group that has nucleofilic characteristics. In s-SMEDDS, obtained with spray drying and adsorption technique, pronounced decrease in content of CARV was observed that could not be explained solely with the formation of related substances. Prefilling the pores of the carrier with API-free SMEDDS or HPMC was investigated as means of preventing partial irreversible adsorption of SMEDDS or migration of SMEDDS into the deeper regions of pores. However relative CARV content (ratio between determined amount of CARV and theoretical amount of incorporated CARV) could not have been increased by prefilling pores, which can be attributed to the deposition of pore-filling agent onto the carrier%s surface rather than in the deep pore regions. Jelena Mandić, Doctoral thesis 3 In the last chapter (Chapter 4) a condensed overview of impact of process and formulation variables on process yield and characteristics of s-SMEDDS in all solidification techniques was made. Moreover, key product characteristics were compared for all three SMEDDS% solidification techniques. This research has shown that in all studied solidification technologies, process parameters had considerable impact on process yield, as optimized conditions decreased sticking and agglomeration of the product. Formulation variables on the other hand had different impact on product characteristics, depending on the choice of technology. Nevertheless, it was demonstrated that poorly investigated, however perspective industrially applicable technologies, enable successful solidification of SMEDDS with high drug loading, preserved SME properties and fast drug release.
Secondary keywords: topnost zdravilnih učinkovin;samo-mikroemulgirajoči sistemi;karvedilol;granuliranje v zvrtinčenih plasteh;solidifikacijske metode;Farmacevtska industrija;Topnost;Zdravilne učinkovine;
Type (COBISS): Dissertation
Thesis comment: Univ. v Ljubljani, Fak. za farmacijo
Pages: 210 str.
ID: 15504133