Vpliv hidrodinamsko-mehanskih dogodkov in sestavin hrane na sproščanje učinkovine iz ogrodnih tablet

doktorska disertacija

Ana Glavač (Author), Marija Bogataj (Mentor)

Abstract

Hidrofilne ogrodne tablete so po zaužitju lahko izpostavljene širokemu spektru pogojev z vidika sestave medija v katerem se nahajajo in hidrodinamsko-mehanskih dogodkov okolice. To lahko povzroči bistvene spremembe v sproščanju učinkovine iz ogrodja. Namen doktorskega dela je bil proučiti vpliv nekaterih parametrov tega širokega spektra. Za opazovanje in ocenjevanje teh vplivov so bile razvite in ovrednotene nove metodologije za spremljanje nabrekanja in sproščanja učinkovine. Tako smo optimizirali gibanje tablete v napravi s steklenimi kroglicami v smeri ponazarjanja fizioloških vrednosti ter opredelili uporabnost sistema s kamerami za ocenjevanje nabrekanja tablet. Obenem pa smo tudi želeli preučiti vpliv nekaterih pogosto prisotnih sestavin hrane na sproščanje in nabrekanje ogrodnih tablet iz hipromeloze (HPMC). V nadaljevanju smo preverili ali ima prisotnost stika ogrodne tablete s steklenimi kroglicami ključen vpliv na erozijo in sproščanje iz tablet ob prisotnosti izbranih komponent hrane. S karakterizacijo in optimizacijo gibanja tablete v napravi s steklenimi kroglicami smo določili območje parametrov, in sicer količino kroglic (15, 30 ali 55 g) ter obrate mešanja (med 6 in 18 rpm), ki lahko izzovejo ustrezno hitrost gibanja tablete in frekvenco spreminjanja njene hitrosti, tako da se približa fiziološkemu območju gibanj v želodcu na tešče in po obroku. Za ponazoritev velikih nihanj v frekvenci spreminjanja hitrosti, ki se pojavijo po obroku v področju antruma, se je izkazala najprimernejša uporaba velike količine kroglic (55 g). Za primer kratkotrajnih visokih hitrosti v pogojih na tešče pa lahko uporabimo visoke hitrosti mešanja (120 rpm). Menimo, da smo tako naredili korak bliže k omogočanju biorelevantnih testov sproščanja. Ovrednotili smo tudi uporabnost sistema s kamerami, ki je povezan z napravo z vesli, za opazovanje obnašanja HPMC ogrodnih tablet z vidika nabrekanja in sproščanja. Pokazali smo, da je določevanje volumna ogrodne tablete preko kamere za oceno nabrekanja v dobri korelaciji z metodo tehtanja v testiranem pH območju medijev. Sproščanje učinkovine iz tablet je bilo veliki meri odvisno od topnosti učinkovine, kar je vplivalo tudi na obseg nabrekanja in prosojnost gelske plasti tablete. Sistem s kamerami nam tako lahko poleg spremljanja samega obnašanja farmacevtske oblike nudi oporo tudi pri razumevanju procesa raztapljanja ter omogoča oceno nabrekanja ogrodja brez fizičnega posega v postopek testiranja sproščanja. V prvem delu sklopa o vplivu sestavin hrane smo proučevali učinek ionske moči medija na sproščanje in nabrekanje hidrofilnih ogrodnih tablet. V in vivo okolju tablete se lahko pojavi širok interval vrednosti ionske moči. Testirali smo ogrodne tablete s paracetamolom in HPMC (2906) različnih viskoznostnih stopenj (50, 400, 1500 in 4000 mPa·s) z vidika sproščanja učinkovine in spremembe mase ogrodja po izpostavitvi mediju z različno ionsko močjo v območju fizioloških vrednosti in višje (0,09; 0,15; 0,31 in 0,52 M kalijev fosfatni pufer z dodatkom NaCl). Pri ionski moči 0.31 M so samo tablete iz višjih viskoznostih stopenj, pokazale obsežno takojšnje nabrekanje ter hitro sproščanje. Odziv tablet z nižjimi viskoznostnimi stopenjami HPMC je primerljiv z odzivom pri nizki ionski moči, tukaj se namreč pojavi postopno nabrekanje ogrodja in podaljšano sproščanje učinkovine. Ugotovili smo, da v primeru, ko se takoj po izpostavitvi mediju pojavi izrazito in obsežno nabrekanje ogrodja, lahko pričakujemo hitro sproščanje iz ogrodnih tablet in je sposobnost zagotavljanja podaljšanega sproščanja izgubljena. Pri preučevanem tipu HPMC (2906) v mediju s kritično koncentracijo topljencev, ki vplivajo na hidratacijo HPMC, lahko pričakujemo večjo sposobnost zagotavljanja podaljšanega sproščanja v primeru nižjih viskoznostnih stopenj polimera. Dosedanje raziskave so sicer preučevale drug tip HPMC (2208), vendar so se tam višje viskoznostne stopnje HPMC izkazale kot manj občutljive na povišano koncentracijo topljencev. V nadaljevanju smo raziskovali vpliv saharoze in pektina, ki sta pogosti komponenti v vsakdanji prehrani, na obnašanje ogrodnih tablet. Pokazali smo, da se že znanemu vplivu visokih koncentracij saharoze na izgubo podaljšanega sproščanje iz HPMC ogrodnih tablet lahko deloma izognemo s prisotnostjo pektina kot gradnika ogrodja tablete ali sestavine medija za raztapljanje. Poleg testov sproščanja in morfološkega opazovanja hidratiranih ogrodij tablet smo uporabili tudi druge tehnike za preučevanje in karakterizacijo lastnosti polimernih raztopin. Meritve so pokazale, da temperaturo točke zamotnitve zniža poleg saharoze tudi pektin, kar nakazuje na zmanjšano hidratacijo HPMC. S pomočjo diferenčne dinamične kalorimetrije smo potrdili možnost interakcij med saharozo in pektinom. Reološke meritve so pokazale večjo viskoznost ter prevlado elastičnega modula nad plastičnim modulom pri HPMC-pektin raztopinah kot v primeru samo HPMC raztopin v prisotnosti višjih koncentracij saharoze. Ti rezultati nakazujejo na večjo zgostitev in prepletenost polimernih raztopin za kombinacijo HPMC-pektin-saharoza. Menimo, da se v primeru ogrodnih tablet iz pektina in HPMC v mediju s saharozo izoblikuje močan gelski sloj, ki predstavlja večjo oviro za vstop vode v ogrodje, ter posledično zmanjšano difuzijo učinkovine iz ogrodja. V primeru pektina kot komponente medija pa je njegov vpliv na hidratacijo HPMC ogrodja morda lahko preko interakcij saharoza-pektin-HPMC na površini ogrodja ali večje viskoznosti medija za sproščanje. Vendar bodo za boljšo pojasnitev mehanizmov v proučevanih interakcijah potrebne še nadaljnje raziskave. Po zaužitju tablete so v njeni okolici poleg različnih komponent iz hrane prisotni tudi hidrodinamsko-mehanski dogodki. V zadnjem sklopu doktorske disertacije smo združili oba segmenta in ugotavljali, ali različna mehanska obremenitev bistveno vpliva na obnašanje HPMC ogrodnih tablet v primeru medijev z različno koncentracijo topljencev (saharoza, natrijev klorid). Uporabili smo napravo s steklenimi kroglicami ter farmakopejsko napravo z vesli, ki omogočata različne mehanske obremenitve in hidrodinamiko. V ogrodje testirane tablete je bila vključena visoka (90SH-100000SR) ali nizka (90SH-100SR) viskoznostna stopnja HPMC ter topno (laktoza) ali netopno (mikrokristalna celuloza, MCC) polnilo. Razlike med napravama z vidika profilov sproščanja učinkovine so se pokazale pri višjih koncentracijah topljencev za vse testirane tipe tablet, saj je bilo sproščanje učinkovine hitrejše v napravi s steklenimi kroglicami, kot pa v napravi z vesli. Predvidevamo, da premikanje ogrodne tablete po plasti steklenih kroglic pomembno vpliva na odstranjevanje gelske plasti. Še posebno je bilo to izraženo, ko smo uporabili medije z visokimi koncentracijami topljencev, iz česar sklepamo, da je v teh primerih integriteta gelskega sloja nižja. Dodatno smo spremljali tudi erozijo ogrodja in morfologijo hidratirane tablete, oba parametra sta nakazala večji obseg erozije ob uporabi naprave s steklenimi kroglicami. Naprava s steklenimi kroglicami nam lahko omogoča dodaten pogled na obnašanje ogrodnih tablet v kritičnih medijih, ko je izražen večji vpliv mehanskih obremenitev na ustrezno izoblikovanje gelske plasti. Raziskovalno delo v okviru doktorske disertacije tako bistveno prispeva k boljšemu poznavanje vplivov na sproščanje iz ogrodnih HPMC tablet, predvsem preko razumevanja občutljivosti ogrodja na hidrodinamsko- mehanske obremenitve in zmožnosti izoblikovanja ustrezne integritete ogrodja ob prisotnosti nekaterih komponent iz hrane. Dodatno so bile razvite metode s katerimi smo lahko ovrednotili in opazovali testirane parametre, ki vplivajo na proces nabrekanja in sproščanja iz ogrodja tablet.

Keywords

hidrofilne ogrodne tablete;ogrodne tablete;hipromeloza;zdravilne učinkovine;nabrekanje;sproščanje;vplivi;hrana;disertacije;

Data

Language:	Slovenian
Year of publishing:	2017
Typology:	2.08 - Doctoral Dissertation
Organization:	UL FFA - Faculty of Pharmacy
Publisher:	[A. Krese]
UDC:	615.453.015(043.3)
COBISS:	290003200
Views:	155
Downloads:	0
Average score:	0 (0 votes)
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Other data

Secondary language:	English
Secondary title:	Effects of hydrodynamic-mechanic events and food components on drug release from matrix tablets
Secondary abstract:	After oral administration the hydrophilic matrix tablets are influenced by broad spectrum of conditions in the aspect of surrounding media compositions and hydrodynamic – mechanic events. Therefore, drug release from the matrix could be significantly altered. The aim of the doctoral thesis was to investigate the effect of selected parameters from this broad spectrum. New methodologies were developed to enable observation and evaluation of tested parameters during drug relase and matrix swelling. In this manner, the optimization of tablet movement in glass bead device was performed for better simulation of physiological values and the camera system for monitoring matrix swelling was evaluated. Additionally, the presence of some food components on drug release and swelling of matrix tablet containing hypromellose (HPMC) was studied. Further, the influence of tablet contact with glass beads on drug release and matrix erosion was tested. With characterization and optimization of tablet movement in the glass bead device suitable tablet velocities and frequency of velocity fluctuations were provoked by varying the amount of glass beads (15, 30 or 55 g) and stirring rate (between 6 and 18 rpm) in order to reflect the physiological range of these two parameters in the fasted and fed state stomach. For the simulation of higher frequency of velocity fluctuations that can be expressed in antrum in fed state the use of higher amount of glass beads (55 g) is recommended. For achievement of short period with high velocities the high stirring rates (120 rpm) are applied. We believe that due to this research we made a step closer to enabling biorelevant dissolution testing. Additionally, applicability of bottom-view cameras for evaluation of tablet behaviour during dissolution testing with paddle apparatus was performed. HPMC matrix tablets were observed in the aspects of swelling and drug release. A high correlation between the relative change in tablet volume using the camera system and relative change in tablet mass based on tablet weighing was demonstrated in tested media pH range. Drug release from the matrix is affected to great extent by drug solubility and influences the swelling and transparency of the gel layer. Bottom-view camera system enables tracking of dosage form behavior and provides supplementary information for understanding the dissolution process. Also the evaluation of the matrix swelling is provided without physical interruption of dissolution test. In the first part of section regarding influence of food component the effects of ionic strength on drug release and swelling of hydrophilic matrix tablet were investigated since a tablet in in vivo enviroment can be exposued to values of ionic strength within broad interval. Matrix tablets with paracetamol and HPMC (2906) of various viscosity grades (50, 400, 1500 and 4000 mPa·s) were tested for drug release and change of matrix mass in media with different ionic strengths (0,09; 0,15; 0,31 in 0,52 M) that are within physiological range and higher. At 0,31 M the matrices of higher viscosity grades express extensive initial swelling and drug release. Matrices of lower HPMC viscosity grade responded similar as in the case of lower ionic strength media where slow and gradual swelling as well as extended drug release is observed. Nevertheless, when massive initial swelling occurs shortly after exposure to the medium the high release rates and loss of extended release from the matrices can be expected. In media with critical concentration of solutes, that effect the HPMC (2906) hydration, higher ability for enabling extended release from lower viscosity grades matrices is expected. In previous studies it was demonstrated that higher viscosity grades provide higher resistance to high solutes concentrations, however the studied type of HPMC (2208) was different. Further, the influence of sucrose and pectin, two commomnly present components in everyday diet, was investigated on matrix tablet behavior. The known effect of media with high sucrose concentration on HPMC matrix tablet can be obviated with the use of pectin as a matrix component or constituent of dissolution media. Beside drug release studies and morphological observations other techniques were applied for investigation and characterization of polymer solutions properties. Measurements of turbidity indicated decrease in cloud point by pectin beside the sucrose therefore lower hydration of HPMC is assumed. The interaction between sucrose and pectin was detected using differential scanning calorimetry. Moreover, rheological measurements demonstrated more expressed dominance of storage modulus over loss modulus for pectin-HPMC solution in sucrose media with respect to HPMC solution. Therefore higher entanglement of pectin-HPMC solution is assumed. For pectin-HPMC matrices in sucrose media we assume that stronger gel layer with sufficient integrity was formed and thus water ingress and drug diffusion was restricted. The explanation for controlled release from HPMC matrices in pectin-sucrose media might be in interaction of pectin-sucrose-HPMC on the matrix surface or in higher viscosity of dissolution media that effects the hydration of the matrix. However, further examinations are needed for explanation of mechanisms in investigated interactions. In physiological environment of a tablet are present besides food components also hydrodynamic-mechanic events. In final section of the thesis both segments were linked and tested. Therefore, the influence of mechanical stress on matrix tablets behavoir in media with various solutes concentration (sucrose, sodium chloride) was evaluated. The glass beads device and USP paddle apparatus were used since different mechanical stress and hydrodynamic are enabled. High (90SH-100000SR) or low (90SH-100SR) HPMC viscosity grade was incorporated in matrix with soluble (lactose) or insoluble (microcrystalline cellulose, MCC) diluent. At higher solutes concentration of tested range the higher drug release was observed in glass beads device. We assume that removal of the matrix gel layer is enhanced by matrix movement on glass beads surface. The effect is more expressed at higher solutes concentration since the lower integrity of the gel layer is proposed. Additionally, tablets erosion and morphology of hydrated matrices were monitored. By both parameters higher influence of matrix erosion using glass beads was indicated. The glass bead device enables additional insight in behaviour of HPMC matrix tablet in critical media where formation of gel layer is affected by mechanical stress. Presented findings of the doctoral dissertation contribute to an improved knowledge of influences on drug release from HPMC matrix tablets, especially with understanding of the matrix sensitivity to hydrodynamic and mechanic stress as well as matrix ability to form high integrity matrix when certain food components are present in the media. Additionally, the methodologies were developed to enable evaluation and observation of tested parameters that influence the swelling and release from matrix tablets.
Type (COBISS):	Dissertation
Thesis comment:	Univ. v Ljubljani, Fak. za farmacijo
Pages:	193 str.
ID:	15654901