Vpliv lastnosti polietilen oksida na načrtovanje in izdelavo ogrodnih tablet

doktorska disertacija

Petra Draksler (Author), Biljana Janković (Mentor)

Abstract

Hidrofilni polimeri predstavljajo osnovo večine farmacevtskih oblik (FO) s podaljšanim sproščanjem. Med njimi se pogosto uporabljajo visokomolekularni polietilen oksidi (PEO), ki predstavljajo netoksične, neionske in dobro topne polimere. Kritična lastnost PEO polimera je njegova molska masa, ki vpliva na lastnosti polimera na nivoju raztopin, filmov, prahov in tablet. Poznavanje lastnosti, na katere vpliva, je ključno za ustrezno načrtovanje ogrodnih tablet z željeno kinetiko sproščanja ter zagotovitev enakomerne in varne plazemske koncentracije zdravilne učinkovine (ZU). Prav zaradi naštetega smo v sklopu doktorske naloge želeli določiti kritične lastnosti PEO polimera in pokazati, kako vplivajo na končne lastnosti pripravljenih PEO polimernih raztopin, filmov, prahov in tablet. Sistematično smo preučevali vplive PEO polimerov z različnimi molskimi masami (1 x 106 g/mol, 2 x 106 g/mol in 4 x 106 g/mol) in njihovih koncentracij na lastnosti njihovih raztopin, filmov, prahov ter tablet s poudarkom na pojasnjevanju razlik v kinetiki sproščanja ZU iz pripravljenih ogrodnih tablet. S pomočjo rotacijske in oscilacijske metode za določanje viskoznosti polimerov smo med proučevanimi raztopinami izbranih molskih mas PEO zaznali značilne razlike in potrdili, da je molska masa kritična lastnost polimerov, ki vpliva na viskoznost pripravljenih raztopin PEO in posledično tudi na njihove lastnosti na nivoju filmov in tablet. S pomočjo oscilacijske metode smo določili kritične koncentracije raztopin, ki predstavljajo koncentracijo polimera v raztopini, pri kateri pride do nastanka gela. Kritične koncentracije raztopin padajo z naraščajočo molsko maso in znašajo za PEO z molsko maso 1 x 106 g/mol 4,4 %, za PEO z molsko maso 2 x 106 g/mol 3,2 % ter za PEO z molsko maso 4 x 106 g/mol 1,8 % koncentracije polimera. V nadaljevanju raziskave smo uporabili še metode rentgenske praškovne difrakcije (XRD), diferencialne dinamične kalorimetrije (DSC), ozkokotnega rentgenskega sipanja (SAXS), širokokotnega rentgenskega sipanja (WAXS) in nanovtiskovanja, s pomočjo katerih smo želeli potrditi razlike med posameznimi PEO molskimi masami še na nivoju filmov in prahov. Z metodami DSC, XRD in WAXS ter metodo nanovtiskovanja nismo zaznali razlik med posameznimi PEO molskimi masami na nobenem izmed nivojev, medtem ko so rezultati metode SAXS potrdili drugačno fizikalno obnašanje PEO z molsko maso 4 x 106 g/mol na nivoju prahov kot posledice različne velikosti nanostruktur in razlike v fraktalnih dimenzijah površin, kar vpliva na odpornost sistema za difuzijo in upočasnjuje sproščanje ZU, kar smo naknadno potrdili tudi z rezultati metod za sproščanje na nivoju tablet. Dodatno smo s pomočjo DSC metode z dodatkom optične mikroskopije z grelno mizico določili entalpijo koalescence PEO prahov med 164 °C in 170 °C. Povezali smo razlike v fraktalnih dimenzijah površin, pridobljenih z metodo SAXS, in razmerjem med entalpijo koalescence ter talilno toploto, ki sta bili pridobljeni z metodo DSC, in na osnovi tega razmerja ločili posamezne molske mase PEO polimerov. Ugotovili smo, da lahko z metodo nanovtiskovanja na nivoju filma statistično značilno razlikujemo med različnimi vrstami polimerov (PEO, hidroksipropilmetil celuloze (HPMC), ksantana in polivinil alkohola (PVA)). Zaznane razlike na nivoju PEO raztopin, prahov in filmov smo v nadaljevanju potrdili na nivoju tablet s pomočjo magnetnoresonančnega slikanja (MRI). Identificirali smo penetracijsko, nabrekajočo in erozijsko fronto, ki nastajajo med nabrekanjem PEO polimerov z izbranimi molskimi masami, in vrednotili vpliv vodotopnih pomožnih snovi in ZU nanje. Ogrodne tablete smo izpostavili statičnim pogojem (brez pretoka) in dinamičnim pogojem (pretok medija: 12 ml/min in 64 ml/min). Pokazali smo, da je sproščanje ZU značilno hitrejše v primeru dinamičnih pogojev in se še pospeši s povečanjem pretoka medija. Nasprotno je pri statičnih pogojih hitrost nabrekanja PEO ogrodnih tablet neodvisna od njegove molske mase. Razlike med posameznimi PEO molskimi masami je moč zaznati le v začetni hitrosti penetracije medija, ki je največja pri PEO z največjo molsko maso (4 x 106 g/mol), pri nižjih molskih masah (1 x 106 g/mol in 2 x 106 g/mol) pa je hitrost penetracije medija v ogrodne tablete primerljiva, kar je posledica razlik v kristalnosti in kompleksnosti strukture polimera, ki se z naraščanjem molske mase zmanjšujeta. Nasprotno je hitrost erozije največja pri PEO z najnižjo molsko maso in se sorazmerno poveča pri vpeljavi dinamičnih pogojev. Razlike v debelinah gelov so posledica razlike v viskoznosti nastalih gelov in povezav med molekulami polimera, ki so odvisne od molske mase PEO in dodatka vodotopnih pomožnih snovi (polnil, veziv, polietilen glikola), ki dodatno pospešijo nastanek in razpad gela ter posledično sproščanje ZU iz ogrodnih tablet. Zaključke smo dodatno potrdili še s pomočjo izračunanih modelov in dokazali, da je pri statičnih pogojih sproščanje ZU iz ogrodnih tablet nadzorovano z difuzijo, delež sproščene ZU pa močno korelira (determinacijski koeficient (r²) = 0,91) z debelino nastale gelske plasti. Pri dinamičnih pogojih je sproščanje ZU pogojeno z difuzijo ZU in erozijo polimera, kar potrjuje tudi povezava med koeficientom erozije in debelino gelske plasti (r2 ≥ 0,98). Na nivoju tablet smo izdelali binarne sisteme PEO polimerov z izbrano molsko maso in ZU ter jim določili perkolacijski prag. Perkolacijski prag dobro kolerira z molsko maso (r² = 1,00) in za PEO z molsko maso 1 x 106 g/mol znaša 18 %, za PEO z molsko maso 2 x 106 g/mol 16 %, za molsko maso PEO 4 x 106 g/mol pa 12 %. Pokazali smo, da dodatek vodotopnih pomožnih snovi in povečana površina tablet značilno povečata (> 27 %) perkolacijski prag PEO polimera z molsko maso 2 x 106 g/mol. Rezultate smo dodatno podkrepili s korelacijami z in vivo rezultati, na podlagi katerih smo pokazali dobro ujemanje med viskoznostjo raztopin in maksimalno plazemsko koncentracijo (Cmax) (r² = 1,00) ter površino pod krivuljo (AUC) (r² = 0,94). Prav tako smo pokazali dobro korelacijo (r² ≥ 0,88) med in vivo podatki (Cmax in AUC) in elastičnim modulom (E), pridobljenim z metodo nanovtiskovanja. V zadnjem delu naloge smo pokazali, da je z uporabo ustrezne koncentracije (53 %) PEO polimera z molsko maso 5 x 106 g/mol mogoče izdelati enako učinkovite in robustne ogrodne tablete, kot jih imajo ogrodne tablete, ki vsebujejo 37 % HPMC K4M (tip substitucije 2208). Prikazali smo tudi, kako izbira in vitro metode za vrednotenje mehanske odpornosti ogrodnih tablet vpliva na podobnost med izbranima PEO in HPMC FO. Z raziskavami, uporabljenimi v naši doktorski nalogi, smo potrdili, da je molska masa ključna kritična lastnost PEO polimera, ki določa mehanske lastnosti njegovih prahov, raztopin, filmov in tablet.

Keywords

polietilen oksid;lastnosti PEO polimera;ogrodne tablete;lastnosti polimerov;

Data

Language:	Slovenian
Year of publishing:	2020
Typology:	2.08 - Doctoral Dissertation
Organization:	UL FFA - Faculty of Pharmacy
Publisher:	[P. Draksler]
UDC:	532.135:678.7(043.3)
COBISS:	25937667
Views:	146
Downloads:	0
Average score:	0 (0 votes)
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Other data

Secondary language:	English
Secondary title:	ǂThe ǂinfluence of polyethylene oxide properties on design and manufacture of matrix tablets
Secondary abstract:	Hydrophilic polymers represent the basis for prolonged-release dosage forms. High molecular weight (Mw) polyethylene oxides (PEO), which are non-toxic, non-ionic and well-soluble polymers, are commonly used. The Mw of the PEO polymer is a crucial property that determines the properties of the polymer on the solutions, films, powders, and tablets levels. Identification of these properties is crucial for the proper design of the matrix tablets with the desired release kinetics and constant and safe plasma concentration of the active substance. Our doctoral thesis thus focused on the determination of the critical properties of the PEO polymer and their impact on the final properties of prepared PEO polymers on the solutions, films, powders, and tablets levels. We systematically studied the impact of PEO polymers with several Mw (1 x 106 g / mol, 2 x 106 g / mol and 4 x 106 g / mol) and their concentrations on the properties of their solutions, films, powders and tablets, with emphasis on explaining the difference in the release kinetics of the active substance from the prepared matrix tablets. Using the rotation and oscillation methods for determining polymer viscosity, we detected significant differences between the studied solutions of selected Mw of PEOs. We confirmed that Mw is a crucial property of polymers that determines the viscosity of prepared PEO solutions and consequently also their properties on the films and tablets levels. Using the oscillation method, we determined critical solution concentrations, which represent the polymer solution concentration at which the gel is formed. The critical polymer solution concentrations decrease as the Mw increases, and were 4.4% for a PEO with Mw of 1 x 106 g / mol, 3.2% for a PEO with Mw of 2 x 106 g / mol, and 1.8% for a PEO with Mw of 4 x 106 g / mol. Further, we used X-ray diffraction (XRD), differential dynamic calorimetry (DSC), small-angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS), and nanoindentation (NI) methods to confirm the differences between individual Mw of PEOs on the films and powders levels. No differences between individual Mw of PEOs on any of the studied levels were detected using the DSC, XRD, WAXS, and NI methods, while results obtained with the SAXS method confirmed a different physical behaviour of PEO with a Mw of 4 x 106 g / mol on the powders level due to the differences in the size of nanostructures and fractal dimensions of surfaces, which have an impact on the resistance of the diffusion system, and slow down the release of the active substance. Additionally, we used the DSC method with hot-stage optical microscopy to determine the heat of coalescence for PEO powders bteween 164 and 170 °C. The correlation between fractal surface dimensions obtained by the SAXS method and the ratio between the heat of coalescence and the heat of fusion measured by the DSC method indicates the differences between the selected PEO polymer Mws. We established that at the film level, the NI method can detect statistically significant differences between the different types of polymers (PEO, hydroxypropyl methylcellulose (HPMC), xanthan, and polyvinyl alcohol (PVA)). Further on, the detected differences in the solutions, powders, and films levels were confirmed on the level of tablets by using magnetic resonance imaging (MRI). We identified the penetration, swelling, and erosion fronts that form during the swelling of PEO polymers with selected Mw, and evaluated the effect water-soluble substances (excipients and active substance) have on them. The matrix tablets were exposed to static (no medium flow) and dynamic (medium flow: 12 ml / min and 64 ml / min) conditions. The release of the active substance was significantly faster under dynamic conditions and was even further accelerated by increased media flow. Under static conditions, the swelling rate of the PEO matrix tablets is independent of its Mw. The differences between individual PEO Mw are detected only at the beginning of the medium penetration rate. This rate is the highest in PEOs with the highest Mw (4 x 106 g/mol), and comparable in PEOs with lower Mw (1 x 106 g / mol and 2 x 106 g / mol) due to the differences in the crystallinity and complexity of the polymer structure, which decrease as the Mw increases. In contrast, the erosion rate is the highest in PEOs with the lowest Mw. It becomes proportionaly pronounced under dynamic conditions. The differences in gel thickness are the result of different levels of viscosity of the formed gels and polymer connections, which depend on PEO Mw and the addition of water-soluble excipients (fillers, binders and polyethylene glycol), which accelerate the formation and decomposition of the gel and cause the release of the active substance from the matrix tablets. Our conclusions were further confirmed by model calculations, and we proved that under static conditions the release of the active substance from matrix tablets is diffusion-controlled, and the proportion of the released active substance strongly correlates (r2 = 0.91) with the thickness of the formed gel layer. Under dynamic conditions, the release of the active substance depends on both processes; diffusion of the active substance and erosion of the polymer, which is confirmed by the relationship between the erosion coefficient and the thickness of the gel layer (r2 ≥ 0.98). On the level of tablets, we prepared binary systems of PEO polymers with selected Mw and the active substance, and determined their percolation threshold. The percolation threshold correlate well with Mw (r² = 1.00), and was 18% for PEO with Mw of 1 x 106 g / mol, 16% for PEO with Mw 2 x 106 g / mol, and 12% for PEO with Mw 4 x 106 g / mol. We concluded that the addition of water-soluble excipients and the increased surface area of tablets significantly increased (>27%) the percolation threshold of the PEO polymer with a Mw of 2 x 106 g / mol. Our results were further supported by the correlations with in vivo results, and demonstrated a good correspondence between solution viscosity and the maximum plasma concentration (Cmax) (r² = 1.00), as well as with area under the curve (AUC) (r² = 0.94). Additionally, good correlation (r² ≥ 0.88) was detected between the in vivo data (Cmax and AUC), and the elastic modulus (E) determined by the NI method. In the last part of our thesis, we showed that by use of appropriate PEO polymer concentration (53%) with Mw of 5 x 106 g / mol, we can produce matrix tablets with efficacy and robustness properties similar to those of matrix tablets containing 37% HPMC K4M (substitution type 2208). We showed how the choice of in vitro methods for evaluating the mechanical resistance of matrix tablets impacts the similarity between the selected PEO and HPMC dosage forms. Through research concluded within the scope of our doctoral thesis we showed that Mw represents a crucial property of the PEO polymer in that it determines the mechanical properties of its powders, solutions, films, and tablets.
Secondary keywords:	Reologija;Polimeri;
Type (COBISS):	Dissertation
Thesis comment:	Univ. v Ljubljani, Fak. za farmacijo
Pages:	XII, 143 str.
ID:	15504116