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Simulated migrating motor complex and its impact on the release properties of hydrophilic matrix systems
Journal of Drug Delivery Science and Technology 55 (2020) 101338
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Journal of Drug Delivery Science and Technology journal homepage: www.elsevier.com/locate/jddst
Simulated migrating motor complex and its impact on the release properties of hydrophilic matrix systems
T
Helena Vrbanaca, Jurij Trontelja,∗, Sandra Berglezb, Klemen Krefta, Dejan Krajcarb, Igor Legenb a b
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia Lek Pharmaceuticals, Inc., a Sandoz Company, Verovškova Ulica 57, 1000, Ljubljana, Slovenia
ARTICLE INFO
ABSTRACT
Keywords: Stomach Migrating motor complex (MMC) Matrix tablets HPMC Dissolution testing Erosion SmartPill® Wireless motility capsule (WMC)
Following ingestion, the dosage forms are exposed to high mechanical stresses, mainly due to the movement of gastric musculature and passage through the sphincters. The generated mechanical forces can have a profound impact on the release properties of the mechanically sensitive formulations, which may result in greater in vivo variability. The aim of the study was to prepare a new programme sequence for our bio-relevant in vitro dissolution model, the advanced gastric simulator (AGS), which would closely resemble the four phases of the migrating motor complex (MMC) and to evaluate the influence of the simulated mechanical stress on the drug release rate and the gel layer properties of the model hydrophilic matrix system. For this purpose, two kinds of HPMC matrix tablets were used, which have previously been tested in vivo. In vivo pressure measurements in human fasted stomach were gathered from literature and compared to the measurements obtained with the wireless motility capsule (WMC) in AGS. Dissolution studies conducted in AGS were compared to the experiments performed in USP2. Properties of the gel layer were evaluated with texture analysis and matrix erosion determination. Our in vitro measured pressure profiles of simulated MMC were found to be within the same range as those observed in vivo. The simulated MMC was shown to significantly affect the drug release kinetics from tested hydrophilic matrices. Compared to USP2, the AGS was shown to have a higher discriminatory power in distinguishing the differences in behaviour of the tested formulations, in accordance with in vivo data.
1. Introduction While passing along the digestive tract, orally administrated dosage forms are exposed to various mechanical and chemical influences affecting their integrity. To reach the systemic blood circulation, the active pharmaceutical ingredient (API) in conventional solid dosage forms must first dissolve in the fluids of the digestive tract to be later absorbed [1]. The estimated time of passage through the digestive tract is approximately 0–2 h for the stomach, 3–4 h for the small intestine and 8–15 h for the colon [1–3]. During this time, dosage forms are exposed to destructive mechanical forces intended to process the ingested food to smaller particles and to prepare the gastrointestinal tract (GIT) for the next meal [4–6]. Ingested dosage forms are first exposed to conditions in the stomach, which dictate the passage of the formulation or released drug into the small intestine – the major site for the drug absorption [7–9]. The frequency and the intensity of the stomach contraction waves differ in fed and fasted state conditions. The motor activity of the fasted stomach is carried out in cycles, known as the migrating motor complex
∗
(MMC). The complex lasts in average 1.5–2 h and is transferred from the stomach to the small intestine. The physiological importance of interdigestive motility of the stomach is mechanical and chemical cleansing in the process of preparation for the next meal. MMC is characterized by a fluctuation of the muscle contractions intensity that can be divided into four phases. Phase I is quiescent period of 30–60 min with no contractions present. Increased frequency and amplitude of medium-strong contractions, lasting 20–40 min are noticed in phase II. Phase III of the MMC lasts 10–20 min and is characterized by strong contractions at maximum frequency. At this point, the pylorus opens widely, thus allowing larger undigested particles to leave the stomach. In the phase IV, the intensity of the contractions decreases back to the quiescent phase I. The MMC motility is interrupted with food intake [10–12]. Controlled release dosage forms can be influenced by several physiological conditions such as pH, ions, enzymes and motility of the GIT [13]. However, they must be able to maintain the drug release within certain acceptable tolerance limits. For example, the thickness of swelled polymer layer on the hydrophilic matrix surface, which acts as
Corresponding author. E-mail address: [email protected] (J. Trontelj).
https://doi.org/10.1016/j.jddst.2019.101338 Received 26 April 2019; Received in revised form 2 October 2019; Accepted 19 October 2019 Available online 23 October 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved.
Journal of Drug Delivery Science and Technology 55 (2020) 101338
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a diffusion barrier for the drug release, is strongly dependent on several factors: composition of formulation, the friction between the formulation and the stomach wall mucosa, the amount of the mechanical pressure applied to the formulation and the composition of surrounding media [7,14,15]. The presence of food in the surrounding media of matrix tablets can affect the gel layer formation and the release properties of the formulation [16,17]. Nevertheless, among various parameters in GIT affecting drug release and absorption from matrix tablets, luminal forces are of great importance, especially in the case of mechanically sensitive dosage forms, such as hydrophilic matrices. Several in vivo studies have shown that hydrophilic matrices may be less robust than observed during in vitro experiments [18,19]. Disruption of the gel layer due to mechanical stress applied during the GIT transit may have an effect on the drug plasma levels. For instance, in vivo erosion of less robust matrix tablets can be highly variable. Due to destructive forces, a drug burst release can also be observed. The above may be reflected in highly variable plasma concentrations, manifested as low therapeutic effectiveness or increased incidences of drug adverse effects [18–21]. The extent of mechanical destructive forces of GIT wall have been evaluated with several methodologies: Kamba et al. [22] obtained a range of mechanical forces in the human stomach using Teflon® tablets with predetermined crushing strength, containing a marker drug. Bortolotti et al. [23] observed circadian antroduodenal motor activity during interdigestive and digestive period with ambulatory antroduodenal manometry. In several studies [6,24–26] the wireless motility capsule (SmartPill®) has been used to evaluate the motility-related parameters along the GIT. Several in vitro models simulating conditions occurring in vivo have been proposed. Garbacz et al. [8,27] have developed stress test device to simulate the impact of physiological mechanical stress occurring during GIT passage. Bogataj et al. developed glass bead device enabling physical contact and movement of the tablet on the surface of the glass bead layer [28]. Klančar et al. [21] modified USP3 apparatus with addition of the plastic beads in the reciprocating cylinder, establishing a level A in vitro-in vivo correlation. In addition, more complex devices were also developed, such as TIM-1 simulator, which enables simulation of conditions present in stomach as well as in the small intestine [29]. With intention for better simulation of the motility, hydrodynamic and mechanical stress in the GIT, Legen et al. [30] developed innovative biorelevant intestinal model for simulating peristaltic action (IMSPA) and advanced gastric simulator (AGS). Biorelevant in vitro dissolution testing aims to bring a closer prediction of the dosage form performance in vivo. The main goal is finding a strong correlation between in vitro drug release kinetics and in vivo plasma levels which can reduce the number of necessary clinical trials during the new formulation development. The closer the resemblance of the biorelevant dissolution systems to the actual in vivo conditions, the better predictability of in vivo formulation behaviour is expected. Therefore, assessing the similarity of the newly developed in vitro system performance to the true in vivo conditions is highly relevant for the evaluation of its predictive power and its applicability to IVIVC studies. In the present study, we prepared a programme sequence on the AGS to simulate similar motility and pressure events as measured in fasted stomach in vivo and studied its’ impact on the release properties of chosen HPMC matrix tablets.
contains a battery and sensors for pH, temperature and pressure, all enclosed in a polyurethane shell. The WMC transmits real time measurements of its immediate surroundings to a data receiver device, at a radio carrier frequency of 434 MHz. Sensors in the capsule are able to measure the pH values within the range of 0.05–9.0 pH units with an accuracy of ± 0.5 pH units, the pressure values in the range of 0–350 mmHg with an accuracy of ± 5 mmHg and the temperature within 25–49 °C with an accuracy of ± 1 °C. The recorded data can be downloaded from the data receiver through the docking station with a USB connection to a Windows PC compatible computer [26,31,32]. 2.2. Tablets Two kinds of HPMC matrix tablets were used in this study; the formulation A containing Methocel K15 M (20% of tablet mass) and the formulation B with a mixture Methocel K100LV (10% of tablet mass) and Methocel K15 M (35% of tablet mass) polymer (DOW, California, USA). The model drug has one dissociation constant and exists mainly in anionic form under weak-basic conditions. The model drug has low solubility and shows good apparent permeability throughout the GIT, therefore it is classified as BCS class II. The calculated dose/solubility volume in aqueous solutions within the physiological pH range of 1–7.5 is less than 16 mL. The dissolution testing was thus being undertaken under sink conditions. The reagents for dissolution testing and HPLC assay were purchased from Merck, Germany. This includes KH2PO4, HCl titrisol, NaCl, KCl, CaCl2x2H2O, Na2EDTA (Titriplex® III) and glacial acetic acid. SIF powder was purchased from Biorelevant.com Ltd. Acetonitrile (HPLC gradient grade) and methanol (ultra HPLC gradient grade) were obtained from J.T.Baker, USA. 3. Methods 3.1. Assessment of motility related parameters The capsule activation was done according to manufacturer's instructions. For testing the prepared programme sequence, 0.01 M HCl with 2 g/ L NaCl was used for all experiments. The data receiver was placed in a close proximity to the dissolution apparatus (AGS) during the experiment and was not further apart than 50 cm from the WMC. Each test lasted 20 min and was performed in 6 parallels. During the test performance, motility-related parameters were recorded with the function of live monitoring of the transmitted data to the MotiliGi software. At the end of the experiments, the WMC was deactivated and data was downloaded from the data receiver to the MotiliGi software. 3.2. Advanced gastric simulator (AGS) – apparatus description Advanced gastric simulator is a dynamic in vitro model, simulating the function of the human stomach. Its' advantages compared to conventional dissolution apparatus, such as USP1 or USP2, are realistic mimicking of the stomach wall dynamic and its' contents movement. The apparatus main elements include a flexible vessel, eight mechatronic constriction mechanisms, a “pyloric” valve, temperature controlled chamber and computer software. The vessel is a soft and flexible container made of silicone rubber (DragonSkin FX, Smooth-On Inc., USA). The vessel retains its' shape when filled with dissolution media and relaxes when emptied, without significant shrinkage. The vessel measures approximately 30 cm along greater curvature and approximately 24 cm along lesser curvature. At its’ widest point, it measures 10 cm and narrows towards the pyloric part to approximately 1 cm. On the inner side of the thin walls, the vessel is wrinkled in the longitudinal direction, allowing the well reproducible wall deformation during the contractions. The vessel is open at both of its ends; the top inlet is wider and resembles the cardia while the lower end of the vessel narrows to a
2. Materials 2.1. Wireless motility capsule For the purpose of this study, the SmartPill® (WMC) data recording device was used. The WMC dimensions are 26.8 mm in length and 11.7 mm in diameter. Usually, it is administrated orally for diagnostic purposes in gastroenterology. The measurements of GIT transit time conducted with WMC are a useful tool in recognition of motility disorders, such as gastroparesis and chronic constipation. The capsule 2
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Fig. 1. The set-up of advanced gastric simulator (right) and 3D scan of flexible vessel from different angles (left).
tubular opening, resembling the pyloric sphincter. The flexibility of the silicone rubber enables comparable volumes (up to 1 L) and mechanical properties of the vessel to those of the human stomach. AGS and 3D scan of the flexible vessel from different angles are presented in Fig. 1. The vessel's shape deformation is triggered by eight (iris) constriction mechanisms (NT57-586, Edmund Optics, United States), arranged along the outer surface of the vessel. The majority of the constriction mechanisms are gathered at the lower (antropyloric) part of the stomach, where strong mixing and mechanical processing of solid food is expected in vivo. The space between constriction mechanisms is 1.5–2 cm. Each constriction mechanism consists of 20 spring steel blades, attached to a custom-made stainless steel worm gear (Fig. 2). Changing the aperture diameter leads to change of shape and volume of the flexible vessel. Synchronised opening and closing of the constriction mechanisms with time delay to each other, simulates a contraction travelling along the stomach wall. Duration of a travelling contraction depends on the individual program settings. In our study, the duration of an average contraction was 30–40 s. However, it should be noted that each new contraction begins before the previous one is completed, providing up to 3 contractions per minute. Actuation of the individual constriction mechanism is controlled by an electric step motor (ST2818, Nanotec electronic GmbH & Co., Germany), connected to a computer with USB/ RS485 converter (Brainboxes). Custom-made software (Faculty of Engineering, University of Ljubljana, Slovenia) enables a controlled motion of each constriction mechanism. The software allows separate settings of the amplitude and period that the user can save as an
individual program. With the “program sequence” feature, the software allows user to select multiple programs with different settings and automatic shuffle between the selected programs in the following order. Such program sequence enables a creation of realistic gastric movement patterns. Furthermore, the lower, tubular outlet of the flexible vessel is tightened with a custom made “pyloric” valve consisting of two steel pins (PFCLEA-D8-L55-M4, Misumi United States), one positioned stationary relative to the stomach container and the other movable, attached to a liner slide (SE2BZ10-115, Misumi, United States). Opening of the pyloric valve and thus the flow rate from the stomach is controlled with a separate custom-made software (Faculty of Engineering, University of Ljubljana, Slovenia). All of the above listed components of the device – constriction mechanisms, flexible vessel, step motors with a worm gear and “pyloric” valve are positioned inside a thermal chamber (SP-55 Easy, Kambič, Slovenia), which enables the standard temperature conditions of 37 °C during performance of dissolution tests. The structure and the function of individual parts of the apparatus were described also in our previous works [30,33–35]. 3.3. Dissolution testing Dissolution tests were performed in AGS with prepared programme sequence, simulating MMC. The volume of dissolution media, resembling fasted stated gastric fluid (FaSSGF pH 1.6 or 0.01 M HCl with ions) was 250 mL. FaSSGF pH 1.6 was prepared according to Biorelevant.com Ltd instructions. 0.01 M HCl with ions was prepared by adding 10 mL of 1 M HCl titrisol® to 900 mL of deionised water and further dissolving 4 g of NaCl, 1.20 g of KCl and 0.084 g of CaCl2 x 2H2O and then filling the volume of the flask to 1000 mL. The media temperature was set to 37 ± 0.5 °C. For each time point, 10 mL sample was manually collected and replaced with respective dissolution media heated to 37 ± 0.5 °C. The samples were filtered through LLG-Syringe nonsterile filters (PVDF, 0.45-μm) to 2.0-mL vials. The sampling time points for experiments in AGS were 15, 30, 45, 70, 80, 90, 105, 110, 115 and 125 min. After completion of the test in AGS, the tablets were carefully removed from the flexible vessel, placed in Japanese basket sinkers and transferred to USP2. A total of 900 mL of 50 mM phosphate buffer pH 6.8, preheated to 37 ± 0.5 °C was poured in standard vessels with paddles. Tests were performed using dissolution system (AT dissolution apparatus, Xtend™, Sotax, Switzerland) with rotating speed of 75 rpm, coupled with an automatic sampler (CP Xtend™ pump, Sotax, Switzerland). The amount of the drug dissolved in each vessel was determined at 60, 120, 180, 240, 300, 360, 420, 480, 540, 600 min. Samples of 1.7 mL were automatically collected and filtered through the Full Flow 1 μm filters (P/N FIL001-EW) into 2.0-mL vials. Dissolution test using only USP2 was first performed in 900 mL of acidic media (FaSSGF pH 1.6 or 0.01 M HCl with ions) with the
Fig. 2. Schematic presentation of individual constriction mechanism. 3
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following sampling time points: 15, 30, 60 and 120 min. After that, the tablets in Japanese sinkers were carefully removed and the dissolution media was replaced with 900 mL of 50 mM phosphate buffer pH 6.8 preheated to 37 ± 0.5 °C within a few minutes. Tablets were then placed back into vessels and testing was continued with the following sampling time points: 180, 240, 300 360, 420, 480, 540, 600, 660, 720 min. Samples of 1.7 mL were automatically collected and filtered through the Full Flow 1 μm filters (P/N FIL001-EW) to 2.0-mL vials. Experiments were performed in three parallels. The samples were analysed using HPLC-UV.
Norwood, Massachusetts USA). Formulations were placed in dissolution vessels (in AGS and USP2) under the same conditions as for dissolution testing, described above. Tablets were removed from media at predetermined time points and tested with flat-end, round shaped stainless steel probe with Ø 2 mm tip and length of 30 mm. All experiments were performed in triplicate for each tested time point. Texture analyser was equipped with 100 N load cell and Bluehill 3 software. During analysis the probe moved toward the tested tablet at a rate of 0.5 mm/s, until the surface of the tablet was detected at the force of 0.005 N. At this point, the probe penetrated the gel layer at the rate of 0.2 mm/s until the maximal non-destructive resistance force of 1 N was detected, at which point the probe retracted to its original position. The properties of the gel layer were studied at 60 and 120 min for experiments in USP2 and at 60, 100 and 125 min for experiments in AGS followed by USP2 and collected by texture analyser software (Bluehill3). The tests were not performed at later time points since the amount of the remaining dry core was insignificant and the probe with a force of 1 N would penetrate it. The thickness of the swollen matrix was determined by measuring the total travel distance of the needle probe.
3.4. Analysis of dissolution samples The amount of model drug in collected samples was quantified using a validated HPLC method with UV-detection (Water separation module 2695D, Waters, USA) at 254 nm. The HPLC system was equipped with analytical column Chromolith Speed ROD RP-18e (Merck, Darmstadt, Germany) with dimensions of 50 × 4.6 mm. The column was maintained at 36 °C and samples at 4 °C during analysis. The mobile phase consisted of acetonitrile/methanol/NaEDTA/glacial acetic acid in the volume ration 275:175:550:1. The NaEDTA solution was prepared by dissolving 1 g of NaEDTA in 5000 mL of purified water. The volume of injected samples was 100 μm. At flow rate of 2 mL/min, the retention time of the model drug was around 1 min and the total run time of the analysis was 1.3 min for the injected sample.
3.7. Erosion studies Each tablet was weighted before dissolution testing. At 120, 360 and 720 min of the experiments in USP2 and at 125, 365 and 725 min of the experiments in the AGS followed by USP2 tablets were carefully removed from the working vessel, lightly patted with tissue paper to remove any liquid excess and dried in vacuum chamber at 60 °C until constant weight was achieved. Percent of eroded matrix was determined in triplicate for each time point using the following equation:
3.5. Pharmacokinetic study protocol Both of the formulations were tested in vivo under fasting conditions within two separate pharmacokinetic (PK) studies, conducted in separate contract research organisation (CRO). Tested formulations were thus not directly compared, however both of them were comparative studies, using the same reference formulation C (Table 1). 24 healthy male volunteers were included in the randomized, crossover PK study comparing formulation A and C. A total of 23 blood samples were collected up to 96 h post-dose from each individual in each period. There was a 14-day washout period between both treatments. The PK study comparing formulations B and C was also an open-label, randomized crossover study conducted on 26 volunteers. A total of 24 blood samples were collected up to 96 h post-dose from each individual in each period. The washout before the second period was at least 14 days. Both of the studies were approved by the National Health Authority and Independent Ethics Committee. Concentration of the active ingredient in plasma samples were determined by a high-performance liquid chromatography connected to mass spectrometry, validated according to the FDA guidelines for bioanalytical method validation.
Erosion (%) =
4.1. Mechanical biorelevance of the prepared programme sequence Established relationship between the intensity of the tested programme and the generated pressure profiles is necessary in order to develop motility patterns, closely resembling the in vivo gastric dynamics. The correlation between the aperture diameter of the constriction mechanism and the average and maximum generated pressure peak is shown in Fig. 3. The measurements were performed with aperture diameters ranging from 25 to 40 mm. It should be noted the highest possible closing of the constriction mechanism is up to 20 mm, although, due to the size of the WMC and the overall thickness of the surrounding flexible vessel, such a programme was not tested to avoid damage of the WMC. The correlation for the aperture diameter and the average pressure measured was linear (R2 = 0.9466) and for the maximal observed pressure peak, exponential (Fig. 3, note: the scale of the x-axis is descending). Individual maximal observed pressure peak was 451 mbar, which closely coincides with the reported in vivo detected maximal pressure peak (460 mbar [25]). The dependence between constriction mechanism aperture and applied pressure on the WMC has been already investigated in a previous study [33], however the set-up of tested programmes and the range of the studied correlation differed in both studies. The initial position of the constriction mechanisms in this study was 15 mm wider (starting position of 65 mm) and the range of closed aperture diameter was from 25 to 40 mm. Average and maximal pressure peaks were measured at 7 different apertures. In our study average pressures are higher and the correlation for the occurring maximal pressure peaks is exponential compared to already published data [33]. The step motors, which drive the constriction mechanisms have a constant torque at all rotational speeds (depending on the setting
Table 1 Pharmacokinetic parameters of formulations A and B compared to the same refrence product C. PK parameters
Cmax [ng/mL] AUCt [h*ng/ mL] tmax [h] Cmax [ng/mL] AUCt [h*ng/ mL] tmax [h]
formulation A vs C
formulation B vs C
106.09 101.06
– –
90% confidence interval 99.68–113.17 95.87–106.84
– 92.51 69.58
12.80 – –
– 97.66–99.75 99.99–102.33
–
16.00
–
100%
4. Results
The properties of the gel layer on the matrix surface were determined with Instron 3342 single column texture analyser (Instron,
ratio
remaining dry weight dry weight
Where: dry weight – initial tablet weight; remaining dry weight – tablet dry weight at each sampling time.
3.6. Texture analysis of hydrated tablets
parameter
dry weight
4
Journal of Drug Delivery Science and Technology 55 (2020) 101338
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Fig. 3. The average pressure values and maximal pressure peaks (mbar) detected with SmartPill® as a function of the maximal aperture of the AGS constriction mechanisms.
of the opening - closing period). The motor torque is then transferred to the constriction mechanism, where different forces are expected due to different aperture dimensions. The exponential correlation of the maximal observed pressure peaks therefore suggests that there is a dependence on the starting point of the constriction mechanism. Consequently, the peak pressures to which a formulation is exposed to during iris contraction depends on its size. With the help of the observed correlation, programmes simulating the individual MMC phases were designed. The motility-related parameters obtained with simulated MMC and in vivo measurements gathered from the available literature are presented in Table 2. The range of average pressure, generated by simultaneous closing and opening of the constriction mechanism in the prepared program sequence was 71–131 mbar, which is lower than in vivo (30–304 mbar [25]), but nevertheless within the same order of magnitude. Maximum peak amplitude detected with WMC for the tested sequence was 451 mbar, which coincidences with in vivo detected maximal pressure peak. The difference in extent of the generated mechanical stress by individual program can be observed in Fig. 4. During the program ags_MMC_1, which simulates the phase 1 of MMC, contractions were not detected. On the other hand, average detected motility during the rest of the simulated MMC phases was 3 contractions/ min.
4.2. Comparing drug release using AGS and USP apparatus 2 In Fig. 5, extended drug release profiles are presented in different acidic media: FaSSGF pH 1.6 and 0.01 M HCl with ions. Dissolution tests were performed firstly in FaSSGF pH 1.6 or in 0.01 M HCl with ions for 2 h and continued in phosphate buffer pH 6.8. Dissolution in acidic media, simulating the fasted stomach conditions, was performed in AGS using the prepared program sequence or in USP2 at the stirring rate of 75 rpm, and in both cases continued in USP2 with the speed rotation of 75 rpm. In the case of FaSSGF pH 1.6 the noteworthy differences can be observed – higher release rates are generated by AGS (in 120 min of experiments approximately 10% higher drug release for formulation A and approximately 8% higher for formulation B) with respect to USP2, which is also evident in further dissolution in USP2 in the case of both formulations tested (approximately 14% higher drug release for formulation A and approximately 8% higher for formulation B). In the case of 0.01 M HCl with ions release was slightly higher in the case of USP2, however there were no statistically significant differences observed in drug release profiles with both dissolution methods in this media. Additionally, greater difference in the release rate of the model drug from the formulations A and B can be observed in FaSSGF pH 1.6 using the dissolution method with AGS with respect to the tests performed only in USP2. In the case of 0.01 M HCl with ions, no significant differences in drug release profiles of formulations A and B were observed.
Table 2 Comparison of the motility-related parameters obtained in the AGS to the in vivo available data. AGS: MMC program sequence MMC phase
program
duration [min]
maximum pressure peak amplitude [mbar]
mean pressure peak amplitude [mbar]
mean contractions/min
I. II. III. IV.
ags_MMC_1 ags_MMC_2 ags_MMC_3 ags_MMC_4
60 40 20 5
16 (6) 181 (33) 451 (101) 181 (33)
3 (6) 71 (14) 130 (19) 71 (14)
0 3 3 3
maximum pressure [mbar]
contractions/min
reference
notes
406 NA NA NA NA 87
NA NA 0.85 NA 2–3 NA
[25] [23] [24] [23] [24] [22]
WMC study not a WMC study (antroduodenal manometry) not a WMC study (antroduodenal manometry) not a WMC study (antroduodenal manometry) not a WMC study (antroduodenal manometry) not a WMC study (teflon tablet with predetermined strength)
in vivo available data phase pressure [mbar] fasted II. III. fasted
30-304 (range) 53 53 107 117 NA
Standard deviation values of experiments in AGS are presented in brackets next to in vitro experimental values. 5
(0.02) (0.31) (0.13) (0.31)
Journal of Drug Delivery Science and Technology 55 (2020) 101338
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Fig. 4. Pressure profiles [mmHg] of prepared program sequence of AGS obtained with SmartPill®. Each event point marks the beginning of individual program, resembling the respective MMC phase.
Fig. 5. Drug release from formulation A (upper diagrams) and B (lower diagrams) I tested media, in both conventional (USP2) and a non-conventional (AGS combined with USP2) dissolution method.
4.3. Properties of the gel layer and tablets erosion
(resistance to the rupture of dry tablets). For formulation A and 203.8 ± 3.3 mg and 127–163 N for formulation B. Textural analysis of the gel layer covered the time points of the simulated gastric passage, which are expected to be crucial for the later drug release. Noteworthy
Tablets measured 6.8 mm in diameter and 3.0 mm in axial direction, with the average weight of 208.3 ± 2.3 mg and strength of 107–119 N 6
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points capturing the whole release profile. An independent-samples ttest was used to check the mechanical influences of both dissolution methods on the tablet mass loss. Significant differences (p < 0,05) in the amount of eroded gel layer were observed for formulation A in both dissolution media (Fig. 8, marked with stars). The percentage of eroded gel layer of formulation A at 2 h time point was significantly higher when test was conducted in AGS. In FaSSGF pH 1.6 the amount of erosion was significantly higher for both formulations when tests were conducted with AGS, at 2 h time point as well as at the end of the test. On the other hand, in 0.01 M HCl with ions the amount of eroded gel layer for formulation B was not significantly different for both dissolution methods (Fig. 8). 5. Discussion One of the major challenges in the process of new formulation development is to develop a dissolution method with high discriminatory power and ability to predict the clinical efficacy of a new formulation. Current compendial dissolution methods are not always reliable to predict the in vivo behaviour of pharmaceutical formulation; therefore, there is a strong need of biorelevant predictive dissolution methods [36]. Variable conditions in digestive tract are quite difficult to simulate in vitro. Nevertheless, with biorelevant composition of the dissolution media [37] and innovative dissolution apparatuses [38–40], the process of achieving biorelevance in vitro is in tremendous progress. The aim of our study was to develop a program sequence for the advanced gastric simulator (AGS) closely resembling the migrating motor complex of a fasted human stomach. In vivo occurring pressure events have been simulated in vitro in previous studies [29,41]. Nevertheless, the prepared program sequence is a physiologically relevant dissolution tool capturing the principle properties of all 4-phases of MMC. The flexible vessel of the AGS is constricted circularly, resembling the gastric musculature and the pressure from the containers’ wall is transferred to its interior content. In order to simulate the
Fig. 6. Typical force – distance profiles of formulation A at specific time points of experiments conducted in AGS and USP2. The measurements below the 0.5 N threshold are below the specified precision limit (0.5 N), according to the texture analyser manufacturer (Instron).
differences were observed in the length the probe travelled when different dissolution methodologies were used. In the case of tablets tested in AGS, the extension of the probe was shorter compared to tablets tested in the USP2 due to greater gel layer deformation, abrasion and erosion caused by the constricting peristaltic action of the AGS’ flexible wall (Figs. 6 and 7). At later time points, the tablets were almost completely hydrated, forming compact gel with small amount or no dry core present at all. To further evaluate the mechanical effect of the AGS on the release properties of the tested tablets, tablet mass loss was measured in three time
Fig. 7. Extension of probe, travelling through the gel layer at different time points using different dissolution technologies. 7
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Fig. 8. Erosion of formulation A and B with different dissolution technologies.
peristaltic wave travelling along the stomach wall, the periodic rate of changing the inner diameter of each constriction mechanism can be individually programed. As it can be observed from the program settings, each program was designed to widen the contraction diameter as it approaches the antropyloric part of the stomach. The motility-related parameters obtained from available literature data and the ones observed in the AGS show that the innovative apparatus has the ability of providing similar luminal pressure effects on dosage form to the ones observed in vivo. It should be noted that some of the in vivo measured values cannot be directly compared due to the differences in the measuring technology. The tested programs exerted different pressure profiles on the WMC (Table 2). The pressure values of individual programs are in the range of in vivo measurements. Results suggest that different gastric pressure profiles can be simulated with AGS, reflecting the human physiologic MMC-pressure profile (Fig. 3). Although the AGS is a much more dynamic model compared to commercially available dissolution apparatuses, it is still too rigid in its current form compared to the human stomach to fully capture the powerful hydrodynamics and mixing of gastric content in vivo. Mechanically biorelevant dissolution models have the potential to explain the unexpected in vivo drug release profiles. Such examples are hydrophilic matrix tablets, which are prone to variable stresses along the gastrointestinal tract. As a result of these stresses, the process of swelling and eroding of the matrices could be strongly affected,
resulting in a variable plasma concentration levels or an unexpected burst release [21]. In our study, two kinds of hydrophilic matrix tablets were used in order to reflect the differences in the mechanical stress generated by the AGS and the USP2. However, it must be noted that since the SmartPill® is larger in diameter than the tablets tested, the contact with the tablets and thus the exertion of the stresses may be lower than those on the SmartPill®. Both of the formulations were previously tested in vivo within two separate pharmacokinetic (PK) studies, conducted in separate contract research organisation. Formulations were thus not directly compared, however both of them were tested with the same reference sample C (Table 1). In this PK study the Cmax ratio for A/C was 106.09% with tmax of 12.8 h, while the Cmax ratio for B/C was 92.51% with tmax of 16.0 h, indicating the in vivo release rate of the model drug from the formulation B was slower compared to formulation A. The extended drug release profiles from matrices in tested media using two dissolution methods, AGS combined with USP2 or USP2 alone, are presented in Fig. 5. In 0.01 M HCl with ions drug release was slightly faster compared to AGS. However, it should be noted that the slope of the drug release in the AGS was higher, leading to complete overlaying of the both release profiles at later time points. On the other hand, a trend of higher drug release from both formulations in FaSSGF pH 1.6 is observed when using the AGS. The rationale for the observed differences in susceptibility of the matrix for mechanic stress generated by AGS could be due to different amount of ions present in dissolution 8
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media. Higher concentration of solutes in 0.01 M HCl with ions could affect the swelling of HPMC. It has been already observed in previous studies [15,16,41–43] that the presence of ions results in the formation of a compacted gel layer on the matrix surface. This could slow down the penetration of water molecules into the formulation and thereby dissolution of the active substance and its diffusion through the gel layer to the surrounding medium. On the other hand, the model drug is classified as BCS class II due to its low solubility. FaSSGF is a biorelevant dissolution medium, containing sodium taurocholate and lecithin – surface active substances, simulating a minor part of pancreatic and bile secretions present in stomach as a result of a physiologically occurring reflux [1,37]. The presence of surfactants in FaSSGF in combination with higher shear stress generated by AGS could be the reason for the observed greater amount of the released drug. Properties of the gel layer formed on the surface of the hydrophilic matrix systems are considered as one of the key parameters affecting the release of the active ingredient. Formation of the hydrophilic gel layer is highly dependent both on water penetration and erosion rate of the fully hydrated polymer on the surface of a matrix system [45]. The process of swelling and water penetration has been reported as pH dependent [46], which is of great importance since the pH values in vivo vary, from 1 to 3 in the stomach, to 7–8 in the colon. It has been suggested that diffusion of the medium is considerably quicker at low pH values and the concentration of solution is constant in the gel layer. On the other hand, the concentration of the neutral to alkaline solution in the gel layer increases when going from the dry core of polymer to external edge of the layer. However, in our study, we have observed the erosion of the matrices already in the acidic media although the drug release was quite low, which could be due to low solubility of the model drug in acidic media. Furthermore, the degree of erosion and drug release were higher after the formulations were exposed to the K-phosphate buffer with higher pH (Figs. 8 and 5, respectively). Textural analysis of the gel layer and erosion of the matrix tablets were studied at predefined time points. Textural studies are presented as the length the needle probe has travelled through the gel layer of each tested tablet (Fig. 7), which corresponds to the thickness of the gel layer. It can be observed that the extension was shorter in the case of tablets tested in the AGS, suggesting the gel layer thickness was smaller compared to the tablets tested in the USP2. In the AGS, tablets were in contact with the wall of the flexible vessel in a greater proportion of an experiment, while the main determinant of mechanical stress in the USP2 was agitation of the dissolution media. In the latter case, the erosion of the swollen gel layer is expected to be slow, allowing the formation of a thicker gel layer. As described above, the release rate in 0.01 M HCl with ions was slightly faster in the USP2. Nonetheless, higher amount of tablet erosion measured at earlier time points of experiments (Fig. 8) indicates the thickness of the gel layer was lower for formulation tested in AGS due to presumably higher shear forces applied to the formulation surface. Dissolution rate in AGS had a higher slope, resulting in complete overlaying of the both release profiles at later time points. In previous studies, three types of ionic strength effects on the release properties of hydrophilic matrices have been observed. In some cases lower ionic strength slowed the release rate by allowing formation of a thicker and more robust gel layer [41,43,44]. In other cases, the presence of ions in dissolution media prevented hydration of polymer particles and provoked formation of incoherent gel layer. The release rate in the latter case was accelerated, in some cases even burst release was observed [15,16]. Lastly, in some cases no effect of ions present in dissolution media on the release kinetics was observed [44]. Which effect will prevail depends on both, the ionic strength of dissolution media as well as composition of the formulation. It may be assumed the ionic strength of dissolution media in our study was too low (0.09 M) to show major effects on the gel layer structure of the tested formulations. The barrier function of the tested matrices seemed to withstand the effect of the ions in dissolution media,
while outer front of the gel layer was still able to fully hydrate and thus erode more extensively during tests in AGS. In FaSSGF pH 1.6 a trend of higher drug release from both formulations in AGS corresponds to the shorter extension measured in textural analysis. The percent of eroded hydrophilic matrix is higher for tablets tested in AGS followed by USP2, confirming the importance of the gastric destructive forces for the drug release behaviour. Additionally, the influence of different type and amounts of HPMC polymer used for both formulations was observed in dissolution tests with FaSSGF pH 1.6 in AGS followed by USP2. Previous studies have shown that higher HPMC content promotes water intake into matrices, forming a complete diffusion barrier resulting in a retarded drug release [47,48]. Furthermore, slower drug release has been also observed from matrices containing higher viscosity grade HPMC polymer [49,50]. Formulation B, which contained a combination of high and low viscosity grade HPMC polymer in a higher tablet mass percentage (45%) compared to formulation A (20%), showed to be more resistant for the mechanical influences of the simulated MMC (Fig. 6) in both dissolution media. 5.1. Advantages of the AGS and future prospects In this study, AGS showed to have a higher discriminatory power in distinguishing the differences in formulation robustness and better correlation with in vivo results compared to the standard dissolution apparatus. Like most biorelevant models, AGS allows different pH and volume selection of various dissolution media, maintaining constant temperature. However, the advantage of the presented model is the anatomical similarity of the flexible vessel with the human stomach, the ability to mimic peristaltic waves and gastric emptying. The apparatus offers two types of experiments; closed loop (sampling at the upper opening of the vessel) or open loop with a flow through the “pyloric” valve. By changing the flow rate and motility, different transit times can be created. In the light of these findings, the novel device could be a very useful tool in the design of more robust formulations, which would be a great advantage primarily for patient safety. This, combined with the observed in vivo similarity of the generated pressures, sets the new system as an important scientific contribution to the research of drug release from MR formulations. 6. Conclusions In this study, we present the advanced gastric simulator programme to mimic the mechanical pressure stress on pharmaceutical formulation as observed during the 4 MMC phases in vivo. In vitro measured pressure profiles were within the range reported from in vivo studies and showed the ability of the presented model to significantly affect the drug release from mechanically sensitive hydrophilic matrix systems. Although observed differences in extended release rate of tested formulations were not significant, AGS has shown better ability to distinguish different formulation behaviour compared to USP2. However, to reach more realistic simulation of the GIT transit additional investigation of the model is required. These results will undoubtedly lead to further model optimisation for even higher confidence in prediction of the release kinetics from such formulations in patients leading to the reduction of necessary in vivo trials and better prediction and identification of nonrobust formulations. Declaration of competing interest The authors declared no conflicts of interest related to this article. Acknowledgments The authors would like to acknowledge Ms. Katja Olenik from University of Ljubljana, Faculty of Pharmacy for assistance in 9
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conducting experiments. The authors from University of Ljubljana, Faculty of Pharmacy were supported by the Slovenian Research Agency (ARRS) [P1-0189].
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Simulated migrating motor complex and its impact on the release properties of hydrophilic matrix systems
T
Helena Vrbanaca, Jurij Trontelja,∗, Sandra Berglezb, Klemen Krefta, Dejan Krajcarb, Igor Legenb a b
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia Lek Pharmaceuticals, Inc., a Sandoz Company, Verovškova Ulica 57, 1000, Ljubljana, Slovenia
ARTICLE INFO
ABSTRACT
Keywords: Stomach Migrating motor complex (MMC) Matrix tablets HPMC Dissolution testing Erosion SmartPill® Wireless motility capsule (WMC)
Following ingestion, the dosage forms are exposed to high mechanical stresses, mainly due to the movement of gastric musculature and passage through the sphincters. The generated mechanical forces can have a profound impact on the release properties of the mechanically sensitive formulations, which may result in greater in vivo variability. The aim of the study was to prepare a new programme sequence for our bio-relevant in vitro dissolution model, the advanced gastric simulator (AGS), which would closely resemble the four phases of the migrating motor complex (MMC) and to evaluate the influence of the simulated mechanical stress on the drug release rate and the gel layer properties of the model hydrophilic matrix system. For this purpose, two kinds of HPMC matrix tablets were used, which have previously been tested in vivo. In vivo pressure measurements in human fasted stomach were gathered from literature and compared to the measurements obtained with the wireless motility capsule (WMC) in AGS. Dissolution studies conducted in AGS were compared to the experiments performed in USP2. Properties of the gel layer were evaluated with texture analysis and matrix erosion determination. Our in vitro measured pressure profiles of simulated MMC were found to be within the same range as those observed in vivo. The simulated MMC was shown to significantly affect the drug release kinetics from tested hydrophilic matrices. Compared to USP2, the AGS was shown to have a higher discriminatory power in distinguishing the differences in behaviour of the tested formulations, in accordance with in vivo data.
1. Introduction While passing along the digestive tract, orally administrated dosage forms are exposed to various mechanical and chemical influences affecting their integrity. To reach the systemic blood circulation, the active pharmaceutical ingredient (API) in conventional solid dosage forms must first dissolve in the fluids of the digestive tract to be later absorbed [1]. The estimated time of passage through the digestive tract is approximately 0–2 h for the stomach, 3–4 h for the small intestine and 8–15 h for the colon [1–3]. During this time, dosage forms are exposed to destructive mechanical forces intended to process the ingested food to smaller particles and to prepare the gastrointestinal tract (GIT) for the next meal [4–6]. Ingested dosage forms are first exposed to conditions in the stomach, which dictate the passage of the formulation or released drug into the small intestine – the major site for the drug absorption [7–9]. The frequency and the intensity of the stomach contraction waves differ in fed and fasted state conditions. The motor activity of the fasted stomach is carried out in cycles, known as the migrating motor complex
∗
(MMC). The complex lasts in average 1.5–2 h and is transferred from the stomach to the small intestine. The physiological importance of interdigestive motility of the stomach is mechanical and chemical cleansing in the process of preparation for the next meal. MMC is characterized by a fluctuation of the muscle contractions intensity that can be divided into four phases. Phase I is quiescent period of 30–60 min with no contractions present. Increased frequency and amplitude of medium-strong contractions, lasting 20–40 min are noticed in phase II. Phase III of the MMC lasts 10–20 min and is characterized by strong contractions at maximum frequency. At this point, the pylorus opens widely, thus allowing larger undigested particles to leave the stomach. In the phase IV, the intensity of the contractions decreases back to the quiescent phase I. The MMC motility is interrupted with food intake [10–12]. Controlled release dosage forms can be influenced by several physiological conditions such as pH, ions, enzymes and motility of the GIT [13]. However, they must be able to maintain the drug release within certain acceptable tolerance limits. For example, the thickness of swelled polymer layer on the hydrophilic matrix surface, which acts as
Corresponding author. E-mail address: [email protected] (J. Trontelj).
https://doi.org/10.1016/j.jddst.2019.101338 Received 26 April 2019; Received in revised form 2 October 2019; Accepted 19 October 2019 Available online 23 October 2019 1773-2247/ © 2019 Elsevier B.V. All rights reserved.
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a diffusion barrier for the drug release, is strongly dependent on several factors: composition of formulation, the friction between the formulation and the stomach wall mucosa, the amount of the mechanical pressure applied to the formulation and the composition of surrounding media [7,14,15]. The presence of food in the surrounding media of matrix tablets can affect the gel layer formation and the release properties of the formulation [16,17]. Nevertheless, among various parameters in GIT affecting drug release and absorption from matrix tablets, luminal forces are of great importance, especially in the case of mechanically sensitive dosage forms, such as hydrophilic matrices. Several in vivo studies have shown that hydrophilic matrices may be less robust than observed during in vitro experiments [18,19]. Disruption of the gel layer due to mechanical stress applied during the GIT transit may have an effect on the drug plasma levels. For instance, in vivo erosion of less robust matrix tablets can be highly variable. Due to destructive forces, a drug burst release can also be observed. The above may be reflected in highly variable plasma concentrations, manifested as low therapeutic effectiveness or increased incidences of drug adverse effects [18–21]. The extent of mechanical destructive forces of GIT wall have been evaluated with several methodologies: Kamba et al. [22] obtained a range of mechanical forces in the human stomach using Teflon® tablets with predetermined crushing strength, containing a marker drug. Bortolotti et al. [23] observed circadian antroduodenal motor activity during interdigestive and digestive period with ambulatory antroduodenal manometry. In several studies [6,24–26] the wireless motility capsule (SmartPill®) has been used to evaluate the motility-related parameters along the GIT. Several in vitro models simulating conditions occurring in vivo have been proposed. Garbacz et al. [8,27] have developed stress test device to simulate the impact of physiological mechanical stress occurring during GIT passage. Bogataj et al. developed glass bead device enabling physical contact and movement of the tablet on the surface of the glass bead layer [28]. Klančar et al. [21] modified USP3 apparatus with addition of the plastic beads in the reciprocating cylinder, establishing a level A in vitro-in vivo correlation. In addition, more complex devices were also developed, such as TIM-1 simulator, which enables simulation of conditions present in stomach as well as in the small intestine [29]. With intention for better simulation of the motility, hydrodynamic and mechanical stress in the GIT, Legen et al. [30] developed innovative biorelevant intestinal model for simulating peristaltic action (IMSPA) and advanced gastric simulator (AGS). Biorelevant in vitro dissolution testing aims to bring a closer prediction of the dosage form performance in vivo. The main goal is finding a strong correlation between in vitro drug release kinetics and in vivo plasma levels which can reduce the number of necessary clinical trials during the new formulation development. The closer the resemblance of the biorelevant dissolution systems to the actual in vivo conditions, the better predictability of in vivo formulation behaviour is expected. Therefore, assessing the similarity of the newly developed in vitro system performance to the true in vivo conditions is highly relevant for the evaluation of its predictive power and its applicability to IVIVC studies. In the present study, we prepared a programme sequence on the AGS to simulate similar motility and pressure events as measured in fasted stomach in vivo and studied its’ impact on the release properties of chosen HPMC matrix tablets.
contains a battery and sensors for pH, temperature and pressure, all enclosed in a polyurethane shell. The WMC transmits real time measurements of its immediate surroundings to a data receiver device, at a radio carrier frequency of 434 MHz. Sensors in the capsule are able to measure the pH values within the range of 0.05–9.0 pH units with an accuracy of ± 0.5 pH units, the pressure values in the range of 0–350 mmHg with an accuracy of ± 5 mmHg and the temperature within 25–49 °C with an accuracy of ± 1 °C. The recorded data can be downloaded from the data receiver through the docking station with a USB connection to a Windows PC compatible computer [26,31,32]. 2.2. Tablets Two kinds of HPMC matrix tablets were used in this study; the formulation A containing Methocel K15 M (20% of tablet mass) and the formulation B with a mixture Methocel K100LV (10% of tablet mass) and Methocel K15 M (35% of tablet mass) polymer (DOW, California, USA). The model drug has one dissociation constant and exists mainly in anionic form under weak-basic conditions. The model drug has low solubility and shows good apparent permeability throughout the GIT, therefore it is classified as BCS class II. The calculated dose/solubility volume in aqueous solutions within the physiological pH range of 1–7.5 is less than 16 mL. The dissolution testing was thus being undertaken under sink conditions. The reagents for dissolution testing and HPLC assay were purchased from Merck, Germany. This includes KH2PO4, HCl titrisol, NaCl, KCl, CaCl2x2H2O, Na2EDTA (Titriplex® III) and glacial acetic acid. SIF powder was purchased from Biorelevant.com Ltd. Acetonitrile (HPLC gradient grade) and methanol (ultra HPLC gradient grade) were obtained from J.T.Baker, USA. 3. Methods 3.1. Assessment of motility related parameters The capsule activation was done according to manufacturer's instructions. For testing the prepared programme sequence, 0.01 M HCl with 2 g/ L NaCl was used for all experiments. The data receiver was placed in a close proximity to the dissolution apparatus (AGS) during the experiment and was not further apart than 50 cm from the WMC. Each test lasted 20 min and was performed in 6 parallels. During the test performance, motility-related parameters were recorded with the function of live monitoring of the transmitted data to the MotiliGi software. At the end of the experiments, the WMC was deactivated and data was downloaded from the data receiver to the MotiliGi software. 3.2. Advanced gastric simulator (AGS) – apparatus description Advanced gastric simulator is a dynamic in vitro model, simulating the function of the human stomach. Its' advantages compared to conventional dissolution apparatus, such as USP1 or USP2, are realistic mimicking of the stomach wall dynamic and its' contents movement. The apparatus main elements include a flexible vessel, eight mechatronic constriction mechanisms, a “pyloric” valve, temperature controlled chamber and computer software. The vessel is a soft and flexible container made of silicone rubber (DragonSkin FX, Smooth-On Inc., USA). The vessel retains its' shape when filled with dissolution media and relaxes when emptied, without significant shrinkage. The vessel measures approximately 30 cm along greater curvature and approximately 24 cm along lesser curvature. At its’ widest point, it measures 10 cm and narrows towards the pyloric part to approximately 1 cm. On the inner side of the thin walls, the vessel is wrinkled in the longitudinal direction, allowing the well reproducible wall deformation during the contractions. The vessel is open at both of its ends; the top inlet is wider and resembles the cardia while the lower end of the vessel narrows to a
2. Materials 2.1. Wireless motility capsule For the purpose of this study, the SmartPill® (WMC) data recording device was used. The WMC dimensions are 26.8 mm in length and 11.7 mm in diameter. Usually, it is administrated orally for diagnostic purposes in gastroenterology. The measurements of GIT transit time conducted with WMC are a useful tool in recognition of motility disorders, such as gastroparesis and chronic constipation. The capsule 2
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Fig. 1. The set-up of advanced gastric simulator (right) and 3D scan of flexible vessel from different angles (left).
tubular opening, resembling the pyloric sphincter. The flexibility of the silicone rubber enables comparable volumes (up to 1 L) and mechanical properties of the vessel to those of the human stomach. AGS and 3D scan of the flexible vessel from different angles are presented in Fig. 1. The vessel's shape deformation is triggered by eight (iris) constriction mechanisms (NT57-586, Edmund Optics, United States), arranged along the outer surface of the vessel. The majority of the constriction mechanisms are gathered at the lower (antropyloric) part of the stomach, where strong mixing and mechanical processing of solid food is expected in vivo. The space between constriction mechanisms is 1.5–2 cm. Each constriction mechanism consists of 20 spring steel blades, attached to a custom-made stainless steel worm gear (Fig. 2). Changing the aperture diameter leads to change of shape and volume of the flexible vessel. Synchronised opening and closing of the constriction mechanisms with time delay to each other, simulates a contraction travelling along the stomach wall. Duration of a travelling contraction depends on the individual program settings. In our study, the duration of an average contraction was 30–40 s. However, it should be noted that each new contraction begins before the previous one is completed, providing up to 3 contractions per minute. Actuation of the individual constriction mechanism is controlled by an electric step motor (ST2818, Nanotec electronic GmbH & Co., Germany), connected to a computer with USB/ RS485 converter (Brainboxes). Custom-made software (Faculty of Engineering, University of Ljubljana, Slovenia) enables a controlled motion of each constriction mechanism. The software allows separate settings of the amplitude and period that the user can save as an
individual program. With the “program sequence” feature, the software allows user to select multiple programs with different settings and automatic shuffle between the selected programs in the following order. Such program sequence enables a creation of realistic gastric movement patterns. Furthermore, the lower, tubular outlet of the flexible vessel is tightened with a custom made “pyloric” valve consisting of two steel pins (PFCLEA-D8-L55-M4, Misumi United States), one positioned stationary relative to the stomach container and the other movable, attached to a liner slide (SE2BZ10-115, Misumi, United States). Opening of the pyloric valve and thus the flow rate from the stomach is controlled with a separate custom-made software (Faculty of Engineering, University of Ljubljana, Slovenia). All of the above listed components of the device – constriction mechanisms, flexible vessel, step motors with a worm gear and “pyloric” valve are positioned inside a thermal chamber (SP-55 Easy, Kambič, Slovenia), which enables the standard temperature conditions of 37 °C during performance of dissolution tests. The structure and the function of individual parts of the apparatus were described also in our previous works [30,33–35]. 3.3. Dissolution testing Dissolution tests were performed in AGS with prepared programme sequence, simulating MMC. The volume of dissolution media, resembling fasted stated gastric fluid (FaSSGF pH 1.6 or 0.01 M HCl with ions) was 250 mL. FaSSGF pH 1.6 was prepared according to Biorelevant.com Ltd instructions. 0.01 M HCl with ions was prepared by adding 10 mL of 1 M HCl titrisol® to 900 mL of deionised water and further dissolving 4 g of NaCl, 1.20 g of KCl and 0.084 g of CaCl2 x 2H2O and then filling the volume of the flask to 1000 mL. The media temperature was set to 37 ± 0.5 °C. For each time point, 10 mL sample was manually collected and replaced with respective dissolution media heated to 37 ± 0.5 °C. The samples were filtered through LLG-Syringe nonsterile filters (PVDF, 0.45-μm) to 2.0-mL vials. The sampling time points for experiments in AGS were 15, 30, 45, 70, 80, 90, 105, 110, 115 and 125 min. After completion of the test in AGS, the tablets were carefully removed from the flexible vessel, placed in Japanese basket sinkers and transferred to USP2. A total of 900 mL of 50 mM phosphate buffer pH 6.8, preheated to 37 ± 0.5 °C was poured in standard vessels with paddles. Tests were performed using dissolution system (AT dissolution apparatus, Xtend™, Sotax, Switzerland) with rotating speed of 75 rpm, coupled with an automatic sampler (CP Xtend™ pump, Sotax, Switzerland). The amount of the drug dissolved in each vessel was determined at 60, 120, 180, 240, 300, 360, 420, 480, 540, 600 min. Samples of 1.7 mL were automatically collected and filtered through the Full Flow 1 μm filters (P/N FIL001-EW) into 2.0-mL vials. Dissolution test using only USP2 was first performed in 900 mL of acidic media (FaSSGF pH 1.6 or 0.01 M HCl with ions) with the
Fig. 2. Schematic presentation of individual constriction mechanism. 3
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following sampling time points: 15, 30, 60 and 120 min. After that, the tablets in Japanese sinkers were carefully removed and the dissolution media was replaced with 900 mL of 50 mM phosphate buffer pH 6.8 preheated to 37 ± 0.5 °C within a few minutes. Tablets were then placed back into vessels and testing was continued with the following sampling time points: 180, 240, 300 360, 420, 480, 540, 600, 660, 720 min. Samples of 1.7 mL were automatically collected and filtered through the Full Flow 1 μm filters (P/N FIL001-EW) to 2.0-mL vials. Experiments were performed in three parallels. The samples were analysed using HPLC-UV.
Norwood, Massachusetts USA). Formulations were placed in dissolution vessels (in AGS and USP2) under the same conditions as for dissolution testing, described above. Tablets were removed from media at predetermined time points and tested with flat-end, round shaped stainless steel probe with Ø 2 mm tip and length of 30 mm. All experiments were performed in triplicate for each tested time point. Texture analyser was equipped with 100 N load cell and Bluehill 3 software. During analysis the probe moved toward the tested tablet at a rate of 0.5 mm/s, until the surface of the tablet was detected at the force of 0.005 N. At this point, the probe penetrated the gel layer at the rate of 0.2 mm/s until the maximal non-destructive resistance force of 1 N was detected, at which point the probe retracted to its original position. The properties of the gel layer were studied at 60 and 120 min for experiments in USP2 and at 60, 100 and 125 min for experiments in AGS followed by USP2 and collected by texture analyser software (Bluehill3). The tests were not performed at later time points since the amount of the remaining dry core was insignificant and the probe with a force of 1 N would penetrate it. The thickness of the swollen matrix was determined by measuring the total travel distance of the needle probe.
3.4. Analysis of dissolution samples The amount of model drug in collected samples was quantified using a validated HPLC method with UV-detection (Water separation module 2695D, Waters, USA) at 254 nm. The HPLC system was equipped with analytical column Chromolith Speed ROD RP-18e (Merck, Darmstadt, Germany) with dimensions of 50 × 4.6 mm. The column was maintained at 36 °C and samples at 4 °C during analysis. The mobile phase consisted of acetonitrile/methanol/NaEDTA/glacial acetic acid in the volume ration 275:175:550:1. The NaEDTA solution was prepared by dissolving 1 g of NaEDTA in 5000 mL of purified water. The volume of injected samples was 100 μm. At flow rate of 2 mL/min, the retention time of the model drug was around 1 min and the total run time of the analysis was 1.3 min for the injected sample.
3.7. Erosion studies Each tablet was weighted before dissolution testing. At 120, 360 and 720 min of the experiments in USP2 and at 125, 365 and 725 min of the experiments in the AGS followed by USP2 tablets were carefully removed from the working vessel, lightly patted with tissue paper to remove any liquid excess and dried in vacuum chamber at 60 °C until constant weight was achieved. Percent of eroded matrix was determined in triplicate for each time point using the following equation:
3.5. Pharmacokinetic study protocol Both of the formulations were tested in vivo under fasting conditions within two separate pharmacokinetic (PK) studies, conducted in separate contract research organisation (CRO). Tested formulations were thus not directly compared, however both of them were comparative studies, using the same reference formulation C (Table 1). 24 healthy male volunteers were included in the randomized, crossover PK study comparing formulation A and C. A total of 23 blood samples were collected up to 96 h post-dose from each individual in each period. There was a 14-day washout period between both treatments. The PK study comparing formulations B and C was also an open-label, randomized crossover study conducted on 26 volunteers. A total of 24 blood samples were collected up to 96 h post-dose from each individual in each period. The washout before the second period was at least 14 days. Both of the studies were approved by the National Health Authority and Independent Ethics Committee. Concentration of the active ingredient in plasma samples were determined by a high-performance liquid chromatography connected to mass spectrometry, validated according to the FDA guidelines for bioanalytical method validation.
Erosion (%) =
4.1. Mechanical biorelevance of the prepared programme sequence Established relationship between the intensity of the tested programme and the generated pressure profiles is necessary in order to develop motility patterns, closely resembling the in vivo gastric dynamics. The correlation between the aperture diameter of the constriction mechanism and the average and maximum generated pressure peak is shown in Fig. 3. The measurements were performed with aperture diameters ranging from 25 to 40 mm. It should be noted the highest possible closing of the constriction mechanism is up to 20 mm, although, due to the size of the WMC and the overall thickness of the surrounding flexible vessel, such a programme was not tested to avoid damage of the WMC. The correlation for the aperture diameter and the average pressure measured was linear (R2 = 0.9466) and for the maximal observed pressure peak, exponential (Fig. 3, note: the scale of the x-axis is descending). Individual maximal observed pressure peak was 451 mbar, which closely coincides with the reported in vivo detected maximal pressure peak (460 mbar [25]). The dependence between constriction mechanism aperture and applied pressure on the WMC has been already investigated in a previous study [33], however the set-up of tested programmes and the range of the studied correlation differed in both studies. The initial position of the constriction mechanisms in this study was 15 mm wider (starting position of 65 mm) and the range of closed aperture diameter was from 25 to 40 mm. Average and maximal pressure peaks were measured at 7 different apertures. In our study average pressures are higher and the correlation for the occurring maximal pressure peaks is exponential compared to already published data [33]. The step motors, which drive the constriction mechanisms have a constant torque at all rotational speeds (depending on the setting
Table 1 Pharmacokinetic parameters of formulations A and B compared to the same refrence product C. PK parameters
Cmax [ng/mL] AUCt [h*ng/ mL] tmax [h] Cmax [ng/mL] AUCt [h*ng/ mL] tmax [h]
formulation A vs C
formulation B vs C
106.09 101.06
– –
90% confidence interval 99.68–113.17 95.87–106.84
– 92.51 69.58
12.80 – –
– 97.66–99.75 99.99–102.33
–
16.00
–
100%
4. Results
The properties of the gel layer on the matrix surface were determined with Instron 3342 single column texture analyser (Instron,
ratio
remaining dry weight dry weight
Where: dry weight – initial tablet weight; remaining dry weight – tablet dry weight at each sampling time.
3.6. Texture analysis of hydrated tablets
parameter
dry weight
4
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Fig. 3. The average pressure values and maximal pressure peaks (mbar) detected with SmartPill® as a function of the maximal aperture of the AGS constriction mechanisms.
of the opening - closing period). The motor torque is then transferred to the constriction mechanism, where different forces are expected due to different aperture dimensions. The exponential correlation of the maximal observed pressure peaks therefore suggests that there is a dependence on the starting point of the constriction mechanism. Consequently, the peak pressures to which a formulation is exposed to during iris contraction depends on its size. With the help of the observed correlation, programmes simulating the individual MMC phases were designed. The motility-related parameters obtained with simulated MMC and in vivo measurements gathered from the available literature are presented in Table 2. The range of average pressure, generated by simultaneous closing and opening of the constriction mechanism in the prepared program sequence was 71–131 mbar, which is lower than in vivo (30–304 mbar [25]), but nevertheless within the same order of magnitude. Maximum peak amplitude detected with WMC for the tested sequence was 451 mbar, which coincidences with in vivo detected maximal pressure peak. The difference in extent of the generated mechanical stress by individual program can be observed in Fig. 4. During the program ags_MMC_1, which simulates the phase 1 of MMC, contractions were not detected. On the other hand, average detected motility during the rest of the simulated MMC phases was 3 contractions/ min.
4.2. Comparing drug release using AGS and USP apparatus 2 In Fig. 5, extended drug release profiles are presented in different acidic media: FaSSGF pH 1.6 and 0.01 M HCl with ions. Dissolution tests were performed firstly in FaSSGF pH 1.6 or in 0.01 M HCl with ions for 2 h and continued in phosphate buffer pH 6.8. Dissolution in acidic media, simulating the fasted stomach conditions, was performed in AGS using the prepared program sequence or in USP2 at the stirring rate of 75 rpm, and in both cases continued in USP2 with the speed rotation of 75 rpm. In the case of FaSSGF pH 1.6 the noteworthy differences can be observed – higher release rates are generated by AGS (in 120 min of experiments approximately 10% higher drug release for formulation A and approximately 8% higher for formulation B) with respect to USP2, which is also evident in further dissolution in USP2 in the case of both formulations tested (approximately 14% higher drug release for formulation A and approximately 8% higher for formulation B). In the case of 0.01 M HCl with ions release was slightly higher in the case of USP2, however there were no statistically significant differences observed in drug release profiles with both dissolution methods in this media. Additionally, greater difference in the release rate of the model drug from the formulations A and B can be observed in FaSSGF pH 1.6 using the dissolution method with AGS with respect to the tests performed only in USP2. In the case of 0.01 M HCl with ions, no significant differences in drug release profiles of formulations A and B were observed.
Table 2 Comparison of the motility-related parameters obtained in the AGS to the in vivo available data. AGS: MMC program sequence MMC phase
program
duration [min]
maximum pressure peak amplitude [mbar]
mean pressure peak amplitude [mbar]
mean contractions/min
I. II. III. IV.
ags_MMC_1 ags_MMC_2 ags_MMC_3 ags_MMC_4
60 40 20 5
16 (6) 181 (33) 451 (101) 181 (33)
3 (6) 71 (14) 130 (19) 71 (14)
0 3 3 3
maximum pressure [mbar]
contractions/min
reference
notes
406 NA NA NA NA 87
NA NA 0.85 NA 2–3 NA
[25] [23] [24] [23] [24] [22]
WMC study not a WMC study (antroduodenal manometry) not a WMC study (antroduodenal manometry) not a WMC study (antroduodenal manometry) not a WMC study (antroduodenal manometry) not a WMC study (teflon tablet with predetermined strength)
in vivo available data phase pressure [mbar] fasted II. III. fasted
30-304 (range) 53 53 107 117 NA
Standard deviation values of experiments in AGS are presented in brackets next to in vitro experimental values. 5
(0.02) (0.31) (0.13) (0.31)
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Fig. 4. Pressure profiles [mmHg] of prepared program sequence of AGS obtained with SmartPill®. Each event point marks the beginning of individual program, resembling the respective MMC phase.
Fig. 5. Drug release from formulation A (upper diagrams) and B (lower diagrams) I tested media, in both conventional (USP2) and a non-conventional (AGS combined with USP2) dissolution method.
4.3. Properties of the gel layer and tablets erosion
(resistance to the rupture of dry tablets). For formulation A and 203.8 ± 3.3 mg and 127–163 N for formulation B. Textural analysis of the gel layer covered the time points of the simulated gastric passage, which are expected to be crucial for the later drug release. Noteworthy
Tablets measured 6.8 mm in diameter and 3.0 mm in axial direction, with the average weight of 208.3 ± 2.3 mg and strength of 107–119 N 6
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points capturing the whole release profile. An independent-samples ttest was used to check the mechanical influences of both dissolution methods on the tablet mass loss. Significant differences (p < 0,05) in the amount of eroded gel layer were observed for formulation A in both dissolution media (Fig. 8, marked with stars). The percentage of eroded gel layer of formulation A at 2 h time point was significantly higher when test was conducted in AGS. In FaSSGF pH 1.6 the amount of erosion was significantly higher for both formulations when tests were conducted with AGS, at 2 h time point as well as at the end of the test. On the other hand, in 0.01 M HCl with ions the amount of eroded gel layer for formulation B was not significantly different for both dissolution methods (Fig. 8). 5. Discussion One of the major challenges in the process of new formulation development is to develop a dissolution method with high discriminatory power and ability to predict the clinical efficacy of a new formulation. Current compendial dissolution methods are not always reliable to predict the in vivo behaviour of pharmaceutical formulation; therefore, there is a strong need of biorelevant predictive dissolution methods [36]. Variable conditions in digestive tract are quite difficult to simulate in vitro. Nevertheless, with biorelevant composition of the dissolution media [37] and innovative dissolution apparatuses [38–40], the process of achieving biorelevance in vitro is in tremendous progress. The aim of our study was to develop a program sequence for the advanced gastric simulator (AGS) closely resembling the migrating motor complex of a fasted human stomach. In vivo occurring pressure events have been simulated in vitro in previous studies [29,41]. Nevertheless, the prepared program sequence is a physiologically relevant dissolution tool capturing the principle properties of all 4-phases of MMC. The flexible vessel of the AGS is constricted circularly, resembling the gastric musculature and the pressure from the containers’ wall is transferred to its interior content. In order to simulate the
Fig. 6. Typical force – distance profiles of formulation A at specific time points of experiments conducted in AGS and USP2. The measurements below the 0.5 N threshold are below the specified precision limit (0.5 N), according to the texture analyser manufacturer (Instron).
differences were observed in the length the probe travelled when different dissolution methodologies were used. In the case of tablets tested in AGS, the extension of the probe was shorter compared to tablets tested in the USP2 due to greater gel layer deformation, abrasion and erosion caused by the constricting peristaltic action of the AGS’ flexible wall (Figs. 6 and 7). At later time points, the tablets were almost completely hydrated, forming compact gel with small amount or no dry core present at all. To further evaluate the mechanical effect of the AGS on the release properties of the tested tablets, tablet mass loss was measured in three time
Fig. 7. Extension of probe, travelling through the gel layer at different time points using different dissolution technologies. 7
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Fig. 8. Erosion of formulation A and B with different dissolution technologies.
peristaltic wave travelling along the stomach wall, the periodic rate of changing the inner diameter of each constriction mechanism can be individually programed. As it can be observed from the program settings, each program was designed to widen the contraction diameter as it approaches the antropyloric part of the stomach. The motility-related parameters obtained from available literature data and the ones observed in the AGS show that the innovative apparatus has the ability of providing similar luminal pressure effects on dosage form to the ones observed in vivo. It should be noted that some of the in vivo measured values cannot be directly compared due to the differences in the measuring technology. The tested programs exerted different pressure profiles on the WMC (Table 2). The pressure values of individual programs are in the range of in vivo measurements. Results suggest that different gastric pressure profiles can be simulated with AGS, reflecting the human physiologic MMC-pressure profile (Fig. 3). Although the AGS is a much more dynamic model compared to commercially available dissolution apparatuses, it is still too rigid in its current form compared to the human stomach to fully capture the powerful hydrodynamics and mixing of gastric content in vivo. Mechanically biorelevant dissolution models have the potential to explain the unexpected in vivo drug release profiles. Such examples are hydrophilic matrix tablets, which are prone to variable stresses along the gastrointestinal tract. As a result of these stresses, the process of swelling and eroding of the matrices could be strongly affected,
resulting in a variable plasma concentration levels or an unexpected burst release [21]. In our study, two kinds of hydrophilic matrix tablets were used in order to reflect the differences in the mechanical stress generated by the AGS and the USP2. However, it must be noted that since the SmartPill® is larger in diameter than the tablets tested, the contact with the tablets and thus the exertion of the stresses may be lower than those on the SmartPill®. Both of the formulations were previously tested in vivo within two separate pharmacokinetic (PK) studies, conducted in separate contract research organisation. Formulations were thus not directly compared, however both of them were tested with the same reference sample C (Table 1). In this PK study the Cmax ratio for A/C was 106.09% with tmax of 12.8 h, while the Cmax ratio for B/C was 92.51% with tmax of 16.0 h, indicating the in vivo release rate of the model drug from the formulation B was slower compared to formulation A. The extended drug release profiles from matrices in tested media using two dissolution methods, AGS combined with USP2 or USP2 alone, are presented in Fig. 5. In 0.01 M HCl with ions drug release was slightly faster compared to AGS. However, it should be noted that the slope of the drug release in the AGS was higher, leading to complete overlaying of the both release profiles at later time points. On the other hand, a trend of higher drug release from both formulations in FaSSGF pH 1.6 is observed when using the AGS. The rationale for the observed differences in susceptibility of the matrix for mechanic stress generated by AGS could be due to different amount of ions present in dissolution 8
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media. Higher concentration of solutes in 0.01 M HCl with ions could affect the swelling of HPMC. It has been already observed in previous studies [15,16,41–43] that the presence of ions results in the formation of a compacted gel layer on the matrix surface. This could slow down the penetration of water molecules into the formulation and thereby dissolution of the active substance and its diffusion through the gel layer to the surrounding medium. On the other hand, the model drug is classified as BCS class II due to its low solubility. FaSSGF is a biorelevant dissolution medium, containing sodium taurocholate and lecithin – surface active substances, simulating a minor part of pancreatic and bile secretions present in stomach as a result of a physiologically occurring reflux [1,37]. The presence of surfactants in FaSSGF in combination with higher shear stress generated by AGS could be the reason for the observed greater amount of the released drug. Properties of the gel layer formed on the surface of the hydrophilic matrix systems are considered as one of the key parameters affecting the release of the active ingredient. Formation of the hydrophilic gel layer is highly dependent both on water penetration and erosion rate of the fully hydrated polymer on the surface of a matrix system [45]. The process of swelling and water penetration has been reported as pH dependent [46], which is of great importance since the pH values in vivo vary, from 1 to 3 in the stomach, to 7–8 in the colon. It has been suggested that diffusion of the medium is considerably quicker at low pH values and the concentration of solution is constant in the gel layer. On the other hand, the concentration of the neutral to alkaline solution in the gel layer increases when going from the dry core of polymer to external edge of the layer. However, in our study, we have observed the erosion of the matrices already in the acidic media although the drug release was quite low, which could be due to low solubility of the model drug in acidic media. Furthermore, the degree of erosion and drug release were higher after the formulations were exposed to the K-phosphate buffer with higher pH (Figs. 8 and 5, respectively). Textural analysis of the gel layer and erosion of the matrix tablets were studied at predefined time points. Textural studies are presented as the length the needle probe has travelled through the gel layer of each tested tablet (Fig. 7), which corresponds to the thickness of the gel layer. It can be observed that the extension was shorter in the case of tablets tested in the AGS, suggesting the gel layer thickness was smaller compared to the tablets tested in the USP2. In the AGS, tablets were in contact with the wall of the flexible vessel in a greater proportion of an experiment, while the main determinant of mechanical stress in the USP2 was agitation of the dissolution media. In the latter case, the erosion of the swollen gel layer is expected to be slow, allowing the formation of a thicker gel layer. As described above, the release rate in 0.01 M HCl with ions was slightly faster in the USP2. Nonetheless, higher amount of tablet erosion measured at earlier time points of experiments (Fig. 8) indicates the thickness of the gel layer was lower for formulation tested in AGS due to presumably higher shear forces applied to the formulation surface. Dissolution rate in AGS had a higher slope, resulting in complete overlaying of the both release profiles at later time points. In previous studies, three types of ionic strength effects on the release properties of hydrophilic matrices have been observed. In some cases lower ionic strength slowed the release rate by allowing formation of a thicker and more robust gel layer [41,43,44]. In other cases, the presence of ions in dissolution media prevented hydration of polymer particles and provoked formation of incoherent gel layer. The release rate in the latter case was accelerated, in some cases even burst release was observed [15,16]. Lastly, in some cases no effect of ions present in dissolution media on the release kinetics was observed [44]. Which effect will prevail depends on both, the ionic strength of dissolution media as well as composition of the formulation. It may be assumed the ionic strength of dissolution media in our study was too low (0.09 M) to show major effects on the gel layer structure of the tested formulations. The barrier function of the tested matrices seemed to withstand the effect of the ions in dissolution media,
while outer front of the gel layer was still able to fully hydrate and thus erode more extensively during tests in AGS. In FaSSGF pH 1.6 a trend of higher drug release from both formulations in AGS corresponds to the shorter extension measured in textural analysis. The percent of eroded hydrophilic matrix is higher for tablets tested in AGS followed by USP2, confirming the importance of the gastric destructive forces for the drug release behaviour. Additionally, the influence of different type and amounts of HPMC polymer used for both formulations was observed in dissolution tests with FaSSGF pH 1.6 in AGS followed by USP2. Previous studies have shown that higher HPMC content promotes water intake into matrices, forming a complete diffusion barrier resulting in a retarded drug release [47,48]. Furthermore, slower drug release has been also observed from matrices containing higher viscosity grade HPMC polymer [49,50]. Formulation B, which contained a combination of high and low viscosity grade HPMC polymer in a higher tablet mass percentage (45%) compared to formulation A (20%), showed to be more resistant for the mechanical influences of the simulated MMC (Fig. 6) in both dissolution media. 5.1. Advantages of the AGS and future prospects In this study, AGS showed to have a higher discriminatory power in distinguishing the differences in formulation robustness and better correlation with in vivo results compared to the standard dissolution apparatus. Like most biorelevant models, AGS allows different pH and volume selection of various dissolution media, maintaining constant temperature. However, the advantage of the presented model is the anatomical similarity of the flexible vessel with the human stomach, the ability to mimic peristaltic waves and gastric emptying. The apparatus offers two types of experiments; closed loop (sampling at the upper opening of the vessel) or open loop with a flow through the “pyloric” valve. By changing the flow rate and motility, different transit times can be created. In the light of these findings, the novel device could be a very useful tool in the design of more robust formulations, which would be a great advantage primarily for patient safety. This, combined with the observed in vivo similarity of the generated pressures, sets the new system as an important scientific contribution to the research of drug release from MR formulations. 6. Conclusions In this study, we present the advanced gastric simulator programme to mimic the mechanical pressure stress on pharmaceutical formulation as observed during the 4 MMC phases in vivo. In vitro measured pressure profiles were within the range reported from in vivo studies and showed the ability of the presented model to significantly affect the drug release from mechanically sensitive hydrophilic matrix systems. Although observed differences in extended release rate of tested formulations were not significant, AGS has shown better ability to distinguish different formulation behaviour compared to USP2. However, to reach more realistic simulation of the GIT transit additional investigation of the model is required. These results will undoubtedly lead to further model optimisation for even higher confidence in prediction of the release kinetics from such formulations in patients leading to the reduction of necessary in vivo trials and better prediction and identification of nonrobust formulations. Declaration of competing interest The authors declared no conflicts of interest related to this article. Acknowledgments The authors would like to acknowledge Ms. Katja Olenik from University of Ljubljana, Faculty of Pharmacy for assistance in 9
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conducting experiments. The authors from University of Ljubljana, Faculty of Pharmacy were supported by the Slovenian Research Agency (ARRS) [P1-0189].
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