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The purpose of the present study was to study tablet disintegration by direct visualization, in vivo and in vitro. Based on literature data, a standard conventional paracetamol (CP) tablet, Panodil®, and a rapidly absorbed paracetamol (RP) tablet, Panodil® Zapp, were chosen as model systems to study tablet disintegration in the human stomach. Based on the obtained in vivo results, an in vitro disintegration method was designed to reproduce the visualized disintegration process occurring in the human stomach. For the clinical study, CP and RP tablets fastened to digital endoscopic camera capsules were administered to fasted human volunteers (n = 4). The disintegration time and process were visualized by the real time video recordings, using the endoscopic camera capsule. The average disintegration time was found to be 26 ± 13 min and 10 ± 7 min, for CP (n = 4) and RP (n = 4) tablets, respectively. It was possible to reproduce the in vivo disintegration data in vitro using a USP 2 dissolution apparatus with 250 mL of viscous Fasted State Simulated Gastric Fluid (vFaSSGF*), simulating the rheological profile of human fasted state gastric fluid following administration of a glass of water. The viscosity of the simulated fasted state gastric fluid was found to have a large impact on the disintegration time of the tested immediate release tablets. Therefore, it is recommended to mimic gastric fluid viscosity during in vitro tablet disintegration studies.

Poor aqueous drug solubility represents a major challenge in oral drug delivery. A novel approach to overcome this challenge is drug amorphization inside a tablet, that is, on-demand drug amorphization. The amorphous form is a thermodynamically instable, disordered solid-state with increased dissolution rate and solubility compared to its crystalline counterpart. During on-demand drug amorphization, the drug molecularly disperses into a polymer to form an amorphous solid at elevated temperatures inside a tablet. This study investigates, for the first time, the utilization of photothermal plasmonic nanoparticles for on-demand drug amorphization as a new pharmaceutical application. For this, near-IR photothermal plasmonic nanoparticles were tableted together with a crystalline drug (celecoxib) and a polymer (polyvinylpyrrolidone). The tablets were subjected to a near-IR laser at different intensities and durations to study the rate of drug amorphization under each condition. During laser irradiation, the plasmonic nanoparticles homogeneously heated the tablet. The temperature was directly related to the rate and degree of amorphization. Exposure times as low as 180 s at 1.12 W cm-2 laser intensity with only 0.25 wt % plasmonic nanoparticles and up to 50 wt % drug load resulted in complete drug amorphization. Therefore, near-IR photothermal plasmonic nanoparticles are promising excipients for on-demand drug amorphization with laser irradiation.

The aim of the study was to implement a gastric digestion step using recombinant human gastric lipase (rHGL) in an in vitro pediatric gastro-intestinal digestion model to achieve a physiologically relevant gastric contribution to total gastro-intestinal lipid digestion. A commercial infant formula (NAN Comfort stage 1 (NAN1)) with 3.4% lipid and an in-lab prepared oil-in-water emulsion, emulsified with soy phosphatidylcholine (SPCemul), with 3.5% lipid (oil-blend containing Akonino NS, MEG-3 and ARASCO oils) were subjected to in vitro gastro-intestinal digestion. To achieve a physiologically relevant level of gastric digestion, 50 min of in vitro gastric digestion, using either 0, 3.75 or 7.5 TBU mL-1 rHGL, was followed by 90 min of in vitro intestinal digestion, using either 0 or 26.5 TBU mL-1 pancreatic triglyceride lipase (PTL) from porcine pancreatin. The digestion of the substrates was assessed using titration-based quantification supported by HPLC-ELSD analysis. In vitro gastric digestion of NAN1 and SPCemul with either 3.75 or 7.5 TBU mL-1 rHGL contributed with 10-27% of the total gastro-intestinal digestion, corresponding to the reported contribution in human infants. At the end of the gastro-intestinal digestion (t = 140 min), the combined lipolytic effect of rHGL and PTL was additive during digestion of SPCemul, but not for the digestion of NAN1, as all lipase activity combinations resulted in a similar degree of NAN1 digestion. The effect of gastric digestion with rHGL on total digestion therefore appeared to be substrate dependent. To conclude, a gastric digestion step using rHGL resulting in physiologically relevant gastric contribution to the observed gastro-intestinal digestion was successfully implemented into an in vitro pediatric gastro-intestinal digestion model.

Microwave-induced in situ amorphization is a promising approach to circumvent stability and manufacturing issues associated with amorphous solid dispersions (ASD). Using in situ amorphization, the crystalline state of the drug is converted into its amorphous form inside the dosage form, e.g. a compact, upon exposure to microwave radiation. The study aimed to investigate the feasibility of using glycerol as an enabling excipient in compacts prepared from mixtures of indomethacin and Soluplus®. Additionally, the possibility to form a supersaturated ASD upon exposure to microwave radiation due to elevated temperatures was investigated. It was found that glycerol i) acts as a dielectric heating source absorbing the microwaves, ii) plasticizes the polymer Soluplus® and iii) increases the solubility of the drug indomethacin in the polymer Soluplus®. Additionally, it was found that fully amorphous ASDs could be achieved with drug loadings below -, and slightly above the saturation solubility of indomethacin in the Soluplus®/glycerol mixtures, after exposure to 20 min of microwave radiation. Hence, glycerol was a feasible excipient for the microwave-induced in situ amorphization and allowed the preparation of a, at room temperature, supersaturated ASD, due to the elevated temperatures obtained during exposure to microwave radiation.

Drug release from a lipid-based drug delivery system (LbDDS) is typically studied in vitro using a one-step intestinal digestion model. However, lately the importance of incorporating gastric digestion has been stressed. The aim of the present study was to compare a two-step gastro-intestinal (GI) in vitro digestion model to the commonly used one-step intestinal digestion model. The models were evaluated by studying release of the model drug A1260 from two LbDDSs (F-I and F-II), for which in vivo pharmacokinetic data from oral administration to beagle dogs were available. The amount of A1260 recovered in the aqueous phases during and after the GI digestion of F-I and F-II was related to the Cmax and AUC0-48h of the plasma concentration-time profiles of each formulation and produced a rank order in vitro-in vivo (IVIV) relation. In comparison, a similar IVIV rank ordering was obtained when relating the amount of A1260 recovered in the aqueous phase prior (t = 0 min), and following 15 min of intestinal digestion, to the plasma concentration-time profiles. However, after 60 min of intestinal digestion, the LbDDSs performed equally in the one-step in vitro digestion model, contrary to what was observed in the two-step digestion model, and in vivo. As the GI digestion model produced a clearer distinction in terms of LbDDS rank ordering of the two LbDDSs, compared to the intestinal digestion model, it was found to be a promising in vitro model to study and estimate the LbDDS behavior in vivo.

In this study, the impact of drug and polymer particle size on the in situ amorphization using microwave irradiation at a frequency of 2.45 GHz were investigated. Using ball milling and sieve fractioning, the crystalline drug celecoxib (CCX) and the polymer polyvinylpyrrolidone (PVP) were divided into two particle size fractions, i.e. small ( 71 µm) particles. Subsequently, compacts containing a drug load of 30% (w/w) crystalline CCX in PVP were prepared and subjected to microwave radiation for an accumulated duration of 600 sec in intervals of 60 sec as well as continuously for 600 sec. It was found that the compacts containing small CCX particles displayed faster rates of amorphization and a higher degree of amorphization during microwave irradiation as compared to the compacts containing large CCX particles. For compacts with small CCX particles, interval exposure to microwave radiation resulted in a maximum degree of amorphization of 24%, whilst a fully amorphous solid dispersion (100%) was achieved after 600 sec of continuous exposure to microwave radiation. By monitoring the temperature in the core of the compacts during exposure to microwave radiation using a fiber optic temperature probe, it was found that the total exposure time above the glass transition temperature (Tg) was shorter for the interval exposure method compared to continuous exposure to microwave radiation. Therefore, it is proposed that the in situ formation of an amorphous solid dispersion is governed by the dissolution of drug into the polymer, which most likely is accelerated above the Tg of the compacts. Hence, prolonging the exposure time above the Tg, and increasing the surface area of the drug by particle size reduction will increase the dissolution rate and thus, rate and degree of amorphization of CCX during exposure to microwave radiation.

To elucidate the critical parameters affecting drug dissolution in the human stomach, the intrinsic dissolution rate (IDR) of cinnarizine was determined in aspirated and simulated human gastric fluids (HGF). Fasted aspirated HGF (aspHGF) was collected from 23 healthy volunteers during a gastroscopic examination. Hydrochloric acid (HCl) pH 1.2, fasted state simulated gastric fluid (FaSSGF), and simulated human gastric fluid (simHGF) developed to have rheological, and physico-chemical properties similar to aspHGF, were used as simulated HGFs. The IDR of cinnarizine was significantly higher in HCl pH 1.2 (952 ± 27 µg/(cm2·min)) than in FaSSGF pH 1.6 (444 ± 7 µg/(cm2·min)), and simHGF pH 2.5 (49 ± 5 µg/(cm2·min)) due to the pH dependent drug solubility and viscosity differences of the three simulated HGFs. The shear thinning behavior of aspHGF had a significant impact on the IDR of cinnarizine, indicating that the use of FaSSGF, with viscosity similar to water, to evaluate gastric drug dissolution, might overestimate the IDR by a factor of 100–10.000, compared to the non-Newtonian, more viscous, fluids in the human stomach. The developed simHGF simulated the viscosity of the gastric fluids, as well as the IDR of the model drug, making it a very promising medium to study gastric drug dissolution in vitro.

Microwave-induced in situ amorphization of a drug into a polymeric amorphous solid dispersion (ASD) has been suggested to follow a dissolution process of the drug into the polymeric network, at temperatures above the glass transition temperature (Tg) of the polymer. Thus, increasing the compact temperature, above the Tg of the polymer, is expected to increase the rate of drug dissolution in the mobile polymer, i.e., the rate of amorphization, in a direct proportional fashion. To test this hypothesis, the present study aimed at establishing a linear correlation between the compact temperature and the rate of drug amorphization using celecoxib (CCX) and the polymers polyvinylpyrrolidone (PVP) 12 and PVP17 as the model systems. Water sorbed into the drug–polymer compacts during 2 weeks of storage at 75% relative humidity was used as the dielectric heating source for the present drug amorphization process, and therefore directly affected the compact temperature during exposure to microwave radiation, the loss of water during heating was also studied. For this, compacts prepared with 30 wt% CCX, 69.5 wt% PVP12 or PVP17 and 0.5 wt% magnesium stearate (lubricant) were conditioned to have a final water content of approx. 20 wt%. The conditioned compacts were exposed to microwave radiation for 10 min at variable power outputs to achieve different compact temperatures. For compacts containing CCX in both PVP12 and PVP17, a linear correlation was established between the measured compact end temperature and the rate of drug amorphization during 10 min of exposure to microwave radiation. For compacts containing CCX in PVP12, a fully amorphous ASD was obtained after 10 min of exposure to microwave radiation with a measured compact end temperature of 71 °C. For compacts containing CCX in PVP17, it was not possible to obtain a fully amorphous ASD. The reason for this is most likely that a fast evaporation of the sorbed water increased the Tg of the conditioned drug–polymer compacts to temperatures above the highest reachable compact temperature during exposure to microwave radiation in the utilized experimental setup. Supporting this conclusion, evaporation of the sorbed water was observed to be faster for compacts containing PVP17 compared to compacts containing PVP12.

Laser radiation has been shown to be a promising approach for in situ amorphization, i.e., drug amorphization inside the final dosage form. Upon exposure to laser radiation, elevated temperatures in the compacts are obtained. At temperatures above the glass transition temperature (Tg) of the polymer, the drug dissolves into the mobile polymer. Hence, the dissolution kinetics are dependent on the viscosity of the polymer, indirectly determined by the molecular weight (Mw) of the polymer, the solubility of the drug in the polymer, the particle size of the drug and the molecular size of the drug. Using compacts containing 30 wt% of the drug celecoxib (CCX), 69.25 wt% of three different Mw of polyvinylpyrrolidone (PVP: PVP12, PVP17 or PVP25), 0.25 wt% plasmonic nanoaggregates (PNs) and 0.5 wt% lubricant, the effect of the polymer Mw on the dissolution kinetics upon exposure to laser radiation was investigated. Furthermore, the effect of the model drug on the dissolution kinetics was investigated using compacts containing 30 wt% of three different drugs (CCX, indomethacin (IND) and naproxen (NAP)), 69.25 wt% PVP12, 0.25 wt% PN and 0.5 wt% lubricant. In perfect correlation to the Noyes–Whitney equation, this study showed that the use of PVP with the lowest viscosity, i.e., the lowest Mw (here PVP12), led to the fastest rate of amorphization compared to PVP17 and PVP25. Furthermore, NAP showed the fastest rate of amorphization, followed by IND and CCX in PVP12 due to its high solubility and small molecular size.

In this study, laser-induced in situ amorphization (i.e., amorphization inside the final dosage form) of the model drug celecoxib (CCX) with six different polymers was investigated. The drug–polymer combinations were studied with regard to the influence of (i) the physicochemical properties of the polymer, e.g., the glass transition temperature (Tg) and (ii) the drug–polymer solubility on the rate and degree of in situ drug amorphization. Compacts were prepared containing 30 wt% CCX, 69.25 wt% polymer, 0.5 wt% lubricant, and 0.25 wt% plasmonic nanoparticles (PNs) and exposed to near-infrared laser radiation. Upon exposure to laser radiation, the PNs generated heat, which allowed drug dissolution into the polymer at temperatures above its Tg, yielding an amorphous solid dispersion. It was found that in situ drug amorphization was possible for drug–polymer combinations, where the temperature reached during exposure to laser radiation was above the onset temperature for a dissolution process of the drug into the polymer, i.e., TDStart. The findings of this study showed that the concept of laser-induced in situ drug amorphization is applicable to a range of polymers if the drug is soluble in the polymer and temperatures during the process are above TDStart.

Amorphisation within the final dosage form, i.e. in situ amorphisation, seeks to circumvent the potential stability issues associated with poorly soluble drugs in amorphous solid dispersions (ASDs). Microwave irradiation has previously been shown to enable in situ preparation of ASDs, when a high amount of microwave absorbing water was introduced into the final dosage form by conditioning at high relative humidity. In this study, an alternative to this conditioning step was investigated by introducing crystal water in form of sodium dihydrogen phosphate (NaH2PO4) di-, and monohydrate, in compacts prepared with 30 % w/w celecoxib (CCX) in polyvinylpyrrolidone K12 (PVP). As controls, compacts prepared with NaH2PO4 anhydrate and without NaH2PO4 were included in the study. The quantification of amorphous CCX after microwave irradiation showed an increase in CCX amorphicity for compacts containing NaH2PO4 di-, and monohydrate with increasing irradiation time. Complete amorphisation of CCX in compacts containing NaH2PO4 di-, and monohydrate was observed after 6 min, while no appreciable amorphisation was observed for the control compacts containing NaH2PO4 anhydrate and without NaH2PO4. Modulated differential scanning calorimetric analysis revealed that a homogenous ASD was formed after 12 min and 6 min for compacts containing NaH2PO4 di-, and monohydrate, respectively. Thermal gravimetric analysis indicated that NaH2PO4 monohydrate showed higher dehydration rates compared to the dihydrate, which in turn resulted in higher compact temperatures, and overall increased the rate of amorphisation and reduced the microwave irradiation time necessary to achieve a homogenous ASD. The present results confirmed the suitability of NaH2PO4 di- and monohydrate as alternative sources of water, the primary microwave absorbing material, for in situ microwave amorphisation. The use of crystalline hydrates as water reservoirs for in situ amorphisation circumvents the time-consuming and highly impractical conditioning step previously reported in order to achieve complete amorphisation. Additionally, it allows for easier and more accurate adjustment of the compacts water content, which directly affects the temperature reached during microwave irradiation, and thus, the rate of amorphisation.

The aim of this study was to design an in vitro lipolysis-permeation method to estimate drug absorption following the oral administration of self-nanoemulsifying drug delivery systems (SNEDDSs). The method was evaluated by testing five oral formulations containing cinnarizine (four SNEDDSs and one aqueous suspension) from a previously published pharmacokinetic study in rats. In that study, the pharmacokinetic profiles of the five formulations did not correlate with the drug solubilization profiles obtained during in vitro intestinal lipolysis. Using the designed lipolysis-permeation method, in vitro lipolysis of the five formulations was followed by in vitro drug permeation in Franz diffusion cells equipped with PermeaPad® barriers. A linear in vivo–in vitro correlation was obtained when comparing the area under the in vitro drug permeation–time curve (AUC0–3h), to the AUC0–3h of the plasma concentration–time profile obtained from the in vivo study. Based on these results, the evaluated lipolysis-permeation method was found to be a promising tool for estimating the in vivo performance of SNEDDSs, but more studies are needed to evaluate the method further.

The use of a mixture of polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) was investigated for microwave-induced in situ amorphization of celecoxib (CCX) inside compacts. Such amorphization requires the presence of a dipolar excipient in the formulation to ensure heating of the compact by absorption of the microwaves. Previously, the hygroscopic nature of PVP was exploited for this purpose. By exposing PVP-based compacts for set time intervals at defined relative humidity, controlled water sorption into the compacts was achieved. In the present study, PEG was proposed as the microwave absorbing excipient instead of water, to avoid the water sorption step. However, it was found that PEG alone melted upon exposure to microwave radiation and caused the compact to deform. Furthermore, CCX was found to recrystallize upon cooling in PEG-based formulations. Hence, a mixture of PEG and PVP was used, where the presence of PVP preserved the physical shape of the compact, and the physical state of the amorphous solid dispersion. To study the impact of the polymer mixture, different compact compositions of CCX, PEG and PVP were prepared. When exposing the compacts to microwave radiation, it was found that the PEG:PVP ratio was critical for in situ amorphization and that complete amorphization was only achieved above a certain temperature threshold.

The aim of this work was to develop a new in vitro lipolysis-permeation model to predict the in vivo absorption of fenofibrate in self-nanoemulsifying drug delivery systems (SNEDDSs). More specifically, the in vitro intestinal lipolysis model was combined with the mucus-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model. Biosimilar mucus (BM) was added to the surface of the PVPA barriers to closer simulate the intestinal mucosa. SNEDDSs for which pharmacokinetic data after oral dosing to rats was available in the literature were prepared, and the ability of the SNEDDSs to maintain fenofibrate solubilized during in vitro lipolysis was determined, followed by the assessment of drug permeation across the mucus-PVPA barriers. The amount of drug solubilized over time during in vitro lipolysis did not correlate with the AUC (area under the curve) of the plasma drug concentration curve. However, the AUC of the drug permeated after in vitro lipolysis displayed a good correlation with the in vivo AUC (R-2 > 0.9). Thus, it was concluded that the in vitro lipolysisemucus-PVPA permeation model, simulating the physiological digestion and absorption processes, was able to predict in vivo absorption data, exhibiting great potential for further prediction of in vivo performance of SNEDDSs. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

Microwaved-induced in situ amorphization of a drug in a polymer has been suggested to follow a dissolution process, with the drug dissolving into the mobile polymer at temperatures above the glass transition temperature (Tg) of the polymer. Thus, based on the Noyes–Whitney and the Stoke–Einstein equations, the temperature and the viscosity are expected to directly impact the rate and degree of drug amorphization. By investigating two different viscosity grades of polyethylene glycol (PEG), i.e., PEG 3000 and PEG 4000, and controlling the temperature of the microwave oven, it was possible to study the influence of both, temperature and viscosity, on the in situ amorphization of the model drug celecoxib (CCX) during exposure to microwave radiation. In this study, compacts containing 30 wt% CCX, 69 wt% PEG 3000 or PEG 4000 and 1 wt% lubricant (magnesium stearate) were exposed to microwave radiation at (i) a target temperature, or (ii) a target viscosity. It was found that at the target temperature, compacts containing PEG 3000 displayed a faster rate of amorphization as compared to compacts containing PEG 4000, due to the lower viscosity of PEG 3000 compared to PEG 4000. Furthermore, at the target viscosity, which was achieved by setting different temperatures for compacts containing PEG 3000 and PEG 4000, respectively, the compacts containing PEG 3000 displayed a slower rate of amorphization, due to a lower target temperature, than compacts containing PEG 4000. In conclusion, with lower viscosity of the polymer, at temperatures above its Tg, and with higher temperatures, both increasing the diffusion coefficient of the drug into the polymer, the rate of amorphization was increased allowing a faster in situ amorphization during exposure to microwave radiation. Hereby, the theory that the microwave-induced in situ amorphization process can be described as a dissolution process of the drug into the polymer, at temperatures above the Tg, is further strengthened.

To increase the understanding of how drugs behave following oral administration to the pediatric population, the aim of the present study was to investigate the solubilization of fluconazole and ibuprofen during simulated gastro-intestinal (GI) digestion, using an immediate transfer model mimicking pediatric GI digestion. The effects of infant formula and digestion, on the drug solubilization, were studied using simulated fasted and fed state digestion media in the presence and absence of digestive enzymes. Additionally, the effect of digestion media viscosity on the solubilization process was investigated. It was found that the solubilization of fluconazole was unaffected by all tested parameters, as the entire estimated dose equivalent was solubilized in the aqueous phase throughout all digestion studies. In contrast, the solubilization of ibuprofen was affected by all the tested parameters, i.e. in the fasted state, the solubilization of ibuprofen was limited by its solubility in the aqueous phase of the simulated GI digestion media, whereas the solubilization in the fed state was affected by drug partitioning between the lipid and the aqueous phases, and therefore by the digestion of the lipid phase. Adding Nestle Thicken Up™, containing xanthan gum as a thickening agent, to the digestion medium increased its viscosity, which in turn resulted in a reduced initial digestion rate, increased pH fluctuations, as well as high variability in all drug solubilization data as evident in large standard deviations. Furthermore, the increased digestion medium viscosity decreased the drug recovery from the combined pellet and aqueous phase. The observed viscosity effects might translate into a more variable and lower oral bioavailability.

Drug release from a lipid-based drug delivery system (LbDDS) is typically studied

Objective To test whether a side-by-side diffusion model is suitable for studying drug supersaturation in an absorptive environment. Methods The µD/P model and the µFLUX model, using a Caco-2 cell monolayer/PAMPA membrane as the permeation barrier, respectively, were compared in terms of robustness and ease of handling, while studying the drug supersaturation–precipitation–permeation interplay. Continuing with the best model, the impact of the acceptor media and the importance of studying drug supersaturation in a combined dissolution–permeation model, as compared to a simple dissolution model, were evaluated. Key findings The two models produced similar results in terms of supersaturation, precipitation and permeation. The µFLUX model was considered more robust and easier to handle based on its cell-free permeation system. Using the µFLUX model, it was found that an acceptor medium with a high surfactant concentration increased the amount of permeated drug. The effect of absorption on drug supersaturation was found to be dependent on the drug, and the tested level of supersaturation. Conclusion The tested models were comparable; however, Caco-2 cell monolayers were considered too sensitive to be used to study drug supersaturation. Further studies are needed to evaluate the observed drug-dependent effects of absorption on drug supersaturation.

During the past two decades, a range of in vitro models simulating the digestion processes occurring in the stomach and small intestine have been developed to characterize lipid based drug delivery systems (LbDDSs). This review describes the presently existing range of in vitro digestion models and their use in the field of oral drug delivery. The models are evaluated in terms of their suitability to assess LbDDSs, and their ability to produce in vitro - in vivo correlations (IVIVCs). While the pH-stat lipolysis model is by far the most commonly utilized in vitro digestion model in relation to characterizing LbDDSs, a series of recent studies have shown a lack of IVIVCs limiting its future use. Presently, no single in vitro digestion model exists which is able to predict the in vivo performance of various LbDDSs. However, recent research has shown the potential of combined digestion-permeation models as well as species specific digestion models.

The objective of the present study was to develop a combined dissolution-permeation model, compatible with the μDiss Profiler™ (μD/P model), to ensure continuous in situ monitoring of dissolved and permeated drug, respectively. A μD/P model consisting of two connected compartments made of acrylic plastic was designed and constructed to fit in the μDiss Profiler™. A Caco-2 cell monolayer grown on a Snapwell™ membrane insert was mounted between the apical and basolateral compartment serving as a permeability barrier. Fasted state biorelevant medium consisting of HBSS pH 6.5 supplemented with bile salts and lecithin was used as the apical dissolution media, while HBSS pH 7.4 was used as the basolateral medium. The apparent permeability (Papp) and dissolution-time profiles for albendazole, felodipine and fenofibrate were determined concomitantly using the μD/P model, and separately using a previously validated, common cell transwell permeability setup with Caco-2 cells as the permeability barrier, and the μDiss Profiler™, respectively. The results were found to be in same range, when comparing data obtained using the different experimental setups. In conclusion, a μDiss compatible D/P model was developed enabling in situ measurement of apical drug concentrations and simultaneous determination of the amount of drug permeated across a Caco-2 cell monolayer.

This study describes various complications related to sample preparation (filtration) during development of a dissolution method intended to discriminate among different fenofibrate immediate-release formulations. Several dissolution apparatus and sample preparation techniques were tested. The flow-through cell apparatus (USP 4) was found unfit for dissolution testing of fenofibrate MeltDose formulations due to clogging of filters and varying flow rates. A mini paddle dissolution setup produced dissolution profiles of the tested formulations that correlated well with clinical data. The work towards the mini paddle dissolution method demonstrates that sample preparation influenced the results. The investigations show that excipients from the formulations directly affected the drug–filter interaction, thereby affecting the dissolution profiles and the ability to predict the in vivo data. With the tested drug–formulation combination, the best in vivo–in vitro correlation was found after filtration of the dissolution samples through 0.45-μm hydrophobic PTFE membrane filters.

Lipid based drug delivery systems (LbDDSs) present an effective solution for increasing the apparent solubility and eliminating the slow dissolution process of many poorly water-soluble compounds. Typically, an initial step in designing a LbDDS is to measure the equilibrium solubility of the compound in various LbDDS excipients, which often are viscous. Equilibrium solubility is usually measured by the classical saturation shake-flask (SSF) method with centrifugation for phase separation. The concentration of the compound in the supernatant is determined as the solubility. As complete phase separation is necessary to determine the equilibrium solubility, but difficult to achieve in viscous solvents, the aim of the present study was to evaluate the effect of centrifugation speed on the measured solubility. In the present study, the solubility of seven poorly water-soluble compounds: amphotericin B, nystatin, β-carotene, curcumin, itraconazole, cinnarizine and fenofibrate was measured in five viscous solvents using the SSF method. For five out of the seven compounds (amphotericin B, nystatin, β-carotene, curcumin and itraconazole) the centrifugation speed had a significant effect on the measured solubility, i.e. different centrifugation speeds led to differences in the measured solubility. The supernatants of all the tested samples, following 15 min of centrifugation at 900 × g (3K RPM), 4.7K × g (7K RPM) and 17K × g (13.3K RPM), were evaluated for particle presence by polarized light microscopy. Presence of particles in the supernatants of the five affected compounds indicated that complete phase separation was not obtained, and that the measured solubility did not represent the true equilibrium solubility. Studying the physicochemical properties of the tested compounds, it was found, that the compounds, for which the measured solubility was affected by the centrifugation speed, all display high melting points. In conclusion, to avoid overestimating the equilibrium solubility, especially for compounds with high melting points, it is recommended to use the highest possible centrifugation speed, and to evaluate the effect of centrifugation speed on the solubility measurement, when conducting solubility experiments in viscous solvents using centrifugation for phase separation.

Objective The aim of the present study was to study the oral performance of furosemide in neonates and young infants using a newly developed in vitro model simulating digestion and drug solubilization in the gastrointestinal (GI) tract of the human neonate and young infant population (age 0–2 months). Methods The utilized in vitro model was designed to mimic the digestion and drug solubilization processes occurring in the stomach, and the small intestine of the neonate and young infant population, using physiologically relevant media, volumes and digestive enzymes. Overall the experimental model setup was based on the dynamic in vitro lipolysis model previously described by Fernandez et al. (2009) . The amount of furosemide solubilized in the aqueous phase during a digestion study was used as an estimate for the amount of drug available for absorption in vivo. By varying different factors in the model setup, e.g. presence of food (food-effect), effect of digestion (tested with and without addition of digestive enzymes), and properties of the dosage form, it was possible to estimate the importance of these factors in vivo. Key findings and conclusions The present in vitro data suggest that the oral performance of furosemide in neonates and young infants will be increased by the presence of food (frequent feedings) due to increased drug solubilization, however, not influenced by the GI digestion of this food. The properties of the dosage form (immediate release tablets) did not affect the drug solubilization as compared to administration of the pure drug powder.

Objectives Transepithelial di/tripeptide transport in enterocytes occurs via the apical proton-coupled peptide transporter, hPEPT1 (SLC15A1) and a basolateral peptide transporter, which has only been characterized functionally. In this study we examined the pH dependency, substrate uptake kinetics and substrate specificity of the transporter. Methods We studied the uptake of [14C]Gly-Sar from basolateral solution into Caco-2 cell monolayers grown for 17–22 days on permeable supports, at a range of basolateral pH values. Key findings Basolateral Gly-Sar uptake was pH dependent, with a maximal uptake rate at a basolateral pH of 5.5. Uptake of Gly-Sar decreased in the presence of the protonophore nigericin, indicating that the uptake was proton-coupled. The uptake was saturable, with a maximal flux (Vmax) of 408 ± 71, 307 ± 25 and 188 ± 19 pmol/cm2/min (mean ± S.E., n = 3) at basolateral pH 5.0, 6.0 and 7.4, respectively. The compounds Gly-Asp, Glu-Phe-Tyr, Gly-Glu-Gly, Gly-Phe-Gly, lidocaine and, to a smaller degree, para-aminohippuric acid were all shown to inhibit the basolateral uptake of Gly-Sar. Conclusions The study showed that basolateral Gly-Sar transport in the intestinal cell line Caco-2 is proton-coupled. The inhibitor profile indicated that the transporter has broad substrate specificity.

The focus on drug delivery for the pediatric population has been steadily increasing in the last decades. In terms of developing in vitro models simulating characteristics of the targeted pediatric population, with the purpose of predicting drug product performance after oral administration, it is important to simulate the gastro-intestinal conditions and processes the drug will encounter upon oral administration. When a drug is administered in the fed state, which is commonly the case for neonates, as they are typically fed every 3 h, the digestion of the milk will affect the composition of the fluid available for drug dissolution/solubilization. Therefore, in order to predict the solubilized amount of drug available for absorption, an in vitro model simulating digestion in the gastro-intestinal tract should be utilized. In order to simulate the digestion process and the drug solubilization taking place in vivo, the following aspects should be considered; physiologically relevant media, media volume, use of physiological enzymes in proper amounts, as well as correct pH and addition of relevant co-factors, e.g., bile salts and co-enzymes. Furthermore, physiological transit times and appropriate mixing should be considered and mimicked as close as possible. This paper presents a literature review on physiological factors relevant for digestion and drug solubilization in neonates. Based on the available literature data, a novel in vitro digestion model simulating digestion and drug solubilization in the neonate and young infant pediatric population (2 months old and younger) was designed.

Selection of excipients for drug formulations requires both intellectual and experimental considerations as many of the used excipients are affected by physiological factors, e.g., they may be digested by pancreatic enzymes in the gastrointestinal tract. In the present paper we have looked systematically into the differences between Kolliphor ELP, EL, and RH40 and how they affect the bioavailability of fenofibrate, through pharmacokinetic studies in rats and in vitro lipolysis studies. The study design was made as simple as possible to avoid confounding factors, for which reason the tested formulations only comprised an aqueous micellar solution of the model drug (fenofibrate) in varying concentrations (2-25% (w/v)) of the three tested surfactants. Increased concentrations of Kolliphor ELP and EL led to increased fenofibrate AUC0-24h values. For the Kolliphor RH40 formulations, an apparent fenofibrate absorption optimum was seen at 15% (w/v) surfactant, displaying both the highest AUC0-24h and Cmax. The reduced absorption of fenofibrate from the formulation containing the highest level of surfactant (25% w/v) was thought to be caused by some degree of trapping within Kolliphor RH40 micelles. In vitro, Kolliphor ELP and EL were found to be more prone to digestion than Kolliphor RH40, though not affecting the in vivo results. The highest fenofibrate bioavailability was attained from formulations with high Kolliphor ELP/EL levels (25% (w/v)), indicating that these surfactants are the better choice for solubilizing fenofibrate in order to increase the absorption upon oral administration. Due to drug dependent effects of the different types of Kolliphor, more studies are recommended in order to understand which type of Kolliphor is best suited for a given drug.

For the past decades a range of dissolution models has been developed and routineously used to evaluate drug release from semisolid and solid oral dosage forms. Their use has been for both research and development, and quality control (QC) purposes. It is thus not surprising that the different dissolution models span a large range in terms of complexity; from simple systems like the pharmacopoeial QC tests to more complex systems like the transfer model and the biphasic dissolution model. In this chapter the basic principle of the dissolution process for orally administrated drugs is described alongside a series of different dissolution models including pharmacopoeial models, dissolution models utilising physiologically relevant dissolution media, small volume and biphasic dissolution models, transfer models and combined dissolution-permeation models. All models are evaluated in terms of their common use and limitations.