Characterizing interregional differences in the rheological properties and composition of rat small intestinal mucus.

The mucus layer in the small intestine is generally regarded as a barrier to drug absorption. However, the mucus layer is a complex system, and presently, only a few studies have been conducted to elucidate its physicochemical properties. The current study hypothesizes that the mucus layer contains solubility-enhancing surfactants and thus might aid the oral absorption of poorly water-soluble drugs. Mucus was sampled from sections of the small intestine of fasted rats to analyze the rheological properties and determine the mucus pH and concentrations of proteins and endogenous surfactants, i.e., bile salts, polar lipids, and neutral lipids. The mucus layer in the two proximal sections of the small intestine exhibited different rheological properties such as higher zero-shear viscosity and lower loss tangent and higher protein concentrations compared to all subsequent sections of the small intestine. The pH of the mucus layer was stable at ~ 6.5 throughout most of the small intestine, but increased to 7.5 in the ileum. The bile salt concentrations increased from the duodenum (16.0 ± 2.2 mM) until the mid jejunum (55.1 ± 9.5 mM), whereas the concentrations of polar lipids and neutral lipids decreased from the duodenum (17.4 ± 2.2 mM and 37.8 ± 1.6 mM, respectively) until the ileum (4.8 ± 0.4 mM and 10.7 ± 1.1 mM, respectively). In conclusion, the mucus layer of the rat small intestine contains endogenous surfactants at levels that might benefit solubilization and absorption of orally administered poorly water-soluble drugs.

Assessing acute colitis induced by dextran sulfate sodium in rats and its impact on gastrointestinal fluids.

Dextran sulfate sodium (DSS) is commonly used to induce colitis in rats. While the DSS-induced colitis rat model can be used to test new oral drug formulations for the treatment of inflammatory bowel disease, the effect of the DSS treatment on the gastrointestinal tract has not been thoroughly characterized. Additionally, the use of different markers to assess and confirm successful induction of colitis is somewhat inconsistent. This study aimed to investigate the DSS model to improve the preclinical evaluation of new oral drug formulations. The induction of colitis was evaluated based on the disease activity index (DAI) score, colon length, histological tissue evaluation, spleen weight, plasma C-reactive protein, and plasma lipocalin-2. Furthermore, the study investigated how the DSS-induced colitis affected the luminal pH, lipase activity, and concentrations of bile salts, polar lipids, and neutral lipids. For all evaluated parameters, healthy rats were used as a reference. The DAI score, colon length, and histological evaluation of the colon were effective disease indicators in DSS-induced colitis rats, while spleen weight, plasma C-reactive protein, and plasma lipocalin-2 were not. The luminal pH of the colon and bile salt- and neutral lipid concentrations in regions of the small intestine were lower in DSS-induced rats compared to healthy rats. Overall, the colitis model was deemed relevant for investigating ulcerative colitis-specific formulations.

Amphotericin B and monoacyl-phosphatidylcholine form a stable amorphous complex.

Amphotericin B (AmB) is a "life-saving" medicine for the treatment of invasive fungal infections and visceral leishmaniasis. To date, all marketed AmB formulations require parenteral administration, which causes high rates of acute infusion-related side effects and dose-dependent nephrotoxicity. The development of an oral AmB formulation will entail numerous advantages including increased patient compliance, eliminated infusion-related toxicities and reduced nephrotoxicity. Unfortunately, the gastrointestinal absorption of AmB is negligible due to its extremely low solubility in both aqueous and lipid solvents, and its poor gastrointestinal permeability. Drug-phospholipid complexation is an emerging strategy for oral delivery of poorly soluble drugs. In this study, monoacyl-phosphatidylcholine (MAPC) was complexed with AmB forming an AmB-MAPC complex (APC), to enhance the dissolution rate and aqueous solubility of AmB, in order to enable oral delivery of AmB. X-ray powder diffraction demonstrated that AmB was transformed to its amorphous form following complexation with MAPC, i.e. in the APC. Fourier-transform infrared spectroscopy suggested molecular interactions between AmB and MAPC. Dynamic light scattering indicated formation of colloidal structures after aqueous dispersion of APC; Cryogenic transmission electron microscopy showed that APC formed small round, "rod-like" and "worm-like" micellar structures and Small-angle neutron scattering provided three-dimensional micellar structures formed by APC upon aqueous dispersion, which indicated that AmB was inserted into the micellar mono-layer membrane formed by MAPC. Additionally, APC showed an increased dissolution rate and a higher amount of AmB solubilized in fasted state simulated intestinal fluid, compared to AmB/MAPC physical mixtures and crystalline AmB. In conclusion, an APC exhibiting amorphous properties was developed, the APC showed improved dissolution rate and increased apparent aqueous solubility compared to AmB, indicating that the application of APC could be a promising strategy to enable the oral delivery of AmB.

Development of a multiparticulate drug delivery system for in situ amorphisation.

In the current study, the concept of multiparticulate drug delivery systems (MDDS) was applied to tablets intended for the amorphisation of supersaturated granular ASDs in situ, i.e. amorphisation within the final dosage form by microwave irradiation. The MDDS concept was hypothesised to ensure geometric and structural stability of the dosage form and to improve the in vitro disintegration and dissolution characteristics. Granules were prepared in two sizes (small and large) containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) at a 50 % w/w drug load as well as sodium dihydrogen phosphate monohydrate as the microwave absorbing excipient. The granules were subsequently embedded in an extra-granular tablet phase composed of either the filler microcrystalline cellulose (MCC) or mannitol (MAN), as well as the disintegrant crospovidone and the lubricant magnesium stearate. The tensile strength and disintegration time were investigated prior to and after 10 min of microwave irradiation (800 and 1000 W) and the formed ASDs were characterised by X-ray powder diffraction and modulated differential scanning calorimetry. Additionally, the internal structure was elucidated by X-ray micro-Computed Tomography (XµCT) and, finally, the dissolution performance of selected tablets was investigated. The MDDS tablets displayed no geometrical changes after microwave irradiation, however, the tensile strength and disintegration time generally increased. Complete amorphisation of CCX was achieved only for the MCC-based tablets at a power input of 1000 W, while MAN-based tablets displayed partial amorphisation independent of power input. The complete amorphisation of CCX was associated with the fusion of individual ASD granules within the tablets, which negatively impacted the subsequent disintegration and dissolution performance. For these tablets, supersaturation was only observed after 60 min. On the other hand, the partially amorphised MDDS tablets displayed complete disintegration during the dissolution experiments, resulting in a fast onset of supersaturation within 5 min and an approx. 3.5-fold degree of supersaturation within the experimental timeframe (3 h). Overall, the MDDS concept was shown to potentially be a feasible dosage form for in situ amorphisation, however, there is still room for improvement to obtain a both fully amorphous and disintegrating system.

Direct visualizing of paracetamol immediate release tablet disintegration in vivo and in vitro.

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.

Supersaturated amorphous solid dispersions of celecoxib prepared in situ by microwave irradiation.

This study investigated the ability of in situ amorphisation using microwave irradiation in order to prepare highly supersaturated ASDs, i.e. ASDs with drug loads higher than the saturation solubility in the polymer at ambient temperature. For this purpose, compacts containing the crystalline drug celecoxib (CCX) and polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA), or polyvinyl acetate (PVAc), were prepared at drug loads between 30 and 90 % w/w. Sodium dihydrogen phosphate (NaH2PO4) monohydrate was included in all compacts, as a source of water, to facilitate the dielectric heating of the compacts upon dehydration during microwave irradiation. After processing, the samples were analysed towards their solid state using X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC). Complete amorphisation of CCX was achieved across all the investigated polymers and with a maximal drug load of 90, 80, and 50 % w/w in PVP, PVP/VA, and PVAc, respectively. These drug loads corresponded to a 2.3-, 2.4-, and 10.0-fold supersaturation in the investigated polymers at ambient temperature. However, dissolution experiments with the in situ prepared ASDs in fasted state simulated intestinal fluid (FaSSIF), showed a lower initial drug release (0-2 h) compared to equivalent physical mixtures of crystalline CCX and polymers or crystalline CCX alone. The lower drug release rate was explained by the fusion of individual drug and polymer particles during microwave irradiation and, subsequently, a lack of disintegration of the monolithic ASDs. Nevertheless, supersaturation of CCX in FaSSIF was achieved with the in situ amorphised ASDs with PVP and PVP/VA, albeit only after 3-24 h. Overall, the present study confirmed that it is feasible to prepare supersaturated ASDs in situ. However, in the current experimental setup, the monolithic nature of the resulting ASDs is considered a limiting factor in the practical applicability of this preparation method, due to limited disintegration and the associated negative effect on the drug release.

Physico-chemical characterization of aspirated and simulated human gastric fluids to study their influence on the intrinsic dissolution rate of cinnarizine.

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.

Studying the Impact of the Temperature and Sorbed Water during Microwave-Induced In Situ Amorphization: A Case Study of Celecoxib and Polyvinylpyrrolidone.

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.

The Influence of Drug-Polymer Solubility on Laser-Induced In Situ Drug Amorphization Using Photothermal Plasmonic Nanoparticles.

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.

The Effect of the Molecular Weight of Polyvinylpyrrolidone and the Model Drug on Laser-Induced In Situ Amorphization.

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.

Utilizing Laser Activation of Photothermal Plasmonic Nanoparticles to Induce On-Demand Drug Amorphization inside a Tablet.

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.

Microwave-Induced in Situ Drug Amorphization Using a Mixture of Polyethylene Glycol and Polyvinylpyrrolidone.

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.

Microwave induced in situ amorphisation facilitated by crystalline hydrates.

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.

Estimating the Oral Absorption from Self-Nanoemulsifying Drug Delivery Systems Using an In Vitro Lipolysis-Permeation Method.

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.

Drug solubilization during simulated pediatric gastro-intestinal digestion.

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 Nestlé 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.

Effects of recombinant human gastric lipase and pancreatin during in vitro pediatric gastro-intestinal digestion.

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.

The Use of Glycerol as an Enabling Excipient for Microwave-Induced In Situ Drug Amorphization.

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.

Predicting Oral Absorption of fenofibrate in Lipid-Based Drug Delivery Systems by Combining In Vitro Lipolysis with the Mucus-PVPA Permeability Model.

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 (R2 > 0.9). Thus, it was concluded that the in vitro lipolysis-mucus-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.

Adding a Gastric Step to the Intestinal In Vitro Digestion Model Improves the Prediction of Pharmacokinetic Data in Beagle Dogs of Two Lipid-Based Drug Delivery Systems.

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.

Convection-Induced vs. Microwave Radiation-Induced in situ Drug Amorphization.

The aim of the study was to investigate the suitability of a convection oven to induce in situ amorphization. The study was conducted using microwave radiation-induced in situ amorphization as reference, as it has recently been shown to enable the preparation of a fully (100%) amorphous solid dispersion of celecoxib (CCX) in polyvinylpyrrolidone (PVP) after 10 min of continuous microwaving. For comparison, the experimental setup of the microwave-induced method was mimicked for the convection-induced method. Compacts containing crystalline CCX and PVP were prepared and either pre-conditioned at 75% relative humidity or kept dry to investigate the effect of sorbed water on the amorphization kinetics. Subsequently, the compacts were heated for 5, 10, 15, 20, or 30 min in the convection oven at 100 °C. The degree of amorphization of CCX in the compacts was subsequently quantified using transmission Raman spectroscopy. Using the convection oven, the maximum degree of amorphization achieved was 96.1% ± 2.1% (n = 3) for the conditioned compacts after 30 min of heating and 14.3% ± 1.4% (n = 3) for the dry compacts after 20 min of heating, respectively. Based on the results from the convection and the microwave oven, it was found that the sorbed water acts as a plasticizer in the conditioned compacts (i.e., increasing molecular mobility), which is advantageous for in situ amorphization in both methods. Since the underlying mechanism of heating between the convection oven and microwave oven differs, it was found that convection-induced in situ amorphization is inferior to microwave radiation-induced in situ amorphization in terms of amorphization kinetics with the present experimental setup.