Model-Informed Drug Development: In Silico Assessment of Drug Bioperformance following Oral and Percutaneous Administration.

The pharmaceutical industry has faced significant changes in recent years, primarily influenced by regulatory standards, market competition, and the need to accelerate drug development. Model-informed drug development (MIDD) leverages quantitative computational models to facilitate decision-making processes. This approach sheds light on the complex interplay between the influence of a drug's performance and the resulting clinical outcomes. This comprehensive review aims to explain the mechanisms that control the dissolution and/or release of drugs and their subsequent permeation through biological membranes. Furthermore, the importance of simulating these processes through a variety of in silico models is emphasized. Advanced compartmental absorption models provide an analytical framework to understand the kinetics of transit, dissolution, and absorption associated with orally administered drugs. In contrast, for topical and transdermal drug delivery systems, the prediction of drug permeation is predominantly based on quantitative structure-permeation relationships and molecular dynamics simulations. This review describes a variety of modeling strategies, ranging from mechanistic to empirical equations, and highlights the growing importance of state-of-the-art tools such as artificial intelligence, as well as advanced imaging and spectroscopic techniques.

The Complexity of Bariatric Patient's Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass.

Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1-5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.

In Vitro and In Vivo Evaluation of Inhalable Ciprofloxacin Sustained Release Formulations.

Respiratory antibiotics delivery has been appreciated for its high local concentration at the infection sites. Certain formulation strategies are required to improve pulmonary drug exposure and to achieve effective antimicrobial activity, especially for highly permeable antibiotics. This study aimed to investigate lung exposure to various inhalable ciprofloxacin (CIP) formulations with different drug release rates in a rat model. Four formulations were prepared, i.e., CIP-loaded PLGA micro-particles (CHPM), CIP microcrystalline dry powder (CMDP), CIP nanocrystalline dry powder (CNDP), and CIP spray-dried powder (CHDP), which served as a reference. The physicochemical properties, drug dissolution rate, and aerosolization performance of these powders were characterized in vitro. Pharmacokinetic profiles were evaluated in rats. All formulations were suitable for inhalation (mass median aerodynamic diameter < 5 µm). CIP in CHPM and CHDP was amorphous, whereas the drug in CMDP and CNDP remained predominantly crystalline. CHDP exhibited the fastest drug release rate, while CMDP and CNDP exhibited much slower drug release. In addition, CMDP and CNDP exhibited significantly higher in vivo lung exposure to CIP compared with CHDP and CHPM. This study suggests that lung exposure to inhaled drugs with high permeability is governed by drug release rate, implying that lung exposure of inhaled antibiotics could be improved by a sustained-release formulation strategy.

Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics.

Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs.Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivoin aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles.For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased âˆ¼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower Cmax and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery.This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery.

Numerical Modeling of Particle Dynamics Inside a Dry Powder Inhaler.

The development of novel dry powders for dry powder inhalers (DPIs) requires the in vitro assessment of DPI aerodynamic performance. As a potential complementary method, in silico numerical simulations can provide additional information about the mechanisms that guide the particles and their behavior inside DPIs. The aim of this study was to apply computational fluid dynamics (CFDs) coupled with a discrete phase model (DPM) to describe the forces and particle trajectories inside the RS01® as a model DPI device. The methodology included standard fluid flow equations but also additional equations for the particle sticking mechanism, as well as particle behavior after contacting the DPI wall surface, including the particle detachment process. The results show that the coefficient of restitution between the particle and the impact surface does not have a high impact on the results, meaning that all tested combinations gave similar output efficiencies and particle behaviors. No sliding or rolling mechanisms were observed for the particle detachment process, meaning that simple bouncing off or deposition particle behavior is present inside DPIs. The developed methodology can serve as a basis for the additional understanding of the particles' behavior inside DPIs, which is not possible using only in vitro experiments; this implies the possibility of increasing the efficiency of DPIs.

The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil.

The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 µM), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low/high BSC permeability class benchmark.

Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery.

Gastrointestinal anatomical/physiological changes after bariatric surgery influence variables affecting the fate of drugs after ingestion, and medication management of these patients requires a thorough and complex mechanistic analysis. The aim of this research was to study whether loratadine/desloratadine antiallergic treatment of bariatric patients is at risk of being ineffective due to impaired solubility/dissolution. The pH-dependent solubility of loratadine/desloratadine was studied in vitro, as well as ex vivo, in gastric content aspirated from patients before versus after bariatric surgery. Then, a biorelevant dissolution method was developed to simulate the gastric conditions after sleeve gastrectomy (SG) or one-anastomosis gastric bypass (OAGB), accounting for key variables (intragastric volume, pH, and contractility), and the dissolution of loratadine/desloratadine was studied pre- versus post-surgery. Dissolution was also studied after tablet crushing or syrup ingestion, as these actions are recommended after bariatric surgery. Finally, these experimental data were implemented in a newly developed physiologically based pharmacokinetic (PBPK) model to simulate loratadine/desloratadine PK profiles pre- versus post-surgery. For both drugs, pH-dependent solubility was demonstrated, with decreased solubility at higher pH; over the pH range 1-7, loratadine solubility decreased ∼2000-fold, and desloratadine decreased ∼120-fold. Ex vivo solubility in aspirated human gastric fluid pre- versus post-surgery was in good agreement with these in vitro results and revealed that while desloratadine solubility still allows complete dissolution post-surgery, loratadine solubility post-surgery is much lower than the threshold required for the complete dissolution of the drug dose. Indeed, severely hampered loratadine dissolution was revealed, dropping from 100% pre-surgery to only 3 and 1% post-SG and post-OAGB, respectively. Tablet crushing did not increase loratadine dissolution in any post-bariatric condition, nor did loratadine syrup in post-OAGB (pH 7) media, while in post-laparoscopic SG conditions (pH 5), the syrup provided partial improvement of up to 40% dissolution. Desloratadine exhibited quick and complete dissolution across all pre-/post-surgery conditions. PBPK simulations revealed pronounced impaired absorption of loratadine post-surgery, with 84-88% decreased Cmax, 28-36% decreased Fa, and 24-31% decreased overall bioavailability, depending on the type of bariatric procedure. Desloratadine absorption remained unchanged post-surgery. We propose that desloratadine should be preferred over loratadine in bariatric patients, and as loratadine is an over-the-counter medication, antiallergic therapy after bariatric surgery requires special attention by patients and clinicians alike. This mechanistic approach that reveals potential post-surgery complexity, and at the same time provides adequate substitutions, may contribute to better pharmacotherapy and overall patient care after bariatric surgery.

In-Depth Analysis of Physiologically Based Pharmacokinetic (PBPK) Modeling Utilization in Different Application Fields Using Text Mining Tools.

In the past decade, only a small number of papers have elaborated on the application of physiologically based pharmacokinetic (PBPK) modeling across different areas. In this review, an in-depth analysis of the distribution of PBPK modeling in relation to its application in various research topics and model validation was conducted by text mining tools. Orange 3.32.0, an open-source data mining program was used for text mining. PubMed was used for data retrieval, and the collected articles were analyzed by several widgets. A total of 2699 articles related to PBPK modeling met the predefined criteria. The number of publications per year has been rising steadily. Regarding the application areas, the results revealed that 26% of the publications described the use of PBPK modeling in early drug development, risk assessment and toxicity assessment, followed by absorption/formulation modeling (25%), prediction of drug-disease interactions (20%), drug-drug interactions (DDIs) (17%) and pediatric drug development (12%). Furthermore, the analysis showed that only 12% of the publications mentioned model validation, of which 51% referred to literature-based validation and 26% to experimentally validated models. The obtained results present a valuable review of the state-of-the-art regarding PBPK modeling applications in drug discovery and development and related fields.

3D Printed Buccal Films for Prolonged-Release of Propranolol Hydrochloride: Development, Characterization and Bioavailability Prediction.

Gelatin-polyvinylpyrrolidone (PVP) and gelatin-poly(vinyl alcohol) (PVA) mucoadhesive buccal films loaded with propranolol hydrochloride (PRH) were prepared by semi-solid extrusion 3D printing. The aim of this study was to evaluate the effects of the synthetic polymers PVP and PVA on thermal and mechanical properties and drug release profiles of gelatin-based films. The Fourier-transform infrared spectroscopy showed that hydrogen bonding between gelatin and PVP formed during printing. In the other blend, neither the esterification of PVA nor gelatin occurred. Differential scanning calorimetry revealed the presence of partial helical structures. In line with these results, the mechanical properties and drug release profiles were different for each blend. Formulation with gelatin-PVP and PRH showed higher tensile strength, hardness, and adhesive strength but slower drug release than formulation with gelatin-PVA and PRH. The in silico population simulations indicated increased drug bioavailability and decreased inter-individual variations in the resulting pharmacokinetic profiles compared to immediate-release tablets. Moreover, the simulation results suggested that reduced PRH daily dosing can be achieved with prolonged-release buccal films, which improves patient compliance.

Mucoadhesive buccal tablets with propranolol hydrochloride: Formulation development and in vivo performances in experimental essential hypertension.

The objective of this study was to formulate extended-release mucoadhesive buccal tablets of propranolol hydrochloride in order to provide a prolonged absorption of propranolol hydrochloride from the buccal mucosa and to reduce presystemic metabolism and thus provide a better therapeutic effect. Besides, the aim was to perform comparative in vivo pharmacokinetic and hemodynamic studies of the developed extended-release (ER) propranolol hydrochloride 10 mg mucoadhesive buccal tablets and commercial immediate-release (IR) propranolol hydrochloride 10 mg tablets in spontaneously hypertensive rats. Formulation with 15% polyethylene oxide showed the highest degree of propranolol hydrochloride permeation, satisfactory mucoadhesiveness, and extended-release of propranolol hydrochloride, thus it was selected for further in vivo study. The pharmacokinetic study in rats showed the superiority of ER mucoadhesive buccal tablets over IR tablets in terms of propranolol hydrochloride absorption extent (AUC values: 70.32 ± 19.56 versus 31.69 ± 6.97 µg·h/mL), although lower maximum plasma propranolol hydrochloride concentration (Cmax) was achieved. However, no statistically significant difference was observed in Cmax between these treatments. The hemodynamic study showed that ER mucoadhesive buccal tablets provide a more pronounced decrease primarily in heart rate, but also in systolic and diastolic arterial pressure, as well as a longer heart rate reduction compared to IR tablets.

The evaluation of the effect of different superdisintegrants on the drug release from FDM 3D printed tablets through different applied strategies: In vitro-in silico assessment.

Paracetamol-loaded tablets were printed by fused deposition modelling technique, using polyvinyl alcohol as a backbone polymer and Affinisol™ HPMC as a plasticizer in all formulations. Four different strategies were applied in order to accelerate the drug release from the tablets. First, different release enhancers were added: sodium starch glycolate, croscarmellose sodium, Kollidon CL and mannitol. Kollidon CL and mannitol showed the greatest influence on the drug dissolution rate. The second strategy included lowering the infill density, which did not make any significant changes in dissolution profiles, according to the calculated similarity factor. Then the best two release enhancers from the first strategy were combined (Kollidon CL and mannitol) and this proved to be the most effective in the drug release acceleration. The fourth strategy, increasing the percentage of the release enhancers in formulation, revealed the importance of their concentration limits. In summary, the drug release accelerated from 58% released after 5 h to reaching the plateau within 2 h. In silico physiologically-based biopharmaceutics modelling showed that formulations with mannitol and Kollidon CL, especially the formulation containing a combination of these release enhancers, can provide relatively fast drug release and extent of drug absorption that complies with an immediate release tablet.

Comparative Assessment of In Vitro and In Silico Methods for Aerodynamic Characterization of Powders for Inhalation.

In vitro assessment of dry powders for inhalation (DPIs) aerodynamic performance is an inevitable test in DPI development. However, contemporary trends in drug development also implicate the use of in silico methods, e.g., computational fluid dynamics (CFD) coupled with discrete phase modeling (DPM). The aim of this study was to compare the designed CFD-DPM outcomes with the results of three in vitro methods for aerodynamic assessment of solid lipid microparticle DPIs. The model was able to simulate particle-to-wall sticking and estimate fractions of particles that stick or bounce off the inhaler's wall; however, we observed notable differences between the in silico and in vitro results. The predicted emitted fractions (EFs) were comparable to the in vitro determined EFs, whereas the predicted fine particle fractions (FPFs) were generally lower than the corresponding in vitro values. In addition, CFD-DPM predicted higher mass median aerodynamic diameter (MMAD) in comparison to the in vitro values. The outcomes of different in vitro methods also diverged, implying that these methods are not interchangeable. Overall, our results support the utility of CFD-DPM in the DPI development, but highlight the need for additional improvements in these models to capture all the key processes influencing aerodynamic performance of specific DPIs.

In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug.

This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide (BUD) as a model drug. The formulations investigated in this study are: (i) commercially available micronized BUD mixed with lactose (BUD-PT), (ii) BUD nanocrystal suspension (BUD-NC), (iii) BUD nanocrystals embedded hyaluronic acid microparticles (BUD-NEM). The deposition patterns of the three inhaled formulations in the rats' lungs were determined in vivo and in silico predicted, which were used as inputs in GastroPlus™ software to predict drug absorption following aerosolization of the tested formulations. BUD pharmacokinetics, estimated based on intravenous data in rats, was used to establish a drug-specific in silico absorption model. The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM, respectively. In the case of BUD-PT, the in silico model revealed significant gastrointestinal absorption of BUD, which could be overlooked by traditional in vivo experimental observation. This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations, which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.

Application of Machine-Learning Algorithms for Better Understanding of Tableting Properties of Lactose Co-Processed with Lipid Excipients.

Co-processing (CP) provides superior properties to excipients and has become a reliable option to facilitated formulation and manufacturing of variety of solid dosage forms. Development of directly compressible formulations with high doses of poorly flowing/compressible active pharmaceutical ingredients, such as paracetamol, remains a great challenge for the pharmaceutical industry due to the lack of understanding of the interplay between the formulation properties, process of compaction, and stages of tablets' detachment and ejection. The aim of this study was to analyze the influence of the compression load, excipients' co-processing and the addition of paracetamol on the obtained tablets' tensile strength and the specific parameters of the tableting process, such as (net) compression work, elastic recovery, detachment, and ejection work, as well as the ejection force. Two types of neural networks were used to analyze the data: classification (Kohonen network) and regression networks (multilayer perceptron and radial basis function), to build prediction models and identify the variables that are predominantly affecting the tableting process and the obtained tablets' tensile strength. It has been demonstrated that sophisticated data-mining methods are necessary to interpret complex phenomena regarding the effect of co-processing on tableting properties of directly compressible excipients.

Interaction between Omeprazole and Gliclazide in Relation to CYP2C19 Phenotype.

The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4-1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease.

Considering the urgent need for novel therapeutics in ongoing COVID-19 pandemic, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we designed an integrative in silico drug repurposing approach for rapid selection of potential candidates against SARS-CoV-2 Main Protease (Mpro ). To screen FDA-approved drugs, we implemented structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data mining analysis of drug-gene-COVID-19 association. Through presented approach, we selected the most promising FDA approved drugs for further COVID-19 drug development campaigns and analysed them in context of available experimental data. To the best of our knowledge, this is unique in silico study which integrates structure-based molecular modeling of Mpro inhibitors with predictions of their tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects of selected candidates.

Mucoadhesive Gelatin Buccal Films with Propranolol Hydrochloride: Evaluation of Mechanical, Mucoadhesive, and Biopharmaceutical Properties.

This study processes and characterizes propranolol hydrochloride/gelatin mucoadhesive buccal films. Two types of gelatin are used: Gelatin from porcine skin, type A (GA), and gelatin from bovine skin (GB). The influence of gelatin type on mechanical, mucoadhesive, and biopharmaceutical characteristics of buccal films is evaluated. Fourier-Transfer infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analysis show that GA with propranolol hydrochloride (PRH) in the film (GAP) formed a physical mixture, whereas GB with PRH (GBP) form a compound-complex. Results of mechanical testing (tensile test, hardness) revealed that GAP films exhibit higher elastic modulus, tensile strength, and hardness. A mucoahesion test shows that GBP has higher adhesion strength, while GAP shows higher work of adhesion. Both in vitro release study and in silico simulation indicated that processed films can provide effective drug transport through the buccal mucosa. In silico simulation shows improved bioavailability from buccal films, in comparison to the immediate-release tablets-indicating that the therapeutic drug dose can be markedly reduced.

Paracetamol extended release FDM 3D printlets: Evaluation of formulation variables on printability and drug release.

Paracetamol printlets were prepared via hot-melt extrusion process and fused deposition modelling, using two types of backbone polymers. Polycaprolactone (PCL) and Polyethylene oxides (PEO) 100 K and 200 K were used, while Arabic gum was used as a plasticizer to facilitate the material flow and Gelucire® 44/14 as an enhancer of drug release. Different drug/polymer ratios were prepared. Extrusion temperature was adjusted according to the mixture/polymer types. It was possible to produce filaments with maximum of 60% w/w of drug. Mechanical properties of filaments were evaluated using three-point bend test, while obtained parameters were modelled using decision tree as a data mining method. Correlation between maximum displacement, maximum force and printability was obtained with accuracy of 84.85% and can be a useful tool for predicting printability of filaments. This study briefly demonstrated that backbone polymer in formulation plays crucial role in obtaining FDM printlets with desired properties. PEO-based filaments were more prone to be clogged in printcore, but their printlets showed much faster drug release. Drug release from all printlets was prolonged: from 50% in 8 h (PCL), to complete release in 4 h (PEO). Paracetamol release kinetics was guided by anomalous transport, attributed to the diffusion and erosion process.

Development of solid lipid microparticles by melt-emulsification/spray-drying processes as carriers for pulmonary drug delivery.

The aim of this study was to optimize the parameters of the complex melt-emulsification process coupled with the spray-drying, in order to maintain the balance between solid lipid microparticles (SLMs) powders aerodynamic performance and salbutamol sulfate release rate. Quality target product profile was identified and risk management and principal component analysis were used to guide formulation development. Obtained dry powders for inhalation (DPIs) were evaluated in terms of SLMs size distribution, morphology, true density, drug content, solid state characterization studies, in vitro aerosol performance and in vitro drug release. SLMs micrographs indicated spherical, porous particles. Selected powders showed satisfactory aerosol performance with a mean mass aerodynamic diameter of around 3 µm and acceptable fine particle fraction (FPF). Addition of trehalose positively affected SLMs aerodynamic properties. The results of in vitro dissolution testing indicated that salbutamol sulfate release from the tested SLMs formulations was modified, in comparison to the raw drug release. In conclusion, SLMs in a form of DPIs were successfully developed and numerous factors that affects SLMs properties were identified in this study. Further research is required for full understanding of each factor's influence on SLMs properties and optimization of DPIs with maximized FPFs.

BCS Class IV Oral Drugs and Absorption Windows: Regional-Dependent Intestinal Permeability of Furosemide.

Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus®) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed; as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pKa, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide's regional-dependent permeability on its absorption, as well as the critical role of the drug's absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products.