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Text mining (TM) applications in the field of biomedicine are gaining great interest. TM tools can facilitate formulation development by analyzing textual information from patent databases, scientific articles, summary of products characteristics, etc. The aim of this study was to utilize TM tools to perform qualitative analysis of paracetamol (PAR) and ibuprofen (IBU) formulations, in terms of identifying and evaluating the presence of excipients specific to the active pharmaceutical ingredient (API) and/or dosage form. A total of 152 products were analyzed. Web-scraping was used to retrieve the data, and Python-based open-source software Orange 3.31.1 was used for TM and statistical analysis (ANOVA) of the obtained results. The majority of marketed products for both APIs were tablets. The predominant excipients in all tablet formulations were povidone, starch, microcrystalline cellulose and hypromellose. Povidone, stearic acid, potassium sorbate, maize starch and pregelatinized starch occurred more frequently in PAR tablets. On the other hand, titanium dioxide, lactose, shellac, sucrose and ammonium hydroxide were specific to IBU tablets. PAR oral suspensions more frequently contained dispersible cellulose; liquid sorbitol; methyl and propyl parahydroxybenzoate, glycerol and acesulfame potassium. Specific excipients in other PAR dosage forms, such as effervescent tablets, hard capsules, oral powders, solutions and suspensions, as well as IBU gels and soft capsules, were also evaluated.

The treatment of respiratory infections in children requires special attention, since the paediatric population has rather specific characteristics and consists of heterogenous subgroups. In this context, the choice of a suitable drug dosage form is of particular importance, depending on the active substance properties, along with the age and general condition of a paediatric patient. The most commonly used pharmaceutical products for respiratory infections in children include oral, parenteral and inhalation dosage forms, although a large number of drugs are not available in a suitable dosage form and/or strength for paediatric age, leading to the frequent use of unauthorized drugs (i.e., unlicensed use). Other important issues that should be considered when choosing the appropriate paediatric dosage form and/or compounding procedure are related to the careful considerations of the pharmaceutical product composition (safety of excipients) and the choice of administration/dosing device in relation to a child's age. This paper provides an overview of paediatric dosage forms used in the treatment of respiratory infections in children, their benefits and limitations. The review includes examples of various pharmaceutical products, along with the considerations regarding administration/dosing devices. Specific characteristics of paediatric populations affecting the decision on the choice of age-appropriate paediatric formulation are also addressed.

Liquisolid systems represent an emerging approach in the preparation of solid dosage forms with liquid lipophilic drug or poorly water-soluble drug solution/suspension in suitable liquid vehicle. This study addresses the lack of data regarding the compaction behavior of liquisolid systems, with the aim to investigate the influence of liquid load, carrier to coating ratio, carrier type (microcrystalline cellulose vs. spray dried calcium hydrogen phosphate, anhydrous (Fujicalin®)) on flowability and compaction properties of liquisolid systems and to determine the optimum liquid loads. Liquisolid admixtures with Fujicalin® showed notably better flowability than those with microcrystalline cellulose. An increase in carrier to coating ratio led to enhanced flowability of the admixtures. Compacts with Fujicalin® had good mechanical properties up to 24.7% liquid, while those with microcrystalline cellulose had acceptable mechanical strength up to 16.2% liquid. Liquisolid systems with Fujicalin® showed similar tabletability profiles as those with microcrystalline cellulose, despite having higher liquid content. The ejection stress values indicated that the addition of lubricant might be needed in the case of liquisolid systems with Fujicalin®. Superior properties of Fujicalin® as a carrier for liquisolid tablets were revealed, and dynamic compaction analysis was found to be a valuable tool for the assessment of compaction behavior of liquisolid systems.

Hot-melt coating (HMC) is an alternative, solvent-free coating method generally used to modify substrate release rate and/or mask its unpleasant taste. The aim of this study was to assess two HMC methods (pan-coating and mortar-coating) by assaying functional properties of the coated material. The selected substrates included highly soluble sodium chloride (model substance) and caffeine (bitter drug), and the coating agent was glycerol distearate without/with the addition of liquid paraffin. Experiments with sodium chloride revealed that pan-coating yielded particles of more regular shape, while mortar-coating yielded samples of more uniform coating layer. The flowability of the coated material depended on the particle size. Sustained sodium chloride release was achieved for all mortar-coated and some pan-coated samples. The analysis of the results indicated mortar-coating as a preferable HMC method for caffeine coating. The resulting caffeine yield in the coated samples was high (99%), the material showed satisfactory mechanical properties and drug release from the coated particles was sustained. Overall, the obtained results suggest that both pan-and mortar-coating can be used to sustain the release of drugs with unpleasant taste, but mortar-coating can be considered as a more simple and practical method that can be potentially used in compounding pharmacies.

The development of solid dosage forms that are both convenient for administration and allow precise drug dosing for pediatric patients is one of the great challenges in contemporary pharmaceutical technology. The presented study has utilized propranolol hydrochloride, as one of the most frequently prescribed drugs that require manipulation of the conventional dosage forms to be administered to children. Multiparticulate oral formulations, powderand granulefilled capsules, as well as mini tablets, were prepared and characterized in terms of their mass and content uniformity and compared to conventional marketed tablets split into halves and quarters. The obtained results have demonstrated the superiority of the multiparticulate formulations, in terms of their average mass and drug content uniformity. It has also been demonstrated that, due to improved flowability, granule-filled capsules are more conveniently compounded and provide higher content uniformity compared to powder-filled capsules. The presented compounding method could be easily employed in community pharmacy settings. Mini tablets with high and uniform content of propranolol hydrochloride have been successfully prepared, thereby presenting a viable strategy for efficient drug dose adjustment.

Computer-based (in silico) modeling & simulation tools have been embraced in different fields of pharmaceutics for a variety of applications. Among these, physiologically-based pharmacokinetic/biopharmaceutics modeling (PBPK/PBBM) emerged as a particularly useful tool in formulation development. PBPK/PBBM facilitated strategies have been increasingly evaluated over the past few years, as demonstrated by several reports from the pharmaceutical industry, and a number of research and review papers on this subject. Also, the leading regulatory authorities have recently issued guidance on the use of PBPK modeling in formulation design. In silico PBPK models can comprise different dosing routes (oral, intraoral, parenteral, inhalation, ocular, dermal etc.), although the majority of published examples refer to modeling of oral drugs performance. In order to facilitate the use of PBPK modeling tools, a couple of companies have launched commercially available software such as GastroPlus™, Simcyp™ PBPK Simulator and PK-Sim®. This paper highlights various application fields of PBPK/PBBM modeling, along with the basic principles, advantages and limitations of this approach, and provides relevant examples to demonstrate the practical utility of modeling & simulation tools in different stages of formulation development.

The importance of biopharmaceutical considerations in pharmaceutical development and drug characterization has been well recognized both by pharmaceutical industry and regulatory authorities as a tool to establish predictive relationships between drug product quality attributes (in vitro data) and its clinical performance (in vivo data). In the present paper, contemporary biopharmaceutics toolkit including in vivo predictive dissolution testing, Biopharmaceutics Classification System, physiologically based pharmacokinetic and biopharmaceutics modeling and simulation, in vitro-in vivo correlation and biowaiver, are reviewed with regards to relevant general principles and applicability. The recently introduced innovative strategy for patient-centric drug development using an integrated systems approach grounded in fundamental biopharmaceutics concepts, clinical insights and therapeutic drug delivery targets, described as Biopharmaceutics Risk Assessment Roadmap (BioRAM) is also presented. Further development in the field will benefit from joint efforts and exchange of knowledge and experiences between pharmaceutical industry and regulatory authorities for the common goal to accelerate development of effective and safe drug products designed in accordance with patients’ needs and expectations.

Orodispersible dosage forms are intended to be placed on tongue where, in contact with limited saliva volume, fast disintegration, followed by facilitated swallowing, occurred. Intraoral disintegration might be accompanied by drug release and dissolution in oral cavity. Dissolved drug could interact with receptors on taste buds causing taste sensation. The most important critical quality attributes of orodispersible dosage forms are acceptable mechanical resistance, fast disintegration and pleasant taste which have to be monitored and evaluated during formulation development and production. However, compendial methods for orodispersible dosage forms characterization are still lacking, while many authors attempt to develop different, more suitable approaches. The highest variability during determination of disintegration properties is observed. It can be concluded that for the proper disintegration assessment influence of tongue force have to be considered, especially in the case of different polymeric orodispersible films. For reliable development of in vivo study for evaluation of tastemasking efficacy, proper selection and training of panelists accompanied by bitterness threshold determination are of the utmost importance. In order to correlate in vitro and in vivo data, it is necessary to develop analytical method for evaluation of taste-masking efficacy that mimic, in great extent, physiological intraoral conditions.

Depression is the most common mental disorder in the general population and often requires long-term administration of antidepressants. Development of the modified release antidepressant products has led to the lower incidence of the adverse effects and improvement in the adherence, and subsequently to better therapeutic outcomes. Modified release may involve delayed and/or prolonged release of antidepressants. There is an increasing number of marketed antidepressant products in the form of orally dispersible tablets, for the treatment of a particular group of patients with impaired swallowing. Pharmacotherapy of depression in children represents a great challenge due to insufficient data regarding efficacy and safety. Furthermore, in the market of Republic of Serbia, there are no antidepressant products in the age-appropriate dosage forms for pediatric patients. It is, therefore, of great importance to address the risks related to the application of the conventional dosage forms of marketed antidepressants (tablets, hard capsules) to children. Novel treatment options include development of carriers for targeted delivery of antidepressants in the central nervous system. Intranasal administration of antidepressants is particularly favored since it allows the delivery of active ingredients via olfactory and trigeminal nerves. Other transmucosal routes of administration, such as buccal or sublingual, can provide improved therapeutic outcomes, compared to the conventional oral administration, due to circumvention of the intense metabolism of the active ingredients and undesired gastrointestinal side effects.

Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased risk of serious gastrointestinal side effects. Therefore, recent trends in the development of NSAIDs aim to reduce the incidence of side effects, and improve patient compliance. One of the strategies to improve efficacy and safety of oral NSAIDs is the development of combination products that contain gastroprotective agents. Several products containing NSAID in combination with proton pump inhibitors (ketoprofen/omeprazole, naproxen/esomeprazole), H2-receptor antagonists (ibuprofen/famotidine), and prostaglandin analogues (diclofenac/misoprostol) are currently available on the market. Another approach refer to the special formulation design to allow dose reduction while preserving drug therapeutic efficacy. An example is SoluMatrix® technology, a manufacturing process that produce submicron-sized drug particles with enhanced dissolution and absorption properties. Patented SoluMatrix® technology has been successfully employed to develop low-dose diclofenac, meloxicam, indomethacin and naproxen products. Topical NSAID formulations enable drug delivery to target tissues, while reducing systemic exposure and concomitant side effects associated with oral NSAIDs. Dermal/transdermal NSAID delivery systems are subject of intensive investigation. So far, several 'advanced' drug delivery systems with diclofenac, ibuprofen and ketoprofen have been designed.

Conventional granulation methods are associated with significant disadvantages which have led to increased interest and investment in the development of alternative techniques. Melt granulation is an alternative technique with significant potential for the application in production of solid dosage forms. Melt granulation involves the use of binders with relatively low melting point (50 to 100°C) that act as a molten binding liquid in agglomeration process. Considering that solvent is not required, drying phase is avoided, and number of processing steps and costs is reduced in comparison with the traditional wet granulation process. Process is suitable for moisture-sensitive drugs, and by selecting the suitable binder, it can be used to prepare modified or immediate release dosage forms, with improved bioavailability of poorly water soluble drugs, as well as to achieve taste masking. Melt granulation can be performed in the equipment commonly used for wet granulation, such as high shear mixers, fluid bed granulators, and extruders. Numerous formulation variables, process parameters, and equipment-related factors can affect the agglomeration mechanism and characteristics of the granules obtained. Well controlled melt granulation process requires thorough knowledge and understanding of the influence of these factors. Therefore, this research area still requires an intense and often multidisciplinary research.

Achieving wider recognition is part of the development agenda of contemporary cities, which are all confronted with the need to stand out and compete against one another. City branding reads as and plays an important role in this struggle for recognition. The identity of a city is generated over a long period, as it undergoes historical change, resulting in cultural diversity as the product of a specific environment. This paper discusses the possibility of using the cultural and historical heritage of Trebinje and its identity as an asset to create its city brand. Trebinje is a small city situated in the vicinity of Dubrovnik, a major tourist destination with a rich cultural and historical heritage and an excellent city brand. Dubrovnik may be seen as jeopardising the development of Trebinje’s authentic identity; on the other hand, the strong historical ties between the two cities can actually be used as an asset to develop Trebinje’s city brand. The material and non-material heritage which helped the formation of Trebinje’s identity, is analysed. The Mediterranean region in which it is located, its rich history, authentic architecture and different cultural influences, including the national poet Jovan Dučić, have all helped create Trebinje’s genius loci. The same factors may be used to communicate its new image. After that, the paper outlines models of the possible use of the recognised assets to brand the city and emphasise the importance of the effective presentation of these assets for creating a recognisable city image. It also proposes specific actions and interventions that may contribute to branding the city.

This paper considers the possibility of including cultural heritage in cultural and tourist development policies. The tourist potential of historically and artistically significant urban entities will be described and assessed in the paper, with a focus on the cases of Trebinje and Jajce two Bosnian and Herzegovinian towns with preserved historical town cores. The two towns were both founded in the Middle Ages and have developed to this day, with their urban areas continuously expanding and being built up. Their spatial and cultural historical complexes are diverse and multilayered, with various natural and man-made structures dating back to different epochs. They are the greatest cultural monuments and a testimony of the past, of the physical and spiritual development of these communities. Trebinje is an old town located at the intersection of various influences and interests, with a rich and long history which has altered not only the appearance and contents of its town core, but also its significance and its functional impact on the broader surroundings. The Old Town, a surviving historical complex, which originated in the Middle Ages and developed considerably under Turkish rule is one of Trebinje's tourist resources. Nowadays, tourism is becoming one of the world's most important industries, its appeal coming from the natural cultural and historical values of towns and cities. Due to that, the natural cultural and historical values of Trebinje and Jajce can be preserved only if their economic potential is also taken into account.

This study focuses on the designing and characterization, and anticancer evaluation of chitosan-based nanoparticles (NPs) loaded (enriched) with a Biginelli hybrid compound (BH). NPs based on chitosan (CH) or chitosan oligosaccharide lactate (CHOL), are carefully designed to encapsulate a tetrahydropyrimidine derivative (BH) with already proven anticancer properties. The formulations were evaluated for their physicochemical properties, including particle size distribution and morphology, using techniques such as infrared spectroscopy, scanning electron microscopy, and X-ray diffraction. The cytotoxicity profiles were assessed on different cancer cell lines, showing a higher selectivity towards HeLa and A549 cells related to BH. BH-CH showed better cytotoxic profile related to BH-CHOL NPs. A cell cycle analysis revealed an accumulation of cells in the G 2 /M phase after a treatment with these NPs, indicating the ability to induce mitotic arrest in cancer cells. In summary, the results underscore the promising application of CH-based natural nanocarriers for the targeted delivery of Biginelli hybrids, showcasing a significant potential for further in vivo testing., Competing Interests: The authors confirm that they do not have any competing financial interests or personal relationships that could have influenced the work reported in this article., (This journal is © The Royal Society of Chemistry.)

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 t max ) and reduced C max , 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.

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 ∼1000-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 C max 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

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.

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.

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 C max , 28-36% decreased F a , 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.

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.

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 (C max ) was achieved. However, no statistically significant difference was observed in C max 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.

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.

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., Competing Interests: The authors declare that there is no conflict of interest., (© 2021 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

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 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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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, pK a , 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.

In this study, we aimed to elucidate biopharmaceutical characteristics of the anti-ulcer drug rebamipide, with special emphasis on the influence of gastrointestinal (GI) mucus on rebamipide segmental-dependent permeability and absorption. Experimental studies and physiologically-based pharmacokinetic (GastroPlus TM ) simulations were used to elucidate segmental-dependent absorption and pharmacokinetic (PK) profile, accounting for various drug properties, including solubility/dissolution limitations, regional-dependent drug affinity to mucus and membrane permeability, as well as physiological factors such as regional-pH differences along the intestine, thickness and types of mucus, transit time and surface areas. Low permeability and extensive binding to GI mucus were the key modeling features, and accounting for these resulted in good fitting between the predicted and in-vivo PK profiles, validating the ability of the model to pinpoint the underlying mechanisms of rebamipide limited oral bioavailability. Furthermore, the simulations indicated regional-dependent intestinal permeability of rebamipide, with absorption rank order of jejunum>ileum>duodenum>colon, mainly attributable to segmental mucus differences. Food effect simulations indicated somewhat decreased rebamipide absorption in the fed state, in corroboration with previous reports. Since this anti-ulcer drug is currently examined for additional indications, this work provides important input for future development of rebamipide., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Liquisolid technology, as a promising approach for bioavailability enhancement, has received increasing attention in recent years. However, literature reports addressing the challenges for its industrial application, particularly those related to compaction behavior of liquisolid systems, are scarce. The aim of this study was to investigate the influence of process parameters and formulation variables on the flowability, wetting, and compaction properties of the liquisolid systems prepared in a fluid bed processor. The experiments with microcrystalline cellulose, as a carrier, were performed according to 2 3 full factorial design. The effects of liquid content, spray air pressure, and liquid feed rate on the properties of liquisolid systems were investigated. Liquisolid admixtures with microcrystalline cellulose were compared with those prepared with novel carriers, Fujicalin ® and Neusilin ® US2. "Out-die" Heckel, modified Walker, and Kuentz-Leuenberger models were used to analyze the compressibility of liquisolid admixtures. The results obtained showed that an increase in liquid content (in the range of 10 to 15%) led to a decrease in flowability of liquisolid admixtures with microcrystalline cellulose, as well as more pronounced influence of spraying conditions. On the other hand, higher liquid content led to higher compressibility. Fujicalin ® and Neusilin ® US2 liquisolid admixtures were found to have superior flowability and compressibility in comparison with those with microcrystalline cellulose, despite the considerably higher liquid load (50-55% liquid content in Neusilin ® US2 compacts). Acceptable compactibility of the investigated liquisolid systems was observed. The fluid bed processor was shown to be suitable equipment for production of liquisolid systems, but with careful adjustment of process parameters.

Three-dimensional (3D) printing enables the production of different objects adjusted for the specific application, which has particular importance of providing personalized therapy, whereby the challenge is to apply pharmaceutical materials into 3D printing technology. In this study, effect of poly(ethylene glycol) 400 (PEG 400), sodium chloride (NaCl), and mannitol, as hydrophilic excipients, was investigated in order to overcome very slow and incomplete drug release from tablets (printlets) fabricated by photopolymerization using digital light processing (DLP) technology. Paracetamol (acetaminophen) was used as a model drug, while polyethylene glycol diacrylate (PEGDA) was used as a photopolymer and diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide as a photoinitiator in photoreactive mixtures. Most of printlet formulations exhibit sustained release over 8 h, wherein drug release kinetics is the best described with Korsmeyer-Peppas kinetics. Variation in the content of photopolymer and excipients had an influence on the dissolution rate, mechanical characteristics, and internal structure of the investigated samples. The addition of hydrophilic polymers increased drug release rate, while PEGDA had the greatest influence on the tensile strength of printlets. The results indicate the possibility of implementation of traditional excipients into different formulations for photopolymerization based 3D printing for the production of small batches of tablets with tailored drug release., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Consumption of alcoholic beverages with sustained-release oral dosage forms may pose a risk to patients due to potential alcohol-induced dose dumping (ADD). Regulatory guidances recommend in vitro dissolution testing to identify the risk of ADD, but the question remains whether currently proposed test conditions can be considered biopredictive. The purpose of this study was to evaluate different dissolution setups to assess ADD, and the potential of combined in vitro-in silico approach to predict drug absorption after concomitant alcohol intake for hydrophilic and lipophilic sustained-release tablets containing ibuprofen or diclofenac sodium. According to the obtained results, the impact of ethanol was predominantly governed by the influence on matrix integrity, with the increase in drug solubility being less significant. Hydrophilic matrix tablets were less susceptible to ADD than lipophilic matrices, although the conclusion on formulation ethanol-vulnerability depended on the employed experimental conditions. In silico predictions indicated that the observed changes in drug dissolution would not result in plasma concentrations beyond therapeutic window, but sustained-release characteristics of the formulations might be lost. Overall, the study demonstrated that in vitro-in silico approach may provide insight into the effect of ADD on drug clinical performance, and serve as a tool for ADD risk assessment.

This study aimed to improve dissolution rate of valsartan in an acidic environment and consequently its oral bioavailability by solid dispersion formulation. Valsartan was selected as a model drug due to its low oral bioavailability (~23%) caused by poor solubility of this drug in the low pH region of gastrointestinal tract (GIT) and presence of absorption window in the upper part of GIT. Solid dispersions were prepared by solvent evaporation method with Eudragit® E100, Soluplus® or polyvinylpyrrolidone K25 (PVP K25) in drug:polymer weight ratios of 1:1, 1:2, 1:4 and 1:6 and further subjected to solid-state characterization and in vitro drug dissolution testing in 0.1 M HCl. The expected drug plasma concentration vs. time profiles after oral administration of the selected solid dispersion formulations were predicted using physiologically-based in silico modeling. Fast and complete dissolution of valsartan, with >80% of dissolved drug within the first 10 min of testing, was observed only from solid dispersions prepared with Eudragit® E100 in drug:polymer ratios of 1:2, 1:4 and 1:6. In all other samples, valsartan dissolution was slow and incomplete. Solid-state characterization showed amorphous nature of both pure drug and solid dispersion samples, as well as favourable intermolecular interactions between valsartan and polymers over interactions between drug molecules. The constructed in silico model predicted >40% of increase in valsartan bioavailability, C max and AUC values from selected solid dispersion formulations compared to conventional solid oral dosage form such as IR capsules. Based on the results of the in vitro-in silico study, formulation of solid dispersions of valsartan with Eudragit® E100 polymer can be considered as a promising approach for improving valsartan bioavailability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The aims of this study were to formulate simvastatin (SV)-loaded self-microemulsifying drug delivery systems (SMEDDS), and explore the potential of these drug delivery systems to improve SV solubility, and also to identify the optimal place in the gastrointestinal (GI) tract for the release of SV using coupled in vitro/in silico approach., Significance: In comparison to other published results, this study considered the extensive pre-systemic clearance of SV, which could significantly decrease its systemic and hepatic bioavailability if SV is delivered into the small intestine., Methods: SV-loaded SMEDDS were formulated using various proportions of oils (PEG 300 oleic glycerides, propylene glycol monocaprylate, propylene glycol monolaurate), surfactant (PEG 400 caprylic/capric glycerides) and cosurfactant (polysorbate 80) and subjected to characterization, and physiologically-based pharmacokinetic (PBPK) modeling., Results: According to the in vitro results, the selected SMEDDS consisted of 10.0% PEG 300 oleic glycerides, 67.5% PEG 400 caprylic/capric glycerides, and 22.5% polysorbate 80. The use of acid-resistant capsules filled with SV-loaded SMEDDS was found helpful in protecting the drug against early degradation in proximal parts of the GI tract, however, in silico simulations indicated that pH-controlled drug release system that dissolve in the distal parts of the intestine might further improve SV bioavailability (up to 7.20%)., Conclusion: The obtained results suggested that combined strategy for the improvement of SV bioavailability should comprise solubility enhancement and delayed drug release. The developed SV-specific PBPK model could potentially be used to assess the influence of formulation factors on drug absorption and disposition when developing SV oral dosage forms.

One of the critical components of the respiratory drug delivery is the manner in which the inhaled aerosol is deposited in respiratory tract compartments. Depending on formulation properties, device characteristics and breathing pattern, only a certain fraction of the dose will reach the target site in the lungs, while the rest of the drug will deposit in the inhalation device or in the mouth-throat region. The aim of this study was to link the Computational fluid dynamics (CFD) with physiologically-based pharmacokinetic (PBPK) modelling in order to predict aerolisolization of different dry powder formulations, and estimate concomitant in vivo deposition and absorption of amiloride hydrochloride. Drug physicochemical properties were experimentally determined and used as inputs for the CFD simulations of particle flow in the generated 3D geometric model of Aerolizer® dry powder inhaler (DPI). CFD simulations were used to simulate air flow through Aerolizer® inhaler and Discrete Phase Method (DPM) was used to simulate aerosol particles deposition within the fluid domain. The simulated values for the percent emitted dose were comparable to the values obtained using Andersen cascade impactor (ACI). However, CFD predictions indicated that aerosolized DPI have smaller particle size and narrower size distribution than assumed based on ACI measurements. Comparison with the literature in vivo data revealed that the constructed drug-specific PBPK model was able to capture amiloride absorption pattern following oral and inhalation administration. The PBPK simulation results, based on the CFD generated particle distribution data as input, illustrated the influence of formulation properties on the expected drug plasma concentration profiles. The model also predicted the influence of potential changes in physiological parameters on the extent of inhaled amiloride absorption. Overall, this study demonstrated the potential of the combined CFD-PBPK approach to model inhaled drug bioperformance, and suggested that CFD generated results might serve as input for the prediction of drug deposition pattern in vivo., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Within the last decades, physiologically based pharmacokinetic models have emerged into a biopharmaceutical toolkit that has been proven useful in understanding how physicochemical, formulation and physiological factors affect oral drug absorption. The purpose of this study was to develop a drug specific physiologically based pharmacokinetic model that will allow mechanistic interpretation of oral absorption from dosage forms exhibiting different in vitro and different in vivo performance (i.e. immediate release and sustained release tablets) and identification of bioperformance dissolution testing. Ibuprofen was chosen to be used for the "proof of concept" considering it is well characterised and the necessary physicochemical, biopharmaceutical and pharmacokinetic properties for model development could be found in the literature. Gastrointestinal simulation technology implemented in Simcyp® was successful in estimating ibuprofen oral absorption. The developed model exhibited good generalisation ability for the dosage forms studied. The obtained results indicate that the model was sensitive to input kinetics represented by the in vitro drug release profiles obtained under various dissolution conditions. According to the obtained results, reciprocating cylinder apparatus with biorepresentative change in media pH might be considered as bioperformance dissolution in the case of the two ibuprofen SR products studied. These results further justify the use of integrated in vitro-in vivo-in silico approach in estimating bioperformance of oral solid dosage forms., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The integrated in vitro--in silico--in vivo approach has emerged into a biopharmaceutical toolkit that could accelerate drug development and improve drug product clinical performance in patients. In the present study, the influence of physiologically based media and dynamic dissolution testing on drug release from two metformin hydrochloride immediate release products with proven bioequivalence was tested. Metformin-specific physiologically based pharmacokinetic (PBPK) model was developed based on a range of literature or in silico predicted data using gastrointestinal simulation technology implemented in the Simcyp software package. Various approaches were employed in order to estimate the human effective permeability which was used as input for metformin plasma profile simulation. Influence of the rate and extent of metformin dissolution on drug absorption was evaluated. Both convolution and deconvolution approaches were used in order to establish a correlation between the in vitro and in vivo data. The results obtained indicate that physiologically based dissolution media and glass bead dissolution device exhibit certain advantages over the compendial dissolution apparatus and simple buffers which tended to be over-discriminative. Gastrointestinal simulation technology implemented in the Simcyp Simulator was successfully used in developing drug-specific PBPK model for metformin. Simulations indicate that in vitro dissolution kinetics has no significant effect on metformin absorption, if more than 65% of drug is released in 1 hour. Level A in vitro-in vivo correlation was obtained using both convolution and deconvolution approaches.

The purpose of this study was to mechanistically interpret the oral absorption pattern of trospium in fasted and fed states by means of gastrointestinal simulation technology. A drug absorption model was built on the basis of experimental data. According to the generated model, low permeability across the intestinal epithelium, delayed gastric emptying time and a prolonged residence time in the small intestine are the key factors governing trospium absorption in the fasted state. Furthermore, in silico modelling provided a plausible explanation of the pronounced reduction in the oral bioavailability of trospium when administered with food. The simulation results support the decreased dissolution in viscous medium, and the reduced drug permeability in the fed state as the predominant mechanisms for the food effect on trospium absorption., (Copyright © 2014 John Wiley & Sons, Ltd.)

Concomitant food intake can diminish oral absorption of drugs with limited permeability and an absorption window in the proximal intestine, due to viscosity-mediated decrease in dosage form disintegration time and drug dissolution rate. Three poorly-permeable drugs (atenolol, metformin hydrochloride, and furosemide) exhibiting negative food effect, and one highly-soluble and highly-permeable (metoprolol tartrate), serving as a negative control, were selected for the study. In vitro and in silico tools were used to evaluate the influence of media viscosity on drug bioperformance under fasted and fed conditions. The obtained results demonstrated that increased medium viscosity in the presence of food is one of the key factors limiting oral absorption of drugs with limited permeability and absorption restricted to the upper parts of the intestine, while having negligible effect on pharmacokinetic profile of drugs with pH- and site-independent absorption. Dissolution medium pH 4.6 with the addition of hydroxypropyl methylcellulose was suggested to simulate postprandial gastric conditions for drugs whose solubility under these conditions is not the limiting factor for drug absorption. In addition, drug formulation was found to be an interfering factor in relation to the impact of medium viscosity on the rate and extent of drug absorption., (Copyright © 2014 Elsevier B.V. All rights reserved.)