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The study explains the preparation of spherical agglomerates (SA) of telmisartan (TLS), a BCS class II drug used to improve it's physicochemical and bulk properties. Drugs of this class could potentially exhibit dissolution rate limited absorption. TLS spherical agglomerates were designed using hydrophilic polymer (PVP K-30), dimethyl formamide (DMF), water and ethyl acetate (bridging liquid) by solvent change method and evaluated for micromeritic properties. The SA were characterized by particle size determination, FTIR, PXRD and SEM. The results of micromeritic studies indicated that SA showed improved flow properties due to their spherical shape and bigger size. Absence of strong interaction at molecular level and alteration in the crystal structure of TLS with modification in crystallinity was confirmed by FTIR and PXRD respectively. TLS solubility characteristics were improved by this approach. [ABSTRACT FROM AUTHOR]

This document provides a summary of various scientific articles related to the drug ivermectin. The articles cover topics such as the solubility and dissolution enhancement of ivermectin, the development of topical formulations, the effects of polymers on drug solubility, and the potential anticancer properties of ivermectin. The articles also discuss the use of solid dispersion techniques to improve the bioavailability of poorly water-soluble drugs and the application of biopharmaceutical classification systems in drug development. These articles offer valuable information for researchers and practitioners interested in the pharmacological effects and formulation strategies of ivermectin. [Extracted from the article]

[Display omitted] The prediction of oral absorption from a supersaturating drug delivery system (SDDS) remains a significant challenge. Here we evaluated the effects of the degree and duration of supersaturation on in vivo absorption for dipyridamole and ketoconazole. Various dose concentrations of supersaturated suspensions were prepared by a pH shift method, and in vitro dissolution and in vivo absorption profiles were determined. For dipyridamole, the duration of supersaturation decreased with the increase of the dose concentration owing to rapid precipitation. For ketoconazole, the initially constant dissolved concentrations due probably to the liquid–liquid phase separation (LLPS) as a reservoir were observed at high dose concentrations. However, the LLPS did not delay the peak plasma concentration of ketoconazole in rats, indicating that drug molecules were immediately released from the oil phase to the bulk aqueous phase. For both model drugs, the degree of supersaturation, but not the duration of supersaturation, correlated with systemic exposure, indicating quick drug absorption before precipitation. Therefore, the degree of supersaturation is an important parameter compared with the duration of supersaturation for enhancing the in vivo absorption of highly permeable drugs. These findings would help develop a promising SDDS. [ABSTRACT FROM AUTHOR]

Poor aqueous solubility and dissolution limit the oral bioavailability of Biopharmaceutics Classification System (BCS) class II drugs. In this study, we aimed to improve the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RLX), a BCS class II drug, using a self-microemulsifying drug delivery system (SMEDDS). Based on the solubilities of RLX, Capryol 90, Tween 80/Labrasol ALF, and polyethylene glycol 400 (PEG-400) were selected as the oil, surfactant mixture, and cosurfactant, respectively. Pseudo-ternary phase diagrams were constructed to determine the optimal composition (Capryol 90/Tween 80/Labrasol ALF/PEG-400 in 150/478.1/159.4/212.5 volume ratio) for RLX-SMEDDS with a small droplet size (147.1 nm) and stable microemulsification (PDI: 0.227). Differential scanning calorimetry and powder X-ray diffraction of lyophilized RLX-SMEDDS revealed the loss of crystallinity, suggesting a molecularly dissolved or amorphous state of RLX in the SMEDDS formulation. Moreover, RLX-SMEDDS exhibited significantly higher saturation solubility and dissolution rate in water, simulated gastric fluid (pH 1.2), and simulated intestinal fluid (pH 6.8) than RLX powder. Additionally, oral administration of RLX-SMEDDS to female rats resulted in 1.94- and 1.80-fold higher area under the curve and maximum plasma concentration, respectively, than the RLX dispersion. Collectively, our findings suggest SMEDDS is a promising oral formulation to enhance the therapeutic efficacy of RLX. [ABSTRACT FROM AUTHOR]

Carvedilol (CVD) is a non-selective β-blocker. CVD is included in BCS class II. It has low water solubility. In this research, solid dispersion was used to increase the solubility and dissolution profile of CVD. In silico study using the ligand-ligand docking method. The preparation of solid dispersion using the kneading method with a weight ratio of 1:1, 1:2, 1:3, and 1:4, evaluation of solid dispersion includes solubility and dissolution. The best solid dispersion was characterized using FTIR, DSC, and PXRD. In silico study showed complexes CVD-SA, CVD-GG, CVD-XG and CVD-LBG have a hydrogen interaction. SA and XG were chosen as carriers in solid dispersion. CVD solid dispersion showed increased solubility in all samples, with the highest increase at 90.63 times at CVD: XG (1:4). The results of the dissolution profile obtained at 60 min are 64.95 ± 0.45% at pure CVD, 83.32 ± 1.19% at CVD:SA (1:4), and 72.56 ± 3.62% at CVD: XG (1:4). The FTIR spectrum indicates an interaction between CVD and SA. The thermogram indicated the amorphous drug, and the diffractogram showed a decrease in crystallinity. Solid dispersion is proven to increase the solubility and dissolution profile of CVD. Solid dispersion CVD: SA (1:4) showed the highest solubility and dissolution profile.

Multicomponent crystallization is a method that can modify the physicochemical properties of Carvedilol (CVD), thereby increasing its solubility. Based on in silico screening the coformers (Benzoic Acid, Isonicotinamide, and Saccharin) showed non-covalent interactions with CVD, so the multicomponent crystal preparation of CVD by solvent evaporation method used these coformers with mole ratios of 1:1, 1:2, and 2:1. Multicomponent CVD:Isonicotinamide (1:2) exhibits increased saturation solubility of up to 140 mg/L and increased dissolution of up to 99.48%. The infra-red (IR) spectrum showed a peak shift, a thermogram pattern that was different from the DSC results, and a new peak on the XRD multicomponent crystal diffractogram indicating the formation of a new solid phase compared to pure Carvedilol. Therefore, the formation of multicomponent crystals can increase the solubility and dissolution rate of CVD, and all characteristics indicate the presence of interaction between CVD and Isonicotinamide, and the formation of a new solid phase. [ABSTRACT FROM AUTHOR]

Purpose: Incorporating high-dose insoluble drugs in quick release films has been a challenge. Given the limited size and shape of an orally disintegrating film, it becomes difficult to load a large amount of drug, especially when the drug is not freely soluble. Hot melt extrusion (HME) technology can be effectively utilized to address this issue. Due to the variety of limitations associated with solvent casting, there is an unmet need for an eco-friendly, patient compliant and continuous manufacturing process for the manufacturing of ODF. Method: The current research work utilizes HME for the continuous manufacture of oral soluble film of a high-dose BCS II, a nonsteroidal anti-inflammatory drug, nimesulide, for pain management. The formulation variables can be analysed by quality by design (QbD)-based design of experiment (DoE) to investigate the effect of the formulation variables on the quality of the final formulation. Analysis by DoE provided a sound statistical basis for choosing the concentration of the formulation variables to achieve optimized disintegration time, plasticity and drug release. Result: The optimized formulation was evaluated for mechanistic attributes, physicochemical properties, in vitro release and stability. The resultant formulation was stable with optimum mechanical strength and release profile. Conclusion: ODF with percent drug loading as high as 21.73% w/w was formulated and analysed successfully by QbD-based DoE using HME. The results confirmed the suitability of the HME technique for the formulation of ODFs with high-dose BCS class 2 drugs. [ABSTRACT FROM AUTHOR]

The discovery of new drug molecules in the current era has come with incidences of low water solubility. The less solubility of drug in water decreases oral bioavailability of the drug molecules. According to biopharmaceutics classification system, the drugs are categorized as per their solubility and membrane permeability. BCS class II shows high membrane penetration with low water solubility. The low water solubility of drugs presents a problem in their release when given orally. Formulation of SLN (solid lipid nanoparticle) is one of the leading approach to improve the poor water solubility of the drug. Its ability to encapsulate the drug in lipid matrix offers a precursor in advanced level of drug targeting. Griseofulvin is widely used anti-fungal drug of BCS class II. In this study, the griseofulvin containing solid lipid nanoparticles were formulated by three methods. The method optimization was done on entrapment efficiency, size of particles and yield. The optimization of variables was done using response surface method using 33 factorial designs. In this technique, three factors were investigated, at two different levels, and formulation trials were carried out over 27 possible combinations. The surfactant concentration (A), drug: lipid ratio (B), stabilizer concentration (C) were considered independent variables whereas the size of particles (X) and polydispersity index (Y) were considered as dependent variables. The in-vitro release investigation of drug containing solid lipid nanoparticles was compared with pure drug suspension where the solid lipid nanoparticles showed extended release of drug up to 24 hours with 89.47 %. [ABSTRACT FROM AUTHOR]

Objective: Regardless of having desired therapeutic properties many of the recently approved drugs are removed from the developmental pipeline for their clinical use due to low solubility and permeability. Conventional dosage forms are found relatively unsuitable for achieving desired pharmacokinetic and pharmacodynamics profiles. Cilnidipine is 1,4 dihydropyridine derivative calcium channel blocker used for the treatment of hypertension., Method: The aim and objective of this study was to develop a precise and significant method in LC-MS/MS for quantification of pharmacokinetic parameters of a cilnidipine-loaded self-micro-emulsifying drug delivery system in rat plasma and simultaneously assessed pharmacodynamic characters in comparison with the marketed cilnidipine tablet. Another potential aim of this study is to reduce the dose of the drug in order to counter the dose-dependent toxicities related to chronic use. In the present study, the parent and product ion of cilnidipine was m/z 491.3\237.1., Result: The plasma was extracted by protein precipitation technique. The calibration standard concentrations were 1.875, 3.75, 7.50, 15.00, 30.00, 60.00ng/mL and LLOQ, low-quality control, middle-quality control and high-quality control were 1.87, 5.62, 22.50, 45.00ng/mL, respectively. The mobile phase composition was 0.1% formic acid in Milli Q water with 10mM Ammonium acetate as an aqueous solvent and 0.1% formic acid in methanol as an organic solvent. Following oral administration of optimized formulation C max (peak plasma concentration) was achieved 21.02±3.17ng/mL at 0.866±0.11h (Tmax), whereas in the case of marketed tablet C max (peak plasma concentration) was achieved 10.16±0.89ng/mL at 0.93±0.11h (Tmax)., Discussion: The in-vivo characterizations of the optimized SMEDDS showed significantly better pharmacokinetic parameters in Wistar rats and showed almost 2.4 times enhanced relative bioavailability as compared to the marketed tablet of cilnidipine which was observed to be correlating to our findings with noninvasive blood pressure parameter of Wistar rats., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Development of novel active pharmaceutical ingredients (API) for oral use often face challenges due to low bioavailability. Nanoparticle-based drug delivery systems and cyclodextrin (CD) encapsulation offer promising solutions by enhancing API solubility or dissolution rates. Porous silicon nanoparticles have shown potential to encapsulate APIs in their amorphous form within the pores, improving their dissolution rates compared to crystalline counterparts. A novel synthesis approach, circumventing the expensive and tedious synthesis from Si wafer material, has been developed using centrifugal Chemical Vapor Deposition (cCVD). Herein, various cCVD Si particles were evaluated for their ability to enhance the dissolution rate of the model drugs celecoxib (CEL), phenytoin (PHT), griseofulvin (GRI), diclofenac (DCF) and naproxen (NAP). Our findings demonstrate increased dissolution rates of all tested APIs when formulated with cCVD Si particles, compared to free API in pH 7.4 or pH 2.0. Particle characteristics were largely retained after loading, and the solid state of the loaded APIs were evaluated using Differential Scanning Calorimetry (DSC). Dissolution kinetics were influenced by the particle properties, mass loading and API characteristics. Loading of CD-CEL, -GRI and -DCF complexes into the cCVD Si particles showed a potential for further enhanced dissolution rates, representing the first reported investigation of this combination. In conclusion, the cCVD Si particles are promising for improving the dissolution rate of poorly soluble drugs, potentially due to precipitation of amorphous or metastable forms. Further enhancements were observed upon loading CD-drug complexes, thereby offering promising strategies for optimizing drug bioavailability., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jo Klaveness, Werner Filtvedt and Hennie Marie Johnsen are inventors of a patent application with the title “Silicon particles for drug delivery”. The assignee of the patent application is Nacamed AS. Werner Filtvedt and Jo Klaveness have shares in Nacamed AS. Marianne Hiorth is an editor for the “Journal of Drug Delivery Science and Technology”., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Glyburide is a drug for the treatment of diabetes mellitus and has a potential effect on Alzheimer's disease. It is also a BCS Class 2 drug with low solubility and low permeability. Developing a nanosuspension formulation and increasing the solubility and dissolution rate of glyburide is required to overcome this challenge., Methods: Thus, the goal of this work was to create glyburide nanosuspensions by ball milling and homogenizing glyburide to increase its solubility and rate of dissolution. To achieve this, the nanosuspension formulation was optimized using a central composite design. Zeta potential, particle size distribution and solubility were selected by way of dependent variables, and ball milling time, homogenization cycles, and Pluronic F-127/glyburide ratio were chosen as independent variables. Glyburide nanosuspensions were obtained with a particle size of 244.6 ± 2.685 nm. In vitro release and solubility studies were conducted following optimization., Results: The saturation solubility of glyburide was nearly doubled as a result of the nanocrystal formation. Xray diffraction (XRD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR) were used to assess the nanosuspension. SEM images confirmed that the nanocrystal formation process was successful. Glyburide and the excipients have no incompatibilities, their physical states have not changed, and the preparation method has not affected the stability of glyburide, according to DCS, XRD, and FT-IR analyses., Conclusion: These studies indicated that a combination of ball milling and homogenization techniques significantly enhanced the solubility of glyburide and its release from the formulation. Consequently, this approach can be applied to formulations characterized by low absorption and limited bioavailability., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Poor aqueous solubility and dissolution limit the oral bioavailability of Biopharmaceutics Classification System (BCS) class II drugs. In this study, we aimed to improve the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RLX), a BCS class II drug, using a self-microemulsifying drug delivery system (SMEDDS). Based on the solubilities of RLX, Capryol 90, Tween 80/Labrasol ALF, and polyethylene glycol 400 (PEG-400) were selected as the oil, surfactant mixture, and cosurfactant, respectively. Pseudo-ternary phase diagrams were constructed to determine the optimal composition (Capryol 90/Tween 80/Labrasol ALF/PEG-400 in 150/478.1/159.4/212.5 volume ratio) for RLX-SMEDDS with a small droplet size (147.1 nm) and stable microemulsification (PDI: 0.227). Differential scanning calorimetry and powder X-ray diffraction of lyophilized RLX-SMEDDS revealed the loss of crystallinity, suggesting a molecularly dissolved or amorphous state of RLX in the SMEDDS formulation. Moreover, RLX-SMEDDS exhibited significantly higher saturation solubility and dissolution rate in water, simulated gastric fluid (pH 1.2), and simulated intestinal fluid (pH 6.8) than RLX powder. Additionally, oral administration of RLX-SMEDDS to female rats resulted in 1.94- and 1.80-fold higher area under the curve and maximum plasma concentration, respectively, than the RLX dispersion. Collectively, our findings suggest SMEDDS is a promising oral formulation to enhance the therapeutic efficacy of RLX.

Though oral drug delivery is the most preferred route of administration, there is high drug pharmacokinetic variability associated with the oral route. Change in drug substance particle size distribution, formulation composition, or manufacturing process may impact the dissolution and, hence, the systemic drug absorption in biopharmaceutics classification system class II compounds. In the present research, using a Boehringer Ingelheim investigational drug substance as the model compound, the tiny-TIM in vitro data and in silico pharmacokinetic model were used to establish in vitro–in vivo correlation and to predict the oral bioavailability. The level C in vitro–in vivo correlation between in vivo AUC and in vitro amount dissolved in both fasted and fed states could be established. Furthermore, level A in vitro–in vivo correlation was established between in vivo fraction absorbed and bioaccessibility from tiny-TIM dissolution in both fasted and fed states. Prediction of positive food effect from tiny-TIM dissolution was consistent with conclusion from clinical studies. Such predictive models developed using the minimum clinical data and the in vitro tiny-TIM data have the potential to reduce the animal and human experiments and to expedite the overall drug development process. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel THEDES using CBD as a model drug was generated and characterized. • The hydrophobic nature of the obtained DES was adopted for the generation of SEDDS. • The compatibility of THEDES with surfactant and co-surfactant was deeply investigated. • In vitro studies on Caco-2 cells confirmed the safety of the formulation and CBD-enhanced permeability. In this study, Cannabidiol crystals (CBD) were used as a BCS class II model drug to generate a novel therapeutic deep eutectic solvent (THEDES) with easy preparation using caprylic acid (CA). The hydrogen bonding interaction was confirmed by different techniques such as FT-IR and NMR, resulting in a hydrophobic system suitable for liquid formulations. The CBD-based THEDES, combined with a specific mixture of surfactants and co-surfactants, successfully formed a self-emulsifying drug delivery system (SEDDS) that generated uniform nano-sized droplets once dispersed in water. Hence, the THEDES showed compatibility with the self-emulsifying approach, offering an alternative method to load drugs at their therapeutic dosage. Physical stability concerns regarding the unconventional oily phase were addressed through stress tests using multiple and dynamic light scattering, demonstrating the robustness of the system. In addition, the formulated SEDDS proved effective in protecting CBD from the harsh acidic gastric environment for up to 2 h at pH 1.2. Furthermore, in vitro studies have confirmed the safety of the formulation and the ability of CBD to permeate Caco-2 cells when formulated. This investigation highlights the potential incorporation of THEDES in lipid-based formulations like SEDDS, expanding the avenues for innovative oral drug delivery approaches. [ABSTRACT FROM AUTHOR]

The objective of the present investigation was to develop and optimize spray dried solid dispersion for dissolution enhancement of an anti-HIV drug, Nevirapine. The pareto chart of Plackett and Burman screening design revealed that drug: polymer ratio, concentration of silicon dioxide, and feed flow rate had a significant effect on production yield and drug release (Q60). These factors were further studied using central composite design to obtain optimized formulation. Optimized formulation was characterized by DSC, XRD, and SEM, and studied for drug release and accelerated stability. Spray dried solid dispersion formulated with drug: polymer ratio of 1:2, 2% w/w silicon dioxide and 1 mL/min flow rate gave the best result of 69.02% production yield and 80.46% drug release. [ABSTRACT FROM AUTHOR]

Objectives: Bionanocomposites (BNCs) are biopolymers or a natural polymers embedded in a combination of two or more different chemicals using natural carriers or bio. BNCs are widely used in drug formulation and in the development of new drugs for various therapeutic drugs, new dosage forms and in pharmacological medicine. Materials and Methods: Useful and improved melting was achieved by converting selected Biopharmaceutics Classification System (BCS) class II drug into BNCs using natural carriers such as the gums of Moringa oleifera Lam. and Aegle marmelos (L.) Correa, respectively. The current work focuses on the enhancement of the novel natural polymers such as M. oleifera and A. marmelos, used to prepare BNC for BCS class II orlistat using a microwave system designed for the distribution method. The natural polymer helps improve the melting of the dispersion when it converts them into BNC. Definitions of orlistat, natural carriers, and prepared BNCs were developed and studied comparatively. The fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) study revealed that there was no communication between drug associations and environmental carriers. Results: Crowd reduction studies were conducted to investigate the material that enhances the melting of BNC compounds dissolving and in vitro disposal of BNCs prepared by DSC, scanning electron microscopy, X-ray diffraction studies, and FTIR. BNCs affect orlistat: M. oleifera (OSMOBNC-1: 3), orlistat: A. marmelos (OSAM-BNC-1: 4) is well developed. Conclusion: Ornat BNCs developed with M. oleifera and A. marmelos provide significant improvements in dissolve and highlight their use in reducing fortification. Additionally, land melting limits were applied and determined for the melting of BNCs prepared using the Hansen Solubility parameters in particular, Hoy's, Fedor and Van Krevelen system and it was found that this report there was a significant increase in the melting of batches prepared for BNCs. [ABSTRACT FROM AUTHOR]

Crystal engineering is an integral part of the drug development research. Crystal forms can modify the physicochemical properties of the parent drug molecule. The present work was aimed at the synthesis and characterization of crystalline product of lamotrigine (LT), an U.S. Food and Drug Administration approved anti-epileptic drug, with citric acid (CA) to improve its release in gastric region and oral absorption. The crystalline products of LT–CA were developed by solvent evaporation method using ethanol-water as the solvent system. Appearance of new characteristic peaks in the FTIR spectra for the crystal products indicated formation of new crystal state. In DSC thermogram, melting point of the experimental crystal products was different than that of the pure drug. Further, formation of new crystalline phase was confirmed from XRD data through the identification of new sharp peaks for the selected crystal products. A higher cumulative percentage of drug release was observed for the crystal products than for the free drug within 60 min of drug release in simulated gastric fluid. However, in vivo studies are warranted for the future technology transfer of the product at industrial scale.

Abstract Background The goal of the current investigation was to formulate, evaluate co-crystal, and further design of solid unit dosage form of antihyperlipidemic BCS class II drug fenofibrate (FNO). Co-crystals composed of a structurally homogeneous crystalline material that contains two or more components in a definite stoichiometric amount helps in increasing yield, the capability to regulator polymorph fabrication, enhanced invention crystallinity. Ball milling method is used for co-crystal formulation, optimized via 32 full factorial design and characterized by saturation solubility, particle size analysis, Fourier transform infrared spectroscopy (FT-IR) study analysis, powder X-ray diffraction (PXRD) study analysis, surface morphology by scanning electron microscopy (SEM) study, flow properties, and ex vivo intestinal permeation study via non-everted rat intestinal sac model. Furthermore, optimized batch compressed into tablets is evaluated for disintegration time, hardness, friability, in vitro drug release study and stability study. Results It demonstrated that co-crystal formulation FNOCC7 shows higher saturation solubility 0.3874 ± 2.82 g/ml with less particle size 221.231 ± 0.456 nm, FT-IR spectra confirmed significant structural alterations in the formulation indicating the hetero-molecular interaction, the presence of hydrogen bonding had occurred in the co-crystals, PXRD spectra of formulation determined by the increase in the crystalline nature. FNO co-crystals show flux (F) and permeability coefficient (P app) 0.322 ± 0.068 μg/min, 5.38 ± 0.093 cm/min respectively increased compared to the pure drug makes in an enhancement of solubility as well as the bioavailability of BCS class II drug. Conclusions The solubility and dissolution percentage of FNO can be improved by the utilization of Co-crystal of FNO with PEG 4000. The solubilization impact of PEG 4000 might be contributed because of the decrease of molecule conglomeration of the drug presence of crystallinity, expanded wettability, and dispersibility; pharmaceutical co-crystals speak to a beneficial class of crystal form with regard of pharmaceuticals.

This work aims to evaluate the ability of biorelevant dissolution media to simulate the bioavailability of efavirenz tablets, establish an in vitro–in vivo relationship (IVIVR) based on in vivo data using GastroPlus® and simulate formulation changes using DDDPlus™. Solubility and drug release profiles were conducted in SLS 0.5% and biorelevant media, such as FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2. The efavirenz physicochemical properties were used to simulate the plasma concentration profile and compare the simulated pharmacokinetic parameters in fasted and fed states. An IVIVR was developed using Loo-Riegelman as the deconvolution method to estimate drug bioavailability. DDDPlus™ was used to perform virtual trials of formulations to evaluate whether formulations changes and the efavirenz particle size could influence the bioavailability. The drug dissolution displayed higher levels in the biorelevant media that simulated gut-fed state (FeSSIF and FeSSIF-V2). The absorption model successfully predicted the efavirenz pharmacokinetics, and FeSSIF-V2 was chosen as the predictive dissolution media, while an IVIVR was established using the Loo-Riegelman deconvolution method. The present work provides valuable information about efavirenz solubility and kinetics in the gastrointestinal tract, allowing an IVIVR to support future formulation changes. This understanding is essential for rational science-driven formulation development. At least, this study also showed the validity and applicability of in vitro and in silico tools in the regulatory scenario helping on drug development. [ABSTRACT FROM AUTHOR]

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Objective: The objective of the current research was to prepare self-micro-emulsifying drug delivery systems (SMEDDS) for BCS class II drug, nilotinib to enhance its oral bioavailability. Methodology: Different types of excipients like oil, surfactant, and co-surfactant were evaluated for drug solubility. Among the screened excipients, Capryol 90, Transcutol HP, and Tween 80 were selected as oil, co-surfactant, and surfactant, respectively, to construct a ternary phase diagram to identify a homogenous mixture. Characterization performed for the prepared SMEDDS for its particle size/droplet size, emulsification time, phase separation, droplet morphology, in vitro drug release, and oral bioavailability. Results: Prepared SMEDDS showed the highest of 87% drug release in in vitro drug release experiment. SMEDDS drug release was superior over suspension formulation, which could be attributed to oil/surfactant ratios and particle size of the SMEDDS. The acquired pharmacokinetic parameters indicate that twofold increase in systemic exposure of SMEDDS compared with nilotinib suspension formulation. A similar twofold increase in relative oral bioavailability was also observed when compared SMEDDS formulation with suspension formulation. Delayed Tmax (time to reach peak plasma concentrations) was observed with SMEDDS over suspension formulation, which was evident by slow rate of absorption of nilotinib from SMEDDS. Conclusion: This research demonstrated that SMEDDS could be an effective approach to improve solubility and oral bioavailability for the BCS class II poorly soluble nilotinib. [ABSTRACT FROM AUTHOR]

Cilostazol (CLZ) is categorized as a biopharmaceutical classification system (BCS) class II drug. CLZ suspensions of jet-milled particles were orally administered to beagle dogs in fasted and fed states, for which food was given 0.5 h before the experiment. The mean highest concentration of CLZ (Cmax) and the area under the serum concentration–time curve (AUCt) fed/fasted ratios were 2.90 and 2.85, respectively, indicating a large and variable food effect. Additionally, CLZ was administered to the same dogs at 2 and 4 h after food or 0.5 h before food. The serum concentrations of CLZ were similar when dosed 0.5 and 2 h after food; however, they were significantly lower when dosed 4 h after food but still greater compared with the fasted state. Furthermore, the ratio of fed/fasted in AUCt was better correlated than that in Cmax. Additionally, the serum concentrations were similar to the fasted states when CLZ was dosed 0.5 h before food. Therefore, the results of this study showed that the serum concentration–time profile of CLZ was significantly affected by the timing of food administration, and that a good correlation was observed between food administration time and the Cmax and AUCt fed/fasted ratios. [ABSTRACT FROM AUTHOR]

The objective of this study is to enhance the dissolution properties of leflunomide, a class BCS-II drug by incorporating the self emulsifying (SE) form of the drug onto liquisolid systems in the form of tablets. Different formulae were prepared by dissolving leflunomide in PEG300 then forming SE systems using tween 80 as surfactant and either sesame oil and paraffin oil then adsorbing on powder excipients to form SE liquisolid powders. The prepared powders showed adequate flowability. The drug and excipients showed compatibility by analysis with DSC, XRD and FTIR. After compression, all tablets showed adequate weight variation, friability and disintegration time with disintegration time ranging between 8.45 ± 0.16 min and 10.7 ± 0.29 min. All liquisolid tablets exhibited higher in vitro dissolution in distilled water compared to physical mixture and the commercial tablets (Arthfree®) with formula containing sesame oil and highest amount of solvent (TS04) exhibiting the highest dissolution profile and it did not change by the change in the pH of the dissolution medium. The tablets showed stability during a 6 months accelerated stability study according to appearance, drug content, disintegration time and dissolution profile. Thus it can be concluded that combining self emulsifying drug delivery technique and liquisolid technology can be a promising tool to enhance the dissolution profile of leflunomide in vitro.

Navya Sree Kola Srinivas,1 Ruchi Verma,2 Girish Pai Kulyadi,1 Lalit Kumar1 1Department of Pharmaceutics, 2Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India Abstract: Gefitinib is an anticancer agent which acts by inhibiting epidermal growth factor receptor tyrosine kinase receptors. The aim of the present study was to prepare gefitinib nanosuspension. Gefitinib was encapsulated in Eudragit® RL100 and then dispersed in stabilizer solution, polyvinyl alcohol, and polyvinylpyrrolidone K30. Nanosuspension was prepared by using homogenization and ultrasonication techniques. The quality by design approach was also used in the study to understand the effect of critical material attributes (CMAs) and critical processing parameters (CPPs) on critical quality attributes and to improve the quality and safety of formulation. To study the effect of CMAs and CPPs, 23 full factorial design was applied. The particle size, polydispersity index, and zeta potential of the optimized solution were 248.20 nm, 0.391, and -5.62 mV, respectively. Drug content of the optimized nanoformulation was found to be 87.74%±1.19%. Atomic force microscopy studies of the optimized formulation confirmed that the prepared nanoparticles are smooth and spherical in nature. In vitro cytotoxicity studies of the nanosuspension on Vero cell line revealed that the formulation is nontoxic. The gefitinib nanosuspension released 60.03%±4.09% drug over a period of 84 h, whereas standard drug dispersion released only 10.39%±3.37% drug in the same duration. From the pharmacokinetic studies, half-life, Cmax, and Tmax of the drug of an optimized nanosuspension were found to be 8.65±1.99 h, 46,211.04±5,805.97 ng/mL, and 6.67±1.77 h, respectively. A 1.812-fold increase in relative bioavailability of nanosuspension was found, which confirmed that the present formulation is suitable to enhance the oral bioavailability of gefitinib. Keywords: gefitinib, cancer, epidermal growth factor receptor tyrosine kinase receptors inhibitor, bioavailability, Eudragit® RL100, PVP K30, PVA, Biopharmaceutical Classification System class II, QbD, design of experiment, full factorial design

The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental dissolution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior.

In oral absorption of a drug, the drug first dissolves and then is absorbed by diffusion through gastrointestinal membranes. The gastrointestinal environment is aqueous in nature and it is well-known that one-third of the drug population is water insoluble. Hence, there is a need for enhancement of the solubility and dissolution of such drugs. In this work, enhancement of the solubility and dissolution of the practically insoluble drug Rosuvastatin Calcium was achieved by formation of nanohybrids using microwave-induced diffusion (MIND), which ultimately leads to bioavailability enhancement. nanohybrids were formed by using natural carriers such as acacia, guar gum and PVP k-30 with the help of microwaves. Selection of carriers was based on their surfactant and wetting properties. Solubility studies were carried out to establish the solubility-enhancing property of the nanohybrids. To support solubility analysis results, dissolution studies (i.e. powder dissolution and in-vitro dissolution) were carried out. The nanohybrids were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction studies, scanning electron microscopy and transmission electron microscopy. It was found that as the concentration of polymer in the composite increased the solubility and dissolution of rosuvastatin calcium were enhanced. The optimised ratio (drug : polymer) for all the composites was found to be 1:4. The novelty of this work is the green and cost-effective way of forming drug nanocomposites with the help of microwave, which can be scaled up to an industrial level. The method gives an immaculate means of solubilisation by generating drug dispersion at the micro and nanoscale level in natural biodegradable stabilising media. Hence, this study demonstrates the use of nanohybrids in solubility and dissolution enhancement. [ABSTRACT FROM AUTHOR]

Purpose: The study aims to investigate the transfer behavior of the weakly basic BCS class II model drug carvedilol from the stomach to the small intestine and compare the concentration profiles of carvedilol that were determined during the in vitro transfer model and dissolution testing. Methods: An in vitro transfer model, previously introduced by Kostewicz et al., was used in this study. A donor phase of simulated gastric fluid was used to predissolve Dilatrend® tablet (25 mg carvedilol). Media that simulate and cover the physiological pH and buffer capacity ranges of the intestinal fluid were used as acceptor phases. pH measurements were reported to investigate the effect of addition of donor phase containing predissolved carvedilol on lowering the pH of the acceptor media. The f2 similarity factor was used to compare the concentration profiles of carvedilol determined during the in vitro transfer model. Results: Carvedilol was completely dissolved in all tested acceptor phases, resulted in no precipitation. The buffering capacity of the acceptor phase plays an important role in determining its pH. A discrepancy was found between the concentrations of carvedilol in all tested acceptor phases obtained using the transfer model and those reported using dissolution apparatus II in corresponding media. Conclusions: Results showed that dissolution testing using apparatus II might not be sufficient to predict its transfer from the stomach into the small intestine and that the in vitro transfer model may be more effective at mimicking the conditions in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

In order the drug bioavailable in human body must absorb it, and in oral treatments absorption takes place, after drug dissolution by diffusion of the molecules through gastrointestinal membranes. It was found that BCS class -II drug has poor aqueous solubility in GI tract greatly influences the drug release; particularly it affects the bioavailability of drug. Solubilization of water insoluble drug is a big issue of pharmaceutical research. Nanohybrids are combination of two or more different materials with different properties of each and that are fused, by an effort to blend the best properties of both. In nanohybrids there is use of natural and synthetic polymers. The present review mainly focusing on the simple and convenient method of preparation of nanohybrids with the help of Microwave irradiation Method by using natural/synthetic carriers such as acacia, gelatin, cassia, ghatti gum, and HPMC, MC etc. to enhance the solubility of poorly water soluble BCS Class -II Drugs and improved its rate of dissolution for such drug entities which affects the bioavailability. Prepared nanohybrids can be characterized by Scanning Electron Microscopy, Fourier transform infrared spectroscopy, Differential Scanning Calorimetry, X-Ray Diffraction Studies and transmission Electron Microscopy. Further, this review mainly highlights the application and future prospective use of nanohybrids, which will help in formulation of drug with improved bioavailability. [ABSTRACT FROM AUTHOR]

Abstract The current study documents enhanced apparent solubility of the BCS class II drug celecoxib (CXB) when formulated as solid phospholipid dispersion (SPD) with either mono- or diacyl-phospholipids by freeze drying from hydro-alcoholic solvent. The enhanced solubility upon dispersion in buffer or fasted state simulated intestinal fluid (FaSSIF) is interpreted to be due to two effects: (1) amorphization of CXB, inducing supersaturation, which is also observed when CXB is freeze dried in the absence of phospholipids and (2) association of CXB with spontaneously forming colloidal structures, such as vesicles and/or micelles, promoting solubilization. The latter effect depended on the CXB-to-phospholipid ratio, where monoacyl-phospholipid was a more efficient solubilizer than diacyl-phospholipid. In the case of diacyl-phospholipid, solubilization also depended strongly on the dispersion medium, where FaSSIF induced a more pronounced solubilization effect than buffer. In contrast, a significantly enhanced in-vitro permeability of CXB across a biomimetic barrier (Permeapad®) was found only with low lipid contents up to a CXB to phospholipid mass-ratio of 1:10 or in the absence of phospholipid; above this critical ratio, permeability was not enhanced, i.e. comparable to that observed with a suspension of non-processed (crystalline) drug. This non-linear dissolution-/permeation-behavior was observed independently of (1) the type of phospholipid (monoacyl- or diacyl-) employed and (2) the dispersion medium (buffer or FaSSIF), despite the fact that different patterns of co-existing colloidal states were observed from mono-/diacyl-phospholipid formulations in buffer/FaSSIF (small bile salt micelles, intermediate size mixed micelles and large vesicular structures), assessed by asymmetric flow field-flow fractionation/multi angle laser light scattering. A uniform mechanistic hypothesis is presented to describe the impact of phospholipids on CXB permeation behavior: Obviously, the critical drug-to-phospholipid ratio represents a compromise between optimal stabilization of the amorphous state-induced supersaturation and reduced thermodynamic activity of CXB due to association with colloidal states, where the type of colloidal state (vesicle or micelle) appears to be of minor importance. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The present work evaluates the food effect on the absorption of rivaroxaban (Riva), a BCS II drug, from the orally administered commercial immediate-release tablet (Xarelto IR) using physiologically based pharmacokinetic (PBPK) and conventional in vitro–in vivo correlation (IVIVC) models. The bioavailability of Riva upon oral administration of Xarelto IR tablet is reported to exhibit a positive food effect. The PBPK model for Riva was developed and verified using the previously reported in vivo data for oral solution (5 and 10 mg) and Xarelto IR tablet (5 and 10 mg dose strength). Once the PBPK model was established, the in vivo performance of the tablet formulation with the higher dose strength (Xarelto IR tablet 20 mg in fasted and fed state) was predicted using the experimentally obtained data of in vitro permeability, biorelevant solubility and in vitro dynamic dissolution data using United States Pharmacopeia (USP) IV flow-through cell apparatus. In addition, the mathematical IVIVC model was developed using the in vitro dissolution and in vivo profile of 20 mg strength Xarelto IR tablet in fasted condition. Using the developed IVIVC model, the pharmacokinetic (PK) profile of the Xarelto IR tablet in fed condition was predicted and compared with the PK parameters obtained via the PBPK model. A virtual in vivo PK study was designed using a single-dose, 3-treatment cross-over trial in 50 subjects to predict the PK profile of the Xarelto® IR tablet in the fed state. Overall, the results obtained from the IVIVC model were found to be comparable with those from the PBPK model. The outcome from both models pointed to the positive food effect on the in vivo profile of the Riva. The developed models thus can be effectively extended to establish bioequivalence for the marketed and novel complex formulations of Riva such as amorphous solid dispersions.

[Display omitted] • Cyclodextrin-based deep eutectic solvents (CycloDES) could be exploit for poorly soluble drug solubilization. • The improved performance of CycloDES against equimolar hydroxypropyl-β-cyclodextrin water solution was observed through solubility studies. • CycloDES resulted to maintain the drug in solution once diluted in water, while a significant loss of solubilized drug was observed in the model Choline Chloride:Glucose DES. The aim of this work was to develop a new class of deep eutectic solvent (DES) composed of a complexation agent, namely hydroxy-propyl-β-cyclodextrin (HPβCD), to exploit a synergic solubilization-enhancing approach. For this purpose, cyclodextrin-based supramolecular DES (CycloDES) were physical–chemical characterized and loaded with three different BCS class II model drugs, specifically Cannabidiol, Indomethacin, and Dexamethasone, evaluating the influence of different factors on the observed solubility and permeation compared with the only HPβCD/drug complexation. Hence, CycloDESs were presented as a possible vehicle for drugs and represent a novel potential approach for solving BCS class II and IV solubility issues, demonstrating at least a 100-fold improvement in the investigated drug solubilities. Furthermore, CycloDESs demonstrated a significantly improved resistance to dilution preserving a high percentage of drug in solution (i.e. 93% for Indomethacin) when water is added to the DES if compared with a glucose-choline chloride DES, used as a standard. This evidence guarantees the solubility-enhancing effect useful for the delivery of BCS class II and IV drugs converting solid raw material to advantageous liquid vehicles bypassing the rate-determining dissolution step. [ABSTRACT FROM AUTHOR]

Compromised oral drug absorption, due to poor aqueous solubility, is one of the major challenges faced by the pharmaceutical industry in the drug discovery and development process. Scientific community is striving to develop tools for accurate prediction of the oral absorption profile of drugs. Weak bases form a major class of drugs exhibiting poor aqueous solubility. Numerous tools such as biorelevant in vitro dissolution testing and in silico modeling are being developed to investigate and understand the in vivo absorption and pharmacokinetics for this class of drugs. Biorelevant dissolution coupled with physiologically based pharmacokinetics (PBPK) modeling has fast emerged as a reliable tool to support pharmaceutical development and minimize the need for animal/human testing. The present review discusses the evolution, present status, and future trends on the applicability of these techniques for predicting oral absorption and pharmacokinetics of poorly soluble weakly basic drugs. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the transfer behavior of the weakly acidic BCS class II drug valsartan from the stomach to the small intestine during fasted and fed states. An in vitro transfer model previously introduced by Kostewicz et al. (J Pharm Pharmacol 56(1):43-51, 2004) based on a syringe pump and a USP paddle apparatus was used to determine the concentration profiles of valsartan in the small intestine. Donor phases of simulated gastric fluid during fasted (FaSSGF) and fed (FeSSGF) states were used to predisperse Diovan® tablets (160 mg valsartan). The initial concentrations of valsartan in FaSSGF and FeSSGF were 6.2 and 91.8%, respectively. Valsartan dispersions were then transferred to acceptor phases that simulate intestinal fluid and cover the physiological properties (pH, buffer capacity, and ionic strength) of the gastrointestinal fluid at a flow rate of 2 mL/min. The pH measurements were reported at time intervals corresponded to those of the transfer experiments to investigate the effect of percent dissolved of valsartan in the donor phase on lowering the pH of the acceptor phases. The f2 similarity test was used to compare the concentration profiles in the acceptor phases. In fasted state, the concentration of valsartan in the acceptor phases ranged between 33.1 and 89.4% after 240 min. Whereas in fed state, valsartan was fully dissolved in all acceptor phases within a range of 94.5-104.9% after 240 min. Therefore, the transfer model provides a useful screen for the concentrations of valsartan in the small intestine during fasted and fed states. [ABSTRACT FROM AUTHOR]

Long-acting or extended release parenteral dosage forms have attracted extensive attention due to their ability to maintain therapeutic drug concentrations over long periods of time and reduce administration frequency, thus improving patient compliance. It is essential to have an in vitro release (IVR) testing method that can be used to assure product quality during routine production as well as predict and understand the in vivo performance of a formulation. The purpose of this work was to develop a discriminatory in vitro release method to guide formulation and process development of long-acting parenteral (LAP) nanosuspension formulations composed of poorly water-soluble drugs (BCS class II). Injectable nanosuspension formulations were developed to serve as test articles for method development. Several different IVR methods were evaluated for their application to the formulation screening and process development including (1) USP apparatus 2, (2) dialysis and reverse dialysis sac, and (3) continuous flow-through cell (USP apparatus 4). Preliminary data shows the promising results to support the utilization of USP 4 over more widely accepted USP 2 and dialysis methods. A combination of more representative in vivo hydrodynamics and ease of maintaining sink conditions yields the USP 4 flow-through cell method a more suitable in vitro release method for nanosuspension-based LAP formulations of poorly water-soluble compounds, such as compounds A and B. [ABSTRACT FROM AUTHOR]

To counter the poor aqueous solubility of itraconazole (ITC), its sulfate salt (ITCSUL) was synthesized and characterized by 1H NMR, MS, FTIR, DSC, XRPD, DLS and SEM. Antifungal properties of ITCSUL were confirmed against different fungal pathogens by broth microdilution method. Enhanced solubility of the salt in various pharmaceutical solvents was observed. Approximately 5.5 fold increase in percentage drug release from ITCSUL than that of ITC in 3 h was observed. Further, the physical mixtures of ITCSUL with two cyclodextrins; β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD) were prepared in 3 M ratios. The in vitro release studies of CD mixtures of ITC and ITCSUL exhibited markedly enhanced dissolution in comparison to ITC and ITCSUL respectively. The promising in vitro performance of ITCSUL and ITCSUL CD mixtures along with advantage of expedient preparation suggest their potential applications in designing a better oral drug delivery system.

The novel self- nanoemulsifying self-nanosuspension (SNESNS) combines the advantages of two efficient solubilization technologies; the nanoemulsion and the nanosuspension. The aim of this study is to test the efficiency of phospholipid based self-nanoemulsifying self-nanosuspension (p-SNESNS) formulation as a powerful tool to diminish the food effect on bioavailability of lurasidone hydrochloride as BCS Class II model drug. Phospholipid was incorporated into SNESNS to increase the solubilization power of the in-situ formed nanoemulsion and facilitate the dispersion of the in-situ formed nanosized drug particles. P-SNESNS was evaluated for particle size, Polydispersity index, in vitro dissolution and transmission electron microscopy (TEM). The drug amount dissolved after water dilution of LSD p-SNESNS was ~ 2 folds that dissolved after dilution of non-phospholipid SNESNS. The self-nanosuspension obtained by aqueous dilution of p-SNESNS kept the cubic morphology of LSD macroparticles. The high in vitro dissolution of LSD in the non-sink dissolution media (water and Phosphate buffer pH 6.8) indicated that the p-SNESNS formulation had successfully increased the drug solubility irrespective of pH of the medium. The pharmacokinetics parameters of LSD p-SNESNS in humans were the same in both the fasted and fed states and were similar to those of LSD capsules in the fed state. Our results propose that p-SNESNS could be promising to increase patient compliance and drug efficiency of BCS class II antipsychotics by diminishing the food effect on their oral absorption and preventing the necessity to administer them with food. [ABSTRACT FROM AUTHOR]

The objective of this study is to enhance the dissolution properties of leflunomide, a class BCS-II drug by incorporating the self emulsifying (SE) form of the drug onto liquisolid systems in the form of tablets. Different formulae were prepared by dissolving leflunomide in PEG300 then forming SE systems using tween 80 as surfactant and either sesame oil and paraffin oil then adsorbing on powder excipients to form SE liquisolid powders. The prepared powders showed adequate flowability. The drug and excipients showed compatibility by analysis with DSC, XRD and FTIR. After compression, all tablets showed adequate weight variation, friability and disintegration time with disintegration time ranging between 8.45 ± 0.16 min and 10.7 ± 0.29 min. All liquisolid tablets exhibited higher in vitro dissolution in distilled water compared to physical mixture and the commercial tablets (Arthfree®) with formula containing sesame oil and highest amount of solvent (TS04) exhibiting the highest dissolution profile and it did not change by the change in the pH of the dissolution medium. The tablets showed stability during a 6 months accelerated stability study according to appearance, drug content, disintegration time and dissolution profile. Thus it can be concluded that combining self emulsifying drug delivery technique and liquisolid technology can be a promising tool to enhance the dissolution profile of leflunomide in vitro. [ABSTRACT FROM AUTHOR]

Valsartan is a specific angiotensin II antagonist used for the treatment of hypertension. It suffers from low aqueous solubility and high variability in its absorption after oral administration. The aim of this study was to improve the dissolution and thereby the bioavailability of Valsartan through the development of self nano-emulsifying drug delivery systems. Four ternary phase diagrams were constructed to identify the self-emulsification region of Capmul® MCM, Labrafil® M1944, Capryol™ 90 and Labrafac® PG together with Cremophore® RH 40 and Transcutol™ HP as oil, surfactant and co-surfactant, respectively. The effect of oil type, oil and surfactant concentration on droplet size andin vitroValsartan dissolution were studied. The protective effect of the optimum formula F5 in adrenaline-induced oxidative stress in rats during myocardial infarction was determined. Formula F5 exhibited globule size of (13.95 nm) with 76.07% ± 1.10 of Valsartan dissolved after five minutes compared to Disartan 80 mg capsules (13.43%). Results revealed a significant reduction (p < 0.05) in serum aspartate transaminase, creatine kinase myocardial band and malondialdehyde levels, while a significant increase (p < 0.05) in serum glutathione in F5. Therefore, self nano-emulsifying drug delivery systems could be considered as a promising approach to improve the dissolution and thereby the bioavailability of Valsartan. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to examine the influence of the formulation and process variables on the entrapment efficiency of simvastatin-phospholipid complex (SPC), prepared with a goal of improving the solubility and permeability of simvastatin. Methods: The SPC was prepared using a solvent evaporation method. The influence of formulation and process variables on simvastatin entrapment was assessed using a central composite design. An additional SPC was prepared using the optimized variables from the developed quadratic model. This formulation was characterized for its physical-chemical properties. The functional attributes of the optimized SPC formulation were analyzed by apparent aqueous solubility analysis, in vitro dissolution studies, dissolution efficiency analysis, and ex vivo permeability studies. Results: The factors studied were found to significantly influence the entrapment efficiency. The developed model was validated using the optimized levels of formulation and process variables. The physical-chemical characterization confirmed a formation of the complex. The optimized SPC demonstrated over 25-fold higher aqueous solubility of simvastatin, compared to that of pure simvastatin. The optimized SPC exhibited a significantly higher rate and extent of simvastatin dissolution (>98 %), compared to that of pure simvastatin (∼16 %). The calculated dissolution efficiency was also found to be significantly higher for the SPC (∼54 %), compared to that of pure simvastatin (∼8 %). Finally, the optimized SPC exhibited a significantly higher simvastatin permeability (>78 %), compared to that of pure simvastatin (∼11 %). Conclusion: The present study shows that SPC can be a promising strategy for improving the delivery of simvastatin and similar drugs with low aqueous solubility. [ABSTRACT FROM AUTHOR]

The objective of the present study was to improve solubility, dissolution rate and therapeutic efficacy of a BCS Class II drug, glibenclamide by using oral self nano emulsifying powder. The powder was prepared by adsorbing the mixture of oil, surfactant and co-surfactant onto a carrier with large surface area; Aerosil 200. The ratios of oil and Smix (surfactant/co-surfactant mixture) required to produce an emulsion was optimized based on percentage transmittance studies and particle size determinations. The optimized formulation was subjected to in vitro dissolution study and in vivo therapeutic efficacy in rabbits by monitoring blood glucose levels. Scanning electron microscopy, differential scanning calorimetry and X-ray powder diffraction studies revealed that the drug was present in amorphous form in the final formulation. The in vivo study in rabbits indicated the improved therapeutic efficacy of glibenclamide in self-nanoemulsifying powder compared to plain drug. [ABSTRACT FROM AUTHOR]

This work summarizes the pharmaceutical evaluation of a preclinical drug candidate with poor physicochemical properties. Compound 1 is a weakly basic, GPR-119 agonist designated to Biopharmaceutics Classification System Class II because of good permeability in a Caco-2 cell line model and poor solubility. Compound 1 showed good oral bioavailability from a solution formulation at low doses and oral exposure sufficient for toxicological evaluation at high doses from a nanosuspension of Form A-the only known polymorph of 1 during drug discovery. The identification of the thermodynamically stable polymorph, Form B, during early development adversely affected the bioperformance of the nanosuspension. The poor solubility of Form B resulted in a significant reduction in the oral exposure from a nanosuspension to a level that was insufficient for toxicological evaluation of compound 1. Subsequent to the discovery of Form B, multiple form and formulation engineering strategies were evaluated for their ability to enhance the oral exposure of 1. Formulations based on cocrystals and amorphous solid dispersions showed a statistically significant increase in exposure, sixfold and sevenfold, respectively, over the benchmark formulation, a suspension of Form B. The physicochemical characterization of 1, and the solid form and formulation engineering approaches explored to address the insufficient oral exposure of Form B are discussed along with insights on improving the physicochemical properties of the follow-on drug candidates in discovery. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3007-3021, 2014 [ABSTRACT FROM AUTHOR]

Abstract: The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include sub-specification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro–in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance. [Copyright &y& Elsevier]

To counter the poor aqueous solubility of itraconazole (ITC), its sulfate salt (ITCSUL) was synthesized and characterized by ¹H NMR, MS, FTIR, DSC, XRPD, DLS and SEM. Antifungal properties of ITCSUL were confirmed against different fungal pathogens by broth microdilution method. Enhanced solubility of the salt in various pharmaceutical solvents was observed. Approximately 5.5 fold increase in percentage drug release from ITCSUL than that of ITC in 3 h was observed. Further, the physical mixtures of ITCSUL with two cyclodextrins; β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD) were prepared in 3 M ratios. The in vitro release studies of CD mixtures of ITC and ITCSUL exhibited markedly enhanced dissolution in comparison to ITC and ITCSUL respectively. The promising in vitro performance of ITCSUL and ITCSUL CD mixtures along with advantage of expedient preparation suggest their potential applications in designing a better oral drug delivery system. [ABSTRACT FROM AUTHOR]