Computational Modeling of Drug Dissolution in the Human Stomach

A computational model of drug dissolution in the human stomach is developed to investigate the interaction between gastric flow and orally administrated drug in the form of a solid tablet. The stomach model is derived from the anatomical imaging data and the motion and dissolution of the drug in the stomach are modeled via fluid-structure interaction combined with mass transport simulations. The effects of gastric motility and the associated fluid dynamics on the dissolution characteristics are investigated. Two different pill densities are considered to study the effects of the gastric flow as well as the gravitational force on the motion of the pill. The average mass transfer coefficient and the spatial distributions of the dissolved drug concentration are analyzed in detail. The results show that the retropulsive jet and recirculating flow in the antrum generated by the antral contraction wave play an important role in the motion of the pill as well as the transport and mixing of the dissolved drug concentration. It is also found that the gastric flow can increase the dissolution mass flux, especially when there is substantial relative motion between the gastric flow and the pill.

Performance Evaluation of Montelukast Pediatric Formulations: Part II — a PBPK Modelling Approach

This study aimed to build a physiologically based pharmacokinetic (PBPK) model coupled with age-appropriate in vitro dissolution data to describe drug performance in adults and pediatric patients. Montelukast sodium was chosen as a model drug. Two case studies were investigated: case study 1 focused on the description of formulation performance from adults to children; case study 2 focused on the description of the impact of medicine co-administration with vehicles on drug exposure in infants. The PBPK model for adults and pediatric patients was developed in Simcyp® v18.2 informed by age-appropriate in vitro dissolution results obtained in a previous study. Oral administration of montelukast was simulated with the ADAM™ model. For case study 1, the developed PBPK model accurately described montelukast exposure in adults and children populations after the administration of montelukast chewable tablets. Two-stage dissolution testing in simulated fasted gastric to intestinal conditions resulted in the best description of in vivo drug performance in adults and children. For case study 2, a good description of in vivo drug performance in infants after medicine co-administration with vehicles was achieved by incorporating in vitro drug dissolution (under simulated fasted gastric to fed intestinal conditions) into a fed state PBPK model with consideration of the in vivo dosing conditions (mixing of formulation with applesauce or formula). The case studies presented demonstrate how a PBPK absorption modelling strategy can facilitate the description of drug performance in the pediatric population to support decision-making and biopharmaceutics understanding during pediatric drug development. Graphical abstract

Exploration of Neusilin® US2 as an Acceptable Filler in HPMC Matrix Systems—Comparison of Pharmacopoeial and Dynamic Biorelevant Dissolution Study

Modern pharmaceutical technology still seeks new excipients and investigates the further use in already known ones. An example is magnesium aluminometasilicate Neusilin® US2 (NEU), a commonly used inert filler with unique properties that are usable in various pharmaceutical fields of interest. We aimed to explore its application in hypromellose matrix systems (HPMC content 10–30%) compared to the traditionally used microcrystalline cellulose (MCC) PH 102. The properties of powder mixtures and directly compressed tablets containing individual fillers NEU or MCC, or their blend with ratios of 1.5:1, 1:1, and 0.5:1 were investigated. Besides the routine pharmaceutical testing, we have enriched the matrices’ evaluation with a biorelevant dynamic dissolution study and advanced statistical analysis. Under the USP apparatus 2 dissolution test, NEU, individually, did not provide advantages compared to MCC. The primary limitations were the burst effect increase followed by faster drug release at the 10–20% HPMC concentrations. However, the biorelevant dynamic dissolution study did not confirm these findings and showed similarities in dissolution profiles. It indicates the limitations of pharmacopoeial methods in matrix tablet development. Surprisingly, the NEU/MCC blend matrices at the same HPMC concentration showed technologically advantageous properties. Besides improved flowability, tablet hardness, and a positive impact on the in vitro drug dissolution profile toward zero-order kinetics, the USP 2 dissolution data of the samples N75M50 and N50M50 showed a similarity to those obtained from the dynamic biorelevant apparatus with multi-compartment structure. This finding demonstrates the more predictable in vivo behaviour of the developed matrix systems in human organisms.

Solid Dispersions of Gefitinib Prepared by Spray Drying with Improved Mucoadhesive and Drug Dissolution Properties

Gefitinib is a tyrosine kinase inhibitor that is intended for oral administration yet suffers poor bioavailability along with undesirable side effects. To enhance its solubility and allow colon targeting, gefitinib (ZD) and blends of different ratios of polymers (ternary dispersion) were prepared in organic solution, and solid dispersions were generated employing the spray drying (SD) technique. The methylmethacrylate polymer Eudragit S 100 was incorporated for colon targeting; polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) were utilised to improve the solubility of ZD. SEM, DSC, XRPD, FT-IR, dissolution and cytotoxicity studies were undertaken to characterise and evaluate the developed formulations. SEM images revealed that the rod-shaped crystals of ZD were transformed into collapsed spheres with smaller particle size in the spray-dried particles. DSC, FTIR and XRPD studies showed that ZD loaded in the spray-dried dispersions was amorphous. ZD dissolution and release studies revealed that while a significant (P < 0.05) increase in the ZD dissolution and release was observed from HPMC-based solid dispersion at pH 7.2 (up to 95% in 15 h), practically no drug was released at pH 1.2 and pH 6.5. Furthermore, the HPMC-based solid dispersions displayed enhanced mucoadhesive properties compared with PVP-based ones. Interestingly, cell viability studies using the neutral red assay showed that PVP and HPMC-based solid dispersions had no additional inhibitory effect on Caco-2 cell line compared to the pure drug.

FORMULATION AND EVALUATION OF MEDICATED TENOFOVIR ALAFENAMIDE FUMARATE CANDY FOR TREATMENT OF HUMAN IMMUNODEFICIENCY SYNDROME

Medicated candies are solid oral dosage form containing medicaments in a flavored and sweetened base. The main advantages associated with buccal drug delivery are systemic absorption of drug, also increased bioavailability and avoidance of hepatic first pass metabolism. Tenofovir alafenamide fumarate is a drug of choice for the treatment of human immunodeficiency virus due to its potency and fewer side effects over tenofovir disoproxil fumarate. The aim of the present research work was to formulate and evaluate candy of tenofovir alafenamide fumarate for pediatric and geriatric patients for better patient acceptability. Medicated candies of tenofovir alafenamide fumarate were prepared by using heating and congealing method, and the prepared formulations were evaluated for various parameters such as organoleptic properties, weight variation, friability, hardness, drug content and in vitro drug dissolution time profile. On the basis of the above studies, it can be concluded that medicated candy can be utilized as alternative option for oral drug delivery for pediatric and geriatric patients.

DEVELOPMENT OF CIPROFLOXACIN LOADED THROAT PAINT FOR THE TREATMENT OF STREP THROAT INFECTION

Objective: This study is to enhance the solubility and sustained release of ciprofloxacin (CPX) drug by amplifying the adhesive capability of formulation by forming throat paint for the Streptococcal pharyngitis, a sore throat infection. Methods: Solid dispersion was prepared by solvent evaporation technique, in which three different ratios of Polyethylene glycol-6000 (PEG-6000) were selected, and the best ratio of solid dispersion was selected after characterization including Scanning electron microscopy (SEM) and Differential scanning calorimetry (DSC) with evaluation parameters including % yield, drug content, and drug solubility. In the case of throat paint, out of six different formulations, the best formulation was selected through viscosity, in vitro mucoadhesion, in situ release study, and spreadability parameters. Results: The DSC and SEM data proved that solid dispersion has a different moiety than its ingredients but it is quite a stable form. Formulation MD-2 was selected as the best formulation which able to increase the solubility of the drug by more than 3.5 folds, at the same time it shows the highest rate of drug dissolution of 13.951 μg/ml with % yield (97.199±0.167%) and drug content (96.425%). Throat paint was formed by fusion and trituration process and out of all six formulations F3 was selected as the best formulation on the basis of Viscosity (11932 Centi poise), Spreadability (17.621), Mucoadhesion (3937.481 dyne/cm2), and drug release (90.336±0.6%). Conclusion: Solid dispersion was successfully prepared with 3.5 times of solubility enhancement capability in comparison with pure CPX drug. The throat paint releases the drug (≥3 h) in a sustained manner with high mucoadhesive force.

Characterization and In Vitro and In Vivo Evaluation of Tacrolimus-Loaded Poly(ε-Caprolactone) Nanocapsules for the Management of Atopic Dermatitis

Background: Tacrolimus (TAC) is a drug of natural origin used in conventional topical dosage forms to control atopic dermatitis. However, direct application of the drug often causes adverse side effects in some patients. Hence, drug nanoencapsulation could be used as an improved novel therapy to mitigate the adverse effects and enhance bioavailability of the drug. Methods: Physicochemical properties, in vitro drug release experiments, and in vivo anti-inflammatory activity studies were performed. Results: TAC-loaded nanocapsules were successfully prepared by the interfacial deposition of preformed polymer using poly(ε-caprolactone) (PCL). The nanoparticulate systems presented a spherical shape with a smooth and regular surface, adequate diameter (226 to 250 nm), polydispersity index below 0.3, and suitable electrical stability (−38 to −42 mV). X-ray diffraction confirmed that the encapsulation method provided mainly the drug molecular dispersion in the nanocapsule oily core. Fourier-transform infrared spectra suggested that nanoencapsulation did not result in chemical bonds between drug and polymer. In vitro drug dissolution experiments showed a controlled release with a slight initial burst. The release kinetics showed zero-order kinetics. As per the Korsmeyer–Peppas model, anomalous transport features were observed. TAC-loaded PCL nanocapsules exhibited excellent anti-inflammatory activity when compared to the free drug. Conclusions: TAC-loaded PCL nanocapsules can be suitably used as a novel nano-based dosage form to control atopic dermatitis.

Alternative Methods for Dissolution Profile Comparison in the Dissolution Test

Introduction. The article discusses the problem of assessing the similarity of the dissolution profiles of two batches of the nebivolol. The use of a generally accepted similarity factor for assessing equivalence is unacceptable in some cases, for example, for drugs with a high variability in the values of the release of the active substance from the formulation. At the same time, at present, there are no generally accepted approaches to comparing the profiles of the dissolution kinetics of drugs, with the exception of the method for assessing the comparability of profiles based on the mathematical calculation of the similarity factor f2, which has certain criteria that limit its application.Aim. To demonstrate alternative methods for assessing the similarity between the dissolution profiles of two drugs using a practical example.Materials and methods. The results of the comparative dissolution test of two series of nebivolol at a dosage of 5 mg. Five model-independent methods for assessing the equivalence of drug dissolution were used. Statistical data processing was performed using Microsoft Excel software.Results and discussion. The paper presents a practical example of using five alternative model-independent methods for assessing the equivalence of the dissolution profile. An example is used to illustrate the proposed equivalence limits and statistical methodology. Also, various approaches to determining the boundaries of equivalence have been proposed to assess the similarity of the dissolution profiles of an active substance.Conclusion. According to the results of the comparative dissolution test of two batches of nebivolol, it was shown that the use of the similarity factor as a criterion for assessing dissolution profiles led to a false positive result. In such cases, the possibility of using alternative methods for assessing the equivalence of dissolution profiles described in the article, or other methods presented in the scientific literature, should be considered, with a justification of their acceptability in each specific case.

Nanosuspension of Poorly Soluble Anti-Diabetic Drug for Enhancement of Solubility and Dissolution

Canagliflozin is an anti-diabetic drug used in the adjuvant therapy for type-II diabetes as the inhibitor of sodium‐glucose co‐transporter-2 in the renal tubules. The poor solubility and permeability of the drug show limitations in the formulation development and therapeutic plasma concentration. The objective of the work was to improve the solubility and dissolution of the BCS class IV drug through surfactant stabilized nanosuspension formulation. Nanoparticles were developed by Nano precipitation-solvent evaporation method using Poly vinyl alcohol and Pluronic as surfactants at 1%, 3% and 5% concentration. Formulation optimized with Pluronic exhibited nano size particles (81-117 nm) with monodisperse nature and high stability zeta potential. The nanosuspension prepared using 1% and 3% Pluronic F127 showed 2-fold and 5- fold increase in the drug dissolution compared to the pure drug aqueous dispersion. The drug and surfactant exhibited mild interactions due to hydrogen bonding and hydrophobic interactions as confirmed by the FTIR and TG-DSC analysis, which favoured the formation of stable nanoparticles. The SEM proved the formation of smooth surface spherical shaped nanoparticles. Hence, the development of Canagliflozin nano-formulation was evidenced be an optimized approach to enhance the dissolution of the drug.