Combined Atomistic Molecular Calculations and Experimental Investigations for the Architecture, Screening, Optimization, and Characterization of Pyrazinamide Containing Oral Film Formulations for Tuberculosis Management

Abstract

To date, effective treatment, prophylaxis, and control of tuberculosis (TB) infection is mainly dependent on the use of drugs. However, patient noncompliance with prescribed anti-TB treatment schemes remains a major problem confronting successful pharmacotherapeutic outcomes. Thus, the development of alternative delivery systems that can improve adherence for the existing anti-TB bioactives has been intensified in recent times. The aim of this investigation was to engineer an optimal, thermodynamically stable oral film (OF) formulation containing a key anti-TB agent, pyrazinamide (PYZ), employing molecular modeling and experimental tools. Four PYZ-loaded film variants (OF 1, OF 2, OF 3, OF 4) were constructed in silico and then prepared in vitro using the Accelrys Materials Studio software and solvent casting method, respectively. Screening and selection of the optimal OF was based on the computation of the total interaction energy (ET), kinetic energy (EK), solubility parameter (S), and cohesive energy density (CED) as well as determining mass, thickness, dissolution and disintegration times, dissolution pH, drug loading capacity, and surface morphology in vitro. OF 2 was selected as the optimal formulation as it displayed the lowest ET (-8006.28 kcal/mol), dissolution time (9.96 min), disintegration time (56.49 s), and weight (39.33 mg); moderate EK (1052.98 kcal/mol); highest S (44.55 (J/cm(3))(0.5)) and CED (1.99 × 10(9) J/m(3)), slim dimension (166 μm), good and unvarying drug loading capacity (98.04%), acceptable dissolution pH (6.70), and well-layered surface topography. The drug release behavior of the optimal OF 2 was best elucidated with the zero order (R(2) = 0.97) and Korsmeyer-Peppas (R(2) = 0.99) models. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) analyses showed that OF 2 was made of physically mixed multiple component polymeric and nonpolymeric compounds. OF 2 was semicrystalline in nature and displayed a dual phased ex vivo mucosal permeation pattern. In silico and in vitro physicomechanical quantities revealed OF 2's flexibility, robustness, and compressibility. OF 2 was most stable under controlled environmental humidity, pressure, and temperature conditions in silico and in vitro. OF 2 was potentially non-cytotoxic and biocompatible. Succinctly, this work demonstrated the applicability of a combination of atomistic molecular mechanics and dynamics calculations as well as experimental analyses to the fabrication, screening, optimization, and characterization of drug formulations. Lastly, the fabricated OF 2 formulation can function as a potential alternative for the effective loading and delivery of PYZ.

Oromucosal films: from patient centricity to production by printing techniques

“…The most common used polymers are cellulose derivates, such as hypromellose and hydroxypropylcellulose [2,39]. Furthermore, formulations with polyvinylalcohol are often mentioned in literature [9,[40][41][42][43][44][45].…”

Optimal Design, Characterization and Preliminary Safety Evaluation of an Edible Orodispersible Formulation for Pediatric Tuberculosis Pharmacotherapy

“…The dependent variables or responses were parameters key to the performance of the formulation and these included disintegration time (Y 1 ), dissolution pH (Y 2 ) and formulation weight (Y 3 ). Factor level selection for each excipient was set on their ability to produce stable orodispersible formulations, which was based upon the one-variable-at-a-time approach (OVAT) [38,61]. The OVAT approach was implemented by changing one variable per time while keeping the others constant so as to determine the influence exhibited by each excipient.…”

“…The in vitro disintegration time of the 27 experimental design orodispersible formulations was measured utilizing a modified petri dish method [63,64]. Disintegration time represents the specific period when formulation matrix collapse begins [38]. The disintegration time was determined visually using a dual-display digital stopwatch (Fotronic Corporation, Melrose, MA, USA).…”

“…PZA is highly bactericidal, and acts by sterilizing slowly metabolizing tubercle bacilli, resulting in low incidence of bacteriological relapse post completion of chemotherapeutic regimen. It facilitates treatment shortening, leading to greater patient compliance [32,[34][35][36][37][38][39]. It is a prodrug which undergoes conversion into active pyrazinoic acid by the bacterial enzyme pyrazinamidase at or below pH 5.6 [33].…”

“…The PZA loaded formulation was prepared using a combination of pharmaceutical excipients which included copolymer polyvinyl alcohol-polyethylene glycol as a matrix and film forming agent, citric acid as a natural preservative, sodium starch glycolate as a superdisintegrant and xylitol as a sweetener acceptable for pediatric use as documented by Dixit and Puthli [42]. Formulation preparation and optimization were facilitated using a response surface method based on a 4-factor, 3-level Box Behnken experimental design (Minitab ® 18 Statistical Software (Minitab LLC, State College, PA, USA), a robust, high performance quadratic template widely applied in the development of viable drug carriers [38,43,44]. The optimized orodispersible film formulation was then physicochemically characterized in vitro by determining its mass, dimensions (inner and outer diameter), disintegration time, drug release and kinetics, drug content, dissolution pH, surface morphology changes, thermal behavior, crystallinity and structural chemical backbone transitioning.…”