Development of 3D DLP Printed Sustained Release Ibuprofen Tablets and Their Pharmacokinetic Evaluation in Rats.

The objective of the present study was to develop digital light processing (DLP) 3D printed sustained release ibuprofen (IBU) tablets using 3D DLP printers for evaluation in in vitro release and in vivo pharmacokinetic studies with their in vitro-in vivo correlation. The resin formulation and printing parameters were optimized using quality by design (QbD) approach, and IBU tablets were printed using DLP printers which works at 385 and 405 nm wavelengths. Our results demonstrated that formulation consisting of polyethylene glycol diacrylate (PEGDA) 700, water, IBU, and riboflavin printed at 40-s bottom layer exposure time and 30-s exposure time produced tablets using both 385 and 405 nm wavelengths. In vitro dissolution studies showed > 70% drug release at the end of 24 h when printed at 405 nm wavelength with no significant difference between tablets printed at 385 nm. In vivo pharmacokinetic evaluation of the optimized 3D printed tablets printed at 405 nm at oral dose of 30 mg/kg in rats showed sustained release of IBU with significantly (p < 0.05) higher Cmax of 30.12 ± 2.45 µg/mL and AUC(0-24 h) of 318.97 ± 16.98 (µg/mL × h) compared to marketed IBU tablet (control). In vivo-in vitro correlation studies showed 80% of drug was absorbed in vivo within 3 h from the pulverized 3D printed tablet, whereas intact 3D tablet showed sustained release of IBU with > 75% IBU release in 24 h in vitro. Overall, IBU tablets fabricated using DLP printing demonstrated sustained release and enhanced systemic absorption with no significant difference in their release profile at different wavelengths.

Biphasic burst and sustained transdermal delivery in vivo using an AI-optimized 3D-printed MN patch.

The objective of the present study was to fabricate microneedles for delivering lipophilic active ingredients (APIs) using digital light processing (DLP) printing technology and quality by design (QbD) supplemented by artificial intelligence (AI) algorithms. In the present study, dissolvable microneedle (MN) patches using ibuprofen (IBU) as a model drug were successfully fabricated with DLP printing technology at âˆ¼ 750 µm height, ∼250 µm base diameter, and tip with radius of curvature (RoC) of âˆ¼ 15 µm. MN patches were comprised of IBU, photoinitiator, Lithium phenyl (2,4,6-trimethylbenzoyl) phosphinate (LAP), polyethylene glycol dimethacrylate (PEGDAMA)550 and distilled water and were developed using the QbD optimization approach. Optimization of print fidelity and needle morphology were achieved using AI implementing a semi-supervised machine learning approach. Mechanical strength tests demonstrated that IBU MNs formed pores both on Parafilm M® and human cadaver skin. IBU-MNs consisting of 0.23 %w/v and 0.49 %w/v LAP with 10 %w/v water showed âˆ¼ 2 mg/cm2 sustained drug permeation at 72 h in skin permeation experiments with flux of âˆ¼ 40 µg/cm2/h. Pharmacokinetic studies in rats displayed biphasic rapid first-order absorption with sustained zero-order input of Ko = 150ug/hr, AUC0-48h = 62812.02 ± 11128.39 ng/ml*h, Tmax = 2.66 ± 1.12 h, and Cmax = 3717.43 ± 782.25 ng/ml (using 0.23 %w/v LAP IBU MN patch). An in vitro in vivo relation (IVIVR) was conducted identifying a polynomial relationship between patch release and fraction absorbed in vivo. This study demonstrates fabrication of dissolvable DLP-printed microneedle patches for lipophilic API delivery with biphasic rapid first-order and sustained zero-order release.

Role of nano-lipid formulation of CARP-1 mimetic, CFM-4.17 to improve systemic exposure and response in osimertinib resistant non-small cell lung cancer.

BACKGROUND: EGFR mutated NSCLCs have been shown to employ the use of CARP-1 in overriding the signaling inhibition of tyrosine kinase inhibitors (such as Osimertinib). CFM 4.17 is a CARP-1 inhibitor which has a promising role in overcoming Tyrosine Kinase Inhibitor (TKI) resistance when used as a pre-treatment through promoting apoptosis. Lack of solubility, hydrophobicity leading to poor systemic exposure are the limitations of CFM 4.17. This can be overcome by nano lipid-based formulation (NLPF) of CFM 4.17 which can enhance systemic exposure in preclinical animal models as well as improve therapeutic efficacy in drug-resistant cancer cell lines. METHODS: Molecular docking simulation studies were performed for CFM 4.17. CFM 4.17-NLPF was formulated by melt dispersion technique and optimized using a Box-Behnken designed surface response methodology approach using Design Expert and MATLAB. In vitro, CFM 4.17 release studies were performed in simulated gastric fluids (SGF-pH-1.2) and simulated intestinal fluids (SIF- pH-6.8). Cell viability assays were performed with HCC827 and H1975 Osimertinib resistant and non-resistant cells in 2D and 3D culture models of Non-small cell lung cancer to determine the effects of CFM 4.17 pre-treatment in Osimertinib response. In vivo pharmacokinetics in rats were performed measuring the effects of NLPF on CFM 4.17 to improve the systemic exposure. RESULTS: CFM 4.17 was well accommodated in the active pocket of the active site of human EGFR tyrosine kinase. CFM 4.17 NLPF was optimized with robust experimental design with particle size less than 300 nm and % entrapment efficiency of 92.3 ± 1.23. Sustained diffusion-based release of CFM 4.17 was observed from NLPF in SGF and SIFs with Peppas and Higuchi based release kinetics, respectively. CFM 4.17 pretreatment improved response by decreasing IC50 value by 2-fold when compared to single treatment Osimertinib in both 2D monolayer and 3D spheroid assays in HCC827 and H1975 Osimertinib resistant and non-resistant cells of Non-small cell lung cancer. There were no differences between CFM 4.17 NLPF and suspension in 2D monolayer culture pretreatments; however, The 3D culture assays showed that CFM 4.17 NLPF improved combination sensitivity. Pharmacokinetic analysis showed that CFM 4.17 NLPF displayed higher AUCtot (2.9-fold) and Cmax (1.18-fold) as compared to free CFM 4.17. In contrast, the animal groups administered CFM 4.17 NLPF showed a 4.73-fold (in half-life) and a 3.07-fold increase (in MRT) when compared to equivalent dosed suspension. CONCLUSION: We have successfully formulated CFM 4.17 NLPFs by robust RSM design approach displaying improved response through sensitizing cells to Osimertinib treatment as well as improving the oral bioavailability of CFM 4.17.

Rheological properties of rice-blackgram batter while replacing white rice with brown rice.

Rice-blackgram batter is a raw material for many traditional convenience foods in Asia. Reformulation of traditional convenience food by replacing white rice with whole rice (brown rice) is a novel method to reduce the consumption of refined grain and increase the intake of whole grain in our diet. In this study, rheological properties of rice-blackgram batter was investigated while replacing white rice with brown rice at five levels (T1--0% replacement (control), T2--25% replacement, T3--50% replacement, T4--75% replacement, and T5--100% replacement). The shear stress versus shear rate plot indicates that the rice-blackgram batter exhibited non-Newtonian fluid behavior (shear thinning property) even after 100% replacement of white rice with brown rice. The rheological characteristics of rice-blackgram batters fitted reasonably well in Cassan (r2 = 0.8521-0.9856) and power law (r2 = 0.8042-0.9823) models. Brown rice replacement at all levels did not affect the flow behavior index, yield stress, consistency coefficient, and apparent viscosity of batter at 25 degrees C. However, at higher temperature, the viscosity was greater for T4 and T5 (no difference between them) than T1, T2, and T3 (no difference between them) batters. Further research is required to determine the sensory attributes and acceptability of the cooked products with brown rice-blended batter.