In silico-assisted development of supersaturable preconcentrated isotropic mixture of atazanavir for augmenting biopharmaceutical performance in the presence of H2-receptor antagonist.

The therapeutic potential of atazanavir (BCS Class II drug), a highly selective inhibitor of human immunodeficiency virus (HIV-1), has been largely limited due to its low intrinsic solubility at elevated pH resulting in low oral bioavailability. Thus, the current work describes the systematic development, optimization, and evaluation of hydroxypropyl methylcellulose acetate succinate (HPMC-AS)-based supersaturable preconcentrate isotropic mixture (SP-IM) containing long-chain triglyceride to improve intestinal lymphatic transport and augment oral bioavailability of atazanavir (ATZ). A D-optimal mixture design was employed for optimization of plain IM containing corn oil, oleic acid, Tween 80, and propylene glycol, evaluating various critical quality attributes (CQAs) like particle size, polydispersity index, self-emulsification time, % transmittance, and drug content. In silico analysis and in vitro supersaturation test facilitated the selection of HPMC-AS as a best suited polymeric precipitation inhibitor (PPI) for formulating ATZ loaded SP-IM (ATZ-SP-IM). In vitro dissolution data indicated that ATZ-SP-IM exhibits superior performance in 0.025 N HCl and pH 6.8 over pure drug. Ex vivo permeation and in vivo pharmacokinetic study of ATZ-SP-IM corroborated enhanced permeation (2.03 fold) and improved drug absorption via lymphatic transport in Wistar rats. Further, the pharmacokinetic performance of ATZ-SP-IM was not affected in presence of H2 receptor antagonist. Therefore, the results showed that ATZ-SP-IM can significantly improve the biopharmaceutical attributes of ATZ so as to lay a foundation of further research on the new dosage form of ATZ.

Atazanavir-Concentrate Loaded Soft Gelatin Capsule for Enhanced Concentration in Plasma, Brain, Spleen, and Lymphatics.

This study investigates the development of atazanavir-concentrate loaded soft gelatin capsule for achieving enhanced atazanavir (ATV) concentration in plasma, brain, spleen, and lymphatics beneficial in the significant reduction of viral load in HIV infection. For this purpose, ATV-concentrate in the presence and absence of Soluplus with corn oil, oleic acid, tween 80, and propylene glycol was developed. The developed ATV-concentrate was found to have enhanced dispersibility with no signs of precipitation after dilution with simulated G.I fluid as evident from particle size (16.49±0.32 nm) and PDI (0.217±0.02) analysis. The rheological and molecular docking studies explainedthe reduction of viscosity of SuATV-C due to the intermolecular H-bond between ATV and Soluplus that helps to retard crystallization. The shell of the soft gelatin capsule retains its integrity when subjected to a folding endurance test on a texture analyzer depicting that the concentrate did not affect the integrity of the soft gelatin capsule shell. An ex vivo and in vivo pharmacokinetic study in rats revealed that the SuATV-C soft gelatin capsule (SuATV-C SGC) indicated 2.9 fold improvement in rate and extent of permeation and absorption than that of ATV-suspension. The tissue distribution study also exhibited higher drug concentration in the brain (2.5 fold), lymph nodes (2.7 fold), and spleen (1.2 fold) administered with SuATV-C SGC, revealing the overwhelming influence of Soluplus and corn oil. In a nutshell, these studies demonstrated that SuATV-C SGC seems to have the potential to deliver an anti-retroviral drug to the viral sanctuaries for the better management of HIV.

Exploring the feasibility of carbamoylethyl pullulan-g-palmitic acid polymeric micelles for the effective targeting of raloxifene to breast tumor: Optimization and preclinical evaluation.

Carbamoylethyl pullulan-grafted palmitic acid (CP-g-PA), a novel self-assembled polymer was synthesized and examined for its efficacy in delivering the raloxifene (RA) to mammary carcinoma. The synthesized CP-g-PA was confirmed by evaluating through various spectral and morphological attributes. Further, the central composite design-response surface methodology with two factors at three levels was utilized to obtain the optimized and stable polymeric micelles. The optimized formulation was subjected to in vitro and in vivo evaluation. RA loaded polymeric micelles (RA-PMs) were spherical in shape with particle size less than 100 nm and high entrapment efficiency (77.02%). The developed formulation exhibited pH-dependent release profile of RA when loaded in polymeric micelles and provides substantial compatibility to erythrocytes. In vivo pharmacokinetic study demonstrates that RA-PMs offers higher mean residence time and volume of distribution as compared to pure RA. Besides, the biodistribution study manifested enhanced drug concentration in tumor and decreased concentration in other tissue as compared to pure drug. The treatment with RA-PMs also increases the median survival time, tumor inhibition rate and % increase in life span of the tumor bearing rats. Overall, the results pointed towards the overwhelming response of RA when loaded into micelles made from CP-g-PA.

Assessing the viability of carbamoylethyl pullulan-g-stearic acid based smart polymeric micelles for tumor targeting of raloxifene.

The present investigation entails the synthesis of smart pullulan polymeric micelles for evaluating its tumor targeting potential. For this purpose, two step polymerization synthesis reactions were conducted. In the first step, carbamoylethylation occurs by reaction of the free alcoholic moieties at 6th position of glucopyranose unit of pullulan with acrylamide in presence of alkali to obtain carbamoylethyl pullulan (CmP). In the second step, CmP undergoes graft polymerization with stearic acid (SA) to obtain CmP-g-stearic acid diblock co-polymer (CmP-g-SA) as evident from FTIR and NMR analysis. The XpRD spectra showed crystalline nature that was further confirmed by SEM indicating rough and poly-porous morphology. The QbD based optimized formulations of raloxifene HCl (RLX) loaded polymeric micelles (RLX PMs) exhibited pH-dependent release profile with added advantage of 1.2 times reduction in percentage hemolysis giving substantial compatibility with erythrocytes. In vivo pharmacokinetic performance of RLX PMs suggested enhanced mean residence time and volume of distribution. Besides, the biodistribution study of RLX PMs manifested enhanced entry of RLX in mammary carcinoma tissues as compared to normal tissues suggested that CmP-g-SA based micelles enhanced the anti-tumor activity of RLX. Overall, the findings pointed toward the biocompatibility of CmP-g-SA as a potential carrier system for the delivery of RLX.

A spray dried Nelfinavir Mesylate particles for enhanced oral bioavailability: Systematic formulation optimization and in-vivo performance.

The current endeavor was aimed to fabricate spray dried Nelfinavir Mesylate particles (SDNPs) that upon reconstitution with body fluids releases amorphous Nelfinavir Mesylate with enhanced oral bioavailability. For this purpose, feed mixture was prepared containing solubilized NFM, solid substrate and solvent system. The NFM was solubilized in a mixture of Maisine 35-1 (200 mg), Tween80 (500 mg) and Transcutol HP (300 mg). Three different solid substrates with high specific surface area were used: Neusilin® UFL2, (magnesium aluminometasilicate), Aerosil 200® (colloidal silica) and Syloid 244 FP® (porous silicon dioxide). Central composite design-response surface methodology (CCD-RSM) with three-factor (two numeric and one categorical) at three-level was used to select the appropriate solid substrate and to develop optimized SDNPs. The solid characterization by scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction studies indicated the absence of crystalline NFM in the formulations. The drug distribution analysis using raman spectroscopy suggested uniform distribution of amorphous NFM in optimized SDNPs-1 formulation. The transmission electron microscopy revealed the spherical structure of reconstituted SDNPs that releases amorphous NFM with globules size less than 110 nm. The solid substrate had significant and positive effect in drug dissolution; the mean dissolution time of NFM loaded in SDNPs was considerably improved. The bioavailability study resulted in enhanced magnitude of Cmax and AUC for SDNPs. The tissue distribution studies exhibited significantly higher brain and lymph nodes distribution as compared to putative form. Overall, the results pointed towards the overwhelming response of the SDNPs to be used for HIV treatment.

Lipid based delivery of Efavirenz: An answer to its erratic absorption and food effect.

The current investigation entails systematic development of EFV (Efavirenz) loaded isotropic mixture prepared with long chain triglycerides for obliterating food associated variability and minimizing the erratic absorption behavior. For this purpose, the optimized isotropic mixture (EF1) consists of Maisine 35-1 (20%), Transcutol HP (17.7% w/w) and Cremophor RH 40:Labrasol (1:1) (62.3% w/w) was formulated by employing D-optimal mixture design that after numerical optimization showed highest desirability of 0.995. Further, the dissolution behavior of EFV suspension in biorelevant dissolution media's simulate the fed and fasted small intestine conditions, clearly anticipated that there is an influence of food effect for EFV. However, when EFV loaded into isotropic mixture, the food effect was abolished and no significant difference was seen in biorelevant dissolution media's. The tissue distribution of EFV from EF1 follows order: blood plasma > heart > brain > lymph nodes > liver. Interestingly, the in-vivo animal pharmacokinetic performance showed positive food effect after administration of EFV suspension and marketed formulation. However, the developed formulation (EF1) nullifies this food effect. In nutshell, these studies suggested significant enhancement in the biopharmaceutical attributes of a stable and robust EFV loaded isotropic mixture.

Armamentarium of nanoscaled lipid drug delivery systems customized for oral administration: In silico docking patronage, absorption phenomenon, preclinical status, clinical status and future prospects.

Poor drug solubility and bioavailability remain a significant and frequently encountered concern for pharmaceutical scientists. Nanoscaled lipid drug delivery systems (NSLDDS) have exhibited great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successful clinical products. In the past few years, we have find out that optimized composition of drug in lipid, surfactant, or mixture of lipid and surfactant omits the solubility, permeability and bioavailability issues, which are potential limitations for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect on biopharmaceutical aspects of drug absorption and distribution both in vitro and in vivo. Therefore, in current critical review, a comprehensive overview of the different lipid based nanostructured drug delivery systems intended for oral administration has been presented. In addition, implication of in silico docking in designing of NSLDDS as well as mechanism of absorption of different lipid based nanoformulations through intestinal absorption window has also been offered. Moreover, attention has also been paid to NSLDDS that are currently undergoing preclinical or clinical analysis.

A QbD approach for the fabrication of immediate and prolong buoyant cinnarizine tablet using polyacrylamide-g-corn fibre gum.

The main hurdle in the oral delivery of cinnarizine is its supersaturation, precipitation and re-dissolution process, influencing the oral bioavailability. To overcome this problem, an attempt was made to develop immediate and prolong buoyant tablet of cinnarizine. For this purpose, polyacrylamide-g-corn fibre gum (p-CFG) was synthesized as mucoadhesive cum swellable polymer and it was compared with already used HPMC K4M polymer. The central composite design with two numeric and one categorical factor was choosen to optimize conc. of p-CFG (X1), concentration of NaHCO3 (X2) and type of effervescent agents (X3). The bioadhesive strength of p-CFG tablet was 2.4 times higher than HPMC K4M containing tablet. The formulation composition comprises of p-CFG (64.3%), sodium bi­carbonate (12.9%) and citric acid (2%) (FCNZ) fulfilled the maximum requirement of an optimized formulation. The in-vivo animal pharmacokinetic performance revealed larger plasma half-life and reduced elimination rate as compared to CNZ suspension. Interestingly, the absorption of CNZ from optimized formulation was 3 times enhanced than from CNZ suspension. Overall, the enhancement in the oral bioavailability of CNZ was evident that is due to its prolonged gastric residence time. Furthermore, the swelling associated floating followed by mucoadhesive nature of tablet was observed by X-ray imaging studies.

Investigating the potential of Tamarindus indica pectin-chitosan conjugate for reducing recovery period in TNBS induced colitis.

The present study was aimed at exploiting the wound healing applications and tablet coating potential of Tamarindus indica pectin-chitosan (PCH) conjugate for reducing recovery period from TNBS induced colitis. The PCH (60:40, 3% w/v) solution when spray coated followed by drying at 50°C created hydrophobic surface, that may be due to interaction of pectin with chitosan as evident from temperature ramping rheological investigations. Further, the 15% w/v coating was sufficient to prevent Mesalamine (Ma) release in pH 1.2. The AUC and AUMC of PCH coated tablets were 1.98 and 17.69 fold increased as compared to uncoated tablets. A synergistic therapeutic effect of PCH conjugate with Ma was evident from the colon/body weight ratio, clinical activity and damage score. Overall, the findings suggested PCH and Ma (20mg) reduces the recovery period from 5 to 4days with reduction in dose.

QbD based synthesis and characterization of polyacrylamide grafted corn fibre gum.

The aim of present investigation was to utilize quality by design approach for the synthesis of polyacrylamide corn fibre gum (PAAm-g-CFG) from corn fibre gum (CFG) by varying concentration of acrylamide and initiator. The spectral analysis (ATR-FTIR, 1H NMR, DSC, X-ray and Mass spectroscopy) was conducted to assure grafting copolymerization of CFG with acrylamide. The powder flow properties confirm the porous nature of PAAm-g-CFG. The grafted copolymer dispersion showed shear thinning behaviour that follows Herschel Bulkley model. The viscoelastic analysis suggested viscous liquid like nature of PAAm-g-CFG and its viscosity increases with increase in concentration of PAAm-g-CFG. The mucoadhesive strength of synthesized PAAm-g-CFG was found to be higher than moringa oleifera gum, karaya gum, guar gum, xanthan gum, chitosan and gelatin. Further, the results pointed toward enhanced thermal stability of PAAm-g-CFG. Thus, PAAm-g-CFG has a great potential to be used in food and pharmaceutical industry.