Concurrent oral delivery of non-oncology drugs through solid self-emulsifying system for repurposing in hepatocellular carcinoma.

OBJECTIVE: The present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma (HCC) treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs. SIGNIFICANCE: The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations. METHODS: The non-oncology drugs (alone and in combinations) were screened in vitro for anticancer effect (against HepG2 cells) using (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as ketoconazole (KCZ), disulfiram (DSR), tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin® US2 (adsorbent carrier), which was developed and characterized. RESULTS: The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 pmol), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The DTX inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm), and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower in vivo toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss). CONCLUSION: The current study revealed a non-oncology drug combination effective against HCC. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer.

Inclusion complexes of cefuroxime axetil with ß-cyclodextrin: Physicochemical characterization, molecular modeling and effect of l-arginine on complexation.

The inclusion complexes of poorly water-soluble cephalosporin, cefuroxime axetil (CFA), were prepared with ß-cyclodextrin (ßCD) with or without addition of l-arginine (ARG) to improve its physicochemical properties. We also investigated the effect of ARG on complexation efficiency (CE) of ßCD towards CFA in an aqueous medium through phase solubility behaviour according to Higuchi and Connors. Although phase solubility studies showed AL (linear) type of solubility curve in presence and absence of ARG, the CE and association constant (Ks) of ßCD towards CFA were significantly promoted in presence of ARG, justifying its use as a ternary component. The solid systems of CFA with ßCD were obtained by spray drying technique with or without incorporation of ARG and characterized by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), scanning electron microscopy (SEM), and saturation solubility and dissolution studies. The molecular modeling studies provided a better insight into geometry and inclusion mode of CFA inside ßCD cavity. The solubility and dissolution rate of CFA were significantly improved upon complexation with ßCD as compared to CFA alone. However, ternary system incorporated with ARG performed better than binary system in physicochemical evaluation. In conclusion, ARG could be exploited as a ternary component to improve the physicochemical properties of CFA via ßCD complexation.

Molecular Docking Studies of Phytocompounds from the Phyllanthus Species as Potential Chronic Pain Modulators.

The study of inflammatory pain has been one of the most rapidly advancing and expanding areas of pain research in recent years. Studies from our lab have demonstrated the chronic pain-modulating potential of the Phyllanthus species and their probable interaction with various inflammatory mediators involving enzymes like COX-2 and PGE synthase, cytokines like TNF-alpha and IL-1 beta, and with the NMDA receptor. Inflammatory mediators which play a crucial role in chronic inflammatory hyperalgesia and its subsequent modulation were selected for their interactions with 86 structurally diverse phytoconstituents identified from the Phyllanthus species. The docking analysis of the target proteins with the phytochemical ligands was performed using VLifeMDS software. The docking scores and analysis of the interactions of the phytocompounds with target proteins suggest that important molecules like lupeol, phyllanthin, hypopyllanthin, corilagin, epicatechin, and most of the other compounds have the ability to bind to multiple targets involved in inflammatory hyperalgesia. Our study strongly suggests that the findings of the present study could be exploited in the future for designing ligands in order to obtain novel molecules for the treatment and management of chronic pain.

Physicochemical and molecular modeling studies of cefixime-L-arginine-cyclodextrin ternary inclusion compounds.

In an attempt to improve the physicochemical properties of cefixime (CEF), its supramolecular inclusion compounds were prepared with ß-cyclodextrin (ßCD) and hydroxypropyl-ß-cyclodextrin (HPßCD) in presence and/or absence of ternary component L-arginine (ARG) using spray drying technique. Initially, the phase solubility studies revealed a stoichiometry of 1:1 molar ratio with an AL-type of phase solubility curve. The stability constants of binary systems were remarkably improved in presence of ARG, indicating positive effect of its addition. The inclusion complexes were characterized by FTIR, XRPD, DSC, SEM, particle size analysis, and dissolution studies. Further, molecular mechanic (MM) calculations were performed to investigate the possible orientations of CEF inside ßCD cavity in presence and/or absence of ternary component. In case of physicochemical studies, the ternary systems performed well as a result of comprehensive effect of ternary complexation and particle size reduction achieved by a spray drying technology.

Physicochemical investigations and stability studies of amorphous gliclazide.

Gliclazide (GLI), a poorly water-soluble antidiabetic, was transformed into a glassy state by melt quench technique in order to improve its physicochemical properties. Chemical stability of GLI during formation of glass was assessed by monitoring thin-layer chromatography, and an existence of amorphous form was confirmed by differential scanning calorimetry and X-ray powder diffractometry. The glass transition occurred at 67.5°C. The amorphous material thus generated was examined for its in vitro dissolution performance in phosphate buffer (pH 6.8). Surprisingly, amorphous GLI did not perform well and was unable to improve the dissolution characteristics compared to pure drug over entire period of dissolution studies. These unexpected results might be due to the formation of a cohesive supercooled liquid state and structural relaxation of amorphous form toward the supercooled liquid region which indicated functional inability of amorphous GLI from stability point of view. Hence, stabilization of amorphous GLI was attempted by elevation of T(g) via formation of solid dispersion systems involving comprehensive antiplasticizing as well as surface adsorption mechanisms. The binary and ternary amorphous dispersions prepared with polyvinylpyrrolidone K30 (as antiplasticizer for elevation of T (g)) and Aerosil 200® and/or Sylysia® 350 (as adsorbent) in the ratio of 1:1:1 (w/w) using kneading and spray-drying techniques demonstrated significant enhancement in rate and extent of dissolution of drug initially. During accelerated stability studies, ternary systems showed no significant reduction in drug dissolution performance over a period of 3 months indicating excellent stabilization of amorphous GLI.

Physicochemical characterization of solid dispersion systems of tadalafil with poloxamer 407.

Dissolution behaviour of a poorly water-soluble drug, tadalafil, from its solid dispersion systems with poloxamer 407 has been investigated. Solid dispersion systems of tadalafil were prepared with poloxamer 407 in 1:0.5, 1:1.5 and 1:2.5 ratios using the melting method. Characterization of binary systems with FTIR and XRPD studies demonstrated the presence of strong hydrogen bonding interactions, a significant decrease in crystallinity and the possibility of existence of amorphous entities of the drug. In the binary systems tested, 1:0.5 proportion of tadalafil/poloxamer 407 showed rapid dissolution of tadalafil (DE(30) 70.9 + or - 3.6 %). In contrast, higher proportions of poloxamer 407 (1:1.5 and 1:2.5) offered no advantage towards dissolution enhancement of the drug, indicating altered rheological characteristics of the polymer at its higher concentration, which might have retarded the release rate of tadalafil.

Physicochemical investigation of the solid dispersion systems of etoricoxib with poloxamer 188.

Solid dispersion systems of a poorly water-soluble drug, etoricoxib were prepared with poloxamer 188 in 1:0.5, 1:1.5 and 1:2.5 ratios and evaluated by FTIR, powder XRD and dissolution studies. Physical studies demonstrated a strong hydrogen bonding with significant decrease in the crystallinity and formation of amorphous etoricoxib in its binary systems. All binary systems of etoricoxib showed faster dissolution than pure drug alone (P < 0.001). However, 1:2.5 proportion of etoricoxib: poloxamer 188 showed superior performance (DE45: 71.27% +/- 3.85) in enhancing solubility and dissolution rate of etoricoxib suggesting optimum ratio of the carrier.

Effect of PVP K30 and/or L-arginine on stability constant of etoricoxib-HPbetaCD inclusion complex: preparation and characterization of etoricoxib-HPbetaCD binary system.

The effect of polyvinyl pyrrolidone (PVP) K30 and/or L-arginine on etoricoxib-HPbetaCD complex was investigated. The phase solubility profiles were classified as A(L)-type, both in absence or presence of auxiliary substances used. The apparent stability constant (K(c)) of binary complex obtained at room temperature, 371.80 +/- 2.61 M(-1), was decreased with the addition of PVP and arginine indicating no benefit of addition of auxiliary substances to promote higher complexation efficiency. Therefore, solid etoricoxib-HPbetaCD binary systems were prepared and characterized by proton nuclear magnetic resonance spectroscopy (1HNMR), X-ray powder diffractometry, Fourier transformation-infrared spectroscopy, and dissolution studies. Among all binary systems, a lyophilized product showed superior performance in enhancing dissolution of etoricoxib.

Enhanced solubility and dissolution rate of lamotrigine by inclusion complexation and solid dispersion technique.

The solid-state properties and dissolution behaviour of lamotrigine in its inclusion complex with beta-cyclodextrin (betaCD) and solid dispersions with polyvinylpyrrolidone K30 (PVP K30) and polyethyleneglycol 6000 were investigated. The phase solubility profile of lamotrigine with betaCD was classified as AL-type, indicating formation of a 1:1 stoichiometry inclusion complex, with a stability constant of 369.96+/-2.26 M(-1). Solvent evaporation and kneading methods were used to prepare solid dispersions and inclusion complexes, respectively. The interaction of lamotrigine with these hydrophilic carriers was evaluated by powder X-ray diffractometry, Fourier transform infrared spectroscopy and differential scanning calorimetry. These studies revealed that the drug was no longer present in crystalline state but was converted to an amorphous form. Among the binary systems tested, PVP K30 (1:5) showed greatest enhancement of the solubility and dissolution of lamotrigine.

Effect of beta-cyclodextrin and hydroxypropyl beta-cyclodextrin complexation on physicochemical properties and antimicrobial activity of cefdinir.

The solid-state properties, dissolution profile and antimicrobial activity of inclusion complexes of cefdinir (CEF) with beta-cyclodextrin (betaCD) and hydroxypropyl beta-cyclodextrin (HPbetaCD) were investigated. The phase solubility profiles of cefdinir with betaCD and HPbetaCD were classified as A(L)-type, which indicates the formation of 1:1 stoichiometry inclusion complexes. Stability constants with 1:1 molar ratio obtained from the phase solubility diagrams were 120.38+/-1.07 and 58.60+/-1.20 M(-1) for betaCD and HPbetaCD, respectively. Binary systems of CEF with betaCD and HPbetaCD prepared by kneading method were characterized by Fourier transformation-infrared spectroscopy (FTIR) and X-ray powder diffractometry (XRD). The aqueous solubility of CEF was enhanced by 101% for betaCD and 23.4% for HPbetaCD, respectively. The dissolution profiles of inclusion complexes were determined and compared with those of CEF alone and their physical mixtures. The dissolution rate of CEF was increased by betaCD and HPbetaCD inclusion complexation moderately. However, the antimicrobial activity of CEF was increased significantly (p<0.001) by betaCD and HPbetaCD inclusion complexation against S. aureus and E. coli. In all these studies, HPbetaCD had superior antimicrobial activity than that of betaCD while betaCD had greater effect on solubility enhancement of CEF.