Quality by Design Enabled Development of Oral Self-Nanoemulsifying Drug Delivery System of a Novel Calcimimetic Cinacalcet HCl Using a Porous Carrier: In Vitro and In Vivo Characterisation.

In this present research, work quality by design-enabled development of cinacalcet HCl (CH)-loaded solid self-nanoemulsifying drug delivery system (S-SNEDDS) was conducted using a porous carrier in order to achieve immediate drug release and better oral bioavailability. Capmul MCM (CAP), Tween 20 (TW 20) and Transcutol P (TRP) were selected as excipients. Cumulative % drug release at 30 min (Q30), emulsification times (ET), mean globule size (GS) and polydispersity index (PDI) were identified as critical quality attributes (CQAs). Factor mode effect analysis (FMEA) and Taguchi screening design were applied for screening of factors. The optimised single dose of S-SNEDDS obtained using Box-Behnken design (BBD) consisted of 30 mg of CH, 50 mg of CAP, 149.75 mg of TW 20, 55 mg of TRP and 260.75 mg of Neusilin US2. It showed an average Q30 of 97.6%, ET of 23.3 min, GS of 89.5 nm and PDI of 0.211. DSC, XRD and SEM predict the amorphous form of S-SNEDDS. In vivo pharmacokinetic study revealed better pharmacokinetic parameters of S-SNEDDS. The above study concluded that the optimised S-SNEDDS is effective to achieve the desired objective. Graphical Abstract.

Improvement in Dissolution Rate of Cefuroxime Axetil by using Poloxamer 188 and Neusilin US2.

A combination of fusion and surface adsorption techniques was used to enhance the dissolution rate of cefuroxime axetil. Solid dispersions of cefuroxime axetil were prepared by two methods, namely fusion method using poloxamer 188 alone and combination of poloxamer 188 and Neusilin US2 by fusion and surface adsorption method. Solid dispersions were evaluated for solubility, phase solubility, flowability, compressibility, Kawakita analysis, Fourier transform-infrared spectra, differential scanning calorimetry, powder X-ray diffraction study, in vitro drug release, and stability study. Solubility studies showed 12- and 14-fold increase in solubility for solid dispersions by fusion method, and fusion and surface adsorption method, respectively. Phase solubility studies showed negative ΔG (0) tr values for poloxamer 188 at various concentrations (0, 0.25, 0.5, 0.75 and 1%) indicating spontaneous nature of solubilisation. Fourier transform-infrared spectra and differential scanning calorimetry spectra showed that drug and excipients are compatible with each other. Powder X-ray diffraction study studies indicated that presence of Neusilin US2 is less likely to promote the reversion of the amorphous cefuroxime axetil to crystalline state. in vitro dissolution studies, T50% and mean dissolution time have shown better dissolution rate for solid dispersions by fusion and surface adsorption method. Cefuroxime axetil release at 15 min (Q15) and DE15 exhibited 23- and 20-fold improvement in dissolution rate. The optimized solid dispersion formulation was stable for 6 months of stability study as per ICH guidelines. The stability was ascertained from drug content, in vitro dissolution, Fourier transform-infrared spectra and differential scanning calorimetry study. Hence, this combined approach of fusion and surface adsorption can be used successfully to improve the dissolution rate of poorly soluble biopharmaceutical classification system class II drug cefuroxime axetil.

Development of solid self-nanoemulsifying granules (SSNEGs) of ondansetron hydrochloride with enhanced bioavailability potential.

The current work aims to prepare the solid self-nanoemulsifying granules (SSNEGs) of ondansetron hydrochloride (ONH) to enhance its oral bioavailability by improving its aqueous solubility and facilitating its absorption though lymphatic pathways. Preformulation studies including screening of excipients for solubility and pseudoternary phase diagrams suggested the suitability of Capmul MCM as lipid, Labrasol as surfactant, and Tween 20 as cosurfactant for preparation of self-emulsifying formulations. Preliminary composition of the SNEDDS formulations were selected from the phase diagrams and subjected to thermodynamic stability studies and dispersibility tests. The prepared liquid SNEDDS formulations were characterized for viscosity, refractive index, droplet size and zeta potential. The TEM study confirmed the formation of nanoemulsion following dilution of liquid SNEDDS. The optimized liquid SNEDDS were transformed into free flowing granules by adsorption on the porous carriers like Sylysia (350, 550, and 730) and Neusilin™ US2. Solid state characterization employing the FTIR, DSC and powder XRD studies indicated lack of any significant interaction of drug with the lipidic and emulsifying excipients, and porous carriers. In vitro drug release studies indicated faster solubilization of the drug by optimized SSNEGs (over 80% within 30 min) vis-à-vis the pure drug (only 35% within 30 min). In vivo pharmacokinetic studies in Wistar rats observed significant increase in C(max) (3.01-fold) and AUC (5.34-fold) using SSNEGs compared to pure drug, whereas no significant difference (p>0.1) was observed with the liquid SNEDDS. Thus, the present studies ratify the bioavailability enhancement potential of SSNEGs of ONH prepared using porous carriers.

Development, optimization, and characterization of solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers.

The present studies entail formulation development of novel solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of valsartan with improved oral bioavailability, and evaluation of their in vitro and in vivo performance. Preliminary solubility studies were carried out and pseudoternary phase diagrams were constructed using blends of oil (Capmul MCM), surfactant (Labrasol), and cosurfactant (Tween 20). The SNEDDS were systematically optimized by response surface methodology employing 3(3-)Box-Behnken design. The prepared SNEDDS were characterized for viscocity, refractive index, globule size, zeta potential, and TEM. Optimized liquid SNEDDS were formulated into free flowing granules by adsorption on the porous carriers like Aerosil 200, Sylysia (350, 550, and 730) and Neusilin US2, and compressed into tablets. In vitro dissolution studies of S-SNEDDS revealed 3-3.5-fold increased in dissolution rate of the drug due to enhanced solubility. In vivo pharmacodynamic studies in Wistar rats showed significant reduction in mean systolic BP by S-SNEDDS vis-à-vis oral suspension (p < 0.05) owing to the drug absorption through lymphatic pathways. Solid-state characterization of S-SNEDDS using FT-IR and powder XRD studies confirmed lack of any significant interaction of drug with lipidic excipients and porous carriers. Further, the accelerated stability studies for 6 months revealed that S-SNEDDS are found to be stable without any change in physiochemical properties. Thus, the present studies demonstrated the bioavailability enhancement potential of porous carriers based S-SNEDDS for a BCS class II drug, valsartan.

Influence of Momordica charantia on oxidative stress-induced perturbations in brain monoamines and plasma corticosterone in albino rats.

OBJECTIVES: The objective of this study was to evaluate the antistress activity of Momordica charantia (MC) fruit extract on stress-induced changes in albino rats and also to explore attenuating effects of MC on in vitro lipid peroxidation in rat brain. MATERIALS AND METHODS: In this study, Wistar albino rats (180-200 g) were used. Plasma corticosterone and monoamines-5-hydroxy tryptamine (5-HT), norepinephrine (NE), epinephrine (E) and dopamine (DA) in cortex, hypothalamus and hippocampus regions of brain were determined in animals under different stressful conditions. Ethanolic fruit extract of MC, at doses of 200 and 400 mg/kg, was used. The oxidative stress paradigms used in in vivo models were acute stress (AS) and chronic unpredictable stress (CUS). Panax quinquefolium (PQ) was used as a standard in in vivo models and ascorbic acid was used as a reference standard in the in vitro method. RESULTS: Subjecting the animals to AS (immobilization for 150 min once only) resulted in significant elevation of plasma corticosterone levels and brain monoamine levels. Pretreatment with MC at doses of 200 and 400 mg/kg p.o. significantly countered AS-induced changes and a similar effect was exhibited by PQ at 100 mg/kg p.o. In the CUS regimen (different stressors for 7 days), plasma corticosterone levels were significantly elevated whereas the levels of 5-HT, NE, E, and DA were depleted significantly. Pretreatment with MC (200 and 400 mg/kg) attenuated the CUS-induced changes in the levels of above monoamines in cortex, hypothalamus, and hippocampus regions of brain and plasma corticosterone in a dose-dependent manner. Furthermore, MC extract (1000-5000 µg/mL) exhibited a significant quenching effect on in vitro lipid peroxidation indicating its strong antioxidant activity which was compared with ascorbic acid. CONCLUSIONS: This study reveals the antistress activity of MC as it significantly reverted the stress-induced changes, and the activity might be attributed to its antioxidant activity since stress is known to involve several oxidative mechanisms.

Advanced techniques for penetration enhancement in transdermal drug delivery system.

Transdermal route has been recognized as a promising drug delivery system for systemic delivery of drugs and provides the advantage of avoidance of first-pass effect, ease of use, better patient compliance, maintaining constant blood level for longer period of time and decrease side effects. The major pitfalls of this route lie with difficulty in permeation of drugs through the skin. Several literatures have been published for enhancing the permeation of drugs by chemical approaches. However the present review highlighted about the advanced physical techniques used for enhancing delivery of drugs such as structure-based, electrically based, velocity based and several other miscellaneous physical techniques for enhancing the permeation of drugs. In addition to these, the present review also gives an exhaustive account on clinical data about these techniques and regulatory considerations for new drugs as well as generic product approval in transdermal drug delivery.

Development and in vitro evaluation of buccoadhesive carvedilol tablets.

Buccoadhesive tablets of carvedilol were prepared using HPMC K4M, HPMC K15M and Carbopol 934 as mucoadhesive polymers. Fifteen formulations were developed with varying concentrations of polymers. Formulations of the BC or BD series were composed of HPMC K4M or HPMC K15M in ratios of 1:1 to 1:5 whereas in the BE series Carbopol 934 was used (1:0.25 to 1:1.50). The formulations were tested for in vitro drug release, in vitro bioadhesion, moisture absorption and in vitro drug permeation through porcine buccal mucosa. Formulation BC3 showed maximum release of the drug (88.7 +/- 0.4%) with the Higuchi model release profile and permeated 21.5 +/- 2.9% of the drug (flux 8.35 +/- 0.291 microg h(-1)cm(-2)) permeation coefficient 1.34 +/- 0.05 cm h(-1)) through porcine buccal membrane. BC3 formulation showed 1.62 +/- 0.15 N of peak detachment force and 0.24 +/- 0.11 mJ of work of adhesion. FTIR results showed no evidence of interaction between the drug and polymers. XRD study revealed that the drug is in crystalline form in the polymer matrix. The results indicate that suitable bioadhesive buccal tablets with desired permeability could be prepared.

Nanosuspensions as the most promising approach in nanoparticulate drug delivery systems.

Over the years, controlled drug delivery as well as site-specific delivery have made considerable advances. One area that contributed significantly to this progress is the rapidly developing field of colloidal drug delivery systems. Nanoparticles, one of the colloidal drug delivery systems, may enable new possibilities for therapy that presently have not been investigated. Recent advances in nanoparticle research are discussed here. The present review highlights new and upcoming developments such as nanosuspensions and solid lipid nanoparticles.