Pharmacokinetic and pharmacodynamic studies of nisoldipine-loaded solid lipid nanoparticles developed by central composite design

Abstract

Objective: Nisoldipine (ND) is a potential antihypertensive drug with low oral bioavailability. The aim was to develop an optimal formulation of ND-loaded solid lipid nanoparticles (ND-SLNs) for improved oral bioavailability and pharmacodynamic effect by using a two-factor, three-level central composite design. Glyceryl trimyristate (Dynasan 114) and egg lecithin were selected as independent variables. Particle size (Y₁), PDI (Y₂) and entrapment efficiency (EE) (Y₃) of SLNs were selected as dependent response variables.

Methods: The ND-SLNs were prepared by hot homogenization followed by ultrasonication. The size, PDI, zeta potential, EE, assay, in vitro release and morphology of ND-SLNs were characterized. Further, the pharmacokinetic (PK) and pharmacodynamic behavior of ND-SLNs was evaluated in male Wistar rats.

Results: The optimal ND-SLN formulation had particle size of 104.4?±?2.13?nm, PDI of 0.241?±?0.02 and EE of 89.84?±?0.52%. The differential scanning calorimetry and X-ray diffraction analyses indicated that the drug incorporated into ND-SLNs was in amorphous form. The morphology of ND-SLNs was found to be nearly spherical by scanning electron microscopy. The optimized formulation was stable at refrigerated and room temperature for 3 months. PK studies showed that 2.17-fold increase in oral bioavailability when compared with a drug suspension. In pharmacodynamic studies, a significant reduction in the systolic blood pressure was observed, which sustained for a period of 36?h when compared with a controlled suspension.

Conclusion: Taken together, the results conclusively demonstrated that the developed optimal ND-SLNs caused significant enhancement in oral bioavailability along with pharmacodynamic effect.     

Improved oral bioavailability of valsartan using proliposomes: design,characterization and in vivo pharmacokinetics

Abstract

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6?±?2.9% with a vesicle size of 364.1?±?14.9?nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12?h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.     

Lipid nanoparticles of zaleplon for improved oral delivery by Box–Behnken design: optimization,in vitro and in vivo evaluation

Purpose: Zaleplon (ZL) is a hypnotic drug prescribed for the management of insomnia and convulsions. The oral bioavailability of ZL was low (～30%) owing to poor water solubility and hepatic first-pass metabolism. The cornerstone of this investigation is to develop and optimize solid lipid nanoparticles (SLNs) of ZL with the aid of Box–Behnken design (BBD) to improve the oral bioavailability.

Methods: A design space with three formulation variables at three levels were evaluated in BBD. Amount of lipid (A₁), amount of surfactant (A₂) and concentration of co-surfactant (%) (A₃) were selected as independent variables, whereas, particle size (B₁), entrapment efficiency (B₂) and zeta potential (ZP, B₃) as responses. ZL-SLNs were prepared by hot homogenization with ultrasonication method and evaluated for responses to obtain optimized formulation. Morphology of nanoparticles was observed under SEM. DSC and XRD studies were examined to understand the native crystalline behavior of drug in SLN formulations. Further, in vivo studies were performed in Wistar rats.

Results: The optimized formulation with 132.89?mg of lipid, 106.7?mg of surfactant and 0.2% w/v of co-surfactant ensued in the nanoparticles with 219.9?±?3.7?nm of size, ?25.66?±?2.83?mV surface charge and 86.83?±?2.65% of entrapment efficiency. SEM studies confirmed the spherical shape of SLN formulations. The DSC and XRD studies revealed the transformation of crystalline drug to amorphous form in SLN formulation. In conclusion, in vivo studies in male Wistar rats demonstrated an improvement in the oral bioavailability of ZL from SLN over control ZL suspension.

Conclusions: The enhancement in the oral bioavailability of ZL from SLNs, developed with the aid of BBD, explicated the potential of lipid-based nanoparticles as a potential carrier in improving the oral delivery of this poorly soluble drug.     

Formulation design,in vitro characterizations and anti-malarial investigations of artemether and lumefantrine-entrapped solid lipid microparticles

Context: Poor aqueous solubility of artemether and lumefantrine makes it important to seek better ways of enhancing their oral delivery and bioavailability.

Objective: To formulate and carry out in vitro and anti-malarial pharmacodynamic evaluations of solidified reverse micellar solutions (SRMS)-based solid lipid microparticles (SLMs) of artemether and lumefantrine for oral delivery and improved bioavailability.

Materials and methods: Rational blends of Softisan^®154 and Phospholipon^®90H lipid matrices, and different concentrations of artemether and lumefantrine were used to formulate several batches of SLMs. Drug-free SLMs were also formulated. Morphology, particle size, encapsulation efficiency (EE%) and pH studies were performed. In vitro release studies were performed in alcoholic buffer, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes. Anti-malarial pharmacodynamic studies were conducted in mice.

Results: Stable, smooth and spherical particles with sizes ranging from 4.2?±?0.02 to 9.3?±?0.8?µm were formed. EE% of 92.2–97.3% and 30.2–84.7% and pH of 3.0?±?0.02 to 4.9?±?0.12 and 3.0?±?0.02 to 5.8?±?0.05 were obtained for artemether and lumefantrine SLMs, respectively. Release of 100, 88.28 and 75.49%, as well as 63.26, 34.31 and 56.17% were recorded for artemether and lumefantrine in alcoholic buffer, SGF and SIF, respectively. Pharmacodynamic studies indicated very significant (p?Conclusion: Oral delivery and bioavailability of artemether and lumefantrine could be improved using SRMS-based SLMs.     

Self-emulsifying drug delivery system for enhanced solubility of asenapine maleate: design,characterization, in vitro,ex vivo and in vivo appraisal

Self-emulsifying drug delivery systems (SES) were developed to improve oral bioavailability of asenapine maleate (ASM), an antipsychotic drug with challenging amphiphobic nature and extensive pre-systemic metabolism. ASM-SES was prepared by choosing the proportion of oil, surfactant, co-surfactant from constructed phase diagram. The in vitro and ex vivo evaluation was done. In vivo evaluation was done through pharmacokinetic and pharmacodynamic studies. Role of lymphatic absorption was studied by lymphatic absorption inhibition study. A formulation consisting of 9.9%, 59.4%, 29.7% and 1% of oil, surfactant, co-surfactant, and drug respectively was considered as optimized formulation. After various evaluation test, the globule size and zeta potential for optimized formulation (SES₄) were found to be 137.9?nm and ?28.8?mV respectively. A maximum of 99.64?±?0.16% of ASM was released from SES₄ in 60?minutes of time. The flux (ex vivo study) increased by 2.33 folds, which prove the enhanced release and permeation of ASM when loaded into SES. The animals administered with SES₄ showed higher activity and good pharmacodynamic response than the control and ASM-Suspension, which may be due to the greater availability of the drug. The maximum pharmacodynamic response was observed at the t_max determined by Pharmacokinetic studies. The bioavailability increased by 1.64 folds with 16.55?±?3.11% as extend of lymphatic absorption (r?=?0.9732). Good in vitro in vivo correlation was observed. ASM-SES is a novel approach to effectively deliver ASM and improve the oral bioavailability.     

Creatinine-based non-phospholipid vesicular carrier for improved oral bioavailability of Azithromycin

Context: Novel, safe, efficient and cost effective nano-carriers from renewable resources have got greater interest for enhancing solubility and bioavailability of hydrophobic dugs.

Objectives: This study reports the synthesis of a novel biocompatible non-phospholipid human metabolite "Creatinine" based niosomal delivery system for Azithromycin improved oral bioavailability.

Methods: Synthesized surfactant was characterized through spectroscopic and spectrometric techniques and then the potential for niosomal vesicle formation was evaluated using Azithromycin as model drug. Drug loaded vesicles were characterized for size, polydispersity index (PDI), shape, drug encapsulation efficiency (EE), in vitro release and drug–excipient interaction using zetasizer, atomic force microscope (AFM), LC–MS/MS and FTIR. The biocompatibility of surfactant was investigated through cells cytotoxicity, blood hemolysis and acute toxicity. Azithromycin encapsulated in niosomes was investigated for in vivo bioavailability in rabbits.

Results: The vesicles were spherical with 247?±?4.67?nm diameter hosting 73.29?±?3.51% of the drug. Surfactant was nontoxic against cell cultures and caused 5.80?±?0.51% hemolysis at 1000?µg/mL. It was also found safe in mice up to 2.5?g/kg body weight. Synthesized surfactant based niosomal vesicles revealed enhanced oral bioavailability of Azithromycin in rabbits.

Conclusions: The results of the present study confirm that the novel surfactant is highly biocompatible and the niosomal vesicles can be efficiently used for improving the oral bioavailability of poor water soluble drugs.     

Gastrointestinal stability,physicochemical characterization and oral bioavailability of chitosan or its derivative-modified solid lipid nanoparticles loading docetaxel

Abstract

Objective: The purpose of this study was to prepare the positively charged chitosan (CS)- or hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-modified solid lipid nanoparticles (SLNs) loading docetaxel (DTX), and to evaluate their properties in vitro and in vivo.

Methods: The DTX-loaded SLNs (DTX-SLNs) were prepared through an emulsion solvent evaporation method and further modified with CS or HACC (CS-DTX-SLNs or HACC-DTX-SLNs) via noncovalent interactions. The gastrointestinal (GI) stability, dissolution rate, physicochemical properties and cytotoxicities of SLNs were investigated. In addition, the GI mucosa irritation and oral bioavailability of SLNs were also evaluated in rats.

Results: The HACC-DTX-SLNs were highly stable in simulated gastric and intestinal fluids (SGF and SIF). By contrast, the CS-DTX-SLNs were less stable in SIF than in SGF. The drug dissolution remarkably increased when DTX was incorporated into the SLNs, which may be attributed to the change in the crystallinity of DTX and some molecular interactions that occurred between DTX and the carriers. The SLNs showed low toxicity in Caco-2 cells and no GI mucosa irritations were observed in rats. A 2.45-fold increase in the area under the curve of DTX was found in the HACC-DTX-SLN group compared with the DTX group after the modified SLNs were orally administered to rats. However, the oral absorption of DTX-SLN or CS-DTX-SLN group showed no significant difference compared with that of DTX group.

Conclusions: The positively charged HACC-DTX-SLNs with a stable particle size could provide the enhanced oral bioavailability of DTX in rats.     

Preparation,characterization and pharmacokinetic evaluation of rosuvastatin calcium incorporated cyclodextrin-polyanhydride nanoparticles

Abstract

Objective: The aim of the study was to formulate, cyclodextrin (CD)-polyanhydride (PA) nanoparticles (CPNs) with rosuvastatin calcium (RCa) in order to enhance the poor oral bioavailability.

Methods: CPNs containing RCa/CD complexes were prepared by a modified solvent displacement method and morphological analyses, particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), DSC, FT-IR, XRD, ¹H-NMR analyses were performed. In vitro release properties, release kinetics, cytotoxicity, in vitro permeability and pharmacokinetic studies were also studied. The stability of the formulations were evaluated during the storage period of 3?months.

Results: The physicochemical studies showed that the RCa/CD complexes were well incorporated into CPNs resulted in nanosized particles (215.22 and 189.13?nm) with homogenous size distribution (PDI: 0.203 and 0.182) with relatively high incorporation capacity (76.11 and 68.18%) for the CPN1 and CPN2 formulations respectively. Sustained release of RCa from CPNs were achieved. The cytotoxicity values showed that the safety of the formulations. According to permeability studies, pure RCa had lowest permeability data (3.08?×?10^?7?cm?s^?1 P_app value) while CPNs gained higher permeability data (1.36?×?10^?5 and 1.12?×?10^?5?cm?s^?1 P_app values) for the CPN1 and CPN2 formulations respectively. CPN2 formulation was selected for pharmacokinetic studies and analyses results demonstrated that approximately 8-fold relative oral bioavailability enhancement compared to the pure RCa was achieved.

Conclusion: Considering the analyses results of the study, CPNs can be regarded as suitable, safe, functional oral delivery systems for RCa with enhanced oral bioavailability.     

Nanosized nasal emulgel of resveratrol: preparation,optimization, in vitro evaluation and in vivo pharmacokinetic study

Abstract

Nano-emulgel has become one of the most significant controlled release systems, which has the advantages of both gels and nano-emulsions. This work aims at the formulation of nasal nano-emulgel for resveratrol, employing carbopol 934 and poloxamer 407 as the gelling agents. The optimum nano-emulsion was determined through further characterization of the selected system. The nasal nano-emulgel was prepared and tested for the in vitro release, the release kinetics, FTIR, ex vivo permeation, nasal mucosa toxicity, and in vivo pharmacokinetic study. The optimum nano-emulsion consisted of Tween 20, Capryol 90, and Transcutol at a ratio of (54.26: 23.81: 21.93%v/v), and it exhibited transmittance of 100%, resveratrol solubility of 159.9?±?6.4?mg/mL, globule size of 30.65?nm. The in vitro resveratrol released from nano-emulsion and nasal nano-emulgel was 96.17?±?4.43% and 78.53?±?4.7%, respectively. Ex vivo permeation was sustained during 12?h up to 63.95?±?4.7%. The histopathological study demonstrated that the formula is safe and tolerable to the nasal mucosa. C_max and AUC _(0–∞) of resveratrol obtained after nasal administration of nasal nano-emulgel was 2.23 and 8.05 times, respectively. Similarly, T_max was increased up to 3.67?±?0.82?h. The optimized nasal nano-emulgel established intranasal safety and bioavailability enhancement so it is considered as a well-designed system to target the brain.     

Preparation,characterization, and pharmacokinetics study of a novel genistein-loaded mixed micelles system

Genistein (GEN), is a natural dietary isoflavone, has been reported to show anticancer activities. However, its poor aqueous solubility and oral bioavailability limit its clinical application. We designed a novel genistein-loaded mixed micelles (GEN-M) system composed of Soluplus^® and Vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared by organic solvent evaporation aimed to overcome the challenges of GEN’s poor solubility and then further improve its oral bioavailability. The optimized, spherical-shaped GEN-M was obtained at a ratio of 10:1 (Soluplus^®:TPGS). The mean particle size of GEN-M was 184.7?±?2.8?nm, with a narrow polydispersity index (PDI) of 0.162?±?0.002. The zeta potential value of GEN-M was ?2.92?±?0.01?mV. The micelles solutions was transparent with blue opalescence has high the entrapment efficiency (EE) and drug loading (DL) of 97.12?±?2.11 and 3.87?±?1.26%, respectively. GEN-M was demonstrated a sustained release behavior when formed micelles shown in drug release in vitro. The solubility of GEN in water increased to 1.53?±?0.04?mg/mL after encapsulation. The permeability of GEN across a Caco-2 cell monolayer was enhanced, and the pharmacokinetics study of GEN-M showed a 2.42-fold increase in relative oral bioavailability compared with free GEN. Based on these findings, we conclude that this novel nanomicelles drug delivery system could be leveraged to deliver GEN and other hydrophobic drugs.     

In vitro and in vivo effects of morin on the intestinal absorption and pharmacokinetics of olmesartan medoxomil solid dispersions

Abstract

Purpose: In-situ evaluation to corroborate morin effects on the intestinal absorption and pharmacokinetic behavior of freeze-dried OLM-loaded solid dispersions with Caco-2 and in-vivo studies

Methods: Intestinal transport and absorption studies were examined by Caco-2 permeability, in-situ single pass perfusion and closed-loop models along with in-vivo pharmacokinetic studies to evaluate and confirm the effect of P-gp-mediated activity of morin. We evaluated the intestinal membrane damage in the presence of morin by measuring the release of protein and lactate dehydrogenase (LDH) followed by using qualitative and quantitative morphometric analysis to describe the surface characteristics of intestinal epithelium.

Results: Morin showed the highest P_eff value 13.8?±?0.34?×?10^?6?cm/s in jejunum than ileum (p?<?.01) at 100?µM with absorption enhancement of 1.31-fold together with enhanced (p?<?.01) secretory transport of 6.27?±?0.27?×?10?^?6?cm/s in Caco-2 monolayer cells. Our findings noticed 2.37 (in-situ); 2.39 (in-vivo) and 1.43 (in-situ); 1.36 (in-vivo) fold increase in AUC_0–t with elevated C_max and shortened T_max for freeze-dried solid dispersion in the presence of morin as compared to pure OLM and freeze-dried solid dispersions without morin, respectively.

Conclusions: Our study demonstrated that increased solubilization through freeze-dried OLM-loaded solid dispersion together with efflux inhibition improved intestinal permeability to one system that might lead to novel solubilization and efflux pump inhibition as a novel alternative potential to increase oral absorption and bioavailability of OLM.     

Influence of omega fatty acids on skin permeation of a coenzyme Q10 nanoemulsion cream formulation: characterization,in silico and ex vivo determination

Objective: The aim of this study was to develop a coenzyme Q10 nanoemulsion cream, characterize and to determine the influence of omega fatty acids on the delivery of coenzyme Q10 across model skin membrane via ex vivo and in silico techniques.

Methods: Coenzyme Q10 nanoemulsion creams were prepared using natural edible oils such as linseed, evening primrose, and olive oil. Their mechanical features and ability to deliver CoQ10 across rat skin were characterized. Computational docking analysis was performed for in silico evaluation of CoQ10 and omega fatty acid interactions.

Results: Linseed, evening primrose, and olive oils each produced nano-sized emulsion creams (343.93–409.86?nm) and exhibited excellent rheological features. The computerized docking studies showed favorable interactions between CoQ10 and omega fatty acids that could improve skin permeation. The three edible-oil nanoemulsion creams displayed higher ex vivo skin permeation and drug flux compared to the liquid-paraffin control cream. The linseed oil formulation displayed the highest skin permeation (3.97?±?0.91?mg/cm²) and drug flux (0.19?±?0.05?mg/cm²/h).

Conclusion: CoQ10 loaded-linseed oil nanoemulsion cream displayed the highest skin permeation. The highest permeation showed by linseed oil nanoemulsion cream may be due to the presence of omega-3, -6, and -9 fatty acids which might serve as permeation enhancers. This indicated that the edible oil nanoemulsion creams have potential as drug vehicles that enhance CoQ10 delivery across skin.     

The characterization,pharmacokinetic, and tissue distribution studies of TPGS-modified artesunate liposome in rats

Objective: The objective of this study (ARS-TPGS-Lipo) was to enhance the stability, encapsulation efficiency (EE), improve AUC, circulation time and liver targeting of ARS-TPGS-Lipo.

Methods: ARS-TPGS-Lipo was prepared by thin-film dispersion method and characterized by TEM. The EE, in vitro release and stability of ARS-TPGS-Lipo were detected by HPLC and UV. In addition to the safety evaluation, the pharmacokinetics and tissue distribution studies were also carried out after i.v. administration.

Results: The size, PDI, zeta potential, and EE of ARS-TPGS-Lipo were 126.7?±?9.9?nm, 0.182?±?0.016, ?10.1?±?1.43?mV, and 78.8?±?1.89%, respectively. ARS-TPGS-Lipo showed the slow-release effect in vitro release experiments. The AUC of ARS in the ARS-TPGS-Lipo group was 7.51 times higher than in the ARS group after i.v. administration and the circulation time was significantly prolonged. The tissue distribution results showed the components of artesunate and its metabolism DHA of the ARS-TPGS-Lipo group were much higher in liver than the ARS-Lipo group.

Conclusion: ARS-TPGS-Lipo was prepared successfully, which had the smaller vesicles size with a better PDI, better stability, higher EE, and slow-release. The results of safety evaluation indicated that ARS-TPGS-Lipo had no hematotoxicity and hepatorenal toxicity. The pharmacokinetic studies indicated ARS-TPGS-Lipo had higher AUC, longer circulation time and better liver targeting.     

Formulation,optimization, and characterization of rifampicin-loaded solid lipid nanoparticles for the treatment of tuberculosis

Abstract

Mycobacterium tuberculosis, being the causative infectious agent, is the leading cause of death worldwide amongst the infectious disease. The low bioavailability of rifampicin (RIF), one of the vital constituent of antitubercular therapy, instigates an urge to develop nanocarrier, which can prevent its degradation in the acidic pH of the stomach. Solid lipid nanoparticles (SLNs) have been proven to be promising versatile platform for oral delivery of lipophilic drugs. Therefore, the current investigation demonstrates development of RIF-loaded solid lipid nanoparticles (RIF-SLNs) using high-pressure homogenization technique by employing a three-level, three-factor Box–Behnken design. Concentration of drug, concentration of emulsifier, and homogenization pressure were selected as an independent variables, and %drug loading (%DL), %entrapment efficiency (%EE), and particle size were selected as dependent variables. The developed RIF-SLNs were characterized for particle size, polydispersity index, zeta potential, %EE, %DL, differential scanning calorimetry, X-ray diffraction, and TEM analysis. The mean diameter of RIF-SLNs was found to be 456?±?11?nm, %EE of 84.12?±?2.78%, and %DL of 15.68?±?1.52%. The in vitro lipolysis experiments revealed that RIF-SLNs stabilized using poloxamer 188, exhibited antilipolytic effect. Furthermore, the in vitro GI stability studies (at pH 1.2, pH 4.5, pH 6.8, and pH 7.4) revealed that the developed system could withstand various gastrointestinal tract media. The in vitro dissolution studies depicted biphasic drug release profile for drug-loaded SLNs revealing best fit with Weibull model. The accelerated stability studies for 6?months does not revealed any significant change in characteristics of developed RIF-SLNs.     

Enhanced oral delivery and anti-gastroesophageal reflux activity of curcumin by binary mixed micelles

The aim of this study was to improve the solubility, oral bioavailability, and anti-gastroesophageal reflux activity of curcumin (CM) by preparing two CM-loaded, novel, binary mixed micelles (CM-M). The two CM-M were prepared by ethanol thin-film hydration method. One (CM-T) was prepared using D-alpha-tocopheryl polyethylene glycol 1000 succinate and Solutol^®HS15, and the other (CM-F) was prepared using Pluronic^®F127 and Solutol^®HS15. The entrapment efficiency and drug loading of CM-T were 83.61?±?0.54% and 2.20?±?0.65%, respectively, which were lower than those of CM-F (88.66?±?0.12% and 1.47?±?0.26%, respectively). TEM results demonstrated that CM-T and CM-F were homogeneous and spherical. The permeability of CM delivered via CM-T and CM-F was enhanced across a Caco-2 cell monolayer, and CM-T and CM-F showed a 5.24- and 4.76-fold increase in relative oral bioavailability, respectively compared with free CM. In addition, the in vivo anti-gastroesophageal reflux study showed that CM-T and CM-F achieved higher anti-gastroesophageal reflux efficacy compared with free CM. Collectively, these findings were indicative of an oral micelle formulation of CM with increased solubility, oral bioavailability, and anti-gastroesophageal reflux activity.     

Hyperoside nanocrystals for HBV treatment: process optimization,in vitro and in vivo evaluation

The aim of this study was to develop hyperoside (Hyp) nanocrystals to enhance its dissolution rate, oral bioavailability and anti-HBV activity. Hyp nanocrystals were prepared using high pressure homogenization technique followed by lyophilization. A Box–Behnken design approach was employed for process optimization. The physicochemical properties, pharmacokinetics and anti-HBV activity in vivo of Hyp nanocrystal prepared with the optimized formulation were systematically investigated. Hyp nanocrystals prepared with the optimized formulation was found to be rod shaped with particle size of 384?±?21?nm and PDI of 0.172?±?0.027. XRPD studies suggested slight crystalline change in drug. Dissolution rate obtained from Hyp nanocrystals were markedly higher than pure Hyp. The nanocrystals exhibited enhanced C_max (7.42?±?0.73 versus 3.80?±?0.66?mg/L) and AUC_0???t (193.61?±?16.30 versus 91.92?±?17.95?mg·h/L) with a 210.63% increase in relative bioavailability. Hyp nanocrystals exhibited significantly greater anti-HBV activity than Hyp. These results suggested that the developed nanocrystals formulation had a great potential as a viable approach to enhance the bioavailability of Hyp.     

Development,optimization, and characterization of a novel tea tree oil nanogel using response surface methodology

Purpose: To develop and optimize nanoemulsion (NE)-based emulgel (EG) formulation as a potential vehicle for topical delivery of tea tree oil (TTO).

Methodology: Central composite design was adopted for optimizing the processing conditions for NE preparation by high energy emulsification method viz. surfactant concentration, co-surfactant concentration, and stirring speed. The optimized NE was developed into emulgel (EG) using pH sensitive polymer Carbopol 940 and triethanolamine as alkalizer. The prepared EG was evaluated for its pH, viscosity, and texture parameters, ex vivo permeation at 37?°C and stability. Antimicrobial evaluation of EG in comparison to conventional gel and pure TTO was also carried out against selected microbial strains.

Results and discussion: Optimized NE had particle size and zeta potential of 16.23?±?0.411?nm and 36.11?±?1.234?mV, respectively. TEM analysis revealed the spherical shape of droplets. The pH of EG (5.57?±?0.05?) was found to be in accordance with the range of human skin pH. EG also illustrated efficient permeation (79.58?μL/cm²) and flux value (J_SS) of 7.96?μL cm²/h through skin in 10?h. Viscosity and texture parameters, firmness (9.3?±?0.08?g), spreadability (2.26?±?0.06?mJ), extrudability (61.6?±?0.05?mJ), and adhesiveness (8.66?±?0.08?g) depict its suitability for topical application. Antimicrobial evaluation of EG with same amount of TTO as conventional gel revealed broader zones of growth inhibitions against all the selected microbial strains. Moreover, EG was also found to be nonirritant (PII 0.0833). These parameters were consistent over 90 d.

Conclusion: TTO EG turned out to be a promising vehicle for the topical delivery of TTO with enhanced therapeutic efficacy.     

Nanosuspension of efavirenz for improved oral bioavailability: formulation optimization,in vitro,in situ and in vivo evaluation

Context: Nanosuspensions (NSs) of poorly water-soluble drugs are known to increase the oral bioavailability.

Objectives: The purpose of this study was to develop NS of efavirenz (EFV) and to investigate its potential in enhancing the oral bioavailability of EFV.

Materials and methods: EFV NS was prepared using the media milling technique. The Box–Behnken design was used for optimization of the factors affecting EFV NS. Sodium lauryl sulfate and PVP K30 were used to stabilize the NS. Freeze-dried NS was completely re-dispersed with double-distilled filtered water.

Results: Mean particle size and zeta potential of the optimized NS were found to be 320.4?±?3.62?nm and –32.8?±?0.4 mV, respectively. X-ray diffraction and differential scanning calorimetric analysis indicated no phase transitions. Rate and extent of drug dissolution in the dissolution medium for NS was significantly higher compared to marketed formulation. The parallel artificial membrane permeability assay revealed that NS successfully enhanced the permeation of EFV. Results of in situ absorption studies showed a significant difference in absorption parameters such as K_a, t_1/2 and uptake percentages between lyophilized NS and marketed formulation of EFV. Oral bioavailability of EFV in rabbits resulting from NS was increased by 2.19-fold compared to the marketed formulation.

Conclusion: Thus, it can be concluded that NS formulation of EFV can provide improved oral bioavailability due to enhanced solubility, dissolution velocity, permeability and hence absorption.     

Enhancement of oral bioavailability of anti-HIV drug rilpivirine HCl through nanosponge formulation*

Objective: To synthesize β cyclodextrin nanosponges using a novel and efficient microwave mediated method for enhancing bioavailability of Rilpivirine HCl (RLP).

Significance: Belonging to BCS class II RLP has pH dependent solubility and poor oral bioavailability. However, a fatty meal enhances its absorption hence the therapy indicates that the dosage form be consumed with a meal. But then it becomes tedious and inconvenient to continue the therapy for years with having to face the associated gastric side effects such as nausea.

Method: Microwave synthesizer was used to mediate the poly-condensation reaction between β-cyclodextrin and cross-linker diphenylcarbonate. Critical parameters selected were polymer to cross-linker ratio, Watt power, reaction time and solvent volume. Characterization studies were performed using FTIR, DSC, SEM, ¹H-NMR and PXRD. Molecular modeling was applied to confirm the possibility of drug entrapment. In vitro drug dissolution followed by oral bioavailability studies was performed in Sprawley rats. Samples were analyzed using HPLC.

Results: Microwave synthesis yields para-crystalline, porous nanosponges (～205?nm). Drug entrapment led to enhancement of solubility and a two-fold increase in drug dissolution (P?C_max and AUC_0-∞ increases significantly (C_max of NS～ 586?±?5.91?ng/mL; plain RLP ～310?±?5. 74?ng/mL).

Conclusion: The approach offers a comfortable dosing zone for AIDs patients, negating the requirement of consuming the formulation in a fed state due to enhancement in drugs’ oral bioavailability.     

Chlorogenic acid stabilized nanostructured lipid carriers (NLC) of atorvastatin: formulation,design and in vivo evaluation

The present work was aimed at developing an optimized oral nanostructured lipid carrier (NLC) formulation of poorly soluble atorvastatin Ca (AT Ca) and assessing its in vitro release, oral bioavailability and pharmacodynamic activity. In this study, chlorogenic acid, a novel excipient having synergistic cholesterol lowering activity was utilized and explored in NLC formulation development. The drug-loaded NLC formulations were prepared using a high pressure homogenization technique and optimized by the Box-Behnken statistical design using the Design-Expert software. The optimized NLC formulation was composed of oleic acid and stearic acid as lipid phase (0.9% w/v), poloxamer 188 as surfactant (1% w/v) and chlorogenic acid (0.05% w/v). The mean particle size, polydispersity index (PDI) and % drug entrapment efficiency of optimized NLC were 203.56?±?8.57?nm, 0.27?±?0.028 and 83.66?±?5.69, respectively. In vitro release studies showed that the release of drug from optimized NLC formulations were markedly enhanced as compared to solid lipid nanoparticles (SLN) and drug suspension. The plasma concentration time profile of AT Ca in rats showed 3.08- and 4.89-fold increase in relative bioavailability of developed NLC with respect to marketed preparation (ATORVA® tablet) and drug suspension, respectively. Pharmacodynamic study suggested highly significant (**p?0.01) reduction in the cholesterol and triglyceride values by NLC in comparison with ATORVA® tablet. Therefore, the results of in vivo studies demonstrated promising prospects for successful oral delivery of AT Ca by means of its chlorogenic acid integrated NLC.