Self-nanoemulsifying drug delivery system of docosahexanoic acid: development,in vitro,in vivo characterization

Context: Docosahexanoic acid (DHA) is an essential omega-3 fatty acid for normal brain development and its use has increased considerably in recent years.

Objective: The aim of this study is to develop and evaluate self-nanoemulsifying drug delivery systems (SNEDDS) of DHA for improved palatability, dispersibility and bioavailability.

Methods: The SNEDDS were prepared and evaluated for miscibility, employing different combinations of olive oil and soyabean oil as oil phase, Span 80, Span 20, soya phosphatidylcholine, Labrafil M 1944 CS as surfactants while Tween 80, PEG 400, Cremophor RH40 and propylene glycol as cosurfactants. Thermodynamically stable SNEDDS were characterized for dispersibility, self-emulsification time, droplet size, zeta potential along with sensory analysis. The optimized formulation was subjected to ex vivo and in vivo evaluation such as intestinal permeability, memory performance test, brain concentration and histopathology studies.

Results: The optimized SNEDDS formulation showed emulsification time of 27?±?4.7?s with droplet size of 17.6?±?3.5?nm and zeta potential of??37.6?±?0.5?mV. Intestinal absorption study depicted 18.3%, 21.5%, 41.5%, 98.7% absorption of DHA with SNEDDS-based formulation in comparison to 8.2%, 15.1%, 28.8%, 46.1% absorption of DHA with oil-based marketed formulation after 0.5, 1, 2 and 4?h. DHA concentration in brain homogenate was found to be increased to 2.6-fold in comparison to DHA-marketed formulation. This could be ascribed to enhanced dispersibility and bioavailability of DHA from nanosized formulation.

Conclusion: The developed formulation led to enhanced dispersibility and bioavailability of DHA due to the formation of nanodroplets.     

Fabrication of solid lipid nanoparticles of lurasidone HCl for oral delivery: optimization,in vitro characterization,cell line studies and in vivo efficacy in schizophrenia

Objective: The aim of the present investigation was to investigate the efficacy of solid lipid nanoparticles (SLNs) to enhance the absorption and bioavailability of lurasidone hydrochloride (LH) following oral administration.

Methods: The LH loaded SLNs (LH-SLNs) were prepared by high pressure homogenization (HPH) method, optimized using box Behnken design and evaluated for particle size (PS), entrapment efficiency (EE), morphology, FTIR, DSC, XRD, in vitro release, ex vivo permeation, transport studies across Caco-2 cell line and in vivo pharmacokinetic and pharmacodynamic studies.

Results: The LH-SLNs had PS of 139.8?±?5.5?nm, EE of 79.10?±?2.50% and zeta potential of ?30.8?±?3.5?mV. TEM images showed that LH-SLNs had a uniform size distribution and spherical shape. The in vitro release from LH-SLNs followed the Higuchi model. The ex vivo permeability study demonstrated enhanced drug permeation from LH-SLNs (>90%) through rat intestine as compared to LH-suspension. The SLNs were found to be taken up by energy dependent, endocytic mechanism which was mediated by clathrin/caveolae-mediated endocytosis across Caco-2 cell line. The pharmacokinetic results showed that oral bioavailability of LH was improved over 5.16-fold after incorporation into SLNs as compared to LH-suspension. The pharmacodynamic study proved the antipsychotic potential of LH-SLNs in the treatment of schizophrenia.

Conclusion: It was concluded that oral administration of LH-SLNs in rats improved the bioavailability of LH via lymphatic uptake along with improved therapeutic effect in MK-801 induced schizophrenia model in rats.     

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.     

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.     

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.     

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.     

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.     

Development of isradipine loaded self-nano emulsifying powders for improved oral delivery: in vitro and in vivo evaluation

Isradipine (ISR) is a potent calcium channel blocker with low oral bioavailability due to low aqueous solubility, extensive first-pass metabolism and P-glycoprotein (P-gp)-mediated efflux transport. In the present investigation, an attempt was made to develop isradipine-loaded self-nano emulsifying powders (SNEP) for improved oral delivery. The liquid self-nano emulsifying formulations (L-SNEF/SNEF) of isradipine were developed using vehicles with highest drug solubility, i.e. Labrafil® M 2125 CS as oil phase, Capmul® MCM L8 and Cremophor® EL as surfactant/co-surfactant mixture. The developed formulations revealed desirable characteristics of self-emulsifying system such as nano-size globules ranging from 32.7 to 40.2?nm, rapid emulsification (around 60?s), thermodynamic stability and robustness to dilution. The optimized stable self-nano emulsifying formulation (SNEF₂) was transformed into SNEP using Neusilin US2 (SNEP_N) as adsorbent inert carrier, which exhibited similar characteristics of liquid SNEF. The solid state characterization of SNEP_N by Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopic studies shown transformation of crystalline drug into amorphous form or molecular state without any chemical interaction. The in vitro dissolution of SNEP_N compared to pure drug was indicated by 18-fold increased drug release within 5?min. In vivo pharmacokinetic studies in Wistar rats showed significant improvement of oral bioavailability of isradipine from SNEP_N with 3- and 2.5-fold increments in peak drug concentration (C_max), area under curve (AUC_0–∞) compared to pure isradipine. In conclusion, these results signify the improved oral delivery of isradipine from developed SNEP.     

Preparation and in vitro/in vivo evaluation of azilsartan osmotic pump tablets based on the preformulation investigation

The objective of this study was to design and evaluate azilsartan osmotic pump tablets. Preformulation properties of azilsartan were investigated for formulation design. Azilsartan osmotic pump tablets were prepared by incorporation of drug in the core and subsequent coating with cellulose acetate and polyethylene glycol 4000 as semi-permeable membrane, then drilled an orifice at the center of one side. The influence of different cores, compositions of semipermeable membrane and orifice diameter on azilsartan release were evaluated. The formulation of core tablet was optimized by orthogonal design and the release profiles of various formulations were evaluated by similarity factor (f₂). The optimal formulation achieved to deliver azilsartan at an approximate zero-order up to 14?h. The pharmacokinetic study was performed in beagle dogs. The azilsartan osmotic pump tablets exhibited less fluctuation in blood concentration and higher bioavailability compared to immediate-release tablets. Moreover, there was a good correlation between the in vitro dissolution and in vivo absorption of the tablets. In summary, azilsartan osmotic pump tablets presented controlled release in vitro, high bioavailability in vivo and a good in vitro-in vivo correlation.     

In situ intestinal permeability and in vivo absorption characteristics of olmesartan medoxomil in self-microemulsifying drug delivery system

To characterize the intestinal absorption behavior of olmesartan medoxomil (OLM) and to evaluate the absorption-improving potential of a self-microemulsifying drug delivery system (SMEDDS), we performed in situ single-pass intestinal perfusion (SPIP) and in vivo pharmacokinetic studies in rats. The SPIP study revealed that OLM is absorbed throughout whole intestinal regions, favoring proximal segments, at drug levels of 10–90 μM. The greatest value for effective permeability coefficient (P_eff) was 11.4?×?10^?6 cm/s in the duodenum (90 μM); the lowest value was 2.9?×?10^?6 cm/s in the ileum (10 μM). A SMEDDS formulation consisting of Capryol 90, Labrasol, and Transcutol, which has a droplet size of 200?nm and self-dispersion time of 21 s, doubled upper intestinal permeability of OLM. The SMEDDS also improved oral bioavailability of OLM in vivo: a 2.7-fold increase in the area under the curve (AUC) with elevated maximum plasma concentration (C_max) and shortened peak time (T_max) compared to an OLM suspension. A strong correlation (r²?=?0.955) was also found between the in situ jejunal P_eff and the in vivo AUC values. Our study illustrates that the SMEDDS formulation holds great potential as an alternative to increased oral absorption of OLM.     

Development and evaluation of novel microemulsion based oral formulations of 5-fluorouracil using non-everted rat intestine sac model

Oral formulations of 5-fluorouracil (5-FU) with enhanced bioavailability were developed using microemulsion as a drug carrier system. The formulations were evaluated for drug content, physicochemical characteristics such as globule size, zeta potential, viscosity, stability and permeation characteristics. Ex vivo permeation studies were performed using non-everted rat intestinal sac technique. Results of the ex vivo permeation studies revealed that from aqueous solution only 25.08% drug was permeated, whereas, the optimized microemulsion formulation showed 97.5% drug permeation in 8?h, suggesting, approximately, four times enhancement in the drug permeability. Also a 7-fold increase in the flux of drug was observed from microemulsion formulation when compared with the aqueous solution. Further, in vivo pharmacodynamic studies were carried to check the therapeutic efficacy against benzo(a)pyrene [B(a)P]-induced stomach tumors in albino mice (Balb/C strain). The treatment of mice with 5-FU and microemulsion (5-FU II), after the last dose of B(a)P i.e. during the initiation period, resulted in 25% and 67% reduction in tumor incidence, respectively suggesting significant enhancement in the bioavailability and therapeutic efficacy of 5-FU when it was formulated as a microemulsion. These promising results suggest that microemulsion formulation of 5-FU may be used for the treatment of human cancers after pharmacokinetic and clinical evaluation.     

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state

Objective: The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs).

Methods: The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control.

Results: The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5?min. Pharmacokinetic study showed that the AUC_(0–∞) and C_max for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption.

Conclusion: It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.     

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.     

Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits

Objective: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability.

Methods: Liquid SNEDDS (L-SNEDDS) composed of Capryol? 90 (oil), Cremophor^® RH40 (surfactant), and Transcutol^® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits.

Results: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in t_max, AUC_(0–12), and AUC_(0–∞) at p?<?.05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product.

Conclusions: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.     

Ceramide–palmitic acid complex based Curcumin solid lipid nanoparticles for transdermal delivery: pharmacokinetic and pharmacodynamic study

Curcumin is an important anti-inflammatory natural compound with low bioavailability which is due to poor solubility and absorption. Solid lipid nanoparticles (SLNs) loaded with Curcumin were formulated and evaluated for physical parameters and in vitro/ex vivo permeation. Further the optimised SLN was assessed for pharmacokinetic/pharmacodynamic considerations. SLNs were formulated by emulsion-solvent evaporation technique and evaluated for physical properties and in vitro drug release. Selected SLNs were evaluated for stability and then characterised for pharmacokinetic parameters and anti-inflammatory activity with reference to a commercial formulation. Spherical SLNs were obtained in the size range of 102–156 nm with negative potential. C-SLN category has shown highest entrapment efficiency. The order of drug release was S-SLN > G-SLN > C-SLN. Selected SLN formulation C-SLN-3 has shown good stability under various conditions. C-SLN-3 has demonstrated highest drug permeation through human skin and 171.623 mg drug content permeated in 24 h. It has also shown lowest lag time 0.375 h. Similarly, it has shown maximum value for C_max in in vivo determination and increased the bioavailability upto 68.12%. C-SLN-3 provided 90.75% edema inhibition in 6 h. Present study shows that nature of lipids and its physical-chemical properties are critical for SLN formulation and can be used for designing better drug delivery systems with optimum transdermal permeation.     

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization,in vitro and in vivo pharmacokinetic studies

Objectives: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS).

Methods: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3² factorial design was done using Polyox WSR 303 (X₁) and HPMC K₄M (X₂) as independent variables and cumulative percentage drug released at 6?h (Q6h) as dependent variable.

Results: Optimized formulation showed floating lag time of 4–5 s, floated for more than 12?h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6?h. In vivo pharmacokinetic studies in rabbits showed C_max of 189.96?±?13.04?ng/mL and T_max of 4?±?0.35?h for GFDDS. The difference for AUC_(0–T) and AUC_(0–∞) between the test and reference formulation was statistically significant (p > 0.05). AUC_(0–T) and AUC_(0–∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively.

Conclusion: GFDDS provided prolonged gastric residence and showed significant increase in bi oavailability of baclofen.     

Development of self-microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride

The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Berberine hydrochloride (BBH), an important bioactive compound from Chinese Medicines with poor water solubility. Pseudoternary phase diagrams were constructed using oil, surfactant and co-surfactant types to identify the efficient self-microemulsification region. SMEDDS was characterized by morphological observation, droplet size, zeta-potential determination, stability, in vitro release and in vivo bioavailability study. The optimal formulation with the best self-microemulsifying and solubilization ability consisted of 40% (w/w) of ethyl linoleate and oleic acid (2:1), 35% (w/w) Tween-80 and 25% (w/w) glycerol. The SMEDDS of BBH could exhibit good stability. In vitro release test showed a complete release of BBH from SMEDDS was in 5 h. In vivo results indicated that the peak plasma concentration (C_max) and the area under the curve (AUC_{0→12 h}) of SMEDDS of BBH were higher than the commercial tablet by 163.4% and 154.2%, respectively. The relative bioavailability of SMEDDS of BBH was enhanced about 2.42-fold compared with the commercial tablet in rats. The study confirmed that the SMEDDS formulation could be used as a possible alternative to traditional oral formulations of BBH to improve its bioavailability.     

In vitro–in vivo correlation study for the dermatopharmacokinetics of terbinafine hydrochloride topical cream

Background: To investigate the relationship between dermatopharmacokinetic (DPK) tape stripping from in vitro and in vivo using 1% terbinafine hydrochloride topical cream as the model formulation.

Methodology: In vitro and in vivo tape strippings were conducted on separated pig ear skin used as a biological membrane for franz diffusion cell testing and the non-hairy skin area at the ventral forearms of healthy volunteers, respectively. Terbinafine (1%) topical cream was applied to the skin for 0.5, 2, and 4?h. The drug profiles of terbinafine across the stratum corneum were determined immediately (time 0?h), and at 0.5, 1, 2, and 4?h after removing the formulation. The amounts of terbinafine were analyzed by a validated high-performance liquid chromatography-ultraviolet method. The area under the curve (AUC) and the maximum amounts of terbinafine absorption (Q_max) were obtained from pharmacokinetic software. Partition coefficient (K_SC/veh) and diffusion parameter (D/L²) were derived from the Fick’s second law equation. During the schedule time of 8?h, the deviations of in vitro and in vivo data were 6.61 and 30.46% for AUC and Q_max, respectively. There was insignificant difference of the K_SC/veh and the D/L² between excised pig ear and human skin. In addition, K_SC/veh and D/L² at T_max of 2?h were used to predict the AUC presented the value of 4.7481 %h whereas the true value calculated from pharmacokinetic software provided the value of 5.9311 %h differing from each other in approximate of 20%.

Conclusions: In vitro tape stripping using the separated pig ear skin as a viable membrane of the franz diffusion cell testing demonstrates the potential to represent in vivo tape stripping in human for topical bioavailability/bioequivalence study of terbinafine hydrochloride 1% topical cream.     

Design and optimization of gastric floating sustained-release mini-tablets of alfuzosin hydrochloride based on a factorial design: in vitro/in vivo evaluation

Abstract

The purpose of this research was to develop multiple-unit gastric floating mini-tablets and to evaluate the possibility of using these mini-tablets as a delivery system to improve the drug absorption for drugs with a narrow absorption window. Mini-tablets were prepared using hydroxypropyl methylcellulose (HPMC K100M) and carbopol 971P as release retarding agents and sodium bicarbonate (NaHCO₃) as gas-forming agent. The properties of the prepared mini-tablets in terms of floating characteristic parameters and in vitro release were evaluated. Furthermore, in vivo gastric retention study in rats and in vivo pharmacokinetic study in rabbits of the optimized formulation were performed. The optimized mini-tablets containing 45% HPMC K100M, 15% stearyl alcohol, 13% carbopol 971P, and 12% NaHCO₃ were found to float immediately within 1?min and duration more than 9?h. The in vivo gastric retention study results indicated that the mini-tablets could retain in the stomach for more than 6.67?h. Furthermore, the AUC_0?t of the floating mini-tablets (6849.83?±?753.80?h ng·mL^?1) was significantly higher than that of marketed sustained-release tablets XATRAL®XL (4970.16?±?924.60?h ng·mL^?1). All these results illustrated that the gastric floating mini-tablets might be a promising drug delivery system for drugs with a narrow absorption window.