Solvent Diffusion Evaporation Method Research Articles

Chrysin-loaded Soluplus-TPGS mixed micelles: Optimization, characterization and anticancer activity against hepatocellular carcinoma cell line

Chrysin is a natural flavonoid found in various plants, and it has shown potential therapeutic benefits such as anti-inflammatory, antioxidant, and anticancer properties. However, its clinical application is limited due to poor solubility and low bioavailability. Mixed micelles can help overcome these problems. This study focuses on preparation of Chrysin-loaded mixed micelles with the help of solvent diffusion evaporation method. Soluplus and TPGS were the main components of the formulation, and their proportions were optimized with the help of the central composite design matrix. Thirteen batches were constructed to optimize the mixed micelle formulation based on different Soluplus: Chrysin ratios and TPGS percentages. Response surface methodology and various models were employed to analyze micellar size, size distribution, encapsulation efficiency, and drug loading. The optimized formulation, CHR-MM1, exhibited a particle size of 132.2 ± 7.9 nm, encapsulation efficiency of 98.01 ± 2.27 %, and a zeta potential of −2.10 mV. TEM images revealed that the micelles were spherical in shape. Characterization studies, including FTIR and X-ray diffraction, confirmed the successful encapsulation of Chrysin in an amorphous form within the mixed micelles. The in vitro release studies demonstrated a sustained release behavior in both acidic and neutral pH conditions. The Korsmeyer-Peppas model best described the drug release kinetics. Cellular uptake studies using fluorescence microscopy revealed enhanced internalization of the mixed micelles into Hep G2 cells. Moreover, MTT assays indicated a concentration- and time-dependent cytotoxicity of Chrysin-loaded mixed micelles against Hep G2 cells, outperforming free Chrysin. The flow cytometry analysis results suggested an enhanced apoptotic activity of Chrysin in the mixed micelles as compared to free drug. This study provides a promising strategy for improving the solubility, cellular uptake, and cytotoxicity of Chrysin. Therefore, our results point to the potential of Chrysin-loaded mixed micelles to serve as a therapeutic option for hepatocellular carcinoma.

Formulation, optimization and characterization of raloxifene hydrochloride loaded PLGA nanoparticles by using Taguchi design for breast cancer application.

Multidrug resistance in breast cancer and the associated side-effects of anticancer therapies are significant hurdles in chemotherapy-based treatment. Biodegradable polymeric nano-based targeted drug delivery technologies showed tremendous advantages in targeted local delivery with limited off-targeted side effects. Therefore, there is a persistent need to develop targeted nanomedicine systems for treatment of breast cancer. The current research attempted to develop poly (lactic-co-glycolic acid) nanoparticles loaded with raloxifene by modified emulsification solvent diffusion evaporation method to improve oral bioavailability by using Taguchi design. It was observed that the optimized formulation (1:4 drug to polymer ratio) poly (lactic-co-glycolic acid) showed a mean particle size and Polydispersity index of 218 ± 23.7nm and 0.231 ± 0.04, respectively. The entrapment efficiency was found to be 82.30% ± 1.02%. In vitro drug delivery was found to be 92.5% ± 1.48% in 40 h. The nanoparticles were to remain stable at 2°C-8°C even after 30 days. Differential scanning calorimetry and Fourier transform infrared spectroscopy characterization techniques showed that there was no interaction between the drug and excipient. Stability studies indicate that polymeric nanoparticles were stable at 2°C-8°C after 6months. Raloxifene nanoparticles may be the most potent targeting moieties to treat highly invasive and metastatic MCF-7 breast cancer cells.

Development and Characterization of Floating Microspheres of Dexrabeprazole Sodium for the Treatment of Peptic Ulcer

Dexrabeprazole sodium (DEX) is R (+)-isomer of rabeprazole. DEX has been used in the treatment of gastroesophageal reflux disease by suppressing gastric acid secretion. It acts as a proton pump inhibitor of the H+ /K+ ATPase enzyme. The purpose of this research was to prepare a floating drug delivery system of DEX. The floating microspheres can be prepared for the improvement of absorption and bioavailability of DEX by retaining the system in the stomach for prolonged period of time. Floating microspheres of DEX were prepared using different polymers like ethyl cellulose, hydroxy propyl methyl cellulose by solvent diffusion-evaporation method. The drug to polymer ratio used to prepare the different formulations was 1:7. The prepared floating microspheres were characterized for shape and surface morphology, size, percent drug loading, floating behavior, percentage yield and in vitro drug release. Formulation F1 showed good results with respect to the various evaluation parameters among various batches (F1-F8). The particle size increased with increase in polymer concentration. The drug entrapment efficiency was increased with increase in concentration of polymers. Buoyancy and the in vitro drug release decreased with respect to increase in concentration of polymers. In-vitro release and release kinetics data was subjected to different dissolution models. It was concluded that developed floating microspheres of DEX offers a suitable and practical approach for prolonged release of drug over an extended period of time and thus oral bioavailability, efficacy and patient compliance is improved.
 Keywords: Dexrabeprazole sodium, Floating drug delivery system, Microspheres, Solvent diffusion-evaporation method

Formulation and Evaluation of Zolmitriptan Loaded Nano-Structured Lipid Carriers for Effective Treatment in Migraine

Objective: Zolmitriptan is a BCS class II drug having low solubility and poor bioavailability by formulating Nanostructured lipid carriers that will sustain the release of the drug for a longer period which leads to reduced dose and frequency of dose.
 Method: Zolmiptriptan-loaded Nanostructured lipid carriers were fabricated by a solvent diffusion evaporation method. The formulation parameters like the selection of solid (Precirol ATO 5) and liquid lipid (Miglyol 812), solid to liquid lipid ratio (3:1), drug: solid lipid ratio (1:4), the ratio of the organic phase (Acetone: Ethanol, 1:1), the concentration of surfactant (1.5% Tween 80) and temperature (70 °C) of secondary phase were optimized. NLC dispersion was finally lyophilized and converted into a tablet. A stability study of freeze-dried NLCs tablet was performed according to ICH Q1A (R2) guidelines.
 Result: Optimized formulation contained Particle size 11.39 ± 0.85 nm, Zeta potential -38.30 and %EE 76.56 ± 0.12. Characterization was performed by TEM and FTIR analysis. The residual solvent test confirms the concentration of organic solvents was in the acceptable range as per ICH guidelines. In-vitro drug permeation study of NLCs shows 88.91±0.238 % drug release while pure drug suspension shows 58.9±0.578 % drug release after 12 hrs. 
 Conclusion: Zolmitriptan-loaded NLCs show better absorption as compared to pure drug suspension which indicates prolonged release of medicament which may reduce dose or dose frequency.

Quality by Design (QbD) driven Systematic Development of Nano-lipoidal Carrier of Poorly Water Soluble Anti-tubercular agent-Rifabutin.

ABSTRACT In the present research work, Rifabutin, drug used for tuberculosis infection, was encapsulated in lipidic nanoparticles with a view to develop a sustained release oral formulation. The nanocarrier loaded rifabutin, prepared by the solvent diffusion evaporation method and evaluated for its physical (nanoparticles size distribution) and chemical (drug content) stability. To optimize the identified independent variables, Box-Behnken Design (BBD) was utilized effectively. The result showed that a size of optimized formulation was found to be 315 ± 10.96 nm and PDI of 0.310 ± 0.05; the encapsulation efficiency was found to be (66.3 ± 3.85). On encapsulation, the nanocarrier showed amorphous pattern of drug studied using X-ray Diffractometric analysis. The release pattern of rifabutin loaded nanocarrier revealed that it represents the sustained release kinetics in comparison to plain drug. Thus, nanotechnology-based formulation may reduce frequency, provide medications more efficaciously, ultimately reducing patient avoidance.

Predicting pharmacokinetic parameters by convolution: An in vitro approach for investigating bifunctional capsulated dosage form

The present research was aimed to mathematically predict the pharmacokinetic parameters by convolution of the optimized bifunctional capsulated dosage form containing floating microspheres of atorvastatin calcium (ATC) and immediate release (IR) granules of amlodipine besylate (AMB). Solvent diffusion evaporation method was used for optimizing the floating microspheres of ATC using Eudragit RSPO and HPMC 3K and assessed for pharmaceutical parameters. The floating microspheres were incorporated along with IR granules of AMB to obtain a bifunctional capsulated dosage form. The in vitro dissolution data was subjected to mathematical convolution for prediction of pharmacokinetic parameters and hence IVIVC; and compared with the in vivo literature data. The spherical hollow floating microspheres of AMB showed high encapsulation efficiency (79.88±1.50%). The in vitro drug release showed a biphasic mode having rapid release initially, followed by sustained release for 8 hour and followed Higuchi kinetics. The optimized formulation was combined with IR granules of AMB. The in vitro simultaneous drug release from the capsulated formulation exhibited sustained drug release of 80.76±1.00 % in 8 h for ATC and 97.75 ± 0.65% in 25 min from IR granules of AMB. The predicted Cmax and AUC were 3.41 ± 0.34 ng/ml and 80.916 ± 12 ng.h/ml for ATC. Bifunctional capsulated dosage form of ATC and AMB with good buoyancy and dual release were developed. The pharmacokinetic parameters of the bifunctional dosage form were predicted that concluded sustained drug release of ATC.

Floating Microspheres Based Nizatidine Gastro Retentive Formulation to Control the Release of Drug

Present research aimed at formulation development and characterization of the floating drug delivery system of Nizatidine, a H2-receptor antagonist, widely prescribed in gastric ulcers and duodenal ulcers. Nizatidine loaded floating microspheres were developed by the solvent diffusion-evaporation method using polymers hydroxypropyl methylcellulose (HPMC) and microcrystalline cellulose (MCC) to prolong the gastric retention time of the drug for the therapeutic management of gastric disorders like ulcers. Further, the developed formulations were characterized for percentage yield, drug entrapment, floating behavior, shape and surface morphology, in vitro drug release, determination of particle size and Zeta potential, in vitro stability studies, and antimicrobial activity. The percentage yield of the different formulation was found to be a range of 75.65– 81.25%, drug entrapment efficacies of different formulations were in the range of 65.56- 75.65% w/w, formulation F4 of floating microsphere was found to be 178.5 nm, Zeta potential of optimized formulation F4 of floating microsphere was found -33.6 Mv, Surface morphology of formulation examines at two different magnification 55X which illustrate the smooth surface of Microspheres. The in vitro drug release pattern of Nizatidine loaded optimized floating microsphere was subjected to the goodness of fit test by linear regression analysis, and it was observed that ‘r’ values of microsphere were maximum for zero-order, i.e., 0.969 hence indicating drug release from formulations follow zero-order kinetics with non-fickian diffusion mechanism which in turn prolonged drug release. The antimicrobial activity of the optimized formulation showed clear fluid with no development of turbidity. It inferred better clearance from infection than plain drug solution at the same doses. Floating microspheres of Nizatidine as gastro retentive dosage forms precisely control the release rate of Nizatidine to a peculiar site and expedite an immense impact on health care.

Pharmacokinetics, Biodistribution and Toxicity Studies for Nanocarrier of Antitubercular Agent- Rifabutin

Introduction: Rifabutin (RFB) is a lipophilic, semi-synthetic antibiotic given for the treatment of atypical mycobacterial infections along with drug susceptible tuberculosis infections. The major challenges in its usage include low oral bioavailability (~20%) mainly due to its low solubility and extensive first pass metabolism. Aim: The present study aims to explore the pharmacokinetics, biodistribution and toxicity of nanocarrier of RFB. Materials and Methods: An experimental animal study was carried out in Institute for Industrial Research and Toxicology, Ghaziabad, Uttar Pradesh, India. RFB nanocarriers were formulated by using solvent diffusion evaporation method with minor modifications and characterised for its physicochemical properties by using various techniques like Field Emission Scanning Electron Microscopy (FESEM), Dynamic Light Scattering (DLS) method, High-Performance Liquid Chromatography (HPLC), X-ray Diffractometry (XRD), in-vitro release study etc. Further nanocarriers were also studied for in-vivo analysis using pharmacokinetics, biodistribution and toxicity studies. GraphPad Prism Software (Version 5.02) was used for the statistical analysis. Results: Nanocarriers of RFB were developed and evaluated for its safety and efficacy. The results of evaluation of nanocarrier for physical and chemical attributes revealed that its particle size obtained was 305-325 nm with low Poly Dispersity Index (PDI) of 0.26-0.36 and the high drug encapsulation efficiency (62.45-70.15%). The nanocarrier formulation showed a sustained release pattern in Simulated Intestinal Fluid (SIF) upto 48 hours and in Physiological Buffer System (PBS) upto 7 days. The in-vivo study showed that the nano-lipoidal drug has significant higher Tmax and Cmax plasma value with higher t1/2(h) values in comparison to plain drug. Moreover, the slow elimination rate (Kel) resulted in significant (p<0.001) prolonged half-life (t1/2), which was many fold higher than the plain drug. No significant change was observed in haematological and liver enzyme profile of rats in plain drug and drug with nano-lipoidal carrier. Nanocarriers showed that there was an increase cell survival rate in MTT assay as compared to normal drug. Conclusion: By using nanotechnology based formulations, dose and dosing frequency of drug administration can be reduced. Thus, RFB drug can be administered in more efficacious manner reducing its toxic side effects, which ultimately improves patient compliance.

Quality by design-enabled development and characterisation of nanocarrier of azithromycin

Background: Azithromycin is an antibiotic, which is preferentially used in the treatment of Mycobacterium Avium Complex (MAC). However, it suffers from drawbacks such as poor solubility, poor bioavailability and adverse effects such as gastrointestinal intolerance, resulting into poor patient compliance. Aim: To develop and optimize lipid based nanocarriers of Azithromycin using QbD approach. Methods: Nanostructured lipid carrier (NLC) were developed by using the solvent diffusion evaporation method with view to release drug in a sustained release manner. The initial factors screening and risk assessment done through Taguchi design and afterwards the optimization of independent factors along with final outcome i.e. critical quality attributes (CQAs) were done by Box Behnken Design (BBD). Results: The results of Physicochemical analysis revealed that a size of optimized Azithromycin Nanocarrier is 346.18 ± 12.90 nm and Polydispersity Index (PDI) of 0.21 ± 0.08; the entrapment efficiency (% EE) of 68.45 ± 4.42% w/w and drug loading of 47.16 ± 0.80 % w/w. The in vitro release study of the Azithromycin Nanocarrier showed a biphasic drug release pattern in simulated intestinal fluid (SIF) nanocarrier shown sustained release kinetics up to 02 days and similar pattern shown in Phosphate buffer saline (PBS) pH 7.4, release kinetics shows initial burst release upto 12 hr followed by sustained release upto 04 days in PBS, pH7.4. The sustained release pattern of the formulation is beneficial to improve the oral bioavailability of the drug. Conclusion: Thus, present research leads to development of formulations which may reduce dose of drug, dosing frequency and enhanced efficaciously of drug. Ultimately it reducing the patient avoidance in treatment.

Formulation Development and Evaluation of Floating Microsphere of Famotidine for the Treatment of Peptic Ulcer

The purpose of this research was to prepare a floating drug delivery system of famotidine. The floating microspheres can be prepared for the improvement of absorption and bioavailability of famotidine by retaining the system in the stomach for prolonged period of time. Floating microspheres of famotidine were prepared using different polymers like ethyl cellulose, hydroxy propyl methyl cellulose by solvent diffusion-evaporation method. The microspheres had smooth surfaces with free-flowing and good-packing properties. The yield of the microspheres was up to 73.32±0.14% and ethyl cellulose microspheres entrapped the maximum amount of the drug. Scanning electron microscopy confirmed their hollow structures with sizes in 331.6 nm. The prepared microspheres exhibited prolonged drug release and Percentage buoyancy was found to 73.25±0.23. The formulated batches were evaluated for percentage yield, particle size measurement, flow properties, percent entrapment efficiency, swelling studies. The formulations were subjected to stability studies and In-vitro release and release kinetics data was subjected to different dissolution models. It was concluded that developed floating microspheres of famotidine offers a suitable and practical approach for prolonged release of drug over an extended period of time and thus oral bioavailability, efficacy and patient compliance is improved.
 Keywords: Famotidine, Solvent diffusion evaporation method, Ethyl cellulose, Hydroxyl propyl methyl cellulose

Probing the effect of various lipids and polymer blends on clopidogrel encapsulated floating microcarriers.

Clopidogrel (CLOP) is an antiplatelet drug with poor solubility in intestinal fluid, which limits its bioavailability after oral administration. Current study focuses on developing site-specific floating microcarriers of CLOP using solvent diffusion evaporation method (SDEM) for retaining the drug in the stomach, thus improving the solubility of drug for better absorption. SDEM was employed to formulate floating microcarriers using lipidic excipients, namely Gelucires (GL) to impart floating properties, in combination with ethyl cellulose as release retarding polymer. Prepared particles were 169 ± 6μm to 375 ± 13μm in size, whilst encapsulation efficiency was ranged from 39.6 ± 0.60% to 96.50 ± 3.50%. Electron micrographs depicted discrete spherical microcarriers with porous structure, which amplified with increasing HLB value of GL and concentration of Eudragit E100. FTIR study confirmed absence of major drug polymer interactions while DSC and XRD studies revealed the presence of non-crystalline nature of drug in all formulations. Drug release at pH1.2 enhanced more than 2-folds with increasing HLB value with 32% cumulative drug release for GL 43/01 and 69% for GL 50/13. More interestingly, adding various proportions of Eudragit E100 to GL 43/01 based formulations resulted in increased drug release as high as 71%. In all formulations, the drug release followed diffusion dependent process. It is envisaged that this formulation strategy for CLOP is promising and could possibly be tested in future for its in vivo performance. Graphical abstract Lipid based floating microcarriers of clopidogrel.

FORMULATION, CHARACTERIZATION AND IN VITRO EVALUATION OF FLOATING MICROSPHERES OF MEBENDAZOLE AS A GASTRO RETENTIVE DOSAGE FORM

The present study involves preparation and evaluation of floating microspheres using Mebendazole (MBZ) as a model drug for improving the drug bioavailability by prolongation of gastric retention time. Ethyl cellulose, hydroxyl propyl methyl cellulose microspheres loaded with mebendazole were prepared by solvent diffusion evaporation method. The microspheres had smooth surfaces, with free-flowing and good-packing properties. The yield of the microspheres was up to 85.65±0.14% and ethyl cellulose microspheres entrapped the maximum amount of the drug. Scanning electron microscopy confirmed their hollow structures with sizes in the range 215.1 to 251.80 nm. The prepared microspheres exhibited prolonged drug release and Percentage buoyancy was found to70.25±0.15. The formulated batches were evaluated for percentage yield, particle size measurement, flow properties, percent entrapment efficiency, swelling studies. The formulations were subjected to Stability studies and In-vitro release and Release kinetics data was subjected to different dissolution models.
 Keywords: solvent diffusion evaporation method, Mebendazole, Ethyl cellulose, Hydroxyl propyl methyl cellulose

Tacrolimus Loaded PEG-Cholecalciferol Based Micelles for Treatment of Ocular Inflammation.

Poor corneal permeability, nasolacrimal drainage and requirement of chronic administration are major drawbacks of existing therapies for ocular inflammation. Hence, we designed topical micelles of PEG2000 conjugated with cholecalciferol (PEGCCF). Integrin targeted tacrolimus loaded PEGCCF micelles (TTM) were prepared by solvent diffusion evaporation method and characterized for particle size, osmolality, encapsulation efficiency and drug loading. Therapeutic potential of TTM was evaluated in benzalkonium chloride induced ocular inflammation model in BALB/c mice. Corneal flourescein staining and histopathological analysis of corneal sections was performed. TTM had a particle size of 45.3 ± 5.3nm, encapsulation efficiency (88.7 ± 0.9%w/w) and osmolality of 292-296 mOsmol/Kg. TTM significantly reduced the corneal fluorescence as compared to tacrolimus suspension (TACS). H&E staining showed that TTM could restore corneal epithelial thickness, reduce stromal edema (p < 0.05) and decrease number of inflammatory cells (p < 0.01) compared with TACS. Immunohistochemistry analysis demonstrated lower expression of Ki67 + ve cells (p < 0.05) and IL-6 throughout the cornea against TACS (p < 0.01) and the control (p < 0.001). TTM is an innovative delivery system for improving ocular inflammation due to a) integrin targeting b) PEGCCF in the form of carrier and c) anti-inflammatory and synergistic effect (due to Pgp inhibition) with TAC.

Polymer blends used to develop felodipine-loaded hollow microspheres for improved oral bioavailability

Felodipine (FD) has been widely used in anti-hypertensive treatment. However, it has extremely low aqueous solubility and poor bioavailability. To address these problems, FD hollow microspheres as multiple-unit dosage forms were synthesized by a solvent diffusion evaporation method. Particle size of the hollow microspheres, types of ethylcellulose (EC), amounts of EC, polyvinyl pyrrolidone (PVP) and FD were investigated based on an orthogonal experiment of three factors and three levels. In addition, the release kinetics in vitro and pharmacokinetics in beagle dogs of the optimized FD hollow microspheres was investigated and compared with Plendil (commercial FD sustained-release tablets) as a single-unit dosage form. Results showed that the optimal formulation was composed of EC10 cp:PVP:FD (0.9:0.16:0.36, w/w). The FD hollow microspheres were globular with a hollow structure and have high drug loading (17.69±0.44%) and floating rate (93.82±4.05%) in simulated human gastric fluid after 24h. Pharmacokinetic data showed that FD hollow microspheres exhibited sustained-release behavior and significantly improved relative bioavailability of FD compared with the control. Pharmacodynamic study showed that the FD hollow microspheres could effectively lower blood pressure. Therefore, these findings demonstrated that the hollow microspheres were an effective sustained-release delivery system for FD.

Formulation and Development of Gastroretentive Dipyridamole Microspheres: Proof of Concept by In vitro-In vivo Assessment

The present research was aimed at development and optimization of dipyridamole gastroretentive microspheres. Gastro retention was achieved using swellable polymeric material such as hydroxypropylmethylcellulose K4M, ethyl cellulose as release retardant using solvent diffusion evaporation method. 32 factorial design was applied for the development of best optimized formulation. The design was developed by considering two independent variables, ethyl cellulose, and stirring speed. Their effect on drug release, entrapment efficiency, particle size was analysed using response surface methodology. Formulation B1 among all formulations tested was found to be the best as it demonstrated prolonged floating time, maximum entrapment efficiency and drug release in a controlled manner. Formulation B1 was characterized further for presence of residual solvent by gas chromatography/mass spectrometry and the result showed absence of residual solvent. Gastro retention was assessed using the in vivo gamma scintigraphy technique in Albino rabbits and the results indicated prolonged gastric retention. Pharmacokinetic study comparing pure dipyridamole and dipyridamole microspheres was conducted and Cmax, Tmax and Kel were estimated. In vitro-in vivo correlation was determined using Wagner-Nelson function. Pharmacokinetic study revealed improved bioavailability (30 %) as compared to pure dipyridamole. Good correlation was obtained with a regression coefficient of 0.9704. The in vivo gamma scintigraphy and pharmacokinetic studies confirmed gastric retention of the prepared dipyridamole floating microspheres. Accelerated stability studies indicated integrity of the developed formulation.

Co-delivery nanoparticles with characteristics of intracellular precision release drugs for overcoming multidrug resistance.

Combination chemotherapy in clinical practice has been generally accepted as a feasible strategy for overcoming multidrug resistance (MDR). Here, we designed and successfully prepared a co-delivery system named S-D1@L-D2 NPs, where denoted some smaller nanoparticles (NPs) carrying a drug doxorubicin (DOX) were loaded into a larger NP containing another drug (vincristine [VCR]) via water-in-oil-in-water double-emulsion solvent diffusion-evaporation method. Chitosan-alginate nanoparticles carrying DOX (CS-ALG-DOX NPs) with a smaller diameter of about 20 nm formed S-D1 NPs; vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles carrying VCR (TPGS-PLGA-VCR NPs) with a larger diameter of about 200 nm constituted L-D2 NPs. Some CS-ALG-DOX NPs loaded into TPGS-PLGA-VCR NPs formed CS-ALG-DOX@TPGS-PLGA-VCR NPs. Under the acidic environment of cytosol and endosome or lysosome in MDR cell, CS-ALG-DOX@TPGS-PLGA-VCR NPs released VCR and CS-ALG-DOX NPs. VCR could arrest cell cycles at metaphase by inhibiting microtubule polymerization in the cytoplasm. After CS-ALG-DOX NPs escaped from endosome, they entered the nucleus through the nuclear pore and released DOX in the intra-nuclear alkaline environment, which interacted with DNA to stop the replication of MDR cells. These results indicated that S-D1@L-D2 NPs was a co-delivery system of intracellular precision release loaded drugs with pH-sensitive characteristics. S-D1@L-D2 NPs could obviously enhance the in vitro cytotoxicity and the in vivo anticancer efficiency of co-delivery drugs, while reducing their adverse effects. Overall, S-D1@L-D2 NPs can be considered an innovative platform for the co-delivery drugs of clinical combination chemotherapy for the treatment of MDR tumor.

DEVELOPMENT AND IN VITRO EVALUATION OF FLOATING DRUG DELIVERY SYSTEM OF ACECLOFENAC

The objective of the present investigation is to attain optimized floating drug delivery system for aceclofenac by determining the effects of some important factors for the prolongation of gastric residence time. Floating microspheres were prepared by solvent diffusion–evaporation method using ethyl cellulose and hydroxypropylmethylcellulose. A central composite design was applied to optimize the formulation. An appropriate balance between the levels of the polymer and stirring speed was imperative to acquire maximum drug entrapment efficiency, sustained release of the drug, floating ability and adequate particle size.

Lipid Nanocarrier-Mediated Drug Delivery System to Enhance the Oral Bioavailability of Rifabutin.

Rifabutin (RFB) is prescribed for the treatment of tuberculosis infections as well as Mycobacterium avium complex (MAC) infection in immunocompromised individuals and HIV patients. With a view to develop a sustained release oral solid lipid nanoformulation (SLN), RFB was encapsulated in glyceryl monostearate (GMS) nanoparticles. The rifabutin solid lipid nanoparticles (RFB-SLNs), prepared by the solvent diffusion evaporation method, had a size of 345 ± 17.96nm and PDI of 0.321 ± 0.09. The stability of RFB-SLNs was investigated in simulated gastric fluid (SGF) pH2.0, simulated intestinal fluid (SIF) pH6.8 and physiological buffer (PBS) pH7.4. The gastric medium did not affect the SLNs and were found to be stable, while a sustained release was observed in SIF up to 48h and in PBS up to 7days. The pharmacokinetic profile of a single oral administration of RFB-SLNs in mice showed maintenance of therapeutic drug concentrations in plasma for 4days and in the tissues (lungs, liver and spleen) for 7days. Oral administration of free RFB showed clearance from plasma within 24h. The relative bioavailability of RFB from SLNs was five fold higher as compared to administration with free RFB. The intent of using lipid nanocarriers is primarily to enhance the oral bioavailability of rifabutin and eventually decrease the dose and dosing frequency for successful management of MAC infection.

A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice.

5-Fluorouracil (5-FU) was loaded in hollow microspheres to improve its oral bioavailability. 5-FU hollow microspheres were developed by a solvent diffusion–evaporation method. The effect of Span 80 concentration, ether/ethanol volume ratio, and polyvinyl pyrrolidone/ethyl cellulose weight ratio on physicochemical characteristics, floating, and in vitro release behaviors of 5-FU hollow microspheres was investigated and optimized. The formulation and technology composed of Span 80 (1.5%, w/v), ether/ethanol (1.0:10.0, v/v), and polyvinyl pyrrolidone/ethyl cellulose (1.0:10.0, w/w) were employed to develop three batch samples, which showed an excellent reproducibility. The microspheres were spherical with a hollow structure with high drug loading amount (28.4%±0.5%) and production yield (74.2%±0.6%); they exhibited excellent floating and sustained release characteristics in simulated gastric and intestinal fluid. Pharmacokinetic studies demonstrated that 5-FU hollow microspheres significantly enhanced oral bioavailability (area under curve, [AUC](0−t): 12.53±1.65 mg/L*h vs 7.80±0.83 and 5.82±0.83 mg/L*h) with longer elimination half-life (t1/2) (15.43±2.12 hours vs 2.25±0.22 and 1.43±0.18 hours) and mean residence time (7.65±0.97 hours vs 3.61±0.41 and 2.34±0.35 hours), in comparison with its solid microspheres and powder. In vivo distribution results from tumor-bearing nude mice demonstrated that the animals administered with 5-FU hollow microspheres had much higher drug content in tumor, plasma, and stomach at 1 and 8 hours except for 0.5 hours sample collection time point in comparison with those administered with 5-FU solid microspheres and its powder. These results suggested that the hollow microspheres would be a promising controlled drug delivery system for an oral chemotherapy agent like 5-FU.

Development of novel docetaxel phospholipid nanoparticles for intravenous administration: quality by design approach.

The objective of this study was to develop novel docetaxel phospholipid nanoparticles (NDPNs) for intravenous administration. Modified solvent diffusion-evaporation method was adopted in the NDPN preparation. Central composite design (CCD) was employed in the optimization of the critical formulation factor (drug content) and process variable (stirring rate) to obtain NDPNs with 215.53 ± 1.9-nm particle size, 0.329 ± 0.02 polydispersity index (PDI), and 75.41 ± 4.81% entrapment efficiency. The morphological examination by transmission electron microscopy revealed spherical structure composed of a drug core stabilized within the phospholipid shell. Enhanced cell uptake of coumarin-6-loaded phospholipid nanoparticles by MCF-7 cell line indicated NDPN-efficient cell uptake. In vitro hemolysis test confirmed the safety of the phospholipid nanoparticles. NDPNs exhibited increased area under the curve (AUC) and mean residence time (MRT) by 3.0- and 3.3-fold, respectively, in comparison with the existing docetaxel parenteral formulation (Taxotere®), indicating a potential for sustained action. Thus, the novel NDPNs exhibit an ability to be an intravenous docetaxel formulation with enhanced uptake, decreased toxicity, and prolonged activity.