Double Emulsion Solvent Diffusion Research Articles

Design of mesalamine loaded micro-particles: Preparation, in vitro and in-vivo characterization

The goal of this study was to develop mesalamine (MS) microparticles that could be ingested by the colon without first passing via the stomach and small intestines. Without resorting to the time-consuming and laborious double emulsion solvent diffusion method, microparticles were successfully fabricated using the Box-Behnken Design method. Microparticle production was optimized, and the effects of many parameters were analyzed (X1: Eudragit S100, X2: Span 80 and X3: agitation speed). Using the Box-Behnken design (BBD), we compared the chosen optimized microparticles to the pure drug solution utilizing in vivo pharmacokinetic study for particle size (Y1), entrapment efficiency (Y2), and drug-release (Y3). It was simple to create spherical, free-flowing, smooth-surfaced microparticles with a zeta potential of −36.52 mV and a size distribution of 264.35 ± 6.28–652.34 ± 6.49 nm. Coefficients of 264.35 ± 6.28–652.34 ± 6.49%, 42.31 ± 2.43–89.74 ± 2.17%, and 52.31 ± 0.43–93.51 ± 0.33% from a quadratic model best fit the observed values of dependent variables. Formulation F4 was selected as the best option because it prevented the drug from being released in the upper GIT before it was ready and instead released it only in the colon, where the pH is optimal. The formulation had a particle size of 266.597 μm, an entrapment efficiency of 93.735%, a cumulative drug release of 95.578 percent, and a desirability factor of 0.998. In comparison to drug solution pharmacokinetics, microparticle pharmacokinetics showed a 6.35-fold decrease in Cmax and MS with an appropriately increased half-life of 8.13 h. (13.67 and 3.46). This enhanced bioavailability of MS released from microparticles is probably due to an increase in the half-life, mean residence time (MRT), and area under the concentration–time curve (AUC0-24) of MS. Over a long length of time with no increase in plasma MS level, it became clear that the novel method of MS-loaded microparticles would provide successful therapy for ulcerative colitis. A pharmacodynamic study found that mesalamine-loaded microparticles dramatically decreased colon edema, necrosis, and bleeding compared to free drug solution. Results from this study suggest that mesalamine-loaded microparticles may be an effective pharmaceutical delivery strategy for the management of ulcerative colitis.

Preparation and characterization of reusable water/ethylcellulose phase change cold storage microcapsules with high latent heat

To improve the applicability of water-based cold storage materials in short-distance cold chain transport, low-temperature phase change microcapsules with water core and ethylcellulose (EC) wall were prepared by double-emulsion solvent diffusion. Core–shell microspheres with an average particle size of 1.6 µm were obtained under process parameters optimized using the response surface methodology. The presence of hydrogen bonds between water and EC was confirmed by Fourier transform infrared spectroscopy. The results of differential scanning calorimetry and thermal conductivity show that the microcapsules exhibited superior thermal storage (286.51 J/g) and the thermal conductivity is 0.4655 W/m·K. On the basis of the temperature-time curve, the time that the microcapsules were kept within the cold storage temperature range (0–7 °C) was 13.3 times that for water, and the refrigeration capacity of the microcapsules was significantly improved. After 100 freeze–thaw cycles, the supercooling degree of the microcapsules remained 0.7 °C lower than that of water without phase separation. Additionally, thermogravimetric analysis and leakage testing were used to characterize the thermal stability and reusability. Furthermore, the simulation of application conditions shows that the refrigeration time of the combined thermal insulation materials and microcapsules could reach 137 min, which was 63.1% longer than that of the control group. All the results suggest that water/EC microcapsules show potential as cold thermal energy storage material that can be reused in short-distance cold chain transport.

Utilization of PLGA nanoparticles in yeast cell wall particle system for oral targeted delivery of exenatide to improve its hypoglycemic efficacy

Oral delivery of exenatide (EXE), a high-efficiency therapeutic peptide, is urgently needed for long-term treatment of diabetes. In this study, a polylactide-co-glycoside (PLGA) nanoparticles (NPs) in yeast cell wall particle (YCWP) system was built to improve the intestinal absorption of EXE by efficient protection of EXE against gastrointestinal degradation and intestinal phagocytic cell targeted delivery. The EXE-loaded PLGA NPs were prepared by a double emulsion solvent diffusion method and exhibited a uniformly spherical appearance, a nano size (92.4 ± 4.6 nm) and a positive surface charge (+32.3 ± 3.8 mV). And then, the NPs were successfully loaded into the YCWPs by a solvent hydration − lyophilization cycle method to obtain the EXE-PLGA NPs @YCWPs, which was verified by scanning electron microscope and confocal laser scanning microscopy. An obvious sustained drug release and a reduced burst release were achieved by this nano-in-micro carrier. Moreover, the gastrointestinal stability of EXE in PLGA NPs @YCWPs was significantly higher than that in PLGA NPs in the simulated gastrointestinal environment, which were useful in enhancing the intestinal absorption of EXE. In biodistribution study, the EXE-PLGA NPs @YCWPs could quickly reached the root of the villi, and even partly entered the inner of the villi, especially in ileum and Peyer’s patches. In vitro cell evaluation demonstrated an efficient β-glucan receptor mediated endocytosis and transport of EXE-PLGA NPs @YCWPs by the macrophage RAW 264.7 cells, suggesting a potential intestinal macrophage targeted absorptive pathway. The in vivo pharmacokinetic study showed a preferred hypoglycemic effect and an increased pharmacological availability (13.7 ± 4.1%) after oral administration of the EXE-PLGA NPs @YCWPs. It is believed that the PLGA nanoparticles in YCWP system could become an efficient strategy to orally deliver therapeutic peptide drugs.

Encapsulation of Ficus deltoidea Extract in Nanostructured Lipid Carrier for Anti-melanogenic Activity

Nanostructured lipid carrier (NLC) was studied as a system to transport Ficus deltoidea extracts through the skin. The thin film ultra-sonication dispersion (TFUD) technique and double-emulsion solvent diffusion (DESD) techniques were performed to compare encapsulation efficiency (EE) of the two methods. The DESD displayed superior performance for encapsulation of F. deltoidea extracts which was 67.92 ± 10.55%. Next, different types of lipids were assessed to determine their effects on the characteristics of F. deltoidea–loaded NLC prepared via the DESD method. Fatty acids were superior to triglycerides for the formulation of NLC. The final NLC formulation selected was stearic acid (SA) as solid lipid and oleic acid (OA) as liquid lipid, at a total ratio of 1:1, and poly(vinyl alcohol) (PVA) as a stabiliser. The delivery system exerted exceptional transdermal transport properties. F. deltoidea–loaded NLC successfully and more effectively reduced melanin, when compared with non-entrapped F. deltoidea extract.

Preparation of microspheres encapsulating sorafenib and catalase and their application in rabbit VX2 liver tumor

BackgroundTranscatheter arterial chemoembolization (TACE) is extensively used in the treatment of advanced hepatocellular carcinoma (HCC). However, the efficacy of TACE is usually limited to secondary tumor hypoxia and hypoxia-related tumor angiogenesis. MethodsIn this study, poly(lactic-co-glycolic acid) (PLGA) microspheres (SOR-CAT-PLGA MSs) encapsulating sorafenib (SOR) and catalase (CAT) were prepared by double-emulsion solvent diffusion method. Sorafenib inhibits tumor angiogenesis, and catalase decomposes hydrogen peroxide (H2O2) to generate oxygen in the tumor. ResultsIn vitro and in vivo, SOR -CAT-PLGA MSs could significantly improve the efficacy of hepatic artery embolization in the treatment of rabbit VX2 liver tumors, regulate tumor hypoxia and immunosuppressive microenvironment, then achieved near-complete and rapid necrosis of liver tumors. ConclusionsThe application of new SOR -CAT-PLGA MSs in hepatic artery chemoembolization of rabbit VX2 liver tumor is a promising approach to improve the therapeutic effect of liver tumors and has a broad clinical application prospect.

Preparation, in vitro and in vivo evaluation of PLGA/Chitosan based nano-complex as a novel insulin delivery formulation.

The smart self-regulated drug delivery systems for insulin administration are desirable to achieve glycemic control, and decrease the long-term micro- and macro vascular complications. In this study, we developed an injectable nano-complex formulation for closed-loop insulin delivery after subcutaneous administration and release of insulin in response to increased blood glucose levels. The nano-complex was prepared by mixing oppositely charged chitosan and PLGA nanoparticles. PLGA nanoparticles were prepared using double-emulsion solvent diffusion method, and were loaded with glucose oxidase (GOx) and catalase (CAT) enzymes. These negatively charged particles decrease micro-environmental pH, by gluconic acid production in the glucose molecules presence. Positively charged chitosan nanoparticles were prepared using ionic gelation method, and were loaded with insulin. These nanoparticles (NPs) released insulin by dissociation in acidic pH caused by the GOx activity. Following in vitro studies, in vivo evaluation of nano-complex formulations in streptozocin induced diabetic rats showed significant glycemic regulation up to 98 h after subcutaneous administration.

Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy.

Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide derived from apolipoprotein B100 (ApoB-P), the protein moiety of low-density lipoprotein, was used to target siRNA-loaded PEGylated NPs to the extracellular matrix/proteoglycans (ECM/PGs) of a mammary carcinoma tumor. siRNA against osteopontin (siOPN), a protein involved in breast cancer development and progression, was encapsulated into PEGylated poly(d,l-lactic-co-glycolic acid) (PLGA) NPs using the double emulsion solvent diffusion technique. The NPs obtained possessed desired physicochemical properties including ~200 nm size, a neutral surface charge, and high siOPN loading of ~5 µg/mg. ApoB-P-targeted NPs exhibited both enhanced binding to isolated ECM and internalization by MDA-MB-231 human mammary carcinoma cells, in comparison to non-targeted NPs. Increased accumulation of the targeted NPs was achieved in the primary mammary tumor of mice xenografted with MDA-MB-231 mammary carcinoma cells as well as in the lungs, one of the main sites affected by metastases. siOPN NPs treatment resulted in significant inhibition of tumor growth (similar bioactivity of both formulations), accompanied with significant reduction of OPN mRNA levels (~40% knockdown of mRNA levels). We demonstrated that targeted NPs possessed enhanced tumor accumulation with increased therapeutic potential in mice models of mammary carcinoma.

Knockdown of human telomerase reverse transcriptase induces apoptosis in cervical cancer cell line.

Background & objectives:Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase enzyme that maintains telomere ends by the addition of telomeric repeats to the ends of chromosomal DNA, and that may generate immortal cancer cells. Hence, the activity of telomerase is raised in cancer cells including cervical cancer. The present study aimed to validate the unique siRNA loaded chitosan coated poly-lactic-co-glycolic acid (PLGA) nanoparticle targeting hTERT mRNA to knock down the expression of hTERT in HeLa cells.Methods:The siRNA loaded chitosan coated polylactic-co-glycolic acid (PLGA) nanoparticles were synthesized by double emulsion solvent diffusion method. The characterization of nano-formulation was done to determine efficient siRNA delivery. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate silencing efficiency of nano-formulation.Results:Size, zeta potential and encapsulation efficiency of nanoparticles were 249.2 nm, 12.4 mV and 80.5 per cent, respectively. Sustained release of siRNA from prepared nanoparticle was studied for 72 h by ultraviolet method. Staining assays were performed to confirm senescence and apoptosis. Silencing of hTERT mRNA and protein expression were analyzed in HeLa cells by RT-PCR and Western blot.Interpretation & conclusions:The findings showed that biodegradable chitosan coated PLGA nanoparticles possessed an ability for efficient and successful siRNA delivery. The siRNA-loaded PLGA nanoparticles induced apoptosis in HeLa cells. Further studies need to be done with animal model.

Comparative in-vivo Evaluation of Anti-Cancer Drugs Loaded Nanospheres

Abstract: Objectives: objective of present research was to formulate and evaluate nanospheres of selected anticancer drugs, viz., Capecitabine (CPN), Tamoxifen (TAM) and Doxorubicin (DXO). The adverse effects associated with anticancer drugs which include are bonemarrow depression, cardio toxicity, diarrhoea, nausea and vomiting, stomatitis and dermatitis. Materials and Methods: Drug loaded nanospheres of polycaprolactone-chitosan in various drug: polymer ratios, cross linked with Tripolyphosphate were prepared by double emulsion solvent evaporation and solvent diffusion methods. Male white New Zeeland Rabbits(weighing about 2500 gm) were selected as the animalmodel. The rabbits selected for the study had no medicationfor two weeks prior to the study. Results and Discussion: The parameters like AUC(0-24) of DXO nanospheres 2362.0 ng.h/mL, whereas DXO pure drug was 1956.5 ng.h/mL. AUC (0-24) of TAM nanospheres 5646.00 ng.h/mL. Whereas TAM unadulterated medication was 4786.30ng.h/mL. AUC (0-24) of CPN nanospheres 4927.40 ng.h/mL. Whereas CPN pure drug was 4027.5ng.h/mL. Conclusion: In vivo results showed a significant increase in the bioavailability of drugs from DXO6, CPN6 and TAM6 nanospheres when compared to those of the standard drugs. This enhanced bioavailability could be helpful in reducing the dose of DXO, CPN and TAM and also reduce their toxicities. This enhanced bioavailability could be helpful in reducing the dose and also reduce the toxicities of the selected drugs. Key words: Doxorubicin, Tamoxifen, Capecitabine, Nanospheres, in vivo studies.

PREPARATION, CHARACTERIZATION AND EVALUATION OF POLY (LACTIDE –CO –GLYCOLIDE) MICROSPHERES FOR THE CONTROLLED RELEASE OF ZIDOVUDINE

Objective: The purpose of this research work was to develop and evaluate microspheres appropriate for controlled release of zidovudine (AZT).Methods: The AZT loaded polylactide-co-glycolide (PLGA) microspheres were prepared by W/O/O double emulsion solvent diffusion method. Compatibility of drug and polymer was studied by Fourier-transform infrared spectroscopy (FTIR). The influence of formulation factors (drug: polymer ratio, stirring speed, the concentration of surfactant) on particle size encapsulation efficiency and in vitro release characteristics of the microspheres was investigated. Release kinetics was studied and stability study was performed as per ICH guidelines.Results: Scanning electron microscopy (SEM) images show good reproducibility of microspheres from different batches. The average particle size was in the range of 216-306 μm. The drug-loaded microspheres showed 74.42±5.08% entrapment efficiency. The cumulative percentage released in phosphate Buffer solution (PBS) buffer was found to be 55.32±5.89 to 74.42±5.08 %. The highest regressions (0.981) were obtained for zero order kinetics followed by Higuchi (0.968) and first order (0.803).Conclusion: Microsphere prepared by double emulsion solvent diffusion method was investigated and the results revealed that 216-306 μm microsphere was successfully encapsulated in a polymer. FT-IR analysis, entrapment efficiency and SEM Studies revealed the good reproducibility from batch to batch. The microspheres were of an appropriate size and suitable for oral administration. Thus the current investigation show promising results of PLGA microspheres as a matrix for drug delivery and merit for In vivo studies for scale up the technology.

Injectable deferoxamine nanoparticles loaded chitosan-hyaluronic acid coacervate hydrogel for therapeutic angiogenesis

In this study, an injectable chitosan-hyaluronic acid (CS-HA) based hydrogel was designed incorporating pro-angiogenic molecule, deferoxamine loaded PLGA nanoparticles (DFO NPs), for enhancing angiogenesis. DFO-NPs were prepared by double emulsion solvent diffusion technique and characterized for their physicochemical properties. The DLS and SEM analysis showed an average particle size of 220±71nm with spherical morphology and the encapsulation efficiency was found to be 30±5%. An ECM mimicking chitosan-hyaluronic acid (CS-HA) coacervate hydrogel was prepared. Both free DFO and DFO NPs were entrapped into the prepared CS-HA composite hydrogel. The hydrogels were characterized by SEM, FTIR and Rheology. Addition of DFO NPs did not affect the injectablility and flowability of developed hydrogels. In vitro DFO release from the prepared composite hydrogels showed controlled release over a period of 10days. Both the hydrogel systems showed excellent cyto-compatability and good cell proliferation for rASCs as well as HUVECs. The DFO and DFO NPs loaded composite hydrogels revealed effective tube formation in comparison with control hydrogels without DFO and DFO NPs. The in vivo angiogenic evaluation of the free DFO and DFO NPs (0.025%w/w) loaded composite hydrogels were studied by injecting the developed hydrogel subcutaneously into mice for 2–4 weeks. The DFO NPs loaded composite hydrogel had enhanced neovascularization when compared to control gels. Thus, the developed DFO NPs loaded composite hydrogel could potentially be used for therapeutic angiogenesis.

Polymeric nanoparticles of siRNA prepared by a double-emulsion solvent-diffusion technique: Physicochemical properties, toxicity, biodistribution and efficacy in a mammary carcinoma mice model

siRNA-loaded nanoparticles (NPs) administered systemically can overcome the poor stability and rapid elimination of free double-stranded RNA in circulation, resulting in increased tumor accumulation and efficacy. siRNA against osteopontin (siOPN), a protein involved in breast cancer development, was encapsulated in poly(D,L-lactic-co-glycolic acid) NPs by a double emulsion solvent diffusion (DESD) technique. We also compared the effect of polyethylenimine (PEI) molecular weight (800Da and 25kDa), used as the counter-ion for siRNA complexation, on the physicochemical properties of the NPs, cytotoxicity, and cellular uptake. NPs prepared by the DESD technique were obtained at the desired size (∼170nm) using both types of PEIs, and were characterized with a neutral surface charge, high encapsulation yield (up to ∼60%), siOPN concentration of 5.6-8.4μg/mg, stability in physiologic conditions invitro and invivo, and long-term shelf-life stability (> 3 years). The NPs prepared using both PEIs exhibited no cytotoxicity in primary smooth muscle culture, and no detrimental effect on mice liver enzymes following their IV administration. Following cellular uptake and biodistribution studies, the therapeutic potential of the NPs was demonstrated by a significant decrease of tumor progression and size in an ectopic xenograft model of mammary carcinoma in mice.

Synthesis, characterization, and in vitro activity against Candida spp. of fluconazole encapsulated on cationic and conventional nanoparticles of poly(lactic-co-glycolic acid).

In this study, nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA) loaded with fluconazole (FLZ) and FLZ-NPs coated with the cationic polymer polyethylenimine (PEI) (FLZ-NP-PEI) were synthetized in order to improve antimycotic activity against four strains of Candida spp. of clinical relevance. FLZ-NPs and FLZ-NP-PEI were synthesized by double emulsion solvent-diffusion (DES-D) and characterized. Minimum inhibitory concentration (MIC50) and minimum fungicide concentration (MFC) were determined in vitro by culturing Candida strains in the presence of these nanocompounds. FLZ-NPs were spherical in shape with hydrodynamic sizes of ~222 nm and surface charge of −11.6 mV. The surface charges of these NPs were successfully modified using PEI (FLZ-NP-PEI) with mean hydrodynamic sizes of 281 nm and surface charge of 23.5 mV. The efficiency of encapsulation (~53%) and a quick release of FLZ (≥90% after 3 h) were obtained. Cytotoxicity assay showed a good cell viability for FLZ-NPs (≥86%), and PEI-modified NPs presented a decrease in cell viability (~38%). FLZ-NPs showed an increasing antifungal activity of FLZ for sensitive (Candida parapsilosis ATCC22019 and Candida albicans ATCC10231, MIC50 =0.5 and 0.1 µg/mL, respectively) and resistant strains (Candida glabrata EMLM14 and Candida krusei ATCC6258, MIC50 =0.1 and 0.5 µg/mL, respectively). FLZ-NP-PEI showed fungicidal activity even against C. glabrata and C. krusei (MFC =4 and 8 µg/mL, respectively). MIC50 values showed best results for FLZ-NPs and FLZ-NP-PEI. Nevertheless, only FLZ-NP-PEI displayed fungicidal activity against the studied strains.

Optimized Formulation of Colon Targeted Microsheres for Prednisolone Sodium Phosphate: Application of Taguchi Experimental Design

Microspheres of ethyl cellulose containing prednisolone sodium phosphate were prepared by double emulsion solvent diffusion method. A statistical design was used to study and optimize the variables that affect the preparation of microspheres. The experimental results showed that the drug: polymer ratio, stirring speed, concentration of surfactant, and volume of processing media played an important role in the formulation of microspheres. The prepared microspheres were characterized on the basis of particle size, scanning electron microscopy, entrapment efficiency and <italic>in vitro</italic> release. Taguchi experimental design helped to reduce the number of experiments. Optimized formulation exhibited Higuchi square root kinetics displaying diffusion from the microspheres as the main mechanism for drug release.

Optimized Formulation of Colon Targeted Microsheres for Prednisolone Sodium Phosphate: Application of Taguchi Experimental Design

Microspheres of ethyl cellulose containing prednisolone sodium phosphate were prepared by double emulsion solvent diffusion method. A statistical design was used to study and optimize the variables that affect the preparation of microspheres. The experimental results showed that the drug: polymer ratio, stirring speed, concentration of surfactant, and volume of processing media played an important role in the formulation of microspheres. The prepared microspheres were characterized on the basis of particle size, scanning electron microscopy, entrapment efficiency and <italic>in vitro</italic> release. Taguchi experimental design helped to reduce the number of experiments. Optimized formulation exhibited Higuchi square root kinetics displaying diffusion from the microspheres as the main mechanism for drug release.

Development of zolmitriptan loaded PLGA/poloxamer nanoparticles for migraine using quality by design approach

The purpose of this investigation was to develop Poly (D,L Lactide-co-Glycolide) (PLGA)/poloxamer nanoparticles (NPs) of the hydrophilic drug Zolmitriptan using quality-by-design approach for brain targeting. Randomized 24 full factorial design was employed to achieve the critical quality attributes of minimized particle size and maximized encapsulation efficiency. The PLGA/poloxamer NPs were fabricated using modified double emulsion solvent diffusion technique and particle size varied from 165.4–245.4nm, encapsulation efficiency was in the range of 48.96–95.97% and percent cumulative drug release varied from 43.32 to 100%. The optimized nanoparticles were characterized by FTIR spectroscopy and powder X-ray diffraction technique which indicated the loading of drug in NPs without any chemical interactions between drug and the excipients. The uniform and spherical shape of the particles was affirmed from TEM analysis. The in-vivo studies for determination of brain uptake potential demonstrated a 14.13 fold increase in drug delivered to brain from the NPs as compared to the free drug. The pharmacodynamic studies involving Swiss albino mice further confirmed successful delivery of drug to brain circumventing the blood brain barrier, through significantly enhanced anti-migraine potential. This investigation thus presents the suitability of zolmitriptan loaded PLGA/poloxamer NPs in brain targeting for the efficient treatment of migraine.

Formulation, Characterization and In vitro Evaluation of Capecitabine Loaded Polycaprolactone-Chitosan Nanospheres

The aim of this study is to formulate the capecitabine loaded nanospheres of polycaprolactone-chitosan, cross linked with Tripolyphosphate for anticancer therapy, in order to enhance the bioavailability and to reduce the dose frequency. Formulations of capecitabine loaded nanospheres were prepared by double emulsion solvent evaporation and solvent diffusion methods. Fourier transmission infrared spectroscopy studies indicated no chemical interaction between drug and polymer. Scanning electron microscopy showed nanospheres having a discrete spherial structure without aggregation. The average particle size was found as 616 ± 110 to 713 ± 115 nm. In vitro release studies were performed by the dialysis membrane method. All the drug loaded batches were follwed zero order and sustained drug release over a period of 24 hrs. DOI: http://dx.doi.org/10.3329/bpj.v17i1.22309 Bangladesh Pharmaceutical Journal 17(1): 18-24, 2014

Formulation and Evaluation of pH Sensitive Mucoadhesive Microspheres of Fluvastatin Sodium

The present work was aimed to develop a pH sensitive mucoadhesive microspheres sustained drug delivery system of fluvastatin sodium, a water soluble and poorly bioavailable drug (24%), unstable at gastric pH. Mucoadhesive microspheres were formulated using polymethacrylate polymer (EL 100 and ES 100) having excellent mucoadhesive property. Microspheres formed were discrete, free flowing and exhibited good mucoadhesive properties. pH sensitive mucoadhesive microspheres were formulated by w/o/o double emulsion solvent diffusion method. Parameters such as particle size analysis, drug entrapment efficiency, scanning electron microscopy (SEM) analysis, in vitro wash-off test, in vitro release studies and drug polymer compatibility studies were investigated. Results showed that the polymer concentration affected size, entrapment efficiency, mucoadhesion property and drug release from the microspheres. The good result was obtained for the formulation F10 (Drug: EL 100 (1: 2.5). At this ratio, the mean particle size, entrapment efficiency, swelling index of mucoadhesive microspheres was increased and drug release was sustained when compared to the other formulations. Also this formulation showed highest mucoadhesion time when compared to other formulations. This was confirmed in vitro wash-off test. Fourier Transform-Infra Red Spectroscopy (FT-IR) and Differential Scanning Calorimetric studies (DSC) did not show any drug, polymer interactions. The results of powder X-ray diffraction (PXRD) studies showed the reduced crystal nature of the drug. Conclusively, a pH sensitive mucoadhesive drug delivery system was successfully developed that showed sustained and delayed release up to 12 hours and could be potentially useful to overcome poor bioavailability problems associated with fluvastatin sodium.

Process and formulation variables of pregabalin microspheres prepared by w/o/o double emulsion solvent diffusion method and their clinical application by animal modeling studies

Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. In conventional therapy recommended dose for pregabalin is 75 mg twice daily or 50 mg three times a day, with maximum dosage of 600 mg/d. To achieve maximum therapeutic effect with a low risk of adverse effects and to reduce often drug dosing, modified release preparations; such as microspheres might be helpful. However, most of the microencapsulation techniques have been used for lipophilic drugs, since hydrophilic drugs like pregabalin, showed low-loading efficiency and rapid dissolution of compounds into the aqueous continous phase. The purpose of this study was to improve loading efficiency of a water-soluble drug and modulate release profiles, and to test the efficiency of the prepared microspheres with the help of animal modeling studies. Pregabalin is a water soluble drug, and it was encapsulated within anionic acrylic resin (Eudragit S 100) microspheres by water in oil in oil (w/o/o) double emulsion solvent diffusion method. Dichloromethane and corn oil were chosen primary and secondary oil phases, respectively. The presence of internal water phase was necessary to form stable emulsion droplets and it accelerated the hardening of microspheres. Tween 80 and Span 80 were used as surfactants to stabilize the water and corn oil phases, respectively. The optimum concentration of Tween 80 was 0.25% (v/v) and Span 80 was 0.02% (v/v). The volume of the continous phase was affected the size of the microspheres. As the volume of the continous phase increased, the size of microspheres decreased. All microsphere formulations were evaluated with the help of in vitro characterization parameters. Microsphere formulations (P1–P5) exhibited entrapment efficiency ranged between 57.00 ± 0.72 and 69.70 ± 0.49%; yield ranged between 80.95 ± 1.21 and 93.05 ± 1.42%; and mean particle size were between 136.09 ± 2.57 and 279.09 ± 1.97 µm. Pregabalin microspheres having better results among all formulations (Table 3) were chosen for further studies such as differential scanning calorimetry, Fourier transform infrared analysis and dissolution studies. In the last step, the best pregabalin microsphere formulation (P3) was chosen for in vivo animal studies. The pregabalin-loaded microspheres (P3) and conventional pregabalin capsules were applied orally in rats for three days, resulted in clinical improvement of cold allodynia, an indicator of peripheral neuropathy. This result when evaluated together with the serum pregabalin levels and in vitro release studies suggests that the pregabalin microspheres prepared with w/o/o double emulsion solvent diffusion method can be an alternative form for neuropathic pain therapy. Conclusively, a drug delivery system successfully developed that showed modified release up to 10 h and could be potentially useful to overcome the frequent dosing problems associated with pregabalin conventional dosage form.

Effects of process parameters on the colloidal properties of polycaprolactone microparticles prepared by double emulsion like process

Preparation of polycaprolactone (PCL) based microparticles by double emulsion solvent diffusion like process was studied in this work. The double emulsion was prepared in two steps. In first step, the inner aqueous phase (W1) was added to dichloromethane (DCM) solution containing PCL and homogenized to form primary emulsion (W1/O). In the second step, the primary emulsion (W1/O) was emulsified with the outer aqueous phase (W2) containing polyvinyl alcohol (PVA) as stabilizer using ultra-turrax at a specific speed and time in order to achieve the double emulsion (W1/O/W2). Effects of various parameters such as stirring time and speed, polymer amount and the volume fraction of each phase on hydrodynamic particle size, size distribution and zeta potential were investigated.As a general tendency, zeta potential of all prepared particles was found to be constant irrespective of investigated parameter. Whereas, the increase in polymer amount leads to large particles size and lowest sizes were obtained when high stirring speed was used during the second emulsification step.