Long circulating PEGylated PLGA nanoparticles of cytarabine for targeting leukemia

The present investigation was aimed at developing PEGylated PLGA nanoparticles of cytarabine. PLGA Nanoparticles were prepared by modified nanoprecipitation method, optimized for mean particle size (152?±?6?nm) and entrapment efficiency (41.1?±?0.8%) by a 3² factorial design. The PEGylated PLGA nanoparticles of cytarabine had a zeta potential of ?7.5?±?1.3?mV and sustained the release of cytarabine for 48?h by Fickian diffusion. The IC₅₀ values for L1210 cells were 6.5, 5.3, and 2.2?µM for cytarabine, cytarabine loaded PLGA nanoparticles and cytarabine loaded PLGA-mPEG nanoparticles respectively. Confocal microscopy and flow cytometry showed that the nanoparticles were internalized by the L1210 cells and not simply bound to their surface. Biodistribution studies showed that the PEGylated nanoparticles of cytarabine were present in significantly higher concentrations in blood circulation as well as in brain and bones and avoided RES uptake as compared to the free drug.     

In vitro/in vivo evaluation of agar nanospheres for pulmonary delivery of bupropion HCl

Abstract

Bupropion HCl is an atypical antidepressant drug with rapid and high first-pass metabolism. Sustained release dosage form of this drug is suggested for reducing its side effects which are mainly seizures. The aim of the present study was to design pulmonary agar nanospheres of bupropion HCl with effective systemic absorption and extended release properties. Bupropion HCl was encapsulated in agar nanospheres by ionic gelation, and characterized for physical and release properties. Pharmacokinetic studies on nanospheres were performed on rats by intratracheal spraying of 5?mg/kg of drug in form of nanospheres compared to intravenous and pulmonary delivery of the same dose as simple solution of the drug. The optimized nanoparticles showed particle size of 320?±?90?nm with polydispersity index of 0.85, the zeta potential of ?29.6?mV, drug loading efficiency of 43.1?±?0.28% and release efficiency of 66.7?±?2%. The area under the serum concentration–time profile for the pulmonary nanospheres versus simple solution was 10?237.84 versus 28.8?µg/ml?min, T_max of 360 versus 60?min and the C_max of 1927.93 versus9.93?ng/ml, respectively. The absolute bioavailability of the drug was 86.69% for nanospheres and 0.25% for pulmonary simple solution. Our results indicate that pulmonary delivery of bupropion loaded agar nanospheres achieves systemic exposure and extends serum levels of the drug.     

Encapsulation of low lipophilic and slightly water-soluble dihydroartemisinin in PLGA nanoparticles with phospholipid to enhance encapsulation efficiency and in vitro bioactivity

Context: PLGA nanoparticles have been widely utilised to encapsulate lipophilic drugs for sustained release.

Objective: This study was to enhance encapsulation efficiency and drug loading for the poorly lipophilic drug dihydroartemisinin (DHA) in PLGA nanoparticles, where amphiphilic phospholipid was employed as the intermediate. Materials and methods: DHA-phospholipid complex formulation was optimised using the response surface method. DHA-phospholipid complex-nanoparticles (DHA-PLC-NPs) were prepared using the solvent evaporation method. Results: The particle size, zeta potential, entrapment efficiency and drug loading of the nanoparticles were 265.3?±?7.9?nm, ?21.4?±?6.3?mV, 74.2?±?6.5% and 2.80?±?0.35%, respectively. Compared with the rapidly released free form, DHA underwent sustained release from the nanoparticles. DHA-PLC-NPs presented stronger cell proliferative inhibition than DHA treatment alone and apoptosis was obviously induced after DHA-PLC-NPs treatment. Conclusion: Phospholipid complexes are useful intermediate to improve the lipophilicity of drugs, the interaction with the hydrophobic core of PLGA and the encapsulation efficiency of poorly lipophilic drugs in polymeric nanoparticles.     

Nanoparticle-based topical ophthalmic formulation for sustained release of stereoisomeric dipeptide prodrugs of ganciclovir

Poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NP) of Val-Val dipeptide monoester prodrugs of ganciclovir (GCV) including L-Val-L-Val-GCV (LLGCV), L-Val-D-Val-GCV (LDGCV) and D-Val-L-Val-GCV (DLGCV) were formulated and dispersed in thermosensitive PLGA-PEG-PLGA polymer gel for the treatment of herpes simplex virus type 1 (HSV-1)-induced viral corneal keratitis. Nanoparticles containing prodrugs of GCV were prepared by a double-emulsion solvent evaporation technique using various PLGA polymers with different drug/polymer ratios. Nanoparticles were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential and crystallinity. Prodrugs-loaded NP were incorporated into in situ gelling system. These formulations were examined for in vitro release and cytotoxicity. The results of optimized entrapment efficiencies of LLGCV-, LDGCV- and DLGCV-loaded NP are of 38.7?±?2.0%, 41.8?±?1.9%, and 45.3?±?2.2%; drug loadings 3.87?±?0.20%, 2.79?±?0.13% and 3.02?±?0.15%; yield 85.2?±?3.0%, 86.9?±?4.6% and 76.9?±?2.1%; particle sizes 116.6?±?4.5, 143.0?±?3.8 and 134.1?±?5.2?nm; and zeta potential ?15.0?±?4.96, ?13.8?±?5.26 and ?13.9?±?5.14?mV, respectively. Cytotoxicity studies suggested that all the formulations are non-toxic. In vitro release of prodrugs from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when NP were suspended in thermosensitive gels with near zero-order release kinetics. Prodrugs-loaded PLGA NP dispersed in thermosensitive gels can thus serve as a promising drug delivery system for the treatment of anterior eye diseases.     

Preparation of psoralen polymer–lipid hybrid nanoparticles and their reversal of multidrug resistance in MCF-7/ADR cells

Multidrug resistance (MDR) is the leading cause of failure for breast cancer in the clinic. Thus far, polymer–lipid hybrid nanoparticles (PLN) loaded chemotherapeutic agents has been used to overcome MDR in breast cancer. In this study, we prepared psoralen polymer–lipid hybrid nanoparticles (PSO-PLN) to reverse drug resistant MCF-7/ADR cells in vitro and in vivo. PSO-PLN was prepared by the emulsification evaporation-low temperature solidification method. The formulation, water solubility and bioavailability, particle size, zeta potential and entrapment efficiency, and in vitro release experiments were optimized in order to improve the activity of PSO to reverse MDR. Optimal formulation: soybean phospholipids 50?mg, poly(lactic-co-glycolic) acid (PLGA) 15?mg, PSO 3?mg, and Tween-80 1%. The PSO-PLN possessed a round appearance, uniform size, exhibited no adhesion. The average particle size was 93.59?±?2.87?nm, the dispersion co-efficient was 0.249?±?0.06, the zeta potential was 25.47?±?2.84?mV. In vitro analyses revealed that PSO resistance index was 3.2, and PSO-PLN resistance index was 5.6, indicating that PSO-PLN versus MCF-7/ADR reversal effect was significant. Moreover, PSO-PLN is somewhat targeted to the liver, and has an antitumor effect in the xenograft model of drug-resistant MCF-7/ADR cells. In conclusion, PSO-PLN not only reverses MDR but also improves therapeutic efficiency by enhancing sustained release of PSO.     

Targeted delivery of monoclonal antibody conjugated docetaxel loaded PLGA nanoparticles into EGFR overexpressed lung tumour cells

The aim of this study was to develop anti-EGFR antibody conjugated poly(lactide-co-glycolide) nanoparticles (NPs) to target epidermal growth factor receptor, highly expressed on non-small cell lung cancer cells to improve cytotoxicity and site specificity. Cetuximab was conjugated to docetaxel (DTX) loaded PLGA NPs by known EDC/NHS chemistry and characterised for size, zeta potential, conjugation efficiency and the results were 128.4?±?3.6?nm, –31.0?±?0.8?mV, and 39.77?±?3.4%, respectively. In vitro release study demonstrated sustained release of drug from NPs with 25% release at pH 5.5 after 48?h. In vitro cytotoxicity studies demonstrated higher anti-proliferative activity of NPs than unconjugated NPs. Cell cycle analysis and apoptosis study were performed to evaluate extent of cell arrest at different phases and apoptotic potential for the formulations, respectively. In vivo efficacy study showed significant reduction in tumour growth and so antibody conjugated NPs present a promising active targeting carrier for tumour selective therapeutic treatment.     

Novel Topical Ophthalmic Formulations for Management of Glaucoma

Purpose

Preparation of topical ophthalmic formulations containing brimonidine-loaded nanoparticles prepared from various biodegradable polymers—PCL, PLA and PLGA—for sustained release of brimonidine as a once daily regimen for management of glaucoma.

Methods

Nanoparticles were prepared using spontaneous emulsification solvent diffusion method then characterized regarding their particle size, zeta potential, morphology and drug contents. Brimonidine-loaded nanoparticles were incorporated into eye drops, temperature-triggered in situ gelling system and preformed gel and characterized regarding their pH, viscosity, uniformity of drug contents, in vitro release study, in vitro cytotoxicity and in vivo intraocular pressure (IOP) lowering effects.

Results

The results of optimized brimonidine-loaded PCL-, PLGA- and PLA-NPs respectively, are: particle sizes of 117.33?±?4.58 nm, 125.67?±?5.15 nm and 131.67?±?3.79 nm; zeta potentials of ?18.5?±?2.87 mV, ?21.82?±?2.7 mV and ?28.11?±?2.21 mV; and encapsulation efficiencies of 77.97?±?1.38%, 68.65?±?3.35% and 73.52?±?2.92%. TEM analyses revealed that all NPs have spherical shapes with dense core and distinct coat. In vitro release data showed a sustained release without any burst effect with Higuchi non-Fickian diffusion mechanism. Cytotoxicity studies revealed that all formulations are non-toxic. Also all formulations possessed a sustained IOP lowering effect compared to Alphagan® P eye drops.

Conclusions

Our formulations showed prolonged management of glaucoma that should meet with better patient compliance as a once-daily formulation.     

Long circulating nanoparticles of etoposide using PLGA‐MPEG and PLGA‐pluronic block copolymers: characterization,drug‐release,blood‐clearance,and biodistribution studies

The anti‐leukemic drug, etoposide (ETO), has variable oral bioavailability ranging from 24–74% with a short terminal half‐life of 1.5 h i.v. necessitating continuous infusion for 24–34 h for the treatment of leukemia. In the present study, etoposide‐loaded PLGA‐based surface‐modified nanoparticles (NPs) with long circulation were designed as an alternative to continuous i.v. administration. PLGA‐mPEG and PLGA‐PLURONIC copolymers were synthesised and used to prepared ETO‐loaded NPs by high‐pressure homogenization. The mean particle size of ETO‐loaded PLGA‐MPEG nanoparticles was 94.02±3.4 nm, with an Entrapment Efficiency (EE) of 71.2% and zeta potential value of −6.9±1.3 mV. ETO‐loaded PLGA‐pluronic nanoparticles had a mean particle size of 148.0±2.1 nm, an EE of 73.12±2.7%, and zeta potential value of −21.5±1.6 mV. In vitro release of the pure drug was complete within 4 h, but was sustained up to 7 days from PLGA‐mPEG nanoparticles and for 5 days from PLGA‐pluronic nanoparticles. Release was first order and followed non‐Fickian diffusion kinetics in both instances. ETO and ETO‐loaded PLGA nanoparticles labeled with ^99mTc were used in blood clearance studies in rats where the two coated NPs, ^99mTc‐ ETO‐PLGA‐PLU NP and ^99mTc‐ ETO‐PLGA‐mPEG NP, were found to be available in higher concentrations in the circulation as compared to the pure drug. Biodistribution studies in mice showed that ETO‐loaded PLGA‐MPEG NP and PLGA‐PLURONIC NP had reduced uptake by the RES due to their steric barrier properties and were present in the circulation for a longer time. Moreover, the NPs had greater uptake in bone and brain where concentration of the free drug, ETO, was negligible. Drug delivered from these NPs could result in a single i.v. injection that would release the drug for a number of days, which would be potentially beneficial and in better control of leukemia therapy. Drug Dev Res 71: 228–239, 2010. © 2010 Wiley‐Liss, Inc.     

Dextran microspheres could enhance immune responses against PLGA nanospheres encapsulated with tetanus toxoid and Quillaja saponins after nasal immunization in rabbit

Potent immunoadjuvants are needed to elicit responses following mucosal delivery. PLGA (poly[D,L-lactic-co-glycolic acid]) nanospheres, Quillaja saponin (QS) and cross-linked dextran microspheres (CDM) as drug delivery and absorption enhancer adjuvants were evaluated. PLGA nanospheres were prepared by solvent evaporation method. Particulate characteristics of nanospheres were studied by optical and scanning electron microscopes and dynamic light scattering technique. The mean diameter of nanospheres encapsulated with TT and TT?+?QS determined as 425 and 390?nm. Loadings of TT and QS were 30?±?1.9% and 23?±?2.8%. Nanospheres encapsulated with TT or QS were intranasally administered to rabbits, three times in two-week intervals and the serum IgG and nasal lavage IgA titers were determined by ELISA. The serum IgG titer induced with (TT)_PLGA nanospheres was higher than TT solution (P?<?0.001). IgG titers induced with (TT?+?QS)_PLGA was higher than (TT)_PLGA (P?<?0.0001). When (TT)_PLGA and (TT?+?QS)_PLGA nanospheres were mixed with CDM, higher IgG titers were induced (P?<?0.001). The highest mucosal sIgA titers were seen in animals immunized with (TT?+?QS)_PLGA?+?CDM. Co-encapsulation of QS and TT in PLGA nanospheres increased sIgA titers. In conclusion, the highest immune responses were observed by concomitant use of three adjuvants.     

Effects of formulation parameters on encapsulation efficiency and release behavior of thienorphine loaded PLGA microspheres

To develop a long-acting injectable thienorphine biodegradable poly (d, l-lactide-co-glycolide) (PLGA) microsphere for the therapy of opioid addiction, the effects of formulation parameters on encapsulation efficiency and release behavior were studied. The thienorphine loaded PLGA microspheres were prepared by o/w solvent evaporation method and characterized by HPLC, SEM, laser particle size analysis, residual solvent content and sterility testing. The microspheres were sterilized by gamma irradiation (2.5 kGy). The results indicated that the morphology of the thienorphine PLGA microspheres presented a spherical shape with smooth surface, the particle size was distributed from 30.19?±?1.17 to 59.15?±?0.67μm and the drug encapsulation efficiency was influenced by drug/polymer ratio, homogeneous rotation speed, PVA concentration in the water phase and the polymer concentration in the oil phase. These changes were also reflected in drug release. The plasma drug concentration vs. time profiles were relatively smooth for about 25 days after injection of the thienorphine loaded PLGA microspheres to beagle dogs. In vitro and in vivo correlation was established.     

Lipid Based nanoformulation of lycopene improves oral delivery: formulation optimization,ex vivo assessment and its efficacy against breast cancer

This study aims at developing an optimised nanostructured lipid carrier (NLC) of lycopene for efficient absorption following oral administration. The optimised formulation showed an average particle size of 121.9?±?3.66?nm, polydispersity index (PDI) 0.370?±?0.97 and zeta potential ?29.0?±?0.83?mV. Encapsulation Efficiency (% EE) and drug loading (% DL) was found to be 84.50%?±?4.38 and 9.54%?±?2.65, respectively. In vitro release studies demonstrated the burst release within 4–9?h followed by sustained release over 48?h. The IC₅₀ value of lycopene extract and optimised NLC for ABTS^+? were found to be 172.37?μg Trolox equivalent and 184.17?μg Trolox equivalent whereas, for DPPH^?, 117.76?μg Trolox equivalent and 143.08?μg Trolox equivalent respectively. Ex vivo studies and MTT assay revealed that the NLC had better permeation and cause sufficiently more cytotoxicity as compared to drug extract due to higher bioavailability and greater penetration.     

Formulation and in vitro characterization of poly(dl-lactide-co-glycolide)/Eudragit RLPO or RS30D nanoparticles as an oral carrier of levofloxacin hemihydrate

The main objective of this study was to design positively charged Levofloxacin Hemihydrate (Levo-h)-loaded nanoparticles with improved entrapment efficiency and antibacterial activity. PLGA alone or in combinations with Eudragit® RLPO or RS30D with or without positively charged inducing agent; 1,2-dioleoyl-3-trimethylammonium-propane, chloride salt (DOTAP); were used for preparation of nanoparticles. Blending between PLGA and Eudragit® RLPO or RS30D with inclusion of DOTAP caused a marked increase in entrapment efficiency and switched zeta potential from negative to positive. Nanoparticle formulations; NR3 (Levo-h:PLGA:Eudragit® RLPO; 1:1:1 w/w with DOTAP) and NS3 (Levo-h:PLGA:Eudragit® RS30D; 1:1:1 w/w with DOTAP) that possess high positive zeta potential (59.3?±?7.5 and 55.1?±?8.2?mV, respectively) and Efficient Levo-h entrapment (89.54?±?1.5 and 77.65?±?1.8%, respectively) were selected for further examinations; in vitro release, physical stability and microbiological study. NR3 and NS3 showed significant sustained release of Levo-h. NR3 and NS3 exhibited good stability after storage at room temperature. Microbiological assay showed strengthened antibacterial activity of NR3 against both types of gram-negative bacteria (E. coli, Ps. aeruginosa) and of NS3 against Ps. aeruginosa compared to free Levo-h solution. NR3 and NS3 appear to be promising oral delivery system for Levo-h.     

Effects of alginate coated on PLGA microspheres for delivery tetracycline hydrochloride to periodontal pockets

The effects of alginate coated on tetracycline (Tc) loaded poly (D, L-lactic-co-glycolic acid) (PLGA) microspheres fabricated by double emulsion solvent evaporation technique for local delivery to periodontal pocket were investigated. Alginate coated PLGA microspheres showed smoother surface but enlarged their particle sizes compared with those of uncoated ones. In addition, alginate coated microspheres enhanced Tc encapsulation efficiency (E.E.) from 11.5?±?0.5% of uncoated ones to 17.9?±?0.5%. Moreover, all of the coated PLGA microspheres even fabricated at different conditions could prolong Tc release from 9–12 days with 50% or higher in cumulative release of Tc compared with those of uncoated ones. The swelling ratios of PLGA microspheres for alginate coated or uncoated ones, one of the possible mechanisms for enhancing Tc release for the coated ones, were measured. The results showed that 20% or higher in swelling ratio for the coated microspheres at the earlier stage of hydration (e.g.?≤?24?h) could be an important factor to result in high Tc release compared to the uncoated ones. In conclusion, alginate coated Tc loaded PLGA microspheres could enhance Tc delivery to periodontal pocket by enhancing drug encapsulated efficiency, released quantities and sustained release period compared with uncoated ones.     

Controlled release behaviour of protein-loaded microparticles prepared via coaxial or emulsion electrospray

Biodegradable poly (lactic-co-glycolic acid) (PLGA) microparticles are an effective way to achieve sustained drug release. In this study, we investigated a sustained release model of PLGA microparticles with incorporated protein via either emulsion or coaxial electrospray techniques. PLGA (75:25) was used as the carrier, and bovine serum albumin as a model protein. Coaxial electrospray resulted in a type of core–shell structure with mean diameters of 2.41?±?0.60?µm and a centralised protein distribution within the core. Emulsion electrospray formed bigger microparticles with mean diameters of 22.75?±?8.05?µm and a heterogeneous protein distribution throughout the microparticles. The coaxial electrospray microparticles presented a much slighter burst release than the emulsion electrospray microparticles. Loading efficiency was significantly higher (p?<?0.05) in the coaxial group than emulsion group. This indicated that both emulsion and coaxial electrospray could produce protein-loaded microparticles with sustained release behaviour, but the former revealed a superior approach for drug delivery.     

5-Fluorouracil-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: Characterization and drug release

5-Fluorouracil (5-FU), a hydrosoluble anti-neoplastic drug, was encapsulated in microspheres of poly(D,L-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) polymers using the spray-drying technique, in order to obtain small size microspheres with a significant drug entrapment efficiency. Drug-loaded microspheres included between 47?±?11 and 67?±?12?µg 5-FU?mg^?1 microspheres and the percentage of entrapment efficiency was between 52?±?12 and 74?±?13. Microspheres were of small size (average diameter: 0.9?±?0.4–1.4?±?0.8?µm microspheres without drug; 1.1?±?0.5–1.7?±?0.9?µm 5-FU-loaded microspheres) and their surface was smooth and slightly porous, some hollows or deformations were observed in microspheres prepared from polymers with larger T_g. A fractionation process of the raw polymer during the formation of microspheres was observed as an increase of the average molecular weight and also of T_g of the polymer of the microspheres. The presence of 5-FU did not modify the T_g values of the microspheres. Significant interactions between the drug and each one of the polymers did not take place and total release of the included drug was observed in all cases. The time needed for the total drug release (28–129?h) was in the order PLA?>?PLGA 75/25?>?PLGA 50/50. A burst effect (17–20%) was observed during the first hour and then a period of constant release rate (3.52?±?0.82–1.46?±?0.26?µg 5-FU?h^?1 per milligram of microspheres) up to 8 or 13?h, depending on the polymer, was obtained.     

Preparation,Physicochemical Characterization and Anti-fungal Evaluation of Nystatin-Loaded PLGA-Glucosamine Nanoparticles

Purpose

Nystatin loaded PLGA and PLGA-Glucosamine nanoparticles were formulated. PLGA were functionalized with Glucosamine (PLGA-GlcN) to enhance the adhesion of nanoparticles to Candida Albicans (C.albicans) cell walls.

Method

Quasi-emulsion solvent diffusion method was employed using PLGA and PLGA-GlcN with various drug–polymer ratios for the preparation of nanoparticles. The nanoparticles were evaluated for size, zeta potential, polydispersity index, drug crystallinity, loading efficiency and release properties. DSC, SEM, XRPD, ¹H-NMR, and FT-IR were performed to analyze the physicochemical properties of the nanoparticles. Antifungal activity of the nanoparticles was evaluated by determination of MICs against C.albicans.

Results

The spectra of ¹H-NMR and FT-IR analysis ensured GlcN functionalization on PLGA nanoparticles. SEM characterization confirmed that particles were in the nanosize range and the particle size for PLGA and PLGA-GlcN nanoparticles were in the range of 108.63?±?4.5 to 168.8?±?5.65 nm and 208.76?±?16.85 nm, respectively. DSC and XRPD analysis ensured reduction of the drug crystallinity in the nanoparticles. PLGA-GlcN nanoparticles exhibit higher antifungal activity than PLGA nanoparticles.

Conclusion

PLGA-GlcN nanoparticles showed more antifungal activity with appropriate physicochemical properties than pure Nystatin and PLGA nanoparticles.

     

Development and evaluation of long-acting epidural “smart” thermoreversible injection loaded with spray-dried polymeric nanospheres using experimental design

Context: Reduction of injection frequency as well as localization of drug absorption in the injection site are important requirements in epidural pain treatment. Purpose: Our objective is to explore the production feasibility of controlled release thermoresponsive spray-dried tramadol HCl (TmH) nanospheres for localized epidural injection. Methods: A 2⁴ factorial design was employed to study the effect of some selected variables. Results: F15 having the most extended release (MDT = 89.03?±?0.76?min) was selected, based on regression analysis, for further investigation and characterization. The selected nanospheres (particle diameter = 832.5?±?10.61?nm) with good flowing properties (θ = 28.076?±?1.20) was reconstituted with different concentrations of Poloxamer 407 (P407) solution. The optimum reconstituted F15 nanospheres, prepared using 20% w/w P407, was liquid at room temperature, exhibited sol-gel transition at 37°C, was easily withdrawn and injected using 23G needle. The evaluation of the analgesic effect of the selected formula using hot plate method showed a desired rapid onset, yet, extended analgesic effect up to 24?h. The AUC_{0–24 h} (2998.072?±?61.830) as well as E_max (200.788?±?12.123) were significantly higher than drug solution and control while T_max (2.200?±?1.095) was non-significant compared to both. Conclusion: the designed formula offers a promising approach as safe depot epidural analgesic.     

Improved bioavailability of orally delivered insulin using Eudragit-L30D coated PLGA microparticles

Large porous microparticles of PLGA entrapping insulin were prepared by solvent evaporation method and evaluated in diabetes induced rat for its efficacy in maintaining blood sugar level from a single oral dose. Incorporation of Eudragit L30D (0.03% w/v) in the external aqueous phase resulted in formation of pH responsive enteric coated polymer particles which release most of the entrapped insulin in alkaline pH. At acidic pH, release of insulin from uncoated PLGA microparticles and Eudragit L30D coated PLGA microparticles was 31.62?±?1.8% and 17.5?±?1.29%, respectively, for initial 30 min. However, in 24 h, in vitro released insulin from uncoated PLGA and Eudragit coated particles was 96.29?±?1.01% and 88.30?±?1%, respectively. Released insulin from composite polymer particles were mostly in monomer form without aggregation and was stable for a month at 37°C. Oral administration of insulin loaded PLGA (50 : 50) and Eudragit L30D coated PLGA (50 : 50) microparticles (equivalent to 25 IU insulin/kg of animal weight) in alloxan induced diabetic rats resulted in 37.3?±?11% and 62.7?±?3.8% reduction in blood glucose level, respectively, in 2 h. This effect continued up to 24 h in the case of Eudragit L30D coated PLGA microparticles. Results demonstrate that use of stabilizers during PLGA particle formulation, large porous particle for quick release of insulin and coating with Eudragit L30D resulted in a novel oral formulation for once a day delivery of insulin.     

Revisiting the nanoformulation design approach for effective delivery of topotecan in its stable form: an appraisal of its in vitro Behavior and tumor amelioration potential

Topotecan (TPT) is indicated against a variety of solid tumors, but has restricted clinical use owing to associated pharmaceutical caveats. This study is focused at formulating a successful TPT PLGA nanosystem which ameliorates the rapid conversion of active lactone form of drug to its inactive carboxylate form and consequently improvises its efficacy. TPT PLGA nanoparticles were formulated by a double emulsion-solvent evaporation technique with sequential optimization to obtain desired particle size, PDI, zeta potential, and entrapment efficiency. Stability of TPT was ensured by maintaining an acidic pH in the drug-containing phase and the system was evaluated for in vitro–in vivo performance including cytotoxic potency. The optimized nanosystem had a particle size of 187.33?±?7.50?nm, a PDI of 0.179?±?0.05, and an entrapment efficiency of 56?±?1.2%. Low pH in the interior of nanoparticles stabilized the drug to remain in its active lactone form and revealed a biphasic release pattern till 15?d. Additionally, an in vitro cytotoxicity testing as well as in vivo antitumor efficacy demonstrated a significant potential of higher proliferation inhibition as compared with neat drug (TPT). Thus, the investigation summarized an innovative simple tool for developing stable TPT NPs for effective delivery for treating solid tumors.     

Preparation and in vitro–in vivo evaluation of surface-modified poly(lactide-co-glycolide) nanoparticles as controlled release carriers for flutamide delivery

Abstract

This investigation explores the use of methoxy polyethylene glycol (mPEG) functionalised poly(d,l-lactide-co-glycolide) (PLGA) nanocrystals of flutamide (FLT) with enhanced solubility, bioavailability and blood circulation time for targeting prostate cancer. FLT had Log P 3.27, short half life 5–6?h, low water solubility, permeability and bioavailability with extensive first-pass metabolism. FLT-loaded nanocrystals were prepared using nanoprecipitation method with surface coating by mPEG and characterised through differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray powder diffraction, scanning electronic microscopy, particle size, zeta potential, percent entrapment efficiency (% EE), in vitro dissolution, haemolysis, sterility, bioavailability and stability studies. The percent cumulative drug release and % EE of optimised formulation was found to be 95.21?±?1.18 and 88.36?±?1.20, respectively, for 48?h. In addition, FLT-loaded PEGylated PLGA nanocrystals exhibited significantly delayed blood clearance with drug level of about 766.71?ng/mL at 48?h. In conclusion, PEGylated PLGA FLT nanocrystals could be demonstrated as a novel approach to enhance solubility, bioavailability and blood circulation time.