Novel in situ gelling vaginal sponges of sildenafil citrate-based cubosomes for uterine targeting

Sildenafil citrate (SIL), a type 5-specific phosphodiesterase inhibitor, demonstrates valuable results in the management of infertility in women; however, the absence of vaginal dosage form in addition to the associated oral adverse effects minimize its clinical performance. The present study is concerned with SIL uterine targeting following intravaginal administration via optimization of cubosomal in situ gelling sponges (CIS). An emulsification method was employed for preparation of cubosomal dispersions incorporating glyceryl monooleate as a lipid phase and poloxamer 407 as a surfactant with or without polyvinyl alcohol as a stabilizer. Cubosomes were estimated regarding entrapment efficiency (EE%), particle size, and in vitro drug release. Chitosan (2% w/w) was incorporated into the optimum formulation and then lyophilized into small sponges. For the CIS, in vivo histopathological and pharmacokinetic studies were conducted on female Wistar rats and compared with intravaginal free SIL sponges (FIS) and oral SIL solution. SIL-loaded cubosomes showed EE% ranging between 32.15 and 72.01%, particle size in the range of 150.81–446.02?nm and sustained drug release over 8?h. Histopathological study revealed a significant enlargement in endometrial thickness with congestion and dilatation of endometrial blood vessels in intravaginal CIS compared to intravaginal FIS and oral-treated groups. The pharmacokinetic study demonstrated higher AUC_0–∞ and C_max with oral administration compared to intravaginal CIS or intravaginal FIS indicating potential involvement of first uterine pass effect after intravaginal administration. Finally, intravaginal CIS could be considered as a promising platform for SIL uterine targeting with minimized systemic exposure and side effects.     

Recent advances in drug delivery applications of cubosomes,hexosomes, and solid lipid nanoparticles

The use of lipid nanocarriers for drug delivery applications is an active research area, and a great interest has particularly been shown in the past two decades. Among different lipid nanocarriers, ISAsomes (Internally self-assembled somes or particles), including cubosomes and hexosomes, and solid lipid nanoparticles (SLNs) have unique structural features, making them attractive as nanocarriers for drug delivery. In this contribution, we focus exclusively on recent advances in formation and characterization of ISAsomes, mainly cubosomes and hexosomes, and their use as versatile nanocarriers for different drug delivery applications. Additionally, the advantages of SLNs and their application in oral and pulmonary drug delivery are discussed with focus on the biological fates of these lipid nanocarriers in vivo. Despite the demonstrated advantages in in vitro and in vivo evaluations including preclinical studies, further investigations on improved understanding of the interactions of these nanoparticles with biological fluids and tissues of the target sites is necessary for efficient designing of drug nanocarriers and exploring potential clinical applications.KEY WORDS: Biological fate, Cubosomes, Drug delivery, Hexosomes, Inverse non-lamellar liquid crystalline phases, Nano-self-assemblies, Solid crystalline phases, Solid lipid nanoparticles     

Cubic liquid crystalline nanoparticles containing a polysaccharide from Ulva fasciata with potent antihyperlipidaemic activity

The present study involves the preparation of cubic liquid crystalline nanoparticles (cubsomes) for liver targeting to assess the potential of a formulated bioactive polysaccharide isolated from the hot aqueous extract of Ulva fasciata as an alternative natural agent with anti-hyperlipidaemic activity. Cubosomal nanoparticles were prepared by disrupting the cubic gel phase of the polysaccharide and water in the presence of a surfactant. Different lipid matrices and stabilizers were tested. All the formulations were in the nanosize range and showed sufficient negative charge to inhibit the aggregation of the cubosomes. Drug entrapment efficiencies (EEs%) were determined and in vitro release studies were performed. Transmission electron microscopy (TEM) and differential scanning calorimetry were used to analyze the loaded cubosomal nanoparticles containing glyceryl monostearate (GMO 2.25?g), poloxamer 407 (0.25?g) and 50?mg of the polysaccharide. A preclinical study comparing the cubic liquid crystalline nanoparticles containing polysaccharide to fluvastatin as a reference drug in hyperlipidaemic rats was conducted. The rats treated with the polysaccharide- loaded cubosomes showed significant decreases in total cholesterol (TC), triglycerides (TG) and total lipid (TL) compared to the untreated HL rats. In addition, oxidative stress and antioxidant biomarkers were measured in the HL rats. Compared to the untreated HL rats, the cubosome treated rats showed a significant reduction in malondialdehyde (MDA), whereas insignificant changes were detected in nitric oxide (NO), glutathione (GSH) levels and total antioxidant capacity (TAC). Further, vascular and intercellular adhesion molecules (VCAM, ICAM), and myeloperoxidase were demonstrated. A histopathological examination was conducted to study the alterations in histopathological lesions and to document the biochemical results. In conclusion, this study demonstrates the superiority of using a natural lipid regulator such as polysaccharide loaded cubosomes instead of fluvastatin.     

Preparation of phytantriol cubosomes by solvent precursor dilution for the delivery of protein vaccines

Different delivery strategies to improve the immunogenicity of peptide/protein-based vaccines are currently under investigation. In this study, the preparation and physicochemical characterisation of cubosomes, a novel lipid-based particulate system currently being explored for vaccine delivery, was investigated. Cubosomes were prepared from a liquid precursor mixture containing phytantriol or glycerylmonooleate (GMO), F127 for particle stabilisation, and a hydrotrope (ethanol or polyethylene glycol (PEG₂₀₀) or propylene glycol (PG)). Several liquid precursors were prepared, and the effect of varying the concentrations of F127 and the hydrotrope on cubosome formation was investigated. Formulations were prepared by fragmentation for comparison. The model protein ovalbumin (Ova) was also entrapped within selected formulations. Submicron-sized particles (180-300 nm) were formed spontaneously upon dilution of the liquid precursors, circumventing the need for the preformed cubic phase used in traditional fragmentation-based methods. The nanostructure of the phytantriol dispersions was determined to be cubic phase using SAXS whilst GMO dispersions had a reverse hexagonal nanostructure coexisting with cubic phase. The greatest entrapment of Ova was within phytantriol cubosomes prepared from liquid precursors. Release of Ova from the various formulations was sustained; however, release was significantly faster and the extent of release was greater from fragmented dispersions compared to liquid precursor formulations. Taken together, these results suggest that phytantriol cubosomes can be prepared using liquid precursors and that it is a suitable alternative to GMO. Furthermore, the high entrapment and the slow release of Ova in vitro highlight the potential of phytantriol cubosomes prepared using liquid precursors as a novel vaccine delivery system.     

Preparation and Characterization of PEG-albumin-curcumin Nanoparticles Intended to Treat Breast Cancer

The aim of present research was to prepare novel serum stable long circulating polymeric nanoparticles for curcumin with a modification to the well known and novel nanoparticle albumin bound technology. polyethylene glycol-albumin-curcumin nanoparticles were prepared using serum albumin and poly ethylene glycol using desolvation technique. Nanoparticles were characterized for encapsulation efficiency, particle size and surface morphology. Drug excipient compatibility was determined using fourier transform infrared spectroscopy. Physical state of the drug in the formulations was known by differential scanning colorimetry. In vitro release and solubility of the drug from nanoparticles were determined. In vivo Drug release, tissue uptake and kupffer cell uptake was determined with optimized nanoformulation in rats after intravenous administration. Cell viability assay was determined using breast cancer cell line MD-MB-231. Entrapment efficiency for prepared nanoparticle was above 95%. The polyethylene glycol-albumin-curcumin nanoparticles exhibited an interesting release profile with small initial burst followed by slower and controlled release. Solubility of the drug from the formulation was increased. A sustained release of drug from nanoparticles was observed for 35 days in both in vitro and in vivo studies with the optimized formulation. Polyethylene glycol-albumin-curcumin nanoparticles showed lesser liver and kupffer cell uptake as compared to that of curcumin-albumin nanoparticles suggesting the bestowment of stealthness to nanoparticles with pegylation. Also, the antiproliferative activity of polyethylene glycol-albumin-curcumin nanoparticle formulation was more as compared to native curcumin. Polyethylene glycol-albumin-curcumin nanoparticles thus developed can be conveniently used in breast cancer with improved efficacy compared to conventional therapies and as an alternate to nanoparticle albumin bound technology which is used in producing Abraxane, albumin based breast cancer targeting nanoparticles of paclitaxel.     

Cubosomes as a Potential Oral Drug Delivery System for Enhancing the Hepatoprotective Effect of Coenzyme Q10

Coenzyme Q10 (CoQ10) acts as an antioxidant that protects the cells by preventing lipid peroxidation. Owing to its low solubility, CoQ10 has shown poor delivery properties and poor bioavailability. The aim of this study is to develop CoQ10 loaded cubosomes in order to enhance its oral delivery and hepatoprotective activity. Cubosomes are cubic nanostructured systems resulting from the colloidal dispersion of cubic liquid crystalline structure in water. CoQ10 loaded cubosomes were prepared using poloxamer 407 and glyceryl monooleate at three weight ratios (1:2.5, 1:5 and 1:7.5) and were further characterized. They were investigated for their hepatoprotective effect in thioacetamide (TAA) induced hepatotoxicity in Wistar rats. The developed CoQ10 cubosomes exhibited moderate to high entrapment efficiency percentages (44.69–75.96%), nanometric dimensions (132.4–223.2 nm), and negatively charged zeta potential values (<-21.3). In-vitro release profiles showed a sustained release of CoQ10 from the developed cubosomes up to 48 h. In-vivo study revealed an improved hepatoprotective effect of CoQ10 cubosomes via reducing liver enzymes, nitric oxide and malondialdehyde as well as elevating phosphoinositide 3-kinase, catalase and glutathione peroxidase, compared to plain drug. These results were in good agreement with histopathological investigations. Consequently, the developed cubosomes showed a potential effect in enhancing the hepatoprotective activity of CoQ10.     

Formulation and Characterization of Pyrazinamide Polymeric Nanoparticles for Pulmonary Tuberculosis: Efficiency for Alveolar Macrophage Targeting

Pyrazinamide, a highly specific agent against Mycobacterium tuberculosis is used as first-line drug to treat tuberculosis. The current work aims to formulate polymeric nanoparticles based drug delivery system to sustain the release profile and reduce the dosing frequency of pyrazinamide. Further aim was to target the macrophages within body fluid. These polymeric nanoparticles were prepared by simultaneous double-emulsion (W/O/W) solvent evaporation/diffusion technique. The prepared dispersions were characterized for various biopharmaceutical parameters such as particle size, zeta potential, polydispersity index, drug loading capacity, entrapment efficiency and targeting to alveolar macrophages. The formulated polymeric nanoparticles were in the particle size range of 45.51 to 300.4 nm with a maximum drug entrapment efficiency of 80.9%. The stability study of optimized batch conducted at 40±2°/75±5% relative humidity showed no significant changes up to 90 days. X-Ray Diffraction spectrum exhibits the transformation of crystalline form of drug to amorphous in the formulation. Scanning Electron Microscope image showed nanoparticles spherical in shape with smooth surface. In vitro release profiles were biphasic in nature with burst release followed by controlled release over a period of 24 h obeying diffusion mechanism. In vivo and ex vivo studies results of the study show significant uptake of the nanoparticles by alveolar macrophages through fluorescent micrograph. Polymeric nanoparticles formulation of pyrazinamide could encompass significant uptake by alveolar macrophages, the high first-pass metabolism, sustain the release of drug leading to reduction in dose, toxicity and improvement of patient compliance.     

Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route

Intranasal drug administration is receiving increased attention as a delivery method for bypassing the blood–brain barrier and rapidly targeting therapeutics to the CNS. However, rapid mucociliary clearance in the nasal cavity is a major hurdle. The purpose of this study was to evaluate the effect of mucoadhesive polymers in enhancing the delivery of nimodipine microemulsion to the brain via the intranasal route. The optimized mucoadhesive microemulsion was characterized, and the in vitro drug release and in vivo nasal absorption of drug from the new formulation were evaluated in rats. The optimized formulation consisted of Capmul MCM as oil, Labrasol as surfactant, and Transcutol P as co-surfactant, with a particle size of 250 nm and zeta potential value of −15 mV. In vitro and ex vivo permeation studies showed an initial burst of drug release at 30 min and sustained release up to 6 h, attributable to the presence of free drug entrapped in the mucoadhesive layer. In vivo pharmacokinetic studies in rats showed that the use of the mucoadhesive microemulsion enhanced brain and plasma concentrations of nimodipine. These results suggest that incorporation of a mucoadhesive agent in a microemulsion intranasal delivery system can increase the retention time of the formulation and enhance brain delivery of drugs.KEY WORDS: Blood–brain barrier, Entrapment, Permeation, Pharmacokinetics, Nasal mucosa     

Superiority of liquid crystalline cubic nanocarriers as hormonal transdermal vehicle: comparative human skin permeation-supported evidence

ABSTRACT

Objectives: The aim of this investigation was to explore the feasibility of various nanocarriers to enhance progesterone penetration via the human abdominal skin.

Methods: Four progesterone-loaded nanocarriers; cubosomes, nanoliposomes, nanoemulsions and nanomicelles were formulated and characterized regarding particle size, zeta potential, % drug encapsulation and in vitro release. Structural elucidation of each nanoplatform was performed using transmission electron microscopy. Ex vivo skin permeation, deposition ability and histopathological examination were evaluated using Franz diffusion cells.

Results: Each nanocarrier was fabricated with a negative surface, nanometric size (≤ 270 nm), narrow size distribution and reasonable encapsulation efficiency. In vitro progesterone release showed a sustained release pattern for 24 h following a non-Fickian transport diffusion mechanism. All nanocarriers exhibited higher transdermal flux relative to free progesterone. Cubosomes revealed a higher skin penetration with transdermal steady flux of 48.57.10^–2 ± 0.7 µg/cm² h. Nanoliposomes offered a higher percentage of skin progesterone deposition compared to other nanocarriers. Based on the histopathological examination, cubosomes and nanoliposomes were found to be biocompatible for transdermal application. Confocal laser scanning microscopy confirmed the ability of fluoro-labeled cubosomes to penetrate through the whole skin layers.

Conclusion: The elaborated cubosomes proved to be a promising non-invasive nanocarrier for transdermal hormonal delivery.     

PCL films incorporated with paclitaxel/5-fluorouracil: Effects of formulation and spacial architecture on drug release

The bi/tri-layered poly(?-caprolactone) (PCL)-based films co-loaded with 5-fluorouracil (5-FU) and paclitaxel (PTX) are presented for biodegradable film-based stent application. A gradient elution HPLC analytical method was used for simultaneous quantification of 5-FU and PTX. Scanning electron microscopy (SEM) was performed to observe the microscopic architecture and morphologies, and X-ray diffraction (XRD) was employed for analyzing the physical state of the components in the single layer film. Horizontal cells diffusion test results indicated that the multi-layered structure endowed the film with drug release in unidirectional pattern. The in vitro release results showed that drug release was dependent on the drug loading, the ratio of 5-FU/PTX, the composition of surface layer, as well as the addition of hydrophilic PEG. The cytotoxicity results indicated that the PCL-based films co-loaded with 5-FU and PTX could effectively inhibit the proliferation of Eca-109 cells. The in vivo drug release results showed that the in vivo drug release was highly correlative with the in vitro drug releases. This study provided PCL-based films co-loaded with 5-FU and PTX with great potential for anti-tumor stent application, due to their unidirectional and rate-tunable drug release characteristics and dual drug loading capacity.     

Formulation and optimization of coated PLGA – Zidovudine nanoparticles using factorial design and in vitro in vivo evaluations to determine brain targeting efficiency

In the current study zidovudine loaded PLGA nanoparticles were prepared, coated and further investigated for its effectiveness in brain targeting. IR and DSC studies were performed to determine the interaction between excipients used and to find out the nature of drug in the formulation. Formulations were prepared by adopting 2³ factorial designs to evaluate the effects of process and formulation variables. The prepared formulations were subjected for in vitro and in vivo evaluations. In vitro evaluations showed particle size below 100 nm, entrapment efficiency of formulations ranges of 28–57%, process yield of 60–76% was achieved and drug release for the formulations were in the range of 50–85%. The drug release from the formulations was found to follow Higuchi release pattern, n–value obtained after Korsemeyer plot was in the range of 0.56–0.78. In vivo evaluations were performed in mice after intraperitoneal administration of zidovudine drug solution, uncoated and coated formulation. Formulation when coated with Tween 80 achieved a higher concentration in the brain than that of the drug in solution and of the uncoated formulation. Stability studies indicated that there was no degradation of the drug in the formulation after 90 days of preparation when stored in refrigerated condition.     

Development and characterization of 5-FU bearing ferritin appended solid lipid nanoparticles for tumour targeting

Ferritin coupled solid lipid nanoparticles were investigated for tumour targeting. Solid lipid nanoparticles were prepared using HSPC, cholesterol, DSPE and triolien. The SLNs without ferritin which has similar lipid composition were used for comparison. SLNs preparations were characterized for shape, size and percentage entrapment. The average size of SLNs was found to be in the range 110–152 nm and maximum drug entrapment was found to be 34.6–39.1%. In vitro drug release from the formulations is obeying fickian release kinetics. Cellular uptake and IC₅₀ values of the formulation were determined in vitro in MDA-MB-468 breast cancer cells. In vitro cell binding of Fr-SLN exhibits 7.7-folds higher binding to MDA-MB-468 breast cancer cells in comparison to plain SLNs. Ex-vivo cytotoxicity assay on targeted nanoparticles gave IC₅₀ of 1.28 µM and non-targeted nanoparticles gave IC₅₀ of 3.56 µM. In therapeutic experiments, 5-FU, SLNs and Fr-SLNs were administered at the dose of 10 mg 5-FU/kg body weight to MDA-MB-468 tumour bearing Balb/c mice. Administration of Fr-SLNs formulation results in effective reduction in tumour growth as compared with free 5-FU and plain SLNs. The result demonstrates that this delivery system possessed an enhanced anti-tumour activity. The results warrant further evaluation of this delivery system.     

Etodolac transdermal cubosomes for the treatment of rheumatoid arthritis: ex vivo permeation and in vivo pharmacokinetic studies

In this study, transdermal etodolac-loaded cubosomes were developed in order to relieve patient pain and joints stiffness by providing stable etodolac concentration at the targeting sites through controlled drug delivery via the noninvasive skin route with more sustaining and less frequent dosing. Different ratios and percentages of poloxamer 407 and monoolein were used to formulate the cubosomes using emulsification and homogenization processes. The etodolac-loaded cubosomes showed particle size values ranging from 135.95 to 288.35?nm and zeta potential values ranging from ?18.40 to ?36.10?mV. All the cubosomes offered an encapsulation efficiency value of about 100% and showed drug loading capacity ranging from 1.28 to 6.09%. The in vitro drug release studies revealed a controlled drug release profile with a drug release rate up to 15.08%/h. Increasing poloxamer concentration in etodolac-loaded cubosomes resulted in nanoparticles with less particle size and faster drug release. The particles exhibited cubic and hexagonal shapes. The DSC and X-ray analysis demonstrated that the drug was encapsulated in the cubosomes bicontinuous structures in amorphous form. In addition, investigated cubosomes exhibited fast drug penetration through excited mice skin followed by slower drug penetration for up to 24?h. The pharmacokinetic study in human volunteers showed that the selected etodolac-loaded cubosomes enhanced the bioavailability of etodolac as compared to the oral capsules (266.11%) with evidence of longer half-life and higher MRT that reached 18.86 and 29.55?h, respectively. The etodolac-loaded cubosomes propose a promising system for treatment of arthritis simply through skin application.     

Aging erythrocyte membranes as biomimetic nanometer carriers of liver-targeting chromium poisoning treatment

Chromium poisoning has become one of the most common heavy metal poisoning occupational diseases with high morbidity and mortality. However, most antidotes detoxify the whole body and are highly toxic. To achieve hepato-targeted chromium poisoning detoxification, a novel hepato-targeted strategy was developed using aging erythrocyte membranes (AEMs) as biomimetic material coated with a dimercaptosuccinic acid (DMSA) nanostructured lipid carrier to construct a biomimetic nano-drug delivery system. The particle size, potential, drug loading, encapsulation rate, in vitro release, and stability of the nanoparticles (NPs) were characterized. Confocal microscopy and flow cytometry showed that the prepared NPs could be phagocytized by RAW264.7 macrophage cells. The efficacy of AEM-DMSA-NPs for targeted liver detoxification was evaluated by in vitro MTT analysis and an in vivo model of chromium poisoning. The results showed that the NPs could safely and efficiently achieve targeted liver chromium poisoning detoxification. All the results indicated that the biomimetic nano-drug delivery system mediated by aging erythrocyte membranes and containing DMSA nanoparticles could be used as a novel therapeutic drug delivery system potentially targeting liver detoxification.     

Formulation and Targeting Efficiency of Cisplatin Engineered Solid Lipid Nanoparticles

The present study is aimed at the overall improvement in the efficacy, reduced toxicity and enhancement of therapeutic index of cisplatin. Solid lipid nanoparticulate delivery system of cisplatin has been developed by microemulsification method by using stearic acid, soy lecithin 95% and sodium glycolate. The formulations were then characterized with respect to size and its surface morphology, zeta potential, entrapment efficiency, in vitro drug release profile, in vivo drug targeting studies and its stability under specific conditions. The formulated solid lipid nanoparticles were oval with a diameter ranging from 250 nm to 500 nm. The lowest entrapment efficiency was found to be 47.59% and highest was found to be 74.53%. The zeta potential was in the range of -9.8 to -11.2 mv. In vitro release study was analyzed using various mathematical models. Highest cumulative percent drug release was observed with F-1 (97.22 %) and lowest with F-4 (78.43%) in 16 h. The in vivo result of formulated solid lipid nanoparticles of cisplatin reveals that the drug is preferentially targeting to liver followed by brain and lungs.     

Low Density Lipid Nanoparticles for Solid Tumor Targeting

One of the most significant characteristics of cancer cells is their rapid dividing ability and overexpression of LDL receptors, which offers an opportunity for the selective targeting of these cells. 5-Fluorouracil (5-FU)-encapsulated low density lipid nanoparticles (LDLN) were prepared by the emulsion congealing method which mimics the plasma-derived LDL by acquiring the apolipoprotein B-100 from the blood. The average particle size, transmission electron microscope (TEM), and drug content of the prepared LDLN dispersion were found to be 161±3.5 nm, with spherical shape, and 0.370±0.05 mg/mL, respectively. In vitro release studies revealed a sustained profile which decreased with a lapse of time. In vivo studies of 5-FU serum concentration and biodistribution revealed a 5-FU serum concentration of 8.5% in tumor cells and about 2.1% in the liver at the end of 24 hr from LDLN. Tumor growth suppression studies showed 185.42% average tumor growth and 89.76% tumor height as compared to the control exhibiting tumor growth at 1166.47% and tumor height at 176.07%. On the basis of these collective data, it is suggested that a higher accumulation of LDLN, when given as an IV, in solid tumors is attributed to the active uptake of LDLN via LDL receptors via apolipoprotein B-100.     

Novel vehicle based on cubosomes for ophthalmic delivery of flurbiprofen with low irritancy and high bioavailability

Aim:

To develop a novel vehicle based on cubosomes as an ophthalmic drug delivery system for flurbiprofen (FB) to reduce ocular irritancy and improve bioavailability.

Methods:

FB-loaded cubosomes were prepared using hot and high-pressure homogenization. Cubosomes were then characterized by particle size, zeta potential, encapsulation efficiency, particle morphology, inner cubic structure and in vitro release. Corneal permeation was evaluated using modified Franz-type cells. Ocular irritation was then evaluated using both the Draize method and histological examination. The ocular pharmacokinetics of FB was determined using microdialysis.

Results:

The particle size of each cubosome formulation was about 150 nm. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray scattering (SAXS) analysis. In vitro corneal permeation study revealed that FB formulated in cubosomes exhibited 2.5-fold (F1) and 2.0-fold (F2) increase in P_app compared with FB PBS. In the ocular irritation test, irritation scores for each group were less than 2, indicating that all formulations exhibited excellent ocular tolerance. Histological examination revealed that neither the structure nor the integrity of the cornea was visibly affected after incubation with FB cubosomes. The AUC of FB administered as FB cubosome F2 was 486.36±38.93 ng·mL⁻¹·min·μg⁻¹, which was significantly higher than that of FB Na eye drops (P<0.01). Compared with FB Na eye drops, the T_max of FB cubosome F2 was about 1.6-fold higher and the MRT was also significantly longer (P<0.001).

Conclusion:

This novel low-irritant vehicle based on cubosomes might be a promising system for effective ocular drug delivery.     

Brain targeted delivery of paclitaxel using endogenous ligand

The objective of the present investigation was to formulate nanoparticles constructed using PLGA polymer for the effective targeted delivery to brain via nasal route. The PLGA nanoparticles were optimized using novel design of experiment technique by 2³ full factorial design. Drug: polymer ratio (X₁), surfactant concentration (X₂) and stirring speed (X₃) were identified as critical process parameters, and its impact on particle size (Y₁) and % entrapment efficiency (Y₂) was studied. The optimized nanoparticle formulation was conjugated with glutathione as an endogenous ligand by using carbodiimide chemistry using (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (EDAC) as linker molecule. From Ellman's assay, it was found that a total of 691.27 ± 151 units of glutathione were conjugated upon each PLGA nanoparticle. The in vitro release studies as well as ex vivo studies revealed biphasic pattern of drug release with initial burst release followed by slow exponential release of drug over a period of 24 h. The in vivo biodistribution studies were conducted on rat following nasal administration of the nanoparticle formulation (conjugated and unconjugated) and were compared with plain paclitaxel suspension. The results clearly demonstrated that the brain targeting efficiency was enhanced with the glutathione conjugated formulation (387.474%) as compared to the unconjugated nanoparticle formulation (224.327%). Further, the in vitro in vivo correlation studies revealed good relationship (R² > 0.95) as obtained from the levy plot. Glutathione proves to be an efficient vector for the successful transport of poor bioavailable drug to the brain.     

Composite microparticles with in vivo reduction of the burst release effect

The aim of this study was to develop microparticles containing nanoparticles (composite microparticles) for prolonged drug delivery with reduced burst effect in vitro and in vivo. Such composite microparticles were prepared with hydrophobic and biodegradable polymers [poly(ε-caprolactone), poly(lactic-co-glycolic) acid]. Ibuprofen was chosen as the model drug, and microparticles were prepared by the extraction technique with ethyl acetate as the solvent. Nanoparticles and microparticles and an ibuprofen solution (Pedea^®) were administered subcutaneously at the dose of 1 mg of ibuprofen per kg to overnight-fasted rats (male Wistar). Composite microparticles showed prolonged ibuprofen release and less burst effect when compared to simple microparticles (without nanoparticles inside) or nanoparticles both in vitro (PBS buffer) and in vivo. Moreover, ibuprofen was still detected in the plasma after 96 h with composite microparticles. Consequently, it has been demonstrated that composite microparticles were able to reduce burst release and prolong the release of ibuprofen for a long period of time.