Copolymeric Micelles Overcome the Oral Delivery Challenges of Amphotericin B

Classified as a Biopharmaceutical Classification System (BCS) class IV drug, amphotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. AmB-PM were prepared with polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol copolymer (Soluplus®) as a polymeric carrier and used a modified solvent diffusion and microfluidics (NanoAssemblr®) method. AmB-PM have a mean particle size of ~80 nm and are mono-disperse with a polydispersity index <0.2. The entrapment efficiency of AmB was up to 95% and achieved with a high drug loading up to ~20% (w/w) with a total amount of incorporated drug of 1.08 ± 0.01 mg/mL. Importantly, compared to free drug, AmB-PM protected AmB from degradation in an acidic (simulated gastric) environment. Viability studies in Caco-2 cells confirmed the safety/low toxicity of AmB-PM. In vitro cellular absorption studies confirmed that AmB-PM increased AmB uptake in Caco-2 cells 6-fold more than free AmB (i.e., 25% compared with 4% within 30 min). Furthermore, the permeability of AmB across Caco-2 monolayers was significantly faster (2-fold) and more pronounced for AmB-PM in comparison to free drug (3.5-fold increase). Thus, the developed AmB-PM show promise as a novel oral delivery system for AmB and justifies further investigation.

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Boosting the Brain Delivery of Atazanavir through Nanostructured Lipid Carrier-Based Approach for Mitigating NeuroAIDS

Pharmaceutics ◽

10.3390/pharmaceutics12111059 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1059

Author(s):

Saif Ahmad Khan ◽

Saleha Rehman ◽

Bushra Nabi ◽

Ashif Iqubal ◽

Nida Nehal ◽

...

Keyword(s):

Targeted Delivery ◽

Drug Loading ◽

Entrapment Efficiency ◽

Fold Increase ◽

Pharmacokinetic Studies ◽

Nanostructured Lipid Carrier ◽

Brain Delivery ◽

The Brain

Atazanavir (ATZ) presents poor brain availability when administered orally, which poses a major hurdle in its use as an effective therapy for the management of NeuroAIDS. The utilization of nanostructured lipid carriers (NLCs) in conjunction with the premeditated use of excipients can be a potential approach for overcoming the limited ATZ brain delivery. Methods: ATZ-loaded NLC was formulated using the quality by design-enabled approach and further optimized by employing the Box–Behnken design. The optimized nanoformulation was then characterized for several in vitro and in vivo assessments. Results: The optimized NLC showed small particle size of 227.6 ± 5.4 nm, high entrapment efficiency (71.09% ± 5.84%) and high drug loading capacity (8.12% ± 2.7%). The release pattern was observed to be biphasic exhibiting fast release (60%) during the initial 2 h, then trailed by the sustained release. ATZ-NLC demonstrated a 2.36-fold increase in the cumulative drug permeated across the rat intestine as compared to suspension. Pharmacokinetic studies revealed 2.75-folds greater Cmax in the brain and 4-fold improvement in brain bioavailability signifying the superiority of NLC formulation over drug suspension. Conclusion: Thus, NLC could be a promising avenue for encapsulating hydrophobic drugs and delivering it to their target site. The results suggested that increase in bioavailability and brain-targeted delivery by NLC, in all plausibility, help in improving the therapeutic prospects of atazanavir.

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Amphotericin B Loaded Nanostructured Lipid Carriers for Parenteral Delivery: Characterization, Antifungal and In vitro Toxicity Assessment

Current Drug Delivery ◽

10.2174/1567201816666190729145223 ◽

2019 ◽

Vol 16 (7) ◽

pp. 645-653 ◽

Cited By ~ 3

Author(s):

Pataranapa Nimtrakul ◽

Waree Tiyaboonchai ◽

Supaporn Lamlertthon

Keyword(s):

Amphotericin B ◽

Fungal Infections ◽

In Vitro Release ◽

Entrapment Efficiency ◽

Aqueous Solubility ◽

Toxicity Assessment ◽

Nanostructured Lipid Carriers ◽

In Vitro Toxicity ◽

Drug Release Profile

Background: Amphotericin B (AmB) is important for the treatment of systemic fungal infections. Nowadays, only intravenous administration (IV) of AmB has been available due to its low aqueous solubility. Two forms of AmB are available. The first is Fungizone®, a mixture of AmB and sodium deoxcycholate that produces severe nephrotoxicity. The second are lipid-based formulations that reduce nephrotoxicity, but they are costly and require higher dose than Fungizone®. Thus, a cheaper delivery system with reduced AmB toxicity is required. Objective: To develop and characterize AmB loaded-nanostructured lipid carriers (AmB-loaded NLCs) for IV administration to reduce AmB toxicity. Methods: AmB-loaded NLCs with different solid lipids were prepared by the high-pressure homogenization technique. Their physicochemical properties and the drug release profile were examined. The molecular structure of AmB, antifungal and hemolysis activities of developed AmB-loaded NLCs were also evaluated. Results: AmB-loaded NLCs ~110 to ~140 nm in diameter were successfully produced with a zeta potential of ~-19 mV and entrapment efficiency of ~75%. In vitro release showed fast release characteristics. AmB-loaded NLCs could reduce the AmB molecular aggregation as evident from the absorbance ratio of the first to the fourth peak showing a partial aggregation of AmB. This result suggested that AmB-loaded NLCs could offer less nephrotoxicity compared to Fungizone®. In vitro antifungal activity of AmB-loaded NLCs showed a minimum inhibitory concentration of 0.25 µgmL-1. Conclusion: AmB-loaded NLCs present high potential carriers for effective IV treatment with prolonged circulation time and reduced toxicity.

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Effect of Semi-synthetic Andrographolide Analogue-loaded Polymeric Micelles on HN22 Cell Migration

Walailak Journal of Science and Technology (WJST) ◽

10.48048/wjst.2020.5515 ◽

2018 ◽

Vol 17 (2) ◽

pp. 88-95

Author(s):

Teeratas KANSOM ◽

Rungnapha SAEENG ◽

Tanasait NGAWHIRUNPAT ◽

Theerasak ROJANARATA ◽

Prasopchai TONGLAIROUM ◽

...

Keyword(s):

Cell Migration ◽

Water Solubility ◽

Polymeric Micelles ◽

Drug Loading ◽

Spherical Shape ◽

Entrapment Efficiency ◽

Migration Assay ◽

Negative Surface ◽

Negative Surface Charge

Semi-synthetic andrographolide (AG) analogue, namely 19-tert-butyldiphenylsilyl-8,17-epoxy andrographolide, or 3A.1, is an anticancer drug. However, the major problem of 3A.1 is poor water solubility hindering its clinical applications. To improve the water solubility and anticancer potency of this analogue, 3A.1-loaded polymeric micelles employing N-naphthyl-N-O-succinyl chitosan (NSCS) as amphiphilic copolymer were prepared by the dropping method. The morphology, particle size, entrapment efficiency (%EE), and loading capacity (%LC) were evaluated. The 3A.1-loaded NSCS micelles were successfully prepared. These micelles were nano-size (66.26 to 102.53 nm) and with a spherical shape, with negative surface charge (-30.50 to -22.23 mV). The 3A.1-loaded NSCS micelles with 40 % drug loading exhibited the maximum values of both %EE (90.84 %) and %LC (25.95 %), indicating that a high amount of 3A.1 could be entrapped into the NSCS micelles. In addition, in vitro anticancer activity and cell migration assay on HN22 cells were evaluated. The 3A.1-loaded NSCS micelles exhibited stronger anticancer effect and cell migration suppression than the free drug. Therefore, these NSCS micelles containing 3A.1 may be potential nanocarriers for the treatment of oral cancer.

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Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2020.13.5.7 ◽

2020 ◽

Vol 13 (5) ◽

pp. 5102-5109

Author(s):

Venu Madhav K ◽

Somnath De ◽

Chandra Shekar Bonagiri ◽

Sridhar Babu Gummadi

Keyword(s):

Oral Bioavailability ◽

Oral Delivery ◽

Solid Dispersions ◽

In Vitro Release ◽

Aqueous Solubility ◽

Water Soluble ◽

Scanning Calorimetry ◽

In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension. From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

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Solid Lipid Nanoparticles for Topical Delivery of Acitretin for the Treatment of Psoriasis by Design of Experiment

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2019.12.2.5 ◽

2020 ◽

Vol 12 (2) ◽

pp. 4474-4491

Author(s):

Rajkumar Aland ◽

Ganesan M ◽

P. Rajeswara Rao ◽

Bhikshapathi D. V. R. N.

Keyword(s):

Particle Size ◽

Drug Release ◽

Solid Lipid Nanoparticles ◽

Drug Loading ◽

Entrapment Efficiency ◽

Lipid Nanoparticles ◽

Tem Analysis ◽

In Vitro Drug Release ◽

Solid Lipid

The main objective for this investigation is to develop and optimize the solid lipid nanoparticles formulation of acitretin for the effective drug delivery. Acitretin loaded SLNs were prepared by hot homogenization followed by the ultrasonication using Taguchi’s orthogonal array with eight parameters that could affect the particle size and entrapment efficiency. Based on the results from the analyses of the responses obtained from Taguchi design, three different independent variables including surfactant concentration (%), lipid to drug ratio (w/w) and sonication time (s) were selected for further investigation using central composite design. The lipid Dynasan-116, surfactant poloxomer-188 and co surfactant egg lecithin resulted in better percent drug loading and evaluated for particle size, zeta potential, drug entrapment efficiency, in vitro drug release and stability. All parameters were found to be in an acceptable range. TEM analysis has demonstrated the presence of individual nanoparticles in spherical shape and the results were compatible with particle size measurements. In vitro drug release of optimized SLN formulation (F2) was found to be 95.63 ± 1.52%, whereas pure drug release was 30.12 after 60 min and the major mechanism of drug release follows first order kinetics release data for optimized formulation (F2) with non-Fickian (anomalous) with a strong correlation coefficient (R2 = 0.94572) of Korsemeyer-Peppas model. The total drug content of acitretin gel formulation was found to 99.86 ± 0.012% and the diameter of gel formulation was 6.9 ± 0.021 cm and that of marketed gel was found to be 5.7 ± 0.06 cm, indicating better spreadability of SLN based gel formulation. The viscosity of gel formulation at 5 rpm was found to be 6.1 x 103 ± 0.4 x 103 cp. The release rate (flux) of acitretin across the membrane and excised skin differs significantly, which indicates about the barrier properties of skin. The flux value for SLN based gel formulation (182.754 ± 3.126 μg cm−2 h−1) was found to be higher than that for marketed gel (122.345 ± 4.786 μg cm−2 h−1). The higher flux and Kp values of SLN based gel suggest that it might be able to enter the skin easily as compared with marketed gel with an advantage of low interfacial tension of the emulsifier film that ensures an excellent contact to the skin. This topically oriented SLN based gel formulation could be useful in providing site-specific dermal treatment of psoriasis

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Long-Acting Risperidone Dual Control System: Preparation, Characterization and Evaluation In Vitro and In Vivo

Pharmaceutics ◽

10.3390/pharmaceutics13081210 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1210

Author(s):

Xieguo Yan ◽

Shiqiang Wang ◽

Kaoxiang Sun

Keyword(s):

Drug Loading ◽

Entrapment Efficiency ◽

In Vitro Dissolution ◽

Dissolution Behavior ◽

In Vivo Evaluation ◽

Long Term Treatment ◽

Long Acting

Schizophrenia, a psychiatric disorder, requires long-term treatment; however, large fluctuations in blood drug concentration increase the risk of adverse reactions. We prepared a long-term risperidone (RIS) implantation system that can stabilize RIS release and established in-vitro and in-vivo evaluation systems. Cumulative release, drug loading, and entrapment efficiency were used as evaluation indicators to evaluate the effects of different pore formers, polymer ratios, porogen concentrations, and oil–water ratios on a RIS implant (RIS-IM). We also built a mathematical model to identify the optimized formulation by stepwise regression. We also assessed the crystalline changes, residual solvents, solubility and stability after sterilization, in-vivo polymer degradation, pharmacokinetics, and tissue inflammation in the case of the optimized formulation. The surface of the optimized RIS microspheres was small and hollow with 134.4 ± 3.5 µm particle size, 1.60 SPAN, 46.7% ± 2.3% implant drug loading, and 93.4% entrapment efficiency. The in-vitro dissolution behavior of RIS-IM had zero-order kinetics and stable blood concentration; no lag time was released for over three months. Furthermore, the RIS-IM was not only non-irritating to tissues but also had good biocompatibility and product stability. Long-acting RIS-IMs with microspheres and film coatings can provide a new avenue for treating schizophrenia.

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Development of In Situ Self-Assembly Nanoparticles to Encapsulate Lopinavir and Ritonavir for Long-Acting Subcutaneous Injection

Pharmaceutics ◽

10.3390/pharmaceutics13060904 ◽

2021 ◽

Vol 13 (6) ◽

pp. 904

Author(s):

Irin Tanaudommongkon ◽

Asama Tanaudommongkon ◽

Xiaowei Dong

Keyword(s):

Sustained Release ◽

Trough Concentration ◽

Self Assembly ◽

Subcutaneous Injection ◽

Drug Loading ◽

Entrapment Efficiency ◽

Long Acting

Most antiretroviral medications for human immunodeficiency virus treatment and prevention require high levels of patient adherence, such that medications need to be administered daily without missing doses. Here, a long-acting subcutaneous injection of lopinavir (LPV) in combination with ritonavir (RTV) using in situ self-assembly nanoparticles (ISNPs) was developed to potentially overcome adherence barriers. The ISNP approach can improve the pharmacokinetic profiles of the drugs. The ISNPs were characterized in terms of particle size, drug entrapment efficiency, drug loading, in vitro release study, and in vivo pharmacokinetic study. LPV/RTV ISNPs were 167.8 nm in size, with a polydispersity index of less than 0.35. The entrapment efficiency was over 98% for both LPV and RTV, with drug loadings of 25% LPV and 6.3% RTV. A slow release rate of LPV was observed at about 20% on day 5, followed by a sustained release beyond 14 days. RTV released faster than LPV in the first 5 days and slower than LPV thereafter. LPV trough concentration remained above 160 ng/mL and RTV trough concentration was above 50 ng/mL after 6 days with one subcutaneous injection. Overall, the ISNP-based LPV/RTV injection showed sustained release profiles in both in vitro and in vivo studies.

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Polishing the Therapy of Onychomycosis Induced by Candida spp.: Amphotericin B–Loaded Nail Lacquer

Pharmaceutics ◽

10.3390/pharmaceutics13060784 ◽

2021 ◽

Vol 13 (6) ◽

pp. 784

Author(s):

Aleph M. S. Souza ◽

Renato C. A. Ribeiro ◽

Gleyse K. L. O. Pinheiro ◽

Francisco I. Pinheiro ◽

Wógenes N. Oliveira ◽

...

Keyword(s):

Amphotericin B ◽

Ex Vivo ◽

Drug Loading ◽

Drug Bioavailability ◽

Candida Spp ◽

Drying Time ◽

Analytical Method Validation ◽

Nail Lacquer ◽

In Vitro Adhesion

Onychomycosis induced by Candida spp. has several limitations regarding its treatment. Nail lacquers display the potential to overcome these drawbacks by providing therapeutic compliance and increasing local drug bioavailability. Thus, this work aimed to produce a nail lacquer loaded with Amphotericin B (AmB) and evaluate its performance. The AmB-loaded nail lacquer was produced and preliminarily characterized. An AmB quantification method was developed. Stability, drug release, permeability and anti-Candida activity assays were conducted. The analytical method validation met the acceptance criteria. The drug loading efficiency was 100% (0.02 mg/g of total product), whereas the AmB stability was limited to ≅ 7 days (≅ 90% remaining). The nail lacquer displayed a drying time of 187 s, non-volatile content of around 20%w/w, water-resistance of approximately 2%w/w of weight loss and satisfactory in vitro adhesion. Moreover, the in vitro antifungal activity against different Candida spp. strains was confirmed. The AmB release and the ex vivo permeability studies revealed that AmB leaves the lacquer and permeates the nail matrix in 47.76 ± 0.07% over 24 h. In conclusion, AmB-loaded nail lacquer shows itself as a promising extemporaneous dosage form with remarkable anti-Candida activity related to onychomycosis.

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Plumbagin-Loaded Glycerosome Gel as Topical Delivery System for Skin Cancer Therapy

Polymers ◽

10.3390/polym13060923 ◽

2021 ◽

Vol 13 (6) ◽

pp. 923

Author(s):

Shadab Md ◽

Nabil A. Alhakamy ◽

Hibah M. Aldawsari ◽

Mohammad Husain ◽

Nazia Khan ◽

...

Keyword(s):

Skin Cancer ◽

Zeta Potential ◽

Skin Permeation ◽

Entrapment Efficiency ◽

Aqueous Solubility ◽

Skin Layer ◽

Vesicle Size ◽

Cytotoxicity Activities

Plumbagin (PLM) is a phytochemical which has shown cytotoxicity against of cancer cells both in vitro and in vivo. However, the clinical application of PLM has been hindered due to poor aqueous solubility and low bioavailability. The aim of the present study was to develop, optimize and evaluate PLM-loaded glycerosome (GM) gel and compare with conventional liposome (CL) for therapeutic efficacy against skin cancer. The GM formulations were optimized by employing design expert software by 3-level 3-factor design. The prepared GMs were characterized in vitro for vesicle size, size distribution, zeta potential, vesicle deformability, drug release, skin permeation, retention, texture, antioxidant and cytotoxicity activities. The optimized formulation showed a vesicle size of 119.20 ± 15.67 nm with a polydispersity index (PDI) of 0.145 ± 0.02, the zeta potential of −27 ± 5.12 mV and entrapment efficiency of 76.42 ± 9.98%. The optimized PLM-loaded GM formulation was transformed into a pre-formed gel which was prepared using Carbopol 934 polymer. The drug diffusion fluxes of CL gel and GM-loaded gel were 23.31 ±6.0 and 79.43 ± 12.43 µg/ cm2/h, respectively. The result of texture analysis revealed the adequate hardness, cohesiveness, consistency, and viscosity of the developed GM-loaded gel compared to CL gel. The confocal images showed that glycerosomal gel has deeper skin layer penetration as compared to the control solution. GM-loaded gel treated rat skin showed significantly (p < 0.05) higher drug accumulation in the dermis, higher cytotoxicity and higher antioxidant activity as compared to CL gel and PLM suspension. Thus, findings revealed that novel GM-loaded gel could be potential carriers for therapeutic intervention in skin cancer.

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Effect of Chitosan Coating on PLGA Nanoparticles for Oral Delivery of Thymoquinone: In Vitro, Ex Vivo, and Cancer Cell Line Assessments

Coatings ◽

10.3390/coatings11010006 ◽

2020 ◽

Vol 11 (1) ◽

pp. 6

Author(s):

Sultan Alshehri ◽

Syed Sarim Imam ◽

Md Rizwanullah ◽

Khalid Umar Fakhri ◽

Mohd Moshahid Alam Rizvi ◽

...

Keyword(s):

Breast Cancer ◽

Particle Size ◽

Oral Delivery ◽

Ex Vivo ◽

Cancer Cell Line ◽

Entrapment Efficiency ◽

Plga Nanoparticles ◽

Cancer Management ◽

Mcf 7

In the present study, thymoquinone (TQ)-encapsulated chitosan- (CS)-coated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were formulated using the emulsion evaporation method. NPs were optimized by using 33-QbD approach for improved efficacy against breast cancer. The optimized thymoquinone loaded chitosan coated Poly (d,l-lactide-co-glycolide) nanoparticles (TQ-CS-PLGA-NPs) were successfully characterized by different in vitro and ex vivo experiments as well as evaluated for cytotoxicity in MDA-MB-231 and MCF-7 cell lines. The surface coating of PLGA-NPs was completed by CS coating and there were no significant changes in particle size and entrapment efficiency (EE) observed. The developed TQ-CS-PLGA-NPs showed particle size, polydispersibility index (PDI), and %EE in the range between 126.03–196.71 nm, 0.118–0.205, and 62.75%–92.17%. The high and prolonged TQ release rate was achieved from TQ-PLGA-NPs and TQ-CS-PLGA-NPs. The optimized TQ-CS-PLGA-NPs showed significantly higher mucoadhesion and intestinal permeation compared to uncoated TQ-PLGA-NPs and TQ suspension. Furthermore, TQ-CS-PLGA-NPs showed statistically enhanced antioxidant potential and cytotoxicity against MDA-MB-231 and MCF-7 cells compared to uncoated TQ-PLGA-NPs and pure TQ. On the basis of the above findings, it may be stated that chitosan-coated TQ-PLGA-NPs represent a great potential for breast cancer management.

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