Current Drug Delivery - Volume 18, Issue 6, 2021

New technologies are currently investigated to improve the quality of foods by enhancing their nutritional value, freshness, safety, and shelf-life, as well as by improving their tastes, flavors and textures. Moreover, new technological approaches are being explored, in this field, to address nutritional and metabolism-related diseases (i.e., obesity, diabetes, cardiovascular diseases), to improve targeted nutrition, in particular for specific lifestyles and elderly population, and to maintain the sustainability of food production. A number of new processes and materials, derived from micro- and nano-technology, have been used to provide answers to many of these needs and offer the possibility to control and manipulate properties of foods and their ingredients at the molecular level. The present review focuses on the importance of micro- and nano-technology in the food and nutritional sector and, in particular, provides an overview of the micro- and nano-materials used for the administration of nutritional constituents essential to maintain and improve health, as well as to prevent the development and complications of diseases.

Chemometrics is an important emerging discipline with unique charm formed by the intersection of mathematics, statistics, chemistry and computer science. The application of chemometrics in the field of pharmacy has injected fresh blood into the scientific research and clinical practice of medicine and has provided a sufficient scientific basis for drug analysis and content determination to solve the problem of cancer treatment with combined therapy in different ranges. This paper introduces the basic principles, advantages and disadvantages of several commonly used pattern recognition and multidimensional correction methods of chemometrics, reviews the application of chemometrics for efficiency enhancement and toxicity reduction in cancer treatment with combined therapy and summarizes its development and prospects in the future.

Background: Exosomes, one of the extracellular vesicles, are widely present in all biological fluids and play an important role in intercellular communication. Due to their hydrophobic lipid bilayer and aqueous hydrophilic core structure, they are considered a possible alternative to liposome drug delivery systems. Not only do they protect the cargo like liposomes during delivery, but they are also less toxic and better tolerated. However, due to the lack of sources and methods for obtaining enough exosomes, the therapeutic application of exosomes as drug carriers is limited. Methods: A literature search was performed using the ScienceDirect and PubMed electronic databases to obtain information from published literature on milk exosomes related to drug delivery. Results: Here, we briefly reviewed the current knowledge of exosomes, expounded the advantages of milk-derived exosomes over other delivery vectors, including higher yield, the oral delivery characteristic and additional therapeutic benefits. The purification and drug loading methods of milk exosomes, and the current application of milk exosomes were also introduced. Conclusion: The emergence of milk-derived exosomes is expected to break through the limitations of exosomes as therapeutic carriers of drugs. We hope to raise awareness of the therapeutic potential of milk-derived exosomes as a new drug delivery system.

Background: Fused Deposition Modelling (FDM) 3D printing has received much interest as a fabrication method in the medical and pharmaceutical industry due to its accessibility and cost-effectiveness. A low-cost method to produce biocompatible and biodegradable filaments can improve the usability of FDM 3D printing for biomedical applications. Objectives: The feasibility of producing low-cost filaments suitable for FDM 3D printing via single screw and twin-screw hot melt extrusion was explored. Methods: A single-screw extruder and a twin-screw extruder were used to produce biocompatible filaments composed of varying concentrations of polyethylene glycol (PEG) at 10%, 20%, 30% w/w and polylactic acid (PLA) 90%, 80% and 70% w/w, respectively. DSC, TGA and FTIR were employed to investigate the effect of PEG on the PLA filaments. Results: The presence of PEG lowered the processing temperature of the formulation compositions via melt-extrusion, making it suitable for pharmaceutical applications. The use of PEG can lower the melting point of the PLA polymer to 170°C, hence lowering the printing temperature. PEG can also improve the plasticity of the filaments, as the rupture strain of twin-screw extruded filaments increased up to 10-fold as compared to the commercial filaments. Advanced application of FTIR analysis confirmed the compatibility and miscibility of PEG with PLA. Conclusion: Twin-screw extrusion is more effective in producing a polymeric mixture of filaments as the mixing is more homogenous. The PEG/PLA filament is suitable to be used in 3D printing of medical or pharmaceutical applications such as medical implants, drug delivery systems, or personalised tablets.

Introduction: At present, there are numerous researches on the migration of components in tablets and granules, however, the investigation in the pharmaceutical literatures concerning the effect of drying rate on the migration of water-soluble components of pellets is limited. Temperature and Relative Humidity (RH) are crucial parameters during the drying process, which is an essential step in the preparation of pellets via wet extrusion/spheronization. To quantify these variables, the water loss percentage of pellets per minute is defined as the drying rate. Aim: The study aimed to investigate the influence of drying rate on the migration of water-soluble components in wet pellets and the potential migrated mechanism. Methods: The pellets containing tartrazine as a water-soluble model drug and microcrystalline cellulose as a matrix former were prepared by extrusion/spheronization and dried at four different drying temperatures and relative humidity. Afterwards, the extent of migrated tartrazine was assessed regarding appearance, in-vitro dissolution test, Differential Scanning Calorimetry, X-Ray Powder Diffraction, Attenuated total reflectance Fourier transform infrared spectroscopy and Confocal Raman Mapping. Results: Results demonstrated that red spots of tartrazine appeared on the surface of pellets and more than 40% tartrazine were burst released within 5 minutes when pellets were dried at 60°C/RH 10%. When pellets were dried at 40°C/RH 80%, none of these aforementioned phenomena were observed. Conclusion: In conclusion, the faster the drying rate was, the more tartrazine migrated to the exterior of pellets. Adjusting drying temperature and relative humidity appropriately could inhibit the migration of water-soluble components within wet extrusion/spheronization pellets.

Background: Discovering new chemotherapy drugs and techniques with the least side effects is one of the most important and challenging issues in recent years worldwide. Chlorambucil is an anticancer drug that is still commonly used as a primary treatment in treating some cancers, but it can cause side effects. Objective: In this study, we decided to use chitosan as a carrier to enhance the uptake of chlorambucil and reduce the toxicity of this drug. Methods: After producing this nanoconjugate compound and analysing its structure by FTIR, DLS and AFM analysis, we investigated the therapeutic and biological effects of this nanoconjugate compound on the MCF-7 cell line (breast cancer). Results: The results of the MTT assay showed that this nanoconjugate compound not only retained its anticancer effect against chlorambucil but also showed less abnormal toxicity. In addition, in vitro cellular uptake by flow cytometry indicated the better uptake final product into the MCF-7 cells. The detection of apoptosis induced cell death was confirmed by RT-PCR. Conclusion: This study has created a prospective pathway for targeting cancer cells using chitosan.

Background: Doxycycline (DOX) is used in treating a bacterial infection, especially for periodontitis treatment. Objective: To reduce irritation of DOX for subgingival administration and increase the chemical stability and against enzymatic, the complex of α-cyclodextrin with DOX was prepared and loaded into injectable in situ forming implant based on PLGA. Methods: FTIR, molecular docking studies, X-ray diffraction, and differential scanning calorimetry was performed to characterize the DOX/α-cyclodextrin complex. Finally, the in-vitro drug release and modeling, morphological properties, and cellular cytotoxic effects were also evaluated. Results: The stability of DOX was improved with complex than pure DOX. The main advantage of the complex is the almost complete release (96.31 ± 2.56 %) of the drug within 14 days of the implant, whereas in the formulation containing the pure DOX and the physical mixture the DOX with α-cyclodextrin release is reached to 70.18 ± 3.61 % and 77.03 ± 3.56 %, respectively. This trend is due to elevate of DOX stability in the DOX/ α-cyclodextrin complex form within PLGA implant that confirmed by the results of stability. Conclusion: Our results were indicative that the formulation containing DOX/α-cyclodextrin complex was biocompatible and sustained-release with minimum initial burst release.

Background: Poly Ionic Complex (PIC) nanogels are promising delivery systems with numerous attractions such as simple, fast, and organic solvent-free particle formation and mild drug loading conditions. Among polyelectrolytes, poly (L-amino acid) copolymers, such as poly (ethylene glycol)-block-poly (L-glutamic acid) copolymers (PEG-b-PGlu) are interesting biocompatible and biodegradable candidates bearing carboxylic acid functional groups. Objective: Aiming to solubilize and to preserve short-acting irinotecan active metabolite (SN38), sterically stabilized PIC nanogels were prepared through electrostatic charge neutralization between PEG-b-PGlu and chitosan lysate, a polycationic natural polymer obtained through digestion of chitosan by hydrogen peroxide oxidation and is soluble in a wide range of pH. Methods: Synthesis of PEG-b-PGlu was accomplished by N-carboxy anhydride polymerization of γ -benzyl L-glutamic acid, which is initiated by methoxy PEG-NH2 and successive debenzylation reaction. Results: The resulting block copolymer was characterized by FTIR, ¹H-NMR, and Size Exclusion Chromatography (SEC). Self-assembling properties of the PIC nanogels were investigated by pyrene assay, Dynamic Light Scattering (DLS), and Transmission Electron Microscopy (TEM), indicating the formation of homogeneous spherical particles with a mean size of 28 nm at the PEGb- PGlu concentrations/LMWC weight ratio of 5:1. Upon direct loading of SN38, the drug solubility enhanced more than 4×10³ folds with a mean loading efficiency of 89% and the drug loading of 30%. PIC nanogels exhibited zeta potential of +1 mV, acceptable biocompatibility, and superior cytotoxicity in murine colorectal carcinoma (CT26 cell line) compared to free drug. Conclusion: In addition, the PIC nanogels provided SN38 protection against hydrolytic degradation in physiologic conditions. Conclusively, the well-tuned PIC nanogels are suggested as a potentially biocompatible nanocarrier for SN38 delivery.

Introduction: Nano drug delivery is a broad field of research on the development of novel nano- carrier systems for effective therapeutic delivery of drugs. Here, an anticancer drug, cisplatin (CDDP) conjugated Gold Nanoparticles (GNPs) via L-Lysine (Lys) linker. Methods: The produced nanodrug (GNPs-Lys-CDDP) was characterized by UV-Vis spectroscopy, Dynamic Light Scattering (DLS), Zeta potentials and electron force microscopy. The cytotoxic efficacy of the GNPs-Lys-CDDP against human breast cancer cells (SKBR3) and normal cells (MCF- 10A) was evaluatedby MTT assay. Cell apoptosis and morphology changes were assessed by flowcytometery and Acridine Orange/Ethidium Bromide (AO/EtBr) staining, respectively. Results: It was found that the GNPs-Lys-CDDP with a size of 85 nm and negatively charged with a zeta-potential of about -25 mV could be taken up by tumor cells. A marked change in the UV spectrum of GNPs-Lys-CDDP compare to GNPs showed a strong absorption shift in the 525 nm region. The LD 50 of GNPs-Lys-CDDP against SKBR3 (1 μg.mL -1), was found to be 8 times lower than that of naked CDDP against SKBR3 (8 μg.mL -1). The nanocomplex GNPs-Lys-CDDP also significantly increased the apoptosis of SKBR3 with the lowest cytotoxic effects on normal cells. Discussion: This work indicates that GNPs effectively could decrease the lethal dose of CDDP to 87%. Hence, GNPs modified by Lys, could be a good nano-carrier for chemotherapeutic drugs.

Background: Amikacin is an aminoglycoside antibiotic used for many gram-negative bacterial infections like infections in the urinary tract, infections in brain, lungs and abdomen. Electrochemical determination of amikacin is a challenge in electroanalysis because it shows no voltammetric peak at the surface of bare electrodes. Objective: In this approach, a very simple and easy method for indirect voltammetric determination of amikacin presented in real samples. Gold nanoparticles were electrodeposited at the surface of glassy carbon electrode in constant potential. Methods: The effect of several parameters such as time and potential of deposition, pH and scan rates on signal were studied. The cathodic peak current of Au³⁺ decreased with increasing amikacin concentration. Quantitative analysis of amikacin was performed using differential pulse voltammetry by following cathodic peak current of gold ions. Results: Two dynamic linear ranges of 1.0 × 10⁻⁸–1.0 × 10^-7 M and 5.0 × 10⁻⁷–1.0 × 10^-3 M were obtained and limit of detection was estimated 3.0× 10⁻⁹ M. Conclusion: The method was successfully determined amikacin in pharmaceutical preparation and human serum. The effect of several interference in determination of amikacin was also studied.

Background: Lipid nanocarriers have been widely tested as drug delivery systems to treat diseases due to their bioavailability, controlled release, and low toxicity. For the pulmonary route, the Food and Drug Administration favors the use of substances generally recognized as safe, as well as biodegradable and biocompatible to minimize the possibility of toxicity. Tuberculosis (TB) remains a public health threat worldwide, mainly due to the long treatment duration and adverse effects. Therefore, new drug delivery systems for treating TB are needed. Objective: Physicochemical characterization of different lipid-based nanocarriers was used to optimize carrier properties. Optimized systems were incubated with Mycobacterium tuberculosis to assess whether lipid-based systems act as the energy source for the bacteria, which could be counterproductive to therapy. Methods: Several excipients and surfactants were evaluated to prepare different types of nanocarriers using high-pressure homogenization. Results: A mixture of trimyristin with castor oil was chosen as the lipid matrix after differential scanning calorimetry analysis. A mixture of egg lecithin and PEG-660 stearate was selected as an optimal surfactant system, as this mixture formed the most stable formulations. Three types of lipid nanocarriers, solid lipid nanoparticles, nanostructured lipid carriers (NLC), and nanoemulsions, were prepared, with the NLC systems showing the most suitable properties for further evaluation. It may provide the advantages of increasing the entrapment efficiency, drug release, and the ability to be lyophilized, producing powder for pulmonary administration as an alternative to entrap poor water-soluble molecules. Conclusion: Furthermore, the NLC system can be considered for use as a platform for the treatment of TB through the pulmonary route.

Background: Levofloxacin has been recommended by the WHO for the treatment of pulmonary tuberculosis and inhalable delivery of levofloxacin can be advantageous over conventional delivery. Objective: This study aimed to develop and optimize inhalable levofloxacin Loaded Chitosan Nanoparticles (LCN). The objective was to achieve the mean particle size of LCN less than 300nm, sustain the drug release up to 24 h, and achieve MMAD of LCN of less than 5μm. Methods: LCN were prepared by ionic gelation of chitosan with sodium tripolyphosphate (STPP) and subsequent lyophilization. A Plackett Burman screening design, 32 full factorial design, and overlay plots were sequentially employed to optimize the formulation. The mean particle size, % entrapment efficiency, in vitro drug release, and minimum inhibitory concentration were all evaluated. Results: The Pareto chart from the Placket Burman screening design revealed that the concentrations of chitosan and STPP was found to be significant (p < 0.05). Further analysis by 32 full factorial design revealed that F-ratio for each model generated was found to be greater than the theoretical value (p < 0.05), confirming the significance of each model. Conclusion: The optimized formulation showed a mean particle size of 171.5 nm, sustained the drug release up to 24 h in simulated lung fluid, and revealed MMAD of 3.18 μm, which can confirm delivery of the drug to the deep lung region. However, further in vivo studies are required to design a suitable dosage regimen and establish the fate of nanoparticles for safe and efficacious delivery of the drug.

Background: Methotrexate (MTX) is a water-insoluble, anti-tumor agent that causes adverse effects like bone marrow suppression, chronic interstitial obstructive pulmonary disease, hepatotoxicity, leukopenia, interstitial pneumonitis and nephrotoxicity with slow drug release rate. Objective: The present study aimed to successfully incorporate MTX into novel-targeted Pluronic (PEOPPO- PEO tri-block co-polymer) F127 polymeric micelles intended for intravenous administration with improved drug loading and sustained release behavior necessary to achieve better efficacy of MTX. Methods: MTX-loaded Pluronic F127 micelles were characterized for critical micelle concentration, particle size and zeta potential, ¹H NMR, drug loading, encapsulation efficiency characterization, cell uptake, in vitro release study along with partition coefficient and solubilization thermodynamics. Results: The micellar formulation resulted in nano size 27.32±1.43nm of PF127/SDS, as compared to Pluronic F127 micelles or PF127/Phosphatidyl choline which were 30.52±1.18nm and 154.35±5.5nm in size, respectively. The uptake of PF127/SDS micellar formulation incorporating Rhodamine 123 in MCF7 cancer cells was found to be higher (84.25%) than PF127/PC, PF127 and MTX i.e. 66.26%, 73.59% and 53% respectively. The in vitro MTX release from PF127, PF127/SDS and PF127/PC polymeric micelles formulations was observed to be 69%, 69.5% and 66% at 12 h whereas 80.89%, 77.67% and 78.54% after 24 h, respectively and revealed a sustained release. MTX-loaded PF127/SDS micelles showed high partition coefficient and negative free energy of solubilization compared to PF127 and PF127/PC which signify self-assembly behavior and thermodynamic stability towards higher dissociation. Conclusion: It was finally concluded that MTX-loaded PF127/SDS micelles act as a potential anticancer delivery system in comparison to PF127/PC and PF127 to combat tumor cells by enhancing their cellular uptake targeting with sustained release pattern and reducing the thermodynamic instability. Thus, PF127/SDS micellar formulation can provide a useful alternative dosage form for intravenous administration of MTX.

Background: Intranasal administration of biodegradable nanoparticles has been extensively studied for targeting the drug directly to CNS through the olfactory or trigeminal route bypassing the blood brain barrier. Objective: The objective of the present study was to optimize Clonazepam loaded PLGA nanoparticles (CLO-PNPs) by investigating the effect of process variables on the responses using 3² full factorial design. Methods: Effect of two independent factors-amount of PLGA and concentration of Poloxamer 188, were studied at low, medium, and high levels on three dependent responses-%Entrapment efficiency, Particle size (nm), and % cumulative drug release at 24hr. Results: %EE, Particle size, and %CDR at 24hr of the optimized batch was 63.7%, 165.1 nm, and 86.96%, respectively. Nanoparticles were radiolabeled with ^99mTc and biodistribution was investigated in BALB/c mice after intranasal and intravenous administrations. Significantly higher brain/blood uptake ratios and AUC values in the brain following intranasal administration of CLO-PNPs indicated more effective brain targeting of CLO. Higher brain uptake of intranasal CLO-PNPs was confirmed by rabbit brain scintigraphy imaging. A histopathological study performed on goat nasal mucosa revealed no adverse response of nanoparticles. TEM image exhibited spherical shaped particles in the nano range. DSC and XRD studies suggested Clonazepam encapsulation within the PLGA matrix. The onset of occurrence of PTZ-induced seizures in rats was significantly delayed by intranasal nanoparticles as compared to intranasal and intravenous CLO-SOL. Conclusion: This investigation exhibits rapid rate and higher extent of CLO transport in the brain with intranasal CLO-PNPs suggesting a better option as compared to oral and parenteral route in the management of acute status epilepticus.

Introduction: In the working age population, Diabetic Macular Edema (DME) is the most common cause of visual loss. Purpose: The present study is aimed to assess the safety and efficacy of intravitreal injection of Ranibizumab (IVR) versus intravitreal Dexamethasone implant (IVD) in patients with DME in a tertiary care centre upto 4 months. Methods: This is a comparative, prospective, randomized study that was done on 140 patients with macular edema confirmed on optical coherence tomography (OCT). IVD group received Ozurdex® (Allergan, Inc, Ireland) while the IVR group received Lucentis® (Novartis, Basel, Switzerland); the groups were followed up at day-1 and weeks 4, 8, 12, 16. Patients were divided into Group A, in which patients were given 3 doses (monthly) of IVR 0.3 mg in 0.05 ml (n=70). Group B patients were given a single dose of IVD implant 0.7 mg (n=70). Results: The mean number of injections given was 1 Ozurdex® per patient vs. 3 Lucentis® per patient. The maximum reduction in central macular thickness (CMT) with IVD was 167.8 μm and 138.8μm in the 2nd and 3rd months, respectively, with IVR. The mean best-corrected visual acuity (BCVA) in the 4th month was 0.34 logMAR and 0.33 logMAR, in IVD and IVR groups, respectively, with consistent improvement. Patients with 0-5 letters, 6-10 letters and 10-15 letters, and >15 letters visibility in IVD group were 9.5, 20.6, 4.8, 6.4%, and 20.4, 18.8, 20.3 20.3% in IVR groups, respectively. The maximum intraocular pressure (IOP) rise with IVD was found to be 16 mmHg in 2 patients (3.17%). IOP rise >10 mmHg was observed in 14/63 patients (22.22%); the majority of patients indicated a high rise at 2nd month with all returning to baseline by 4th month. No reports of infectious endophthalmitis or new cataracts were detected in either of the treated groups. Conclusion: Both intravitreal Ranibizumab injection and Dexamethasone implants were found to be safe and effective in lowering CMT and improving BCVA at the 4-month follow up in patients with DME. Since there was no recurrence of CMT in the Dexamethasone implant group, we suggest that early administration before the 4th month may indicate superior efficacy over the ranibizumab injection. Further randomized trials in a large sample size with a longer period follow- up would be performed to justify the obtained results in the present study.