Current Drug Delivery - Volume 18, Issue 9, 2021

A pre-eminent emulsion-based micellar drug delivery system, “microemulsion”, comprising drug in oil or water phase, stabilized by surfactants and co-surfactants, has been evidenced to have a phenomenal role in a number of applications. Oils play an important role in the formation of ME and increase the drug absorption at the site of action. Oils employed in microemulsion formulation solubilize lipophilic drug. As the concept of “natural” therapies is recently gaining importance amongst researchers all over the world, scientists are employing essential oil as an organic component in this system. The active components of essential oils include flavonoids, phenylpropanoids, monoterpenes and polyunsaturated mega-6-fatty acids. These oils are enriched with characteristic intrinsic properties such as anti-oxidant, anti-bacterial, anti-viral, etc., bestowing enhanced supremacy to the whole microemulsion system. This mini-review is the first to document various types of essential oils employed in microemulsion systems and highlight their therapeutic potential and applications as drug delivery vehicles. Key inferences from this study suggest: 1) Clove oil is the most explored oil for incorporation into a microemulsion based system, followed by peppermint and Tea Tree Oil (TTO). 2) Penetration enhancing effects of these oils are due to the presence of terpenic constituents. 3) Essential oil based microemulsions protect volatility of ethereal oils and protect them from degradation in the presence of light, air, temperature. 4) These systems may also be explored for their applications in different industries like aromatherapy, food, drink, fragrance, flavour, cosmeceutical, soap, petroleum and pharmaceutical industry.

In the present review study, the published articles from 2010-2020 that evaluated the effect of chitosan nanocarrier on the efficacy of amphotericin B (AmB) in the treatment of leishmaniasis, have been considered. Leishmania is a parasitic tropical disease in the world and is treated with AmB as one of the main therapeutic agents. However, the clinical application of AmB is limited due to its toxicity and insolubility issues. Using nanoparticles and, in particular, chitosan, nanocarrier seems a promising approach to overcome these problems. Therefore, various doses of AmB have been loaded in chitosan nanoparticles in different studies and the results of these studies demonstrated that by increasing the drug loading efficiency and decreasing the toxicity, the potency of the nanoformulation to inhibit and to kill the parasite is increased. In this regard, the results of a study performed in 2018, demonstrated that chitosan nanoparticles with the higher dose of drug loading were the most effective formulation to inhibit and kill the parasite. Thus, chitosan nanocarrier can consider as an appropriate candidate in the future to inhibit and kill the Leishmania parasite without causing side effects

Despite several quality management tools, none or very few systematic operations are taken into account to assure the quality of the pharmaceutical products. Plan Do Check Act (PDCA) analysis is performed based on the problems encountered during product development. In each step, some of the quality control tools are used for better maintenance of corrective and preventive actions. However, systematic use of these tools has still not been made. Here we present an example of nanoemulsion that will help justify the correct or systematic use of all the seven quality control tools in each section of the PDCA cycle for better execution of Corrective and Preventive Actions (CAPA). The major limitations associated with the nanoemulsion i.e. non-uniform size distribution, lower encapsulation efficiency, lower magnitude of zeta potential, non-scalable and expensive synthesis procedures, are taken into consideration. This review summarizes the productive use of 7 QC tools in the PDCA cycle to ensure the optimum quality of nanoemulsion in an industry.

Background: Despite exhibiting promising anticancer potential, the clinical significance of capecitabine (a potent prodrug of 5-fluorouracil used for the treatment of colorectal cancer) is limited owing to its acidic and enzymatic hydrolysis, lower absorption following the oral administration, poor bioavailability, short plasma half-life, and poor patient compliance. Objectives: The present study was aimed to fabricate the capecitabine as a smart pH-responsive hydrogel network to efficiently facilitate its oral delivery while shielding its stability in the gastric media. Methods: The smart pH-sensitive HP-β-CD/agarose-g-poly(MAA) hydrogel network was developed using an aqueous free radical polymerization technique. The developed hydrogels were characterized for drug-loading efficiency, structural and compositional features, thermal stability, swelling behaviour, morphology, physical form, and release kinetics. The pH-responsive behaviour of developed hydrogels was established by conducting the swelling and release behaviour at different pH values (1.2 and 7.4), demonstrating significantly higher swelling and release at pH 7.4 as compared with pH 1.2. The capecitabine-loaded hydrogels were also screened for acute oral toxicity in animals by analysing the body weight, water and food intake, dermal toxicity, ocular toxicity, biochemical analysis, and histological examination. Results: The characteristic evaluations revealed that capecitabine (anticancer agent) was successfully loaded into the hydrogel network. The range of capecitabine loading was from 71.22% to 90.12%. An interesting feature of hydrogel was its pH-responsive behaviour which triggers release at basic pH (94.25%). Optimum swelling (95%)was seen at pH 7.4. Based upon regression coefficient R2(0.96 – 0.99) the best-fit model was zero-order. The extensive toxicity evaluations evidenced a good safety profile with no signs of oral, dermal, or ocular toxicities, as well as no variations in blood parameters and histology of vital organs. Conclusion: Our findings conclusively evinced that the developed hydrogel exhibited excellent pharmaceutical and therapeutic potential and thus can be employed as a pH-responsive system for the controlled delivery of anticancer agents.

Background: Improved bioavailability of Aceclofenac (ACE) may be achieved through proniosomes, which are considered as one of the most effective drug delivery systems and are expected to represent a valuable approach for the development of better oral dosage form as compared to the existing product. However, the carrier in this system plays a vital role in controlling the drug release and modulating drug dissolution. Accordingly, a comparative study on different carriers can give a clear idea about the selection of carriers to prepare ACE proniosomes. Objective: This study aims to evaluate the role of maltodextrin, glucose, and mannitol as carriers for in vitro and in vivo performance of Aceclofenac (ACE) proniosomes. Methods: Three formulations of proniosomes were prepared by the slurry method using the 100 mg ACE, 500 mg span 60, 250 mg cholesterol with 1300mg of different carriers, i.e., glucose (FN1), maltodextrin (FN2), and mannitol (FN3). In vitro drug release studies were conducted by the USP paddle method, while in vivo studies were performed in albino rats. Pure ACE was used as a reference in all the tests. Lastly, the results were analyzed using the High-Pressure Liquid Chromatography (HPLC) method, and data were evaluated using further kinetic and statistical tools. Results: No significant differences (p > 0.05) in entrapment efficiency (%EE) of FN1, FN2, and FN3 (82 ± 0.5%, 84 ± 0.66%, and 84 ± 0.34% respectively) were observed and formulations were used for further in vitro and in vivo evaluations. During in vitro drug release studies, the dissolved drug was found to be 42% for the pure drug, while 70%, 17%, and 30% for FN1, FN2, and FN3, respectively, at 15 min. After 24 hrs, the pure drug showed a maximum of 50% release while 94%, 80%, and 79% drug release were observed after 24 hr for FN1, FN2, and FN3, respectively. The in vivo study conducted on albino rats showed a higher Cmax and AUC of FN1 and FN2 in comparison with the pure ACE. Moreover, the relative oral bioavailability of proniosomes with maltodextrin and glucose as carriers compared to the pure drug was 183% and 112%, respectively. Mannitol- based formulation exhibited low bioavailability (53.7%) that may be attributed to its osmotic behavior. Conclusion: These findings confirm that a carrier plays a significant role in determining in vitro and in vivo performance of proniosomes and careful selection of carrier is an important aspect of proniosomes optimization.

Background: Studying complexation between a wide variety of drugs and clay is of high importance in expanding the knowledge about controlled drug delivery and its exploitation. This study reports the use of isothermal calorimetry (ITC) in understanding the complexation process occurring between magnesium aluminium silicate (MAS) and metformin hydrochloride (MET), as a potentially controlled release drug delivery system. Objectives: To fully characterise and understand the complexes formed between MAS and MET and how that might impact on controlled release systems. Methods: MAS and MET complex dispersions and particles were formulated and analysed using ITC, DSC, XRPD, ATR-FTIR, SEM/EDX, digital microscopy and 2D-SAXS. Results: The calorimetric results confirmed the binding between MET and MAS at various pHs (5, 7 and 9) and temperatures (25 ºC and 37 ºC). The overall change in enthalpy was found to be exothermic with a comparatively small entropic contribution to the total change in Gibbs free energy, implying that the binding was an enthalpically driven process. These findings suggest that the binding process was dominated by hydrogen bonding and electrostatic interactions. pH and temperature variation did not have a great impact on the binding, as observed from the similarity in enthalpy (ΔH), entropy (ΔS) or Gibbs free energy (ΔG), with the reaction being only slightly more exothermic at pH 5 and at 37 ºC. 2D-SAXS was able to differentiate between MAS particulates and MAS-MET complexes when analysed in their liquid form suggesting the importance of appropriate methodology and instrumentation used in characterisation. Conclusion: ITC was successfully used in understanding the complexation process occurring between MAS and MET. Care and consideration however should thus be taken in the accurate determination and characterisation techniques for the formation of complexes for controlled release using MAS.

Introduction: Among different 2-D nanostructures, molybdenum disulfide (MoS2) has shown great potential as a good candidate in drug delivery systems. However, their biocompatibility and water dispersibility are the main issues for these purposes. With the aim of improving the MoS2 dispersibility, a novel drug delivery system based on polymer-modified MoS2 nanosheets was successfully prepared and characterized.

Methods: In this study, MoS2 nanosheets were prepared using a simple oleum treatment exfoliation approach and then modified by grafting thermos-responsive polymer N- isopropylacrylamide (NIPAM) and polyethylene glycol (PEG). The structural and morphological properties of the MoS2/NIPAM/ PEG nanosheets were characterized via Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), Fourier- Transform Infrared Spectroscopy (FTIR), and Thermogravimetric analysis (TGA/DSC). Initially, the adsorption behavior of the grafted nanoadsorbent was assessed for sorption of doxorubicin as an anticancer drug model. The influence of various parameters such as pH, temperature, and contact time was evaluated. Different kinetic and isotherm models were employed to investigate the (DOX) adsorption mechanism.

Results: The obtained results revealed that the DOX adsorption onto the MoS2/NIPAM/ PEG followed the Langmuir isotherm and pseudo-second-order models. In the next step, polymer grafted MoS2 nanosheets were used as thermos-sensitive drug nanocarriers for near-infrared (NIR) photothermal therapy. The combination of chemotherapy and photothermal therapy was also investigated, which indicated a remarkable improvement of cell apoptotic rate compared to monotherapy. Also, MTT assays showed that the MoS2/NIPAM/ PEG had high biocompatibility.

Conclusion: The novel thermo-responsive MoS2/NIPAM/ PEG showed great potential for targeted and controlled drug delivery.

Background: A capsaicin cream was formulated by optimizing the rheological stability, the release behavior of the drug, and the pharmacological effect. Objectives: This study aimed to: (a) apply the Design of Experiment approach to study the rheological stability and release behaviors of a drug (capsaicin) from a formulated oil-in-water cream and (b) investigate the skin irritation and anti-inflammatory and analgesic effects of the optimized cream. Methods: The cream prepared by the emulsification method was optimized using the central composite design, and then the pharmacological effect in experimental animals was determined using Complete Freund's adjuvant (CFA). Results: The effects of a permeation enhancer (X1), Vaseline (X2), and surfactants (X3) on the fluctuation of the ratio of the viscous modulus (G ') to elastic modulus (G') (tan δ) after three cycles of cooling-heating (10-40°C), flux, and skin deposition of capsaicin after 8 h on mouse skin were statistically analyzed and optimized. The final obtained CAP-cream did not cause irritation in the rabbit model and produced comparable anti-inflammatory and analgesic effects to the reference product (Voltaren® emulgel). Conclusion: This study successfully integrated the DoE approach, rheological science, and pharmacological studies to develop a stable and highly effective semi-solid product containing capsaicin.

Introduction: Surface engineering of nanocrystals for improving the biopharmaceutical features is a multivariate process involving numerous formulation and process variables, thus making it a complicated process to get the desired biopharmaceutical quality profile. Nano-by-design is hereby proposed as an approach to nanonize an orally active, lipid-lowering fenofibrate in order to improve feasibility of product development. Methodology: Top-down wet ball milling (media milling) in zirconia planetary chamber was methodically explored for improving the solubility and bioavailability of fenofibrate by formulating a nanosuspension using polyvinyl alcohol as a stabilizer. Several influencing variables were screened using a systematic one-factor-at-a-time approach. DSC, SEM, XRD, and FTIR were utilized for physical characterization of the product during the development stage and to study the effect of milling time, milling speed, fenofibrate:stabilizer ratio, premilling time and stabilizer concentration. Potential risk factors affecting critical quality biopharmaceutical attributes of fenofibrate nanocrystals like size, zeta potential, in vitro release, crystallinity and intrinsic solubility were optimized to improve pharmacokinetic performance. Result: Formulated nanosized fenofibrate exhibited a crystalize nature as evident from XRD and DSC, 411 nm size, and a rapid but complete dissolution (~99% in 30 min). This resulted in a quick onset of action and improved bioavailability as observed from 51.46% shorter Tmax, 82.63% higher Cmax, and 69.34% higher AUC0–24h, respectively.

Background: Inflammation has become the culmination point for several chronic diseases like skin diseases, asthma, neurological disorders, cancer, and cardiovascular disorders. Mini αA-crystallin peptide, identified from a highly conserved region of human lens protein αA-crystallin, is known to have a chaperone-like function; hence, it has generated interest in exploring the anti-inflammatory potential of the peptide. Objective: The objective of the study was to evaluate the anti-inflammatory potential of mini αA chaperones using in vitro, ex-vivo, and in vivo models. Methods: The peptide was tested for its phosphodiestarase4 B inhibition, anti-inflammatory and free radical scavenging abilities in HaCaT cells. Carbopol gel formulations with varying concentrations of mini αA-crystallin peptide and diclofenac sodium were prepared and optimized. Skin permeation studies of prepared formulations were carried out on excised abdominal skin of Wistar rat using a vertical type diffusion cell. Carrageenan induced rat paw oedema model was used for determining the anti-inflammatory potential of the peptide in prepared gel formulation with or without diclofenac sodium. Results: The peptide exhibited appreciable free radical scavenging and weak PDE4B inhibition. Gel formulation with 1% Tween-80, 1% carbopol, and 10% ethanol showed better permeation compared to other formulations. The in vitro skin permeation studies revealed good improvement in permeation characteristics of diclofenac and peptide from the gels. The peptide was retained within the skin tissue, which is an ideal requirement for the delivery of an anti-inflammatory topical formulation. In preclinical anti-inflammatory studies, gel formulation containing mini αA-peptide and diclofenac sodium showed a significant decrease in paw volume compared to other combinations tested. Conclusion: The study revealed the additive effect in anti-inflammatory activity by combining mini-αA peptide and diclofenac sodium which effectively reduced the inflammation.

Background: Rifampicin is one of the first-line drugs used for tuberculosis therapy. The therapy lasts for a long time. Thus, there is a need to develop a sustained release formulation of rifampicin for intravenous application. Aim: This study is focused on preparing rifampicin-loaded bovine serum albumin nanoparticles (RIF BSA NPs) suitable for intravenous application using systematic quality by design (QbD) approach. Objectives: The main objective of this study is optimizing particle size and entrapment efficiency of rifampicin-loaded bovine serum albumin nanoparticles (RIF BSA NPs) and making them suitable for intravenous application using QbD approach. Methods: Quality target product profile was defined along with critical quality attributes (CQAs) for the formulation. 3² factorial design was used for achieving the predetermined values of CQAs, i.e., mean particle size <200 nm and percent entrapment efficiency>50%. Incubation time of drug with colloidal albumin solution and ratio of rifampicin to albumin, were selected as independent variables. Checkpoint analysis was performed to confirm the suitability of the regression model for optimization. Results: The optimized RIF BSA NPs were characterized by FTIR, DSC, ¹H NMR techniques. The NPs observed by transmission electron microscopy were spherical in shape. The rifampicin release could be sustained for 72 hours from BSA NPs matrix. RIF BSA NPs dispersion was stable at 5 ± 3°C for 72 hours. Non-toxicity of nanoparticles to RAW 264.7 cell line was proved by MTT assay. Conclusion: Development of RIF BSA NPs with desired quality attributes was possible by implementing the QbD approach. The optimized formulation suitable for intravenous application can potentially improve the therapeutic benefits of rifampicin.

Background: The present investigation attempts to optimize Supersaturable lipid based formulation (SS SMEDDS) of Biopharmaceutical Classification System (BCS) class IV drug canagliflozin (CFZ) and evaluating the oral bioavailability of the formulation. Methods: Preliminary screening revealed Poloxamer 188 to most effectively inhibit precipitation of CFZ after dispersion during in vitro supersaturation studies. Box Behnken Design was employed for designing different formulations, and various statistical analyses were done to select an appropriate mathematical model. The optimized formulation (OSS 1) was evaluated for in vitro drug release and ex vivo permeation studies to evaluate drug release and permeation rate. Pharmacokinetic studies have been carried out according to standard methodologies. Results: The optimized formulation (OSS 1) containing 781.1 mg SS SMEDDS and 2.24% w/w Poloxamer 188 was developed at a temperature of 60°C, which revealed nano-globule size with negligible aggregation. Isothermal titration calorimetry revealed the thermodynamic state of formed microemulsion with negative ΔG. The optimized formulation was observed to possess physical stability under different stress conditions and acceptable drug content. In vitro dissolution of optimized SS SMEDDS revealed a higher dissolution rate of CFZ as compared to native forms of CFZ. The permeability of CFZ from optimized SS SMEDDS across various excised segments of rat intestine was observed to be multifold higher as manifested by 2.05-fold higher Cmax and 5.64- fold higher AUC0-36h following oral administration to Wistar rats. Conclusion: The results could be attributed to substantial lymphatic uptake and P-glycoprotein substrate affinity of CFZ in SS SMEDDS investigated through chylomicron and P-glycoprotein inhibition approach, respectively.

Background: Solid lipid nanoparticles (SLNs) is the drug delivery system that has the capability to improve drug release at the desired tumor site. The aim of the present study is to develop glyceryl monostearate (GMS) based SLNs for the controlled delivery of docetaxel. Methods: Hot melt encapsulation (HME) method was employed avoiding the use of organic solvents and, therefore, regarded as green synthesis of SLNs. Results: Optimized DTX-SLNs showed desirable size (100 nm) with low poly dispersity index and excellent entrapment efficiency. Surface charge confirmed the stability of formulation. transmission electron microscope (TEM) analysis showed spherical shaped particles and fourier transform infrared microscopy (FTIR) revealed compatibility among formulation excipients. Differential scanning calorimeter (DSC) analysis revealed that the melting transition peak of optimized formulation was also greater than 40°C indicating that SLNs would be solid at body temperature. In-vitro release profile (68% in 24 hours) revealed the controlled release profile of DTX-SLNs, indicating lipophilic docetaxel drug was entrapped inside high melting point lipid core. Cytotoxicity study revealed that blank SLNs were found to be biocompatible while dose dependent cytotoxicity was shown by DTX-SLNs. Conclusion: These studies suggest that DTX-SLNs have the potential for controlled delivery of docetaxel and improved therapeutic outcome.