Preformulation studies of efavirenz with lipid excipients using thermal and spectroscopic techniques

Investigation and identification of potential lipids for the manufacture of efavirenz loaded solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) was undertaken. Polymorphic modification and characteristics of the lipids with the best solubilising potential for efavirenz was explored using Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC) and Wide-angle X-ray Scattering (WAXS). Lipid screening revealed that EFV is highly soluble in solid and liquid lipids, with glyceryl monostearate (GM) and Transcutol® HP (THP) exhibiting the best solubilising potential for EFV. GM exists in a stable β-polymorphic modification prior to exposure to heat, but exists in an α-polymorphic modification following exposure to heat. However, it was established that the addition of THP to GM revealed the co-existence of the α- and β'-polymorphic modifications of the lipid. EFV (60% w/w) exists in a crystalline state in a 70:30 mixture of GM and THP. Investigation of binary mixtures of EFV/GM and GM/THP, in addition to eutectic mixtures of EFV, GM and THP using FT-IR, DSC and WAXS revealed no potential interactions between EFV and the lipids selected for the production of the nanocarriers

Short term stability testing of efavirenz-loaded solid lipid nanoparticle (SLN) and nanostructured lipid carrier (NLC) dispersions

The short term stability of efavirenz-loaded solid lipid nanoparticle and nanostructured lipid carrier dispersions was investigated. Hot High Pressure Homogenization with the capability for scale up production was successfully used to manufacture the nanocarriers without the use of toxic organic solvents for the first time. Glyceryl monostearate and Transcutol® HP were used as the solid and liquid lipids. Tween® 80 was used to stabilize the lipid nanocarriers. A Box-Behnken Design was used to identify the optimum operating and production conditions viz., 1100 bar for 3 cycles for the solid lipid nanoparticles and 1500 bar for 5 cycles for nanostructured lipid carriers. The optimized nanocarriers were predicted to exhibit 10% efavirenz loading with 3% and 4% Tween® 80 for solid lipid nanoparticles and nanostructured lipid carriers, respectively. Characterization of the optimized solid lipid nanoparticle and nanostructured lipid carrier formulations in relation to shape, surface morphology, polymorphism, crystallinity and compatibility revealed stable formulations with particle sizes in the nanometer range had been produced. The nanocarriers had excellent efavirenz loading with the encapsulation efficiency >90%. The optimized nanocarriers exhibited biphasic in vitro release patterns with an initial burst release during the initial 0–3 h followed by sustained release over a 24 h period The colloidal systems showed excellent stability in terms of Zeta potential, particle size, polydispersity index and encapsulation efficiency when stored for 8 weeks at 25 °C/60% RH in comparison to when stored at 40 °C/75% RH. The formulations manufactured using the optimized conditions and composition proved to be physically stable as aqueous dispersions

The use of quantitative analysis and Hansen solubility parameter predictions for the selection of excipients for lipid nanocarriers to be loaded with water soluble and insoluble compounds

The aim of these studies was to determine the miscibility of different API with lipid excipients to predict drug loading and encapsulation properties for the production of solid lipid nanoparticles and nanostructured lipid carriers. Five API exhibiting different physicochemical characteristics, viz., clarithromycin, efavirenz, minocycline hydrochloride, mometasone furoate, and didanosine were used and six solid lipids in addition to four liquid lipids were investigated. Determination of solid and liquid lipids with the best solubilization potential for each API were performed using a traditional shake-flask method and/or a modification thereof. Hansen solubility parameters of the API and different solid and liquid lipids were estimated from their chemical structure using Hiroshi Yamamoto’s molecular breaking method of Hansen Solubility Parameters in Practice software. Experimental results were in close agreement with solubility parameter predictions for systems with ΔδT larger than 4.0 MPa1/2. A combination of Hansen solubility parameters with experimental drug-lipid miscibility tests can be successfully applied to predict lipids with the best solubilizing potential for different API prior to manufacture of solid lipid nanoparticles and nanostructured lipid carriers

Stability indicating HPLC-ECD method for the analysis of clarithromycin in pharmaceutical dosage forms: Method scaling versus re-validation.

An isocratic high-performance liquid chromatographic method using electrochemical detection (HPLC-ECD) for the quantitation of clarithromycin (CLA) was developed using Response Surface Methodology (RSM) based on a Central Composite Design (CCD). The method was validated using International Conference on Harmonization (ICH) guidelines with an analytical run time of 20 min. Method re-validation following a change in analytical column was successful in reducing the analytical run time to 13 min, decreasing solvent consumption thus facilitating environmental and financial sustainability. The applicability of using the United States Pharmacopeia (USP) method scaling approach in place of method re-validation using a column with a different L–designation to the original analytical column, was investigated. The scaled method met all USP system suitability requirements for resolution, tailing factor and % relative standard deviation (RSD). The re-validated and scaled method was successfully used to resolve CLA from manufacturing excipients in commercially available dosage forms. Although USP method scaling is only permitted for columns within the same L-designation, these data suggest that it may also be applicable to columns of different designation

The use of experimental design for the development and validation of an HPLC-ECD method for the quantitation of efavirenz

A high performance liquid chromatography with electrochemical detection (HPLC-ECD) method for the quantitation of efavirenz (EFV) was developed, since traditional HPLC-UV methods may be inappropriate, given that EFV undergoes photolytic degradation following exposure to UV light. This work describes the use of response surface methodology (RSM) based on a central composite design (CCD) to develop a stability-indicating HPLC method with pulsed ECD in direct current (DC) mode at an applied potential difference and current of +1400 mV and 1.0 μA for the analysis of EFV. Separation of EFV and imipramine was achieved using a Nova-Pak®C18 cartridge column and a mobile phase of phosphate buffer (pH 4.5): acetonitrile (ACN) (55:45 v/v). Mobile phase pH, buffer molarity, ACN concentration and applied potential difference were investigated. The optimized method produced sharp well resolved peaks for imipramine and EFV with retention times of 3.70 and 8.89 minutes. The calibration curve was linear (R2 = 0.9979) over the range 5-70 μg/mL. Repeatability and intermediate precision ranged between 3.37 and 4.34 % RSD and 1.31 and 4.29 % RSD and accuracy between -0.80 and 4.71 % bias. The LOQ and LOD were 5.0 and 1.5 μg/mL. The method was specific for EFV and was used to analyse EFV in commercially available tablets. The HPLC-ECD method is more suitable for quantitative analysis of EFV than HPLC-UV

Vesicular drug delivery for the treatment of topical disorders: current and future perspectives.

OBJECTIVES: Vesicular drug delivery has become a useful approach for therapeutic administration of pharmaceutical compounds. Lipid vesicles have found application in membrane biology, immunology, genetic engineering and theragnostics. This review summarizes topical delivery, specifically dermal/transdermal, ocular and transungual, via these vesicles, including future formulation perspectives. KEY FINDINGS: Liposomes and their subsequent derivatives, viz. niosomes, transferosomes, pharmacososmes and ethosomes, form a significant part of vesicular systems that have been successfully utilized in treating an array of topical disorders. These vesicles are thought to be a safe and effective mode of improving the delivery of lipophilic and hydrophilic drugs. SUMMARY: Several drug molecules are available for topical disorders. However, physicochemical properties and undesirable toxicity have limited their efficacy. Vesicular delivery systems have the potential to overcome these shortcomings due to properties such as high biocompatibility, simplicity of surface modification and suitability as controlled delivery vehicles. However, incorporating these systems into environmentally responsive dispersants such as hydrogels, ionic liquids and deep eutectic solvents may further enhance therapeutic prowess of these delivery systems. Consequently, improved vesicular drug delivery can be achieved by considering combining some of these formulation approaches

Biocompatibility of Biomaterials for Nanoencapsulation: Current Approaches.

Nanoencapsulation is an approach to circumvent shortcomings such as reduced bioavailability, undesirable side effects, frequent dosing and unpleasant organoleptic properties of conventional drug delivery systems. The process of nanoencapsulation involves the use of biomaterials such as surfactants and/or polymers, often in combination with charge inducers and/or ligands for targeting. The biomaterials selected for nanoencapsulation processes must be as biocompatible as possible. The type(s) of biomaterials used for different nanoencapsulation approaches are highlighted and their use and applicability with regard to haemo- and, histocompatibility, cytotoxicity, genotoxicity and carcinogenesis are discussed

Nano-biomimetic drug delivery vehicles: potential approaches for COVID-19 treatment

The current COVID-19 pandemic has tested the resolve of the global community with more than 35 million infections worldwide and numbers increasing with no cure or vaccine available to date. Nanomedicines have an advantage of providing enhanced permeability and retention and have been extensively studied as targeted drug delivery strategies for the treatment of different disease. The role of monocytes, erythrocytes, thrombocytes, and macrophages in diseases, including infectious and inflammatory diseases, cancer, and atherosclerosis, are better understood and have resulted in improved strategies for targeting and in some instances mimicking these cell types to improve therapeutic outcomes. Consequently, these primary cell types can be exploited for the purposes of serving as a “Trojan horse” for targeted delivery to identified organs and sites of inflammation. State of the art and potential utilization of nanocarriers such as nanospheres/nanocapsules, nanocrystals, liposomes, solid lipid nanoparticles/nano-structured lipid carriers, dendrimers, and nanosponges for biomimicry and/or targeted delivery of bioactives to cells are reported herein and their potential use in the treatment of COVID-19 infections discussed. Physicochemical properties, viz., hydrophilicity, particle shape, surface charge, composition, concentration, the use of different target-specific ligands on the surface of carriers, and the impact on carrier efficacy and specificity are also discussed

Muco-adhesive clarithromycin-loaded nanostructured lipid carriers for ocular delivery: Formulation, characterization, cytotoxicity and stability

Topical ophthalmic formulations are the preferred approach to treat the anterior segment of the eye as it is a non-invasive therapeutic approach. The ocular bioavailability of drugs is generally limited, due to the presence of impervious anatomical barriers and low residence time and contact with the target tissue. Optimization of clarithromycin-loaded nanostructured lipid carriers using Design of Experiments was undertaken. Manufacture of nanostructured lipid carriers was achieved using hot emulsification ultrasonication. Formulation and process parameters were successfully identified following screening and subsequently optimized using Tween® 20, as a stabilizer. Muco-adhesive properties that could potentially increase ocular residence time, in vitro clarithromycin release and cytotoxicity against HeLa cells were evaluated. Short term stability studies of the optimized lipidic formulations was assessed at 4 °C and 22 °C. The optimized formulation exhibited muco-adhesive properties under stationary conditions assessed using Laser Doppler Anemometry, sustained release of API over 24 h under in vitro conditions. In vitro cytotoxicity studies revealed that the NLC were less cytotoxic to HeLa cells in comparison to pure API. The results suggest that the optimized carriers may have the potential to enhance precorneal retention, increase ocular availability and permit dose reduction or permit use of a longer dosing frequency

Applications of Electrospun Drug-Eluting Nanofibers in Wound Healing: Current and Future Perspectives

Wounds are a consequence of disruption in the structure, integrity, or function of the skin or tissue. Once a wound is formed following mechanical or chemical damage, the process of wound healing is initiated, which involves a series of chemical signaling and cellular mechanisms that lead to regeneration and/or repair. Disruption in the healing process may result in complications; therefore, interventions to accelerate wound healing are essential. In addition to mechanical support provided by sutures and traditional wound dressings, therapeutic agents play a major role in accelerating wound healing. The medicines known to improve the rate and extent of wound healing include antibacterial, anti-inflammatory, and proliferation enhancing agents. Nonetheless, the development of these agents into eluting nanofibers presents the possibility of fabricating wound dressings and sutures that provide mechanical support with the added advantage of local delivery of therapeutic agents to the site of injury. Herein, the process of wound healing, complications of wound healing, and current practices in wound healing acceleration are highlighted. Furthermore, the potential role of drug-eluting nanofibers in wound management is discussed, and lastly, the economic implications of wounds as well as future perspectives in applying fiber electrospinning in the design of wound dressings and sutures are considered and reported