From lab to industrial development of lipid nanocarriers using quality by design approach.

Lipid nanocarriers have attracted a great deal of interest in the delivery of therapeutic molecules. Despite their many advantages, compliance with quality standards and reproducibility requirements still constrain their industrial production. The relatively high failure rate in lipid nanocarrier research and development can be attributed to immature bottom-up manufacturing practices, leading to suboptimal control of quality attributes. Recently, the pharmaceutical industry has moved toward quality-driven manufacturing, emphasizing the integration of product and process development through the principles of quality by design. Quality by design in the pharmaceutical industry involves a thorough understanding of the quality profile of the target product and involves an assessment of potential risks during the design and development phases of pharmaceutical dosage forms. By identifying essential quality characteristics, such as the active ingredients, excipients and manufacturing processes used during research and development, it becomes possible to effectively control these aspects throughout the life cycle of the drug. Successful commercialization of lipid nanocarriers can be achieved if large-scale challenges are addressed using the QbD approach. QbD has become an essential tool because of its advantages in improving processes and product quality. The application of the QbD approach to the development of lipid nanocarriers can provide comprehensive and remarkable knowledge enabling the manufacture of high-quality products with a high degree of regulatory flexibility. This article reviews the basic considerations of QbD and its application in the laboratory and large-scale development of lipid nanocarriers. Furthermore, it provides forward-looking guidance for the industrial production of lipid nanocarriers using the QbD approach.

Mosquito-Borne Diseases and Their Control Strategies: An Overview Focused on Green Synthesized Plant-Based Metallic Nanoparticles.

Mosquitoes act as vectors of pathogens that cause most life-threatening diseases, such as malaria, Dengue, Chikungunya, Yellow fever, Zika, West Nile, Lymphatic filariasis, etc. To reduce the transmission of these mosquito-borne diseases in humans, several chemical, biological, mechanical, and pharmaceutical methods of control are used. However, these different strategies are facing important and timely challenges that include the rapid spread of highly invasive mosquitoes worldwide, the development of resistance in several mosquito species, and the recent outbreaks of novel arthropod-borne viruses (e.g., Dengue, Rift Valley fever, tick-borne encephalitis, West Nile, yellow fever, etc.). Therefore, the development of novel and effective methods of control is urgently needed to manage mosquito vectors. Adapting the principles of nanobiotechnology to mosquito vector control is one of the current approaches. As a single-step, eco-friendly, and biodegradable method that does not require the use of toxic chemicals, the green synthesis of nanoparticles using active toxic agents from plant extracts available since ancient times exhibits antagonistic responses and broad-spectrum target-specific activities against different species of vector mosquitoes. In this article, the current state of knowledge on the different mosquito control strategies in general, and on repellent and mosquitocidal plant-mediated synthesis of nanoparticles in particular, has been reviewed. By doing so, this review may open new doors for research on mosquito-borne diseases.

Current Advances in Lipid Nanosystems Intended for Topical and Transdermal Drug Delivery Applications.

Skin delivery is an exciting and challenging field. It is a promising approach for effective drug delivery due to its ease of administration, ease of handling, high flexibility, controlled release, prolonged therapeutic effect, adaptability, and many other advantages. The main associated challenge, however, is low skin permeability. The skin is a healthy barrier that serves as the body's primary defence mechanism against foreign particles. New advances in skin delivery (both topical and transdermal) depend on overcoming the challenges associated with drug molecule permeation and skin irritation. These limitations can be overcome by employing new approaches such as lipid nanosystems. Due to their advantages (such as easy scaling, low cost, and remarkable stability) these systems have attracted interest from the scientific community. However, for a successful formulation, several factors including particle size, surface charge, components, etc. have to be understood and controlled. This review provided a brief overview of the structure of the skin as well as the different pathways of nanoparticle penetration. In addition, the main factors influencing the penetration of nanoparticles have been highlighted. Applications of lipid nanosystems for dermal and transdermal delivery, as well as regulatory aspects, were critically discussed.

Reference Intervals for Routine Biochemical Markers and Hematological Indices Derived from Healthy Adults in the Mediterranean Region of Morocco.

BACKGROUND: Reference intervals (RIs) for biochemical and hematological parameters are fundamental tools for clinical diagnosis, management, and therapeutic follow-up. In Morocco, the RIs used by clinical laboratories and physicians are derived from western populations. Also, RIs of biochemical and hematological parameters specific to the various Moroccan areas are lacking. This study aimed to determine RIs for biochemical and hematological parameters in apparently healthy voluntary adults by following the procedures recommended by the IFCC-CLSI guidelines in 2008 and comparing them to those of literature and other countries. METHODS: A total of 768 healthy adults from 18 to 60 years old were recruited. Complete blood count and biochemical analyses were performed using hematology analyzer Sysmex KX21N® (Sysmex Corporation, Kobe, Japan) and COBAS INTEGRA®400 plus biochemistry analyzer (Roche, Diagnostics GmbH, Germany) at the laboratory of the hospital Mohamed VI of M'diq, Morocco, and went into effect between November 2017 and December 2020. The data analysis was made by the software SPSS 20.0 and RIs have been established by using the 2.5th and 97.5th percentiles. RESULTS: RIs established include: glucose 3.90 - 6.76 mmol/L for males and 4.01 - 6.87 mmol/L for females; alanine aminotransferase 5.60 - 40.07 U/L for males and 5.60 - 38.71 U/L for females; aspartate aminotransferase 5.60 - 40.08 for males and 5.89 - 39.90 U/L for females; creatinine 47.73 - 113.15 µmol/L for males and 44.64 - 102.28 µmol/L for females; urea 2.2 - 7.6 mmol/L for males and 1.90 - 7.5 mmol/L for females; total cholesterol 2.71 - 5.46 mmol/L for males and 2.64 - 5.89 mmol/L for females; triglycerides 0.58 - 2.01 mmol/L for males and 0.55 - 2.08 mmol/L for females; high-density lipoprotein cholesterol 1.40 - 1.50 mmol/L for males and 1.40 - 1.65 mmol/L for females; and uric acid 157.3 - 410.8 µmol/L for males and 146.1 - 388.5 µmol/L for females. Concerning the hematological parameters, a significant difference (p < 0.05) between both genders was noted for the majority of pa rameters. CONCLUSIONS: The present study underlines the importance to establish RIs specific to the Moroccan population in each region for a more rational and reliable interpretation of biochemical and hematological testing in order to avoid errors in diagnosis and treatment of patients.

Application of Lipid-Based Nanocarriers for Antitubercular Drug Delivery: A Review.

The antimicrobial drugs currently used for the management of tuberculosis (TB) exhibit poor bioavailability that necessitates prolonged treatment regimens and high dosing frequency to achieve optimal therapeutic outcomes. In addition, these agents cause severe adverse effects, as well as having detrimental interactions with other drugs used in the treatment of comorbid conditions such as HIV/AIDS. The challenges associated with the current TB regimens contribute to low levels of patient adherence and, consequently, the development of multidrug-resistant TB strains. This has led to the urgent need to develop newer drug delivery systems to improve the treatment of TB. Targeted drug delivery systems provide higher drug concentrations at the infection site, thus leading to reduced incidences of adverse effects. Lipid-based nanocarriers have proven to be effective in improving the solubility and bioavailability of antimicrobials whilst decreasing the incidence of adverse effects through targeted delivery. The potential application of lipid-based carriers such as liposomes, niosomes, solid lipid nanoparticles, nanostructured lipid carriers, nano and microemulsions, and self-emulsifying drug delivery systems for the treatment of TB is reviewed herein. The composition of the investigated lipid-based carriers, their characteristics, and their influence on bioavailability, toxicity, and sustained drug delivery are also discussed. Overall, lipid-based systems have shown great promise in anti-TB drug delivery applications. The summary of the reviewed data encourages future efforts to boost the translational development of lipid-based nanocarriers to improve TB therapy.

Quality-by-Design-Based Development of a Voxelotor Self-Nanoemulsifying Drug-Delivery System with Improved Biopharmaceutical Attributes.

Low aqueous solubility and poor oral bioavailability are limiting factors in the oral delivery of voxelotor, an antisickling agent. To overcome these limitations, a voxelotor self-nanoemulsifying drug delivery system was developed. Various oils, surfactants, and cosurfactants were screened for their solubilization potential for the drug. The area of nanoemulsification was identified using a ternary phase diagram. An experimental mixture design and a desirability function were applied to select SNEDDSs that contain a maximum amount of lipids and a minimum amount of surfactant, and that possess optimal emulsification properties (i.e., droplet sizes, polydispersity index (PDI), emulsification time, and transmittance percentage). The optimized SNEDDS formulation was evaluated for the self-emulsifying time (32 s), droplet size (35 nm), and zeta potential (-8 mV). In vitro dissolution studies indicated a 3.1-fold improvement in drug solubility from the optimized SNEDDS over pure drug powder. After 60 min of in vitro lipolysis, 88% of the voxelotor loaded in the SNEDDS remained in the aqueous phase. Cytotoxicity evaluation, using Caco-2 cells, indicated the safety of the formulation at 0.9 mg/mL. The transport of the voxelotor SNEDDS across Caco-2 monolayers was significantly enhanced compared to that of the free drug. Compared to the drug suspension, the developed SNEDDS enhanced the oral bioavailability (1.7-fold) of voxelotor in rats. The results suggest that further development of SNEDDSs for the oral delivery of voxelotor is needed.

Self-Nano-Emulsifying Drug-Delivery Systems: From the Development to the Current Applications and Challenges in Oral Drug Delivery.

Approximately one third of newly discovered drug molecules show insufficient water solubility and therefore low oral bio-availability. Self-nano-emulsifying drug-delivery systems (SNEDDSs) are one of the emerging strategies developed to tackle the issues associated with their oral delivery. SNEDDSs are composed of an oil phase, surfactant, and cosurfactant or cosolvent. SNEDDSs characteristics, their ability to dissolve a drug, and in vivo considerations are determinant factors in the choice of SNEDDSs excipients. A SNEDDS formulation can be optimized through phase diagram approach or statistical design of experiments. The characterization of SNEDDSs includes multiple orthogonal methods required to fully control SNEDDS manufacture, stability, and biological fate. Encapsulating a drug in SNEDDSs can lead to increased solubilization, stability in the gastro-intestinal tract, and absorption, resulting in enhanced bio-availability. The transformation of liquid SNEDDSs into solid dosage forms has been shown to increase the stability and patient compliance. Supersaturated, mucus-permeating, and targeted SNEDDSs can be developed to increase efficacy and patient compliance. Self-emulsification approach has been successful in oral drug delivery. The present review gives an insight of SNEDDSs for the oral administration of both lipophilic and hydrophilic compounds from the experimental bench to marketed products.

Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDSs) for senicapoc.

Senicapoc (SEN), a potent antisickling agent, shows poor water solubility and poor oral bioavailability. To improve the solubility and cell permeation of SEN, self-nanoemulsifying drug delivery systems (SNEDDSs) were developed. Capryol PGMC®, which showed the highest solubilization capacity, was selected as the oil. The self-emulsification ability of two surfactants, viz., Cremophor-EL® and Tween® 80, was compared. Based on a solubility study and ternary phase diagrams, three optimized nanoemulsions with droplet sizes less than 200 nm were prepared. An in vitro dissolution study demonstrated the superior performance of the SNEDDS over the free drug. During in vitro lipolysis, 80% of SEN loaded in the SNEDDS remained solubilized. An in vitro cytotoxicity study using the Caco-2 cell line indicated the safety of the formulations at 1 mg/mL. The transport of SEN-SNEDDSs across Caco-2 monolayers was enhanced 115-fold (p < 0.01) compared to that of the free drug. According to these results, SNEDDS formulations could be promising tools for the oral delivery of SEN.