Application of biorelevant in vitro assays for the assessment and optimization of ASD-based formulations for pediatric patients.

Amorphous solid dispersions (ASD) have been a successful formulation strategy to overcome the poor aqueous solubility of many novel drugs, but the development of pediatric formulations presents a special challenge due to variable gastrointestinal conditions in children. It was the aim of this work to design and apply a staged biopharmaceutical test protocol for the in vitro assessment of ASD-based pediatric formulations. Ritonavir was used as a model drug with poor aqueous solubility. Based on the commercial ASD powder formulation, a mini-tablet and a conventional tablet formulation were prepared. Drug release from the three formulations was studied in different biorelevant in vitro assays (i.e. MicroDiss, two-stage, transfer model, tiny-TIM) to consider different aspects of human GI physiology. Data from the two-stage and transfer model tests indicated that by controlled disintegration and dissolution excessive primary precipitation can be prevented. However, this advantage of the mini-tablet and tablet formulation did not translate into better performance in tiny-TIM. Here, the in vitro bioaccessibility was comparable for all three formulations. In the future, the staged biopharmaceutical action plan established herein will support the development of ASD-based pediatric formulations by improving the mechanistic understanding so that formulations are developed for which drug release is robust against variable physiological conditions.

Development and Characterization of n-Propyl Gallate Encapsulated Solid Lipid Nanoparticles-Loaded Hydrogel for Intranasal Delivery.

The objective of the present study was to develop n-propyl gallate-loaded solid lipid nanoparticles (PG-SLNs) in a hydrogel (HG) formulation using Transcutol-P (TC-P) as a permeation enhancer. Modified solvent injection technique was applied to produce optimized PG-SLNs via the Quality by Design approach and central composite design. The in vitro mucoadhesion, scavenging activity, drug release, permeation studies of PG from PG-SLNs-loaded HG were evaluated under simulated nasal conditions. Compared with in vitro release behavior of PG from SLNs, the drug release from the PG-SLNs-loaded HG showed a lower burst effect and sustained release profile. The cumulative permeation of PG from PG-SLNs-loaded HG with TC-P was 600 µg/cm2 within 60 min, which is 3-60-fold higher than PG-SLNs and native PG, respectively. Raman mapping showed that the distribution of PG-SLNs was more concentrated in HG having lower concentrations of hyaluronic acid. The scavenging assay demonstrated increased antioxidant activity at higher concentrations of HG. Due to enhanced stability and mucoadhesive properties, the developed HG-based SLNs can improve nasal absorption by increasing residence time on nasal mucosa. This study provides in vitro proof of the potential of combining the advantages of SLNs and HG for the intranasal delivery of antioxidants.

A comparison study of lipid and polymeric nanoparticles in the nasal delivery of meloxicam: Formulation, characterization, and in vitro evaluation.

With the increasingly widespread of central nervous system (CNS) disorders and the lack of sufficiently effective medication, meloxicam (MEL) has been reported as a possible medication for Alzheimer's disease (AD) management. Unfortunately, following the conventional application routes, the low brain bioavailability of MEL forms a significant limitation. The intranasal (IN) administration route is considered revolutionary for CNS medications delivery. The objective of the present study was to develop two types of nanocarriers, poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) and solid lipid nanoparticles (SLNs), for the IN delivery of MEL adapting the Quality by Design approach (QbD). Turning then to further enhance the optimized nanoformulation behavior by chitosan-coating. SLNs showed higher encapsulation efficacy (EE) and drug loading (DL) than PLGA NPs 87.26% (EE) and 2.67% (DL); 72.23% (EE) and 2.55% (DL), respectively. MEL encapsulated into the nanoformulations improved in vitro release, mucoadhesion, and permeation behavior compared to the native drug with greater superiority of chitosan-coated SLNs (C-SLNs). In vitro-in vivo correlation (IVIVC) results estimated a significant in vivo brain distribution of the nanoformulations compared to native MEL with estimated greater potential in the C-SLNs. Hence, MEL encapsulation into C-SLNs towards IN route can be promising in enhancing its brain bioavailability.

Regulatory Considerations, Challenges and Risk-based Approach in Nanomedicine Development.

The translation of nanomedicines from the lab level into marketed product faces several challenges, including characterization of physicochemical properties, pharmacodynamics, pharmacokinetics, process control, biocompatibility, and nanotoxicity, scaling-up as well as reproducibility. The challenges of nanomedicine development are in connection with the different requirements from the patient (clinical and therapeutic use), industry (production), and regulatory bodies (authorization process). This paper aims at reviewing the status and regulatory aspects of nano-based drug delivery systems with a focus on the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) regulations. In addition to discussing the risks accompanied by the development of nanomedicine, the potential of following a risk-based methodology from the early stage of the R&D phase is emphasized here to ensure safety and efficacy when developing novel nano-based dosage forms. The R&D of nanomedicines is a complex and multidisciplinary approach, and there are still many challenges in their regulation and legislation. In general, the most critical considerations for nanomedicines are the product quality assessment (physicochemical characteristics, quality control, manufacturing process) and product safety assessment (pharmacokinetics, biodegradation, accumulation, and nanotoxicity). The paper presents a promising paradigm in the development and marketing authorization of nanomedicines, namely the Quality by Design (QbD) approach. Sufficient knowledge on the quality, safety, and efficacy of nanomedicines is necessary to obtain a significant focus on establishing robust, standardized methods for evaluating the critical quality attributes of nanomedicines. The QbD-based submission is highly recommended and required by the regulatory authorities, enabling a smooth clinical translation of the novel nanomedicines.

Regulatory status quo and prospects for biosurfactants in pharmaceutical applications.

The concept of going 'green' and 'cold' has led to utilizing renewable resources for the synthesis of microbial biosurfactants that are both patient and eco-friendly. In this review, we shed light on the potential and regulatory aspects of biosurfactants in pharmaceutical applications and how they can significantly contribute to novel concepts for the Coronavirus 2019 (COVID-19) vaccine and future treatment. We emphasize that more specific guidelines should be formulated to regulate the approval of biosurfactants for human use. It is also crucial to implement a risk-based approach from the early research and development (R&D) phase in addition to establishing more robust standardized techniques and assays to evaluate the characteristics of biosurfactants.

Hydrophobic ion pairing of a GLP-1 analogue for incorporating into lipid nanocarriers designed for oral delivery.

The lipophilic character of peptides can be tremendously improved by hydrophobic ion pairing (HIP) with counterions to be efficiently incorporated into lipid-based nanocarriers (NCs). Herein, HIPs of exenatide with the cationic surfactant tetraheptylammonium bromide (THA) and the anionic surfactant sodium docusate (DOC) were formed to increase its lipophilicity. These HIPs were incorporated into lipid based NCs comprising 41% Capmul MCM, 15% Captex 355, 40% Cremophor RH and 4% propylene glycol. Exenatide-THA NCs showed a log Dlipophilic phase (LPh)/release medium (RM) of 2.29 and 1.92, whereas the log DLPh/RM of exenatide-DOC was 1.2 and -0.9 in simulated intestinal fluid and Hanks' balanced salts buffer (HBSS), respectively. No significant hemolytic activity was induced at a concentration of 0.25% (m/v) of both blank and loaded NCs. Exenatide-THA NCs and exenatide-DOC NCs showed a 10-fold and 3-fold enhancement in intestinal apparent membrane permeability compared to free exenatide, respectively. Furthermore, orally administered exenatide-THA and exenatide-DOC NCs in healthy rats resulted in a relative bioavailability of 27.96 ± 5.24% and 16.29 ± 6.63%, respectively, confirming the comparatively higher potential of the cationic surfactant over the anionic surfactant. Findings of this work highlight the potential of the type of counterion used for HIP as key to successful design of lipid-based NCs for oral exenatide delivery.

Progress and perspectives of brain-targeting lipid-based nanosystems via the nasal route in Alzheimer's disease.

Since health care systems dedicate substantial resources to Alzheimer's disease (AD), it poses an increasing challenge to scientists and health care providers worldwide, especially that many decades of research in the medical field revealed no optimal effective treatment for this disease. The intranasal administration route seems to be a preferable route of anti-AD drug delivery over the oral one as it demonstrates an ability to overcome the related obstacles reflected in low bioavailability, limited brain exposure and undesired pharmacokinetics or side effects. This delivery route can bypass the systemic circulation through the intraneuronal and extraneuronal pathways, providing truly needleless and direct brain drug delivery of the therapeutics due to its large surface area, porous endothelial membrane, the avoidance of the first-pass metabolism, and ready accessibility. Among the different nano-carrier systems developed, lipid-based nanosystems have become increasingly popular and have proven to be effective in managing the common symptoms of AD when administered via the nose-to-brain delivery route, which provides an answer to circumventing the BBB. The design of such lipid-based nanocarriers could be challenging since many factors can contribute to the quality of the final product. Hence, according to the authors, it is recommended to follow the quality by design methodology from the early stage of development to ensure high product quality while saving efforts and costs. This review article aims to draw attention to the up-to-date findings in the field of lipid-based nanosystems and the potential role of developing such forms in the management of AD by means of the nose-to-brain delivery route, in addition to highlighting the significant role of applying QbD methodology in this development.

The Effect of Counterions in Hydrophobic Ion Pairs on Oral Bioavailability of Exenatide.

The aim of this study was to evaluate the potential of n-octadecyl sulfate (SOS) as a counterion for hydrophobic ion pairing (HIP) with exenatide-a potent glucagon-like peptide-1 (GLP-1) analogue in the treatment of diabetes mellitus-to improve its oral bioavailability. Exenatide was ion-paired with SOS and docusate (DOC) serving as the gold standard followed by the incorporation in a self-emulsifying drug delivery system (SEDDS) comprising Capmul MCM EP, Captex 355, Kolliphor RH40, and propylene glycol at a mass ratio of 41:15:40:4. The hydrophobicity of exenatide-SOS and exenatide-DOC was characterized by determining the butanol-water partition coefficient (log Pbutanol/water). Droplet size and zeta potential of the ion pair-loaded SEDDS were characterized followed by intestinal membrane permeability determination on freshly excised rat intestines compared to exenatide solution. Furthermore, the oral bioavailability of exenatide-SOS- and exenatide-DOC-loaded SEDDS was also evaluated in vivo in healthy male Sprague-Dawley rats. Hydrophobic ion pairing increased the log Pbutanol/water of exenatide from -1.9 to 2.0 for exenatide-SOS and to 1.2 for exenatide-DOC. SEDDSs loaded with 0.26% (m/m) exenatide-SOS and 0.17% (m/m) exenatide-DOC had mean droplet size less than 30 nm and negative zeta potential. Ex vivo permeation experiments revealed 3.5-fold and 6.4-fold improvement in membrane permeability of the exenatide-SOS-loaded SEDDS vs. the exenatide-DOC-loaded SEDDS and exenatide solution, respectively. The orally administered exenatide-SOS-loaded SEDDS and exenatide-DOC-loaded SEDDS resulted in relative oral bioavailability vs. subcutaneous injection (SC) of 19.6 and 15.2%, respectively. Within this study, the key role of counterions for oral peptide delivery via HIP could be confirmed, and SOS was identified as a promising surfactant for this purpose.

Nose-to-brain delivery of antiglioblastoma drugs embedded into lipid nanocarrier systems: status quo and outlook.

Glioblastoma multiforme (GBM) is one of the most devastating and deadly types of tumor. Among all the present treatment strategies, the utmost prerequisite is prolonged intervention at the malignant site. The blood-brain barrier (BBB) is the bottleneck in the delivery of anti-GBM drugs and invasive treatment comes with many pitfalls. This review will discuss the potential of embedding antitumor drugs into nanocarriers for intranasal delivery. Additionally, it emphasizes the significance of applying quality by design (QbD) methodology from the early development stages to ensure the high quality, safety and efficacy of the developed carrier system.

Encapsulation in Polymeric Nanoparticles Enhances the Enzymatic Stability and the Permeability of the GLP-1 Analog, Liraglutide, Across a Culture Model of Intestinal Permeability.

The potential of poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) to overcome the intestinal barrier that limits oral liraglutide delivery was evaluated. Liraglutide-loaded PLGA NPs were prepared by the double emulsion solvent evaporation method. In vitro release kinetics and enzymatic degradation studies were conducted, mimicking the gastrointestinal environment. The permeability of liraglutide solution, liraglutide-loaded PLGA NPs, and liraglutide in the presence of the absorption enhancer PN159 peptide was tested on the Caco-2 cell model. Liraglutide release from PLGA NPs showed a biphasic release pattern with a burst effect of less than 15%. The PLGA nanosystem protected the encapsulated liraglutide from the conditions simulating the gastric environment. The permeability of liraglutide encapsulated in PLGA NPs was 1.5-fold higher (24 × 10-6 cm/s) across Caco-2 cells as compared to liraglutide solution. PLGA NPs were as effective at elevating liraglutide penetration as the tight junction-opening PN159 peptide. No morphological changes were seen in the intercellular junctions of Caco-2 cells after treatment with liraglutide-PLGA NPs, confirming the lack of a paracellular component in the transport mechanism. PLGA NPs, by protecting liraglutide from enzyme degradation and enhancing its permeability across intestinal epithelium, hold great potential as carriers for oral GLP-1 analog delivery.

Synthesis and Statistical Optimization of Poly (Lactic-Co-Glycolic Acid) Nanoparticles Encapsulating GLP1 Analog Designed for Oral Delivery.

PURPOSE: To design and stabilize Liraglutide loaded poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) proper for oral administration. METHODS: PLGA NPs were prepared by means of double emulsion solvent evaporation method and optimized by applying 7-factor 2-level Plackett-Burman screening design. RESULTS: Spherical shaped NPs with homogeneous distribution, 188.95 nm particle size and 51.81% encapsulation efficiency were obtained. Liraglutide was successfully entrapped in the NPs while maintaining its native amorphous nature, and its structural integrity as well. CONCLUSION: Lira-PLGA NPs with the required Critical Quality Attributes (CQAs) were successfully designed by implementing a 7-factor 8-run Plackett Burman design into the extended Quality by Design (QbD) model, to elucidate the effect of formulation and process variables on the particle size, size-distribution, encapsulation efficiency and surface charge. As the developed nanoparticles maintained the native structure of the active pharmaceutical ingredient (API), they are promising compositions for the further development for the oral delivery of Lira. Graphical Abstract.

Novel strategies in the oral delivery of antidiabetic peptide drugs - Insulin, GLP 1 and its analogs.

As diabetes is a complex disorder being a major cause of mortality and morbidity in epidemic rates, continuous research has been done on new drug types and administration routes. Up to now, a large number of therapeutic peptides have been produced to treat diabetes including insulin, glucagon-like peptide-1 (GLP-1) and its analogs. The most common route of administration of these antidiabetic peptides is parenteral. Due to several drawbacks associated with this invasive route, delivery of these antidiabetic peptides by the oral route has been a goal of pharmaceutical technology for many decades. Dosage form development should focus on overcoming the limitations facing oral peptides delivery as degradation by proteolytic enzymes and poor absorption in the gastrointestinal tract (GIT). This review focuses on currently developed strategies to improve oral bioavailability of these peptide based drugs; evaluating their advantages and limitations in addition to discussing future perspectives on oral peptides delivery. Depending on the previous reports and papers, the area of nanocarriers systems including polymeric nanoparticles, solid lipid nanoparticles, liposomes and micelles seem to be the most promising strategy that could be applied for successful oral peptides delivery; but still further potential attempts are required to be able to achieve the FDA approved oral antidiabetic peptide delivery system.