Nanocarrier Drug Delivery Systems: Characterization, Limitations, Future Perspectives and Implementation of Artificial Intelligence.

There has been an increasing demand for the development of nanocarriers targeting multiple diseases with a broad range of properties. Due to their tiny size, giant surface area and feasible targetability, nanocarriers have optimized efficacy, decreased side effects and improved stability over conventional drug dosage forms. There are diverse types of nanocarriers that have been synthesized for drug delivery, including dendrimers, liposomes, solid lipid nanoparticles, polymersomes, polymer-drug conjugates, polymeric nanoparticles, peptide nanoparticles, micelles, nanoemulsions, nanospheres, nanocapsules, nanoshells, carbon nanotubes and gold nanoparticles, etc. Several characterization techniques have been proposed and used over the past few decades to control and predict the behavior of nanocarriers both in vitro and in vivo. In this review, we describe some fundamental in vitro, ex vivo, in situ and in vivo characterization methods for most nanocarriers, emphasizing their advantages and limitations, as well as the safety, regulatory and manufacturing aspects that hinder the transfer of nanocarriers from the laboratory to the clinic. Moreover, integration of artificial intelligence with nanotechnology, as well as the advantages and problems of artificial intelligence in the development and optimization of nanocarriers, are also discussed, along with future perspectives.

A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: Preparation, characterization and in vivo evaluation.

This work aimed at designing efficient safe delivery system for intranasal (IN) brain targeting of the water soluble anti- migraine drug Almotriptan malate (ALM). Solid lipid nanoparticles (SLNs) were prepared by w/o/w double emulsion-solvent evaporation method. Selection of the optimized SLNs formula was based on evaluating particle size (PS), poly dispersity index (PDI) and entrapment efficiency (%EE). Optimized formula exhibited acceptable ranges; PS of 207.9 nm, PDI of 0.41 and %EE of 50.81%. Poloxamer 407 (Plx) at different concentrations (16%, 18%, 20% w/v), with different mucoadhesive polymers (Carbopol-974P, Na alginate, Na-CMC) were evaluated for gelling time and temperature, pH and mucoadhesion. The chosen mucoadhesive in-situ gel formula; 18% Plx 407 based-0.75%w/v Na-CMC, showed acceptable results, so that the optimized SLNs formula was further dispersed in it and evaluated for in vitro release, stability, in vivo and pharmacokinetics studies. Biomarkers' evaluation and histopathological examination were also investigated. Results revealed rapid ALM brain delivery of the optimized formula; Brain/blood ratios at 10 min. for NF (SLNs based IN in-situ gel), ND (Free ALM IN in situ gel) and ALM i.v. (ALM IV solution) were 0.89, 0.19 and 0.31, respectively. Toxicological results confirmed the safety of NF for nasal administration. The achieved out comings are encouraging for further clinical trials of the developed system in humans in future research.

Platform for Lipid Based Nanocarriers' Formulation Components and their Potential Effects: A Literature Review.

BACKGROUND: Lipid based nanocarriers have gained recently enormous interest for pharmaceutical application. They have the potential to provide controlled drug release and to target the drug to a specific area. In addition, lipid based nanocarriers can improve the bioavailability of drugs suffering from high hepatic first-pass metabolism, by enhancing their transport via the lymphatic system. The main components of lipid based nanocarriers are lipids and surfactants. Both have great influence on the prepared lipid based systems characteristics. The criteria for their selection are much related to physicochemical properties of the drug and the required administration route. This work gives an overview on the effect of both the type and amount of lipids and surfactants used in the manufacture of lipid based nanocarriers on their behavior and characteristics. CONCLUSION: Recent studies revealed that the properties of the final product including; particle size, homogeneity, drug loading capacity, zeta potential, drug release profile, stability, permeability, pharmacokinetic properties, crystallinity and cytotoxicity, may be significantly influenced not only by the type but also the amount of the lipids and/or surfactants included in the formulation of the lipid based nanocarriers.

Thiolated alginate-based multiple layer mucoadhesive films of metformin forintra-pocket local delivery: in vitro characterization and clinical assessment.

INTRODUCTION: Periodontal disease broadly defines group of conditions in which the supportive structure of the tooth (periodontium) is destroyed. Recent studies suggested that the anti-diabetic drug metformin hydrochloride (MF) has an osteogenic effect and is beneficial for the management of periodontitis. OBJECTIVE: Development of strong mucoadhesive multiple layer film loading small dose of MF for intra-pocket application. METHODOLOGY: Multiple layer film was developed by double casting followed by compression method. Either 6% carboxy methyl cellulose sodium (CMC) or sodium alginate (ALG) constituted the inner drug (0.6%) loaded layer. Thiolated sodium alginate (TSA; 2 or 4%) constituted the outer drug free layers to enhance mucoadhesion and achieve controlled drug release. Optimized formulation was assessed clinically on 20 subjects. RESULTS: Films were uniform, thin and hard enough for easy insertion into periodontal pockets. Based on water uptake and in vitro drug release, CMC based film with 4% TSA as an outer layer was the optimized formulation with enhanced mucoadhesion and controlled drug release (83.73% over 12 h). SEM showed the effective fabrication of the triple layer film in which connective lines between the layers could be observed. FTIR examination suggests possibility of hydrogen bonding between the -NH groups of metformin and -OH groups of CMC. DSC revealed the presence of MF mainly in the amorphous form. Clinical results indicated improvement of all clinical parameters six months post treatment. CONCLUSION: The results suggested that local application of the mucoadhesive multiple layer films loaded with metformin hydrochloride was able to manage moderate chronic periodontitis.

Formulation Approaches of Triptans for Management of Migraine.

BACKGROUND: The use of triptans in the treatment of migraine was a breakthrough. Their selective agonistic action at serotonin (5-hydroxytryptamine) receptors has provided insights into the pathophysiology of migraine and represented a significant advance in migraine pharmacotherapy. Sumatriptan was the first synthesized triptan available for clinical use in the United States. Although it revolutionized the treatment of migraine, it demonstrated some drawbacks, e.g. poor oral bioavailability, erratic absorption, and high rate of headache recurrence. New triptans have been developed namely; almotriptan, zolmitriptan, rizatriptan, eletriptan, frovatriptan and naratriptan, with each one demonstrating specific pharmacokinetic parameters that may be translated into clinical advantage. Although second generation triptans possess better bioavailability compared to sumatriptan, they all still need improvement. OBJECTIVE: This review illustrates a survey for the available researches aimed to enhance triptans' bioavailability and hence effectiveness, either by investigating alternative routes of administration, other than oral route and/or designing appropriate formulations. RESULTS: Promising results were gained by many researchers after studying different routes for triptans' administration, e.g. nasal, buccal, sublingual, transdermal and pulmonary using well designed formulations, e.g. nanocarriers, microcarriers, orodispersible tablets or films, in situ gels, microneedles for transdermal application, etc. CONCLUSION: Utilizing alternative routes for triptans' administration in addition to designing appropriate formulations, were successful approaches. However, further investigations should be conducted to establish their bioavailability and in vitro- in vivo correlation studies are also required, to confirm the potential of the designed formulations for use in humans, hence novel efficient triptans' formulations may appear on the market in the near future.

Development of mucoadhesive microbeads using thiolated sodium alginate for intrapocket delivery of resveratrol.

Resveratrol (Res), a polyphenolic phytoalexin, had shown a promising therapeutic efficacy towards treatment of periodontal disease in vitro. This work aims to develop Res microbeads with strong mucoadhesion using thiolated alginate (TA) for local treatment of periodontal pockets. TA was synthesized by conjugating sodium alginate (A) with thioglycolic acid. Product was evaluated by IR and DSC. Both A and A:TA Res microbeads with different ratios were prepared by ionotropic gelation method. Formulations were evaluated regarding their entrapment efficiency (%EE), swelling index (SI), in vitro drug release and kinetics. Selected formula was examined for its mucoadhesion by ex vivo wash-off method, surface morphology using scanning electron microscope (SEM) and stability against light. Clinical evaluation is running.Formation of TA was confirmed. %EE for all formulations ranged from 83.72 to 104.54%. Results revealed a significant lower SI for TA rich formulation (A/TA 1:1) along with slower release rate and zero-order kinetics, in addition to powerful mucoadhesion; 26% remaining of microbeads after 1h, compared to 2% for A microbeads. SEM micrographs showed a rough surface with drug precipitation. The formula maintained its %EE after 5h exposure to direct sunlight. A/TA 1:1 mucoadhesive Res microbeads could be exploited as a prolonged drug release devices for intrapocket application.

Development of gastroretentive metronidazole floating raft system for targeting Helicobacter pylori.

The study demonstrates the feasibility of prolonging gastric residence time and release rate of metronidazole (Mz) by preparing floating raft system (FRS) using ion-sensitive in situ gel forming polymers. FRSs contained 3, 4, 5 and 0.5, 0.75, 1% w/v sodium alginate (Alg) and gellan gum (G), respectively, 0.25% w/v sodium citrate and calcium carbonate (C). Lipids: glyceryl mono stearate (GMS), Precirol(®) and Compritol(®) were incorporated into G-based formulations (G1%C1%). Mz:lipid ratio was 1:1, except for Mz:GMS, ratios of 1:1.5 and 1:2 were also investigated. Buoyancy, gelation capacity and viscosity parameters were evaluated. Drug release and kinetics for selected formulae were examined. The selected lipid containing formula was subjected to an accelerated stability testing. Alg4%C2% FRS exhibited short gelation lag time (3s), long duration (>24h), floating lag time 1m in and duration >24h, and a reliable sustained drug release (MDT 6h). Gellan gum FRSs achieved successful floating gastroretention, but failed to achieve the required gelation capacity. Incorporation of GMS (Mz:GMS 1:1) enhanced the gelation lag time and duration (6s and >24h, respectively), keeping sustained drug release and formulation stability. The improved characteristics of the selected FRS make them excellent candidates for gastric targeting to eradicate Helicobacter pylori.

Preparation and evaluation of periodontal films based on polyelectrolyte complex formation.

Local intra-pocket drug delivery devices can provide an effective concentration of the antimicrobial agent at the site of action with avoidance of undesirable side effects. This study explored the application of chitosan-alginate and chitosan-pectin polyelectrolyte complex (PEC) films as drug release regulators for tetracycline HCl (Tc) to treat periodontal pockets. Periodontal films with 1:1 Tc:PEC ratio were prepared using 1:1 chitosan (Ch) to sodium alginate (A) or 1:3 Ch to pectin (P). The scanning electron microscope showed acceptable film appearance and differential scanning calorimetry analysis confirmed complex formation. The in vitro release studies for both films showed a burst drug release, followed by prolonged release for 70 h. A prolonged antibacterial activity of both films against Staphylococcus aureus ATCC 6538 was observed over a period of 21 days. Aging studies indicated that the five months storage period in freezer did not significantly influence the drug release profile or the antibacterial activity of both films. Clinical evaluation showed a significant reduction in pocket depth (p < 0.0001) to their normal values (≤3 mm). PEC films could be exploited as a prolonged drug release devices for treatment of periodontal pockets.

Comparative study to investigate the effect of meloxicam or minocycline HCl in situ gel system on local treatment of periodontal pockets.

In situ gelling formulations allow easy application to the target area. Gelation is induced by physiological stimuli at the site of application where the formula attains semisolid properties and exerts sustained drug release. In situ gelling formulations containing either 3% meloxicam (Mx) or 2% minocycline HCl (MH) were prepared for local application into the periodontal pockets. Gel formulations were based on the thermosensitive Pluronic(®) (Pl) and the pH-sensitive Carbopol(®) (C) polymers. C gels were prepared in combination with HPMC (H) to decrease its acidity. The total percent drug released from Pl formulae was 21.72% after 1 week for Mx and 85% after 3 days for MH. Their release kinetics data indicated anomalous non-Fickian behavior that could be controlled by both diffusion and chain relaxation. Addition of MH to C/H gels (1:2.5) resulted in liquefaction, followed by drug precipitation. Regarding C/H gel containing Mx, it showed a prolonged release rate up to 7 days with an initial burst effect; the kinetics data revealed Fickian-diffusion mechanism. The in vitro antibacterial activity studies for MH gel in Pl revealed that the drug released exceeded the minimum inhibitory concentration (MIC) of MH against Staphylococcus aureus ATCC 6538; placebo gel showed no effect on the microorganism. Clinical evaluation of Pl gels containing either Mx or MH showed significant improvement in chronic periodontitis patients, manifested by decrease in pocket depth and gingival index and increase in bone density.