Applications of lipid-based nanocarriers for parenteral drug delivery

This review describes the use of Lipid-based Nanocarriers (LNCs) for the parenteral delivery of pharmaceutical actives. Firstly, the two generation of LNCs such as ‘‘solid lipid nanoparticles’’ (SLNs) and ‘‘nanostructured lipid carriers’’ (NLCs) are explained in term of preparation, characterization and stability. Although the use of LNCs through parenteral administration has shown many benefits, their use is limited by opsonization, an immune process that causes their short half-life (3-5 min). Therefore, many strategies are discussed to realize “stealth” systems suitable for parenteral administration. Successfully, the requirements and applications of parenteral lipid nanoparticles are reviewed for the delivery of natural compounds, synthetic drugs and genetic materials. In the last period, the latter application has been a remarkable interest due to the numerous benefits of mRNA vaccines to fight the Covid-19 pandemic.

Effect of Silicon Dioxide Nanoparticles on Liver Morphology of Rats in Parenteral Administration

The issue of the potential safety of silicon dioxide nanoparticles (SDNPs) remains relevant. In this connection, in order to use the unique capabilities of silicon nanostructures for biomedical purposes, as well as to level their toxic effects, a detailed study of these nanoparticles interaction with cells and tissues in vivo is required.The aim of the research is to reveal morphofunctional changes in a rat's liver after a single parenteral administration of 12 nm silicon dioxide nanoparticles for the period of six months.Material and methods. Using general histological and immunohistochemical methods to study the rats' liver after a single parenteral administration of 1 ml of silicon dioxide nanoparticles at a dose of 7 mg/kg of body weight at a concentration of 2 mg/ml. The sections of the rats' liver were studied by general histological and immunohistochemical methods after injection of 1mL of a SDNPs saline suspension at a concentration of 2 mg/mL (7mg/kg of body weight). Control animals were injected with 1 ml of saline solution. The material was collected in 21 days, 2, 4 and 6 months months after the administration of the SDNPs and it was fixed in 10% neutral formaldehyde.Results. The formation of granulomas in the liver on the 21st day of the experiment and an increase in the number of Kupfer cells were revealed. However, by the 2nd month of the experiment, the number of granulomas significantly decreases compared to the 21st day of the experiment and continues to decrease in subsequent periods. The average size of granulomas decreases during the 2nd month of the experiment and does not change during the subsequent periods of the experiment. After 6 months of the experiment, the morphofunctional state of the liver is characterized by slightly pronounced aseptic inflammation.Conclusion. A single parenteral administration of silicon dioxide nanoparticles causes pronounced aseptic inflammation of the liver, decreasing by the 6th month of the experiment. Connective tissue remodeling in the liver is not observed at all periods of the experiment.

Glibenclamide-Loaded Polyvinylpyrrolidone (PVP) Nanoparticles and Glibenclamide-Loaded Soluplus® Nanomicelles Intended for Parenteral Administration: Effect of Solvents Mixtures on the Electrosprayed Nanoparticles and In vitro Characterization

Background and Objective: Glibenclamide (GB) is showing promising results in central nervous system (CNS) injuries treatment where intravenous administration of GB could overcome the oral limitations and assure maximum bioavailability. Dry powder of GB nanoparticles reconstituted for parenteral administration was prepared through electrospraying. Methods: The drug was incorporated with two polymers, polyvinylpyrrolidone (PVP) and Soluplus® (SP), at ratios 1:4 and 1:2 (GB/polymer). Different solvent mixtures were used to formulate the particles. Physicochemical characteristics were investigated. Results: The size of the GB-PVP nanoparticle ranged between (409-775) nm with a spherical, disk, fractured and, agglomerated morphology, while those of the GB-SP nanomicelles were of (447-785) nm with mostly irregular morphology, in consequence to the used solvents mixtures. The high encapsulation efficiency ≥ 98% reflects the well dispersed drug molecules within the polymer matrix, further confirmed by X-ray diffraction and infrared spectroscopy. GB-SP colloidal dispersions showed neutral zeta potentials with a cloud point of 36 ˚C, indicating prolonged circulation time and stability after parenteral administration. GB/SP nanomicelles at ratio 1:4 showed a sustained drug release reaching ≥ 94% in 36 hours. Conclusion: The GB-SP nanomicelles with extended drug release and regarding physicochemical properties represent a remarkable drug delivery system for parenteral administration.

THE EFFECT OF N-ACETYLCYSTEINE AND DEXAMETHASONE PARENTERAL ADMINISTRATION ON THE BIOCHEMICAL PROCESSES IN THE AQUEOUS HUMOR OF THE ANTERIOR CHAMBER OF THE EYES IN RABBITS WITH EXPERIMENTAL IMMUNOGENIC UVEITIS

Objective. To evaluate the impact and compare the efficiency of parenteral administration of N-acetylcysteine (NAC) and dexamethasone when used as monotherapy or combination therapy in the treatment of experimental immunogenic uveitis (EIU) in rabbits, as well as to explore the changes of biochemical parameters in the aqueous humor of the eyes in experimental animals. Material and Methods. An experimental study was performed on 45 rabbits (90 eyes). Of these 5 healthy intact rabbits (10 eyes) served as a control group. Acute immunogenic uveitis was caused in 40 rabbits by injecting normal horse serum subcutaneously (5 ml) and then intravitreally (0.07 ml). The animals with experimental uveitis were divided into 8 groups (5 animals each). The first 4 groups – control-1, experiment-1, control-3, experiment-3 – received daily intramuscular injections of placebo, NAC, dexamethasone or a combination of NAC and dexamethasone respectively for 3 days, and thereafter they were withdrawn from the experiment. The remaining 4 groups – control-2, experiment-2, control-4, experiment-4 received, respectively, daily intramuscular injections of placebo, NAC, dexamethasone, a combination of NAC and dexamethasone for 7 days, and after that they were also withdrawn from the experiment. The drugs in the aforementioned groups were used from the moment of the horse serum intravitreal injection. When withdrawing animals from the experiment, aqueous humor was taken from the anterior chamber of their eyes, followed by the evaluation of protein (albumin) concentration and the number of leukocytes. Results. A significant elevation of albumin and the number of leukocytes in the aqueous humor of the eyes in the rabbits with experimental immunogenic uveitis was noted. NAC effectively reduced the level of albumin and the number of leukocytes in the aqueous humor. Dexamethasone showed more efficacy in reducing the investigated aqueous humor biochemichal parameters than NAC. Nevertheless, a synergism of the pharmacological action of NAC and dexamethasone was detected, since their combination had the greatest potency in reduction of albumin level and the number of leukocytes in the aqueous humor of the eyes in the rabbits with experimental immunogenic uveitis, even though the dosage of dexamethasone in the groups with combined (NAC and dexamethasone) therapy was reduced by 50% (1 mg / kg body weight). Conclusion. Parenteral administration of NAC significantly reduces inflammation in EIU. Combination of NAC and dexamethasone showed synergy of action in reducing the intensity of inflammatory process in rabbits with EIU, which is an objective rationale for including NAC in the complex therapy of uveitis, which in turn will reduce a single or course dose of dexamethasone and lower the risks of side effects caused by glucocorticoids.

Drug-induced hypophosphatemia

Hypophosphatemia (GF) is defined as a decrease in the level of inorganic phosphorus in the blood serum below 2.5 mg/dl (0.81 mmol/L). One of the reasons for the development of GF can be the use of a number of medications: diuretics, some antibacterial drugs, insulin, antacids, glucose solutions for parenteral administration, antitumor drugs. The true prevalence of drug-induced (DI) HB is unknown, because the phosphate level is not evaluated routinely, but only when GF is suspected. The most common mechanism for the development of DI GF is an increase in the excretion of phosphates by the kidneys. In most cases, DI GF is asymptomatic and regresses after discontinuation of the inducer drug. To compensate for the phosphate deficiency, non-drug methods (diet) and pharmacotherapy are used. Prevention of DI GF involves avoiding the use of drugs, the reception of which is associated with the development of DI GF, especially in patients at risk of developing GF.

DEVELOPMENT AND EVALUATION OF LYOPHILIZED POWDER TO PREPARE SOLUTION FOR INJECTIONS BASED ON DOXYCYCLINE

The range of doxycycline drugs on the pharmaceutical market of the Ukraine is very limited and is represented by solid forms (capsules and tablets) while a rapid effect and maximum bioavailability of the drug can be provided by parenteral administration. The object of the study is the drug doxycycline hyclate in the form of lyophilisate to prepare solution for injections. During the development of the drug it was taken into account that aqueous doxycycline solution is pH dependent and tends to shift the solution pH during long-term storage. Therefore, excipients such as stabilizer and antioxidant providing buffering properties and stability of the solution were introduced into the composition. According to the research results an optimal composition of lyophilized powder was selected, the production technology with the stage of solution treatment with activated carbon was developed which allowed to obtain lyophilized powder with a well-formed porous mass without splits, cracks and fissures, resistant to shaking, and the prepared solution for parenteral administration is stable by the «Degree of coloration» quality indicator during accelerated storage regimen. It was found that doxycycline hyclate in the form of a lyophilisate shows a wide range of antibacterial activity. Comparative studies in vitro for two drugs, in the form of lyophilisate with doxycycline hyclate for injections and hard gelatin capsules with 100 mg of doxycycline hyclate, confirm equivalence of their bacteriostatic action against bacteria causing infectious diseases in humans.

Ethacrynic Acid Is an Inhibitor of Human Factor XIIIa

Ethacrynic acid (EA) is a loop diuretic that is approved orally and parenterally to manage edema-associated diseases. Nevertheless, it was earlier reported that it is also associated with bleeding upon its parenteral administration. In this report, we investigated the effects of EA on human factor XIIIa (FXIIIa) of the coagulation process using a variety of techniques. FXIIIa is a transglutaminase that works at the end of the coagulation process to form an insoluble, rigid, and cross-linked fibrin rich blood clot. In fact, inhibition of FXIIIa-mediated biological processes has been reported to result in a bleeding diathesis. Inhibition of FXIIIa by EA was investigated given the nucleophilic nature of the thiol-containing active site of the enzyme and the Michael acceptor-based electrophilicity of EA. In a bisubstrate-based fluorescence trans-glutamination assay, EA inhibited FXIIIa with a moderate potency (IC50 ~ 105 µM) and efficacy (∆Y ~ 66%). In SDS-PAGE experiment, EA appears to significantly inhibit the FXIIIa-mediated polymerization of fibrin(ogen) as well as the formation of fibrin(ogen) – α2-antiplasmin complex which indicates that EA affects the physiological functions of FXIIIa. Interestingly, EA did not affect the clotting times of human plasma in the activated partial thromboplastin time (APTT) or prothrombin time (PT) assays at the highest concentration tested of 2.5 mM suggesting the lack of effects on the coagulation serine proteases and potentially the functional selectivity of EA with respect to the clotting process. Molecular modeling studies demonstrated that the Michael acceptor of EA forms a covalent bond with catalytic residue of Cys314 in the active site of FXIIIa. Overall, our studies indicate that EA inhibits the physiological function of human FXIIIa in vitro which may potentially contribute to the bleeding complications that were reported with the association of the parenteral administration of EA.

On the issue of milk therapy for certain eye diseases

Currently, by protein therapy or Reiztherapie we mean a number of long-known therapeutic methods: vaccine therapy, serotherapy, venesection, parenteral administration of protein bodies (muscle protein, milk protein, egg white, ovalbumin'a, deuteroalbumos'bi, etc.).

Identification and quantification of glucose degradation products in heat-sterilized glucose solutions for parenteral use by thin-layer chromatography

During heat sterilization of glucose solutions, a variety of glucose degradation products (GDPs) may be formed. GDPs can cause cytotoxic effects after parenteral administration of these solutions. The aim of the current study therefore was to develop a simple and quick high-performance thin-layer chromatography (HPTLC) method by which the major GDPs can be identified and (summarily) quantified in glucose solutions for parenteral administration. All GDPs were derivatized with o-phenylenediamine (OPD). The resulting GDP derivatives (quinoxalines) were applied to an HPTLC plate. After 20 minutes of chamber saturation with the solvent, the HPTLC plate was developed in a mixture of 1,4-dioxane-toluene-glacial acetic acid (49:49:2, v/v/v), treated with thymol-sulfuric acid spray reagent, and heated at 130°C for 10 minutes. Finally, the GDPs were quantified by using a TLC scanner. For validation, the identities of the quinoxaline derivatives were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Glyoxal (GO)/methylglyoxal (MGO) and 3-deoxyglucosone (3-DG)/3-deoxygalactosone (3-DGal) could be identified and quantified in pairs, glucosone (2-KDG), 5-hydroxymethylfurfural (5-HMF), and 3,4-dideoxyglucosone-3-ene (3,4-DGE) each individually. For 2-KDG, the linearity of the method was demonstrated in the range of 1–50 μg/mL, for 5-HMF and 3,4-DGE 1–75 μg/mL, for GO/MGO 2–150 μg/mL, and for 3-DG/3-DGal 10–150 μg/mL. All GDPs achieved a limit of detection (LOD) of 2 μg/mL or less and a limit of quantification (LOQ) of 10 μg/mL or less. R2 was 0.982 for 3.4-DGE, 0.997 for 5-HMF, and 0.999 for 2-KDG, 3-DG/3-DGal, and GO/MGO. The intraday precision was between 0.4 and 14.2% and the accuracy, reported as % recovery, between 86.4 and 112.7%. The proposed HPTLC method appears to be an inexpensive, fast, and sufficiently sensitive approach for routine quantitative analysis of GDPs in heat-sterilized glucose solutions.