Development and in vitro antiviral activity of ivermectin liposomes as a potential drug carrier system.

This study aimed to assess and compare diverse formulations of ivermectin-loaded liposomes, employing lipid film hydration and ethanol injection methods. Three lipids (DOPC, SPC, and DSPC) were used in predetermined molar ratios. A total of 18 formulations were created, and a factorial design determined the optimal formulation based on particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency. The average mean particle size, PDI and zeta potential of the selected formulations (F1, F2, F7, F9, and F11) was, respectively, 196.40 ± 44.60 nm, 0.39 ± 0.09, and -40.24 ± 9.17. The encapsulation efficiency exceeded 80%, with a mean loading capacity of 4.00 ± 1.70%. In vitro studies included transmission electron microscopy, Fourier transform infrared spectroscopy, drug release, and antiviral activity assessments against SARS-CoV-2. The liposomal formulations demonstrated superior antiviral activity compared to free ivermectin, as indicated by lower IC50 values. The results of this study emphasize the effectiveness of ivermectin-loaded liposomes in inhibiting viral activity, highlighting their potential as promising candidates for antiviral therapy. The findings suggest that the strategic use of liposomes as drug carriers can significantly modulate and improve the antiviral properties of ivermectin, offering a novel approach to harnessing its full therapeutic potential. Collectively, these results provide a robust foundation for further exploration of ivermectin as a viral protection tool and optimization of its delivery mechanisms.

An overview on recent approaches for colonic drug delivery systems.

Colon-targeted drug delivery systems have garnered significant interest as potential solutions for delivering various medications susceptible to acidic and catalytic degradation in the gastrointestinal (GI) tract or as a means of treating colonic diseases naturally with fewer overall side effects. The increasing demand for patient-friendly drug administration underscores the importance of colonic drug delivery, particularly through noninvasive methods like nanoparticulate drug delivery technologies. Such systems offer improved patient compliance, cost reduction, and therapeutic advantages. This study places particular emphasis on formulations and discusses recent advancements in various methods for designing colon-targeted drug delivery systems and their medicinal applications.

In Vitro and In Vivo Evaluation of Metformin Hydrochloride Hydrogels Developed with Experimental Design in the Treatment of Burns.

Burns alter the normal skin barrier and affect various host defense processes that help prevent infections. An ineffective repair process can lead to serious damage, such as the onset of an infection or skin loss, which can then harm the surrounding tissues and ultimately the entire organism. This study aims to prepare in situ gels containing metformin hydrochloride, a compound known for its wound healing properties. To achieve this, in situ gels were prepared using three different gelling agents (Poloxamer 407®, Carbopol 934®, and sodium carboxymethyl cellulose (Na-CMC)) and three different concentrations of metformin hydrochloride (4 mg/g, 6 mg/g, and 8 mg/g), which were optimized through experimental design. Metformin concentration and gelling agent type were independent variables, and the loaded amount and the percentage of metformin released after 150 min were chosen as dependent variables in the optimization process. After determining the optimum values of the dependent variables according to the ANOVA analysis results, in vivo studies were conducted with optimized hydrogel formulations. Two groups, each consisting of seven Wistar rats with a burn model, were treated with metformin-poloxamer 407® gels at doses of 4 mg/g and 8 mg/g for 29 days. The results were then compared to untreated and placebo gel groups. Rats treated with in situ Poloxamer 407® hydrogels containing metformin hydrochloride showed a significant reduction in the size of the burned area after 29 days of treatment. However, for a comprehensive understanding of the wound healing mechanism, further studies such as immuno-histochemical and cell culture studies are needed.

Development of pediatric orally disintegrating mini-tablets containing atomoxetine hydrochloride-ß-cyclodextrin inclusion complex using experimental design.

OBJECTIVE: The aim of the study was to develop and evaluate characteristics of orally disintegrating mini-tablet (ODMT) formulations including atomoxetine hydrochloride (ATO)/ß-cyclodextrin (ß-CD) inclusion complex for pediatric therapy of attention deficit and hyperactivity disorder (ADHD). METHODS: Design of experiment approach was used to develop ODMTs. The ODMTs were compressed using direct compression method with two different superdisintegrants (Parteck ODT® and Ac-Di-Sol®) and characterized with quality control tests. In vitro dissolution and taste studies were performed. RESULTS: The hardness and friability values of the optimized three ODMT formulations were determined as 41.7 N, 42.4 N, and 40.8 N and 0.32%, 0.29%, and 0.42%, respectively. The disintegration time of all the optimized formulations was found to be less than one minute. In addition, dissolution profiles of ATO from optimized ODMTs were determined in four different dissolution media (distilled water, pH 1.2, 6.8, and 7.4) and it was determined that the maximum dissolved ATO amount reached at the end of 20 min. CONCLUSION: As a conclusion, the novel formulation of ODMTs with ATO/ß-CD inclusion complex was successfully developed for pediatric use.

Development of ACE2 loaded decoy liposomes and their effect on SARS-CoV-2 for Covid-19 treatment.

SARS-CoV-2 is a novel coronavirus with a positively oriented single-stranded RNA that first appeared in December 2019. In this study, Angiotensin Converting Enzyme 2 (ACE2) loaded decoy liposomes were developed and characterized. ACE2 protein was loaded onto a liposomal carrier system and its toxicity and effectiveness were evaluated in cell culture and in vitro virus neutralization studies. Liposomes were prepared with the film hydration method and adjusted for size with the dialysis membrane method or the ultrasonic homogenization method. All formulations showed high entrapment efficiency between 99.98-79.6%. Liposomes with two different particle sizes above 2 µm and below 500 nm were obtained with the dialysis membrane method and homogenization method. Two optimum formulations, M6-S90 with a PDI value of 0.383 ± 0.053 and particle size of 397.7 ± 28.25 nm which was produced by ultrasonic homogenization and M6-4 with a PDI 0.769 ± 0.205 and particle size of 2606 ± 1396.00 were chosen as optimum formulations for further studies. M6-S90 was stable and showed low toxicity on Calu3 lung epithelial cells. Pre-incubation of M6-S90 with with 3.1 × 105 PFU/mL of SARS-CoV-2 followed by incubation with Vero E6 cells resulted in a 4 log fold change reduction in cell death compared to virus alone. This suggests that MS6-S90 had good neutralization activity on SARS-CoV-2 whilst maintaining viability of the host cell. The novel ACE-2 loaded decoy liposomes described in this study can be further evaluated for the treatment of COVID-19.

An overview on the advantages and limitations of 3D printing of microneedles.

The use of 3D printing (3DP) technology, which has been continuously evolving since the 1980s, has recently become common in healthcare services. The introduction of 3DP into the pharmaceutical industry particularly aims at the development of patient-centered dosage forms based on structure design. It is still a new research direction with potential to create the targeted release of drug delivery systems in freeform geometries. Although the use of 3DP technology for solid oral dosage forms is more preferable, studies on transdermal applications of the technology are also increasing. Microneedle sequences are one of the transdermal drug delivery (TDD) methods which are used to bypass the minimally invasive stratum corneum with novel delivery methods for small molecule drugs and vaccines. Microneedle arrays have advantages over many traditional methods. It is attractive with features such as ease of application, controlled release of active substances and patient compliance. Recently, 3D printers have been used for the production of microneedle patches. After giving a brief overview of 3DP technology, this article includes the materials necessary for the preparation of microneedles and microneedle patches specifically for penetration enhancement, preparation methods, quality parameters, and their application to TDD. In addition, the applicability of 3D microneedles in the pharmaceutical industry has been evaluated.

In vitro and in vivo evaluation of levodopa-loaded nanoparticles for nose to brain delivery.

Parkinson's disease (PD) is a neurodegenerative disease which is characterized by the loss of dopaminergic neurons in the brain. Levodopa is the drug of choice in the treatment of PD but it exhibits low oral bioavailability (30%) and very low brain uptake due to its extensive metabolism by aromatic amino acid decarboxylase in the peripheral circulation. Moreover, levodopa has psychic, gastrointestinal, and cardiovascular side effects, and most importantly, short and frequent stimulation of dopamine receptors lead to undesirable conditions such as dyskinesia over time. The challenges are to increase the therapeutic efficiency, the bioavailability and decreasing the unfavourable side effects of levodopa. Biocompatible nano-sized drug carriers could address these challenges at molecular level. For this purpose, levodopa-loaded Poly (lactide-co-glycolide) acid nanoparticles were prepared by double emulsion-solvent evaporation method for nose to brain drug delivery. Parameters such as homogenization speed, and external and internal phase content were modified to reach the highest loading efficiency. F1-1 coded formulation showed prolonged release up to 9 h. Carbodiimide method was used for surface modification studies of nanoparticles. The efficacy of the selected nanoparticle formulation has been demonstrated by in vivo experiments in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced PD model in mice.

Orally disintegrating tablets and orally disintegrating mini tablets - novel dosage forms for pediatric use.

The oral administration route is considered to be the most widely used route because of its convenience of administration and manufacturing. Dosage forms, like orally disintegrating tablets (ODTs), mini tablets, and orally disintegrating mini tablets (ODMTs), are recognized as promising for use in pediatric patients. ODTs are known to be suitable drug delivery systems, especially for pediatric patients, because of their rapid disintegration properties, use without water, and no swallowing problems. In addition, in recent years, a new formulation approach has been developed. ODMTs, are the newest drug delivery systems. They combine the advantageous properties of ODTs and the small size of mini tablets, aimed for pediatric use. These tablets, which can be formulated as 2-4 mm in diameter, are known as drug delivery systems that have children acceptability age as low as 6-months old. The fact that the ODTs and the ODMTs can be formulated with acceptable flavors for children further increases the importance of these carrier systems in the treatment. The objective of this article is to highlight the development of ODTs and mini-ODTs, their significance, ideal characteristics, various techniques, and aspects related to design and formulation, marketed preparations, and future perspectives, especially for the pediatric patients.

The evaluation of sterile solutions of Ilwensisaponin A and C from Verbascum pterocalycinum var. mutense Hub.-Mor. on antiviral, antinociceptive and anti-inflammatory activities.

Antiviral, antinociceptive and anti-inflammatory activities of the 1% sterile solutions of Ilwensisaponin A and C isolated from the methanolic extract of the flowers of Verbascum pterocalycinum var. mutense Hub.-Mor. were investigated. Antiviral activities of sterile solutions were evaluated against Bovine Herpes Virus Type-1 (BHV-1) (Cooper strain). Both solutions showed cytotoxic effects. However, none of the sterile solutions showed antiviral activity with CPE values. Anti-inflammatory and antinociceptive response were obtained at doses of 100 mg/kg. The results of the evaluation of the anti-inflammatory activities induced by carrageenan showed that these sterile solutions possess active constituents and diminish cyclooxygenase activitiy. In addition, antinociceptive activities using p-benzoquinone-induced writhing model in mice of tested solutions were found to show notable activity in statistical analysis without inducing any apparent acute toxicity as well as gastric damage. To the best of our knowledge, this study is the first investigation of antiviral, anti-inflammatory and antinociceptive activities of sterile solutions of Ilwensisaponin A and C isolated from Verbascum pterocalycinum var. mutense Hub.-Mor. growing in Turkey.

Nanocarriers for Effective Brain Drug Delivery.

Drug delivery to the brain is an engaged research topic in the field of nanomedicine. The passage of therapeutics into the brain parenchyma is more complicated than other body tissues due to it is limited by restrict barrier structure called blood-brain barrier (BBB). Nanotechnology holds great promise to overcome the BBB and thereby enable treatment of neurodegenerative diseases. Nanocarriers have been investigated several times as effective brain drug delivery systems in the past few decades. Physicochemical properties and surface modifications of these carriers play a significant role in terms of brain up-taking of nanocarriers. Chemical structures of possible nano sized drug delivery systems have an importance in terms of interactions between cell membranes of brain endothelial cell lines and these interactions can be modified with surface coating strategies using suitable agents. Particle size, surface charge and total molecular mass are also crucial issues which require special attention in order to better understand appropriate properties of nanocarriers to overcome the BBB structure. Different strategies have been demonstrated to facilitate the passage of nanoparticles into the brain parenchyma including attachment of targeting ligands on the nanoparticles' surfaces; this attempt provides site specific action in the brain tissues. This study aims to provide a review of nanocarriers for effective brain drug delivery, in the light of current literature.

Formulation and in vitro evaluation of ketoprofen fast-dissolving tablets.

Drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated as orally fast-disintegrating tablets (FDTs or ODTs). Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Despite advances in the FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast-disintegrating properties of the formulation. The unpleasant taste of the active drug usually masked by adding flavoring ingredients and sweeteners to improve taste and palatability but in this study a novel approach of using a polymer; Eudragit EPO and a granulation procedure of this polymer with the active drug was applied to mask the bitter taste of ketoprofen. In order to produce ketoprofen FDT formulations, a two-stepped procedure was followed; granulation process with the taste-masking agent (Eudragit EPO) and then direct compression (F3 and F4). In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of Eudragit EPO. As well as observing the effect of taste-masking agent, crospovidone and sodium starch glycolate were used in different concentrations (2, 4 and 8wt%) to examine the influence of superdisintegrants on FDT properties. All the FDTs containing 30 mg ketoprofen (F1, F2, F3 and F4) were evaluated by means of in vitro quality control tests.

Process and formulation variables of pregabalin microspheres prepared by w/o/o double emulsion solvent diffusion method and their clinical application by animal modeling studies.

Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. In conventional therapy recommended dose for pregabalin is 75 mg twice daily or 50 mg three times a day, with maximum dosage of 600 mg/d. To achieve maximum therapeutic effect with a low risk of adverse effects and to reduce often drug dosing, modified release preparations; such as microspheres might be helpful. However, most of the microencapsulation techniques have been used for lipophilic drugs, since hydrophilic drugs like pregabalin, showed low-loading efficiency and rapid dissolution of compounds into the aqueous continous phase. The purpose of this study was to improve loading efficiency of a water-soluble drug and modulate release profiles, and to test the efficiency of the prepared microspheres with the help of animal modeling studies. Pregabalin is a water soluble drug, and it was encapsulated within anionic acrylic resin (Eudragit S 100) microspheres by water in oil in oil (w/o/o) double emulsion solvent diffusion method. Dichloromethane and corn oil were chosen primary and secondary oil phases, respectively. The presence of internal water phase was necessary to form stable emulsion droplets and it accelerated the hardening of microspheres. Tween 80 and Span 80 were used as surfactants to stabilize the water and corn oil phases, respectively. The optimum concentration of Tween 80 was 0.25% (v/v) and Span 80 was 0.02% (v/v). The volume of the continous phase was affected the size of the microspheres. As the volume of the continous phase increased, the size of microspheres decreased. All microsphere formulations were evaluated with the help of in vitro characterization parameters. Microsphere formulations (P1-P5) exhibited entrapment efficiency ranged between 57.00 ± 0.72 and 69.70 ± 0.49%; yield ranged between 80.95 ± 1.21 and 93.05 ± 1.42%; and mean particle size were between 136.09 ± 2.57 and 279.09 ± 1.97 µm. Pregabalin microspheres having better results among all formulations (Table 3) were chosen for further studies such as differential scanning calorimetry, Fourier transform infrared analysis and dissolution studies. In the last step, the best pregabalin microsphere formulation (P3) was chosen for in vivo animal studies. The pregabalin-loaded microspheres (P3) and conventional pregabalin capsules were applied orally in rats for three days, resulted in clinical improvement of cold allodynia, an indicator of peripheral neuropathy. This result when evaluated together with the serum pregabalin levels and in vitro release studies suggests that the pregabalin microspheres prepared with w/o/o double emulsion solvent diffusion method can be an alternative form for neuropathic pain therapy. Conclusively, a drug delivery system successfully developed that showed modified release up to 10 h and could be potentially useful to overcome the frequent dosing problems associated with pregabalin conventional dosage form.

Preparation and evaluation of an orally fast disintegrating tablet formulation containing a hydrophobic drug.

Orally fast disintegrating tablets (FDTs or ODTs) have received ever-increasing demand during the last decade, and the field has become a rapidly growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. Although the FDT area has passed its infancy, as shown by a large number of commercial products on the market, there are still many aspects to improve in the FDT formulations. Despite advances in the FDT technologies, formulation of hydrophobic drugs is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model hydrophobic drug; meloxicam, without affecting the fast disintegrating properties of the formulation. In order to enhance the solubilization of meloxicam in FDT formulations, ß cyclodextrin inclusion complex of the drug is prepared and FDTs containing meloxicam--ß cyclodextrin inclusion complex (F1 A and F2 A) were compared and evaluated with the FDTs containing pure meloxicam (F1 and F2) by means of in vitro quality control tests.

Formulation and evaluation of diclofenac potassium fast-disintegrating tablets and their clinical application in migraine patients.

The aim of this study was to prepare fast-disintegrating tablets (FDTs) of diclofenac potassium with sufficient integrity as well as a pleasant taste, using two different fillers and binders: Tablettose 70(®) and Di-Pac(®). Tablets were made with direct compression method. Tablet properties such as porosity, hardness, and disintegration time were determined. Diclofenac potassium determinations were carried out using a validated spectrophotometric method for the analysis of drug. Furthermore, in vivo experiments were carried out to compare the analgesic effect and the time to relieve migraine headache between the commercial tablets and FDTs of diclofenac potassium against placebo. Results showed that FDTs of diclofenac potassium with durable structure and desirable taste can be prepared using both fillers and binders but tablets prepared with Di-Pac had a better taste so the tablet formulation containing Di-Pac was chosen for in vivo experiments. Placebo controlled in vivo trial demonstrated that 50 mg diclofenac potassium, administered as a single dose of FDTs or commercial tablets, was effective in relieving the pain and both of them were superior to placebo.

Preparation and in vitro evaluation of modified release ketoprofen microsponges.

Microsponges containing ketoprofen and Eudragit RS 100 were prepared by quasi-emulsion solvent diffusion method. The effects of different mixing speeds, drug-polymer ratios, solvent-polymer ratios on the physical characteristics of the microsponges as well as the in vitro release rate of the drug from the microsponges were investigated. All the factors studied had an influence on the physical characteristics of the microsponges. In vitro dissolution results showed that the release rate of ketoprofen was modified in all formulations.

The effects of pressure and direct compression on tabletting of microsponges.

Microsponges are porous, polymeric microspheres that are used mostly for topical and recently for oral administration. Ketoprofen was used as a model drug for systemic drug delivery of microsponges in the study. Ketoprofen microsponges were prepared by quasi-emulsion solvent diffusion method with Eudragit RS 100 and afterwards tablets of microsponges were prepared by direct compression method. Different pressure values were applied to the tablet powder mass in order to determine the optimum pressure value for compression of the tablets. Results indicated that microsponge compressibility was much improved over the physical mixture of the drug and polymer and owing to the plastic deformation of sponge-like structure, microsponges produce mechanically strong tablets.