Intranasal Ion-Triggered In Situ Delivery System of Virus-like Particles: Development Using the Quality by Design Approach.

The rapid growth in the prevalence of infectious diseases requires timely action from drug developers. In recent years, the COVID-19 pandemic has demonstrated the unpreparedness of the population for such emergencies. The introduction of modern methods of Design of Experiments (DoE) is required to accelerate the process of drug development and bring a drug to market. The main objective of this study was to develop an ion-triggered in situ system for intranasal delivery of VLP using a Quality by Design approach. Based on a literature review and initial studies, the key QTPP, CQA, CPP, and CMA were identified to develop a novel delivery system for virus-like particles. As a result of the studies on the quality attributes of the developed delivery system, an ion-triggered in situ gel meeting all the specified parameters was obtained using the Quality by Design method.

Burst Release from In Situ Forming PLGA-Based Implants: 12 Effectors and Ways of Correction.

In modern pharmaceutical technology, modified-release dosage forms, such as in situ formed implants, are gaining rapidly in popularity. These dosage forms are created based on a configurable matrix consisting of phase-sensitive polymers capable of biodegradation, a hydrophilic solvent, and the active substance suspended or dissolved in it. The most used phase-sensitive implants are based on a biocompatible and biodegradable polymer, poly(DL-lactide-co-glycolide) (PLGA). OBJECTIVE: This systematic review examines the reasons for the phenomenon of active ingredient "burst" release, which is a major drawback of PLGA-based in situ formed implants, and the likely ways to correct this phenomenon to improve the quality of in situ formed implants with a poly(DL-lactide-co-glycolide) matrix. DATA SOURCES: Actual and relevant publications in PubMed and Google Scholar databases were studied. STUDY SELECTION: The concept of the review was based on the theory developed during literature analysis of 12 effectors on burst release from in situ forming implants based on PLGA. Only those studies that sufficiently fully disclosed one or another component of the theory were included. RESULTS: The analysis resulted in development of a systematic approach called the "12 Factor System", which considers various constant and variable, endogenous and exogenous factors that can influence the nature of 'burst release' of active ingredients from PLGA polymer-based in situ formed implants. These factors include matrix porosity, polymer swelling, LA:GA ratio, PLGA end groups, polymer molecular weight, active ingredient structure, polymer concentration, polymer loading with active ingredients, polymer combination, use of co-solvents, addition of excipients, and change of dissolution conditions. This review also considered different types of kinetics of active ingredient release from in situ formed implants and the possibility of using the "burst release" phenomenon to modify the active ingredient release profile at the site of application of this dosage form.

Implantation of In Situ Gelling Systems for the Delivery of Chemotherapeutic Agents.

Implantation is a modern method of administering chemotherapeutic agents, with a highly targeted effect and better patient tolerance due to the low frequency of administration. Implants are capable of controlled release, which makes them a viable alternative to infusional chemotherapy, allowing patients to enjoy a better quality of life without the need for prolonged hospitalization. Compared to subcutaneous implantation, intratumoral implantation has a number of significant advantages in terms of targeting and side effects, but this area of chemotherapy is still poorly understood in terms of clinical trials. At the same time, there are more known developments of drugs in the form of implants and injections for intratumoral administration. The disadvantages of classical intratumoral implants are the need for surgical intervention to install the system and the increased risk of tumor rupture noted by some specialists. The new generation of implants are in situ implants-systems formed in the tumor due to a phase transition (sol-gel transition) under the influence of various stimuli. Among this systems some are highly selective for a certain type of malignant neoplasm. Such systems are injected and have all the advantages of intratumoral injections, but due to the phase transition occurring in situ, they form depot forms that allow the long-term release of chemotherapeutic agents.

Thermosensitive Intravitreal In Situ Implant of Cefuroxime Based on Poloxamer 407 and Hyaluronic Acid.

The main method of treatment and prevention of endophthalmitis is a combination of intravitreal and topical administration of antibiotics, such as cefuroxime moxifloxacin or vancomycin. However, this method is ineffective due to the rapid elimination of the drug. This problem can be solved with the help of intravitreal in situ injection systems, which are injected with a syringe into the vitreous body and provide prolonged action of the drug at the focus of inflammation. Under the influence of temperature, the liquid drug undergoes a phase transition and turns into a gel after injection. This ensures its prolonged action. The study aimed to develop an intravitreal in situ cefuroxime delivery system for the treatment of endophthalmitis based on a thermosensitive biodegradable composition of poloxamer 407 and hyaluronic acid. A combination of poloxamer Kolliphor® P407, Kolliphor® P188, and PrincipHYAL® hyaluronic acids of different molecular weights was used as a delivery system. The potency of cefuroxime solid dispersion with polyvinylpyrrolidone-10000, polyethylene glycol-400, and polyethylene glycol-1500 in a 1:2 ratio was studied for prolonged action compared to cefuroxime substance. The experimental formulations were studied for the parameters of gelation temperature in a long-term test (4 months), pH, and release of cefuroxime using dialysis bags. To study the distribution parameter in the vitreous body, an in vitro model (1/13) was developed, which was a hollow agar sphere filled with 1% (w/v) polyacrylate gel. For the superior formulations, a HET-CAM test (chorioallantoic membrane test) was performed to determine the absence of irritant effects. According to the study results, a formulation containing a solid dispersion of cefuroxime:PEG-400 (1:2), the matrix of which contained 18% (w/v) Kolliphor® P407 poloxamer, 3% (w/v) Kolliphor® P188 poloxamer, and 0.5% (w/v) hyaluronic acid (1400-1800), was selected. This sample had an average gelation temperature of 34.6 °C, pH 6.7 ± 0.5, and a pronounced prolonged effect. Only 7.6% was released in 3 h of the experiment, whereas about 38% of cefuroxime was released in 72 h. No irritant effect on the chorioallantoic membrane was observed for any formulations studied.

New Biopharmaceutical Characteristics of In Situ Systems Based on Poloxamer 407.

Thermosensitive systems based on poloxamer 407 are widely used in targeted drug delivery; however, the stability of the phase transition temperature remains insufficiently studied. This article presents the results of a study on the effect of adding polyethylene glycols (PEG) with different molecular weights and some classical gel-forming polymers on the gelation temperature of thermoreversible compositions based on poloxamer 407 in a long-term experiment. The study showed a positive effect of PEG addition with average molecular weights at concentrations of 1.5-2.0%, as well as gelling agents at a concentration below the critical gelation concentration. The proposed rheological test for studying the samples' adhesion can give an indirect forecast of the composition adhesive rate. Based on the conducted studies, three experimental binary systems based on poloxamer 407 were selected, with the addition of HPMC 0.5%, sodium alginate 0.5%, and PEG 1500 1.5%. These systems are the most promising for the further development of in situ targeted drug delivery systems.

Antimicrobial Cu-Doped TiO2 Coatings on the ß Ti-30Nb-5Mo Alloy by Micro-Arc Oxidation.

Among the different surface modification techniques, micro-arc oxidation (MAO) is explored for its ability to enhance the surface properties of Ti alloys by creating a controlled and durable oxide layer. The incorporation of Cu ions during the MAO process introduces additional functionalities to the surface, offering improved corrosion resistance and antimicrobial activity. In this study, the ß-metastable Ti-30Nb-5Mo alloy was oxidated through the MAO method to create a Cu-doped TiO2 coating. The quantity of Cu ions in the electrolyte was changed (1.5, 2.5, and 3.5 mMol) to develop coatings with different Cu concentrations. X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron and atomic force microscopies, contact angle, and Vickers microhardness techniques were applied to characterize the deposited coatings. Cu incorporation increased the antimicrobial activity of the coatings, inhibiting the growth of Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa bacteria strains, and Candida albicans fungus by approximately 44%, 37%, 19%, and 41%, respectively. Meanwhile, the presence of Cu did not inhibit the growth of Escherichia coli. The hardness of all the deposited coatings was between 4 and 5 GPa. All the coatings were non-cytotoxic for adipose tissue-derived mesenchymal stem cells (AMSC), promoting approximately 90% of cell growth and not affecting the AMSC differentiation into the osteogenic lineage.

Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety and Efficacy.

Breast cancer (BC) is the prevailing malignancy and major cause of cancer-related death in females. Doxorubicin is a part of BC neoadjuvant and adjuvant chemotherapy regimens. The administration of anthracycline derivates, such as doxorubicin, may cause several side effects, including hematological disfunction, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity. Cardiotoxicity is a major adverse reaction to anthracyclines, and it may vary depending on individual differences in doxorubicin pharmacokinetics. Determination of specific polymorphisms of genes that can alter doxorubicin metabolism was shown to reduce the risk of adverse reactions and improve the safety and efficacy of doxorubicin. Genes which encode cytochrome P450 enzymes (CYP3A4 and CYP2D6), p-glycoproteins (ATP-binding cassette (ABC) family members such as Multi-Drug Resistance 1 (MDR1) protein), and other detoxifying enzymes were shown to control the metabolism and pharmacokinetics of doxorubicin. The effectiveness of doxorubicin is defined by the polymorphism of cytochrome p450 and p-glycoprotein-encoding genes. This study critically discusses the latest data about the role of gene polymorphisms in the regulation of doxorubicin's anti-BC effects. The correlation of genetic differences with the efficacy and safety of doxorubicin may provide insights for the development of personalized medical treatment for BC patients.

Effect of the Antimicrobial Agents Peppermint Essential Oil and Silver Nanoparticles on Bone Cement Properties.

The main problems directly linked with the use of PMMA bone cements in orthopedic surgery are the improper mechanical bond between cement and bone and the absence of antimicrobial properties. Recently, more research has been devoted to new bone cement with antimicrobial properties using mainly antibiotics or other innovative materials with antimicrobial properties. In this paper, we developed modified PMMA bone cement with antimicrobial properties proposing some experimental antimicrobial agents consisting of silver nanoparticles incorporated in ceramic glass and hydroxyapatite impregnated with peppermint oil. The impact of the addition of antimicrobial agents on the structure, mechanical properties, and biocompatibility of new PMMA bone cements was quantified. It has been shown that the addition of antimicrobial agents improves the flexural strength of the traditional PMMA bone cement, while the yield strength values show a decrease, most likely because this agent acts as a discontinuity inside the material rather than as a reinforcing agent. In the case of all samples, the addition of antimicrobial agents had no significant influence on the thermal stability. The new PMMA bone cement showed good biocompatibility and the possibility of osteoblast proliferation (MTT test) along with a low level of cytotoxicity (LDH test).

Development of Composition and Technologies of Dental Film with Ketorolac Trometamine.

The report presents the results of the development of dental films with ketorolac trometamine based on the natural biodegradable polymers from the groups of sodium alginates and xanthan gums in combination with lightly crosslinked acrylic polymer carbopol. Physicochemical properties, such as moisture, mucoadhesion, thickness, tensile strength, disintegration in phosphate buffer were determined in obtained samples of this dosage form. A comparison of physicochemical properties of experimental samples and commercial model of dental film has allowed establishing the perspective composition of complex matrix of films with ketorolac trometamine for use in dentistry.

Study of the Acute Toxicity of a New Dosage Form of Naloxone Hydrochloride for Intranasal Administration.

The experiment was conducted on 10 Wistar rats, male and female, with initial body weight 270-280 g (males) and 250-260 g (females). The drug was administered using a spray cap in 10 doses of 0.1 mg at 45 min intervals. The average cumulative dose of the drug per naloxone hydrochloride was 36.6 mg/kg for males and 39.4 mg/kg for females. The animals were monitored for 2 weeks after the exposure and then euthanized by a gentle decapitation.We noticed that after each drug administration the animals showed a decrease in motor activity. During the observation period there were no animal deaths or signs of abnormalities in their general state or behavior. Beginning on day 7 a significant increase in body weight of the animals was noted in comparison with the initial data. The relative mass of the internal organs of the treated rats remained within the physiological norm.We conclude that naloxone hydrochloride after an intranasal administration at 36.6 mg/kg for males and 39.4 mg/kg for females does not cause death of animals and or have a toxic effect on their general state, does not change their protein metabolism characteristics or the appearance of the internal organs and their mass.