In Situ Gelling Behavior and Biopharmaceutical Characterization of Nano-Silver-Loaded Poloxamer Matrices Designed for Nasal Drug Delivery.

A combination of Poloxamer 407 (P407) and hydroxypropyl methylcellulose (HPMC) hydrosols is proposed as an in situ thermo-gelling vehicle for the nasal drug delivery of chlorhexidine-silver nanoparticles conjugates (SN-CX). Optimization of the formulation was carried out by applying varying ratios of P407 and HPMC in the presence and absence of SN-CX so that gelation would occur in the temperature range of the nasal cavity (30-34 °C). Mechanisms for the observed gelation phenomena were suggested based on viscosimetry, texture analysis, and dynamic light scattering. Tests were carried out for sprayability, washout time, in vitro drug release, ex vivo permeation, and antimicrobial activity. When applied separately, HPMC was found to lower the P407 gelation temperature (Tg), whereas SN-CX increased it. However, in the presence of HPMC, SN-CX interfered with the P407 micellar organization in a principally contrasting way while leading to an even further decrease in Tg. SN-CX-loaded nasal formulations composed of P407 16% and HPMC 0.1% demonstrated a desired gelation at 31.9 °C, good sprayability (52.95% coverage of the anterior nasal cavity), mucoadhesion for 70 min under simulated nasal clearance, expedient release and permeation, and preserved anti-infective activity against seasonal Influenza virus and beta-coronavirus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus and other pathogens. Our findings suggest that the current development could be considered a potential formulation of a protective nasal spray against respiratory infections.

Tissue Regeneration and Remodeling in Rat Models after Application of Hypericum perforatum L. Extract-Loaded Bigels.

The wound-healing effect of St. John's Wort (SJW) is mainly attributed to hyperforin (HP), but its low stability restricts its topical administration. This study investigates how "free" HP-rich SJW extract (incorporated into a bigel; B/SJW) and extract "protected" by nanostructured lipid carriers (also included in a biphasic semisolid; B/NLC-SJW) affect tissue regeneration in a rat skin excision wound model. Wound diameter, histological changes, and tissue gene expression levels of fibronectin (Fn), matrix metalloproteinase 8 (MMP8), and tumor necrosis factor-alpha (TNF-α) were employed to quantify the healing progress. A significant wound size reduction was achieved after applying both extract-containing semisolids, but after a 21-day application period, the smallest wound size was observed in the B/NLC-SJW-treated animals. However, the inflammatory response was affected more favorably by the bigel containing the "free" SJW extract, as evidenced by histological studies. Moreover, after the application of B/SJW, the expression of Fn, MMP8, and TNF-α was significantly higher than in the positive control. In conclusion, both bigel formulations exhibited beneficial effects on wound healing in rat skin, but B/SJW affected skin restoration processes in a comprehensive and more efficient way.

Therapeutic Potential of Myrtenal and Its Derivatives-A Review.

The investigation of monoterpenes as natural products has gained significant attention in the search for new pharmacological agents due to their ability to exhibit a wide range in biological activities, including antifungal, antibacterial, antioxidant, anticancer, antispasmodic, hypotensive, and vasodilating properties. In vitro and in vivo studies reveal their antidepressant, anxiolytic, and memory-enhancing effects in experimental dementia and Parkinson's disease. Chemical modification of natural substances by conjugation with various synthetic components is a modern method of obtaining new biologically active compounds. The discovery of new potential drugs among monoterpene derivatives is a progressive avenue within experimental pharmacology, offering a promising approach for the therapy of diverse pathological conditions. Biologically active substances such as monoterpenes, for example, borneol, camphor, geraniol, pinene, and thymol, are used to synthesize compounds with analgesic, anti-inflammatory, anticonvulsive, antidepressant, anti-Alzheimer's, antiparkinsonian, antiviral and antibacterial (antituberculosis) properties. Myrtenal is a perspective monoterpenoid with therapeutic potential in various fields of medicine. Its chemical modifications often lead to new or more pronounced biological effects. As an example, the conjugation of myrtenal with the established pharmacophore adamantane enables the augmentation of several of its pivotal properties. Myrtenal-adamantane derivatives exhibited a variety of beneficial characteristics, such as antimicrobial, antifungal, antiviral, anticancer, anxiolytic, and neuroprotective properties, which are worth examining in more detail and at length.

Chlorhexidine-Silver Nanoparticle Conjugation Leading to Antimicrobial Synergism but Enhanced Cytotoxicity.

This study explored the potential synergism within chlorhexidine-silver nanoparticle conjugates against Influenza type A, Staphylococcus aureus, Escherichia coli, and Candida albicans. Silver nanoparticles (SN) were obtained by the reduction of silver ions with green tea total phenolic extract and conjugated with chlorhexidine (Cx). The particles were characterized by UV-Vis and FTIR spectroscopies, dynamic light scattering, X-ray diffraction, and transmission electron microscopy. A stable negatively charged nano-silver colloid (ζ = -50.01) was obtained with an average hydrodynamic diameter of 92.34 nm. In the presence of chlorhexidine, the spectral data and the shift of the zeta potential to positive values (ζ = +44.59) revealed the successful sorption of the drug onto the silver surface. The conjugates (SN-Cx) demonstrated potentiation in their effects against S. aureus and C. albicans and synergism against E. coli with minimal inhibitory concentrations of SN at 5.5 µg/mL + Cx 8.8 µg/mL. The SN showed excellent virucidal properties, increasing with time, and demonstrated low toxicity. However, the coupling of the cationic chlorhexidine with nano-silver did not reduce its intrinsic cytotoxicity on various cell lines (MDCK, BJ, and A549). The newly synthesized antimicrobial agent exhibited an extended and promising therapeutic spectrum and needs to be further evaluated regarding the designated route of administration in three-dimensional cell models (e.g., nasal, bronchial, dermal, ocular, etc.).

Bigel Formulations of Nanoencapsulated St. John's Wort Extract-An Approach for Enhanced Wound Healing.

This study aimed to develop a semisolid vehicle for topical delivery of nanoencapsulated St. John's wort (SJW) extract, rich in hyperforin (HP), and explore its wound-healing potential. Four nanostructured lipid carriers (NLCs) were obtained: blank and HP-rich SJW extract-loaded (HP-NLC). They comprised glyceryl behenate (GB) as a solid lipid, almond oil (AO), or borage oil (BO) representing the liquid lipid, along with polyoxyethylene (20) sorbitan monooleate (PSMO) and sorbitan monooleate (SMO) as surfactants. The dispersions demonstrated anisometric nanoscale particles with acceptable size distribution and disrupted crystalline structure, providing entrapment capacity higher than 70%. The carrier exhibiting preferable characteristics (HP-NLC2) was gelled with Poloxamer 407 (PM407) to serve as the hydrophilic phase of a bigel, to which the combination of BO and sorbitan monostearate (SMS) organogel was added. The eight prepared bigels with different proportions (blank and nanodispersion-loaded) were characterized rheologically and texturally to investigate the impact of the hydrogel-to-oleogel ratio. The therapeutic potential of the superior formulation (HP-NLC-BG2) was evaluated in vivo on Wistar male rats through the tensile strength test on a primary-closed incised wound. Compared with a commercial herbal semisolid and a control group, the highest tear resistance (7.764 ± 0.13 N) was achieved by HP-NLC-BG2, proving its outstanding wound-healing effect.

Recent Progress of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers as Ocular Drug Delivery Platforms.

Sufficient ocular bioavailability is often considered a challenge by the researchers, due to the complex structure of the eye and its protective physiological mechanisms. In addition, the low viscosity of the eye drops and the resulting short ocular residence time further contribute to the observed low drug concentration at the target site. Therefore, various drug delivery platforms are being developed to enhance ocular bioavailability, provide controlled and sustained drug release, reduce the number of applications, and maximize therapy outcomes. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) exhibit all these benefits, in addition to being biocompatible, biodegradable, and susceptible to sterilization and scale-up. Furthermore, their successive surface modification contributes to prolonged ocular residence time (by adding cationic compounds), enhanced penetration, and improved performance. The review highlights the salient characteristics of SLNs and NLCs concerning ocular drug delivery, and updates the research progress in this area.

Advances in the Prophylaxis of Respiratory Infections by the Nasal and the Oromucosal Route: Relevance to the Fight with the SARS-CoV-2 Pandemic.

In this time of COVID-19 pandemic, the strategies for prevention of the infection are a primary concern. Looking more globally on the subject and acknowledging the high degree of misuse of protective face masks from the population, we focused this review on alternative pharmaceutical developments eligible for self-defense against respiratory infections. In particular, the attention herein is directed to the nasal and oromucosal formulations intended to boost the local immunity, neutralize or mechanically "trap" the pathogens at the site of entry (nose or mouth). The current work presents a critical review of the contemporary methods of immune- and chemoprophylaxis and their suitability and applicability in topical mucosal dosage forms for SARS-CoV-2 prophylaxis.

Incorporation of the Dry Blossom Flour of Sambucus nigra L. in the Production of Sponge Cakes.

The present study aims to develop recipe compositions and technology for producing sponge cakes from wholemeal flour, partially replaced with a functional plant component dry blossom flour of Sambucus nigra L. Three designs of sponge cakes with 5, 10, and 15% content of flour of Sambucus nigra L. corrected up to 100% with whole-grain oat flour were studied. Their characteristics were compared with sponge cakes of 100% wheat flour/control. The obtained new products were characterized by reduced carbohydrates, increased content of dietary fiber, and preserved volume compared to the control. The physicochemical parameters of sponge cake and marshmallows with different concentrations of dry flowers of Sambucus nigra L. included in them differed from the control with lower water absorption, pH, and moisture, while having a higher relative mass and ash content and retaining the original size. Pathogenic microorganisms such as Escherichia coli, Salmonella sp., and Staphylococcus aureus, and common coliforms were not detected in the control and experimental samples when determining the microbiological parameters. Therefore, the developed formulations are an excellent alternative to wheat flour, significantly improving some nutritional characteristics such as smell, taste, dietary fiber, and lower carbohydrate content.

Stability study of extemporaneously compounded nitrofurantoin oral suspensions for pediatric patients.

AIM: To evaluate the stability of nitrofurantoin suspended in different extemporaneously compounded vehicles after storage at 4°C and at 25°C. To formulate an effective, readily available vehicle that can guarantee extended stability and precise dosing.

Lipid Nanoparticulate Drug Delivery Systems: Recent Advances in the Treatment of Skin Disorders.

The multifunctional role of the human skin is well known. It acts as a sensory and immune organ that protects the human body from harmful environmental impacts such as chemical, mechanical, and physical threats, reduces UV radiation effects, prevents moisture loss, and helps thermoregulation. In this regard, skin disorders related to skin integrity require adequate treatment. Lipid nanoparticles (LN) are recognized as promising drug delivery systems (DDS) in treating skin disorders. Solid lipid nanoparticles (SLN) together with nanostructured lipid carriers (NLC) exhibit excellent tolerability as these are produced from physiological and biodegradable lipids. Moreover, LN applied to the skin can improve stability, drug targeting, occlusion, penetration enhancement, and increased skin hydration compared with other drug nanocarriers. Furthermore, the features of LN can be enhanced by inclusion in suitable bases such as creams, ointments, gels (i.e., hydrogel, emulgel, bigel), lotions, etc. This review focuses on recent developments in lipid nanoparticle systems and their application to treating skin diseases. We point out and consider the reasons for their creation, pay attention to their advantages and disadvantages, list the main production techniques for obtaining them, and examine the place assigned to them in solving the problems caused by skin disorders.

Dermal Drug Delivery of Phytochemicals with Phenolic Structure via Lipid-Based Nanotechnologies.

Phenolic compounds are a large, heterogeneous group of secondary metabolites found in various plants and herbal substances. From the perspective of dermatology, the most important benefits for human health are their pharmacological effects on oxidation processes, inflammation, vascular pathology, immune response, precancerous and oncological lesions or formations, and microbial growth. Because the nature of phenolic compounds is designed to fit the phytochemical needs of plants and not the biopharmaceutical requirements for a specific route of delivery (dermal or other), their utilization in cutaneous formulations sets challenges to drug development. These are encountered often due to insufficient water solubility, high molecular weight and low permeation and/or high reactivity (inherent for the set of representatives) and subsequent chemical/photochemical instability and ionizability. The inclusion of phenolic phytochemicals in lipid-based nanocarriers (such as nanoemulsions, liposomes and solid lipid nanoparticles) is so far recognized as a strategic physico-chemical approach to improve their in situ stability and introduction to the skin barriers, with a view to enhance bioavailability and therapeutic potency. This current review is focused on recent advances and achievements in this area.

Natural Lipids as Structural Components of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Topical Delivery.

BACKGROUND: Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are useful drug delivery systems for dermal application. Thanks to their biocompatible and biodegradable profile, these carriers offer many advantages such as enhanced bioavailability, low toxicity, viable drug targeting and controlled release. SLN and NLC are composed of well-tolerated lipids, including natural fats and oils that are successfully used in the pharmaceutical and cosmetic dermal formulation. OBJECTIVE: This article presents an overview of the benefits of selecting natural fats and oils as structural components of SLN and NLC for topical application. METHODS: This review is based on data published over the past 20 years about the development of stable and nontoxic lipid nanoparticles with natural lipids. We shed light on the role of natural fats in skin restoration, as well as on the contributed penetration and occlusive properties of SLN and NLC. RESULTS: The deliberate selection of excipients (type and lipid ratio) influences the quality of the final dermal formulation. Natural lipids show good compatibility with different active molecules and are able to create stable lipid matrices that facilitate the biopharmaceutical properties of lipid nanoparticles. Patents involving natural fats and oils in SLN and NLC composition are listed, yet it is important to note that the approved marketed formulations are mainly cosmetic, not pharmaceutical, products. CONCLUSION: Natural lipids can enhance topical drug delivery by adding their ability of improving skin penetration and hydration to the permeation and occlusion properties of SLN and NLC.

Antioxidant Activity of Dry Birch (Betula Pendula) Leaves Extract.

BACKGROUND: Betula pendula is widespread in Europe and Asia. It has been used in traditional medicine since ancient times. Birch leaf extracts are known to exhibit a number of pharmacological activities. Antioxidant activity has also been reported. AIM: The aim of this work was to investigate the antioxidant activity of a dry leaf extract from Betula pendula Roth. MATERIALS AND METHODS: The total flavonoid content was determined. Some of the most commonly used methods were applied to evaluate the antioxidant capacity of the extract in vitro and in vivo. The ability of the extract to scavenge DPPH free radicals was evaluated by the method described by Brand-Williams with suitable modifications. ABTS decolorization assay was also applied. The in vivo assay was performed after acute and chronic administration of the extract into white albino rats, in a dose of 100 and 500 mg/kg bw. The antioxidant potential of the plasma was determined using FRAP reagent. RESULTS: A total flavonoid content of 42.5 mg/g was found, expressed as quercetin. The antioxidant activity against ABTS was concentration and time dependent. For example the concentration of 200 µg/ml led to 70.95% - 99.46% scavenging activity. DPPH scavenging activity was found to be about 98% at a concentration of 80 µg/ml. The extract possesses antioxidant potential, comparable with that of Trolox, in acute application. In chronic application, poorer results are observed, probably due to biotransformation and elimination processes. CONCLUSION: Dried birch leaf extract has a relatively high antioxidant potential and could be used as a natural source of antioxidants.

Characterization Methods for Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC).

BACKGROUND: Solid lipid nanoparticles (SLN) and the next generation of nanostructured lipid carriers (NLC) seem to be a very promising alternative to other colloidal carriers such as liposomes, microemulsions, and polymeric nanoparticles. These combine the advantages of the cited nanocarriers and can improve the dissolution rate in biological fluids, increase the drug absorption, improve the tissue distribution in the target organ, enhance the drug bioavailability and ensure controlled drug release. SLN and NLC can ensure higher drug stability in the harsh environment, cover the bitter taste of the drug, and reduce the first-pass-effect after oral administration. However, these carriers suffer from some disadvantages such as low drug loading capacity, drug expulsion, and unpredictable gelation tendency. METHODS: This article aims to provide detail information about the process of complex characterization of SLN and NLC to produce an effective, quality and safe colloidal DDS with desired properties, based on the literature published in the period from 2000 to 2017. RESULTS: Characterization techniques in terms of size and particle size distribution; surface morphology, functionalization, and zeta potential; structure, depending on the degree of crystallinity, lipid modification, drug incorporation and loading capacity; drug release; co-existence of other nano- and microstructures; and toxicity assessment according to the process of production, lipids and surfactants used and route of administration are discussed in the article. CONCLUSION: The precise characterization of lipid nanocarriers as drug delivery systems ensures guarantees for the quality of the product as an effective and safe form. The typical composition of SLN and NLC requires a comprehensive approach of characterization and in-depth analysis of the results to perform a drug delivery system with desired properties.

Ketoprofen-loaded polymer carriers in bigel formulation: an approach to enhancing drug photostability in topical application forms.

The purpose of the study was to investigate the stability and biopharmaceutical characteristics of ketoprofen, loaded in polymeric carriers, which were included into a bigel in a semisolid dosage form. The polymer carriers with in situ-included ketoprofen were obtained by emulsifier-free emulsion polymerization of the monomers in aqueous medium or a solution of the polymers used. The morphological characteristics of the carriers, the in vitro release and the photochemical stability of ketoprofen were evaluated. The model with optimal characteristics was included in a bigel formulation. The bigel was characterized in terms of pH, rheological behavior, spreadability, and in vitro drug release. Acute skin toxicity, antinociceptive activity, anti-inflammatory activity, and antihyperalgesic effects of the prepared bigel with ketoprofen-loaded polymer carrier were evaluated. The carriers of ketoprofen were characterized by a high yield and drug loading. The particle size distribution varied widely according to the polymer used, and a sustained release was provided for up to 6 hours. The polymer mixture poly(vinyl acetate) and hydroxypropyl cellulose as a drug carrier, alone or included in the bigel composition, improved the photostability of the drug compared with unprotected ketoprofen. The bigel with ketoprofen-loaded particles provided sustained release of the drug and had optimal rheological parameters. In vivo experiments on the bigel showed no skin inflammation or irritation. Four hours after its application, a well-defined analgesic, anti-inflammatory, and antihyperalgesic effect was registered. The polymer mixture of poly(vinyl acetate) and hydroxypropyl cellulose as a carrier of ketoprofen and the bigel in which it was included provided an enhanced photostability and sustained drug release.

A New Direction in Ophthalmic Development: Nanoparticle Drug Delivery Systems.

The purpose of each dosage form is to provide an optimal therapeutic effect with a minimum dose and with minimal side effects. This is particularly relevant for drugs that require systemic administration, higher dosing and/or show lower bioavailability. Тhe eye as an anatomical structure is an extremely protected organ. In this regard, providing an optimal bioavailability in the eye tissues, resulting in the desired therapeutic effect represents a major challenge. This is especially true for the treatment of diseases, affecting the posterior segment after topically administered drug formulations. The use of nano- and microcarriers of drug substances may be an appropriate technological approach, to provide a high bioavailability of the drug substance for a certain interval of time at the right place. The purpose of this review is to indicate how nano- and microcarriers of drug substances can solve the problems with the drug delivery in the ocular tissues, to indicate the possible hazards and side effects, depending on the polymer nature and route of administration, and to visualize the future potential of these carriers in the pharmaceutical practice.

Indomethacin nanoparticles for applications in liquid ocular formulations.

UNLABELLED: Studies in recent years have consistently shown that polymeric drug nanocarriers can be used in drug release and drug delivery systems to treat eye disorders. To achieve effective control over drug delivery, it is of crucial importance what kind of polymer and which method for drug inclusion in the nanoscale carrier we choose and what conditions are needed for the performance of this process. OBJECTIVE: The aim of this study was to produce poly(vinyl acetate) nanoparticles with indomethacin incorporated in them, assess the effect of time for dialysis of the residual monomer and initiator on the degree of incorporation of indomethacin in the nanoparticles and on the kinetics of its release, to include them in ophtalmic formulations. MATERIALS AND METHODS: Poly(vinyl acetate) nanoparticles with indomethacin were obtained by emulsion radical polymerization of vinyl acetate in the presence of indomethacin (in situ inclusion) and the absence of emulsifier. To release the residual monomer and initiator (ammonium persulfate) the obtained latexes were dialysed for 6, 9, 18 and 23 hours and then the nanoparticles were freeze-dried. Structural analysis was performed by transmission electronic microscopy, infrared spectroscopy, differential thermal analysis and thermogravimetry. Release of indomethacin was observed using ultraviolet spectroscopy. RESULTS: We proved the delayed release of indomethacin from the poly(vinyl acetate) nanocarrier and the lack of chemical interaction between the polymer and indomethacin. After 9-hour dialysis the initiator and the residual vinyl acetate were removed from the nanoparticles, while the entrapped indomethacin kept therapeutic concentrations. CONCLUSIONS: Dialysis for more than 6 and no more than 9 hours is recommended to remove the residual monomer and initiator when preparing indomethacin nanoparticles by in situ radical emulsion polymerization of vinyl acetate, for inclusion in liquid ocular formulations.