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Orally administered amoxicillin is recommended as the first-line treatment of acute bacterial rhinosinusitis (ABR) and given in a high-dose regimen. However, the risk of various systemic adverse reactions and low oral bioavailability are unbearable, increasing the threat of antibiotic resistance. Therefore, nasal delivery of amoxicillin can be a potential approach for effectively treating ABR locally, as well as overcoming those drawbacks. In a way to guarantee the effectiveness for local therapy in nasal cavity, the permeation and retention properties are of significant importance considerations. Accordingly, the present work aimed to investigate the characteristics with respect to the nasal applicability of the in situ gelling amoxicillin trihydrate (AMT) and further evaluate its permeability and retention properties through human nasal mucosa. The lyophilized formulations were characterized utilizing the Differential Scanning Calorimetry (DSC) and X-ray Powder Diffraction (XRPD), and also evaluated for its polarity, reconstitution time, droplet size distribution, mucoadhesive properties, and ex vivo permeability and retention studies. The results confirmed that the in situ gelling AMT formulations possess adequate mucoadhesive behavior, especially the formulation containing 0.3 % of gellan gum. Substantially, the in situ gelling AMT formulations were able to retain the drug on the surface of nasal mucosa instead of permeating across the membrane; thus, suitable for treating nasal infections locally. Altogether, the in situ gelling systems demonstrates promising abilities as a delivery platform to enhance local application of AMT within the nasal cavity.

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This study aims to highlight the importance of choosing the appropriate co-polymer or co-polymer mixed combinations in order to design value-added nasal dosage forms. Local therapy of upper respiratory tract-related infections, such as nasal rhinosinusitis is of paramount importance, thus advanced local therapeutic options are required. Dexamethasone was encapsulated into three different polymeric micelle formulations: Soluplus or TPGS-only and their mixed combinations. Dynamic light scattering measurements proved that the particles have a micelle size less than 100 nm in monodisperse distribution, with high encapsulation efficiency above 80% and an at least 7-fold water solubility increase. Tobramycin, as an antimicrobial agent, was co-formulated into the in situ gelling systems which were optimized based on gelation time and gelation temperature. The sol-gel transition takes place between 32-35 °C, which is optimally below the temperature of the nasal cavity in a quick manner below 5 min, a suitable strategic criterion against the mucociliary clearance. In vitro drug release and permeability studies confirmed a rapid kinetics in the case of the encapsulated dexamethasone accompanied with a sustained release of tobramycin, as the hydrophilic drug.

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Nasal systemic drug delivery may provide an easy way to substitute parenteral or oral dosing, however, the excipients have an important role in nasal formulations to increase the permeability of the mucosa and prolong the residence time of the drug. In this work, we aimed to produce meloxicam potassium monohydrate (MXP) containing nasal powders by a nano spray drier with the use of a neutral, an anionic and a cationic ß-cyclodextrin as permeation enhancers, and (polyvinyl)alcohol (PVA) as a water soluble polymer. The following examinations were performed in order to study the effect of the applied excipients on the nasal applicability of the formulations: laser scattering, scanning electron microscope measurement, XRPD, DSC and FTIR measurements, adhesivity, in vitro drug release and permeability tests through an artificial membrane and RPMI 2650 cells. Based on our results, spherical particles were prepared with a size of 1.89-2.21 µm in which MXP was present in an amorphous state. Secondary interactions were formed between the excipients and the drug. The charged cyclodextrin-based formulations showed significantly higher adhesive force values regardless of the presence of PVA. The drug release was fast and complete. The passive diffusion of MXP was influenced not only by the charge of the cyclodextrin, but the presence of PVA, too. The permeation of the drug was enhanced in the presence of the anionic cyclodextrin testing it on RPMI 2650 cell model.

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Microneedle arrays (MNAs) consist of a few dozens of submillimeter needles, which tend to penetrate through the stratum corneum layer of the skin and deliver hardly penetrating drugs to the systemic circulation. The application of this smart dosage form shows several advantages, such as simple use and negligible pain caused by needle punctures compared to conventional subcutaneous injections. Dissolving MNAs (DMNAs) represent a promising form of cutaneous drug delivery due to their high drug content, biocompatibility, and ease of use. Although different technologies are suitable to produce microneedle arrays (e.g., micromilling, chemical etching, laser ablation etc.), many of these are expensive or hardly accessible. Following the exponential growth of the 3D-printing industry in the last decade, high-resolution desktop printers became accessible for researchers to easily and cost-effectively design and produce microstructures, including MNAs. In this work, a low force stereolithography (LFS) 3D-printer was used to develop the dimensionally correct MNA masters for the spin-casting method. The present study aimed to develop and characterize drug-loaded DMNAs using a two-level, full factorial design for three factors focusing on the optimization of DMNA production and adequate drug content. For the preparation of DMNAs, carboxymethylcellulose and trehalose were used in certain amounts as matrices for dexamethasone sodium phosphate (DEX). Investigation of the produced DexDMNAs included mechanical analysis via texture analyzer and optical microscopy, determination of drug content and distribution with HPLC and Raman microscopy, dissolution studies via HPLC, and ex vivo qualitative permeation studies by Raman mapping. It can be concluded that a DEX-containing, mechanically stable, biodegradable DexDMNA system was successfully developed in two dosage strengths, of which both efficiently delivered the drug to the lower layers (dermis) of human skin. Moreover, the ex vivo skin penetration results support that the application of DMNAs for cutaneous drug delivery can be more effective than that of a conventional dermal gel.

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Periodontitis is a serious form of oral gum inflammation with recession of gingival soft tissue, destruction of the periodontal ligament, and absorption of alveolar bone. Management of periodontal tissue and bone destruction, along with the restoration of functionality and structural integrity, is not possible with conventional clinical therapy alone. Guided bone and tissue regeneration therapy employs an occlusive biodegradable barrier membrane and graft biomaterials to guide the formation of alveolar bone and tissues for periodontal restoration and regeneration. Amongst several grafting approaches, alloplastic grafts/biomaterials, either derived from natural sources, synthesization, or a combination of both, offer a wide variety of resources tailored to multiple needs. Examining several pertinent scientific databases (Web of Science, Scopus, PubMed, MEDLINE, and Cochrane Library) provided the foundation to cover the literature on synthetic graft materials and membranes, devoted to achieving periodontal tissue and bone regeneration. This discussion proceeds by highlighting potential grafting and barrier biomaterials, their characteristics, efficiency, regenerative ability, therapy outcomes, and advancements in periodontal guided regeneration therapy. Marketed and standardized quality products made of grafts and membrane biomaterials have been documented in this work. Conclusively, this paper illustrates the challenges, risk factors, and combination of biomaterials and drug delivery systems with which to reconstruct the hierarchical periodontium.

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Lidocaine is generally recognized and preferred for local anaesthesia, but in addition, studies have described additional benefits of lidocaine in cancer therapy, inflammation reduction, and wound healing. These properties contribute to its increasing importance in dermatological applications, and not only in pain relief but also in other potential therapeutic outcomes. Therefore, the purpose of our study was to enhance lidocaine delivery through the skin. A stable nanostructured lipid carrier (NLC), as a passive permeation enhancer, was developed using a 23 full factorial design. The nanosystems were characterized by crystallinity behaviour, particle size, zeta potential, encapsulation efficiency measurements, and one of them was selected for further investigation. Then, NLC gel was formulated for dermal application and compared to a traditional dermal ointment in terms of physicochemical (rheological behaviour) and biopharmaceutical (qualitative Franz diffusion and quantitative Raman investigations) properties. The study also examined the use of 3D printed solid microneedles as active permeation enhancers for these systems, offering a minimally invasive approach to enhance transdermal drug delivery. By actively facilitating drug permeation through the skin, microneedles can complement the passive transport achieved by NLCs, thereby providing an innovative and synergistic approach to improving lidocaine delivery.

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This study focuses on how to define an Analytical Target Profile (ATP) which is intended for use in practice and on facilitating the selection of in vitro release test (IVRT) technology for diclofenac sodium topical hydrogel and cream. The implementation involves incorporating the new draft guidelines of the International Council for Harmonisation (ICH Q14) and USP (United States Pharmacopeia) Chapter 1220. Four IVRT apparatuses were compared (USP Apparatus II with immersion cell, USP Apparatus IV with semisolid adapter, static vertical diffusion cell, and a new, in-house-developed flow-through diffusion cell) with the help of the ATP. Performance characteristics such as accuracy, precision, cumulative amount released at the end of the IVRT experiment, and robustness were investigated. We found that the best apparatus for developing IVRT quality control (QC) tests in both cases was USP II with an immersion cell. All four different IVRT apparatuses were compared with each other and with the data found in the literature.

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Cystinosis is a low-prevalence lysosomal storage disease. The pathomechanism involves abnormal functioning of the cystinosine lysosomal cystine transporter (CTNS), causing intraliposomal accumulation of the amino acid cysteine disulfide, which crystallizes and deposits in several parts of the body. The most common ophthalmic complication of cystinosis is the deposition of "gold dust" cystine crystals on the cornea, which already occurs in infancy and leads to severe photosensitivity and dry eyes as it gradually progresses with age. In the specific treatment of cystinosis, preparations containing cysteamine (CYA) are used. The availability of commercialized eyedrops for the targeted treatment is scarce, and only Cystadrops® are commercially available with strong limitations. Thus, magistral CYA-containing compounded eyedrops (CYA-CED) could have a key role in patient care; however, a rationally designed comprehensive study on the commercialized and magistral products is still missing. This work aims to build up a comprehensive study about commercialized and magistral CYA eye drops, involving pharmacokinetic and physicochemical characterization (applying mucoadhesivity, rheology test, investigation of drug release, and parallel artificial membrane permeability assays), as well as ex vivo tests, well supported by statistical analysis.

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Medicated foams have emerged as promising alternatives to traditional carrier systems in pharmaceutical research. Their rapid and convenient application allows for effective treatment of extensive or hirsute areas, as well as sensitive or inflamed skin surfaces. Foams possess excellent spreading capabilities on the skin, ensuring immediate drug absorption without the need for intense rubbing. Our research focuses on the comparison of physicochemical and biopharmaceutical properties of three drug delivery systems: foam, the foam bulk liquid, and a conventional hydrogel. During the development of the composition, widely used diclofenac sodium was employed. The safety of the formulae was confirmed through an in vitro cytotoxicity assay. Subsequently, the closed Franz diffusion cell was used to determine drug release and permeation in vitro. Ex vivo Raman spectroscopy was employed to investigate the presence of diclofenac sodium in various skin layers. The obtained results of the foam were compared to the bulk liquid and to a conventional hydrogel. In terms of drug release, the foam showed a rapid release, with 80% of diclofenac released within 30 min. In summary, the investigated foam holds promising potential as an alternative to traditional dermal carrier systems, offering faster drug release and permeation.

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Transdermal delivery of active ingredients is a challenge for pharmaceutical technology due to their inadequate penetration properties and the barrier function of the skin. The necessity of painless, effective, topical therapy for the aging population is growing, and a variety of diclofenac sodium-containing semi-solid preparations are available to alleviate the symptoms of these ailments. Our purpose was to formulate a novel composition with higher drug content to enhance drug release and permeation, thereby providing more effective therapy. Another goal was to maintain the concentration of the organic solvent mixture below 30%, to protect the skin barrier. Firstly, literature and market research were conducted, based on which the appropriate excipients for the target formulation were selected. Solubility tests were conducted with binary and ternary mixtures. As a result, the optimal ternary mixture was chosen. Hydrogels containing 1, 5, and 7% of diclofenac sodium were prepared and the stability of the formulations were studied by microscopic measurements and cytotoxicity test were carried out of the components also. The release and permeation of diclofenac sodium were investigated in different concentrations. It can be concluded that we have succeeded in preparing a topically applicable stable diclofenac sodium hydrogel with higher concentration, drug release, and improved skin permeation than the formulations available on the market.

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Nano-range bioactive colloidal carrier systems are envisaged to overcome the challenges associated with treatments of numerous diseases. Lipid nanoparticles (LNPs), one of the extensively investigated drug delivery systems, not only improve pharmacokinetic parameters, transportation, and chemical stability of encapsulated compounds but also provide efficient targeting and reduce the risk of toxicity. Over the last decades, nature-derived polyphenols, vitamins, antioxidants, dietary supplements, and herbs have received more attention due to their remarkable biological and pharmacological health and medical benefits. However, their poor aqueous solubility, compromised stability, insufficient absorption, and accelerated elimination impede research in the nutraceutical sector. Owing to the possibilities offered by various LNPs, their ability to accommodate both hydrophilic and hydrophobic molecules and the availability of various preparation methods suitable for sensitive molecules, loading natural fragile molecules into LNPs offers a promising solution. The primary objective of this work is to explore the synergy between nature and nanotechnology, encompassing a wide range of research aimed at encapsulating natural therapeutic molecules within LNPs.

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In this present formulation study, vinpocetine-loaded nano-spray-dried polymeric micelles were developed via nano-spray-drying. Three different mucoadhesive excipients were applied in the studies, namely chitosan, hyaluronic acid and hydroxypropyl methylcellulose. In all cases, the formulations had a proper particle size and drug content after drying with spherical morphology and amorphous structure. After rapid dissolution in water, the polymeric micelles had a particle size around 100-130 nm, in monodisperse size distribution. The high encapsulation efficiency (>80%) and high solubilization (approx. 300-fold increase in thermodynamic solubility) contributed to rapid drug release (>80% in the first 15 min) and fast passive diffusion at simulated nasal conditions. The formulated prototype preparations fulfilled the demands of a low-viscosity, moderately mucoadhesive nasal drug delivery system, which may be capable of increasing the overall bioavailability of drugs administered via the auspicious nasal drug delivery route.

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Periodontitis is one of the most widespread bacterial infectious oral diseases that affects a significant percentage of the population worldwide. Different bacterial strains are responsible for the chronic inflammation and subgingival plaque that could be effectively treated with prolonged exposure to therapeutic levels of antibiotics and antiseptics in the periodontal pockets. Medicated in situ gels of chlorhexidine (CHX), for extended drug release and long-lasting antiseptic effect in the targeted cavities, were prepared in a two-compartment system. One compartment was loaded with sodium alginate solution while other was filled with CHX and calcium solution. The mixing of the solutions during the application resulted in gelation. Two 33 full factorial designs were applied in this study in order to optimize the gel formulation. Initially, the effects of concentration of gelling agent, crosslinker, and pH of the system on the dependent variables such as gel formation and structure characteristics were investigated. Then, the concentration of the crosslinker was optimized. Afterwards, the effect of gelling agent, loading of the drug, and pH of the gel system were correlated with the gel characteristics through another factorial design. Optimized formulations were tested for mucoadhesion, in vitro drug release, and microbiological investigation. Based on the results of the factorial design, mucoadhesiveness, antimicrobial investigation, and drug release, a 4 % alginate composition can be considered optimal. Overall, the optimized in situ periodontal gel was found to be effective with prolonged retention time and desirable outcomes.

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A recommended first-line acute bacterial rhinosinusitis (ABR) treatment regimen includes a high dose of orally administered amoxicillin, despite its frequent systemic adverse reactions coupled with poor oral bioavailability. Therefore, to overcome these issues, nasal administration of amoxicillin might become a potential approach for treating ABR locally. The present study aimed to develop a suitable carrier system for improved local nasal delivery of amoxicillin employing the combination of albumin nanoparticles and gellan gum, an ionic-sensitive polymer, under the Quality by Design methodology framework. The application of albumin nanocarrier for local nasal antibiotic therapy means a novel approach by hindering the nasal absorption of the drug through embedding into an in situ gelling matrix, further prolonging the drug release in the nasal cavity. The developed formulations were characterized, including mucoadhesive properties, in vitro drug release and antibacterial activities. Based on the results, 0.3 % w/v gellan gum concentration was selected as the optimal in situ gelling matrix. Essentially, each formulation adequately inhibited the growth of five common nasal pathogens in ABR. In conclusion, the preparation of albumin-based nanoparticles integrated with in situ ionic-sensitive polymer provides promising ability as nanocarrier systems for delivering amoxicillin intranasally for local antibiotic therapy.

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The application of enzyme-based therapies has received significant attention in modern drug development. Lipases are one of the most versatile enzymes that can be used as therapeutic agents in basic skin care and medical treatment related to excessive sebum production, acne, and inflammation. The traditional formulations available for skin treatment, such as creams, ointments or gels, are widely applied; however, their use is not always accompanied by good drug penetration properties, stability, or patient adherence. Nanoformulated drugs offer the possibility of combining enzymatic and small molecule formulations, making them a new and exciting alternative in this field. In this study polymeric nanofibrous matrices made of polyvinylpyrrolidone and polylactic acid were developed, entrapping lipases from Candida rugosa and Rizomucor miehei and antibiotic compound nadifloxacin. The effect of the type of polymers and lipases were investigated, and the nanofiber formation process was optimized to provide a promising alternative in topical treatment. Our experiments have shown that entrapment by electrospinning induced two orders of magnitude increase in the specific enzyme activity of lipases. Permeability investigations indicated that all lipase-loaded nanofibrous masks were capable of delivering nadifloxacin to the human epidermis, confirming the viability of electrospinning as a formulation method for topical skin medications.

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Alzheimer's disease (AD) is an incurable, progressive neurodegenerative disorder. AD is a complex and multifactorial disease that is responsible for 60-80% of dementia cases. Aging, genetic factors, and epigenetic changes are the main risk factors for AD. Two aggregation-prone proteins play a decisive role in AD pathogenesis: ß-amyloid (Aß) and hyperphosphorylated tau (pTau). Both of them form deposits and diffusible toxic aggregates in the brain. These proteins are the biomarkers of AD. Different hypotheses have tried to explain AD pathogenesis and served as platforms for AD drug research. Experiments demonstrated that both Aß and pTau might start neurodegenerative processes and are necessary for cognitive decline. The two pathologies act in synergy. Inhibition of the formation of toxic Aß and pTau aggregates has been an old drug target. Recently, successful Aß clearance by monoclonal antibodies has raised new hopes for AD treatments if the disease is detected at early stages. More recently, novel targets, e.g., improvements in amyloid clearance from the brain, application of small heat shock proteins (Hsps), modulation of chronic neuroinflammation by different receptor ligands, modulation of microglial phagocytosis, and increase in myelination have been revealed in AD research.

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Efficient topical treatment of ocular diseases requires a prolonged residence time of drug formulations. An in situ gelling, mucoadhesive system can provide improved residence time while keeps the installation of the formulation easy and accurate due to its low initial viscosity. We synthesized a two-component, biocompatible water-based liquid formulation showing in situ gelation upon mixing. S-protected, preactivated derivatives of thiolated poly(aspartic acid) (PASP-SS-MNA) were synthesized by coupling the free thiol groups of thiolated poly(aspartic acid) (PASP-SH) with 6-mercaptonicotinic acid (MNA). The amount of protecting groups was 242, 341, and 530 µmol/g depending on the degree of thiolation of PASP. The chemical interaction between PASP-SS-MNA and mucin was proven, indicating the mucoadhesive properties. Disulfide cross-linked hydrogels were formed in situ without an oxidizing agent by mixing the aqueous solutions of PASP-SS-MNA and PASP-SH. The gelation time was controlled between 1 and 6 min, while the storage modulus was as high as 4-16 kPa depending on the composition. Swelling experiments showed that hydrogels with no residual thiol groups are stable in phosphate-buffered saline at pH = 7.4. In contrast, the presence of free thiol groups leads to the dissolution of the hydrogel with a rate depending on the excess of thiol groups. The biological safety of the polymers and MNA was confirmed on Madin-Darby Canine Kidney cell line. Furthermore, a prolonged release of ofloxacin was observed at pH = 7.4 compared to a conventional liquid formulation, supporting the potential of the developed biopolymers in ophthalmic drug delivery.

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Ascorbic acid (AA) has a pivotal role in corneal wound healing via stimulating the biosynthesis of highly organized extracellular matrix components, but its rapid degradation and low corneal permeability limits its therapeutic effects. In this paper, we present the pharmacokinetic properties of a liposomal-based formulation of AA in terms of corneal permeation. Chemical stability, shelf-life, and drug release rate of lyophilized liposome (AA-LLipo) formulation was determined in comparison to free-form of AA solution using high-performance liquid chromatography (HPLC) and rapid equilibrium dialysis. In vitro transcorneal permeability was studied using a parallel artificial membrane permeability assay (PAMPA). Ex vivo permeation was examined on AA-LLipo-treated porcine cornea by determining the AA content on the ocular surface, in the cornea as well as in the aqueous humor using HPLC, and by Raman-mapping visualizing the AA-distribution. Our results showed that the liposomal formulation improved the chemical stability of AA, while drug release was observed with the same kinetic efficiency as from the free-form of AA solution. Both corneal-PAMPA and porcine corneal permeability studies showed that AA-LLipo markedly improved the corneal absorption kinetics of AA, thus, increasing the AA content in the cornea and aqueous humor. AA-LLipo formulation could potentially increase the bioavailability of AA in corneal tissues.

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Nepafenac is a highly effective NSAID used for treating postoperative ocular inflammation and pain after cataract surgery and its advantage over conventional topical NSAIDs has been proved many times. However, Nevanac® is a suspension eye drop, which clearly lacks patient compliance causing irritation, blurred vision, foreign body sensation along with problematic dosage due to its sticky, inhomogeneous consistence. In this study, nepafenac containing eye drops were prepared using hydroxypropyl-ß-cyclodextrin to ensure complete dissolution of nepafenac, sodium hyaluronate to provide mucoadhesion and adequate viscosity and a preservative-free officinal formula, Oculogutta Carbomerae containing carbomer (just like Nevanac®), therefore providing a similar base for the new formulations. According to an experimental design, 11 formulations were tested in vitro including two reference formulations by measuring their viscosity, mucoadhesion, drug release and corneal permeability. Finally, two formulations were found promising and investigated further on porcine eyes ex vivo and corneal distribution of nepafenac was determined by RAMAN mapping. The results showed that one formulation possessed better bioavailability ex vivo than Nevanac® 0.1 % suspension, while the other formulation containing only 60 % of the original dose were ex vivo equivalent with Nevanac® opening the way to nepafenac-containing eye drops with better patient compliance in the future.

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In our present series of experiments, we investigated the nasal applicability of the previously developed Soluplus® - meloxicam polymeric micelle formulation. Utilizing the nasal drug investigations, moderately high mucoadhesion was experienced in nasal conditions which alongside the appropriate physicochemical properties in liquid state, contributed to rapid drug absorption through human RPMI 2650 cell line. Ex vivo studies also confirmed that higher nasal mucosal permeation could be expected with the polymeric micelle nanoformulation compared to a regular MEL suspension. Also, the nanoformulation met the requirements to provide rapid drug permeation in less 1 h of our measurement. The non-toxic, non-cell barrier damaging formulation also proved to provide a successful passive transport across excides human nasal mucosa. Based on our in vivo investigations, it can be concluded that the polymeric micelle formulation provides higher meloxicam transport to the central nervous system followed by a slow and long-lasting elimination process compared to prior results where physical particle size reduction methods were applied. With these results, a promising solution and nanocarrier is proposed for the successful transport of non-steroidal anti-inflammatory drugs with acidic character to the brain.

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