Improvement of lidocaine skin permeation by using passive and active enhancer methods.

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.

Lipid Nanoparticles: An Effective Tool to Improve the Bioavailability of Nutraceuticals.

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.

Rheological effects of hypertonic saline and sodium bicarbonate solutions on cystic fibrosis sputum in vitro.

BACKGROUND: Cystic fibrosis (CF) is a life-threatening multiorgan genetic disease, particularly affecting the lungs, where recurrent infections are the main cause of reduced life expectancy. In CF, mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein impair transepithelial electrolyte and water transport, resulting in airway dehydration, and a thickening of the mucus associated with abnormal viscoelastic properties. Our aim was to develop a rheological method to assess the effects of hypertonic saline (NaCl) and NaHCO3 on CF sputum viscoelasticity in vitro, and to identify the critical steps in sample preparation and in the rheological measurements. METHODS: Sputum samples were mixed with hypertonic salt solutions in vitro in a ratio of either 10:4 or 10:1. Distilled water was applied as a reference treatment. The rheological properties of sputum from CF patients, and the effects of these in vitro treatments, were studied with a rheometer at constant frequency and strain, followed by frequency sweep tests, where storage modulus (G'), loss modulus (G″) and loss factor were determined. RESULTS: We identified three distinct categories of sputum: (i) highly elastic (G' > 100,000 Pa), (ii) elastic (100,000 Pa > G' > 1000 Pa), and (iii) viscoelastic (G' < 1000). At the higher additive ratio (10:4), all of the added solutions were found to significantly reduce the gel strength of the sputum, but the most pronounced changes were observed with NaHCO3 (p < 0.001). Samples with high elasticity exhibited the greatest changes while, for less elastic samples, a weakening of the gel structure was observed when they were treated with water or NaHCO3, but not with NaCl. For the viscoelastic samples, the additives did not cause significant changes in the parameters. When the lower additive ratio (10:1) was used, the mean values of the rheological parameters usually decreased, but the changes were not statistically significant. CONCLUSION: Based on the rheological properties of the initial sputum samples, we can predict with some confidence the treatment efficacy of each of the alternative additives. The marked differences between the three categories suggest that it is advisable to evaluate each sample individually using a rheological approach such as that described here.

Comparison of hydrophilic ophthalmic media on silicone oil emulsification.

The aim of this study was to investigate whether and how the biological media which are in contact with silicone oil play a role in the silicone emulsification process. Commercially available Oxane 1300 silicone oil and potential hydrophilic phases of the emulsions in the eye (porcine aqueous humor, porcine vitreous and balanced salt solution) were investigated separately and in a mixture or emulsions by means of surface tension, rheological, zeta potential measurements and microscopic investigation. The surface tension of biological media (vitreous and aqueous humor) was significantly lower than that of non-biological media, especially in the case of aqueous humor, which indicates a remarkable emulsification tendency with these phases. The biological media are able to form both oil-in-water and water-in-oil emulsions, which can be observed in the clinical practice as well. It was established that the vitreous has a more expressed emulsification ability compared with the aqueous humor because smaller and more stable droplets can form with silicon oil when the vitreous is still there. It can be concluded that the vitreous has a higher impact on emulsification than the aqueous medium, which can predict that the vitreous remaining after vitrectomy has a key role in emulsion formation in the eye with silicone oil endotamponade.

Development of Topical Nanocarriers for Skin Cancer Treatment Using Quality by Design Approach.

BACKGROUND: One of the most compelling medical challenges of this century is the treatment of cancer and among them, skin cancer is the most common type. Thus, current treatments need to be renewed continuously to handle this challenge. OBJECTIVE: This review presents considerations which can be employed during the development of nanosized formulations dedicated to the topical treatment of skin cancer. We aimed to collect and organize literature data on the treatment options for skin cancer in order to determine the required quality attributes of an effective dermal anticancer formulation. METHOD: With the consideration of the Quality by Design (QbD) approach related to the development of new pharmaceutical formulations, a cost-saving process ensuring a high-quality product taking into account patient expectations, industrial and regulatory aspects can be achieved. Furthermore, this concept is highly recommended by regulatory agencies. RESULTS: Our work discusses the current therapies, active agents, drug carrier systems, and evaluation methods in connection with the treatment of skin cancer and outlines Critical Quality Attributes which need to be considered during the development of a nanosized dermal anticancer formulation. CONCLUSION: The first part of this review summarizes the most important topical treatment therapies for skin cancer and highlights the future therapeutic perspectives, focusing on the benefits of nanotechnology and dermal administration. The second part outlines the critical points of nanosized dermal anticancer formulation development in the view of QbD approach. Our research emphasizes the application of QbD method for a rationalized and more effective anticancer formulation development process.

A Review of Electroporation-based Antitumor Skin Therapies and Investigation of Betulinic Acid-loaded Ointment.

BACKGROUND: Electrochemotherapy is a novel treatment for cutaneous and subcutaneous tumors utilizing the combination of electroporation and chemotherapeutic agents. Since tumors have an increasing incidence nowadays as a result of environmental and genetic factors, electrochemotherapy could be a promising treatment for cancer patients. OBJECTIVE: The aim of this article is to summarize the novel knowledge about the use of electroporation for antitumor treatments and to present a new application of electrochemotherapy with a well-known plant derived antitumor drug betulinic acid. For the review we have searched the databases of scientific and medical research to collect the available publications about the use of electrochemotherapy in the treatment of various types of cancer. METHOD: By the utilization of the available knowledge, we investigated the effect of electroporation on the penetration of a topically applied betulinic acid formulation into the skin by ex vivo Raman spectroscopy on hairless mouse skin. RESULTS: Raman measurements have demonstrated that the penetration depth of betulinic acid can be remarkably ameliorated by the use of electroporation, so this protocol can be a possibility for the treatment of deeper localized cancer nodules. Furthermore, it proved the influence of various treatment times, since they caused different spatial distributions of the drug in the skin. CONCLUSION: The review demonstrates that electrochemotherapy is a promising tool to treat different kinds of tumors with high efficiency and with only a few moderate adverse effects. Moreover, it presents a non-invasive method to enhance the penetration of antitumor agents, which can offer novel prospects for antitumor therapies.

The effect of the antioxidant on the properties of thiolated poly(aspartic acid) polymers in aqueous ocular formulations.

Thiolated polymers are a promising new group of excipients, but their stability against atmospheric oxidation has not been investigated in detail, and only a few efforts have been made to improve their stability. The oxidation of the thiol groups in solutions of thiolated polymers may result in a decrease of mucoadhesion and unpredictable in situ gelation. The aims of our work were to study the stability of aqueous solutions of thiolated polymers and the effects of stabilizing agents. We investigated thiolated poly(aspartic acid) polymers stabilized with dithiothreitol, glutathione or acetylcysteine. The effects of these antioxidants on the gel structure, mucoadhesion and drug release were determined by means of scanning electron microscopy, swelling, rheology, adhesion and drug release tests. It was concluded that the stability of polymer solutions containing antioxidants is sufficient for one day. Polymers stabilized with dithiotreitol demonstrated fast swelling and drug release, but weaker mucoadhesion as compared with the other samples. Polymers stabilized with glutathione displayed the weakest cohesive properties, resulting in fast and uncontrolled drug release and moderate mucoadhesion. Acetylcysteine-stabilized polymers exhibited an optimum cross-linked structure, with free thiol groups ensuring polymer-mucin interactions, resulting in the best mucoadhesive properties.

ATR-FTIR and Raman spectroscopic investigation of the electroporation-mediated transdermal delivery of a nanocarrier system containing an antitumour drug.

The aim of the present work was the optimization of the transdermal delivery of a lyotropic liquid crystal genistein-based formulation (LLC-GEN). LLC was chosen as medium in view of the poor solubility of GEN in water. Membrane diffusion and penetration studies were carried out with a Franz diffusion cell, through a synthetic membrane in vitro, a chick chorioallantoic membrane ex ovo, and ex vivo excised human epidermis. Thereafter, LLC-GEN was combined with electroporation (EP) to enhance the transdermal drug delivery. The synergistic effect of EP was verified by in vivo ATR-FTIR and ex vivo Raman spectroscopy on hairless mouse skin.

Comparative study of nanosized cross-linked sodium-, linear sodium- and zinc-hyaluronate as potential ocular mucoadhesive drug delivery systems.

Hyaluronic acid (HA) and its derivatives play important roles in many fields of therapy, such as arthritis treatment, plastic surgery, dermatology, otology, ophthalmology, etc. With a view to increase the beneficial properties of HA in ocular drug delivery, many types of chemical structural modifications have been performed. In the course of our research work, we characterized nanosized cross-linked - (CLNaHA), linear sodium hyaluronate (NaHA) and zinc-hyaluronate (ZnHA), as potential ocular drug delivery systems. The aim was to determine the influence of the structure on biocompatibility, mucoadhesion and drug release. The structure was characterized by means of rheology. The cytotoxicity of the samples was determined on rabbit corneal epithelial cells (RCE) by the MTT test. Mucoadhesion measurements were made by a rheological method in vitro and by tensile tests in vitro and ex vivo. The release of sodium diclofenac, a frequently used non-steroidal anti-inflammatory drug with low bioavailability, from the gels was determined with a vertical Franz diffusion cell. The results demonstrated that all three derivatives have adequate mucoadhesive properties and their rapid drug release profiles are beneficial in ocular therapy. Thanks to these properties, the bioavailability of the ophthalmic preparations can be increased, especially with the application of CLNaHA.

The Effect of Electroporation of a Lyotroic Liquid Crystal Genistein-Based Formulation in the Recovery of Murine Melanoma Lesions.

A lamellar lyotropic liquid crystal genistein-based formulation (LLC-Gen) was prepared in order to increase the aqueous solubility of the lipophilic phytocompound genistein. The formulation was applied locally, in a murine model of melanoma, with or without electroporation. The results demonstrated that, when the formulation was applied by electroporation, the tumors appeared later. During the 21 days of the experiment, the LLC-Gen formulation decreased the tumor volume, the amount of melanin and the degree of erythema, but when electroporation was applied, all these parameters indicated a better prognosis even (lower tumor volume, amount of melanin and degree of erythema). Although hematoxylin-eosin (HE) staining confirmed the above events, application of the LLC-Gen formulation by electroporation did not lead to a significant effect in terms of the serum concentrations of the protein S100B and serum neuron specific enolase (NSE), or the tissue expression of the platelet-derived growth factor receptor ß (PDGFRß) antibody.

Development of thermosensitive chitosan/glicerophospate injectable in situ gelling solutions for potential application in intraoperative fluorescence imaging and local therapy of hepatocellular carcinoma: a preliminary study.

OBJECTIVES: Thermosensitive chitosan/glycerophosphate (C/GP) solutions exhibiting sol-gel transition around body temperature were prepared to develop a class of injectable hydrogel platforms for the imaging and loco-regional treatment of hepatocellular carcinoma (HCC). Indocyanine green (ICG) was loaded in the thermosensitive solutions in order to assess their potential for the detection of tumor nodules by fluorescence. METHODS: The gel formation of these formulations as well as their gelling time, injectability, compactness and resistance of gel structure, gelling temperature, storage conditions, biodegradability, and in vitro dye release behavior were investigated. Ex vivo studies were carried out for preliminary evaluation using an isolated bovine liver. RESULTS: Gel strengths and gelation rates increased with the cross-link density between C and GP. These behaviors are more evident for C/GP solutions, which displayed a gel-like precipitation at 4°C. Furthermore, formulations with the lowest cross-link density between C and GP exhibited the best injectability due to a lower resistance to flow. The loading of the dye did not influence the gelation rate. ICG was not released from the hydrogels because of a strong electrostatic interaction between C and ICG. Ex vivo preliminary studies revealed that these injectable formulations remain in correspondence of the injected site. CONCLUSIONS: The developed ICG-loaded hydrogels have the potential for intraoperative fluorescence imaging and local therapy of HCC as embolic agents. They form in situ compact gels and have a good potential for filling vessels and/or body cavities.

Permeability test for transdermal and local therapeutic patches using Skin PAMPA method.

Using the skin as absorption site presents unique advantages that have facilitated the progression of transdermal drug delivery in the past decades. Efforts in drug research have been devoted to find a quick and reproducible model for predicting the skin permeation of molecules. The Parallel Artificial Membrane Permeability Assay (PAMPA) has been extended for prediction of transdermal permeation by developing a model with completely artificial membrane, which can mimic the permeation through the stratum corneum. The present study aims to extend the Skin PAMPA method for testing transdermal and local therapeutic patches. The original method was modified and seven commercially available transdermal and local therapeutic patches with four different active pharmaceutical ingredients (nicotine, fentanyl, rivastigmine and ketoprofen) were studied. Data were compared to the declared delivery rates that are indicated by the manufacturers. Ex vivo permeation study was also performed in order to compare the permeated amount of the released drugs obtained by the two methods. The flux across the artificial membrane as well as the human skin (ex vivo) has been calculated and compared to the in vivo flux deduced from the labelled delivery rate and the active area of the patches. The results suggest that Skin PAMPA system can serve as a useful tool for evaluation and classification of the transdermal patches.

Thiolated poly(aspartic acid) as potential in situ gelling, ocular mucoadhesive drug delivery system.

The ophthalmic formulations on the market suffer from poor bioavailability, and it would therefore be useful to design a new formulation which is able to prolong the residence time and reduce the administration frequency. Polymer matrices which exhibit strong mucoadhesion are promising platforms in ocular drug delivery from the aspect of improved bioavailability. In the present study, an in situ gelling, mucoadhesive drug delivery system was fabricated from thiolated poly(aspartic acid) (ThioPASP). The thiol groups of ThioPASP are able to form disulphide linkages with the mucin glycoproteins and prolong the residence time on the eye. The effects of the thiol groups on the structure, swelling behaviour and mucoadhesive character of the gel and on the drug release profile were determined. The gel structure was characterized by means of rheology. The ThioPASP gel was demonstrated by rheology, tensile test and 'wash away' measurements to display strong mucoadhesion. The drug release from the ThioPASP gel was studied on a vertical Franz diffusion cell: a burst release of sodium diclofenac occurred in the first hour, followed by sustained release of the encapsulated drug for up to 24h. The results proved the importance of the presence of the thiol groups and suggested that a ThioPASP formulation can be useful as an in situ gelling, ocular dosage form.