Hypromellose-, Gelatin- and Gellan Gum-Based Gel Films with Chlorhexidine for Potential Application in Oral Inflammatory Diseases.

The oral cavity is constantly exposed to contact with an external environment. Pathogens can easily access and colonize it, causing a number of medical conditions that are usually accompanied by inflammation, which in turn require medical intervention and cause the deterioration of wellbeing. The aim of this study was to obtain polymer films that could be a carrier for chlorhexidine, an active substance used in the treatment of inflammation in the oral cavity, and at the same time act as a dressing for the application on the mucous membrane. Combinations of three biocompatible and biodegradable polymers were used to prepare the films. The obtained samples were characterized by assessing their water loss after drying, swelling ability, hygroscopicity and tensile strength. It was shown that the mixture of HPMC and gellan gum or gelatin could be used to prepare transparent, flexible polymer films with chlorhexidine. All tested films showed high hygroscopicity and swelling ability. However, it was observed that the composition containing gellan gum was more suitable for obtaining films with prolonged stay at the site of administration, which predisposes it to the role of a local dressing.

3D-printed solid oral dosage forms for mental and neurological disorders: recent advances and future perspectives.

INTRODUCTION: 3D printing (3DP) applications in medicine are intensively investigated, creating an opportunity to provide patient-tailored therapy by delivering a drug with an accurate dose and release profile. Moving away from the 'one size fits all' paradigm, it could be beneficial for treating mental and neurological disorders, improving the efficiency and safety of the therapy. The aim of this critical review is to assess recent advances and identify gaps regarding 3DP in this important and challenging field, by focusing on recent research examples. AREAS COVERED: Applications of the 3DP techniques for solid dosage forms in mental and neurological disorders have been covered and discussed, together with recent advantages, limitations, and future directions. EXPERT OPINION: The personalize treatment, which is considered as the most significant advantage of the 3DP technique, can be beneficial in mental and neurological disorders therapy, where the dose should be adjusted to the patient. Printing of medicines enables creating the structure modifications and thus controlling the drug release or combining multiple drugs into one tablet, simplifying the dose regimen. Medications printed on-demand, in health-care facilities, could address the special needs of pediatric patients and help avoid interruptions in the supply chain. Despite promising advances, the described methods have limitations and need further investigation before being scaled-up to an industrial manufacturing environment. There is also a need to establish protocols for the preparation and registration of 3DP dosage forms.

Phototoxic or Photoprotective?-Advances and Limitations of Titanium (IV) Oxide in Dermal Formulations-A Review.

The widespread role of titanium (IV) oxide (TiO2) in many industries makes this substance of broad scientific interest. TiO2 can act as both a photoprotector and photocatalyst, and the potential for its role in both applications increases when present in nanometer-sized crystals. Its sunlight-scattering properties are used extensively in sunscreens. Furthermore, attempts have been made to incorporate TiO2 into dermal formulations of photolabile drugs. However, the propensity to generate reactive oxygen species (ROS) rendering this material potentially cytotoxic limits its role. Therefore, modifications of TiO2 nanoparticles (e.g., its polymorphic form, size, shape, and surface modifications) are used in an effort to reduce its photocatalytic effects. This review provides an overview of the potential risks arising from and opportunities presented by the use of TiO2 in skin care formulations.

Alginate-Based Materials Loaded with Nanoparticles in Wound Healing.

Alginate is a naturally derived polysaccharide widely applied in drug delivery, as well as regenerative medicine, tissue engineering and wound care. Due to its excellent biocompatibility, low toxicity, and the ability to absorb a high amount of exudate, it is widely used in modern wound dressings. Numerous studies indicate that alginate applied in wound care can be enhanced with the incorporation of nanoparticles, revealing additional properties beneficial in the healing process. Among the most extensively explored materials, composite dressings with alginate loaded with antimicrobial inorganic nanoparticles can be mentioned. However, other types of nanoparticles with antibiotics, growth factors, and other active ingredients are also investigated. This review article focuses on the most recent findings regarding novel alginate-based materials loaded with nanoparticles and their applicability as wound dressings, with special attention paid to the materials of potential use in the treatment of chronic wounds.

Natural Gums in Drug-Loaded Micro- and Nanogels.

Gums are polysaccharide compounds obtained from natural sources, such as plants, algae and bacteria. Because of their excellent biocompatibility and biodegradability, as well as their ability to swell and their sensitivity to degradation by the colon microbiome, they are regarded as interesting potential drug carriers. In order to obtain properties differing from the original compounds, blends with other polymers and chemical modifications are usually applied. Gums and gum-derived compounds can be applied in the form of macroscopic hydrogels or can be formulated into particulate systems that can deliver the drugs via different administration routes. In this review, we present and summarize the most recent studies regarding micro- and nanoparticles obtained with the use of gums extensively investigated in pharmaceutical technology, their derivatives and blends with other polymers. This review focuses on the most important aspects of micro- and nanoparticulate systems formulation and their application as drug carriers, as well as the challenges related to these formulations.

Microneedle-based ocular drug delivery systems - recent advances and challenges.

Eye diseases and injuries constitute a significant clinical problem worldwide. Safe and effective delivery of drugs to the eye is challenging mostly due to the presence of ocular barriers and clearance mechanisms. In everyday practice, the traditional eye drops, gels and ointments are most often used. Unfortunately, they are usually not well tolerated by patients due to the need for frequent use as well as the discomfort during application. Therefore, novel drug delivery systems with improved biopharmaceutical properties are a subject of ongoing scientific investigations. Due to the developments in microtechnology, in recent years, there has been a remarkable advance in the development of microneedle-based systems as an alternative, non-invasive form for administering drugs to the eye. This review summarizes the latest achievements in the field of obtaining microneedle ocular patches. In the manuscript, the most important manufacturing technologies, microneedle classification, and the research studies related to ophthalmic application of microneedles are presented. Finally, the most important advantages and drawbacks, as well as potential challenges related to the unique anatomy and physiology of the eye are summarized and discussed.

Quality by Design Guided Development of Polymeric Nanospheres of Terbinafine Hydrochloride for Topical Treatment of Onychomycosis Using a Nano-Gel Formulation.

Superficial fungal diseases of the skin and nails are an increasingly common occurrence globally, requiring effective topical treatment to avoid systemic adverse effects. Polymeric nanoparticles have demonstrated sustained and effective drug delivery in a variety of topical formulations. The aim of this project was to develop polymeric antifungal nanospheres containing terbinafine hydrochloride (TBH) to be loaded into a hydrogel formulation for topical nail drug delivery. A quality by design (QbD) approach was used to achieve optimized particles with the desired quality target product profile (QTPP). Polyvinyl alcohol (PVA) at 2% w/v and a drug to polymer ratio of 1:4, together with a robust set of processes and material attributes, resulted in nanoparticles of 108.7 nm with a polydispersity index (PDI) of 0.63, 57.43% recovery, and other desirable characteristics such as zeta potential (ZP), particle shape, aggregation, etc. The nanospheres were incorporated into a carbomer-based gel, and the delivery of TBH through this formulation was evaluated by means of in vitro drug release testing (IVRT) and ex vivo nail permeation study. The gel containing the TBH nanospheres demonstrated a slower and controlled drug release profile compared with the control gel, in addition to a more efficient delivery into the nail. These antifungal nanospheres can be utilized for topical therapy of a multitude of superficial fungal infections.

Rheological and textural analysis as tools for investigation of drug-polymer and polymer-polymer interactions on the example of low-acyl gellan gum and mesalazine.

PURPOSE: In the performed study, the rheological and textural parameters of gellan-based hydrogels were investigated and their dependence on three factors was taken into consideration: (i) The presence of the model drug, (ii) The presence and type of the ionic crosslinking agent, and (iii) the composition of the polymer network. The objective was to compare two analytical methods, regarded as complementary, and define to what extent the obtained results correlate with each other. METHODS: The hydrogels contained low-acyl gellan gum or its mixtures with hydroxyethyl cellulose or κ-carrageenan. CaCl2 and MgCl2 were used as gelling agents. Mesalazine was used as a model drug. The rheological analysis included oscillatory stress and frequency sweeping. The texture profile analysis was performed to calculate texture parameters. RESULTS: Placebo gels without the addition of gelling agents had the weakest structure. The drug had the strongest ability to increase the stiffness of the polymer network. The weakest structure revealed the placebo samples without the addition of gelling agents. Texture analysis revealed no significant influence of the drug on the strength of the gels, while rheological measurements indicated clear differences. CONCLUSIONS: It can be concluded that in the case of some parameters methods correlate, that is, the effect related to gelling ions. However, the rheological analysis seems to be more precise and sensitive to some changes in the mechanical properties of the gels.

Sodium Alginate as a Pharmaceutical Excipient: Novel Applications of a Well-known Polymer.

Alginates are naturally occurring polymers revealing low toxicity, good biocompatibility and biodegradability, excellent gelling and thickening properties, as well as low production cost and good availability. One of the most important features typical for alginates is the ability to undergo ionotropic gelation which is gel formation process occurring upon the contact with cations. Because of their advantageous properties, alginates have been extensively utilized in food and pharmaceutical industries. In this review the current knowledge regarding the most recent studies involving both popularly applied dosage forms, like tablets or hydrogels, and novel advanced drug delivery systems applied in targeted therapies are summarized and discussed. The presented studies indicate that although sodium alginate is a well-established polymer, it is still widely applied as pharmaceutical excipient and the presented research studies indicate that there are still research areas that can be explored and provide innovation in drug delivery systems.

Ionotropic Gelation and Chemical Crosslinking as Methods for Fabrication of Modified-Release Gellan Gum-Based Drug Delivery Systems.

Hydrogels have a tridimensional structure. They have the ability to absorb a significant amount of water or other natural or simulated fluids that cause their swelling albeit without losing their structure. Their properties can be exploited for encapsulation and modified targeted drug release. Among the numerous natural polymers suitable for obtaining hydrogels, gellan gum is one gaining much interest. It is a gelling agent with many unique features, and furthermore, it is non-toxic, biocompatible, and biodegradable. Its ability to react with oppositely charged molecules results in the forming of structured physical materials (films, beads, hydrogels, nanoparticles). The properties of obtained hydrogels can be modified by chemical crosslinking, which improves the three-dimensional structure of the gellan hydrogel. In the current review, an overview of gellan gum hydrogels and their properties will be presented as well as the mechanisms of ionotropic gelation or chemical crosslinking. Methods of producing gellan hydrogels and their possible applications related to improved release, bioavailability, and therapeutic activity were described.

Recent Advances in Polymer-Based Vaginal Drug Delivery Systems.

The vagina has been considered a potential drug administration route for centuries. Most of the currently marketed and investigated vaginal formulations are composed with the use of natural or synthetic polymers having different functions in the product. The vaginal route is usually investigated as an administration site for topically acting active ingredients; however, the anatomical and physiological features of the vagina make it suitable also for drug systemic absorption. In this review, the most important natural and synthetic polymers used in vaginal products are summarized and described, with special attention paid to the properties important in terms of vaginal application. Moreover, the current knowledge on the commonly applied and innovative dosage forms designed for vaginal administration was presented. The aim of this work was to highlight the most recent research directions and indicate challenges related to vaginal drug administrations. As revealed in the literature overview, intravaginal products still gain enormous scientific attention, and novel polymers and formulations are still explored. However, there are research areas that require more extensive studies in order to provide the safety of novel vaginal products.

Microemulsion-Based Media in Nose-to-Brain Drug Delivery.

Nose-to-brain drug delivery has recently attracted enormous attention as an alternative to other delivery routes, including the most popular oral one. Due to the unique anatomical features of the nasal cavity, drugs administered intranasally can be delivered directly to the central nervous system. The most important advantage of this approach is the ability to avoid the blood-brain barrier surrounding the brain and blocking the entry of exogenous substances to the central nervous system. Moreover, selective brain targeting could possibly avoid peripheral side effects of pharmacotherapy. The challenges associated with nose-to-brain drug delivery are mostly due to the small volume of the nasal cavity and insufficient drug absorption from nasal mucosa. These issues could be minimized by using a properly designed drug carrier. Microemulsions as potential drug delivery systems offer good solubilizing properties and the ability to enhance drug permeation through biological membranes. The aim of this review is to summarize the current status of the research focused on microemulsion-based systems for nose-to-brain delivery with special attention to the most extensively investigated neurological and psychiatric conditions, such as neurodegenerative diseases, epilepsy, and schizophrenia.

Design and evaluation of pharmaceutical availability, stability and quality of modified viscosity eye drops with choline salicylate.

These studies investigate the possibility of developing and using choline salicylate (CS) in ophthalmic therapy in the form of eye drops with increased viscosity. A 0.5% addition of hydroxypropyl methylcellulose (HPMC) was used as the viscosity increasing agent. The ability of CS to cross a hydrophilic membrane (regenerated cellulose membrane) was assessed by determining a rate constant consistent with zero order kinetics. In studies on a porcine cornea, the ability of CS to penetrate into the structure of the cornea was confirmed by determining the content of CS in the cornea after 5 minutes and 3 hours exposure to eye drops. The quality parameters of eye drops were assessed: pH, viscosity, osmolarity and microbiological purity. Stability tests were also performed on eye drops stored in unit minims packaging and in multi-dose bottle packaging. The following storage conditions were adopted: 40°C/75% RH, 25°C/60% RH, 2-8°C. The sensitivity of CS to light was also confirmed. The UV and HPLC-UV methods were used to assess the CS content, while the HPLC-UV and HPLC-MS/MS methods were used to assess the chromatographic purity.

Topical Delivery of Meloxicam using Liposome and Microemulsion Formulation Approaches.

The aim of this study is to develop, characterize and compare conventional liposome, deformable liposome (transfersome) and microemulsion formulations as potential topical delivery systems for meloxicam. Liposomes were characterized in terms of vesicle size, zeta potential and entrapment efficiency. For microemulsions, particle size, electrical conductivity and viscosity studies were performed to assess the structure of the investigated systems. An ex vivo skin permeation study has been conducted to compare these formulations. The dermal and transdermal delivery of meloxicam using these formulations can be a promising alternative to conventional oral delivery of non-steroidal anti-inflammatory drugs (NSAIDs) with enhanced local and systemic onset of action and reduced side effects.

Gellan gum macrobeads loaded with naproxen: The impact of various naturally derived polymers on pH-dependent behavior.

Aims After oral administration, naproxen generates several side-effects related to stomach malfunction. Undoubtedly, the enteric dosage forms with naproxen can be considered as safer. Moreover, since it has been evidenced that development and growth of colorectal cancer is related to the presence of cyclooxygenase, naproxen is investigated in terms of the tumor prevention. The aim of the present work was to formulate and evaluate the properties of novel naproxen-loaded macrobeads, made on the basis of low-acyl gellan gum and its blends with carrageenans, guar gum, cellulose sulfate, and dextran sulfates. Method Seven formulations were prepared by ionotropic gelation. The morphology of the dried beads was evaluated by scanning electron microscopy. The next step focused on Raman spectroscopy and thermal analysis of naproxen, polymers, and the beads. Next, the swelling behavior was examined in three acceptor fluids at pH = 1.2; 4.5, and 7.4. The beads were evaluated regarding naproxen content and encapsulation efficiency. The last stage of the work concerned the drug release studies. Results Addition of any other polysaccharide than gellan resulted in flattening of the beads upon drying. Differential scanning calorimetry confirmed the crystalline form of naproxen. Raman spectra showed that no apparent interactions occurred. In the acidic environment, all the beads revealed the tendency to absorb water. The beads swelled to the greatest extent at pH = 4.5. Naproxen was released from the beads at a varied rate. At pH = 7.4, the most prolonged release was observed for the beads containing carrageenans. Conclusions We have proved that blending of gellan with various polysaccharides can change the pH-dependent properties of the beads loaded with naproxen. We believe that the information enclosed in the paper will be of particular importance regarding the development and characteristics of novel oral dosage forms based on natural polymers.

Rheological investigation of high-acyl gellan gum hydrogel and its mixtures with simulated body fluids.

Purpose Most of the studies concerning gellan have been focused on its application as a food ingredient, however, gellan is often considered as a candidate for the development of novel pharmaceutical formulations. Taking into account that gellan is ion-sensitive, it can be assumed that its initial mechanical properties can change upon contact with body secretions. Therefore, the aim of the work was to investigate the rheological properties of pure high-acyl gellan gum hydrogel (0.4%) and its mixtures with selected simulated body fluids. Methods The rheological investigations were performed on rotational rheometer and included oscillatory temperature, amplitude, and frequency sweeping. The results enabled estimation of the linear viscoelastic regime, calculation of the cross-over points, and percentage of structure recovery. Results In the case of pure hydrogel no evidence of thermosensitivity was observed in the range of 20-40°C. In pH = 1.2 (NaCl/HCl) the hydrogel structure was almost entirely destroyed. Mixing with phosphate buffer (pH = 4.5) resulted in higher gel strength than after dilution with deionized water. The opposite effect was observed in the case of pH = 7.4. The studies performed for the mixture of GG hydrogel and mucin indicated interaction between the components. The hydrogel elasticity increased in the presence of simulated tear, but decreased in simulated saliva and vaginal fluid. Conclusions In this study, it was shown that the stability of a three-dimensional gellan structure may be affected by pH and the presence of mucin which most probably competed with gellan gum in divalent cations binding. The observations presented in this study may be important in terms of potential application of gellan gum as a potential carrier in drug delivery systems.

pH-Dependent Behavior of Novel Gellan Beads Loaded with Naproxen.

BACKGROUND: Oral administration of non-selective COX inhibitors involves the risk of serious side-effects. In the case of naproxen (NPX), the most frequent are those related to malfunctioning of the gastric mucosa. On the other hand, NPX and other NSAIDs are extensively studied in terms of colorectal cancer (CRC) prevention and inhibition, since it has been evidenced that COX-2 corresponds with the risk of the tumor occurrence and growth. Both side-effects in the stomach and possible antitumor activity of NPX justify the attempts to search for novel carriers for NPX with the site specific release in the colon. Thus, the aim of the work was to design, formulate and characterize low-acyl gellan gum (GG) macro beads as potential carriers for the delivery of NPX to the distal parts of the gastrointestinal tract. METHODS: The beads were obtained by the ionotropic gelation technique. CaCl2 solution was used as a cross-linking medium. After production, the beads were dried and used for further experiments. First, pure NPX and the beads were evaluated by Raman spectroscopy and DSC studies. The surface and morphology of the beads were analyzed by SEM. Next, the drug encapsulation efficiency and content in the beads were determined. The swelling and degradation behavior of the beads were evaluated in four simulated gastrointestinal fluids at different pH (1.2; 4.5; 6.8 and 7.4). The NPX in vitro release studies were conducted on USP I apparatus (rotating basket) at pH=7.4 and compared to the commercial enteric tablet. RESULTS: The polymer content of 0.5 % was considered as too low to obtain spherical beads in the dried form. Raman spectra confirmed that NPX did not undergo structural changes during production process. DSC studies showed that thermal decomposition at lower temperatures was observed for formulations with the lowest amount of GG. It turned out that the most important factor which determined the morphology of the beads was the amount of gellan gum in the initial mixture. The beads revealed 13.9- 39.9% of drug loading and 75.3-99.7% drug encapsulation efficiency. Swelling of the beads was pHdependent as the beads remained stable in the acidic environment but started to absorb water. In pH=7.4 after 3 hours, the beginning of the physical decomposition of the polymer matrix was observed. The drug release studies showed that in pH=7.4 the commercial tablets released 90% of the drug after 45 minutes while the amount of NPX released from pellets after the same time was 40-80%. CONCLUSION: In general, it can be stated that gellan macro beads may be regarded as suitable for site specific delivery of NPX to the colon. However, these simple to obtain beads can be potentially used as carriers for many different drugs whenever it is necessary to omit the stomach.

Rheological Characteristics of Novel Meloxicam-Loaded Complex Organogels Based on Fumed Silica and Poloxamer.

BACKGROUND: Meloxicam is a non-steroidal anti-inflammatory drug revealing poor solubility in water and good permeability through biological membranes. It is currently administered mostly in forms exerting systemic effects, however, in some conditions topical formulations can be equally useful. OBJECTIVE: The objective of the presented work was to formulate and investigate in detail the rheological behavior of non-aqueous gels containing 0.5% of meloxicam in a non-ionic, dissolved form. METHOD: Fumed silica and SynperonicTM PE/L 62 were used as structure forming components. Arlasolve ®, Transcutol®, ethanol and DMSO were applied as solubilizers and potential skin absorption enhancers. Three formulations were selected for further investigation and compared to placebo samples. The gels were examined in terms of rheological properties, spreadability and loss of volatile components. RESULTS: The investigated samples revealed non-Newtonian pseudoplastic behavior with apparent impact of meloxicam on the gel strength. The oscillatory analyses showed an incomplete recovery after structure destruction. Moreover, two yield points were observed, one related to the destruction of fumed silica lattice and the other one to the changes in the spatial arrangement of polymer chains. The tendency to evaporation of volatile components was insignificant. The best spreadability parameter was observed for gels containing Transcutol®. CONCLUSION: In this study organogels with meloxicam in dissolved form were obtained and characterized. The performed tests showed that the mechanical properties of the investigated samples depended both on the presence of the drug and on the selection of excipients. The presented data are important in terms of semi-solid product manufacturing and further application by patients.

Novel microemulsion-based gels for topical delivery of indomethacin: Formulation, physicochemical properties and in vitro drug release studies.

HYPOTHESIS: Microemulsion-based semisolid systems may be considered as an interesting alternative to the traditional dosage forms applied in topical drug delivery. Mechanical properties of topical products are important both in terms of application and dosage form effectiveness. In this study we designed and evaluated novel microemulsion-based gels with indomethacin and analyzed the factors affecting their mechanical characteristics and drug release. EXPERIMENTS: The impact of the microemulsion composition on the extent of isotropic region was investigated with the use of pseudoternary phase diagrams. Selected microemulsions were analyzed in terms of electrical conductivity and surface tension in order to determine the microemulsion type. Microemulsions were transformed into polymer-based gels and subjected to rheological and textural studies. Finally, the indomethacin release from the analyzed gels was studied and compared to commercially available product. FINDINGS: The extent of isotropic domain in pseudoternary phase diagrams seems to be dependent on the polarity of the oil phase. The surface tension and conductivity monitored as a function of water content in microemulsion systems revealed possible structural transformations from w/o through bicontinuous systems into o/w. The mechanical properties of semisolid microemulsion-based systems depended on the composition of surface active agents and the drug presence. The drug release profiles observed in the case of the investigated gels differed from those recorded for the commercially available product which was most probably caused by the different structure of both systems.

Design and characteristics of gellan gum beads for modified release of meloxicam.

The aim of the presented work was to design, formulate and evaluate the properties of low-acyl gellan macro beads with the potential application as carriers for oral delivery of meloxicam (MLX) in the prophylaxis of colorectal cancer. The beads were obtained by means of ionotropic gelation technique. Calcium chloride (1.0%, 9.0 × 10-2 M) was used as the cross-linking agent. Nine different polymer, drug and surfactant (Tween®80) mixtures were used for production of the beads. The quantitative compositions of the mixtures were generated with the application of the Design of Experiments (DoE) modulus from the STATISTICA Software. The prepared formulations revealed 7.2-27.0% of drug loading and 29.2-50.7% drug encapsulation efficiency. It turned out that 0.5% amount of gellan gum in the mixtures was not sufficient to obtain spherical beads. The morphology and surface of the dried beads were analyzed by SEM. Raman spectra confirmed that MLX did not undergo structural changes during production of the beads. The swelling behavior and degradation of the beads were evaluated in three simulated gastrointestinal fluids at different pH (1.2; 4.5; 6.8). The MLX in vitro release studies were conducted on USP apparatus IV, working in the open loop mode. The obtained results showed that MLX release from the dried beads was pH-dependent. The formulations obtained from mixtures containing 1.0 and 1.5% of gellan may be considered as oral dosage forms for MLX, intended to omit the stomach and release the drug in the distal parts of the gastrointestinal tract.