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.

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.

Novel organogels for topical delivery of naproxen: design, physicochemical characteristics and in vitro drug permeation.

Taking into account possible irritation of the skin upon contact with naproxen (NPX) crystals and lower bioavailability after administration of the suspended or ionized drug, the aim of the work was to design and characterize novel and easy-to-formulate gels with the entirely dissolved drug in the acidic form. The formulations contained ethanol, SynperonicTMPE/L 62 and Arlasolve® DMI or Transcutol®. Carbopol®940 was used as the thickener. The properties of organogels were compared with six market products. The rheological measurements included steady flow experiments and oscillatory analysis. The texture profile analysis was conducted to calculate the mechanistic parameters. The in vitro permeation studies were performed on SOTAX CE 7 smart apparatus with the application of Strat-M artificial membranes. The obtained organogels fulfilled the requirements for topical products in terms of consistency, uniformity, stability, drug dissolution and permeation. The permeation studies revealed distinct differences among the commercial hydrogels according to permeation coefficients (kP), drug flux (Jss) and average cumulative amount of NPX per area after 12 h (Q12h). The presented work clearly shows that the organogels can be proposed as an alternative for commercial products where NPX occurs in the form of crystals.

Rheological and textural properties of microemulsion-based polymer gels with indomethacin.

In this paper, we present novel microemulsion (ME)-based semisolid polymer gels designed for topical administration of poorly water soluble non-steroidal anti-inflammatory drugs. Indomethacin (IND) was used as a model compound. The ME consisted of castor oil, water, Tween®80 as a surfactant and ethanol as cosurfactant. To obtain the desired consistency of the formulations Carbopol®960 was applied as a thickening agent. The aim of the study was to analyze in detail the mechanical properties of the obtained systems, with special attention paid to the features crucial for topical application. The rheological and textural experiments performed for samples with and without the incorporated drug clearly indicate that flow characteristics, viscoelastic properties and texture profiles were affected by the presence of IND. Novel semisolid formulations with IND described for the first time in this paper can be considered as an alternative for commercially available conventional topical dosage forms.

Microemulsion-Based Polymer Gels with Ketoprofen and Menthol: Physicochemical Properties and Drug Release Studies.

Ketoprofen is a non-steroidal, anti-inflammatory drug frequently incorporated in topical dosage forms which are an interesting alternatives for oral formulations. However, due to the physiological barrier function of skin, topical formulations may require some approaches to improve drug permeation across the skin. In this study, ketoprofen-loaded microemulsion-based gels with the addition of menthol, commonly known for absorption-enhancing activity in dermal products, were investigated. The main objective of this study was to analyze the physicochemical properties of the obtained gels in terms of topical application and to investigate the correlation between the gel composition and its mechanical properties and the drug release process. Microemulsion composition was selected with the use of a pseudoternary plot and the selected systems were tested for electrical conductivity, viscosity, pH, and particle diameter. The polymer gels obtained with Carbopol® EZ-3 were subjected to rheological and textural studies, as well as the drug release experiment. The obtained results indicate that the presence of ketoprofen slightly decreased yield stress values. A stronger effect was exerted by menthol presence, even though it was independent of menthol concentration. A similar tendency was seen for hardness and adhesiveness, as tested in texture profile analysis. Sample cohesiveness and the drug release rate were independent of the gel composition.

Assessment of Alginate Gel Films as the Orodispersible Dosage Form for Meloxicam.

The aim of this study was to obtain films based on sodium alginate (SA) for disintegration in the oral cavity. The films were prepared with a solvent-casting method, and meloxicam (MLX) as the active ingredient was suspended in a 3% sodium alginate solution. Two different solid-dosage-form additives containing different disintegrating agents, i.e., VIVAPUR 112® (MCC; JRS Pharma, Rosenberg, Germany) and Prosolve EASYtabs SP® (MIX; JRS Pharma, Rosenberg, Germany), were used, and four different combinations of drying time and temperature were tested. The influence of the used disintegrant on the properties of the ODFs (orodispersible films) was investigated. The obtained films were studied for their appearance, elasticity, mass uniformity, water content, meloxicam content and, finally, disintegration time, which was studied using two different methods. The films obtained with the solvent-casting method were flexible and homogeneous in terms of MLX content. Elasticity was slightly better when MIX was used as a disintegrating agent. However, these samples also revealed worse uniformity and mechanical durability. It was concluded that the best properties of the films were achieved using the mildest drying conditions. The type of the disintegrating agent had no effect on the amount of water remaining in the film after drying. The water content depended on the drying conditions. The disintegration time was not affected by the disintegrant type, but some differences were observed when various drying conditions were applied. However, regardless of the formulation type and manufacturing conditions, the analyzed films could not be classified as fast disintegrating films, as the disintegration time exceeded 30 s in all of the tested formulations.

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.

Microneedle System Coated with Hydrogels Containing Protoporphyrin IX for Potential Application in Pharmaceutical Technology.

The article aims to outline the potential of treating malignant skin cancer with microneedles covered with polymer layers containing a photosensitizer-protoporphyrin IX disodium salt (PPIX). The usefulness of stereolithography (SLA), which is a form of 3D-printing technology, for the preparation of a microneedle system with protoporphyrin IX was demonstrated. The SLA method allowed for pyramid-shaped microneedles to be printed that were covered with three different 0.1% PPIX hydrogels based on sodium alginate, xanthan, and poloxamer. Rheological tests and microscopic analysis of the hydrogels were performed. Microneedles coated with two layers of poloxamer-based hydrogel containing 0.1% PPIX were subjected to release tests in Franz diffusion cells. The release profile of PPIX initially increased and then remained relatively constant. The amount of substance released after a four-hour test in three Franz cells was 0.2569 ± 0.0683 mg/cm2. Moreover, the acute toxicity of this type of microneedle was assessed using the Microtox system. The obtained results show the usefulness of further development studies on microneedles as carriers of photosensitizing agents.

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.

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.

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.

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.

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.

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.

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.

3ß-Acet-oxy-12α-chloro-d-friedooleanan-28,14ß-olide.

The title compound, C(32)H(49)ClO(4), was obtained along with nitrile and lactam products in the POCl(3)-catalysed Beckmann rearrangement from 3ß-acet-oxy-12-hydroxyiminoolean-28-olic acid methyl ester. The mechanism of the transformation leading to the title compound remains unclear and requires further investigation. Rings A, B and E are in chair conformations, ring C has a twisted-boat conformation, ring D a conformation halfway between boat and twisted-boat and rings D and E are cis-fused. In the crystal, mol-ecules are connected by weak inter-molecular C-H⋯O hydrogen bonds into layers extending parallel to the bc plane.

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.

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.