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.

Coated Microneedle System for Delivery of Clotrimazole in Deep-Skin Mycoses.

Mycoses of the skin are infectious diseases caused by fungal microorganisms that are generally treated with topical agents. However, such therapy is often ineffective and has to be supported by oral use of active substances, which, in turn, can cause many side effects. A good alternative for the treatment of deep-skin mycoses seems to be microneedles (MNs). The aim of this research was to fabricate and evaluate the properties of innovative MNs coated with a hydrogel as potential carriers for clotrimazole (CLO) in the treatment of deep fungal skin infections. A 3D printing technique using a photo-curable resin was employed to produce MNs, which were coated with hydrogels using a dip-coating method. Hydrogels were prepared with carbopol EZ-3 Polymer (Lubrizol) in addition to glycerol and triisopropanolamine. Clotrimazole was introduced into the gel as the solution in ethanol or was suspended. In the first step of the investigation, a texture analysis of hydrogels was prepared with a texture analyzer, and the drug release studies were conducted with the use of automatic Franz diffusion cells. Next, the release profiles of CLO for coated MNs were checked. The last part of the investigation was the evaluation of the antifungal activity of the prepared systems, and the inhibition of the growth of Candida albicans was checked with the diffusion and suspended-plate methods. The texture profile analysis (TPA) for the tested hydrogels showed that the addition of ethanol significantly affects the following studied parameters: hardness, adhesiveness and gumminess, causing a decrease in their values. On the other hand, for the gels with suspended CLO, better spreadability was seen compared to gels with dissolved CLO. The presence of the active substance did not significantly affect the values of the tested parameters. In the dissolution study, the results showed that higher amounts of CLO were released for MNs coated with a hydrogel containing dissolved CLO. Also, microbiological tests proved its efficacy against fungal cultures. Qualitative tests carried out using the diffusion method showed that circular zones of inhibition of fungal growth on the plate were obtained, confirming the hypothesis of effectiveness. The suspension-plate technique confirmed the inhibitory effect of applied CLO on the growth of Candida albicans. From the analysis of the data, the MNs coated with CLO dissolved in hydrogel showed better antifungal activity. All received results seem to be helpful in developing further studies for MNs as carriers of antifungal substances.

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.

Use of Collagen in Cosmetic Products.

Collagen (CLG) belongs to the family of fibrillar proteins and is composed of left-handed α polypeptide chains, which, twisting around themselves and their axis, form a right-handed superhelix. In the chemical structure, it contains mainly proline, hydroxyproline, glycine, and hydroxylysine. It occurs naturally in the dermis in the form of fibers that provide the skin with proper density and elasticity. The review aimed to present the types of collagen protein, factors affecting its structure and its unusual role in the functioning of the human body. Also, an overview of cosmetic products containing collagen or its derivatives, the characteristics of the formulas of these products, and the effects of their use were presented. Throughout the market, there are many cosmetic and cosmeceutical products containing CLG. They are in the form of fillers administered as injections, belonging to the group of the oldest tissue fillers; products administered orally and for topical use, such as creams, gels, serums, or cosmetic masks. Analyzed studies have shown that the use of products with collagen or its peptides improves the general condition of the skin and delays the aging process by reducing the depth of wrinkles, improving hydration (in the case of oral preparations), reducing transepithelial water loss (TEWL), as well as improving skin density and elasticity. In addition, oral application of bioactive CLG peptides has shown a positive effect on the nails, reducing the frequency of their breakage.

Comparison of Hydroxypropyl Methylcellulose and Alginate Gel Films with Meloxicam as Fast Orodispersible Drug Delivery.

The aim of the study was the preparation and comparison of two types of orodispersible gel films (ODF) by the solvent casting method. Natural polymers: sodium alginate (ALG) or hydroxypropyl methylcellulose (HPMC) were used as the gel film formers, and Kollidon or microcrystalline cellulose was used as the disintegrant. Meloxicam (MLX), the drug used to treat rheumatic diseases for children and adults, was proposed as the active pharmaceutical ingredient (API). The influence of the polymer and disintegrant on the properties of ODF was investigated. The evaluation of prepared gel films was based on appearance description, mass uniformity measurement, disintegration time, API content, film wettability, and water content. Also, the dissolution test was prepared in a basket apparatus using artificial salvia (pH = 6.8) as the medium. The obtained API release profiles were analyzed for the similarity factors (f2) with the DDSolver software. The results showed that independently of the polymer or disintegrant, using the solvent casting method, gel films have a similar appearance and active substance content close to the theoretical value and water content of less than 10%. Only the type of polymer influences the release profiles of MLX. However, the disintegration time was longer than 30 s, which makes the films non-fast-dissolving drug delivery systems. This means that for the ODF system, further evaluation is required, and some changes in the composition of the film have to be done.

Etoricoxib-Cannabidiol Combo: Potential Role in Glioblastoma Treatment and Development of PLGA-Based Nanoparticles.

BACKGROUND: Glioblastoma (GBM) is the most frequently occurring primary malignant central nervous system tumor, with a poor prognosis and median survival below two years. Administration of a combination of non-steroidal anti-inflammatory drugs and natural compounds that exhibit a curative or prophylactic effect in cancer is a new approach to GBM treatment. This study aimed to investigate the synergistic antitumor activity of etoricoxib (ETO) and cannabidiol (CBD) in a GBM cell line model, and to develop poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) for these two substances. METHODS: The activity of ETO+CBD was determined using the MTT test, cell-cycle distribution assay, and apoptosis analysis using two GBM cell lines, namely, T98G and U-138 MG. The PLGA-based NPs were developed using the emulsification and solvent evaporation method. Their physicochemical properties, such as shape, size, entrapment efficiency (EE%), in vitro drug release, and quality attributes, were determined using scanning electron microscopy, diffraction light scattering, high-performance liquid chromatography, infrared spectroscopy, and differential scanning calorimetry. RESULTS: The combination of ETO and CBD reduced the viability of cells in a dose-dependent manner and induced apoptosis in both tested GBM cell lines. The developed method allowed for the preparation of ETO+CBD-NPs with a spherical shape, mean particle size (MPS) below 400 nm, zeta potential (ZP) values from -11 to -17.4 mV, polydispersity index (PDI) values in the range from 0.029 to 0.256, and sufficient EE% of both drugs (78.43% for CBD, 10.94% for ETO). CONCLUSIONS: The combination of ETO and CBD is a promising adjuvant therapeutic in the treatment of GBM, and the prepared ETO+CBD-NPs exhibit a high potential for further pharmaceutical formulation development.

The cytisine-enriched poly(3-hydroxybutyrate) fibers for sustained-release dosage form.

The polymeric cytisine-enriched fibers based on poly(3-hydroxybutyrate) were obtained using electrospinning method. The biocompatibility study, advanced thermal analysis and release of cytisine from the poly(3-hydroxybutyrate) fibers were carried out. The nanofibers' morphology was evaluated by scanning electron microscopy. The formation and description of phases during the thermal processes of fibers by the advanced thermal analysis were examined. The new quantitative thermal analysis of polymeric fibers with cytisine phases based on vibrational, solid and liquid heat capacities was presented. The apparent heat capacity of fibers was measured using the standard differential scanning calorimetry. The quantitative analysis allowed for the study of the glass transition and melting/crystallization process. The mobile amorphous fraction, degree of crystallinity and rigid amorphous fraction were determined depending on the thermal history of semicrystalline polymeric fibers. Furthermore, the cytisine dissolution behaviour was studied. It was observed that the kinetic of the release from polymeric nanofiber is delayed than for the marketed product. The immunosafety of the tested polymeric nanofibers with cytisine was confirmed by the Food and Drug Agency Guidance as well as the European Medicines Agency. The polymeric matrix with cytisine seems to be a promising candidate for the prolonged release formulation.

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.

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.

Progress in drug formulation design and delivery of medicinal substances used in ophthalmology.

Due to the very low bioavailability of drugs administered to the surface of the eyeball, issues related to the formulation of an ophthalmic drug pose a technological challenge. The essence of an ophthalmic drug is the selection of an appropriate active substance (API), but also auxiliary substances that determine the desired drug quality and API availability. The ophthalmic drug is not only classic eye drops. Therefore, on the basis of the literature data, the properties and application of auxiliary substances increasing the pharmaceutical availability of API, improving the penetration of API into the eye structures and modifying the viscosity of eye drops were characterized. The possibility of chemical modification of API and the use of prodrugs in ophthalmic drug forms was also noted. Taking into account the progress in the field of ophthalmic drug formulation, the use of multi-compartment systems (lipid particles, nanoparticles, microparticles, liposomes, niosomes, dendrimers) and modern ophthalmic drug delivery systems (inserts, implants, microneedles, contact lenses, ionophoretic systems) have been indicated. Examples of solutions already used by manufacturers, as well as those in the phase of laboratory or clinical trials, were indicated.

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.

Physicochemical Characterization of a Co-Amorphous Atorvastatin-Irbesartan System with a Potential Application in Fixed-Dose Combination Therapy.

The aim of this study was to characterize a 1:1 molar ratio of a pharmacologically relevant co-amorphous atorvastatin-irbesartan (ATR-IRB) system obtained by quench cooling of the crystalline ATR/IRB physical mixture for potential use in the fixed-dose combination therapy. The system was characterized by employing standard differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and intrinsic dissolution rate studies. Quantum mechanical calculations were performed to obtain information regarding intermolecular interactions in the studied co-amorphous ATR-IRB system. The co-amorphous formulation showed a significant improvement in the intrinsic dissolution rate (IDR) of IRB over pure crystalline as well as its amorphous counterpart. An unusual behavior was observed for ATR, as the IDR of ATR in the co-amorphous formulation was slightly lower than that of amorphous ATR alone. Short-term physical aging studies of up to 8 h proved that the ATR-IRB co-amorphous system remained in the amorphous form. Furthermore, no physical aging occurred in the co-amorphous system. FT-IR, density functional theory calculations, and analysis of T g value of co-amorphous system using the Couchman-Karasz equation revealed the presence of molecular interactions between APIs, which may contribute to the increased physical stability.

Modifying release of poorly soluble active pharmaceutical ingredients with the amine functionalized SBA-16 type mesoporous materials.

SBA-16 and two modified SBA-16 type ordered mesoporous silica were used as the carriers for ibuprofen (anti-inflammatory drug) and furosemide (loop diuretic drug). Modification of the solid carrier was prepared with chitosan or N-3[(amino(poly-propylenoxy)]aminopropyltrimethoxysilane. The samples of carriers and carrier-drug loaded materials were characterized by X-ray diffraction, N2 adsorption, Fourier-transform infrared spectroscopy, thermogravimetry, and differential scanning calorimetry. The release profiles of active pharmaceutical ingredients were performed in media with different pH in the USP 2 apparatus as well as in two biorelevant media (fasted state simulated gastric fluid and fasted state small intestinal fluid) in USP 4 apparatus. The loading of active substances into mesoporous materials was performed with modified immersion method. The maximum content of deposited drug in mesoporous material was close to 12.0 and 2.2 wt.% for ibuprofen and furosemide, respectively. After drug adsorption, the reduction of BET surface area, pore volume and pore diameter of non-modified and modified SBA-16 was observed, while the cubic arrays of siliceous matrix were well preserved. The release profiles of ibuprofen and furosemide loaded in mesoporous materials in media with different pH and biorelevant fasted state simulated gastric fluid and fasted state small intestinal fluid showed that the new SBA-16 type materials modify the release profiles of furosemide, increasing the dissolution rate of these substances in the medium at pH 1.2. The cytotoxicity of the materials and permeability of drugs after their loading on SBA-16 materials were evaluated on Caco-2 model. The results of our study showed that mesoporous materials did not exert cytotoxic effects and did not influence on the permeability of both active pharmaceutical ingredients in relation to pure substances.

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.

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.