Polymer Tablet Matrix Systems for the Controlled Release of Dry Betula pendula Leaf Extract.

The aim of the study was to develop polymer matrix tablets with modified release of dry Betula pendula leaf extract and to investigate basic parameters influencing the drug release pattern. To fully assess the statistical significance of the influence of the individual factors in the tablet formulation development as well as the combination of them, Tukey's tests and a complete 33 factor analysis of variance (ANOVA) were applied. The following three factors were studied at three levels (low, medium and high): influence of the hydrophobic/hydrophilic polymer ratio Ethylcellulose (EC)/Hydroxypropyl methylcellulose (HPMC) (40/60, 25/75 and 10/90), influence of HPMC molecular weight (500 kDa, 750 kDa and 1150 kDa), and influence of the compression force applied (1 t, 1.5 t and 2 t). The effect of these varied parameters on the drug release parameter t80 was evaluated statistically. Twenty-seven tablet models were formulated, including all possible combinations of the variables. The obtained drug release profiles demonstrated that a 25/75 (EC/HPMC) ratio was the most suitable for prolonging the release process. Increasing the molecular weight of HMPC from 500 kDa to 750-1150 kDa and applying higher compression force significantly influenced the studied t80 values and caused sustained drug release (t80 up to 7.97 h). The combination of the hydrophilic HPMC polymer with the hydrophobic EC can result in the formation of a promising drug-carrying matrix, offering effective control of the drug release process.

Application of Starch, Cellulose, and Their Derivatives in the Development of Microparticle Drug-Delivery Systems.

Micro- and nanotechnologies have been intensively studied in recent years as novel platforms for targeting and controlling the delivery of various pharmaceutical substances. Microparticulate drug delivery systems for oral, parenteral, or topical administration are multiple unit formulations, considered as powerful therapeutic tools for the treatment of various diseases, providing sustained drug release, enhanced drug stability, and precise dosing and directing the active substance to specific sites in the organism. The properties of these pharmaceutical formulations are highly dependent on the characteristics of the polymers used as drug carriers for their preparation. Starch and cellulose are among the most preferred biomaterials for biomedical applications due to their biocompatibility, biodegradability, and lack of toxicity. These polysaccharides and their derivatives, like dextrins (maltodextrin, cyclodextrins), ethylcellulose, methylcellulose, hydroxypropyl methylcellulose, carboxy methylcellulose, etc., have been widely used in pharmaceutical technology as excipients for the preparation of solid, semi-solid, and liquid dosage forms. Due to their accessibility and relatively easy particle-forming properties, starch and cellulose are promising materials for designing drug-loaded microparticles for various therapeutic applications. This study aims to summarize some of the basic characteristics of starch and cellulose derivatives related to their potential utilization as microparticulate drug carriers in the pharmaceutical field.

Fucoidan from Ericaria crinita Alleviates Inflammation in Rat Paw Edema, Downregulates Pro-Inflammatory Cytokine Levels, and Shows Antioxidant Activity.

Fucoidans are sulfated polysaccharides detected mainly in the cell walls of brown seaweeds. Here, we examined the effects of single doses of fucoidan derived from Ericaria crinita (formerly Cystoseira crinita) on carrageenan-induced paw inflammation in rats. The serum levels of TNF-α, IL-1ß, IL-6, and IL-10 of rats with LPS-induced systemic inflammation after 14 days of treatment were also evaluated. Subchronic treatment with fucoidan from E. crinita attenuated the inflammation during the late phase of the degraded carrageenan-induced paw edema (3rd to 5th hour after carrageenan injection) with peak activity at the 3rd hour after the application. Both doses of fucoidan from E. crinita (25 and 50 mg/kg bw) significantly decreased the levels of all tested pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6) in the serum of rats with a model of system inflammation but had no effect on the anti-inflammatory cytokine IL-10. The results showed that the repeated application of fucoidan has a more prominent effect on the levels of some pro-inflammatory cytokines in serum in comparison to a single dose of the sulfated polysaccharide. This reveals the potential of E. crinita fucoidan as an anti-inflammatory agent. Furthermore, E. crinita fucoidan exhibited in vitro antioxidant capacity, determined by 2,2-diphenyl-1-picryl-hydrazyl radical scavenging and ferric reducing antioxidant power assays as follows: IC50 = 412 µg/mL and 118.72 µM Trolox equivalent/g, respectively.

Mesoporous Starch Cryoaerogel Material as an Emerging Platform for Oral Drug Delivery: Synthesis and In Vitro Evaluation.

In this study, a starch cryoaerogel formulation was developed as a carrier for poorly water-soluble drugs, like atorvastatin. Cryoaerogels were generated through a sol-gel method combined with a freeze-drying technique, and atorvastatin was incorporated into the obtained mesoporous systems during the solvent exchange stage. The formulated drug-loaded polymer structures were characterized in terms of their physicochemical properties, solid-state behavior, and cytotoxicity. They had a pore size of 27.56 nm and a drug loading size of 38.60%. Fourier transform infrared (FTIR) and scanning electron microscopy (SEM) analyses indicated that atorvastatin was successfully incorporated into the cryoaerogel pores. The amorphous nature of the loaded drug was confirmed via X-ray diffraction (XRD). Furthermore, after the atorvastatin incorporation into the cryogel, the volume of nitrogen adsorbed on one gram of cryoaerogel (Vm), as well as the specific surface area (aBET) were reduced. The comparison between the drug release profiles of crystalline atorvastatin and the loaded formulation of atorvastatin showed that by including the drug into the pores of the developed cryoaerogel matrix its solubility was significantly improved-the time for the dissolution of 30% pure atorvastatin (t30%) was approximately 4 h, whereas the determined t30% for the formulated cryoaerogels was only 1 h. Moreover, the data from the MTT assay illustrated that the designed cryoaerogel could be used as a safe oral atorvastatin delivery system. According to obtained results, it could be concluded that the starch cryoaerogel formulation is a promising candidate for oral delivery of poorly water-soluble therapeutic agents.

Contemporary Aspects of Designing Marine Polysaccharide Microparticles as Drug Carriers for Biomedical Application.

The main goal of modern pharmaceutical technology is to create new drug formulations that are safer and more effective. These formulations should allow targeted drug delivery, improved drug stability and bioavailability, fewer side effects, and reduced drug toxicity. One successful approach for achieving these objectives is using polymer microcarriers for drug delivery. They are effective for treating various diseases through different administration routes. When creating pharmaceutical systems, choosing the right drug carrier is crucial. Biomaterials have become increasingly popular over the past few decades due to their lack of toxicity, renewable sources, and affordability. Marine polysaccharides, in particular, have been widely used as substitutes for synthetic polymers in drug carrier applications. Their inherent properties, such as biodegradability and biocompatibility, make marine polysaccharide-based microcarriers a prospective platform for developing drug delivery systems. This review paper explores the principles of microparticle design using marine polysaccharides as drug carriers. By reviewing the current literature, the paper highlights the challenges of formulating polymer microparticles, and proposes various technological solutions. It also outlines future perspectives for developing marine polysaccharides as drug microcarriers.

Novel Fucoidan Pharmaceutical Formulations and Their Potential Application in Oncology-A Review.

Fucoidan belongs to the family of marine sulfated, L-fucose-rich polysaccharides found in the cell wall matrix of various brown algae species. In the last few years, sulfated polysaccharides have attracted the attention of researchers due to their broad biological activities such as anticoagulant, antithrombotic, antidiabetic, immunomodulatory, anticancer and antiproliferative effects. Recently the application of fucoidan in the field of pharmaceutical technology has been widely investigated. Due to its low toxicity, biocompatibility and biodegradability, fucoidan plays an important role as a drug carrier for the formulation of various drug delivery systems, especially as a biopolymer with anticancer activity, used for targeted delivery of chemotherapeutics in oncology. Furthermore, the presence of sulfate residues with negative charge in its structure enables fucoidan to form ionic complexes with oppositely charged molecules, providing relatively easy structure-forming properties in combination with other polymers. The aim of the present study was to overview essential fucoidan characteristics, related to its application in the development of pharmaceutical formulations as a single drug carrier or in combinations with other polymers. Special focus was placed on micro- and nanosized drug delivery systems with polysaccharides and their application in the field of oncology.

Extraction, Structural Characterization, and In Vivo Anti-Inflammatory Effect of Alginate from Cystoseira crinita (Desf.) Borry Harvested in the Bulgarian Black Sea.

The aim of this study was to identify the chemical composition and sequential structure of alginate isolated from C. crinita harvested in the Bulgarian Black Sea, as well as its effects in histamine-induced paw inflammation in rats. The serum levels of TNF-α, IL-1ß, IL-6, and IL-10 in rats with systemic inflammation, and the levels of TNF-α in a model of acute peritonitis in rats were also investigated. The structural characterization of the polysaccharide was obtained by FTIR, SEC-MALS, and 1H NMR. The extracted alginate had an M/G ratio of 1.018, a molecular weight of 7.31 × 104 g/mol, and a polydispersity index of 1.38. C. crinita alginate in doses of 25 and 100 mg/kg showed well-defined anti-inflammatory activity in the model of paw edema. A significant decrease in serum levels of IL-1ß was observed only in animals treated with C. crinita alginate in a dose of 25 mg/kg bw. The concentrations of TNF-α and IL-6 in serum were significantly reduced in rats treated with both doses of the polysaccharide, but no statistical significance was observed in the levels of the anti-inflammatory cytokine IL-10. A single dose of alginate did not significantly alter the levels of the pro-inflammatory cytokine TNF-α in the peritoneal fluid of rats with a model of peritonitis.

Structural Characterization and In Vivo Anti-Inflammatory Activity of Fucoidan from Cystoseira crinita (Desf.) Borry.

The aim of this study was to evaluate the effects of fucoidan isolated from C. crinita on histamine-induced paw inflammation in rats, and on the serum levels of TNF-α, IL-1ß, IL-6, and IL-10 in rats during systemic inflammation response. The levels of TNF-α in a model of acute peritonitis in rats were also investigated. The isolated crude fucoidan was identified as a sulfated xylogalactofucan with high, medium, and low molecular weight fractions and a content of fucose of 39.74%, xylose of 20.75%, and galactose of 15.51%. Fucoidan from C. crinita showed better anti-inflammatory effects in the rat paw edema model, and this effect was present during all stages of the experiment. When compared to controls, a commercial fucoidan from F. vesiculosus, the results also displayed anti-inflammatory activity on the 60th, 90th, and 120th minute of the experiment. A significant decrease in serum levels of IL-1ß in rats treated with both doses of C. crinita fucoidan was observed in comparison to controls, whereas TNF-α concentrations were reduced only in the group treated with fucoidan from C. crinita at the dose of 25 mg/kg bw. In the model of carrageenan-induced peritonitis, we observed a tendency of decrease in the levels of the pro-inflammatory cytokine TNF-α in peritoneal fluid after a single dose of C. crinita fucoidan, but this did not reach the statistical significance margin. Single doses of C. crinita fucoidan did not alter serum levels of the anti-inflammatory cytokine IL-10 in animals with lipopolysaccharide-induced systemic inflammation.

Polysaccharides and Their Derivatives as Potential Antiviral Molecules.

In the current context of the COVID-19 pandemic, it appears that our scientific resources and the medical community are not sufficiently developed to combat rapid viral spread all over the world. A number of viruses causing epidemics have already disseminated across the world in the last few years, such as the dengue or chinkungunya virus, the Ebola virus, and other coronavirus families such as Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV). The outbreaks of these infectious diseases have demonstrated the difficulty of treating an epidemic before the creation of vaccine. Different antiviral drugs already exist. However, several of them cause side effects or have lost their efficiency because of virus mutations. It is essential to develop new antiviral strategies, but ones that rely on more natural compounds to decrease the secondary effects. Polysaccharides, which have come to be known in recent years for their medicinal properties, including antiviral activities, are an excellent alternative. They are essential for the metabolism of plants, microorganisms, and animals, and are directly extractible. Polysaccharides have attracted more and more attention due to their therapeutic properties, low toxicity, and availability, and seem to be attractive candidates as antiviral drugs of tomorrow.

Polysaccharide-Based Micro- and Nanosized Drug Delivery Systems for Potential Application in the Pediatric Dentistry.

The intensive development of micro- and nanotechnologies in recent years has offered a wide horizon of new possibilities for drug delivery in dentistry. The use of polymeric drug carriers turned out to be a very successful technique for formulating micro- and nanoparticles with controlled or targeted drug release in the oral cavity. Such innovative strategies have the potential to provide an improved therapeutic approach to prevention and treatment of various oral diseases not only for adults, but also in the pediatric dental practice. Due to their biocompatibility, biotolerance and biodegradability, naturally occurring polysaccharides like chitosan, alginate, pectin, dextran, starch, etc., are among the most preferred materials for preparation of micro- and nano-devices for drug delivery, offering simple particle-forming characteristics and easily tunable properties of the formulated structures. Their low immunogenicity and low toxicity provide an advantage over most synthetic polymers for the development of pediatric formulations. This review is focused on micro- and nanoscale polysaccharide biomaterials as dental drug carriers, with an emphasis on their potential application in pediatric dentistry.

Immunomodulatory and Anti-Inflammatory Effects of Fucoidan: A Review.

Inflammation is the initial response of the immune system to potentially harmful stimuli (e.g., injury, stress, and infections). The process involves activation of macrophages and neutrophils, which produce mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), pro-inflammatory and anti-inflammatory cytokines. The pro-inflammatory cytokines interleukin-1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) are considered as biomarkers of inflammation. Even though it occurs as a physiological defense mechanism, its involvement in the pathogenesis of various diseases is reported. Rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, and cardiovascular diseases are only a part of the diseases, in which pathogenesis the chronic inflammation is involved. Fucoidans are complex polysaccharides from brown seaweeds and some marine invertebrates, composed mainly of L-fucose and sulfate ester groups and minor amounts of neutral monosaccharides and uronic acids. Algae-derived fucoidans are studied intensively during the last years regarding their multiple biological activities and possible therapeutic potential. However, the source, species, molecular weight, composition, and structure of the polysaccharides, as well as the route of administration of fucoidans, could be crucial for their effects. Fucoidan is reported to act on different stages of the inflammatory process: (i) blocking of lymphocyte adhesion and invasion, (ii) inhibition of multiple enzymes, and (iii) induction of apoptosis. In this review, we focused on the immunemodulating and anti-inflammatory effects of fucoidans derived from macroalgae and the models used for their evaluation. Additional insights on the molecular structure of the compound are included.

Study of prebiotic potential and antioxidant activity in Plantago spp. leaves after enzymatic hydrolysis with hemicellulase and xylanase.

The leaves of Plantago species have been known as a rich source of polysaccharides, polyphenols, and iridoids. In the recent years, some authors have examined the relative influence of carbohydrate compositions and polyphenols on their antioxidant and prebiotic activity. In this study enzymatic hydrolysis of Plantago major, Plantago lanceolata, and Plantago media leaves with hemicellulase and xylanase was carried out. The chemical composition of the enzyme-derived hydrolysis products was determined. Their antioxidant activity was evaluated using 2,2-diphenyl-2-picryl-hydrazyl-hydrate, ferric reducing antioxidant power, and cupric reducing antioxidant capacity assays. The utilization of the carbohydrate complex from the obtained hydrolysates to stimulate the production of certain glycohydrolases from Lactobacillus plantarum probiotic strains was investigated. The HPLC analysis of the hydrolysis products showed the presence of galactose and arabinose in 1:3 and 1:4 ratios. The highest concentration of total sugars was determined in P. major hydrolysates with hemicellulase (386.71 mg/g dry weight). The antioxidant activity according to the three methods was the highest in P. media hydrolysates, which correlated with their total phenolic concentration. L. plantarum S27 showed the highest values of α-galactosidase activity at the 24-h fermentation process when it was cultivated in a broth with the presence of P. major hydrolysates with hemicellulase and xylanase (0.129 U/mg and 0.133 U/mg, respectively).

Optimization of Chitosan Microspheres Spray Drying via 32 Full Factorial Design.

BACKGROUND: Generally, the preparation of spray-dried microspheres is strongly affected by the process parameters. Particle size and production yield are mainly influenced by the spraying solution concentration and the pump rate of the spray dryer. AIM: The aim of this study was to assess optimum spray drying parameters - polymer concentration and pump rate required for the production of chitosan microspheres with high production yield and targeted for nasal administration particle size. MATERIALS AND METHODS: Full 32 factorial design was used to study the investigated parameters. Three different concentrations of the chitosan solution were selected: a low concentration of 1%, average concentration of 1.5% and high concentration of 2%. The rate of the peristaltic pump was also varied at three levels: low rate of 10%, medium rate of 14% and high rate of 18%. RESULTS: Nine models of chitosan microspheres were formulated and characterized in terms of shape, surface morphology, size, particle size distribution and production yield. The particles obtained from 2% chitosan solutions, sprayed at 10% pump rate were of the highest yield (64.33%) and appropriate for nasal administration median diameter (3,434 µm). CONCLUSION: The two investigated spray-drying parameters interact with each other and their influence on the production yield and the size of the chitosan microspheres should be evaluated together, instead of one at a time. The assessed process parameters allow the production of chitosan microparticles with high yield and desirable characteristics (size, size distribution and shape) for intranasal delivery.

Enzymatic Hydrolysis of Water Extractable Polysaccharides from Leaves of Plantago major L.

BACKGROUND: Plantago major L. leaves have been used for centuries by the traditional medicine in the treatment of infectious disorders of the respiratory, urinary and digestive tracts. Researchers have reported that hot water extracts of Plantago major possess a broad-spectrum of anticancer, antioxidant and antiviral activities, as well as activities which modulate cell-mediated immunity. Their beneficial properties may be due to the significant content of polysaccharides. The polysaccharides that have been isolated from the leaves of Plantago major L. have different structures - pectic substances, galactans, arabinogalactans, glucomannans. AIM: The aim of this paper was to study the correlation between the structure of the water extractable polysaccharides isolated from Plantago major L. leaves and their enzymatic hydrolysis with different carbohydrate hydrolases. MATERIALS AND METHODS: The hydrolysis reactions were performed with the enzymes hemicellulase and mannanase. Spectrophotometric total reducing sugars assay was used to examine the hydrolysis yield. The monosaccharide and oligosaccharide compositions were determined using HPLC analysis. RESULTS: The highest hydrolysis yield of the water extractable polysaccharides from Plantago major leaves was obtained by treatment with hemicellulase. The hydrolysis yield increased with the augmentation of the ratio of enzyme to polysaccharide. Galactose was the prevalent monosaccharide identified in the composition of the isolated polysaccharides. Oligosaccharides with different degree of polymerization were also detected. CONCLUSION: The enzymatic hydrolysis of water extractable polysaccharides from Plantago major leaves allows us to obtain different types of oligosaccharides with beneficial effects on both human health and industry.

Effect of Extracts of Bilberries (Vaccinium myrtillus L.) on Amyloglucosidase and α-Glucosidase Activity.

BACKGROUND: Vaccinium myrtillus L. is a species belonging to the genus Vaccinium of the family Ericaceae. Bilberries have drawn attention due to the multiple benefits for the human health, including antioxidant, anti-inflammatory, anticancer, anti-neurodegenerative, and cardioprotective effects. Recently, bilberries were shown to inhibit the activity of carbohydrate-hydrolysing enzymes that can help reduce the intensity of the metabolic syndrome and prevent type 2 diabetes. AIM: In this study, we investigated the α-glucosidase and amyloglucosidase inhibitory activities of polyphenol-rich extracts from fruit of Vaccinium myrtillus L. from different regions in Bulgaria. MATERIALS AND METHODS: The total phenolic content was determined spectrophotometrically using the Folin-Ciocalteu method. With HPLC analysis, phenolic acid composition of extracts was assessed. Enzymatic inhibitory activities were determined according to the methodology by Borooah et al. (1961), and Dewi et al. (2007). Amyloglucosidase assay and α-glucosidase assay were used to measure the inhibition potential of bilberries' extracts. RESULTS: Phenolic compound content ranged from 1299.60 mg to 510.88 mg GAE/100 g for organic extracts and from 453.63 mg to 290.83 mg GAE/100 g for aqueous extracts. Based on qualitative HPLC analyses, gallic acid and chlorogenic acid were found to be among the major phenolic acids present in bilberries. Methanol and aqueous extracts there were found to be effective inhibitors of α-glucosidase with an IC50 value of 20 µg GAE/ml and 55 µg GAE/ml, respectively. CONCLUSION: The inhibitory activity of bilberries' extracts towards α-glucosidase offers the patients with type 2 diabetes the opportunity to manage their own glycaemic levels with a diet.