Jan Gajdziok

Coated chitosan pellets containing rutin intended for the treatment of inflammatory bowel disease: in vitro characteristics and in vivo evaluation

Preparation of coated pellets intended for rutin colon delivery, their evaluation in vitro and in vivo in experimental colitis in rats was the purpose of this study. Pellets were obtained using extrusion/spheronization and coated with three types of coatings (caffeic acid/hypromellose/alginic acid; sodium alginate/hypromellose/zinc acetate; sodium alginate/chitosan). Dissolution using buffers of pH values, β-glucosidase and times corresponding to gastrointestinal tract (GIT) was provided. Pellets coated with alginate/chitosan showed low rutin dissolution (12-14%) in upper GIT conditions and fast release (87-89%) under colon conditions; that is a good presumption of intended rutin release. After colitis induction and development, the rats were treated with pellets and rutin solution administered orally, solution also rectally. Colon/body weight ratio, myeloperoxidase activity and histological evaluation were performed. Rutin was able to promote colonic healing at the dose of 10mg/kg: colon/body weight ratio decreased and myeloperoxidase activity was significantly suppressed. Pellets coated with alginate/chitosan applied orally and rutin solution administered rectally showed the best efficacy. The combination of rutin as natural product, mucoadhesive chitosan degraded in the colon and sodium alginate as the main coating substance in the form of pellets create a promising preparation for therapy of this severe illness.

Determination of dependencies among in vitro and in vivo properties of prepared mucoadhesive buccal films using multivariate data analysis

Mucoadhesive films represent the most developed medical form of buccal application. Despite the intense focus on buccal film-based systems, there are no standardized methods for their evaluation, which limits the possibility of comparison of obtained data and evaluation of the significance of influence of formulation and process variables on properties of resulting films. The used principal component analysis, together with a partial least squares regression provided a unique insight into the effects of in vitro parameters of mucoadhesive buccal films on their in vivo properties and into interdependencies among the studied variables. In the present study eight various mucoadhesive buccal films based on mucoadhesive polymers (carmellose, polyethylene oxide) were prepared using a solvent casting method or a method of impregnation, respectively. An ethylcellulose or hydrophobic blend of white beeswax and white petrolatum were used as a backing layer. The addition of polyethylene oxide prolonged the in vivo film residence time (from 53.24±5.38-74.18±5.13 min to 71.05±3.15-98.12±1.75 min), and even more when combined with an ethylcellulose backing layer (98.12±1.75 min) and also improved the films appearance. Tested non-woven textile shortened the in vivo film residence time (from 74.18±5.13-98.12±1.75 min to 53.24±5.38-81.00±8.47 min) and generally worsened the films appearance. Mucoadhesive buccal films with a hydrophobic backing layer were associated with increased frequency of adverse effects.

Liquisolid systems and aspects influencing their research and development

Abstract Many modern drugs are poorly water soluble substances, which causes difficulties in the development of solid dosage forms with sufficient bioavailability. Preparation of liquisolid systems (LSS) is a novel technique for improving solubility, dissolution and bioavailability of such drugs. The basic principle of LSS preparation is conversion of the drug in liquid state into a free-flowing, compressible, dry powder through its absorption into suitable excipients - porous carriers (aluminometasilicates, microcrystalline cellulose), subsequently coated with material having high absorption capacity (silicon dioxide commonly known as colloidal silica). LSS exhibit advantages such as lower production costs compared to soft capsules, simple processing and enhanced drug release. The main benefit is higher bioavailability of the liquid drug, caused by a large surface area available for absorption. The article tries to clarify specific aspects connected with the formulation of LSS: properties of excipients (surface area, absorption capacity), variables related to the processing (solubility, liquid load factor) and dosage form evaluation.

Carmellose Mucoadhesive Oral Films Containing Vermiculite/Chlorhexidine Nanocomposites as Innovative Biomaterials for Treatment of Oral Infections

Infectious stomatitis represents the most common oral cavity ailments. Current therapy is insufficiently effective because of the short residence time of topical liquid or semisolid medical formulations. An innovative application form based on bioadhesive polymers featuring prolonged residence time on the oral mucosa may be a solution to this challenge. This formulation consists of a mucoadhesive oral film with incorporated nanocomposite biomaterial that is able to release the drug directly at the target area. This study describes the unique approach of preparing mucoadhesive oral films from carmellose with incorporating a nanotechnologically modified clay mineral intercalated with chlorhexidine. The multivariate data analysis was employed to evaluate the influence of the formulation and process variables on the properties of the medical preparation. This evaluation was complemented by testing the antimicrobial and antimycotic activity of prepared films with the aim of finding the most suitable composition for clinical application. Generally, the best results were obtained with sample containing 20 mg of chlorhexidine diacetate carried by vermiculite, with carmellose in the form of nonwoven textile in its structure. In addition to its promising physicomechanical, chemical, and mucoadhesive properties, the formulation inhibited the growth of Staphylococcus and Candida; the effect was prolonged for tens of hours.

Coated hard capsules as the pH-dependent drug transport systems to ileo-colonic compartment

Purpose: The aim of this study was to investigate the suitability of hard capsules of different composition (gelatin—G, gelatin coated with hydroxypropyl cellulose—G/HPC, and hypromellose—H) for a coating with aqueous dispersion of pH-dependent synthetic polymer Eudragit® FS (EFS) and to evaluate in vitro the coated capsules as transport systems for ileo-colonic drug delivery. Methods: Three sets of hard capsules with increasing coating levels (5–30%) were obtained by Wurster technique. The release of model drug (caffeine) from prepared samples was tested using paddle dissolution method with continual pH change (pH 1.2–2 h, 6.8–4 h and 7.5–2 h). Results: During the coating process, no problems occurred and similar suitability of capsules materials for EFS application was observed in contrast to some published reports. The application of HPC subcoating onto gelatin capsules surface was shown as the redundant step. The samples G/EFS10–15% and H/EFS15–20% with 6 h lag time and fast drug release after the pH adjustment to 7.5 corresponded with the requirements for ileic drug delivery. Samples releasing the drug after the pH change to 7.5 in 2-h interval such as G/EFS 20%, G/HPC/EFS 25% and H/EFS 25% are considered as promising transport systems to ileo-colonic area. Samples G/EFS 25–30%, G/HPC/EFS 30% and H/EFS 30% with 7 h lag time could be used for colon delivery. Conclusion: The desired intestinal part could be targeted without significant formulation changes only by the selection of capsules shell forming material and suitable EFS coating thickness.

Pellets for oral administration of low-molecular-weight heparin

Background: Oral absorption of low-molecular-weight heparin (LMWH) is limited by its molecular size and negative charge. It has been shown previously that orally administered polymeric nano- or microparticles containing encapsulated LMWH have led to gastrointestinal absorption of heparin in rabbits. Method: Based on these investigations, pellets containing two LMWHs, enoxaparin (MW 4500 Da) or bemiparin (MW 3600 Da), and Eudragit®RS30D (ERS), were prepared using extrusion/ spheronization technique. Uncoated or coated (ERS) pellets were evaluated in vitro and in vivo on rabbits. Results: Enoxaparin pellets showed fast in vitro release in phosphate buffer (pH 7.4) and prolonged in vivo drug absorption after a single oral dose of 600 anti-Xa IU/ kg of body weight, leading to relative bioavailabilities ranging from 9.7 ± 1.9% to 12.8 ± 2.7% and anti-Xa activity over the curative dose. Bemiparin included in matrix pellets of ERS and coated with ERS exhibited in vitro prolonged release up to 4 hours and in vivo anti-Xa activity below the therapeutic minimum value of 0.1 IU/mL. Conclusion: This study presents LMWH in a pellet dosage form, which compared to nano- or microparticles, may offer a more convenient and industrializable way of manufacture leading to an easier scale-up process.

Oxycellulose as mucoadhesive polymer in buccal tablets

Background: Oxycellulose (OC) is biodegradable and bioabsorbable cellulose derivative used in medicine to support hemostasis and tissue healing. Recently, its antimicrobial and immunomodulating properties, as well as its potential in modern therapeutic systems as release modifying excipient, drug carrier, and/or mucoadhesive polymer, are widely discussed. Method: To study its last-mentioned characteristics, directly compressed tablets containing 5 mg of cetylpyridinium chloride (CPC) as a model drug and 90 mg of mucoadhesive polymer [oxycellulose sodium (NaOC) alone or in a combination with one of five widely used mucoadhesive polymers] were prepared to ensure 8 hours prolonged release of CPC. Physicochemical and mucoadhesive properties of prepared tablets were evaluated. Results: Based on obtained results, tablets containing OC in combination with hydroxypropylmethylcellulose (Methocel® K100LV) or carboxymethylcellulose sodium showed the best quality parameters (friability < 0.04%, tablet thickness < 2.17 mm, tablet hardness > 85 N, residence time > 256 minutes, mucoadhesive strength > 3.45 mN/mm2) and dissolution profiles (more than 81% of CPC released within 8 hours). Conclusion: NaOC embodies excellent compressing, mechanical, and mucoadhesive properties; however, formulation with higher content of NaOC only showed shorter adhesion time (107 ± 7 minutes) and faster drug release (93.66% of CPC released within 2 hours), because of its good solubility in aqueous media.

Modern Evaluation of Liquisolid Systems with Varying Amounts of Liquid Phase Prepared Using Two Different Methods

Liquisolid systems are an innovative dosage form used for enhancing dissolution rate and improving in vivo bioavailability of poorly soluble drugs. These formulations require specific evaluation methods for their quality assurance (e.g., evaluation of angle of slide, contact angle, or water absorption ratio). The presented study is focused on the preparation, modern in vitro testing, and evaluation of differences of liquisolid systems containing varying amounts of a drug in liquid state (polyethylene glycol 400 solution of rosuvastatin) in relation to an aluminometasilicate carrier (Neusilin US2). Liquisolid powders used for the formulation of final tablets were prepared using two different methods: simple blending and spraying of drug solution onto a carrier in fluid bed equipment. The obtained results imply that the amount of liquid phase in relation to carrier material had an effect on the hardness, friability, and disintegration of tablets, as well as their height. The use of spraying technique enhanced flow properties of the prepared mixtures, increased hardness values, decreased friability, and improved homogeneity of the final dosage form.

Evaluation of the Influence of Formulation and Process Variables on Mechanical Properties of Oral Mucoadhesive Films Using Multivariate Data Analysis

Oral mucosa is an attractive region for the local and systemic application of many drugs. Oral mucoadhesive films are preferred for their prolonged time of residence, the improved bioavailability of the drug they contain, their painless application, their protection against lesions, and their nonirritating properties. This work was focused on preparation of nonmedicated carmellose-based films using both solvent casting and impregnation methods, respectively. Moreover, a modern approach to evaluation of mucoadhesive films applying analysis of texture and subsequent multivariate data analysis was used. In this experiment, puncture strength strongly correlated with tensile strength and could be used to obtain necessary information about the mechanical film characteristics in films prepared using both methods. Puncture work and tensile work were not correlated in films prepared using the solvent casting method, as increasing the amount of glycerol led to an increase in the puncture work in thinner films. All measured texture parameters in films prepared by impregnation were significantly smaller compared to films prepared by solvent casting. Moreover, a relationship between the amount of glycerol and film thickness was observed, and a greater recalculated tensile/puncture strength was needed for an increased thickness in films prepared by impregnation.

The evaluation of formulations for the preparation of new formula pellets

The aim of the study was to prepare pellets of maidenhair tree (Ginkgo biloba), motherwort (Leonurus cardiaca) and hawthorn (Crataegus monogyna) dry extracts by extrusion/spheronization method. The critical step of this process was the amount of added wetting liquid (water-ethanolic mixture) and the amount of extract in the formulation. The samples of pellets containing 30–50% of extracts were formulated: Pellets contained extracts of Ginkgo, Crataegi and Leonuri. The last sample was aimed at the formulation of pellets with the content of 30% of the mixture of Ginkgo, Leonuri and Crataegi extracts in a ratio of 1:5:6. The remainder of the solid compounds in all formulations was microcrystalline cellulose (Avicel® PH-101). It was not possible to find a way to adequately wet the formulations with the content of extracts higher than 30% because of the unsuitable properties of all three extracts used. On the basis of the experiments, pellets with mixtures of all three previously used extracts were prepared. These pellets showed perfect physico-mechanical properties: Hardness (10.00 ± 2.24 N), friability (0.06%), repose angle (20.99 ± 0.41°), flowability (6.97 ± 0.29 s/100g of pellets), sphericity (0.81 ± 0.05), compressibility index (4.65%), intraparticular porosity (0.09%) and interparticular porosity (45.11%), which predetermine them to other testing and usage (feeling into capsules, tableting, coating etc.).