Miloslava Rabišková

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.

Bioadhesive pellets increase local 5-aminosalicylic acid concentration in experimental colitis

Topical delivery of 5-aminosalicylic acid (5-ASA) to the colonic mucosa is important in order to achieve effective drug concentration in the site of inflammation and to minimize its systemic availability. 5-ASA loaded pellets were prepared by an extrusion/spheronization method. Mucoadhesive biopolymer chitosan was incorporated into the pellets, and drug delivery to the colon was controlled by the pH-sensitive polymer Eudragit® FS. Dissolution profiles of coated pellets revealed no drug release at pH 1.2 within 2h and release as intended in the simulated distal ileum and colon. In vivo, chitosan-core drug loaded pellets (AMCh) showed 2.5-fold higher drug metabolite concentration than after chitosan free pellets (AM) administration in the inflamed colonic tissue. Additionally, AMCh demonstrated decreased in AUC in colitis group (1507 ± 400 ng h/ml) compared with AM (1907 ± 122 ng h/ml). In terms of therapeutic efficiency, administration of pellets markedly decreased the colon/body weight ratio (colitis: 0.0355 ± 0.0028; AM 0.0092 ± 0.0033; AMCh 0.0086 ± 0.0022) and myeloperoxidase activity (colitis: 3212 ± 294 U/g tissue; AM 796 ± 211 U/g; AMCh 552 ± 319 U/g). Bioadhesive chitosan pellets showed additional beneficial properties for colonic 5-ASA delivery in the treatment of inflammatory bowel disease by increasing the drug concentration locally.

Differences in Characteristics of Pellets Prepared by Different Pelletization Methods

Pellets are currently a very popular dosage form for oral application. They can be prepared by several pelletization techniques. Extrusion/spheronization, commonly used in the pharmaceutical industry, and modern agglomeration in a rotoprocessor were the methods chosen for pellet preparation in our study. Theophylline (in 10% to 65% concentration) was the model drug, lactose monohydrate was used as filler, microcrystalline cellulose Avicel® PH 101 was thespheronization enhancer, and the wetting agent was purified water. Both techniques led to the formation of pellets of appropriate shape and mechanical properties. Pellets of a higher density, hardness, lower friability, and slightly slower dissolution profiles were obtained by extrusion/spheronization. This method of pelletization also led to production of particles with narrower size distribution and bigger yield of pellets with the requested size.

Soluble filler as a dissolution profile modulator for slightly soluble drugs in matrix tablets.

The purpose of this experimental work was the development of hydrophilic–lipophilic matrix tablets for controlled release of slightly soluble drug represented here by diclofenac sodium (DS). Drug dissolution profile optimization provided by soluble filler was studied. Matrix tablets were based on cetyl alcohol as the lipophilic carrier, povidone as the gel-forming agent, and common soluble filler, that is lactose or sucrose of different particle size. Physical properties of tablets prepared by melt granulation and drug release in a phosphate buffer of pH 6.8 were evaluated. In vitro studies showed that used filler type, filler to povidone ratio and sucrose particle size influenced the drug release rate. DS dissolution profile could be changed within a wide range from about 50% per 24 hours to almost 100% in 10 hours. The release constant values confirmed that DS was released from matrices by the diffusion and anomalous transport. The influence of sucrose particle size on the drug release rate was observed. As the particle size decreased, the drug release increased significantly and its dissolution profile became more uniform. Soluble fillers participated in the pore-forming process according to their solubility and particle size. Formulations containing 100 mg of the drug, 80 mg of cetyl alcohol, 40 mg of povidone, and 80 mg of either lactose or sucrose (particle size 250–125 μm) were considered optimal for 24-hour lasting dissolution of DS.

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.

Multiparticulate systems containing 5-aminosalicylic acid for the treatment of inflammatory bowel disease.

Background: In recent years, many achievements have been realized in the therapy of inflammatory bowel disease (IBD) although its etiology remains unknown. Thus IBD treatment is symptomatic and targets general inflammatory mechanisms. Oral formulations containing 5-aminosalicylic acid (5-ASA) have become the standard therapy for mild-to-moderate IBD. Objective: This article is a review of recently published research dealing with new 5-ASA dosage forms. Thus promising candidates for IBD treatment evaluated in vitro are reported; systems tested in vivo in trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats are mentioned; and 5-ASA formulations used in clinical studies are presented. Moreover, all oral dosage forms containing 5-ASA or its prodrugs are reviewed; their characteristics and utilization in IBD treatment are discussed. Conclusion: In several clinical studies, it has been shown that multiparticulates such as pellets offer more advantages as compared with single unit forms, that is, coated tablets. Prolonged presence close to the site of the action, improved drug bioavailability, and easier administration of large drug doses belong to the benefits of pellets.

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.

Some variables influencing rotoagglomeration in the multiprocessor MP-1

Pellets are of great interest to the pharmaceutical industry for variety reasons, e.g. flexibility in dosage form design and drug efficacy improvement. Rotoagglomeration is the novel method for their production using rotoprocessors or rotogranulators allowing one-piece equipment operation. However this process is sensitive and includes numerous variables that have to be optimalized for successful result-spherical pellets of desired properties. This paper is contributing to study some of them: liquid amount, its spray rate and input powder amount and their influence on lactose-microcrystalline cellulose pellet properties.

Pellet Starters in Layering Technique Using Concentrated Drug Solution

Characteristics of inert starters in drug solution layering are important for successful active pellet formation. Four types of starters composed of sucrose or microcrystalline cellulose (MCC) or lactose and MCC were compared in our study. The active pellets were prepared using Wurster type apparatus. Yield and pellet quality parameters were determined. The highest yield (85.66–89.41%) was obtained for cores composed of MCC due to their insolubility in water (the drug solvent) and good mechanical properties. On the contrary, soluble and brittle sucrose cores dissolved partially during the process forming undesirable agglomerates and giving lower yield (76.2%). All pellet samples showed good flow properties and drug content from 82.4 to 94.5% of the theoretical drug amount.