Lipid-based floating multiparticulate delivery system for bioavailability enhancement of berberine hydrochloride

The objective of the present investigation was to design and optimize lipid-based floating multiparticulate of Berberinehydrochloride (BERH), so as to increase its solubility and to reduce P-Glycoprotein mediated efflux in the intestine,hence to improve oral bioavailability. Solid dispersions were prepared using hydrophilic carriers gelucire 44/14and gelucire 50/13 in different ratio. The prepared solid dispersion of BERH was further formulated into sustainrelease gastroretentive floating pellets using hydrophobic lipid carrier gelucire 43/01 as release retardant, sodiumbicarbonate (NaHCO3) and hydroxylpropyl methyl cellulose K4M (HPMC K4M) as gas former and matrix polymer,respectively. The effect of amount of gelucire 43/01 and NaHCO3: HPMC K4M were studied and optimized using a3-level, 2-factor, factorial design. Solid dispersion of BERH compared to pure drug showed 4-fold enhancement inaqueous solubility. The optimum system could float for more than 8 hours and showed 88.46% drug release in 8 hours.The pharmacokinetic study conducted in male Wistar rats indicated 2.32-fold increase in relative bioavailability ofoptimized formulation compare to the marketed tablet. The lipid-based floating pellets of BERH were obtained andcould be an applicable choice to deliver BERH with improved bioavailability in effective use for various clinicalapplications.

Multiparticulate Drug Delivery System For Gastrointestinal Tuberculosis

Drug solubility poses numerous challenges in design of formulations for drugs with poor aqueous solubility. Ethionamide is an antitubercular drug belonging to biopharmaceutical classification system class II drug having less aqueous solubility. Nanosuspensions were prepared by using various solvents such as methanol, ethanol, acetone and chloroform and it was prepared using anti-solvent precipitation technique by using probe sonication. Various stabilizers such as tocopherolpolythytlene glycol succinate, polyvinylpyrrolidone and tween 80 singly or in combination were studied. A 32 factorial design was employed to study the effect of independent variables, concentration of stabilizers and stirring speed on particle size and cumulative percent drug release. The particle size of the optimized batch was 97.54 ± 8.47 nm with polydispersity index of 0.36 and zeta potential -10.1 ± 2.3 mV. The cumulative percent drug release of optimized batch was found to be 95.01 ± 1.16% in 60 min. Optimized batch was ultracentrifuged and evaluated for saturation solubility studies, stability and powder X-ray Diffraction studies. Optimized nanosuspension was loaded on Espheres by spraying in a coating pan and then coating of Eudragit controlled release polymers. The coated Espheres were evaluated for drug content, friability, scanning electron microscopy, ex-vivo permeation studies and drug release kinetics studies. The friability value for primary coated sphere was found to be 0.8 ± 0.12% and for secondary was 1% and the best fit model was found to be Korsmeyer-Peppas model which is indicative of diffusion controlled release. Ex vivo diffusion studies revealed a moderate increase in permeability.

Physical characterization of multiparticulate systems

ABSTRACT The search for new pharmaceutical dosage forms and different drug delivery systems already used in therapeutics is a global trend, serving as an opportunity to expand the portfolio for the pharmaceutical industry. In this context, multiparticulate systems, such as pellets, granules, and minitablets, represent an attractive alternative, given the range of possibilities they provide. Among the methods used in the production of these systems, we highlight the process of extrusion-spheronization for pellet manufacture, wet granulation and hot-melt extrusion for the obtention of granules, and direct compression for minitablets. Although highly versatile, depending on the technology chosen, many processes and formulation variables can influence the ensuing stages of manufacture, as well as the final product. Therefore, the characterization of these small units is of fundamental importance for achieving batch homogeneity and optimal product performance. Analyses, including particle size distribution, morphology, density, porosity, mechanical strength and disintegration, are example tests used in this characterization. The objective of this review was to address the most widely used tests for the physical evaluation of multiparticulate systems.

Desenvolvimento de sistemas multiparticulados de liberação imediata e modificada para associação de fármacos anti-hipertensivos / Development of immediate and modified release multiparticulate systems for antihypertensive drugs association

Os sistemas multiparticulados são aqueles nos quais a dose do fármaco está dividida em pequenas unidades funcionais, tendo assim, uma série de vantagens sobre os sistemas monolíticos convencionais. Este trabalho teve por objetivo desenvolver formulações multiparticuladas de uso oral para fármacos anti-hipertensivos que serão utilizados na composição de associações. O material está dividido em seis capítulos, sendo inicialmente apresentada uma revisão da literatura a respeito da caracterização física destas pequenas unidades. Ensaios como análise granulométrica, morfologia, densidade, porosidade, avaliação de resistência mecânica e desintegração são os mais empregados para esta finalidade, possibilitando ao formulador conhecer os fatores de maior impacto relacionados às matérias primas e ao processo de fabricação no comportamento das formulações produzidas. Os demais capítulos seguem com o desenvolvimento dos sistemas multiparticulados, que foram embasados em diferentes delineamentos experimentais, seja pela utilização de planejamento fatorial fracionado ou projeto de mistura. Para o metoprolol, fármaco de alta solubilidade, foram produzidas formulações de liberação controlada, sendo a estratégia dividida em três etapas: (I) Produção de minicomprimidos revestidos, nos quais foram avaliadas diferentes combinações do polímero modulador de liberação; (II) otimização do perfil de liberação do fármaco, com avaliação de misturas das formulações produzidas na primeira etapa; (III) Processo de extrusão a quente, no qual diferentes proporções de fármaco e polímero hidrofóbico foram avaliadas. Para os fármacos hidroclorotiazida e olmesartana medoxomila, ambos de baixa solubilidade, a estratégia adotada foi a incorporação de uma dispersão dos fármacos e agentes solubilizantes em grânulos inertes obtidos por extrusão/revestimento. Adicionalmente, também foram produzidas formulações por extrusão a quente de diferentes proporções destes fármacos em polímero hidrofílico. De acordo com os resultados obtidos, foi possível obter formulações de minicomprimidos e grânulos com perfil de dissolução satisfatório, semelhantes aos apresentados pelos medicamentos adotados como referência. Em relação à extrusão a quente foi possível avaliar a influência do processo e polímeros empregados no perfil de dissolução dos grânulos produzidos

Multiparticulate systems are dosage forms in which dose is divided into small functional units presenting some advantages over monolithic conventional systems. The objective of this work was developing multiparticulate formulations for oral use containing antihypertensive drugs to be used in association. The thesis is divided into six issues, been first presented a literature review about physical characterization of multiparticulate systems. Granulometric analysis, morphology, density, porosity, mechanical strength and disintegration are the most used physical characterization tests, enabling formulator knowing the major impact factors related to raw materials and manufacturing process in the performance of the produced formulations. The other issues present the development of the multiparticulate systems based on different statistical experimental design, as fractional factorial design or mixture project. For metoprolol, a highly soluble drug, controlled release formulations were obtained, and the strategy was divided into three steps: (I) coated minitablets production, where different combinations of the controlled release polymer were analyzed; (II) drug release profile optimization, evaluating formulations mixtures produced in the first step; (III) hot melt extrusion process, where different drug: hydrophobic polymer ratios were evaluated. For hydrochlorothiazide and olmesartan medoxomil, both low soluble drugs, the strategy was incorporating a dispersion containing the drugs and solubilizing agents in inert granules obtained by extrusion/coating processes. Additionally, formulations containing different ratios of these drugs and hydrophilic polymers were produced by hot melt extrusion. According to the results, it was possible to obtain minitablets and granules with good dissolution profile, similar to the reference products. Regarding to hot melt extrusion, it was possible to evaluate the influence of process and polymers used in the dissolution profile of the produced granules

Development of a multiparticulate system containing enteric-release mini-tablets of omeprazole

The main aim of this study was to develop a multiparticulate system containing mini-tablets of omeprazole formulated with an enteric polymer with pH-dependent solubility. Pre-formulation studies showed good flow and compaction capacity, leading to the production ofhigh quality mini-tablets. The mini-tablets were coated in a fluidized bed with hydroxypropylmethylcellulose /Eudragit(r) L30D55 and packed into hard gelatin capsules. The dissolution profile showed gastro-resistance and zero-order kinetics. The dissolution profile for the formulation containing lactose as the diluent and coated with 12% (tablet weight gain) of polymer was similar to that ofthe reference drug.

O presente trabalho teve como objetivo desenvolver e avaliar um sistema multiparticulado de liberação modificada, composto por mini-comprimidos revestidos com polímero de liberação pH-dependente, utilizando como fármaco modelo o omeprazol. Os mini-comprimidos (diâmetro de 2,5 mm) foram obtidos em máquina de compresssão excêntrica, revestidos em leito fluidizado com hidroxipropilmetilcelulose/Eudragit(r)L30D55 e, em seguida, acondicionados em cápsulas gelatinosas duras. A partir dos resultados obtidos no perfil de dissolução foi possível demonstrar a liberação gastro-resistente e comportamento cinético de ordem zero. A formulação contendo lactose como diluente, com revestimento de 12% de polímero, demonstrou semelhança com o medicamento referência.

Preparation of pellets containing Pothomorphe umbellata extracts by extrusion-spheronization: improvement of 4-nerolidylcatechol photostability

Pothomorphe umbellata (L.) Miq., Piperaceae, has been extensively used in Brazilian folk medicine and it is well known for its strong antioxidant properties. However, its main active constituent, 4-nerolydilcatechol (4-NC), is sensitive to ultraviolet and visible light, which can limit the use of intermediate and final herbal preparations of this species. In the present work, coated multiparticulate solid dosage forms of P. umbellata were obtained with the purpose of increasing the stability of 4-NC. P. umbellata extract was used as a wetting liquid for the preparation of pellets by extrusion-spheronization. Pellets were coated in a fluidized bed by three different polymers (hydroxypropylmethylcellulose (HPMC), polyvynilpirrolidone K-30 (PVP-K30), and polyvinyl alcohol-polyethylene glycol graft-copolymer (PVAPEG)). 4-NC photostability was evaluated by an accelerated photostability protocol. Pellets showed a narrow size distribution and low friability. 4-NC photodegradation followed a second order degradation kinetics with similar k values for the percolate, uncoated pellets and HPMC coated pellets. Photoprotection was higher in pellets coated with PVP-K30 and PVA-PEG. PVA-PEG coated pellets with 6 and 9% weight gain resulted in a final concentration of 4-NC approximately cinco times higher than uncoated pellets or liquid extracts, suggesting the potential of this formulation as a multiparticulate solid dosage form for P. umbellata extracts.

Multiparticulate formulation of Valdecoxib for the treatment of rheumatoid arthritis.

An oral controlled onset dosage form intended to approximate the chronobiology of rheumatoid arthritis was proposed for colonic targeting. The multiparticulate system comprising of non-pareil seeds coated with Eudragit S100 was designed for chronotherapeutic delivery of valdecoxib. The drug was coated onto non-pareil seeds by powder layering technique using the conventional coating pan. Different coat weights of non-aqueous dispersions were applied onto the drug-coated pellets using spray coating technique. In vitro dissolution tests of the coated pellets were performed in different pH media for a period of 11 hours. The in-vitro dissolution tests showed that the release of valdecoxib from the coated pellets depended on the pH of the dissolution fluid and the coat weights applied. All the formulations exhibited no release of drug in the pH 1.2 and pH 4 buffers; drug release took place in phosphate buffer of pH 7.4. Further intactness of the drug in the formulation and the uniformity of the polymer coating were checked by the infrared study and scanning electron microscopy. Stability studies inferred that the drug undergoes no considerable degradation pattern at room temperature and 40oC even after three weeks. All the above results show that the formulation could be highly advantageous in the chronotherapy of rheumatoid arthritis with appreciable drug release and physiochemical properties.

Sistemas multiparticulados: minicomprimidos / Multiparticulate systems: minitablets

Os sistemas multiparticulados contêm o fármaco subdividido em unidades funcionais, que podem ser pellets, grânulos ou minicomprimidos. Oferecem vantagens tecnológicas e biofarmacotécnicas quando comparados aos sistemas monolíticos, apresentando ainda benefícios terapêuticos para os pacientes. Por isso, têm se destacado cada vez mais dentre as novas formas farmacêuticas e sistemas de liberação de fármacos. Os minicomprimidos possuem diâmetro igual ou inferior a 2 - 3 mm e são obtidos através do processo de compressão, utilizando máquinas de comprimir convencionais adaptadas com punções múltiplos. Quanto ao aspecto tecnológico, oferecem vantagens em relação aos pellets e grânulos. O objetivo desta revisão é, portanto, abordar os principais aspectos tecnológicos envolvidos na sua obtenção, destacando suas vantagens e aplicações.

In multiparticulate systems, the drug is subdivided into functional units, which may be in the form of pellets, granules or minitablets. They have technological and biopharmacotechnical advantages over monolithic systems and also offer therapeutic benefits to patients. For these reasons, they have gained prominence among new pharmaceutical dosage forms and drug delivery systems. Minitablets are between 2 and 3 mm in diameter or smaller and are manufactured by means of the direct compression process, with a conventional tablet press adapted with multi-tip punches. In technological terms, they have advantages over both pellets and granules. The objective of this review is, therefore, to discuss the main technological features of minitablet production, highlighting their advantages and applications.

Fabrication and evaluation of ethyl cellulose and cellulose acetate coated controlled release multiparticulate formulation of ketoprofen by dry powder layering technology.

Multiparticulate is one of the most widely accepted technologies in the pharmaceutical industries. Present study aim is to prepare controlled release multiparticulate of Ketoprofen by drug powder layering technology using two different release retardant (Ethyl Cellulose & Cellulose Acetate) in five different drug: release retardant concentrations (5%, 10%, 20%, 30% & 40%). The most widely used multiparticulate system in pharmaceutical industries is Dry Powder Layering Technique. Powder layering involves the deposition of successive layers of dry powder(s) and excipients on preformed nuclei or cores with the help of binding liquids. The prepared multiparticles were evaluated for friability, drug content uniformity, density and percentage yield. The release rate was evaluated by dissolution studies. To establish drug polymer compatibility DSC and FT IR was done. Study concluded that Dry Powder Layering of Ketoprofen can be effectively used for drug loading on non-pareil seeds. It was also found that formulation having Ethyl Cellulose have more retarding capacity than the Cellulose Acetate in both formulations and drug release follows Zero order kinetics. DSC and FT IR study concluded that there is no interaction between EC and CA. From dissolution parameter of the prepared multiparticles it is concluded that formulation EC3 (20%) and CA4 (30%) posses the required characteristics of oral controlled release formulation. It is assumed that above 90% of the drug will be released within 24 hours. Hence this formulation can be used as once daily dosage regimen for the controlled release of Ketoprofen.