Development and characterization of cross-linked gellan gum and retrograded starch blend hydrogels for drug delivery applications.

The retrogradation of high amylose starch (5% or 10%), by isothermal cycles at 4°C (method 1) or by alternating thermal cycles (method 2) was efficient and promoted important structural modifications. Hydrogels of gellan gum and starch retrograded blends, containing or not ketoprofen, were prepared by ionic and dual cross-linking, at different concentrations of polymer and cross-linkers, and characterized by texture and rheological analysis, X-ray diffraction and morphological analysis. The ionic cross-linking and starch retrograded by method 1 contributed to the improvement of hardness and cohesiveness of hydrogels while the dual cross-linking and starch retrograded by method 2 favored the adhesiveness. The rising of polymer concentration lead to the improvement of all mechanical parameters. Rheological data demonstrated that non-cross-linked dispersions showed a behavior of weak gels and the cross-linked hydrogels presented a predominantly elastic behavior (G'≫G″), peculiar of strong gels. X-ray diffraction, rheological data and the scanning electron microscopy (FEG-SEM) revealed that the increase of polymers and cross-linkers concentration and the presence of drug resulted in stronger and more stable tridimensional structures. The suitable adhesiveness and high strength and elasticity of hydrogels H253IC-KT, H255IC-KT, H21053DC-KT and H21055DC-KT make them more promising materials for the design of mucoadhesive drug delivery systems.

Preparation and Characterization of Amylose Inclusion Complexes for Drug Delivery Applications.

Amylose complexes with nimesulide (NMS) and praziquantel (PZQ) were prepared by a simple and low cost method, so that high yield (>57%) and drug content (up to 68.16%) were achieved. The influence of drug:polymer ratio, temperature, and presence of palmitic acid on the complexes properties was evaluated. Differential scanning calorimetry, X-ray diffraction, and nuclear magnetic resonance data evidenced the drug-polymer interaction and the formation of inclusion complexes with semi-crystalline structures related to type II complexes. The drug release rates from complexes were lowered in acid media (pH 1.2) and phosphate buffer (pH 6.9). The presence of pancreatin promoted a significant acceleration of the release rates of both drugs, evidencing the enzymatic degradability of these complexes. The highest enzymatic resistance of PZQ1:30PA60°C complex makes the release time longer and the full release of PZQ in phosphate buffer with pancreatin occurred at 240 min, whereas the complexes with NMS and PZQ1:5PA90°C did it in 60 min. According to the Weibull model, the drug release process in media without enzyme occurred by complex mechanisms involving diffusion, swelling, and erosion. In media containing pancreatin, generally, the better correlation was with the first order, evidencing the acceleration of the release rates of drugs in the early stages of the test, due to enzymatic degradation.

Mucoadhesive beads of gellan gum/pectin intended to controlled delivery of drugs.

Gellan gum/pectin beads were prepared by ionotropic gelation, using Al(3+) as crosslinker. High yield (92.76%) and entrapment efficiency (52.22-88.78%) were reached. Beads exhibited high circularity (0.730-0.849) and size between 728.95 and 924.56 µm. Particle size and circularity was increased by raising polymer and crosslinker concentrations. Polymers ratio did not influence beads properties. The materials stability and the absence of drug-polymers interactions were evidenced by thermal analysis and FTIR. The high beads mucoadhesiveness was evidenced by in vitro and ex vivo tests. The erosion of beads was greater in acid media while swelling was more pronounced in pH 7.4. Drug release was dependent on pH in which samples 11H1-3, 11H1-5 and 41H1-3 released only 34%, 20% and 22% of ketoprofen in pH 1.2, while in pH 7.4 the drug release was sustained up to 360 min. Korsmeyer-Peppas model demonstrated that drug release occurred according to super case-II transport.

A novel automated alternating current biosusceptometry method to characterization of controlled-release magnetic floating tablets of metronidazole.

CONTEXT: Alternating Current Biosusceptometry is a magnetically method used to characterize drug delivery systems. This work presents a system composed by an automated ACB sensor to acquire magnetic images of floating tablets. OBJECTIVE: The purpose of this study was to use an automated Alternating Current Biosusceptometry (ACB) to characterize magnetic floating tablets for controlled drug delivery. MATERIALS AND METHODS: Floating tablets were prepared with hydroxypropyl methylcellulose (HPMC) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and ferrite as magnetic marker. ACB was used to characterize the floating lag time and the tablet hydration rate, by quantification of the magnetic images to magnetic area. Besides the buoyancy, the floating tablets were evaluated for weight uniformity, hardness, swelling and in vitro drug release. RESULTS: The optimized tablets were prepared with equal amounts of HPMC and ferrite, and began to float within 4 min, maintaining the flotation during more than 24 h. The data of all physical parameters lied within the pharmacopeial limits. Drug release at 24 h was about 40%. CONCLUSIONS: The ACB results showed that this study provided a new approach for in vitro investigation of controlled-release dosage forms. Moreover, using automated ACB will also be possible to test these parameters in humans allowing to establish an in vitro.in vivo correlation (IVIVC).

Films from resistant starch-pectin dispersions intended for colonic drug delivery.

Free films were obtained by the solvent casting method from retrograded starch-pectin dispersions at different polymer proportions and concentrations with and without plasticizer. Film forming dispersions were characterized according to their hardness, birefringence and rheological properties. The polymer dispersions showed a predominantly viscous behavior (G″>G') and the absence of plasticizers lead to building of stronger structures, while the occurrence of Maltese crosses in the retrograded dispersions indicates the occurrence of a crystalline organization. Analyses of the films included mechanical properties, thickness, superficial and cross sectional morphology, water vapor permeability, liquid uptake ability, X-ray diffractometry, in vitro dissolution and enzymatic digestion. The high resistant starch content (65.8-96.8%) assured the resistance of materials against enzymatic digestion by pancreatin. Changes in the X-ray diffraction patterns indicated a more organized and crystalline structure of free films in relation to isolated polymers. Increasing of pectin proportion and pH values favored the dissolution and liquid uptake of films. Films prepared with lower polymer concentration presented better barrier function (WVP and mechanical properties).

Development and in vitro evaluation of coated pellets containing chitosan to potential colonic drug delivery.

In this work pellets containing chitosan for colonic drug delivery were developed. The influence of the polysaccharide in the pellets was evaluated by swelling, drug dissolution and intestinal permeation studies. Drug-loaded pellets containing chitosan as swellable polymer were coated with an inner layer of Kollicoat(®) SR 30 D and an outer layer of the enteric polymer Kollicoat(®) MAE 30 DP in a fluidized-bed apparatus. Metronidazole released from pellets was assessed using Bio-Dis dissolution method. Swelling, drug release and intestinal permeation were dependent on the chitosan and the coating composition. The drug release data fitted well with the Weibull equation, indicating that the drug release was controlled by diffusion, polymer relaxation and erosion occurring simultaneously. The film coating was found to be the main factor controlling the drug release and the chitosan controlling the drug intestinal permeation. Coated pellets containing chitosan show great potential as a system for drug delivery to the colon.

Preparation and characterization of free films of high amylose/pectin mixtures cross-linked with sodium trimetaphosphate.

High amylose and pectin were mixed at 1:1 mass ratio and cross-linked with sodium trimetaphosphate (STMP) in alkaline medium. Films were prepared from aqueous dispersions of these cross-linked polymer blend at three different concentrations (3, 4 and 5%), by solvent casting method. Characterization of the films included thickness, surface morphology, water uptake, water vapor permeability (WVP), tensile strength measurements and enzymatic digestion. The cross-linking allowed to obtain films with improved mechanical properties and reduced WVP. The high resistance to enzymatic digestion exhibited by these films represents a promising approach to their application in the development of colon drug delivery systems.

Mucoadhesive drug delivery systems / Sistemas de entrega de drogas mucoadesiva

Drug actions can be improved by developing new drug delivery systems, such as the mucoadhesive system. These systems remain in close contact with the absorption tissue, the mucous membrane, releasing the drug at the action site leading to a bioavailability increase and both local and systemic effects. Mucoadhesion is currently explained by six theories: electronic, adsorption, wettability, diffusion, fracture and mechanical. Several in vitro and in vivo methodologies are proposed for studying its mechanisms. However, mucoadhesion is not yet well understood. The aim of this study was to review the mechanisms and theories involved in mucoadhesion, as well as to describe the most-used methodologies and polymers in mucoadhesive drug delivery systems.

O efeito de fármacos pode ser potencializado através do desenvolvimento de novos sistemas de liberação como os sistemas mucoadesivos. Estes sistemas permanecem em contato íntimo com o tecido de absorção, as mucosas, liberando o fármaco no local de ação, com o consequente aumento da biodisponibilidade, podendo promover efeitos locais e sistêmicos. A mucoadesão, atualmente, é explicada por seis teorias, a eletrônica, da adsorção, da molhabilidade, da difusão, da fratura e a mecânica. Para estudar seus mecanismos e quantificá-la, são propostas várias metodologias in vitro e in vivo. Porém, a mucoadesão ainda não é totalmente compreendida. Esse trabalho tem por objetivo revisar os mecanismos e as teorias envolvidas na mucoadesão, além de descrever as metodologias e os polímeros mais utilizados em sistemas mucoadesivos para liberação de fármacos.

Thermoanalytical study of praziquantel-loaded PLGA nanoparticles

Polymeric nanoparticles have received great attention as potential controlled drug delivery systems. Biodegradable polymers has been extensively used in the development of these drug carriers, and the polyesters such as polylactic acid, polyglycolic acid and their copolymers as poly-lactide-co-glycolide are the most used, considering its biocompatibility and biodegradability. Thermal analysis techniques have been used for pharmaceutical substances for more than 30 years and are routine methods for screening drug-excipient interactions. The aim of this work is to use thermal analysis to characterize PLGA nanoparticles containing a hydrophobic drug, praziquantel. The results show that the drug is in an amorphous state or in disordered crystalline phase of molecular dispersion in the PLGA polymeric matrix and that the microencapsulation process did not interfere with the chemical structure of the polymer, mantaining the structural drug integrity.

Nanopartículas poliméricas têm recebido grande atenção como potenciais sistemas de liberação controlada de fármacos. Polímeros biodegradáveis são extensivamente usados no desenvolvimento destes sistemas e os poliésteres como ácido poli-láctico e o glicólico, e seus copolímeros, como o ácido poli(láctico-co-glicólico) são os mais usados considerando sua biocompatibilidade e biodegradação. Técnicas de análise térmicas são usadas para substâncias farmacêuticas há mais de 30 anos e são métodos rotineiros para investigação de interações fármaco-excipiente. O objetivo deste trabalho é usar análise térmica para caracterizar nanopartículas de PLGA contendo um fármaco hidrofóbico, o praziquantel. Os resultados mostram que o fármaco apresenta-se em estado amorfo ou em fase cristalina desordenada de dispersão molecular na matriz polimérica e que o processo de microencapsulação não interfere na estrutura química do polímero e manteve a integridade estrutural do fármaco.

Development of praziquantel-loaded PLGA nanoparticles and evaluation of intestinal permeation by the everted gut sac model.

Praziquantel has been shown to be highly effective against all known species of Schistosoma infecting humans. Spherical nanoparticles made of poly(D,L-lactide-co-glycolide) acid with controlled size were designed as drug carriers. Praziquantel, a hydrophobic drug, was entrapped into the polymeric nanoparticles with 30% (w/w) of theoretical loading. The nanoparticles size was approximately of 350 nm with 66% of encapsulation efficiency. The everted gut sac model shows to be efficient to evaluate the drug permeation through the intestinal membrane. The results show that free praziquantel presents 4-fold times more permeation than praziquantel-loaded PLGA nanoparticles and physical mixture. For this drug, in special, this result can be interesting, since the nanoparticulate system can behave as a drug reservoir and/or to have a more localized effect in intestinal membrane for a prolonged period of time, since great amounts of parasites can be usually found in the mesenteric veins.

Liposomes and micro/nanoparticles as colloidal carriers for nasal drug delivery.

The use of the nasal route for drug delivery has attracted much interest in recent years in the pharmaceutical field. Local and principally systemic drug delivery can be achieved by this route of administration. But the nasal route of delivery is not applicable to all drugs. Polar drugs and some macromolecules are not absorbed in sufficient concentration due to poor membrane permeability, rapid clearance and enzymatic degradation into the nasal cavity. Thus, alternative means that help overcome these nasal barriers are currently in development. Absorption enhancers such as phospholipids and surfactants are constantly used, but care must be taken in relation to their concentration. Drug delivery systems including liposomes, cyclodextrins, micro- and nanoparticles are being investigated to increase the bioavailability of drugs delivered intranasally. This review article discusses recent progress and specific development issues relating to colloidal drug delivery systems in nasal drug delivery.

Colloidal carriers for ophthalmic drug delivery.

To achieve effective drug concentration at the intended site for a sufficient period of time is a requisite desired for many drug formulations. For drugs intended to ocular delivery, its poor bioavailability is due to pre-corneal factors. Most ocular diseases are treated by topical drug application in the form of solution, suspension and ointment. However, such dosage forms are no longer sufficient to combat some ocular diseases. Intravitreal drug injection is the current therapy for disorders in posterior segment. The procedure is associated with a high risk of complications, particularly when frequent, repeated injections are required. Thus, sustained-release technologies are being proposed, and the benefits of using colloidal carriers in intravitreal injections are currently under investigation for posterior drug delivery. This review will discuss recent progress and specific development issues relating to colloidal drug delivery systems, such as liposomes, niosomes, nanoparticles, and microemulsions in ocular drug delivery.

Efeito da concentração do amido de milho na liberação de paracetamol de comprimidos / Effect of maize starch concentration on in vitro acetaminophen release from tablets

Este trabalho avaliou a influência da concentração de amido de milho nas características físicas e na liberação in vitro de paracetamol a partir de comprimidos. Os granulados foram analisados quanto à granulometria e densidades aparentes bruta e compactada e os comprimidos quanto ao peso médio, espessura, dureza, friabilidade, tempo de desintegração. Os comprimidos foram preparados a partir de granuladosnobtidos por granulação a úmido, utilizando cozimento de amido a 10 por cento como agente granulante, segundo três formulações. Embora os comprimidos obtidos tenham apresentado características dentro dos limites farmacopéicos, os resultados indicam que variações da concentração de amido provocam diferenças nos diversos parâmetros físicos estudados...

Polissacarídeos biodegradáveis úteis para a preparação de sistemas de liberaçào controlada de fármacos. Parte 1: Quitosana / Biodegradable polysaccharides useful for the preparation of controlled drug delivery systems. Part 1: Chitosan

O interesse crescente por polímeros biodegradáveis tem estímulado, recentemente, a obtenção de um grande número deles. Polímeros produzidos naturalmente, como celulose, amido, quitosana, pectina e alginato, representam materiais biodegradáveis, com baixa toxicidade e de baixo custo. Entre os polissacarídeos, a quitosana vem despertando grande interesse da pesquisa industrial e acadêmica, por suas qualidades especiais de biodegradabilidade e biocompatibilidade e, por outro lado, por sua versatilidade de emprego em diversas formas físicas em diversos produtos. Um crescimento significativo no desenvolvimento de novas formas farmacêuticas capazes de liberar o fármaco de maneira controlada e vetorizada tem sido observado nestes últimos anos. Tais formas farmacêuticas buscam, principalmente, a redução da dose de fármaco administrada e da freqüência da adminstração, a diminuição dos efeitos colaterais e a maior adesão do paciente ao tratamento. O presente artigo descreve a utilização da quitosana em produtos farmacêuticos, especialmente em sistemas de liberação controlada de fármacos.

Sistemas para liberaçäo colônica: uma alternativa para a veiculaçäo de fármacos para efeito local ou sistêmico / Colonic release systems: an alternative to carry drugs for topical or systemic effect

A presença de problemas relacionados com a administraçäo sistêmica de fármacos, como biodistribuiçäo, reduzida seletividade, necessidade de altas doses para obtençäo de níveis adequados do fármaco em locais específicos, toxicidade e efeitos colaterais indesejáveis, tem levado ao desenvolvimento de sistemas capazes de direcionar o fármaco para sítios específicos no organismo. Entre os órgäos-alvo para a vetorizaçäo de fármacos encontra-se o cólon, objetivando-se a aplicaçäo para terapias locais e sistêmicas. No desenvolvimento de sistemas de liberaçäo colônica, algumas estratégias têm sido testadas, como liberaçäo dependente do pH, controlada pela degradaçäo enzimática, pelo tempo e por pressäo. Esta revisäo apresenta uma visäo geral sobre a liberaçäo colônica de fármacos e as estratégias usadas para obtençäo desses sistemas.

Alguns fatores físicos envolvidos na compressäo e suas aplicaçöes na formulaçäo de comprimidos / Some physical factors involved in compression and their applications in tablet formulation

Os aspectos básicos relacionados com a física da compressäo e suas possibilidades de aplicaçäo prática no desenvolvimento de formulaçöes para comprimidos säo discutidos no presente artigo. Assim, säo revisados aspectos como a distribuiçäo de forças no processo de compressäo, o efeito da compressäo na deformaçäo de partículas bem como a influência desta deformaçäo na aglutinaçäo interparticular, os mecanismos básicos de estabilizaçäo física do compacto formado, a avaliaçäo da comprimibilidade de sistemas particulados sólidos e o efeito dos atritos por fricçäo no processo de compressäo.

Celulose fibrosa do bagaço da cana-de-açúcar: avaliaçäo da açäo aglutinante/desagregante em comprimidos contendo fármaco hidrossolúvel / Fibrous cellulose of sugar cane bagasse: valuation of the binder/disintegrating action in tablets that contain water-soluble drug

Uma celulose fibrosa obtida do bagaço de cana-de-açúcar foi analisada, no presente trabalho, quanto à sua açäo aglutinante/desagregante e quanto ao seu grau de interferência na liberaçäo de princípios ativos ("in vitro"), quando incorporada em um sistema compactado incluído de um fármaco hidrossolúvel. Empregou-se como fármaco referência o carbonato de lítio, considerando sua hidrossolubilidade e suas más qualidades de compressibilidade e escoamento. A celulose em questäo foi avaliada em estudo comparativo, envolvendo outra celulose fibrosa correntemente utilizada na obtençäo de comprimidos (Microcel 3E-200). Após a experimentaçäo em metodologias de granulaçäo a seco e a úmido, concluiu-se que as celuloses ensaiadas apresentam adequada eficiência aglutinante e desagregante e que säo equivalentes quanto a estes aspectos

Micro e nanocápsulas: um eficiente sistema, com dimensöes reduzidas, para liberaçäo controlada e direcionamento de fármacos encapsulados / Micro-and nanocapsules: an efficient reduced size system for controlled release and target entrapped drugs

Micro e nanocápsulas/esferas säo sistemas modernos e adequados para a administraçäo controlada e seletiva de compostos de uso terapêutico ou para fins de diagnóstico. As evidências experimentais descritas na literatura demonstram o sucesso destes agregados no transporte de grande variedade de fármacos, tais como enzimas, hormônios, antibióticos, anticancerígenos, antifúngicos, antiinflamatórios, analgésicos, entre outros, para administraçäo oral e parenteral. Apresentamos os processos usuais de obtençäo e vários exemplos de aplicaçöes farmacêuticas, assim como säo discutidos alguns problemas da tecnologia destas estruturas

Celulose fibrosa microfina do bagaço de cana-de-açúcar: análise da aplicabilidade como excipiente aglutinante/desagregante de comprimidos / Microfine fibrous cellulose of sugar cane bagasse: analysis of applicability like binder/disintegrant excipient of tablets

Uma celulose fibrosa microfina, obtida a partir do bagaço de cana-de-açúcar, foi investigada quanto à sua aplicabilidade com excipiente aglutinante/desagregante de comprimidos. Utilizou-se, como parâmetro de comparaçäo, uma celulose de mercado designada pela marca Microcel 3E-200 (Cellulose fibrosa microfina). Do estudo comparativo concluiu-se que a celulose de cana possui características adequadas para aplicaçäo como excipiente aglutinante/desagregante. Os resultados demostraram que o produto em estudo apresenta, em relaçäo à celulose padräo, maior eficiência desagregante e menor poder aglutinante

Dispersöes de carboximetilcelulose e hidroxietilcelulose como veículos estruturados esterilizados: comportamento reológico versus esterilizaçäo pelo calor úmido (AU) / Dispersions of carboxymethylcellulose and hidroxyethylcellulose as structured and sterilized vehicles: rheological behaviour versus moist heat Sterilization method (AU)

Investigou-se comparativamente o comportamento reológico de dispersöes de carboximetilcelulose sódica A.V. e Hidroxietilcelulose (cellosize-QP 15MH) a 0,5, 1,0, e 2,0 por cento, considerando o efeito produzido pelo aquecimento em processos de esterilizaçäo que aplicam calor úmido (vapor sob pressäo e vapor fluente). Procurou-se quantificar o comportamento reológico, antes e após processos de esterilizaçäo, objetivando qualificar os referidos produtos no que tange à sua aplicaçäo na forma de veículos estruturados esterilizados. Os resultados evidenciaram que: a) as dispersöes consideradas apresentaram uma similar perda de consistência independentemente do método de esterilizaçäo aplicado; b) apesar de diminuiçäo de consistência, as características reológicas, concernentes à pseudoplasticidade e tixotropia, foram relativamente bem mantidas; c) as dispersöes apresentaram diferentes graus de reversibilidade de consistência com nítidas vantagens para as dispersöes de hidroxietilcelulose