Biodegradable microparticulate drug delivery system of diltiazem HCl

A eficácia terapêutica de um fármaco depende da manutenção de seu nível plasmático adequado em determinado intervalo de tempo. Nesse sentido, a liberação modificada de fármacos está disponível em muitas vias de administração e oferece muitas vantagens (como micropartículas e nanopartículas) quando comparada às formulações de liberação imediata. Essas vantagens incluem reduzida frequência da dosagem, melhor controle terapêutico e menos efeitos colaterais. Assim sendo, esses produtos apresentam maior aceitação pelos pacientes. Os avanços na ciência dos materiais, na engenharia das partículas, em manufatura e em nanotecnologia permitiram a introdução no mercado de vários produtos de liberação modificada e vários outros se encontram em desenvolvimento pré-clínico e clínico. O objetivo do presente trabalho foi preparar e avaliar o fármaco cloridrato de diltiazem associado a micropartículas de albumina utilizando planejamento fatorial. As micropartículas de albumina, um polímero natural, foram preparadas por método de emulsão empregando estabilização por calor. As formulações selecionadas foram caracterizadas no que se refere à sua eficiência de encapsulamento, tamanho médio de partículas, morfologia de superfície e perfil de liberação do fármaco. A análise de variância relativa à eficiência de encapsulamento indicou superfície de resposta linear. Com referência à morfologia superficial, essa foi avaliada empregando microscopia eletrônica de varredura. Essa análise revelou micropartículas esféricas, não porosas e de aparência uniforme, com superfície lisa. O diâmetro médio das micropartículas foi entre 2 e 9 µm, sendo que mais de 75% das micropartículas se apresentaram abaixo de 3,5 µm. Além disso, a eficiência de encapsulamento foi entre 59,74 e 72,48%. Quanto ao ensaio para avaliação do perfil de liberação in vitro do fármaco associado às micropartículas, as formulações apresentaram liberação lenta até 24 horas. O comportamento foi caracterizado por liberação inicial (efeito burst) seguida por liberação lenta. Todas as fórmulas selecionadas apresentaram liberação prolongada por aproximadamente 24 horas. Na comparação entre os valores de coeficientes de regressão (R²), os modelos propostos por Hixson Crowel, Higuchi e Peppas, para diferentes formulações de micropartículas, demonstraram cinética de liberação de acordo com modelo Fickiano e não-Fickiano. O mecanismo de liberação do fármaco foi regulado pela razão entre o fármaco e o polímero. A análise estatística revelou significativo aumento da eficiência de encapsulamento quando essa razão aumentou. As avaliações relativas à análise dimensional das micropartículas, à eficiência de encapsulamento do fármaco e à morfologia permitiram a seleção da formulação DTM-3 para os ensaios de liberação in vivo e para o estudo da estabilidade. O ensaio de liberação in vivo do fármaco associado às micropartículas demonstrou sítio-alvo preferencial no fígado, seguido pelos pulmões rins e baço. No presente estudo, as micropartículas de albumina contendo cloridrato de diltiazem foram adequadamente preparadas e orientadas satisfatoriamente para vários órgãos. Além disso, a formulação selecionada apresentou estabilidade físico-química a 4 ºC.The efficacy of a drug in a specific application requires the maintenance of appropriate drug blood level concentration during a prolonged period of time. Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. The objective of this work is to prepare and evaluate diltiazem HCl loaded albumin microparticles using a factorial design. Albumin (natural polymer) microparticles were prepared by emulsion heat-stabilization method. Selected formulations were characterized for their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance for entrapment efficiency indicates that entrapment efficiency is best fitted to a response surface linear model. Surface morphology was studied by scanning electron microscopy. Scanning electron microscopy of the microparticles revealed a spherical, nonporous and uniform appearance, with a smooth surface. The geometric mean diameter of the microparticles was found to be 2-9 µm, which more than 75% were below 3.5 µm and drug incorporation efficiency of 59.74 to 72.48% (w/w). In vitro release profile for formulations containing diltiazem HCl loaded BSA microparticles with heat stabilization technique shows slow controlled the release of the drug up to 24 hours. The release pattern was biphasic, characterized by an initial burst effect followed by a slow release. All selected microparticles exhibited a prolonged release for almost 24 hours. On comparing regression-coefficient (r²) values for Hixson Crowel, Higuchi and Peppas kinetic models, different batches of microparticles showed Fickian, non-Fickian, and diffusion kinetics. The release mechanism was regulated by D:P ratio. From the statistical analysis it was observed that as the drug:polymer (D:P) ratio increased, there was a significant increase in the encapsulation efficiency. Based on the particle size, entrapment efficiency and physical appearance, DTM-3 formulations were selected for in vivo release study and stability study. The in vivo result of drug loaded microparticles showed preferential drug targeting to liver followed by lungs, kidneys and spleen. Stability studies showed that maximum drug content and closest in vitro release to initial data were found in the formulation stored at 4 ºC. In present study, diltiazem HCl loaded BSA microparticles were prepared and targeted to various organs to satisfactory level and were found to be stable at 4 ºC

Biodegradable microparticulate drug delivery system of diltiazem HCl

The efficacy of a drug in a specific application requires the maintenance of appropriate drug blood level concentration during a prolonged period of time. Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. The objective of this work is to prepare and evaluate diltiazem HCl loaded albumin microparticles using a factorial design. Albumin (natural polymer) microparticles were prepared by emulsion heat-stabilization method. Selected formulations were characterized for their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance for entrapment efficiency indicates that entrapment efficiency is best fitted to a response surface linear model. Surface morphology was studied by scanning electron microscopy. Scanning electron microscopy of the microparticles revealed a spherical, nonporous and uniform appearance, with a smooth surface. The geometric mean diameter of the microparticles was found to be 2-9 µm, which more than 75% were below 3.5 µm and drug incorporation efficiency of 59.74 to 72.48% (w/w). In vitro release profile for formulations containing diltiazem HCl loaded BSA microparticles with heat stabilization technique shows slow controlled the release of the drug up to 24 hours. The release pattern was biphasic, characterized by an initial burst effect followed by a slow release. All selected microparticles exhibited a prolonged release for almost 24 hours. On comparing regression-coefficient (r²) values for Hixson Crowel, Higuchi and Peppas kinetic models, different batches of microparticles showed Fickian, non-Fickian, and diffusion kinetics. The release mechanism was regulated by D:P ratio. From the statistical analysis it was observed that as the drug:polymer (D:P) ratio increased, there was a significant increase in the encapsulation efficiency. Based on the particle size, entrapment efficiency and physical appearance, DTM-3 formulations were selected for in vivo release study and stability study. The in vivo result of drug loaded microparticles showed preferential drug targeting to liver followed by lungs, kidneys and spleen. Stability studies showed that maximum drug content and closest in vitro release to initial data were found in the formulation stored at 4 ºC. In present study, diltiazem HCl loaded BSA microparticles were prepared and targeted to various organs to satisfactory level and were found to be stable at 4 ºC.A eficácia terapêutica de um fármaco depende da manutenção de seu nível plasmático adequado em determinado intervalo de tempo. Nesse sentido, a liberação modificada de fármacos está disponível em muitas vias de administração e oferece muitas vantagens (como micropartículas e nanopartículas) quando comparada às formulações de liberação imediata. Essas vantagens incluem reduzida frequência da dosagem, melhor controle terapêutico e menos efeitos colaterais. Assim sendo, esses produtos apresentam maior aceitação pelos pacientes. Os avanços na ciência dos materiais, na engenharia das partículas, em manufatura e em nanotecnologia permitiram a introdução no mercado de vários produtos de liberação modificada e vários outros se encontram em desenvolvimento pré-clínico e clínico. O objetivo do presente trabalho foi preparar e avaliar o fármaco cloridrato de diltiazem associado a micropartículas de albumina utilizando planejamento fatorial. As micropartículas de albumina, um polímero natural, foram preparadas por método de emulsão empregando estabilização por calor. As formulações selecionadas foram caracterizadas no que se refere à sua eficiência de encapsulamento, tamanho médio de partículas, morfologia de superfície e perfil de liberação do fármaco. A análise de variância relativa à eficiência de encapsulamento indicou superfície de resposta linear. Com referência à morfologia superficial, essa foi avaliada empregando microscopia eletrônica de varredura. Essa análise revelou micropartículas esféricas, não porosas e de aparência uniforme, com superfície lisa. O diâmetro médio das micropartículas foi entre 2 e 9 µm, sendo que mais de 75% das micropartículas se apresentaram abaixo de 3,5 µm. Além disso, a eficiência de encapsulamento foi entre 59,74 e 72,48%. Quanto ao ensaio para avaliação do perfil de liberação in vitro do fármaco associado às micropartículas, as formulações apresentaram liberação lenta até 24 horas. O comportamento foi caracterizado por liberação inicial (efeito burst) seguida por liberação lenta. Todas as fórmulas selecionadas apresentaram liberação prolongada por aproximadamente 24 horas. Na comparação entre os valores de coeficientes de regressão (R²), os modelos propostos por Hixson Crowel, Higuchi e Peppas, para diferentes formulações de micropartículas, demonstraram cinética de liberação de acordo com modelo Fickiano e não-Fickiano. O mecanismo de liberação do fármaco foi regulado pela razão entre o fármaco e o polímero. A análise estatística revelou significativo aumento da eficiência de encapsulamento quando essa razão aumentou. As avaliações relativas à análise dimensional das micropartículas, à eficiência de encapsulamento do fármaco e à morfologia permitiram a seleção da formulação DTM-3 para os ensaios de liberação in vivo e para o estudo da estabilidade. O ensaio de liberação in vivo do fármaco associado às micropartículas demonstrou sítio-alvo preferencial no fígado, seguido pelos pulmões rins e baço. No presente estudo, as micropartículas de albumina contendo cloridrato de diltiazem foram adequadamente preparadas e orientadas satisfatoriamente para vários órgãos. Além disso, a formulação selecionada apresentou estabilidade físico-química a 4 ºC

Razvoj i biofarmaceutsko vrednovanje pripravka za povećano oslobađanje tramadol hidroklorida na principu osmotske tehnologije

Extended release formulation of tramadol hydrochloride (TRH) based on osmotic technology was developed and evaluated. Target release profile was selected and different variables were optimized to achieve the same. Formulation variables like level of swellable polymer, plasticizer and the coat thickness of semipermeable membrane (SPM) were found to markedly affect the drug release. TRH release was directly proportional to the levels of plasticizer but inversely proportional to the levels of swellable polymer and coat thickness of SPM. Drug release from developed formulations was independent of pH and agitation intensity but dependent on osmotic pressure of the release media. In vivo study was also performed on six healthy human volunteers and various pharmacokinetic parameters (cmax, tmax, AUC0-24, MRT) and relative bioavailability were calculated. The in vitro and in vivo results were compared with performance of two commercial tablets of TRH. The developed formulation provided more prolonged and controlled TRH release as compared to marketed formulation. In vitro-in vivo correlation (IVIVC) was analyzed according to Wagner-Nelson method. The optimized formulation (batch IVB) exhibited good IVIV correlation (R = 0.9750). The manufacturing procedure was found to be reproducible and formulations were stable during 6 months of accelerated stability testing.U radu je opisana priprava i evaluacija pripravaka tramadol hidroklorida (TRH) na principu osmotske tehnologije. Da bi se postigao željeni profil oslobađanja mijenjane su različite varijable. Pokazalo se da najveći utjacaj na oslobađanje ljekovite tvari imaju udjeli polimera koji bubri, plastifikatora i debljina ovojnice polupropusne membrane (SPM). TRH oslobađanje bilo je proporcionalno udjelu plastifikatora, a obrnuto proporcionalno udjelu polimera i vrijednosti SPM. Oslobađanje ljekovite tvari bilo je neovisno o pH i intenzitetu miješanja, a ovisno o osmotskom talku medija. U in vivo studiji provedenoj na šest zdravih volontera određeni su farmakokinetički parametri (cmax, tmax, AUC0-24, MRT) i izračunata relativna bioraspoloživost. Rezultati dobiveni u pokusima in vitro i in vivo uspoređeni su s dvije vrste komercijalno dostupnih tableta TRH: oslobađanje ljekovite tvari iz pripravka razvijenog u ovom radu bilo je dulje i više kontrolirano. In vitro-in vivo korelacija (IVIVC) je analizirana prema Wagner-Nelsonovoj metodi. Optimizirani pripravak (IVB) pokazao je dobru IVIV korelaciju (R = 0,9750). Proizvodni proces je bio reproducibilan i pripravci su bili stabilni tijekom 6 mjeseci u uvjetima ubrzanog starenja

Priprava i in vitro karakterizacija plutajućih zrnaca acetohidroksamske kiseline za iskorjenjivanje H. pylori

Gellan based floating beads of acetohydroxamic acid (AHA) were prepared by the ionotropic gellation method to achieve controlled and sustained drug release for treatment of Helicobacter pylori infection. The prepared beads were evaluated for diameter, surface morphology and encapsulation efficiency. Formulation parameters like concentrations of gellan, chitosan, calcium carbonate and the drug influenced the in vitro drug release characteristics of beads. Drug and polymer interaction studies were carried out using differential scanning calorimetry. Chitosan coating increased encapsulation efficiency of the beads and reduced the initial burst release of the drug from the beads. Kinetic treatment of the drug release data revealed a matrix diffusion mechanism. Prepared floating beads showed good antimicrobial activity (in vitro H. pylori culture) as potent urease inhibitors. In conclusion, an oral dosage form of floating gellan beads containing AHA may form a useful stomach site specific drug delivery system for the treatment of H. pylori infection.Metodom ionotropskog želiranja pripravljena su plutajuća zrnca acetohidroksamske kiseline (AHA) na bazi gelana za kontrolirano i usporeno oslobađanje ljekovite tvari, namijenjena za liječenje infekcija uzrokovanih Helicobacter pylori. Pripravljenim zrncima proučavani su dijametar, površinska morfologija i sposobnost inkapsuliranja. Koncentracija gelana, kitozana, kalcijeva karbonata i ljekovite tvari utjecala je na oslobađanje in vitro. Interakcija između ljekovite tvari i polimera praćena je diferencijalnom pretražnom kalorimetrijom. Oblaganje zrnaca kitozanom povećalo je učinkovitost inkapsuliranja i smanjilo početno naglo oslobađanje. Oslobađanje ljekovite tvari slijedilo je mehanizam difuzije matriksa. Plutajuća zrnca s AHA pokazala su antimikrobno djelovanje in vitro na kulturi H. pylori kao snažni inhibitori ureaze. Može se zaključiti da su plutajuća zrnca s AHA na bazi gelana pogodna za specifičnu isporuku u želucu te korisna u terapiji infekcija uzrokovanih H. pylori

Mucoadhesive microparticles as potential carriers in inhalation delivery of doxycycline hyclate: a comparative study

The present work compares and evaluates the suitability of different polymer-based microparticles for inhalation delivery of doxycycline hyclate. Mucoadhesive polymers, such as sodium carboxymethyl cellulose, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, starch, and carbopol were selected as carriers for inhalation delivery. Microparticles were prepared by spray drying and evaluated in terms of yield, moisture content, morphology, tapped density, encapsulation efficiency, in vitro mucoadhesion, thermal properties and in vitro aerosolization performance. Additionally, the cytotoxicity of the microparticles on H1299 human alveolar cell line was examined. Smooth spherical to collapsed doughnut shaped particles were formed. They exhibited tap densities of 0.202–0.502 g/cm3 and mass median aerodynamic diameter of 3.74–6.54 μm. Mucoadhesion was highest in case of carbopol-based microparticles. Drug release from these microparticles exhibited biphasic Fickian type of diffusion. Only at the highest concentration of microparticles (1 mg/mL) less than 90% cell viability was seen in DX loaded sodium alginate microparticles (DXSA, 87.2%), starch microparticles (DXST, 85.1%) and carbopol microparticles (DXCP, 82.7%) preparations after 48 h of exposure to alveolar cells. The results clearly indicate that sodium carboxymethyl cellulose-based microparticles may serve as an ideal carrier for inhalation delivery of doxycycline hyclate

Mouth Dissolving Tablets I: An Overview of Formulation Technology

Methods to improve patient’s compliance have always attracted scientists towards the development of fancy oral drug delivery systems. Among them, mouth dissolving drug delivery systems (MDDDS) have acquired an important position in the market by overcoming previously encountered administration problems and contributing to extension of patent life. MDDDS have the unique property of rapidly disintegrating and/or dissolving and releasing the drug as soon as they come in contact with saliva, thus obviating the requirement of water during administration. Therefore, these dosage forms have lured the market for a certain section of the patient population which include dysphagic, bed ridden, psychic, geriatric and paediatric patients. Several techniques have been developed in the recent past, to improve the disintegration quality of these delicate dosage forms without affecting their integrity. This article focuses on the technologies available and the advances made so far in the field of fabrication of mouth dissolving tablets. Apart from the conventional methods of fabrication, this review also provides the detailed concept of some unique patented technologies like Zydis, Lyoc, Quicksolv, Orasolv, Durasolv, Flashtab, Oraquick, Wowtab and Ziplet alongwith their advantages and limitations

Mouth Dissolving Tablets II: An Overview of Evaluation Techniques

Mouth dissolving tablets are well established dosage forms available in the market. The numerous advantages that they offer to the patients in terms of compliance as well as to the manufacturers in terms of huge revenues by line extension of products are well known. In spite of such popularity, there seems to be lack of a standardized system to characterize these dosage forms. Enormous work has been done in this field, wherein some of the researchers have developed their own methods of evaluation. This article attempts to present a detailed review regarding technological advances made so far in the area of evaluation of mouth dissolving tablets with respect to special characteristics of these unique dosage forms. In the absence of any available standardized method, the author’s recommendation on critical issues in the field may be considered