Formulation and optimization of floating matrix tablets of clarithromycin using simplex lattice design

The purpose of the present study was to prepare floating matrix tablets of clarithromycin employing simplex lattice design. Hydroxypropyl methylcellulose [HPMC] and Ethyl Cellulose [EC] were used as matrix forming agents; sodium bicarbonate and citric acid as effervescence producing agents. Simplex lattice design was used as optimization technique employing three independent formulation variables viz. concentration of HPMC [X[1]], Citric Acid [X[2]], EC [X[3]] whereas floating lag time, t[50%], t[90%], and MDT [Mean Dissolution Time] were the response [dependent] variables. Seven formulations [F1-F7] were prepared and evaluated for dissolution studies, floating characteristics, weight variation, hardness, thickness, friability.t[50%] of the formulations was found to be ranging from 317 +/- 2.54 to 522 +/- 2.39 minutes. The t[90%] and MDT of the tablets were found to be ranging between 659.65 +/- 1.89 to 967.35 +/- 1.67 minutes and 527.20 +/- 1.22 to 846.78 +/- 2.61 minutes respectively. Total floating time of the formulations was more than 12 hours and the drug content was in the range of 98.54 +/- 0.46 to 99.92 +/- 0.32. The amount of both HPMC and EC were found to play a dominating role in controlling the release of the drug from the formulation whereas ratios of sodium bicarbonate and citric acid were showing significant effect on the floating lag time. The release exponent [n] from Korsmeyer-Peppas model was found to be between 0.62 and 0.75 indicating non-Fickian or anomalous drug release behavior from the formulated floating matrix tablets. Simplex lattice design was reported to be an effective optimization technique for optimizing pharmaceutical formulations against desired responses

simple and rapid approach to evaluate the in vitro in vivo role of release controlling agent ethyl cellulose ether derivative polymer

Diclofenac sodium [DCL-Na] conventional oral tablets exhibit serious side effects when given for a longer period leading to noncompliance. Controlled release matrix tablets of diclofenac sodium were formulated using simple blending [F-1], solvent evaporation [F-2] and co-precipitation techniques [F-3]. Ethocel[R] Standard 7 FP Premium Polymer [15%] was used as a release controlling agent. Drug release study was conducted in 7.4 pH phosphate buffer solutions as dissolution medium in vitro. Pharmacokinetic parameters were evaluated using albino rabbits. Solvent evaporation technique was found to be the best release controlling technique thereby prolonging the release rate up to 24 hours. Accelerated stability studies of the optimized test formulation [F-2] did not show any significant change [p<0.05] in the physicochemical characteristics and release rate when stored for six months. A simple and rapid method was developed for DCL-Na active moiety using HPLC-UV at 276nm. The optimized test tablets [F-2] significantly [p<0.05] exhibited peaks plasma concentration [C[max]=237.66 +/- 1.98] and extended the peak time [t[max]=4.63 +/- 0.24]. Good in-vitro in vivo correlation was found [R[2] =0.9883] against drug absorption and drug release. The study showed that once-daily controlled release matrix tablets of DCL-Na were successfully developed using Ethocel[R] Standard 7 FP Premium

investigation into the drug release from ibuprofen matrix tablets with ethylcellulose and some poly-acrylate polymers

This study was performed to achieve sustained-release Ibuprofen matrix tablets with a zero-order release kinetic while most of the previous formulations have shown Higuchi release kinetic. Considering the results from previous studies, ethyl cellulose, Carbopol 934P, Carbopol 974P, and Pemulen TR-1 were used at different amounts for preparation of the tablets by direct compression. The release profiles were studied in a two-stage release test using nonlinear regression analysis. Carbopols 934P and 974P could not sustain the release adequately while Pemulen TR-1 had too strong sustaining effect. Therefore, combination formulations were considered and studied. The release profiles of ethyl cellulose formulation and the combination formulation consisting Carbopol 934P and Pemulen TR-1 best fitted in Higuchi model, although the zero-order model was not completely rejected. However, the kinetic model of release from the combination formulation consisting Carbopol 974P and Pemulen TR-1 changed to zero-order indicating the most constant release rate among formulations. This was speculated to be due to some erosion of the gel, as well as some interaction of the hydrophobic chain of Pemulen TR-1 with Ibuprofen. Therefore, this formulation is suggested for directly compressed sustained-release matrix tablets of Ibuprofen with a more constant release rate.

Optimization of Gabapentin Release and Targeting Absorption, Through Incorporation into Alginate Beads.

Aims: 1) To study the effect of some formulation variables on drug load, encapsulation efficiency, swelling ratio, mucoadhesion and drug release. 2) Optimize the mucoadhesion capabilities for targeting drug absorption and release-controlling capabilities of alginate beads. Methodology: Alginate beads were prepared by dripping sodium alginate gel into calcium chloride solution and then dried overnight at ambient temperature. The effects of alginate concentration, cross linker concentration, cross linking time, volume of cross linking solution and drug/polymer ratio on drug load, encapsulation efficiency, swelling ratio, mucoadhesion and drug release were investigated. Formulae containing sodium lauryl sulfate (SLS), gabapentin-ethylcellulose solid dispersion, mixture of free drug and solid dispersion were prepared for modifying the drug release rate. Results: Mucoadhesion of alginate beads was shown to be decreased upon adding SLS (30% after 8 hrs). Drug release was so fast (92.46% after 2 hrs). The incorporation of solid dispersion has led to well accepted mucoadhesion (74.44% after 8 hrs) as well as release properties (93.35% after 10 hrs) Beads containing mixtures of drug and ethylcellulose-drug solid dispersion showed acceptable mucoadhesion (74.44% after 8 hrs) and control of gabapentin release (93.35% after 10 hrs). Statistical analysis of variance between groups was performed using the one-way layout ANOVA with duplication. Significant differences in mean values were evaluated by Student's unpaired t test (P < 0.05). Conclusion: A finally optimized formula was suggested by incorporating a combination of solid dispersion and free gabapentin in alginate system to achieve burst release of gabapentin and hence fast effect (33.417% was released during the first 30 minutes in fasting-simulated conditions) and controlled release (91.217% after 6 hrs).

Encapsulation of theophylline into binary blend of ethylcellulose and eudragit microparticles: development, characterization and kinetic release

The objective of this study was to prepare and evaluate microparticles of Eudragit and Ethyl cellulose binary blend loaded with theophylline for controlled release. Microparticles were prepared by Phase separation method. The method is quite simple, rapid, and economical and does not imply the use of toxic organic solvents. Solid, discrete, reproducible free flowing microparticles were obtained. The yield of the microparticles was up to 92%. More than 85% of the isolated microparticles were of particle size range of 325 to 455 micro m. The obtained angle of repose,% carr's index and tapped density values were well within the limits, indicating that prepared microparticles had smooth surface, free flowing and good packing properties. Scanning Electron Microscopy photographs and calculated sphericity factor confirms that the prepared formulations are spherical in nature. Prepared microparticles were sTab. and compatible, as confirmed by DSC and FT-IR studies. The prepared formulations were quantitatively analyzed for the amount of encapsulated drug. It was observed that there is no significant release of the drug at gastric pH. The drug release was controlled more than 12 h. Intestinal drug release from microparticles was studied and compared with the release behavior of commercially available oral formulation Duralyn CR 400. The release kinetics followed different transport mechanisms

Consequences of formulation variables on physicochemical properties of indinavir sulfate microspheres

Indinavir sulfate with ethyl cellulose microspheres was successfully prepared by an oil-in-oil emulsion solvent evaporation technique using acetonitrile: dichloromethane [1:1] and light liquid paraffin as primary and secondary oil phases respectively with span 80 as a droplet stabilizer. In present study the effect of formulation variable e.g., polymer to drug ratio, viscosity of ethyl cellulose, volume of light liquid paraffin and effect of processing temperature on yield, encapsulation efficiency, particle size and in vitro drug release characteristics of the Indinavir microspheres were investigated. The prepared microspheres were spherical with stable nature of drug within the formulations confirmed by Fourier transform infrared spectra. The mean sphere diameter and encapsulation efficiencies depended strongly on the drug to polymer ratio, viscosity of polymer, volume of processing medium and processing temperature. The release of indinavir sulfate was diffusion controlled and influenced by the drug to polymer ratio, viscosity of polymeric phase, volume of light liquid paraffin used and processing temperature condition

Formulation and in vitro evaluation of ofloxacin-ethocel controlled release matrix tablets prepared by wet granulation method: influence of co-excipients on drug release rates

Being controlled release dosage forms, tablets allow an improved absorption and release profiles of Ofloxacin. The fact that drugs with fine particles size can be compressed well after wetting, so in our research studies Ofloxacin controlled release matrix tablets were prepared by wet granulation technique. In order to investigate the potential of Ethyl cellulose ether derivatives as a matrix material, Ofloxacin formulations with different types and grades of Ethocel were prepared at several drug-to-polymer ratios. The method adopted for in vitro drug release studies was USP Method-1 [rotating Basket Method] by Pharma test dissolution apparatus using phosphate buffer 7.4 pH as a dissolution medium. Various Kinetic models were employed to the formulations for the purpose of determination of release mechanism. A comparative study was performed between the tested Ofloxacin-Ethocel formulations and a standard reference obtained from the local market. FI dissimilarity factor and f2 similarity factor were applied to the formulations for the checking of dissimilarities and similarities between the tested formulations and reference standard

Preparation, characterization and in-vitro release of controlled release ketorolac tromethamine cellulose acetate butyrate microspheres

The purpose of this study was to prepare and characterize controlled release ketorolac tromethamine microspheres. To achieve this goal, cellulose acetate butyrate microspheres loaded by ketorolac tromethamine were prepared by the emulsion solvent evaporation method. The prepared ketorolac tromethamine microspheres were evaluated for their production yields, particle size distribution, morphology, drug content and drug release characteristics. Thermal Gravimetric Analysis [TGA] were performed on the drug polymer systems in order to shed a light on the possibility of solid state changes of ketorolac tromethamine with CAB. A Box-Behnken design was selected for formulating ketorolac tromethamine microspheres with revolution per minute [X1], drug-polymer ratio [X2] and span 80 percent [X3] as independent variables. Three levels of the independent variables were used which equal to-1, 0 and +1 for the above design. The values of the corresponding variables were 500, 700 and 900 rpm for the machine speed; 1:1, 1:2 and 1:3 for drug-polymer ratio; 1%, 1.5% and 2% [w/w] for span 80 percent

Preformulation compatibility study of aceclofenac with tablet excipients [natural and synthetic] using differential scanning calorimetry

Differential scanning calorimetry was used as a tool to study the tablet excipient-Aceclofenac interactions in order to assess their compatibility. Compatibility studies were carried on samples of 1:1 physical mixtures of the drug with various excipients [natural and synthetic] viz., Hydroxy propyl methyl cellulose, Ethyl cellulose, Chitosan, Eudragit, and Magnesium stearate as sustained release polymers and lubricant respectively at room temperature. Aceclofenac was found to be compatible with all the excipients viz. Hydroxy propyl methyl cellulose, Ethyl cellulose, Chitosan, Eudragit and Magnesium stearate

[Development of different formulae of sustained release metoclopramide suppositories and studying their in -vitro drug release]

Sustained release suppositories are new preparations, which may relief the patient form applying suppositories many times per a day. Metoclopramide hydrochloride is one of the commonly used medicaments, which are good candidates to be formulated as controlled release suppository, as it has short half life. The suppositories were manufactured using fusion method. The drug release profiles from these suppositories were monitored using dissolution tester. It was found that suppositories formulated form the mixture PEG / Ethyl cellulose [65:35 w:w] released Metoclopramide hydrochloride slowly, as its release time lasted for a period of time of 26 hours. Moreover, the mechanical properties of these suppositories were acceptable

comparative study of various microencapsulation techniques: effect of polymer viscosity on microcapsule characteristics

It is a comparative study of salbutamol sulpahte-ethylcellulose microcapsules prepared by three different microencapsulation techniques i.e. coacervation thermal change, solvent evaporation and coacervation nonsolvent addition by adjusting the ratio of salbutamol sulpahte to ethylcellulose. In vitro release profiles of microcapsules were studied using USP XXIV dissolution apparatus-I in 450 ml double distilled water maintained at 37°C at 50 rpm. Scanning electron microscopic results indicated that all microcapsules were aggregated, whitish and irregular in shape with good entrapment efficiency [86.34 to 97.83], production yield [87.91 +/- 1.34 to 98.33 +/- 1.37] and flow properties. Initial burst effect was observed in the drug release behavior from all microcapsules. A slight increase in actual drug loading but profound increase in mean diameter of microcapsules was observed with the increase in the viscosity of ethylcellulose. UV and FTIR spectroscopy, x-ray diffractometry and thermal analysis verified the absence of any strong chemical interaction between drugs and polymer. The drug release from all the formulations followed anomalous diffusion mechanism and was best fit to Higuchi's kinetic model. The results suggest coacervation thermal change as an appropriate approach to develop slow-release multi-unit oral dosage form of salbutamol sulpahte suggesting at least twice administration in every 24 hours

Mecanismos generales de cesión de principios activos a partir de matrices monolíticas hidrofílicas preparadas con éteres de celulosa / Overall mechanisms that rule the active pharmaceutical ingredient’s delivery process from hydrophilic matrices elaborated with ether cellulose

Las matrices hidrofílicas son uno de los sistemas de liberación controlados más empleados a escala mundial. El reconocido éxito global de este tipo de sistemas está ligado a su manufactura por medio de tecnología convencional para la obtención de comprimidos, además de su bajo costo. Estos sistemas han sido objeto de investigación desde hace ya algunas décadas, mediante el uso de técnicas como la creación de imágenes a partir de resonancia magnética, calorimetría de barrido diferencial y la espectroscopia dieléctrica de baja frecuencia, entre otras. Varios autores han estudiado los diferentes estados del agua dentro de una matriz, así como el estado y los cambios en los estados de los materiales en el tiempo, con el fin de estudiar los mecanismos de cesión de los activos a partir de las matrices, así como para buscar modelos matemáticos que describan la evolución de la concentración en el tiempo. En la actualidad se cuenta con modelos matemáticos de gran utilidad que permiten identificar dichos mecanismos a partir de un análisis de los parámetros de los modelos y que conducen finalmente a predecir la velocidad de liberación a partir de estos sistemas.

The hydrophilic matrices are one of the most used controlled delivery systems in the world, due to the simple technology and low cost. A number of publications, over the last decades, have reported investigations in regard with the mechanisms of drug release from hydrophilic matrices. Nevertheless, the mechanisms of drug release from these systems continue to be a matter of debate. Differential scanning calorimetry, low frequency dielectric spectroscopy and nuclear magnetic resonance have been used to examine the distribution of water within ether cellulose matrices, as well as to describe the state of the materials inside the device. The objective is to study the release and hydration rate of hydrophilic matrices in order to contribute to the rationalization of the design of these controlled release systems through mathematical modeling and to obtain a better knowledge of the processes that occur during the release of the drug.

Avaliação da influência de adjuvantes não-poliméricos solúveis na liberação do nimodipino a partir de formulações matriciais de liberação prolongada / Evaluation of soluble non-polymeric adjuvants in the release of nimodipino from controlled release matrices formulations

Fármacos com características lipofílicas costumam apresentar velocidade de difusão muito baixa a partir de matrizes hidrofílicas de liberação, comprometendo a obtenção de níveis plasmáticos terapeuticamente efetivos. Contudo, a liberação de fármacos lipossolúveis a partir de sistemas matriciais é influenciada pelo pH do meio, que pode facilitar a formação de cargas na molécula, melhorando sua performance. O objetivo deste trabalho foi avaliar a capacidade de adjuvantes não poliméricos em facilitar a solubilização do Nimodipino, “in vitro”, através do perfil de dissolução de cápsulas matriciais de hidroxipropilmetilcelulose (HPMC). As formulações desenvolvidas apresentaram o mecanismo de liberação do fármaco pela matriz governado pelo processo de erosão de acordo com o modelo cinético de Korsmeyer-Peppas, onde n>1. Entretanto algumas formulações apresentaram 0.5> n < 1 demonstrando ser um sistema anômalo dependente de difusão e erosão. Os perfis de dissolução nos dois meios testados mostraram-se distintos podendo observar diferenças significativas entre eles.

Drugs with slow solubility present very low diffusion from hydrophilic matrices, committing the serum levels therapeutically effectives. However, the liberation of lipophilic drugs starting from matrix systems is influenced by the pH of the medium, that it can facilitate the formation of charges in the molecule, improving your performance. The objective of this work was to evaluate the capacity of non-polymeric excipients in facilitating the solubilization of Nimodipino “in vitro”, through the capsules dissolution profiles of hydroxypropylmethylcellulose matrices. The developed formulations presented the release mechanism of drug influenced by erosion process according with the kinetic model of Korsmeyer-Peppas, where n>1. However, some formulations presented 0.5> n <1 demonstrating to be an anomalous system dependent of diffusion and erosion. The dissolution profiles in the two tested mediums showed different, allowing to observe significant differences among them.

novel composite membrane for ph responsive permeation

In this study, a kind of pH sensitive composite membrane was prepared and drug permeation through it was investigated in terms of pH. Rationale of this study originated from the fact that a pH change which may be a result of a disease state in the body can trigger drug release. Here, a kind of pH sensitive composite membrane containing different nanoparticle [1: 1 n-isopropyl acrylamide [Nipam]: metacrylic acid [Maa]] contents in ethylcellulose was prepared by a casting method. Swelling ratios of these nanoparticles and composite membranes with different particle loadings were determined. Permeation of two different drug models with different hydrophilicity and molecular weights, vitamin B12 [vit B12] and paracetamol, through these membranes was studied in terms of pH. It was seen that swelling ratios of nanoparticles and the composite membranes went up as the particle content increased at each pH. Vit B12 and paracetamol permeation through the membranes in pH value below the pKa was much higher than that at pHs above it, but this difference was much more pronounced for vit B12 compared to paracetamol. Permeation through these membranes showed a sharp sensitivity to pH changes. Nanoparticles in the composite membranes could act as nanovalves due to their sharp swelling/shrinkage around the pKa of Maa. These membranes could be considered as an ideal stimuli-sensitive barrier for modulating drug release with a small change in pH

Influência das propriedades de granulados de celulose nas características físicas dos comprimidos / Influence of properties of cellulose granules on the physical characteristics of tablets

O comportamento de compactação dos sistemas sólidos particulados pode ser fortemente influenciado pelas características físico-químicas dos excipientes, pois muitas vezes, estes se apresentam em proporções maiores que o próprio fármaco, na formulação do comprimido. O objetivo deste estudo foi avaliar a influência do tamanho dos granulados de celulose nas características físicas de comprimidos obtidos em diferentes diâmetros de punção, considerando que esta relação não tem sido explorada na literatura. Diferentes tamanhos de granulados foram produzidos por granulação úmida e compactados em diferentes diâmetros de punção pela aplicação de diferentes forças. A distribuição de tamanho, as densidades aparentes e o fluxo dos granulados foram avaliados, bem como as características físicas dos comprimidos (peso, dureza, friabilidadee tempo de desintegração). A redução do tamanho dos granulados levou à obtenção de compactos com resistência mecânica adequada e rápida desintegração, além de permitir a produção dos comprimidos sem autilização de forças que representem o limite máximo do equipamento, o que deve evitar o desgaste precoce. Desta forma, ao selecionar o tamanho dos comprimidos adequados para determinada formulação, a escolha do tamanho dos granulados mostra-se determinante para a resistência mecânica dos compactos.

Effects of sphere size, polymer to drug ratio and plasticizer concentration on the release of theophylline from ethylcellulose microspheres

Theophylline sustained release microspheres were prepared by applying the non-solvent addition method. The in-vitro release of the drug from the prepared microspheres of different size ranges [

Comparing acute clinical intrahemodialysis complications and biocompatibility of polysulfone versus hemophane membranes

The membranes used in haemodialysis may be manufactured from cellulose, modified cellulose or synthetic polymers. Such membranes, when in contact with blood will activate the complement system, which entails changes in leukocyte and platelet counts. Polysulfone is a synthetic membrane of high biocompatibility standards, whereas haemophane membranes are modified cellulose-based membranes. The biocompatible profiles of these membranes, has been studied by clinical reactions [i.e. hypotension, nausea, pruritis, ...] during dialysis sessions. Both kinds of these membranes are used in Iran. The number and severity of these reactions define the degree of dialysis biocompatibility. In a clinical trial study which was carried out in Imam Khomeini hospital hi Tehran, 100 hemodialysis patients were enrolled to this investigation. Their clinical reactions were compared during 3 sessions of hemodialysis with polysulfone and 3 sessions of hemodialysis with hemophan membrane. Each patient was the control of him/herself. Data was analyzed using Chi square test. Mean age of patients was 48.85 +/- 17.56 years and 39% of them were female. The most common complications were hypotension and muscle cramps [each 21.5%]. Hypotension was higher in sessions of polysulfon versus hemophane [18% versus 25%] but was not significantly different. Also other complications such as muscle cramp, nausea, vomiting, dyspnea, headache, chills and fever had no signific n difference. Seizure did not occur in any patient. According to our findings the membrane's type has no role in acute clinical complications during hemodialysis and in most patients, membranes can be used according to their availability. It seems their biocompatibility has no considerable clinical difference

effect of pH and polymer type on release of diltiazem HCI from hydrophilic matrices

Oral administrations have been used for many years as a main method comparing to other methods. Sustained release techniques have been a great interest recently. Matrix polymers are one of the ways used to prepare a sustained-release drug and are most widely used to prepare the controlled-release drugs. Cellulose derivatives are the most common ones. Solubilities of some drugs are pH-dependent due to their acidic or basic nature. Diltiazem Hydrochloride due to having a pH-dependent solubility is a suitable model to investigate the effect of pH and also to prepare pH-independent formulations. In the present study, an attempt was made to form pH-independent formulations using HPMC, lactose, CAP and organic acids in different ratios. The physicochemical properties of tablets prepared [including weight uniformity, hardness, tensile strength, friability and assay] were investigated. Rate of drug release was studied using USP I at pH 1.2 and 7.2, and sampling was done in the time of 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8. The drug release data were analyzed according to four kinetics models. Drug release profile in acid free formulations showed that it was higher in the acidic medium. 50% replacement of HPMC with CAP and 1:1 ratio with drug release was pH-independent. Studying the formulations containing organic acids; citric acid and polymer with 1:1 and 2:1 ratios; -ascorbic acid and polymer with 1:1 and 2:1 ratios and tartaric acid with 1:1 and 2:1 ratios showed their pH independent release characteristics. These results showed the effect of combination of polymers and organic acids on drug release and its kinetic. Thus, the micro-environmental conditions for the dissolution and diffusion of diltiazem HCI were almost kept constant. The release of diltiazem HCI from tablets composed of HPMC and organic acids was found to be pH-independent

Efficacy of cellulose triacetate dialyzer and polysulfone synthetic hemofilter for continuous venovenous hemofiltration in acute renal failure.

OBJECTIVE: To compare the clearance performances and biocompatibility between the modified cellulose membrane and the standard synthetic membrane in continuous renal replacement therapy (CRRT). MATERIAL AND METHOD: Seventeen patients with acute renal failure (ARF) were treated with separated continuous veno venous hemofiltration (CVVH) system conducted with the pre-dilution mode. The modified cellulose used was a Sureflux150E (cellulose triacetate) and the standard synthetic membranes used was an AV-400. Blood and replacement flow rate were kept at 100 and 20 mL/min, respectively. Ultrafiltraion rate was 1,200 mL/hr. Samplings of blood and ultrafiltrate were collected at baseline, 2, 8, 16, and 24 hr. RESULTS: Patients in both methods could similarly tolerate CRRT with only minor complications. Sureflux 150E and AV-400 provided comparable values of sieving coefficients and clearances of small solutes. The albumin loss in ultrafiltrate by Sureflux 150E was greater than AV-400. The values of life span and biocompatability of both hemofilters were not different. CONCLUSION: Because of the excellent efficacy and the much cheaper cost, the modified cellulose membrane could be an appropriate alternative to standard synthetic membrane in CRRT.