Formulation and evaluation of xanthan gum based aceclofenac tablets for colon targeted drug delivery / Formulação e avaliação de goma xantana baseados comprimidos Aceclofenac por câncer de cólon de entrega de drogas alvo

The objective of the present study is to develop a colon targeted drug delivery systems for Aceclofenac using xanthan gum as a carrier. In this study, multilayer coated system that is resistant to gastric and small intestinal conditions but can be easily degraded by colonic bacterial enzymes was designed to achieve effective colon delivery of Aceclofenac. The xanthan gum, the drug and the physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). All the formulations were evaluated for hardness, drug content uniformity and other physical properties. Release aspects of Aceclofenac in simulated gastrointestinal fluid and colonic fluid with enzymes were investigated. From these results, Eudragit coated system exhibited gastric and small intestinal resistance to the release of Aceclofenac. The rapid increase in release of Aceclofenac in SCF was revealed as due to the degradation of the xanthan gum membrane by bacterial enzymes. The designed system could be used potentially as a carrier for colon delivery of Aceclofenac by regulating drug release in stomach and the small intestine.

O presente estudo teve como objetivo o desenvolvimento de sistema de liberação cólon-alvo de aceclofenaco empregando goma xantana. Nesse trabalho, o revestimento de múltiplas camadas com característica de resistência às condições do intestino delgado além de gastrorresistência oferece como vantagem a rápida degradação desse sistema por enzimas bacterianas colônicas. Dessa forma, o planejamento de tal sistema possibilitou a liberação específica do aceclofenaco no cólon. A goma xantana e o fármaco, além da mistura física desses dois componentes, foram caracterizados por espectroscopia no infravermelho com transformada de Fourier (FTIR) e calorimetria diferencial exploratória (DSC). Todas as formulações foram avaliadas no que se refere à dureza, à uniformidade de conteúdo do fármaco além de outras propriedades físicas. Os perfis de liberação do aceclofenaco no fluido gástrico simulado e fluido colônico simulado contendo enzimas foram investigados. Os resultados revelaram que o sistema revestido com Eudragit® exibiu resistência gástrica e intestinal à liberação de aceclofenaco. O rápido aumento na liberação de aceclofenaco no fluido colônico simulado foi atribuido à degradação da goma xantana por enzimas bacterianas. O sistema apresenta aplicação potencial no desenvolvimento de produtos para a liberação cólon-alvo de aceclofenaco.

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 and in-vitro evaluation of sustained release theophylline micro-spheres

A modified emulsion-solvent evaporation technique was utilized to prepare sustained release microspheres containing theophylline [TH]. Two polymers were used for microspheres preparation, namely cellulose propionate [CP] and ethyl cellulose [EC]. The two polymers were used at 1:1, 2:1, and 3:2 [drug - polymer ratios]. The prepared microspheres were evaluated for their total recovery, drug loading, particle size distribution, surface morphology, drug content and drug release rate characteristics. The results have shown that, the total percentages drug recovery reached 96, 97.7and 90.3 for cellulose propionate at 1:1, 2:1 and 3:2 [drug -polymer ratios], and that of drug loading reached 89, 90, and 92 respectively. However, with ethyl cellulose, the total% drug recovery reached 99, 100, and 94 using the same drug -polymer ratios, and the total% drug loading reached, 85, 90, and 90 respectively. The results obtained have shown a significant complete recovery with an excellent drug loading and thus the efficiency of the procedure utilized to encapsulate the drug. The drug release characteristics from the prepared microspheres in simulated gastric fluid [pH 1.2] and phosphate buffer [pH 6.8] were compared with commercial sustained release capsules of theophylline [Theo SR 100]. Results have revealed that, the release rate of theophylline was influenced by the type of polymer, microsphere size, pH as well as drug to polymer ratio. The decrease in particle size of the prepared microspheres led to increase in the release rate. However, the prepared microspheres showed more retarded release of theophylline than from the tested commercial product. Moreover, ethyl cellulose as a polymer was more effective for sustained effect. The release data were fitted to Peppas diffusion equation. Results have indicated that the release pattern of theophylline followed zero-order kinetics

effect of the ratio of two acrylic polymers on the in vitro release kinetics of ketoprofen from pellets prepared by extrusion and spheronisation Technique

The aim of this study was to investigate the effect of physico-chemical properties of the polymers on the release profile of ketoprofen from the pellets dosage form. Ammonio Methacrylate Copolymer Type A [Eudragit RL 30 D] and Ammonio Methacrylate Copolymer Type B [Eudragit RS 30 D] were used as release rate retarding polymers. The drug containing core pellets were prepared by extrusion spheronisation technique and subsequently coated with 15% [w/w] polymer load of the combination of Eudragit RL 30 D and Eudragit RS 30 D having ratio 1:0, 4:1, 3:2, 1:1, 2:3, 1:4, 0:1 respectively. Significant differences were found among the drug release profile from different formulations. It was revealed that Eudragit RL 30 D has the effect to increase the initial drug release more significantly where as Eudragit RS 30 D has the effect to minimize the initial drug release but increase the terminal drug release more significantly. In acid media about 50% drug was released from pellets coated only with Eudragit RL 30 D where was only 5% drug was released in case of Eudragit RS 30 D but maximum 10% drug was released from pellets when coated with the combination of Eudragit RL 30 D and Eudragit RS 30 D. In buffer media, evidence of burst release was observed for the pellets coated with Eudragit RL 30 D and Eudragit RS 30 D having ratio of 1:0, 4:1, 3:2 respectively. It was also observed that drug release increases sharply as well as the release best fit to the zero order release kinetics when pellets coated with 1:1 ratio of Eudragit RL 30 D and Eudragit RS and follows Higuchi's release kinetics when ratio was 1:0 and 3:2. The results generated in this study showed that proper selection of polymeric materials based on their physico-chemical properties is important in designing sustained release pellets dosage form with suitable dissolution profile

Preparation and evaluation of oxytetracycline hydrochloride microbeads for delayed release

Oxytetracycline HCl microbeads were prepared with sodium alginate and pectin using ionic gelation method and evaluated for morphology, flow properties, drug content and in vitro drug release study. SEM confirmed spherical structure of microbeads with rough and porous surfaces and microbeads possessed average particle size range of 639.86 to 685.74 mm. In vitro drug release study was carried out in simulated gastric fluid [SGF] for first 2 h and simulated intestinal fluid [SIF] for next 6 h. Selected formulation was coated using enteric polymer cellulose acetate phthalate to minimize burst drug release along with delayed drug release in intestinal medium

Comparative bioavailability and in vitro in vivo correlation of two sustained release brands of theophylline: tablets and pellets

To investigate the influence of dosage forms on bioavailability, a randomized single-dose crossover study under fasting conditions was conducted using two commercially available sustained release products, Quibron SR tablets and Respro-SR pellets filled Capsules containing 300mg theophylline. A group of 12 healthy, male human subjects participated in this study. Serial blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. Theophylline was measured by high-performance liquid chromatography while absorption profiles were derived using Wagner-Nelson equation. The bioavailability of Quibron SR tablets was compared with Respro-SR pellets filled Capsules 300 mg using pharmacokinetic parameters C[max], T[max], AUC0-t, and AUC0-8. In addition, the 90% confidence interval [CI] for the ratio of logarithmic transformed C[max] and AUC0-8 was also used to determine bioequivalence. The T/R [test/reference] ratio of Quibron SR tablets was quite close to the prescribed limits of bioequivalence i.e. 80-125%. No st atistically difference was observed between the log transformed AUC[0-infinity] [P = 0.971] values as well as log transformed C[max] values [P = 0.854] indicating bio-availability and the extent of absorption of two brands were comparable. Moreover, the value of correlation coefficients for% in vivo absorption versus% in vitro dissolution of the two products was calculated to be 0.9533 for Respro-SR capsule and 0.9789 for Quibron-SR tablets

Concentração sérica de progesterona em bezerras da raça nelore e mestiças tratadas com progesterona em veículo de liberação lenta / Serum progesterone concentration in Nelore and crossbreed heifers treated with long-acting progesterone

Avaliaram-se a eliminação da progesterona em veículo de liberação lenta (P4LA) em animais zebus e mestiços e sua potencial aplicabilidade em programas de sincronização de estro, utilizando-se 60 bezerras, 30 da raça Nelore e 30 mestiças (Gir x Holandês), entre 120 e 150 dias de idade e peso médio de 150kg. Em cada grupo experimental as bezerras foram divididas em três subgrupos (G) de 10 animais, sendo GI = controle (tratado com 5ml de solução fisiológica por via intramuscular); GII = tratado com 450mg P4LA (3ml IM); e GIII = tratado com 750mg P4LA (5ml IM). Amostras de sangue foram coletadas no dia zero, 7 e 13 (D0, D7 e D13) e procedeu-se à análise hormonal por radioimunoensaio de fase sólida. A progesterona de ação prolongada (P4LA), administrada por via intramuscular, manteve-se por 13 dias na corrente sangüínea em concentrações superiores a 1ng/ml. As doses de 450mg e 750mg de P4LA não ocasionaram efeitos adversos sistêmicos clinicamente perceptíveis, e o metabolismo da P4LA foi mais lento nas bezerras Nelore, cuja concentração de progesterona foi maior na corrente sangüínea do que nas bezerras mestiças.

The clearance of long-acting progesterone in microspheres (P4LA) in zebu animals and its potential for use in estrus synchronization were evaluated using 30 Nelore and 30 crossbreed (Holstein x zebu) heifers, with aging between 120 to 150-day-old and weighting 150kg in average. For each breed the animals were divided into three groups of ten animals each, GI= control group treated with saline; GII= treated with 450mg of P4LA; and GIII= treated with 750mg of long-acting progesterone (P4LA). Blood samples were colleted on days 0, 7 and 13 and analysed for progesterone using radioimmunoassay in solid phase. The serum concentration of progesterone was different on days 0, 7 and 13 in relation to the dose of P4LA given. All treated animals presented basal values for progesterone on day 0, increased on day 7 and decreased on day 13, but with values over 1ng/ml. The results show that the drug was absorbed rapidly after its administration and remained in satisfactory concentration in the circulation until day 13. The average total concentration of serum progesterone was higher in Nelore heifers when compared to the concentration in crossbreed ones, indicating difference in the metabolism of the drug between the two genetic groups.

Therapeutic evaluation of sustained-releasing praziquantel (SRP) for clonorchiasis: Phase 1 and 2 clinical studies

Sustained-releasing praziquantel (SRP) tablet was designed for single dose treatment regimen of clonorchiasis. A previous pre-clinical study confirmed its sustained-releasing characteristics and a better cure rate than conventional praziquantel (PZQ). In this clinical study, the pharmacokinetics of this SRP tablet were investigated in human volunteers (phase 1; 12 volunteers), and its curative efficacy was examined in clonorchiasis patients (phase 2; 20 volunteers). In the phase 1 clinical study, blood concentrations of both tablets showed wide individual variation. The AUC(last) of SRP was 497.9+/-519.0 ng.hr/ml (mean+/-SD) and PZQ of 628.6+/-695.5 ng.hr/ml, and the AUC(inf) of SRP was 776.0+/-538.5 ng.hr/ml and of PZQ 658.6+/-709.9 ng.hr/ml. C(max) values of SRP and PZQ were 90.7+/-82.2 ng/ml and 214.9+/-251.9 ng/ml, and T(max) values were 3.42+/-1.43 hr and 1.96+/-1.23 hr, respectively. SRP tablets showed similar AUC values, but lower C(max) and longer T(max) values than PZQ. In the phase 2 study, SRP at 30 mg/kg (single dose) achieved a 60% cure rate and a 95.5% egg reduction rate. The cure rate of a single dose SRP was unsatisfactory compared with that of the conventional PZQ dose, but much better than that achieved by a single dose PZQ.

Géis de monoleína/água para veiculação de fármacos protéicos: estudos microscópicos, reológicos e de liberação in vitro / Monoolein/water gels as delivery systems for proteic drugs: microscopic, rheological and in vitro delivery studies

Géis de fase cúbica de monoleína e água têm sido propostos como sistemas de liberação de fármacos com diferentes características, incluindo moléculas protéicas e peptídicas. O presente trabalho estudou a incorporação de lactoferrina, usada como molécula protéica modelo em várias concentrações em géis de fase cúbica de monoleína e água. A influência da lactoferrina nos géis de monoleína/água foi avaliada por microscopia de luz polarizada e estudo de suas propriedades reológicas, asssim como estudos de liberação in vitro foram realizados. A fase cúbica foi observada na presença da lactoferrina sendo que esta proteína não modificou as transições de fase dos géis, quando observados ao microscópio de luz polarizada...

Comparative steady-state bioavailability of sustained-release theophylline preparations: Theo-Dur, Uni-Dur and Xanthium.

Steady-state bioavailability of sustained-release theophylline (SRT); Theo-Dur, Uni-Dur and Xanthium were compared in 10 healthy males with theophylline clearance ranged from 0.3 - 0.8 ml/min/kg. Each of 400-mg SRT was administered once daily before breakfast for 7 consecutive days, one-week washout period in a crossover fashion. Serial blood samples were collected over 24 hours on days 6 and 7. Serum theophylline concentrations were determined by fluorescence polarized immunoassay. We found that the oral bloavailability relative to Franol (%F [90% CI]) of Theo-Dur, Uni-Dur and Xanthium were 97 (93-106), 85 (79-96) and 77 (72-87), respectively. Average bioequivalence revealed that the Css(min) (microg/ml) of Uni-Dur (5.07) was higher than Theo-Dur (4.29), and Xanthiume (4.18), while the Css(max) and Css(av) (microg/ml) of Theo-Dur (11.02, 7.87) were statistically higher than Uni-Dur (8.51, 6.91) and Xanthium (7.65, 6.27). The extent of absorption assessed by AUCss(0.24) of Theo-Dur was significantly greater than Uni-Dur and Xanthium. However, fluctuation index (% FI) of Theo-Dur (232) was twofold higher than Uni-Dur (137) and Xanthium (113). The median Tss(max) of Uni-Dur was 12 hours which was significantly longer than Xanthium (7 hours) and Theo-Dur (8 hours). There were no statistically significant differences between Uni-Dur and Xanthium regarding bioavailability, Css(max), Css(av) as well as % FI. Moreover, 400 mg OD of Uni-Dur and Xanthium are suitable for subjects with a theophylline clearance of 0.3-0.55 ml/min/kg while 400 mg OD Theo-Dur can be used in subjects with slower clearance rates of 0.3-0.39 ml/min/kg. Subjects with rapid theophylline clearance rates of 0.65-0.8 ml/min/kg required a higher dose of theophylline and twice-daily dosing was more appropriate.

Release kinetics of salbutamol sulfate from HPMC based sustained release matrix: I effect of cetyl alcohol and bees wax

In order to search better combination of water insoluble waxy materials with hydrophilic polymer, investigations have been carried out using cetyl alcohol [CA] and bees wax [BW] as additives to the hydrophilic polymer, HPMC. They were added in increasing amount [up to 40% of the waxy materials] to the HPMC based sustained release [SR] matrix tablets. Excellent correlation was found between the concentration of waxy materials and salbutamol sulfate [SS] Release pattern of SS from HPMC - CA combination matrics were found zero order the release rate of SS decreases linearly with the increase in the concentration of CA in the matrics. On the other hand, release pattern of SS from HPMC - BW combination matrices were found to be bi - phasic. The first phase release was initially rapid, however, the extent of release both in the first and second phase were reduced with the increase of the BW concentration

In-vitro and in-vivo evaluation of commercial and microencapsulated sustained release tablets containing diclofenac sodium

Diclofenac sodium microcapsules were prepared using the phase separation technique induced by non-solvent addition. Ethl1cellulose and Eudragit RS100 were used as well forming materials in two core: wall ratios [1: 1 and 1: 2]. The prepared microcapsules were compressed into tablets without excipients. The influence of tableting type of wall forming material and the core: wall ratio on the release pattern of the drug from microcapsules were determined in Ph 1.2 and pH 6.8. compression of the microcapsules significantly [p < 0.05] decreased the rate of drug release due to the reduction of the surface area. Less than 2.0% of the drug was released in 0.1N HC1 during the first two hours of dissolution from microcapsules before and after tableting. On the other hand, the dissolution results of the tableted ethy1cellulose microcapsules with 1:1 and 1:2 core: wall ratios showed that 88.6 and 70.6% of the drug were released to the phosphate buffer solution, while only 45.0 and 24.4% of the drug in the tableted eudragit microcapsules was released within 8 h of dissolution. The tableted ethy1cellulose microcapsules with 1:2 core: wall ratio showed almost identical release of the drug as that from commercial tablets therefore, it was chosen for bioavailability study in six beagle dogs. The in-vivo data showed that the tableted microcapsules gave bioavailability of 87.5% relative to that of the commercial voltaren retard tablets. The prepared tablets show that it is possible to use ethy1cellulose microcapsules to prepare tablets that are pharmaceutically and biologically equivalent to those of the commercially available voltaren retard tablets

Preparation and pharmacokinetic evaluation of carbamazepine controlled release solid dispersion granules

Solvent evaporation technique was applied to prepare granules of carbamazepine coprecipitates using Eudragit RLPM, Eudragit RS 100, Cellulose acetate phthalate and Ethyl cellulose in 1: 1 and 1:2 drug: polymer w/w. In vitro release of carbamazepine from its coprecipitates with the previously mentioned polymers as well as the commercially available tablets [Tegretol CR200 tablets, Ciba] was carried out in gradient pH media [1.2, 2.5, 4.5, 7, 7.4] for 7 hours. The data were kinetically treated. Pharmacokinetic studies of the selected formula made with ethyl cellulose [1:1] and Tegretol CR 200 mg tablets [Ciba], as a reference standard, as well as carbamazepine powder were done using albino rabbits. Carbamazepine plasma level was determined using HPLC. The in vitro and in vivo data revealed that the suggested formula and the innovator's product exhibit% dissolution, tmax, Cpmax, AUC and /delta[1/2] as follows, 58.4%, 8 hr, 24.15 +/- 5.5/-microg/ml, 277.24hr microg/ml, 5.6hr and 64.22%, 8hr, 28.93 +/- 315.14 microg/ml, 313.6 hr, microg/ml, 5.2 hr respectively. It is worthy to note that the suggested formula showed a more prolonged duration of action

Sustained release of flufenamic acid from drug adsorbed emulsions

Sustained release flufenamic acid O/W dry adsorbed emulsions were prepared. The influence of type of oil [sesame oil and linseed oil], concentration of hydrophilic surfactant [2 and 3% of polysorbate 80] and type of hydrophilic adsorbent [Avicel PH 101 and Aerosil 200] on the tapped density [g/ml], void, flowability of flufenamic acid dry adsorbed emulsions and the percentage of drug released after 8 hours from the emulsions were evaluated using a 23 factorial design. It was found that, tapped density as well as void of flufenamic acid dry absorbed emulsion particles were affected by the type of both oil and hydrophilic adsorbent. While, the flowability of dry emulsions was only affected by the type of hydrophilic adsorbent. The most important factor that affected the drug release from dry adsorbed emulsions was the type of hydrophilic adsorbent

Formulation and evaluation of controlled release erythromycin tablets and capsules

Various formulations of erythromycin base were designed to be controlled release forms. Tablets were prepared using Avicel as a diluent and both of stearic acid and magnesium stearate as hydrophobic materials to control the release. In addition, a control was prepared by direct compression of erythromycin base powder into tablets. On the other h and, microcapsules [MC] and solid dispersions [SD] of erythromycin base, which were prepared in a previous study, were either directly compressed into tablets or filled into hard gelatin capsules. Then, the formulated products were evaluated for hardness, disintegration time, penetration and dissolution rate testing. Also, the bioavailabilities of these products were investigated on humans. It was found that capsules containing MC or SD revealed higher release rate profiles compared to the corresponding tablets. On the other h and, products containing magnesium stearate were found to depict a reduction in drug release upon increasing magnesium stearate. However, the presence of stearic acid in the product resulted in a reverse effect

Formulation and evaluation of sustained release dextromethorphan resinate syrup

Aiming to decrease the dosing frequency of the antitussive dextromethorphan, different coated drug resinates were prepared and formulated in syrup form. Polystyrene divinylbenzene sulfonic acid ion exchanger [Amberlite IRP 69, H+ form] was used to prepare the resinates, which were further coated with different concentrations of carnauba wax, Eudragit RL 100, or ethyl cellulose. The in vitro release performance of the coated and uncoated resinates was determined in simulated gastric and intestinal fluids. Selected systems were formulated in syrup form and evaluated for their physicochemical and release performance when fresh and on storage. Dextromethorphan resinates showed relatively rapid release pattern, where 74.2% of the drug released through two hours in acid medium. The release pattern decreased from coated resinates on increasing polymer coat depending on the type of coating polymer. Coated dextromethorphan resinate syrups acquired mixed zero- and first-order release pattern with optimum release rates and suitable first flush values. The dextromethorphan flush in the first five minutes ranged between 9.1 and 12.3% with first-order release rate constants of 0.0048-0.0097 min-1