Effect of cellulose acetate phthalate and polyethylene glycol on physical properties and release of theophylline from microcapsules

ABSTRACT The present study describes the development of theophylline microcapsules by a non-solvent addition method and the effect of plasticizer addition on microencapsulation. The release was studied in distilled water and the data were analysed by various mathematical models for determining the mechanism of release. Prepared microcapsules were found to be spherical, free flowing and having more than 80% entrapped drug. The polymer - cellulose acetate phthalate and plasticizer - polyethylene glycol was considered to be affecting the properties of microcapsules including drug release (time for 50% drug release, T50). The formulation with the highest proportion of polymer and without plasticizer (F3) showed the slowest release with T50 = 4.3 h, while the formulation with lower proportion of polymer and 20% (w/w) plasticizer (F13 &14) showed the fastest release of drug with T50 values of 1.2 h and 1.3 h, respectively. The drug release from most of the formulations was found to be following Higuchi model. It is concluded from the results of the present study that cellulose acetate phthalate significantly affects the sustained release of the drug in water, whereas the addition of polyethylene glycol slightly enhances the drug release.

RESUMO O presente estudo descreve o desenvolvimento de microcápsulas de teofilina pelo método sem adição de solvente e o efeito da adição de plastificante na microencapsulação. A liberação foi estudada em água destilada e os dados foram analisados por vários modelos matemáticos para determinação do mecanismo de liberação. As microcápsulas preparadas mostraram-se esféricas, livres de corrente e com mais de 80% de fármaco encapsulado. O polímero - ftalato de acetato de celulose e o plastificante - polietileno glicol - afetaram as propriedades das microcápsulas, incluindo a liberação do fármaco (tempo para liberação de 50% do fármaco, T50). A formulação com a maior proporção de polímero e sem plastificante (F3) se mostrou como a de liberação mais lenta, com T50 = 4,3 h, enquanto as formulações com menor proporção de polímero e 20% de plastificante (m/m) (F13 &14) apresentaram a liberação mais rápida do fármaco, com T50 de 1,2 h e 1,3 h, respectivamente. A liberação do fármaco para a maioria das formulações seguiu o modelo de Higuchi. Concluiu-se, dos resultados do presente estudo, que o ftalato do acetato de celulose afeta significativamente a liberação controlada do fármaco em água, enquanto que a adição de polietileno glicol aumenta ligeiramente a liberação do fármaco.

Otimização de comprimidos de liberação prolongada de teofilina aplicando o planejamento estatístico de mistura / Optimization of controlled release matrix tablets of theophylline using design of experiments

Foram produzidos comprimidos de liberação prolongada de teofilina baseados em matrizes hidrofílicas de misturas de hidroxipropilmetilcelulose e etilcelulose e polietilenoglicol. O planejamento estatístico de mistura Design Expert® foi empregado na seleção da composição do sistema de controle da liberação e, numa segunda fase, para otimização das formulações de comprimidos. Foram produzidas 26 formulações por compressão direta e as características físico-químicas dos comprimidos como peso médio, friabilidade, dureza e teor de fármaco foram determinadas. A porcentagem de teofilina liberada foi avaliada conforme o método da Farmacopéia Americana 30 ed. (2007), para cápsulas de liberação prolongada (Teste 10 - pá), por um período de 8 horas. Conforme as farmacopéicas os comprimidos produzidos apresentaram características físico-químicas de acordo com as especificações, com exceção das formulações 2 e 3, para o teste de friabilidade, cujos valores foram superiores. Entretanto, quanto ao ensaio de dissolução, a formulação 13, constituída por 30% de etilcelulose, atendeu aos valores preconizados para liberação prolongada de teofilina. As respostas obtidas dos experimentos foram introduzidas no programa Design Expert® que gerou superfícies de respostas nas quais foi possível avaliar a influência da composição nos parâmetros friabilidade e porcentagem de teofilina liberada na dissolução. Dessa forma, foi possível obter 3 formulações com etilcelulose (13,50% a 15,90%), metilcelulose tipo E4MCR (6,90% a 8,10%) e metilcelulose tipo K4MPRCR (0,30% a 0,60%), com as características desejadas empregando o planejamento estatístico de mistura, com o número mínimo de experimentos sem a necessidade de estudar todas as possíveis combinações experimentais, abreviando o trabalho com ganho de tempo...

Development and in vitro evaluation of extended-release theophylline matrix capsules

Polymers like cellulose (MethocelTM K100MPRCR, K15MPRCR and E4MCR) at different proportions (15-35 percent) were used to slow the release of theophylline (100 mg) from capsules. Volumetric method for powder filling capsules was used to prepare the capsules. Drug release from capsules was performed using apparatus 1, at 100 rpm and 900 mL of intestinal medium without enzymes (pH 7.5), at 37 ºC, following the USP 28th ed. (Test 8). Dissolution profiles were compared to two batches of commercial extended-release capsules. Capsules compounded with 35 percent (wt/wt) of MethocelTM E4MCR showed dissolution profile according to the official especifications. Similar results were reproduced with other ten compounded batches. Commercial extended-release capsules containing theophylline pellets (100 mg) showed quick drug release when submitted to the same test, indicating that, in these conditions, the capsules did not show prolonged release. Mathematical models like zero-order, first-order and Higuchi were applied in kinetic studies of theophylline release from the compounded capsules. Polymers were efficient to control the release of theophylline in capsules involving diffusion and erosion as mechanisms, and that first-order model was the best fitted one for theophylline matrix capsules. These results support that compounded extended-release capsules can be prepared, since the drug release tests can be done.

Cápsulas de liberação modificada contendo 100 mg de teofilina foram preparadas com polímeros derivados da celulose (Methocel® K100MPRCR, K15MPRCR e E4MCR) em diferentes concentrações, 15-35 por cento, empregando-se o método volumétrico. Estudos de liberação do fármaco foram realizados de acordo com a Farmacopéia Americana 28 ed., (Teste 8), empregando aparato 1, rotação de 100 rpm e temperatura de 37 ºC em 900 mL de meio fluido intestinal sem enzimas (pH 7,5). Os perfis de dissolução foram comparados ao de duas especialidades farmacêuticas comerciais. A formulação, com 35 por cento de Methocel® E4MCR, evidenciou perfis de liberação de acordo com as especificações e os resultados foram reprodutíveis para 10 lotes manipulados com a mesma formulação. As cápsulas comerciais de liberação prolongada contendo 100 mg de teofilina (microgrânulos), submetidas ao mesmo ensaio, apresentaram rápida liberação do fármaco, indicando que a liberação não é fator limitante para a absorção. Avaliou-se a cinética de liberação do fármaco empregando os modelos matemáticos de ordem zero, primeira ordem e Higuchi. Conclui-se que as matrizes obtidas foram capazes de modular a liberação, envolvendo os mecanismos de difusão e erosão, prevalecendo o modelo de primeira ordem e que as cápsulas de liberação modificada podem ser manipuladas, desde que testes de liberação sejam realizados.

Multiple dose activated charcoal versus hemodialysis in the management of theophylline overdose: a toxicokinetic-based comparison

Thirty patients with theophylline overdose were selected to study the toxicokinetics of theophylline during intestinal dialysis using multiple-dose activated charcoal [MDAC] and during continuous hemodialysis. Patients were classified according to serum theophylline level [STL] into two groups. Group [I]: comprised 20 patients with a mean STL of 43.29 +/- 15, 02. Treatment in this group was started using MDAC. Group [II]: comprised 10 patients with a mean STL of 81.32 +/- 31.07. Treatment in this group was started using continuous hemodialysis up to vomiting control, then continued using MDAC in the same regimen as group [I]. The enhanced elimination procedures in the two groups were initiated 2 hours post-admission. STL peaked at 3 hours, for both groups [1 hour after initiating the enhanced procedure]. Greater variation in STL among patients in each time interval in the hemodialysis group was clear compared to MDAC group. Following the peak, serum theophylline concentrations, in each treatment group, declined in a biphasic linear fashion. Non significant difference was observed in the pharmacokinetic parameters of theophylline as a result of MDAC; either from the start or following hemodialysis. Elimination rate constant [Ke], elimination half life [t1/2] and total body clearance of theophylline were 0.168 +/- 0.033 hour[-] 1, 4.125 +/- 1.56 hour, and 0.0841 + 0.028 L/kg/ hr, respectively as a result of MDAC modality from the start and 0.186 +/- 0.048 hour[-1], 3.73 +/- 1.087 hour, and 0.093 + 0.031 L/kgl hour, respectively following. hemodialysis. Compared with MDAC, hemodialysis did not significantly increase Elimination rate constant [Ke] of theophylline and consequently did not shorten its elimination half life [t1/2] or increase its clearance significantly. In conclusion, hemodialysis showed no advantages over MDAC in enhancing theophylline elimination in overdose except that it could be used in patients with protracted vomiting

Preparation and characterization of theophylline-chitosan beads as an aapproach to colon delivery

Chitosan with excellent biodegradable and biocompatible characteristics has received attention as an oral drug delivery vehicle for controlled-release formulations. In this study an enteric-coated capsule containing theophylline-chitosan beads based on 2[3] factorial designs was prepared as a colon drug delivery system. The theophylline-chitosan gel beads were formulated by adding the drug-containing solution of chitosan into tripolyphosphate solutions, dropwise. The obtained beads were washed with water and freeze-dried before filling into the capsules. Eudragit[R] S100 was then used to enteric-coat the prepared capsules. Drug entrapment efficiency and the effects of different variables including: bead morphology, swelling behavior of the beads and the release behavior of the system on these parameters were investigated. Results showed that the highest and lowest swelling ratio is obtained at pH 4.5 and 7.2, respectively. These studies have shown that chitosan concentration and drug polymer weight ratio significantly affect the drug entrapment. Decreasing the drug solubility in external phase caused a significant increase in drug loading. External phase saturation with theophylline and tripolyphosphate, as well as decreasing temperature, have increased drug loading. Furthermore, the lowering of temperature had a significant effect on bead's hardness. The release of theophylline from freeze-dried beads filled in enteric-coated capsules was also investigated. Release of theophylline was prolonged with saturation of both drug and tripolyphosphate in the external phase. Results showed that the release of theophylline from chitosan beads is possibly due to more than one mechanism, possibly dissolution, diffusion and relaxation of the polymer chains

study on the in vitro evaluation of Guar Gum as a carrier for oral controlled drug delivery

The objective of the study is to evaluate guar gum as a carrier in the design of oral controlled drug delivery systems. Drugs with varying solubility such as diltiazem HC1 [freely soluble], theophylline [slightly soluble] and glipizide [practically insoluble] were chosen as model drugs. Matrix tablets of diltiazem HC1, theophylline and glipizide using different proportions of guar gum were prepared and subjected to in vitro drug release studies. When the cumulative amount of drug released at different time intervals was plotted, all the guar gum matrix formulations provided controlled drug delivery comparable with the respective commercial sustained release tablets. The results indicated that guar gum is a potential carrier in the design of oral controlled drug delivery systems

Teofilina en asma / Teophylline in asthma

La teofilina ha sido uno de los medicamentos más ampliamente utilizados e intensivamente estudiado para el tratamiento del asma. La teofilina es una xantina metilada, relacionada con las xantinas de la dieta, cafeína, y teobromina. Tradicionalmente utilizada como broncodilatador, su uso actual es predominante como medicamento de mantenimiento para el asma crónica. Para el tratamiento del asma aguda, la teofilina es menos efectiva que los ß-2 agonistas inhalados o inyectados y permanece como una importante medicación en el manejo de síntomas nocturnos refractarios a tratamietno antiinflamatorio; es también útil como manejo de primera línea en pacientes que no cumplen o sin apego al tratamiento antiinflamatorio inhalado. El beneficio y toxicidad de la teofilina está en estrecha relación a las concentraciones séricas, y óptimos beneficios se obtienen a concentraciones de 10µg/mL y la toxicidad es frecuente a concentraciones que exceden 20 µg/mL. El rango de eliminación varía entre individuos, pero generalmente permanece estable en el paciente, excepto cuando cursa con alteraciones fisiológicas o con interacciones medicamentosas. Su uso clínico requiere cuidadosas consideraciones, de las características de absorción, individualización de la dosis, guiada por las concentraciones séricas y educación al paciente sobre los potenciales efectos secundarios y de las interacciones con medicamentos. Recientemente, parece renovarse el entusiasmo por el uso de la teofilina para el tratamiento del asma por sus propiedades antiinflamatorias y efecto inmunomodulador

Comparison between sprague-dawley and wistar rats as an experimental model of pharmacokinetic alterations induced by spinal cord injury

Two strains of rats, Sprague-Dawley and Wistar, were assayed in order to determine which strain is the more suitable experimental model for the study of pharmacokinetic alterations inuced by spinal cord injury. Animals were submitted to spinal cord contusion at the T8-T9 level by the weight drop method. A single acetaminophen oral dose (100 mg/kg) was administered 24 h after injury and blood samples were drawn for a period of 4 h. Acetaminophen concentration in whole blood was determined by high performance liquid chromatography and pharmacokinetic parameters were estimated. For both strains, Cmax and AUC were significantly lower, whereas tmax remained uchanged, in injured animals compared to sham-injured controls. Circulating acetaminophen concentrations were higher; therefore, pharmacokinetic alterations were more easily discerned, in Sprague-Dawley than in Wistar rats. It is concluded that the Sprague-Dawley strain is a more suitable model for the study of pharmacokinetic alternations induced by spinal cord injury

Empleo de la teofilina en pediatría / Therapy use of teophylline in children with asthma

La teofilina es uno de los medicamentos más antiguos utilizados para tratamiento del asma. En este artículo se resumen las indicaciones para su utilización en asma, y se concluye que las principales indicaciones son para asma crónica, particularmente nocturna, aunque se puede utilizar en crisis asmáticas agudas refractarias al manejo inicial con beta agonistas y esteroides

Preparation of sustained release theophylline by using different techniques

Sustained release theophylline has been prepared by using the solid dispersion, wet granulation and microencapsulation techniques. Physical mixture of the drug and ethyl-cellulose showed complete drug release within 80 minutes, a fact that excludes their application in controlling drug release. Co-precipitates of theophylline in ethylcellulose [EC] were prepared using different concentrations of the polymer dissolved in ethanol or in ethanol-chloroform mixture [1:1]. The dissolution studies showed that the concentration of the polymer in the system is a determining factor in controlling the release rate of the drug. The type of solvent also has a marked effect on the rate and pattern of theophylline release. Within half an hour, 32.4% of the drug was released from the solid dispersion prepared using ethanol alone and T50 was 45 minutes, while only 20.9% of the drug was released from the solid dispersion prepared using a mixture of solvents and T50 was 180 minutes. The presence of polyvinyl-pyrrolidone [PVP], modified the release pattern of theophylline. The results showed that by increasing the PVP/EC ratio, the rate of theophylline release increased. Theophylline granules were prepared using different amounts of microcrystalline cellulose, cellulose acetate phthalate and ethylcellulose as fillers. The obtained dissolution results showed that altering the Avicel-ethylcellulose ratio affected the release rate markedly. Theophylline microcapsules showed initial rapid release where about 40% of the core was released within one hour. The obtained results revealed that co-evaporates could be considered as an ideal technique for preparing medicines required for sustained release preparations. This is due to the homogeneous drug distribution and the uniform drug release in comparison to the other techniques used in this study

Theophylline pharmacokinetics in Thai children.

To validate a previously suggested dosing regimen of aminophylline administration for Thai children, we enrolled 13 asthmatic Thai children (5 girls and 8 boys) between the ages of 7.5-13.4 years (mean = 10.4 years) into a 36-hour, multiple-dose, oral theophylline pharmacokinetic study using plain aminophylline tablets at a dosage of 5 mg of theophylline base/kg every 8 hours. All patients were studied in the steady state. Blood samples were obtained every 2 hours for 24 hours; thereafter, samples were obtained more frequently for another 12 hours to determine theophylline pharmacokinetic parameters. Serum theophylline concentrations (STC) were assayed with a fluorescence polarization immunoassay method (TDX). Significant interpatient variations in STCs were observed. Five patients had peak STCs in the toxic range (> 20 micrograms/ml). Most patients had reproducible STC patterns during the study period; however, marked variations of STCs were observed with a mean percent of fluctuations [(Cmax-Cmin)/Cmin *100] of 535.6%. Using the PC Nonlin computer interpolation program by a modification with a baseline decay method and the Lagrange polynominal interpolation technique, approximate pharmacokinetic parameters were calculated and the results were as follows: plasma half life (t1/2) = 3.08 hours, elimination rate constant (Kel) = 0.26 hour-1, absorption rate constant (Ka) = 2.21 hour-1, volume of distribution (Vd) = 0.23 l/kg and plasma clearance (CI) = 56 ml/kg/hour. Since these calculated parameters could be imprecise due to delayed absorption of oral theophylline dosages, a single-dose intravenous theophylline pharmacokinetic study was further examined in another 18 patients (age range = 7-12 years, mean = 8.9 years) to determine more accurate pharmacokinetic data using intravenous aminophylline at dosage of 5.8 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of rifampicin on theophylline pharmacokinetics in human beings.

Theophylline pharmacokinetics before and after rifampicin administration was studied in 10 healthy volunteers. It was seen that Rifampicin significantly increased the volume of distribution of theophylline by 23.41% (p < 0.01) and its metabolic clearance by 47.65% (P < 0.05). This has got clinical significance in the treatment of patients of pulmonary tuberculosis with chronic obstructive airways disease where both the drugs may have to be given concurrently.

CYP1A2 activity as a risk factor for bladder cancer

CYP1A2, CYP2D6 and N-acetyltransferase activities were estimated in 100 patients with bladder cancer and 84 control subjects from measurements of theophylline, metoprolol and isoniazid and their metabolites in urine, respectively. The frequency of occurrence of slow acetylators of isoniazid and poor metabolizers of metoprolol were 16.7% and 1.2% in the control group and 16.3% and 2.0% in the cancer patient group. These differences were not significant. The recovery ratio of 1-methyluric acid(1-MU) from theophylline was significantly higher in patients with bladder cancer than in control subjects(0.340 +/- 0.016 versus 0.260 +/- 0.020, p< 0.05). The 1-MU recovery ratio was a significant, independent risk factor among the metabolic capacities tested as shown by logistic regression analysis, controlling for N-acetylation of isoniazid, hydroxylation of metoprolol, age, sex, and smoking. We concluded that the capacity for 3-demethylation of theophylline, as a reflection of CYP1A2 activity, is significantly associated with increased risk of nonoccupational urinary bladder cancer.

Effect of macrocomponents of food on the pharmacokinetics of a long acting preparation of anhydrous theophylline.

In a single dose crossover study, the effect of macrocomponents of food on the pharmacokinetics of a long acting preparation of anhydrous theophylline was investigated. Compared to fasting subjects, carbohydrate and fat rich diet caused an enhancement of absorption half life and a lower Cmax with a delayed tmax and elimination of the bronchodilator. Protein coadministration decreased AUCO-OC of the drug without significantly altering its absorption or elimination kinetics.

Pharmacokinetic profile of two different pharmaceutical forms of theophylline (a slow release tablet and a syrup) after multiple dose administration to healthy human volunteers

Due to the narrow therapeutic range of theophyline, plasma concentrations of this drug are monitored in patients undergoing chronic therapy. Slow-release preparations avoid the fluctuations in plasma levels and improve patient compliance. In this study, we have compared the pharmacokinetic profiles of a theophylline slow-release tablet and a syrup form, when administered in multiple doses to healthy adult volunteers. The classification based upon releasing patterns is confirmed

Effect of storage on theophylline release from commercially available sustained-release products

Four commercially available sustained- release theophylline products were evaluated with regard to their release rate profile using the USP basket method. The dissoluation medium was phosphate buffer [pH7.5]. a wide variation in the drug release was shown and was attributed to differences in the additives and the method of manufacturing of these products. these brands were stored at 40°C/80% relative humidity [R.H.] and their in-vitro dissolution as well as their theophylline content ere followed for upto twenty months under these storage condition. While no alterationof theophylline content was shown upon storage, changes in drug release patterns were observed in three of these products. dramatic changes in both the T50% and T80% were also found. These results reveal the possibility of a change in the bioavailability of these products upon storage