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Revista Brasileira de Ciências Farmacêuticas

Print version ISSN 1516-9332

Rev. Bras. Cienc. Farm. vol.43 no.2 São Paulo Apr./June 2007

https://doi.org/10.1590/S1516-93322007000200012 

ORIGINAL PAPERS

 

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

 

Desenvolvimento e avaliação in vitro de cápsulas de teofilina de liberação prolongada

 

 

Vanessa Alves Pinheiro; Telma Mary Kaneko; Maria Valéria Robles Velasco; Vladi Olga Consiglieri*

Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo

 

 


ABSTRACT

Polymers like cellulose (MethocelTM K100MPRCR, K15MPRCR and E4MCR) at different proportions (15-35%) 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 °C, following the USP 28th ed. (Test 8). Dissolution profiles were compared to two batches of commercial extended-release capsules. Capsules compounded with 35% (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.

Uniterms: Theophylline, Capsules, Extended-release, Dissolution


RESUMO

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%, 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% 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.

Unitermos: Teofilina. Cápsulas. Liberação prolongada. Dissolução.


 

 

INTRODUCTION

Compounded capsules have some advantages, like adjusting the dosage to the therapeutic patient needs, considering weight, therapeutic objective and side effects. When patients require specific individualized therapy, pharmacists are called upon by physicians to compound a wide range of different products, including extended-release and slow-release capsules (Bogner, Szwejkowski, Houston, 2001).

The modified release term has been used to describe many kinds of therapeutic and/or pharmacokinetic objectives, including sustained-release, sustained action, prolonged action, slow-release, delayed-release, etc (Shargel, Yu, 1999). Extended-release dosage forms have been extensively carried out several decades ago. Production of tablets and capsules with microgranules has been described applying various materials as cellulose and methacrylic acid derivatives (McGinity, Fukuda, Peppas, 2006; Zheng, Sauer, McGinity, 2005; Lopes, Costa, Lobo, 2005; Fu et al., 2004; McGinity et al., 2004; Young, Koleng, McGinity, 2002; Siepmann et al., 2000; Ishikawa et al., 2000)

Compounded, slow-release and extended-release capsules has been part of a group called matrix systems and the most common technique to obtain these matrices involves basically the simple mixture of the drug with an inert, hydrophobic or hydrophilic matrix that can be encapsulated (Ojantakanen et al., 1993).

There are few published researches with compounded matrix capsules. Webster, Al-AlChi, Greenwood (1999) studied dissolution profiles of slow-release capsules with morphine sulfate. These authors claimed that these capsules can be an adequate alternative for the administration of morphine sulfate, based on its release, similar to that of the commercial medications.

In another study with morphine sulfate, the authors got six slow-release capsules formulations with 300 mg dose, prolonging the release with HPMC K100M polymer (Bogner, Szwejkowski, Houston, 2001).

Hydrophilic matrix capsules were also studied with micronized hormones, like progesterone, HPMC E4M Premium and excipients. They were mixed and compacted in gelatin hard capsules. It was concluded that the use of slow-release matrices prolonged the hormone absorption for many hours, allowing the patient to decrease the dose frequency. However, the authors reported the necessity of further pharmacokinetic studies, without which no affirmation could be made about the bioidentical hormones release profiles from slow-release capsules (Timmons, Timmons, 2002).

Theophylline is a good candidate to be encapsulated in slow-release capsules, since the treatment of obstructive chronic pulmonary disease and night crisis depend on keeping seric levels of the drug constant. This explains the existence of a large number of studies about modified release dosage forms with theophylline (Vendruscolo et al., 2005; Zheng, Sauer, McGinity, 2005; McGinity et al., 2005; Ojoe et al., 2005; Chambin et al., 2004; Young, Koleng, McGinity, 2002; Pather et al., 1998).

In spite of these works, there are no studies that prove the compounded extended-release capsules can reduce the drug release in accordance to the official requirements and also present inter-batch uniformity on the drug release profiles.

This research had the purpose of obtaining slow-release compounded capsules with theophylline 100 mg dose, using cellulose derivatives in different rates, studying the "in vitro" drug release. Results were compared to the theophylline release from brand medication (capsules with microgranules). Reproducibility of theophylline release from different batches of capsules was also studied.

 

MATERIAL AND METHODS

The following materials of pharmaceutical grade were used to compound matrix capsules: anhydrous theophylline 99.80% (supplied by Ariston), hydroxypropylmethylcellulose – MethocelTM K100MPRCR, E4MCR and K15MPRCR (Dow ChemicalTM), lactose M200 (GalenaTM). Gastric fluid (pH 1.2) and intestinal fluid (pH 7.5) were prepared, according to United States Pharmacopeia, 28th ed. (2005), with Merck analytic grade reagents. Anhydrous theophylline 99.80% was used for analytical determinations. Colourless, number size 1 capsules (Cardinal HealthTM).

Commercial capsules with prolonged-release microgranules (same manufacturer).

Laboratory B1 (Brand Medication): capsules with 100 mg of prolonged-release theophylline microgranules, batch Z95429; fabrication: 06/2003; beyond-use date: 06/2006;

Laboratory B2 (Brand Medication): capsules with 100 mg of prolonged-release theophylline microgranules, batch Z100857; fabrication: 01/2004; beyond-use date: 12/2006;

Formulations

Six different slow-release formulations of capsules with 100 mg of theophylline were prepared, using volumetric method for powder filling capsules in a manual encapsulator (MultilaborTM) (Allen, 1999). The composition of the compounded capsules is presented on the Table I.

All the components were sieved in 0.090 mm sieve (170 mesh). The drug and the polymer were then weighted. Their apparent volumes were measured in a graduated cylinder (50 mL) and the powders were settled down. The graduated cylinder was gently tapped 10 times and was filled with lactose as excipient. The powders were mixtured in a plastic bag for 10 minutes. All the powder was homogenized another 10 minutes in a mortar.

The powders were carefully spread on the manual encapsulator until the content was completely inside the capsules, and were settled down by tapping the manual encapsulator 10 times. The caps were put over the capsules bodies and locked. Fifty capsules of each batch were prepared.

Weight variation

Twenty capsules of each formulation were individually weighted and average, standard deviation and variation coefficient were calculated. The results were compared to the specifications of USP 28th ed. (2005).

Assay

An in-house spectrophotometric validated method, in pH 7.5 phosphate buffer solution, at 271 nm, was used to quantify the theophylline in the capsules. Samples of powders, corresponding to 100 mg of theophylline were taken and transferred to a volumetric flask (100.0 mL). About 50 mL of ethylic alcohol were added and the volumetric flask was sonicated for 40 minutes. The volume was completed with ethylic alcohol. The solution was centrifugated for 20 minutes and aliquots of 1 mL were taken and diluted into a 100.0 mL volumetric flask with 7.5 pH simulated intestinal fluid.

Sample solutions were recorded in a Beckman Coulter, DU 640, spectrophotometer at 271 nm, in comparison with 10 µg/mL theophylline standard solution, in the same medium. The tests were performed in duplicate.

Drug release

The following test was performed according to American Pharmacopeia 28th ed., for Theophylline Extended-Release Capsules Test 8, using apparatus 1 (basket) with 100 rpm stirring and temperature of 37 °C ± 0.5 °C. A 7.5 pH simulated intestinal fluid (without enzyme) was used as medium (United States Pharmacopeia, 2005).

Aliquots of 10 mL were withdrawn in different times (15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420 and 480 minutes) from the beginning of the test and the medium was replaced with equal volume at the same temperature. The aliquots were then centrifuged, diluted and quantified by ultraviolet spectrophotometric analysis, using a Standard solution with a known concentration of theophylline in the same medium as reference.

Model dependent parameters

Three mathematics models were applied to interpret dissolution kinetic, in order to determine the process order: first-order model, zero-order model and Higuchi model (Abdou, Hanna, Muhammad, 2000; Ferraz, Consiglieri, Storpirtis, 1998; Shah, Noory, Noory, 1995)

Dissolution Efficiency

Dissolution efficiency (DE) was graphically calculated from dissolved drug percentage versus time curves (Khan, Rhodes, 1975). Variance analysis (ANOVA) was used to check the existence of significant differences between DE data.

Model independent parameters

Data from dissolution profiles of chosen batches and the brand medication (Laboratory B) were submitted to simple independent model employing a difference factor (f1) and a similarity factor (f2) to compare the dissolution profiles (Costa, 2001; Shah et al., 1998).

 

RESULTS AND DISCUSSION

Official specifications establish that, for hard capsules up to 300.0 mg, the weight variation allowed is ± 10.0%, and it is not allowed more than two units out of the specification and none of them can be above or under the double of the indicated percentage. The results of weight variation presented in the Tables II and III showed that all the capsules complied with the Pharmacopeia specifications (United States Pharmacopeia, 2005).

 

 

 

 

The compounded capsules showed theophylline amount between 94.6% and 101.22%, and those from the commercial batches B1 and B2 showed 104.45%, respectively, therefore in accordance with the official specifications (United States Pharmacopeia, 2005) (Tables II and III).

The three types of tested MethocelTM showed decrease of theophylline release from the capsules (Figures 1 and 2).

 

 

 

 

According to the dissolution profiles results, the increase of HPMC content, as well as the use of higher viscosity polymers in the formulations, resulted in the decrease of theophylline dissolution rate in compounded capsules. The capsules from the formulation MEE4M351, with 35% (wt/wt) of MethocelTM E4MCR, presented dissolved amount of theophylline in accordance with the specifications of American Pharmacopeia 28th ed, Test 8.

From this formulation, ten batches were compounded to check the reproducibility of the process (Figure 2). All the batches showed dissolved quantities of theophylline in accordance with the specified limits (United States Pharmacopeia, 2005).

When the dissolution profiles of the ten batches of the formulation MEE4M351 and the brand medication (Laboratory B1) were compared through the independent model employing difference factor (f1) and similarity factor (f2), it was possible to verify that f1 values above 15 and f2 values under 50 were obtained. This means that the compounded formulations showed different dissolution profiles when compared to the studied commercial products (Table IV).

 

 

To analyze the variance among the average values of Dissolution Efficiency (DE) obtained from chosen developed batches (Figure 3),the Variance Analysis "ANOVA: Unique Factor" was used . This tool performed a simple variance analysis, in order to check if there was significant difference among the values of DE.

 

 

In this case, it was assumed as null hypothesis that the average of two ou more samples are equals (from population with the same average).

According to Table V, the found value of F was 2.07, and the value of F necessary to 5% significance is 2.12. Therefore, there is no significant difference among the compounded batches.

 

 

The kinetic models most adequated to the preparations and the obtained values for the correlation coefficient (r) of the compounded formulations are described in Table VI.

 

 

According to the correlation coefficients observed, excepted the formulation MEE4M3510, the reproduced batches followed first-order kinetic process, indicating that the dissolution rate of solid particles in a liquid medium depends of the relation between the dissolved amount of drug and the remaining amount of it in the matrix. This means that, possibly, the process occurs as a result of the drug diffusion through the jelly layer and the erosion of the matrix system, process known as Non-Fickian or anomalous.

Only the formulation MEE4M3510, with a correlation coefficient of 0.9925, followed the Higuchi model, in which the quantity of drug released is directly proportional to the "t. In fact, it was not expected that the release followed the Higuchi model, since this model considers the drug release as a diffusion process based on the first law of Fick, not considering other mechanisms, like drug release by erosion.

In the systems that employ hydrophilic matrices to control slightly soluble drug release, the predominant mechanism is generally erosion (Sako et al., 2002). In the case of compounded slow-release capsules, besides this consideration, it must be remembered that due to low compaction, the jelly layer formed by MethocelTM when in contact with the medium tends to be less rigid than one provided from a formulation with the same polymer in tablets dosage forms, due to a higher porosity of the capsule (Bogner, Szwejkowski, Houston, 2001), meeting the first-order model found.

In the dissolution profiles of the commercial capsules with prolonged release of 100 mg theophylline microgranules, it was showed that the formulations presented quick release of the drug, with dissolved amount of theophylline percentage of 104.28% in 60 minutes and 97.18% in 60 minutes (Figure 4), indicating that in these formulations the drug release is not a limit factor to the absorption. They did not complied with the specifications of the Test 8 (United States Pharmacopeia, 2005).

 

 

CONCLUSION

It was possible to obtain compounded modified release matrix capsules with theophylline using different types of hydroxypropylmethylcellulose, like MethocelTM K100MPRCR, MethocelTM K15MPRCR and MethocelTM E4MCR, to decrease the drug release rate. The formulation with 35% (wt/wt) of MethocelTM E4MCR was the one which met the specifications of dissolved drug percentage. Also, it is possible to obtain reproducibility of dissolved drug percentage in extended-release compounded capsules.

 

ACKNOWLEDGMENTS

The authors would like to thank ColorconTM and BlanverTM, São Paulo, Brazil, for the raw-materials.

 

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Recebido para publicação em 27 de julho de 2006.
Aceito para publicação em 25 de abril de 2007.

 

 

* Correspondence:
V. O. Consiglieri
Departamento de Farmácia
Faculdade de Ciências Farmacêuticas
Universidade de São Paulo
Rua Lineu Prestes, 580, Bloco 13B
05508-900 - São Paulo - SP, Brazil
E-mail: siglieri@usp.br

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