Design and optimization of floating drug delivery system of acyclovir

*Corresponding Author:

A. A. Kharia
Oriental College of Pharmacy, Raisen Road, Bhopal-462 021,India
E-mail: ankitanandkharia@yahoo.co.in

Abstract

The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 32 full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t 50% ) and 70% (t 70% ) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t 50% and t 70% indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix.

Keywords

Acyclovir, factorial design, gastro retentive drug delivery, hydroxypropylmethylcellulose, psyllium husk

Introduction

Floating drug delivery systems (FDDS) have been developed for drugs that act either locally in the stomach or absorbed from it, for those drugs that are either poorly soluble at alkaline pH or unstable in the intestinal or colonic environment [1]. These systems help in completely releasing the drug in the vicinity of the absorption window to enhance bioavailability. Several approaches that are currently made to prolong gastric retention time include, floating drug delivery systems, swelling and expanding systems, bioadhesive systems, high density systems and other delayed gastric emptying devices [2-5].

Acyclovir is a guanine analogue used in the treatment of viral diseases. The reported oral bioavailability is 10-20% with a plasma elimination half life of 1-2 h [6]. Acyclovir has its absorption window in the duodenum and small intestine [7]. After per oral administration, only 20% of the drug is absorbed with the remaining 80% of the drug excreted in the feces. After repeated per oral dosing of small amounts of acyclovir the bioavailability can be enhanced [8,9]. These facts indicate that increasing gastric residence time may enhance bioavailability of acyclovir. Therefore, acyclovir was selected as a model drug for the design of a FDDS with a view to improve its oral bioavailability.

Belgamwar and Surana [10] formulated and optimized floating bioadhesive drug delivery systems using psyllium husk and hydroxypropylmethylcellulose (HPMC) K15M for retarding the release and crossprovidone as a swelling agent. In vitro drug release was found to have followed the Higuchi kinetics and release mechanism to be non-Fickian type. Rao et al. [11] developed and optimized FDDS of cephalexin by using HPMC K4M, xanthan gum, guar gum, sodium bicarbonate and tartaric acid. In this study, influence of independent variables like polymer, polymer ratio, polymer type and tartaric acid on floating lag time and cephalexin release profile were studied. The mechanism of drug release for optimized formulation was found to be anomalous type. Prajapati et al. [12] studied the formulation and in vitro evaluation of floating matrix tablets of domperidone by using different combinations of HPMC K4M, Carbopol 934P and sodium alginate. Carbopol 934P showed negative effect on floating properties but was found to be helpful to control the release rate of drug.

In the present work, it was attempted to formulate FDDS of acyclovir using HPMC K4M and psyllium husk as the polymers and sodium bicarbonate as gas generating agent, in order to deliver the drug at a controlled rate to its absorption site so that its oral bioavailability can be enhanced. After preliminary studies, optimization of designed FDDS was performed using 32 full factorial design by conducting experiments to evaluate all the nine batches of acyclovir FDDS. The validity of the derived polynomial equations for the dependent variables (dissolution parameters) was verified by designing and evaluating two extra check point formulations.

Materials and Methods

Acyclovir and psyllium husk were gift samples from M/s Modern Laboratories Pvt. Ltd., Indore, India. HPMC K4M was obtained as a gift sample from Colorcon Asia Pvt. Ltd., Goa, India. Microcrystalline cellulose (MCC) was gifted by Motiff Labs., Goa, India. Polyvinyl pyrolidone K30 (PVP K30) and sodium bicarbonate were purchased from S. D. Fine Chemicals, Mumbai, India. All other ingredients used throughout the study were of analytical grade and were used as received.

Full factorial design

The factorial design is a technique that allows identification of factors involved in a process and assesses their relative importance. In addition, any interaction between factors chosen can be identified. Construction of a factorial design involves the selection of parameters and the choice of responses. Optimization has been done by using 3² full factorial design, where amount of psyllium husk (X₁) and amount of HPMC K4M (X₂) were taken as independent variables and the time required for 50% (t_50%) and 70% (t_70%) drug dissolution as dependent variables. Step-wise backward linear regression analysis was used to develop polynomial equations for the dependent variables t_50% and t_70% values by using PCP Disso 2000 V3 software. The validity of the developed polynomial regression equations was verified by preparing two check point formulations (C1 and C2) [13,14].

Preparation of acyclovir floating drug delivery system

The tablets of acyclovir were prepared by wet granulation method by using psyllium husk and HPMC K4M as the matrix forming polymers, sodium bicarbonate as a gas generating agent and PVP K30 as a binding agent. Each formulation was composed of drug and excipients in various proportions as shown in Table 1. For formulation of tablets, acyclovir, psyllium husk, HPMC K4M, sodium bicarbonate and MCC were sifted through mesh (# 40) and were collected in an octagonal blender and mixed well to get a uniform mixture. The paste of PVP K30 in isopropyl alcohol was used as a granulating agent. The prepared granules (40 mesh sieve) were dried in a conventional hot air oven (Yorko India Pvt. Ltd., Mumbai, India) at 45° and dried granules were further passed through sieve (# 40). Magnesium stearate and talc (1%) were added as a lubricant and the granules were compressed into tablets using a single stroke tablet machine (Rimek, Ahmedabad, India).

Table 1: Composition Of Acyclovir Factorial Design Formulations

Hardness and friability test

The crushing strength of tablets was determined by using Monsanto type hardness tester (Rolex, Chandigarh, India). In all the cases, mean of six replicate determinations were taken. Friability was determined by weighing 10 tablets after dusting, placing them in the friabilator (Riche-Rich Pharma, Bangalore, India) and rotating the plastic cylinder vertically for 100 revolutions [3]. After dusting, the total remaining weight of the tablets was recorded and the percent friability (PF) was calculated using the formula, PF= [(weight_initial–weight_final)/weight_initial]×100.

Uniformity of weight and drug content

Uniformity of weight was determined by dusting of each tablet and placing in the electronic balance (Shimadzu BL-220H, Japan). The weight data from the tablets were analyzed for sample mean and percent deviation. Uniformity of drug content was determined by taking 5 tablets in a glass mortar and powdered, 100 mg of this powder was placed in a 100 ml stoppered conical flask. The drug was extracted with 0.1 N HCl and shaking vigorously on a mechanical gyratory shaker (100 rpm) for 5 h, filtered into 50 ml volumetric flask through cotton wool and filtrate was made up to the mark by passing more 0.1 N HCl through filter. Further appropriate dilution were made and absorbance was measured at 256 nm using 0.1 N HCl as blank solution by UV/Vis double beam spectrophotometer (UV-1800, Shimadzu, Japan).

In vitro buoyancy study

The in vitro buoyancy was characterized by floating lag time and total floating time. The test was performed using a USP XXIII type 2 dissolution test apparatus (Electrolab, India) using 900 ml of 0.1 N HCl at paddle rotation of 50 rpm at 37°±0.5º. The time required for the tablet to rise to the surface of the dissolution medium and the duration of time, the tablet constantly floated on the dissolution medium were noted as floating lag time and floating time, respectively (n=3).

Swelling index

The individual tablets were weighted accurately and kept in 50 ml of water. Tablets were taken out carefully after 60 min blotted with filter paper to remove the water present on the surface and weighed accurately. Percentage swelling index (SI) was calculated by using the formula [15], SI = [(wet weight–dry weight)/dry weight]×100

In vitro dissolution study

The in vitro dissolution studies of FDDS of acyclovir were carried out in USP XXIII type 2 dissolution test apparatus, employing a paddle stirrer at 50 rpm using 900 ml of 0.1 N HCl as dissolution medium. At predetermined time intervals, 5 ml of the samples were withdrawn by means of a syringe fitted with a prefilter. The volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium maintained at 37±0.5°. The samples were analyzed for drug release by measuring the absorbance at 256 nm using UV/Vis double beam spectrophotometer after suitable dilutions. The determinations were performed in triplicate.

Kinetic modeling of drug release

The dissolution profile of all the batches was fitted to zero-order (Eqn. 1), first-order (Eqn. 2), Higuchi (Eqn. 3) and Korsemeyer-peppas (Eqn. 4) models to ascertain the kinetic modeling of drug release [16-19].

where R and UR are the released and unreleased percentages, respectively, at time (t), k₁, k₂, k₃, and k₄, are the rate constants of zero order, first order, Higuchi matrix, and Peppas-Korsmeyer model, respectively.

Results and Discussion

The prepared FDDS tablets were evaluated for hardness, friability, uniformity of weight, uniformity of drug content, swelling index, floating lag time, in vitro buoyancy behavior, in vitro dissolution, short-term stability and drug-polymer interaction. The evaluation data is shown in Table 2. The hardness of the prepared FDDS of acyclovir was found to be in the range of 4.42 to 4.72 kg/cm². The friability of all tablets was less than 1% i.e., in the range of 0.53 to 0.68%. The percentage deviation from the mean weights of all the batches of prepared FDDS was found to be within the prescribed limits. The low values of standard deviation indicate uniform drug content in all the batches (Table 2).