INTRODUCTION:

Drug delivery technology is promising to modify the biodistribution and thereby enhance the therapeutic effects¹. A delivery system is needed for a drug to reach the target site from the site of administration in required concentration, and to maintain optimum therapeutic levels for a sufficient period². The low water solubility of lipophilic drugs always results in poor and variable drug absorption after oral administration³. Simvastatin has been widely used clinically as a therapeutic of hyperlipemia. Simvastatin is a potent inhibitor of hydroxymethylglutaryl coenzyme A reductase, a ratelimiting enzyme for cholesterol biosynthesis through mevalonate pathway. Simvastatin is a low-solubility high-permeability drug by the classification of the biopharmaceutics system, class 2. It is well known that drug release is a crucial and limiting step in the rate and extent absorption of a class 2 drug from a solid dosage form⁴. Microencapsulation techniques have been widely used to achieve a controlled release for drugs. Various microencapsulation methods exist amongst these methods solvent evaporation technique has gained considerable attention and has been commonly applied⁵.

Polymeric microspheres have found numerous applications in drug delivery, vaccination, personal care and medical diagnostics. Microspheres provide an effective means of protecting, releasing and potentially targeting drugs for various biomedical applications⁶. Ethylcellulose, being a biocompatible and non-biodegradable polymer, is studied extensively as encapsulating material for the controlled release of pharmaceuticals. Microspheres with various ethyl cellulose/drug ratios have been prepared to get optimum release of drug for a prolonged period. Many researchers developed ethylcellulose microspheres with higher percentage of polymer to achieve the required sustained release⁷. This study focused on the development and invitro evaluation simvastatin microspheres using ethylcellulose as a rate controlling material.

MATERIALS AND METHODS:

Simvastatin and Ethyl cellulose were gift samples from Caplin Point Laboratories Ltd., Chennai. All other chemicals and solvents were of analytical grade.

Preparation of Microspheres:^8-11

Microspheres containing Simvastatin drug as the core material was prepared by solvent evaporation method (table-1). The drug and ethyl cellulose were dissolved in ethanol using a magnetic stirrer. Further, dichloromethane was added to the above solution. The resultant dispersion medium was added drop wise to the aqueous system containing Span 80 (1%). The solution was stirred at 700rpm by mechanical stirrer equipped with three bladed propellers at room temperature. The solution was stirred for three hours for the formation of microspheres. After three hours the formed microspheres were collected by filtration. The microspheres collected were then air dried at room temperature for 3 hours and stored in desiccators over fused Calcium chloride for further use.

Table No 1: Working formula for formulation of microspheres

INGREDIENTS	FORMULATIONS
INGREDIENTS	F1	F2	F3	F4	F5
Simvastatin	1	1	1	1	1
Ethyl cellulose	0.5	0.75	1	1.5	2
Ethanol (ml)	5	5	5	5	5
Dichloromethane (ml)	5	5	5	5	5
Aqueous Phase with Span 80 (1%)	100 ml	100 ml	100 ml	100 ml	100 ml

Percentage Yield:

The prepared microspheres were collected and weighed. The yield was calculated by dividing the recovered weight of microspheres by the total solids added at the beginning of the preparation.

Percentage Yield = (Weight of the microspheres recovered / total weight of the solids) X 100

Microsphere Size:

Optical microscopic analysis was performed to determine the average size of the microsphere. A sample of microspheres were mounted in the glass slide and examined microscopically. Calibrated eyepiece micrometer and stage micrometer were utilized for the size analysis.

Drug entrapment efficiency (DEE):

50 mg of drug loaded microspheres were dissolved in 10 ml of methanol. Further appropriate dilutions were made and the resulting solution was spectrophotometrically analyzed at 239nm for the drug content. The drug entrapment efficiency was calculated by the equation

DEE= (Pc/Pt) ×100

Where,

Pc is practical content, Pt is theoretical content.

The above three parameter values were shown on the Table 2.

Table No 2: Invitro Characteristics of formulated microspheres.

Formulation code	Percentage Yield	Particle Size (µm)	Drug entrapment Efficiency (%)
F1	49	65.94	48.4
F2	63	71.23	68.0
F3	58	79.85	72.3
F4	48	82.73	83.0
F5	71	97.34	96.8

Scanning Electron Microscopy (SEM)”

The morphological characteristics of Simvastatin microspheres (F5) were examined using Scanning electron microscopy (Hitachi-S3400N, Japan). The dried microspheres were coated with gold foil (100 Aº) under an argon atmosphere in a gold coating unit and scanning electron micrographs was observed.

Figure 1: SEM image of Simvastatin Microsphere (F5)

Invitro drug release study:

In vitro drug release study was carried out in USP paddle type II dissolution test apparatus using phosphate buffer pH 7.4 as the dissolution medium. 50mg of drug loaded microspheres were weighed and placed in 900ml of the dissolution medium. The bath temperature was maintained at 37± 0.5ºC throughout the study. Paddle speed was adjusted to 100 rpm. At an interval of 1 hr, 1ml of sample was withdrawn with replacement of 1 ml fresh medium. 1ml of sample withdrawn was made up to 5ml with fresh medium. This solution was analyzed for drug content by UV-Visible spectrophotometer at 239nm.

Figure 2: Invitro release characteristics of simvastatin microspheres

RESULTS AND DISCUSSIONS:

The Simvastatin loaded microspheres were prepared by oil in water (O/W) solvent evaporation method with ethyl cellulose as the retardant material in different ratio. From the literature it was found that ethanol at an appropriate ratio was a good solvent for Simvastatin and water can be used as the poor solvent. Ethanol has higher solubility in water. As soon as the dispersing solution was added into the continuous medium, ethanol diffused rapidly from the polymer solution. Hence, Dichloromethane was selected as the bridging liquid due to good solvent linkage and their immiscibility in water. When the mixture of ethanol and dichloromethane containing drug and polymer was added into aqueous medium under stirring, a fine dispersion formed immediately. In the preparation of microspheres, the diffusion of the good solvent into the poor solvent encouraged the co precipitation of the drug and the polymer in the droplets and the dichloromethane linked the segments together to form microspheres.

The percentage yield and particle size distribution of all the formulations were found to be satisfactory. Among all the formulation F5 showed high percentage yield, this is due to increased polymer concentration. Increase in polymer concentration increased the viscosity of the solution which further increases the inter-facial viscosity thus reduces the shearing efficiency and prevents the breakdown of the disperse phase into smaller droplets. As a result, increase in ethylcellulose concentration increased the size of the droplets thus forming bigger microspheres.

The morphological characteristics of simvastatin loaded microspheres F5 were obtained by SEM. The microspheres were spherical with smooth surfaces. The smooth walled microspheres had adequate pores which help in the drug release.

The drug entrapment efficiency for all the formulations were calculated. Among which F4 and F5 showed high drug entrapment efficiency. This is due to high polymer concentration. The high content of simvastatin in microspheres is due to its poor solubility in water, thus it is a preferred method for the preparation of simvastatin microspheres.

In vitro drug release studies were performed in phosphate buffer pH7.4 as the dissolution medium. The percentage drug release decreased with increasing ethyl cellulose concentration. The increased concentration of polymer increased the diffusional pathlength which decreases the drug release from the polymer. At lower polymer concentration, microspheres were smaller in size which had larger surface area exposed to the dissolution medium and had faster drug release.

CONCLUSION:

Simvastatin microspheres were prepared successfully by solvent evaporation technique. The release rate of simvastatin from the microspheres could be controlled by adjusting the formulations of the microspheres and the preparation condition. The results of the present study suggest that F5 is the most suited formulation to develop microspheres. Among all formulations F5 have a significantly slower release pattern in terms of their total drug load, as the amount of polymer increased, the drug release decreased. It was observed that concentration of polymer affects all the evaluation parameter significantly. Hence the prepared simvastatin microspheres may prove to be potential candidate for safe and effective sustained drug delivery.

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Received on 13.05.2011 Modified on 28.05.2011

Research J. Pharm. and Tech. 4(8): August 2011; Page 1278-1280