Formulation, Optimization and Evaluation of Controlled Release Alginate Microspheres Using Synergy Gum Blends

 

VN Deshmukh*, JK Jadhav, VJ Masirkar, and DM Sakarkar

Sudhakarrao Naik Institute of Pharmacy, Nagpur Road, Pusad, Dist. Yavatmal - 445 204 (M.S), India.

*Corresponding Author E-mail: go2vilas@rediffmail.com

 

ABSTRACT

The microspheres were prepared by ionic cross-linking technique. Chemical reaction between sodium alginate and calcium chloride to form calcium alginate was utilized for microspheres. For slowing the rate of release from microspheres the hydrophilic polymer Locust bean gum and xanthan gum and their combinations was added in different concentration so that the drug will be release constantly for 12hrs. The formulation prepared showed the angle of repose within acceptable range having a good flow property. The drug entrapment efficacy of all the formulation was in the range of 90.6 – 98.9%. The drug entrapment efficacy of microspheres increases with increase in concentration of hydrophilic gums. Diclofenac sodium in vitro release from microspheres was studied. The microspheres containing 2.5% of Locust bean gum: xanthan gum (6:4) shows 98.8% drug release. The values of co-efficient correlation (r) were calculated and were found to be linear for first order release as compare to zero order release. Scanning electron microscopy of selected formulation indicated that the microspheres are spherical in shape and smooth surface. Stability studies reveled that polymers used were stable and compatible with the drug and there is no significant effect on physical characteristics, drug content and dissolution profile of the microsphere.

 

KEYWORDS:  Microspheres, Diclofenac sodium, Locust bean gum, Xanthan gum, Sodium alginate.

 

INTRODUCTION:

One of the common methods of controlling the rate of drug release is microencpsulation. The encapsulation technique (e.g. solvent evaporation, coacervation-phase separation) normally involve water insoluble polymer as carriers, which requires large quantity of organic solvent for there solubilization1,2. As a result the process become vulnerable to safety hazards, toxicity and increases the cost of production making the technique non reproducible, economically and ecologically at an industrial scale. These concerns demand a technique free from any organic solvent.  Microspheres prepared by Ionotropic gelatin technique has been widely examined and developed. The mechanism of Microsphere formation is based on electrostatic interaction between amine groups of polymer and negatively charge group of polyanion such as tripolyphosphate. Chemical reaction between sodium alginate and calcium chloride to form calcium alginate was utilized for Microsphere formation. The gelation of alginate is cause by forming an egg box junction to associate divalent metal ions of alginate polymer chain. Sodium alginate has been used as matrix material to achieve a control release drug delivery due to its hydrogel forming properties.

 

Gelatin of an anionic polysaccharide, sodium alginate, the primary polymer, was achieved with appositely charged counter ions i.e. Ca++ to form microparticals which were further made sustained by using divalent polymer3. The principle of gelatin is based on the formation of tight junction between the glucoronic acid residues of sodium alginate. The number of apparent cross-linking points formed within the calcium alginate gel beads increase with increase alginate concentration. The increase in the apparent cross linking density delayed the alginate gel disintegration in phosphate buffer due to the retardation of Ca++ exchange with Na++ and eventually increase lag time. The increase alginate gel density per unit volume was also thought to affect the decrease pore size within the gel, and thus drug release becomes slow4.

 

MATERIALS AND METHOD:

Diclofenac sodium was obtained as gift sample from Alkem Laboratories Ltd., Mumbai, Locust bean gum and Xanthan Gum was obtained as gift sample from Crystal Colloids Ltd. Mumbai Sodium Alginate from Sulbha Gums Bangalore, other chemicals used were of analytical grade and was purchased from local market. 

 

Preparation of Microspheres7-9:

The microspheres were prepared by ionic cross-linking technique. The alginate solution comprising 2.5% sodium alginate, 2.5-5% hydrophilic polymer, 0.1% of plasticizer and 100mg of drug were prepared by initially dissolving the polymer in 50% deionized water using gentle heat. On complete dissolution the weighed quantity of drug was add mixed thoroughly and to this solution of sodium alginate was added to afford homogeneous dispersion. The dispersion was added drop wise via 20 gauge hypodermic needle fitted with a 10ml syringe into 50ml 5%w/v of cross linking agent (Calcium chloride) solution, being stirred at 200rpm for 10min. The droplets from the dispersion instantaneously gelled into discrete drug-polymer-alginate matrices upon contact with the solution of cross-linking agent. The formed microspheres were further allowed to stir in the solution of cross-linking agent for an additional of 2hrs. On expiration, cross-linking agent was decanted and microspheres were washed with 3 x 50ml volume of deionized water. The microspheres were there after dried at 80oC for 2hrs in a hot air oven. Compositions of various formulations are shown in Table No.1.         

 

Figure 1:  Photomicrographs of controlled release microspheres

 

Evaluation of Microspheres:

Drug Entrapment Efficacy10-:

Accurately weighed microspheres equivalent to 100mg were suspended in 100ml of simulated intestinal fluid of pH 7.2±o.1 and kept for 24hrs. Next day it was stirred for 5min and filtered. After suitable dissolution, Diclofenac sodium content in the filtrate was analysed spectrophotometrically at 278nm using Shimadzu UV spectrophotometer. Finally, drug encapsulation efficiency is calculated by-

Actual drug content X 100

Theoretical drug content
 
 


Drug Entrapment Efficiency =

 

Flow Property11-:

Angle of repose method was employed to assess the flowability. Microspheres were allowed to fall freely through the funnel fixed at 1cm above the horizontal flat surface until the apex of conical pile just touched the tip of the funnel. The angle of repose (ř) was determined by formula.                      ř = tan-1 (h/r),

 

Where, h- Cone height of microspheres, r- Radius of circular base formed by the microspheres on the ground.

The flow property of microspheres is shown in Table 2

 

Figure 2: Shows smooth texture of controlled release microspheres

 

Figure 3:  Shows pore visibility of controlled release microspheres

 

Stereo Microscopic study:

Stereo microscopic study was conducted by Intel play stereo microscope to study surface morphology of the microspheres. The stereo microscopic photographs of the microspheres are shown in Figure 1, 2 and 3.    

 

In vitro drug release study:

The in vitro dissolution study was carried out using six station dissolution rate test apparatus USP at 50rpm. The dissolution medium consisted of 900ml simulated gastric fluid (pH 1.2) for first 2hrs followed by simulated intestinal fluid (pH 7.2) from 2 to 12hrs. Aliquots of 5ml were withdrawn every one-hour and an equivalent amount of fresh dissolution fluid equilibrated at the same temperature was replaced. Aliquots withdrawn were diluted suitably, filtered and analyzed at 278nm spectrophotometrically. All the release studies were conducted in triplicate and the mean values were plotted versus time with standard deviation less than three indicating reproducibility of result.

 

Stability Study12:

Stability study was carried out on the optimized formulation. The formulation was wrapped in aluminium foil and then placed in an amber colored bottle. It was stored at 40 ± 2oC, 75% ± 6% relative humidity for 6 months. Microspheres were evaluated for in vitro drug release after Two, Four and Six month. Result obtained was compared with the data obtained for zero time at room temperature and humidity (Temperature 28 ± 2oC and humidity 42% ± 2%).

 

 

Table 1:  Compositions of various formulations of microspheres.

Formulation Code

Diclofenac sodium (%w/v)

Sodium Alginate (%w/v)

Locust bean gum  (%w/v)

Karaya gum (%w/v)

Calcium chloride

(%w/v)

Glycerol (%w/v)

F1

1.5

1.5

1.25

--

5

1

F2

1.5

1.5

1.5

--

5

1

F3

1.5

1.5

--

1.25

5

1

F4

1.5

1.5

--

1.5

5

1

F5

1.5

1.5

0.75

0.50

5

1

F6

1.5

1.5

0.90

0.60

5

1

 

Figure 4:  In vitro Drug Release of Diclofenac sodium microspheres

 

RESULT AND DISCUSSION:

Chemical reaction between sodium alginate and calcium chloride to form calcium alginate was utilized for microspheres. For slowing the rate of release from microspheres the hydrophilic polymers was added in different concentration so that the drug will be release constantly for 12hrs. The formulation prepared showed the angle of repose within acceptable range having a good flow property. The drug entrapment efficacy of all the formulation was in the range of 90.6 – 98.9%. The drug entrapment efficacy of microspheres increases with increase in concentration of hydrophilic gums. Diclofenac sodium in vitro release from microspheres was studied in acid buffer (pH 1.2) for initial 2hrs and phosphate buffer (pH 7.2) for the period of 10hrs. The release pattern of microsphere was slow and spread over extended period of time. The microspheres containing 2.5% of Locust bean gum: xanthan gum (6:4) shows 98.8% drug release. The values of co-efficient correlation (r) were calculated and were found to be linear for first order release as compare to zero order release. Stereo microscopic photographs indicated that the microspheres are spherical in shape and with smooth surface. Stability studies reveled that polymers used were stable and compatible with the drug and the formulations were stable.

     

Table 2: Drug entrapment efficacy and Angle of repose of microspheres

Formulation Code

Drug entrapment

efficacy* (%)

Angle of Repose*

(ř)

F1

90.6

25o

F2

94.4

26o

F3

91.2

25o

F4

95.7

27o

F5

98.3

26o

F6

98.9

27o

* Mean of three readings.

 

CONCLUSION:

Controlled release microspheres were successfully prepared employing ionotropic gelation technique. The method of preparation was found to be simple and synergy gum blends can be effectively blended with sodium alginate to form microspheres without using organic solvents.  Microspheres prepared are spherical in shape and having a smooth surface. The drug entrapment capacity is above 98%. The microspheres were found to be effective in sustaining the drug release more than 12hrs. Drug release was diffusion controlled and followed first order kinetics. Stability studies reviewed that there was no significant change in drug content and dissolution profile of microspheres. The process of drug release from the polymer-drug matrix involves solvent penetration into the dry matrix, gelation of the polymer, dissolution of the drug, and diffusion of drug through resultant layer. Concomitantly, the outer layer becomes fully hydrated and dissolves.

 

ACKNOWLEDGEMENT:

The authors are thankful to the Management and Department of Industrial Pharmacy, Sudhakarrao Naik Institute of Pharmacy, Pusad for providing necessary facility for the research work.

 

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Received on   .  .2008       Modified on   .  .2008

Accepted on   .  .2008       © RJPT All right reserved

Research J. Pharm. and Tech.2 (2): April.-June.2009; Page 324-327