INTRODUCTION:

The goal of any ideal drug delivery system is to provide a therapeutic quantity of drug to the proper site in the body to achieve prompt response, and thus maintain the desired drug concentration. Such a conceptualized ideal drug delivery can be possible with intravenous infusion of drug at the positioning of action over a desired period of time. In recent years, scientific and technological advancements have been made within the analysis and development of rate controlled oral drug delivery systems. These formulations are a unit designed to deliver the medicine at a controlled and planned rate, thus maintaining their therapeutically effective concentration in circulation for prolonged periods of your time. A great majority of controlled formulations are formulated in the form of tablets. However, wide physiological and environmental variations in the gastrointestinal tract with respect to the surface area of absorption, pH, fluidity, rate of transit time, presence of food stuffs and co-administered medicine could influence gastric emptying.

If a controlled release product is formulated in the form of tablet which keeps its integrity throughout the gastrointestinal tract, then the location of the tablet will vary under different circumstances. This will result in the variation within the rate of drug delivery to the systemic circulation. Compared with single unit dosage form, multiunit controlled release drug delivery systems like micro beads, microcapsules and microspheres are becoming popular as they pass through the gut avoiding the vagaries of gastric emptying and different transit rates spread over a large area of absorbing mucosa preventing exposure to high drug concentration and release drug in a more predictable manner.

MATERIALS AND METHODS:

Zolmitriptan Hydrochloride was procured from Yarrow Chemicals, Sodium Alginate was supplied by Loba chem. Pvt. Ltd., HPMC-K4M was obtained as a gift sample from Colorcon Pvt Ltd, Goa, Chitosan Hydrochloride and Calcium chloride was purchased from SD Fine chemicals.

FT-IR Study of Zolmitriptan Hydrochloride with other polymers:

The FTIR spectroscopy was employed to further characterize the possible interaction between drug and excipients in the solid state on an Infrared spectrophotometer (Shimadzu Affinity-l) by conventional KBr plate method. 5mg of drug sample was mixed with 500mg of powdered potassium bromide. The mixture was passed with 25.000psi pressure in a press to form a small pellet. IR spectrum of drug was recorded in the frequency range 400-4000cm^-1. The significant peaks were recorded and were matched with standard FTIR.

Standard Calibration Curve of Zolmitriptan Hydrochloride^[4]:

A UV absorption maximum was determined by scanning 10µg/ml solution of Zolmitriptan hydrochloride in phosphate buffer of pH 6.8, in between 200-400nm by using UV-visible spectrophotometer. Further a representative spectrum was drawn of Zolmitriptan hydrochloride in phosphate buffer of pH 6.8.

Preparation of Zolmitriptan Hydrochloride Loaded Microbeads^[5-7]:

The microbeads were prepared by ionotropic gelation technique. At first, sodium alginate and Hydroxyl propyl Methyl Cellulose K4M and Chitosan Hydrochloride was dispersed uniformly in 10ml of distilled water using mechanical stirring or magnetic stirrer maintaining speed at fixed rpm so that the aqueous mucilage of sodium-alginate was obtained. This aqueous mucilage was then kept for 5-10 min. for deaeration process so as to remove all the air bubbles that may have been formed during stirring process. Then to this aqueous mucilage of sodium alginate, the accurately weighed drug (Zolmitriptan HCL) was added very slowly and stirred the whole system at fixed rpm for about 5 minutes and as a result, the drug was uniformly dispersed in the aqueous mucilage of the sodium alginate. The sodium-alginate drug dispersion was added drop-wise via a needle fitted with a 10ml syringe into 100ml of 4% calcium chloride solution for the curing process. After curing for a predetermined time, the micro beads were separated by filtration and washed with distilled water. Then the microbeads were dried at the room temperature.

Table No. 1: Composition of micro beads of Zolmitriptan Hydrochloride

Formulation Code	Zolmitriptan Hcl (mg)	Sodium Alginate (%)	HPMC-K4M (%)	Chitosan Hydrochloride	Calcium Chloride Solution (%)
FZ1	10	1	2.5	-	4%
FZ2	10	1.5	2	-	4%
FZ3	10	1.75	1.5	-	4%
FZ4	10	2	1	-	4%
FZ5	10	1	-	2.5	4%
FZ6	10	1.5	-	2	4%
FZ7	10	1.75	-	1.5	4%
FZ8	10	2	-	1	4%

All these formulations were prepared in the similar manner just by changing the concentrations of polymers (i.e. Sodium Alginate, HPMC-K4M, Chitosan Hydrochloride)

RESULTS:

FT-IR Study of the Drugs and Excipients:

The FT-IR study reveals that there were no chemical or physical interactions between the drugs and the excipients.

Figure No.1: FTIR Spectrum of pure Zolmitriptan Hydrochloride

Figure No.2: FTIR Spectrum of Optimized Formulation (FZ4)

Standard Calibration Curve of Zolmitriptan Hydrochloride:

The maximum absorption (i.e. λmax) of zolmitriptan hydrochloride in phosphate buffer of pH 6.8 was found to be 223nm. The linear equation was found to bey = 0.064x + 0.009and the r²value were found to be 0.998 respectively.

Graph No.1 Standard Calibration curve of Zolmitriptan hydrochloride

Drug Entrapment Efficiency^[8-9]:

Accurately weighed amount of Zolmitriptan HCl loaded beads were kept in 100ml of phosphate buffer of pH 6.8 for 24 hours in a beaker. The solution was filtered and the solution was then diluted with phosphate buffer of pH 6.8 for the spectrophotometric analysis of Zolmitriptan Hydrochloride at 223nm. The drug entrapment efficiency was determined using following formula:

Drug Entrapment Efficiency = EQ/TQ *100

Were,

EQ= Experimental drug content, and

TQ=Theoretical drug content

Table No. 2: Drug Entrapment Efficiency

Sr. No.	Formulation Code	Drug Entrapment Efficiency (%)
1.	FZ1	82.23
2.	FZ2	88.00
3.	FZ3	92.75
4.	FZ4	93.53
5.	FZ5	82.46
6.	FZ6	88.18
7.	FZ7	96.49
8.	FZ8	83.73

Graph No 2: Drug Entrapment Efficiency of Prepared microbeads of Zolmitriptan Hydrochloride

Bead Size Determination:

Beads size of the alginate beads was determined using an optical microscope using a compound microscope. A standard stage micrometer was used to calibrate the optical micrometer.

Table No.3: Bead Size Determination

Sr. No.	Formulation Code	Beads Size (mm)
1.	FZ1	1215
2.	FZ2	1254
3.	FZ3	1183
4.	FZ4	1214
5.	FZ5	973
6.	FZ6	997
7.	FZ7	1006
8.	FZ8	1017

Graph No. 3: Beads Size of micro beads prepared (FZ1-FZ8)

Swelling Ratio^[10-12]:

The swelling ratio of the Zolmitriptan HCL loaded beads was determined by dispensing prepared dry beads in 50ml of phosphate buffer of pH 6.8 and also in a solvent of pH 1.2 and kept it still for 24 hours. The beads were then filtered and separated on tissue paper so that the tissue paper absorbs the excess of solvent. The swelling characteristics were studied by the following formula:

SR = (Ws-Wd)/Wd

were,

Ws= weight of swollen beads and

Wd= weight of dried beads

Table No. 4: Swelling ratio at different pH

Sr. No.	Formulation Code	Swelling Ratio
Sr. No.	Formulation Code	pH 6.8	pH 1.2
1	FZ1	1723	186
2	FZ2	1731	198
3	FZ3	1734	218
4	FZ4	1759	220
5.	FZ5	1910	172
6.	FZ6	2185	153
7.	FZ7	2381	244
8.	FZ8	2541	213

Graph No.4: Swelling Ratio of Prepared micro beads

In-vitro Dissolution Study^[14-16]:

The in-vitro drug release study of prepared microbeads of Zolmitriptan Hydrochloride was carried out by using USP-type II basket apparatus following a pH progression method i.e. pH 1.2 for first 2 h, pH 6.8 for next 3 h and pH 7.4 for rest of studies The prepared formulation batches of FZ1, FZ2, FZ3, FZ4, FZ5, FZ6, FZ7, FZ8 microbeads were put into the basket separately and rotated at a constant speed of 50rpm at a maintained temperature of 37±5⁰C in 900ml of phosphate buffer as a dissolution medium. The samples were withdrawn at time intervals of 0.5hrs, 1hrs, 2hrs, 4hrs, 6hrs, 8hrs, 10hrs, and 12 hrs. At each time interval 5ml of samples were withdrawn and at the same time 5ml of fresh phosphate buffer was added to maintain the sink condition. The withdrawn samples were diluted suitably with the phosphate buffer up to 10ml. The withdrawn samples were analyzed on the double beam UV-spectrophotometer at a wavelength of 223nm to obtain the percentage cumulative drug release.

Table No.5: In-vitro dissolution study of formulation FZ1-FZ4 (% Cumulative Drug Release)

Time (hours)	% Cumulative Drug Release
Time (hours)	FZ1	FZ2	FZ3	FZ4	FZ5	FZ6	FZ7	FZ8
0.5	9.966	2.241	6.126	19.65	1.28	0.203	0.213	1.134
1	13.87	14.81	7.26	22.40	3.34	0.581	0.988	6.786
2	15.87	21.36	8.94	24.67	4.517	3.24	3.137	8.678
4	31.34	49.68	19.87	31.76	52.75	16.24	40.23	38.81
6	32.99	84.34	32.67	44.23	93.66	52.66	62.67	58.87
8	47.89	99.98	47.89	51.56		73.67	75.67	69.67
10	63.04		68.90	63.56		88.75	83.43	85.83
12	79.55		88.34	74.67		99.08	91.07	99.02

Graph No.5: In-vitro dissolution of prepared micro beads of Zolmitriptan Hydrochloride by FZ1-FZ8 (% Cumulative drug release)

Order of Release Study:

All the release data was fitted into various kinetic models like, zero order, Higuchi, and Korsmeyer-Peppas, in order to find out order and mechanism of drug release from microbeads.

Mechanism of release:

The value of ‘n’ gives an indication of the release mechanism; when n = 1, the release rate is independent of time (zero-order) (case II transport), n = 0.5 for Fickian diffusion and when 0.5 < n <1.0, diffusion and non-Fickian transport are implicated. Lastly, when n > 1.0 super case II transport is apparent. Regression coefficient and ‘n’ were calculated the value showed that, the prepared micro beads exhibited zero order kinetics.

The value of n was the formulation FZ4 was found to be 1.351 and of FZ7 was found to be 0.491. Therefore, it was found to be that the optimized formulation FZ4 exhibited super case II transport.

DISCUSSION:

This study reveals that oral sustained release beads of Zolmitriptan Hydrochloride can be successfully achieved by ionotropic gelation technique using sodium alginate with hydrophilic polymers like HPMC K4M and Chitosan Hydrochloride. The FT-IR study of drug and excipients showed no interaction with each other and all the ingredients were compatible with each other.

The prepared microbeads of Zolmitriptan Hydrochloride were prepared by using different concentrations of sodium alginate with various concentrations of hydrophilic polymers like HPMC K4M and Chitosan Hydrochloride with Calcium Chloride as a counter ion.

The drug entrapment efficiency of the formulation with HPMC K4m was found to be in the range of 82% - 94% and with Chitosan Hydrochloride 82% - 84%. The beads size of the formulation with HPMC K4m was found to be in the range of 1200 – 1220mm and with Chitosan Hydrochloride 950– 1100mm. The swelling characteristics of the formulation with HPMC K4m were found to be 180 - 200 in pH 1.2 and 1720 – 1760 in pH 6.8 and with Chitosan Hydrochloride 170 – 220 in pH 1.2 and 1900 – 2550 in pH 6.8. The characteristics of loose surface crystal study of formulation with HPMC K4m were found to be 1 – 4.5% and with Chitosan hydrochloride 0.10 – 0.20%. The percentage cumulative drug release of formulations with HPMC K4m was found to be 9% – 99.8% and with Chitosan Hydrochloride 1% – 99.08%. To find out the formulation with the most sustained release effect the percentage cumulative drug release study was carried out which shows that the maximum sustained release effect with HPMC K4m shows maximum sustained release of the drug i.e.74.67% with the formulation FZ4 while the maximum sustained release effect with Chitosan Hydrochloride was found to be 91.07% with the formulation of FZ7, therefore the formulation FZ4 was concluded as the optimized formulation.

The result of in vitro release and release kinetic indicated sustained release and exhibited zero order kinetic followed by super case II- transport. Zolmitriptan Hydrochloride release from microbeads was influenced by different alginate and different hydrophilic polymers concentrations.

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Received on 25.05.2019 Modified on 28.06.2019

Research J. Pharm. and Tech. 2019; 12(12): 5972-5976.

DOI: 10.5958/0974-360X.2019.01037.0