INTRODUCTION:

Extended-release dosage forms are designed to achieve a prolonged therapeutic effect by continuously releasing drug over an extended period of time after administration of a single dose.^1,2 Extended-release dosage form allows at least two-fold reduction in dosage frequency as compared to that drug presented in immediate release dosage forms. Ex: controlled release, sustained release.³ The advantages of extended-release dosage forms over conventional forms include the less fluctuation in drug blood levels, frequency reduction in dosing, enhanced convenience and compliance, reduction in adverse side effects and reduction in overall health care costs.^4.

Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small, free flowing, spherical or semi spherical units, referred to as pellets. Pellets range in size⁴, typically, between 0.5 – 1.5mm, though other sizes could be prepared. Pellets are for pharmaceutical purposes and produced primarily for the purpose of oral controlled-release dosage forms having gastro resistant or sustained-release properties or the capability of site-specific drug delivery. For such purposes, coated pellets are administered in the form of hard gelatin capsules or disintegrating tablets that quickly liberate their contents of pellets in the stomach. Controlled-release oral solid dosage forms are usually intended either for delivery of the drug at a specific site within the gastrointestinal tract or to sustain the action of drugs over an extended period of time. With pellets, the above- mentioned goals can be obtained through the application of coating materials (mainly different polymers), providing the desired function.^5,6

Mesalamineis mainly used in the treatment of ulcerative colitis, is a form of inflammatory bowel disease (IBD).⁷ Inflammatory bowel disease including irritable bowel syndrome, ulcerative colitis, and Crohn’s disease are considered as serious colonic disorders. Ulcerative colitis is a chronic, lifelong, recurrent disease characterized by inflammation of the colorectal mucosa and characteristic ulcers or open sores in the colon. In the United Kingdom, the annual incidence is around 7 cases per 100,000 populations.⁸ Ulcerative colitis if not treated, leads to colon cancer. More than 66.000 cases of colon cancer are reported to occur every year in India. Cancer of the large intestine accounts for about 15% of cancer deaths in India^9,10

MATERIALS AND METHODS:

FORMULATION:

Preparation of drug layered Pellets^11,12:

Drug layered pellets were prepared by aqueous drug layering coating method. In the present study two different type of drug layered pellets F and F, were prepared. The detailed compositions are given in Table 1.

Table 1: Formulation of Aqueous drug layering on Sugar sphere.

Ingredient	F1 Sugar sphere (30-35) Unit(mg/cap)	W/W	F2 Sugar sphere (20-25) Unit(mg/cap)	W/W
Sugar sphere	80	29.41	110	24.23
Sulfasalazine	180	66.17	320	70.48
Methocel e5	9.0	3.31	18.0	3.96
Talc	2.0	0.73	4.00	0.88
Aerosil	1.0	0.36	2.0	0.44
Purified water	q.s	q.s	q.s	q.s
IPA	q.s	q.s	q.s	q.s

a) Sift sugar sphere to get ASTM #20-25 and 30-35 so that it would not retained on the mesh.

b) Check LOD of sugar sphere (10 min at 105^.C in halogen moisture analyzer) to determine moisture content.

c) Slowly sifted methocel to isopropyl alcohol under stirring. Continuous sittiring and add purified water to it. Till clear solution is formed.

d) At last add API, talc, aerosil under continuous stirring to form dispersion.

e) Load the neutral sphere in to pam glatt gpcg 1.1 and allow to drug layering on to it

f) Dry the pellets in wurster coater at 40^◦C for 10 mins to complete drug layering.

g) The core drug layered pellets were split into 3 equal parts naming batch B-1, B-2 and B-3 and further fuctional coating was done in different ratio of water insoluble and soluble polymer.

Preparation of controlled release polymer coating (functional coating)¹³

a) Add slowly sifted methocel E5 to iso propyl alcohol under stirring. add purified water to it to form a clear solution.

b) Add slowly ethocel 7cps and triethyl citrate to above solution.

c) Load the previously drug layered beads in wurster coater till the given target weight is not achived.

d) Dry the pellets at 40^◦C and check the LOD not more than 0.5%.

Evaluation:

It was based on following three parameters

1. Drug content – Drug layered beads equivalent to 100mg of pure drug is weighed crushed in mortar pestle and mix in 100ml of phosphate buffer. sonicate the solution for 10 mins and pippete out 2ml and mix with 100ml of buffer to form 20mcg solution. Get the absorbance via UV 1700. And calculate the amount of drug present by correlating with standard drug.

2. Drug entrapment efficiency- formulae used

Mass of drug in beads

% Entrapment efficiency = --------------------------- × 100

Mass of drug used in formulation

In-vitro drug release:

In-vitro drug dissolution study was performed for the % drug release of the mesalaminefrom the formulation at the regular time interval.

Table 2: Formulation of extended release polymer coating on drug loaded beads (functional coating).

Batch no	B1		B2		B3
Ingredient	F1 Sugar sphere (30-35)	F2 Sugar sphere (20-25)	F1 Sugar sphere (30-35)	F2 Sugar sphere (20-25)	F1 Sugar sphere (30-35)	F2 Sugar sphere (20-25)
Drug layered beads	272.00	454.00	272.00	454.00	272.00	454
Ethocel 7cps	14.346	23.904	11.95	19.92	9.564	15.936
Methocel 5cps	9.564	15.936	11.95	19.92	14.346	23.904
Tri ethyl citrate	0.56	0.93	0.56	0.93	0.56	0.93
IPA	q.s	q.s	q.s	q.s	q.s	q.s
Purified water	q.s	q.s	q.s	q.s	q.s	q.s

PARAMETERS	SPECIFICATION
Dissolution medium	Phosphate buffer 7.5 pH
Volume of medium	900
Temperature	37.2^.C
Detection Wavelength	330
Paddle rotation speed	100
Sampling interval	1, 2, 4, 8 hrs

Mechanism of drug release¹⁴:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi and Korsmeyer Peppas release model. Drug release rate kinetic of dosage form was calculated by using DDSover, A Microsoft Excel Add-in.

· Zero order release rate kinetics:

To study the zero–order release kinetics the release rate data are fitted to the following equation.

F= Ko.t

Where ‘F’ is the drug release,

‘K’ is the release rate constant and‘t’ is the release time. The plot of % drug release versus time is linear.

· First order release rate kinetics:

The release rate date are fitted to the following equation

Log (100-F) = kt

A plot of log % drug release versus time is linear.

· Higuchi release model

To study the Higuchi release kinetics, the release rate data were fitted to the Following equation,

F = k t^1/2

Where ‘k’ is the Higuchi constant in higuchi model, a plot of % drug release versus square root of time is linear.

· Korsmeyer and Peppas release model

The release rate data were fitted to the following equation,

Mt /M = K.tn

Where, Mt /M is the fraction of drug released, ‘K’ is the release constant,

‘t’ is the release time.

‘n’ is diffusion exponent, if n is equal to 0.89, the release is zero order. If n is equal to 0.45 the release is best explained by Fickian diffusion, and if 0.45 < n < 0.89 then the release is through anomalous diffusion or nonfickian diffusion (swellable and cylinder Matrix).

In this model, a plot of log (Mt/M) versus log (time) is linear.

RESULT:

The three batches prepared after the process of aqueous drug layering method and functional coating. The non pareil beads were evaluated for their various parameters like drug entrapment efficiency and drug content and the results are shown in table 3-

Table 3: Drug content and entrapment efficiency of different batches.

Formulation	Drug content	Entrapment efficiency
B1	93.1 mg	93.1%
B2	95.5 mg	95.5%
B3	89 mg	89%

Table 4: Showing % Drug Release of Different Batches.

S No	Time (hrs)	B1 (6%)	B2 (7%)	B3 (8%)
1	1	22.3	19.8	8.9
2	2	53.4	36.5	23.4
3	4	91.1	67.4	52.8
4	8	105.2	90.4	78.7

Figure 1: Showing % drug release of different batches

DISCUSSION:

The formulation of controlled release beads which were coated by ethyl cellulose 7cps, known to have its release mechanism by diffusion by forming pores in the beads by the use of HPMC 5cps. Optimization of formulation in such a way so that it release occur in following way

At pH 7.5 phosphate buffer, USP type 2 disso apparatus, volume- 900 ml wavelength-330

Time (hour)	% Drug release
1	5-25
2	30-50
4	60-90
8	NLT 85

Objective has been achieved in B-2 whose release is coming under the specification.

hence B-2 formulation is optimized.

Kinetics of drug release of the optimised batch B-2:

Figure 2: Zero Order Release Kinetics of Optimised batch (B2)

According to figure 2, Kinetics was applied to optimised batch B2 which doesn’t show significant correlation coefficient. Hence B2 doesn’t follow zero order kinetics.

Figure 3: First Order Release Kinetics of Optimised Batch (B2)

According to figure 3 kinetics was applied to optimised Batch B2 and regression coefficient was found to R² = 0.8214. Hence B2 doesn’t follow first order kinetics.

Figure 4: Korsmeyer and Peppas Release Kinetics of Optimised Formulation (B2).

From figure 4 kinetics was applied to optimised formulation B2 and regression coefficient was found to R² =0.9769. Hence B2 doesn’t follow Korsmeyer and Peppas Release kinetics

Higuchi Model:

Figure 5: Higuchi matrix Release Kinetics of Optimised Batch (B2).

From figure 5 kinetics was applied to optimised batch B2 and regression coefficient was found to R² =0.981. Hence B2 shows highest regression coefficient near 0.999 the optimised batch B2 follow Higuchi matrix Release Kinetics and it suggests that the drug release occur by diffusion mechanism.

CONCLUSION:

The objective of the present study was to formulate a novel multi particulate drug delivery system for delivering drugs after oral administration to the colon. The combination of water insoluble and soluble polymer in around 50:50 ratio shows the matrix development and the release is dependent on the pore former capacity of water-soluble polymer methocel as the quantity of insoluble polymer is increased release is retard. Formulation B-2 Shows proper in-vitro release those fits into USP specification and showing the release of drug using Higuchi kinetics with highest regression coefficient near to 0.999.

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Received on 24.09.2022 Modified on 12.10.2022

Asian J. Pharm. Tech. 2023; 13(1):25-28.

DOI: 10.52711/2231-5713.2023.00005