Optimization of aqueous based film coating technique for pellets in colon specific delivery of mesalamine

Pramod Salve*

University Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Campus, Mahatma Fuley Shaikshanik Parisar, Amravati Road, Nagpur – 440 033 (MS) India

ABSTRACT:

Mesalamine is an inflammatory agent to treat inflammation of digestive tract (crohn’s disease) and mild to moderate ulcerative colitis. It shows inflammatory activity by blocking cyclooxygenase and prostaglandins production in colon. The multiple unit dosage form of mesalamine in the form of pellets was prepared. The parameters like moisture content, speed of spheronization and spheronization aid (MCC PH 101) were optimized. The pellets were loaded with 40% drug, 90% moisture content, 1% binder PVP K-30 and spheronization speed of 1500 rpm were found to be parameters for pelletization. For drug release in colon inner coating using Eudragit RL RS 30 and outer coating using Eudragit FS 30D was done. In vitro drug release studies clearly revealed that 15% coating levels of eudragit FS 30D withstand acidic media and 1% drug release was observed which was optimum coating level for colon targeting. With aqueous dispersion of eudragit FS 30D (outer coat) at 15% coating level, 1% drug release was observed in pH 1.2 buffer for 2 hours and sustained drug release for 8 hours was obtained in pH 7.2 phosphate buffer. When pH of dissolution media was increased from 6.8 to 7.2, drug release was found to increase from 8.45 to 96.05%. As compared with formulation containing croscarmellose sodium, release rate was decreased with formulation containing crospovidone. Hence, film coated pellets can be used for colonic release of mesalamine.

KEYWORDS: Colonic release, mesalamine, eudragit RL RS 30 and FS 30D

INTRODUCTION:

The colon diseases such as ulcerative colitis, Crohn’s diseases, colon carcinomas, inflammatory bowel disease etc. It is due to less hostile environment with lesser diversity and intensity of enzymatic activities of colon as compared to stomach and small intestine¹. There are problems in colon specific drug delivery as it has small surface area. Colon is reductive medium thus pH sensitive coating can be used². There is low permeability of colonic epithelium⁴. Novel drug delivery systems like liposomes, resealed erythrocytes etc. have disadvantages pertaining to optimization of formulation parameters, stability and route of administration¹. Thus, it was needed to solve these problems, it is done by using multiple drug delivery system. Multiunit drug delivery has advantages over single unit dosage form. As multiunit dosage form shows pharmacological action at right time. As drug is divided into small units, there is no dose dumping. Single unit formulations lead to below minimum effective concentration limit²¹.

The colon pH varies from 6.4 to 7. The variation in pH of colon can be used as a tool for colon specific drug delivery system¹. Majority of drugs are absorbed by passive absorption. Colon targeted drug delivery from oral dosage forms can be achieved by delayed sustained or controlled release mechanisms. Enteric coatings have been used to block drug delivery in stomach. Dissolution controlled mechanisms have been used to block drug delivery in stomach. Dissolution controlled mechanisms have aimed to release a drug in the colon and to ensure its delivery throughout the colon. These mechanisms are highly susceptible to pH, motility and enzymatic attack, making accurate timing and delivery undependable⁶. Multiunit colonic drugs has objective to be protected from degradation due to variation in colonic pH, colonic microflora. Multiunit drug avoid degradation throughout gastrointestinal tract. Palletization technique was followed in multiple colonic drug delivery systems. The principal group of polymers utilized for the preparation of colon targeted dosage forms are the eudragits more specifically eudragit L and S. These are pH dependent. These are anionic polymers which are water impermeable at low pH but become ionized and dissolve at intestinal pH. Eudragits S 100 and L 100 are copolymers of methacrylic acid and methyl methacrylate. The ratio of carboxyl to ester groups is approximately 1:1 in eudragit L100 and 1:2 in eudragit S100. These polymers form salts that dissolve above pH 6 and 7 respectively. Eudragit L 100 55 is a copolymer of methacrylic acid and ethyl acrylate which dissolves above pH 5.5.

Mesalamine is a drug used to treat inflammatory digestive tract diseases. It inhibits arachidonic acid metabolites through cyclooxygenase pathways, prostanoids through lipooxygenase pathways. These drugs inhibit cyclooxygenase enzyme and prostaglandin production in colon. Hence, it is envisaged to use mesalamine for multiple colonic drug delivery system.

MATERIALS:

Mesalamine was obtained as a gift sample from Cosme Pharma Laboratories, Mumbai (India). Microcrystalline cellulose PH 101 and PVP K30 was obtained as sample from Signet Chemical Corporation, Mumbai (India). Eudragit RS, RL 30D and Eudragit FS was obtained from Evonik Degussa India Pvt. Ltd, Mumbai (India).

METHODS:

Moisture content:

The Extrudates were prepared with different moisture content as shown in table 1 and then spheronized at 1500 rpm speed for 15 minutes.

Table 1 Composition of pellets at different moisture level

Formulation code	Quantity of MCC PH 101 (g)	Quantity of PVP K- 30 (g)	Moisture Content (%)
P1	29	1	70
P2	29	1	80
P3	29	1	90
P4	29	1	100
P5	29	1	110

Spheronization speed and spheronization time:

Effects of spheronization speed and spheronization time are shown in table 2

Table 2 Composition of pellets at different spheronization time and friction plate speed

Formulation Code	Quantity of MCC PH 101(g)	uantity of PVP K-30(g)	Spheronization time (Minutes)	Spheronization speed (rpm)
P6	29	1	5	200
P7	29	1	10	200
P8	29	1	15	200
P9	29	1	5	400
P10	29	1	10	400
P11	29	1	15	400
P12	29	1	5	800
P13	29	1	10	800
P14	29	1	15	800
P15	29	1	5	1000
P16	29	1	10	1000
P17	29	1	15	1000
P18	29	1	5	1500
P19	29	1	10	1500
P20	29	1	15	1500

Feed size and spheronization time:

Pellets were developed at varying feed size and spheronization times. The spheronization speed 1500 rpm was kept constant. Effect of feed size and spheronization time are shown in table 3.

Table 3 Composition of pellets at different feed size and spheronization time

Formulation code	feed size (g)	Quantity of PVP K- 30(g)	Spheronization speed (rpm)	Spheronization time (Minutes)
P21	10	1	1500	5
P22	10	1	1500	10
P23	10	1	1500	15
P24	30	1	1500	5
P25	30	1	1500	10
P26	30	1	1500	15
P27	60	1	1500	5
P28	60	1	1500	10
P29	60	1	1500	15

The optimized base formula i.e. 30 g feed size, 90% moisture content, 1500 rpm spheronization speed with 15 minute spheronization time were used for development of drug loaded pellets. Compositions of drug loaded pellets are shown in table 4.

Drug loading:

Pellets were prepared with optimized base formula containing 40% drug loading shown in table 4.

The MCC PH 101 was shifted through sieve 60 # and accurately weighed. The MCC PH 101, disintegrants and drug were blended in geometric way and granulated with aqueous solution of PVP K-30 get suitable wet mass. The damp mass transferred into extruder to obtain extrudate. Extrudates were spheronized at 1500 rpm and were dried at 45-50 ⁰C for 12 hours. Formulation batches P31 and P32 contain croscarmellose sodium and crospovidone respectively, whereas formulation batch P30 was without disintegrants.

Evaluation of pellets:

The prepared pellets were evaluated for drug content, bulk density, tapped density, Hausner’s ratio, granule density, friability, size distribution, yield, angle of repose and packaging stability.

Enteric coating of pellets:

The coating of drug loaded pellets was done using inner coat of eudragit RS-RL 30D aqueous dispersion and outer coat of aqueous polymeric dispersion of eudragit FS 30D.

Coating formulation preparation guidelines:

Mixing Procedure:

Eudragit RL RS 30D dispersion (for inner coating):

The coating formula contained tween 80 (0.2% of dry polymer) as surfactant, glyceryl monosterate (0.5% of dry polymer) as glidant, and triethyl citrate (20% of dry polymer). Tween 80 was dissolved in water and solution was heated, then glyceryl monosterate was slowly added to above solution with stirring and mixing for 30 min. The solution was allowed to cool to room temperature and then triethyl citrate was mixed with above solution by using magnetic stirrer. Eudragit RL 30D and RS 30D were separately mixed and the pre-dispersion was slowly added to the eudragit dispersion using magnetic stirrer. The dispersion was mixed for 10 min.

Eudragit FS 30D (for outer coating):

The coating formula and the method of preparation for eudragit FS 30D dispersion were the same as mentioned above.

Coating of pellets:

For inner coat, the pellets were coated with a combination of eudragit RS RL 30D dispersion (2:8) in pear shaped glass coating pan. The coating pan was rotated and dispersion was sprayed over the cascading pellets using spray gum with spray rate of 1mL for 5 minute and hot air was blown to evaporate the solvent. In process samples at various coating levels (% polymer weight gain) were taken to check morphology of coating. Coating was continued until complete polymer weight gain was achieved. Coated pellets were then oven cured for 24 hours at 40 ⁰C. For initial development, the proportion of 2:8 for mixing eudragit RL and RS and the coating level 6% for inner coat were chosen after reviewing the previous literature reports about sustained release work done using these polymers.

For outer coat, cured pellets containing inner coat of eudragit RS RL 30D were further coated with eudragit FS 30D in pear shaped glass coating pan with spray rate of 1 mL for 5 minute. In process samples at various coating level were taken and coating was continued until complete polymer weight was achieved i.e. 5, 10, and 15% (% polymer weight gain). Coated pellets were then oven cured for 24 hours at 40 ⁰C. Eudragit RL RS 30 D and FS 30D coating was done in glass pear shaped coating pan at 30 rpm rotating speed, 20 psi pressure and 20 g batch size.

In vitro drug releases from uncoated pellets without disintegrants were studied. In vitro drug release from uncoated pellets containing combination of disintegrants like croscarmellose sodium and crospovidone were studied. In vitro dissolution study of coated drug loaded pellets was done in USP Type I method at pH 1.2 buffer for 2 hours.

RESULTS:

The pellets were developed using microcrystalline cellulose PH 101 as spheronizing aid by extrusion spheronization method which involves wet massing of powder blend, extrusion of wet mass and spheronization of extrudates. In present study, the effect of various process variables such as moisture content, spheronization speed, spheronization time, load size and drug loading were studied on physical properties of pellets.

Effect of moisture level on shape of pellets:

Effect of moisture content on physical properties of pellets is shown in table 5.

Table 5 Effect of moisture content on shape of pellets

Sr. No.	Formulation code	Quantity of MCC PH 101	Quantity of PVP 30	Moisture Content (%)	Yield (%)	Fines (%)	Shape
1.	P1	30	1	70	64.6875	6.125	Spherical
2.	P2	30	1	80	69.938	3.415	Spherical
3.	P3	30	1	90	82.489	82.489	Spherical
4.	P4	30	1	100	85.212	85.212	Irregular
5.	P5	30	1	110	86.165	86.165	Irregular

Table 6 Effect of spheronization speed and time on shape of pellets

Sr. No.	Formulation Code	Quantity of MCC PH 101	Quantity of PVP K-30 (g)	Spheronization speed(rpm)	Spheronization Time(Minutes)	Shape of pellets
1	P6	30	1	200	5	Dumbell
2	P7	30	1	200	10	Dumbell
3	P8	30	1	200	15	Dumbell + Oval
4	P9	30	1	400	5	Dumbell
5	P10	30	1	400	10	Dumbell + Irregular
6	P11	30	1	400	15	Dumbell + Oval
7	P12	30	1	800	5	Dumbell
8	P13	30	1	800	10	Dumbell + Oval +Irregular
9	P14	30	1	800	15	Oval + spherical
10	P15	30	1	1000	5	Oval + spherical
11	P16	30	1	1000	10	Irregular + Dumbell
12	P17	30	1	1000	15	Spherical
13	P18	30	1	1500	5	spherical + Oval
14	P19	30	1	1500	10	Spherical
15	P20	30	1	1500	15	More spherical

Table 7 Effect of feed size and spheronization time on shape of pellets

Sr. No.	Formulation Code	Load size (g)	Quantity of PVP K-30(gm)	Spheronization speed (rpm)	Spheronization time (Minutes)	Shape of Pellets
1	P21	10	1	1500	5	Irregular + Dumbell
2	P22	10	1	1500	10	Irregular + Oval
3	P23	10	1	1500	15	Irregular +spherical
4	P24	30	1	1500	5	Irregular
5	P25	30	1	1500	10	Spherical
6	P26	30	1	1500	15	More Spherical
7	P27	60	1	1500	5	Irregular + Oval
8	P28	60	1	1500	10	Irregular
9	P29	60	1	1500	15	Spherical

Effect of drug loading on physical properties of pellets:

Pellets without disintegrants were spherical (formulation batch P30) and retained on 10-18# sieve, also pellets containing croscarmellose sodium (formulation batch P31) and crospovidone (formulation batch P32) were spherical with above process parameter and retained on sieve 10-18, 12-18# respectively. The effect of drug loading on shape of pellets is shown in table 8.

Evaluation of pellets:

Drug content:

Pellets containing formulation code P30 has more drug content than P31 and P32. The drug content of mesalamine loaded pellets are shown in table 9.

Table 9 Drug content of formulation batches

Formulation code	P30	P31	P32
Drug content (%)	99.29	99.05	98.82

Physical properties of drug loaded uncoated pellets:

The physical properties like size yield (%), shape, density and friability of selected batches were evaluated. These physical properties affect flowability, filling efficiency, surface area and release profiles.

In vitro drug release of uncoated and coated pellet:

Without disintegrants:

Figure 1 shows release of mesalamine from uncoated pellets without disintegrants. Thus, effect of combination of disintegrants croscarmellose sodium and crospovidone on drug release.

Figure 1 Drug release of uncoated and coated pellets without disintegrant

With disintegrants:

To study effect of disintegrants i.e. croscarmellose sodium (formulation batch P31) and crospovidone (formulation batch P32) on release of mesalamine from uncoated pellets were evaluated. The results are shown in figure 2. In vitro drug release from pellets containing croscarmellose sodium (formulation batch P31) shown that 93% release was observed in acidic media for 2 hours and complete release was observed in 4 hours in pH 6.8 phosphate buffer. Similarly, in acidic media, release of 91% was observed from formulation containing crospovidone (formulation batchP32) for 2 hours and complete release was observed in 4 hours in pH 6.8 phosphate buffer.

Figure 2 Drug release profiles of uncoated pellets containing croscarmellose sodium and crospovidone

Effect of inner coating on drug release:

The coating level studied was 2, 4 and 6%. At 2% coating level release rate was found to be complete in acidic media for 2 hours and at 4% coating level drug release was found to be 85% in 2 hours and complete release in pH 6.8 phosphate buffer for 4 hours. It indicates that release rate was faster with 2% and 4% coating level. It was not suitable for sustained release characteristics. At higher coating level of 6%, the release rate was found to be sustained for period of 10 hours, hence selected as optimum level for providing sustained release characteristics.

Effect of outer coating level on drug release:

For outer coat, the cured pellets containing inner coat of eudragit RS-RL were further coated with eudragit FS 30D. In-process samples at various coating levels were taken and the coating was continued till weight gain of 15% was achieved. Coating level studied were 5%, 10% and 15% to achieve desired pH dependent drug release in colon.

Effect of 5% coating level on drug:

To study the effect of coating level on release of mesalamine from pellets cured at 40 ⁰C for 24 hours. The results are shown in figure 3.

Figure 3 Drug release profile of 5% eudragit FS 30D coated pellets containing croscarmellose sodium (formulation batch P31) and crospovidone (formulation batch P32) in pH 6.8 buffer

In vitro release studies clearly revealed that at low coating level of eudragit FS 30D (5%) coating was not able to withstand acidic media and 35, 30% drug release was observed for 2 hours and complete drug release was observed in pH 6.8 phosphate buffer in 6 hours respectively. So, 5% coating level of polymer was found to be not suitable for colon targeting.

Effect of 10% coating level on drug release from coated pellet:

It shows drug release from formulation batches containing croscarmelleose sodium and crospovidone in pH 6.8 and 7.0 phosphate buffer.

Figure 4 Drug release profile of 15% eudragit FS 30D coated pellets containing croscarmellose sodium (P31) in pH 6.8, 7.0 and 7.2 phosphate buffer from formulation

In vitro drug release studies clearly revealed that at 15% coating levels of eudragit FS 30D withstand acidic media and only 1% drug release was observed in acidic media for 2 hours, which was ideal coating for colon targeting.

Effect of 15% coating level on release of mesalamine from pellets containing croscarmellose sodium:

To study the effect of coating level on release of mesalamine from pellets cured at 40 0C for 24 hours, the release from formulation containing croscarmellose sodium (P31) was studied. The results are shown in figure 5.

Figure 5 Drug release profile of 15% eudragit FS 30D coated pellets containing croscarmellose sodium (P31) in pH 6.8, 7.0 and 7.2 phosphate buffer

The aqueous dispersion of eudragit FS 30D (outer coat) at 15% coating level dissolves at pH 6.8; since the pH at ileum and ileo-caecal value is reported to be 7-8, it is expected that eudragit FS 30D dissolve in that region and eudragit RS-RL 30D (6%, inner coat) provide sustained drug release in colon. At this coating level, only 1% release was observed in pH 1.2 dissolution media and sustained drug release for 8 hours in pH 7.2 phosphate buffer. It was also observed that increasing pH range from 6.8 to 7.2, release rate was increased i.e. 8.80% to 99.80%, it was due to fact that eudragit FS 30D is an anionic polymer containing carboxyl groups that ionizes in neutral to alkaline medium. There was faster ionization of carboxyl groups at pH 7.2 than pH 7.0, and hence eudragit FS 30D dissolves faster at higher pH.

Effect of 15% coating level on release of mesalamine from 40% drug loaded pellets containing crospovidone:

To study the effect of coating level on release of mesalamine from pellets cured at 40 ⁰C for 24 hours, the release from formulation containing crospovidone (formulation batch P32) was studied. The results are shown in figure 6.

Figure 6 Drug release profile of 15% eudragit FS 30D coated pellets containing crospovidone (P32) in pH 6.8, 7.0 and 7.2 phosphate buffer

The aqueous dispersion of eudragit FS 30D (outer coat) at 15% coating level dissolves at pH 6.8; since the pH at ileum and ileo-caecal value is reported to be 7-8, it is expected that eudragit FS 30D dissolve in that region and eudragit RS RL 30D (6%, inner coat) provide sustained drug release in colon. At this coating level, only 1% release was observed in pH 1.2 dissolution media for 2 hours and sustained drug release for 8 hours in pH 7.2 phosphate buffer. When release profile studied in pH 6.8, 7.0 and 7.2 release was found to be 8.45, 54.24 and 96.05% respectively after 8 hours. This indicates that increasing pH from 6.8 to 7.2, release rate was increased from 8.4 to 96.05%.

Comparative release profile of formulations bathes containing croscarmellose sodium (formulation batch P31) and crospovidone (formulation batch P32):

Comparative dissolution profiles of formulation batches (P31 and P32) containing croscarmellose sodium and crospovidone are shown in figure 7.

Figure 7 Drug release profile of 15% eudragit FS 30D coated pellets containing croscarmellose sodium (formulation batch P31) and crospovidone in pH 6.8, 7.0 and 7.2 phosphate buffers.

DISCUSSION:

Effect of moisture level on shape of pellets:

Increase in amount of water was found to increase pellets diameter whereas low amount of moisture from 70 to 80% (formulation batches P1 and P2) resulted in reduction of the yield of pellets. Further increase in moisture content from 100 to 110% (formulation batches P4 and P5) had lead to an over wetted mass and agglomeration of individual pellets during spheronization resulted in irregular shape of pellets. Thus, the amount of moisture i.e. 90% was found to be optimum so as to get desired size pellets with maximum yield.

Effect of spheronization speed and time on shape of pellets:

At a speed of 1500 rpm, spherical pellets were formed after 15 minutes (formulation batch P20) with maximum yield.

Effect of feed size and spheronization time on shape of pellets:

The feed size of 30 g was observed to be optimum with 1500 rpm speed pellets of spherical form were obtained.

Effect of drug loading on physical properties of pellets:

Evaluation of coated pellets:

In vitro drug release without disintegrants:

When pellets were subjected to dissolution study, dissolution media was not penetrated into pellets and only 8% drug release was observed even for period of 10 hours. (Formulation batch P30).

In vitro drug release with disintegrants:

In vitro drug release from pellets containing croscarmellose sodium (formulation batch P31) shown that 93% release was observed in acidic media for 2 hours and complete release was observed in 4 hours in pH 6.8 phosphate buffer. Similarly, in acidic media, release of 91% was observed from formulation containing crospovidone (formulation batch P32) for 2 hours and complete release was observed in 4 hours in pH 6.8 phosphate buffer.

In vitro drug release study clearly reveals that release rate was faster with formulation containing croscarmellose sodium (formulation batch P31) than crospovidone (formulation batch P33). This was due to higher swelling capacity of croscarmellose sodium than crospovidone.

Effect of inner coating on drug release:

Eudragit RS RL 30D are water insoluble but water swellable polymers over entire pH range, the active ingredients were gradually dissolved by penetrating dissolution media and release is primarily diffusion controlled. The coating level studied was 2, 4 and 6%. At 2% coating level release rate was found to be complete in acidic media for 2 hours and at 4% coating level drug release was found to be 85% in 2 hours and complete release in pH 6.8 phosphate buffer for 4 hours. It indicates that release rate was faster with 2 and 4% coating level. It was not suitable for sustained release characteristics. At higher coating level of 6%, the release rate was found to be sustained for period of 10 hours, hence selected as optimum level for providing sustained release characteristics.

Effect of outer Coating:

In vitro drug release studies clearly revealed that at 15% coating levels of eudragit FS 30D withstand acidic media and only 1% drug release was observed in acidic media, which was optimum coating level for colon targeting.

In vitro drug release study reveals that, at 15% coating level of eudragit FS 30D release rate was faster in formulation batch P31 containing croscarmellose sodium than formulation batch P32 containing crospovidone. It was due to fact that croscarmellose sodium has higher swelling capacity than crospovidone, which result in higher penetration of dissolution medium in croscarmellose sodium containing formulation than crospovidone containing formulation. In vitro drug release studies clearly revealed that at 15% coating levels of eudragit FS 30D withstand acidic media and only 1% drug release was observed in acidic media for 2 hours, which was ideal coating for colon targeting.

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Received on 23.09.2011

Modified on 25.09.2011

Accepted on 02.10.2011

Research J. Science and Tech. 3(5): Sept.-Oct. 2011: 238-246

Formulation code	Quantity of Mesalamine (%)	Quantity of MCC PH 101 (g)	Quantity of PVP K-30 (g)	Moisture content (%)	Shape of pellets	Disintegrant (%)	Size distribution (#)
P30	40	17	1	90	Spherical	-	10-18
P31	40	16.4	1	90	Spherical	2	10-18
P32	40	16.4	1	90	Spherical	2	10-18