AN IN VITRO INVESTIGATION OF SUITABILITY OF PRESS-COATED TABLETS WITH HYDROXYPROPYLMETHYLCELLULOSE ACETATE SUCCINATE (HPMCAS) AND SODIUM ALGINATE IN OUTER SHELL FOR COLON TARGETING

AN IN VITRO INVESTIGATION OF SUITABILITY OF PRESS-COATED TABLETS WITH HYDROXYPROPYLMETHYLCELLULOSE ACETATE SUCCINATE (HPMCAS) AND SODIUM ALGINATE IN OUTER SHELL FOR COLON TARGETING

Krishnakumar Devrao Lone*¹ and Jyoti Arjunrao Dhole ²

JSPM’s Rajarshi Shahu College of Pharmacy and Research ¹, Tathawade, Pune, Maharashtra, India

Department of Botany, Yeshwant Mahavidyalaya ², Nanded, Maharashtra, India

ABSTRACT: The aim of present study was to develop a new colon targeting formulation, which can minimize the escape of Mesalazine completely in upper gastro-intestinal tract and ensure availability of maximum amount of drug to achieve the desired site i.e. distal colon. The use of press coated tablets with Hydroxypropylmethylcellulose acetate succinate (HPMCAS) and sodium alginate in outer shell was investigated. Two coats (upper and lower) were compressed onto the core tablets of Mesalazine using varying quantities of coating composition i.e. 100mg and 150mg each for lower and upper coat. The Mesalazine tablets coated by compressing 100 mg of HPMCAS each as upper and lower coat did not maintain integrity of the coats and released almost 100% of drug within 3 hrs. The tablets coated by compressing 150 mg of HPMCAS on the core tablets maintained good integrity during the dissolution test and prevented escape of Mesalazine totally in acid stage and buffer sage 1. However, the release of Mesalazine in subsequent buffer stage 2 was also affected. Mesalazine tablets coated with 1:1 blends of HPMCAS and sodium alginate could maintain good mechanical strength in acid stage and buffer stage 1 and released 81.65 % of drug within 5 hrs. While the tablets with higher proportion of Sodium alginate in coat although possessed good mechanical strength indicated slower release of drug. The amount of Mesalazine released from the tablets coated with higher proportion of HPMCAS alone was comparable to that released from the tablets coated with equal proportions of two pH sensitive polymers. These release indicating the usefulness of press coated tablets.

Press coated tablet, Mesalazine, ulcerative colitis. HPMCAS, Granulation

INTRODUCTION: Colonic drug delivery has gained increased importance not just for the delivery of drugs for the treatment of local diseases of colon such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis (UC) but also for its potential for the delivery of proteins and therapeutic peptides like insulin ¹.

Inflammatory Bowel Diseases (IBD) includes two conditions Ulcerative colitis and Crohn’s disease. Ulcerative colitis (UC) is a condition that affects a part of large intestine- the rectum and the colon². The affected part becomes inflamed and develops ulcers, causing symptoms that include bloody diarrhoea, abdominal pain and fever.

Mesalazine is considered to be the “Gold standard” drug for treatment of ulcerative colitis and it is available as delayed released tablets, controlled released capsules, enteric coated tablets for oral use and rectal suppositories, enema suspension for rectal use³.

In present study, press coated tablets were prepared using Hydroxypropylmethylcellulose acetate succinate (HPMCAS) as a basic enteric material in the outer shell, and their functions were examined by in vitro dissolution test. In addition the effects of addition of sodium alginate to HPMCAS were investigated to improve the acid resistance and time released function of press coated tablet using HPMCAS ⁴.

MATERIAL AND METHODS: Mesalazine was obtained from Sari Overseas, Mumbai, India, Sodium alginate from Alembic Pharmaceuticals Ltd., Baroda. HPMCAS, povidone (PVP-K30) and microcrystalline cellulose were obtained from Signet Chemical Corporation, Mumbai for free of cost. Talc and Magnesium stearate were procured from Emcure House M.I.D.C. Pune. All the other chemicals and reagents used were of analytical grade. The commercially available Mesalazine product, Asacol was procured from A. Birla hospital (Pune).

 Formulation of compression coated tablets of Mesalazine: The formulation was developed in two stages. Initially the core tablets (weight 300mg) of Mesalazine were prepared using following formula. (Table 1) Subsequently two coatings were compressed onto these cores (upper layer and lower layer) using S.S. punches (diameter 13 mm flat surface) on rotary tablet press. The compression force was maintained in such a way that the hardness of resulting core tablets ranged between 2-3 kg/m^{2 5}.

Preparation of Core tablets of Mesalazine: The physical mixtures of polymers and excipients were prepared by blending the accurately weighed quantities of each of them with Mesalazine in geometric proportions in glass mortar for 15 minutes. Ethnolic solution of PVP K-30 (3% w/v) was used as binder which was added gradually to powder blends with trituration until a coherent moist mass was formed. This mass was passed through screen (22#) to get moderately coarse granules. The wet granules were dried at 50˚C.for 1 hour. The dried granules were again passed through screen (44#) to obtain fine granules. The resulting granules were lubricated with magnesium stearate (Table 1). For the preparation of Core tablets (300 mg), tableting was performed under compression force of 1030kg/cm² and punch speed of 10 mm/min, with a multi station rotary punch tablet compression machine. A flat faced punch 8 mm in diameter was used ⁶.

TABLE1: FORMULAE FOR MESALAZINE CORE TABLETS

The drug contents were maintained at 250 mg for all the formulations

Evaluation of core tablets: The core tablets were evaluated for various tablet characterization viz;

Tests for physical evaluation

• Appearance & dimensions

• Weight variation
• Hardness
• Friability

Tests for performance evaluation

1. Test for % drug content
2. In-vitro drug release

Test for physical evaluation of core tablets were carried out by the procedure described in standard text book Liberman, 2001 ⁷.

In vitro release of Mesalazine from Core tablets: The test was conducted using three tablets of each type of formulation using USP (23) dissolution apparatus (Apparatus I) ⁸. The test was performed using 900 ml of phosphate buffer (pH 7.2). Aliquots were withdrawn at time intervals of 5 minutes carefully over a period of 60 minutes.

Every time the equal volume of fresh dissolution medium, (maintained at same temperature) was added to the bulk to maintain sink conditions. Samples were filtered through Whatman filter paper (No. 41) and their absorbances were recorded at λ_max 303.5nm ⁹.

Coating of core tablets using different polymer compositions: The coating formulae were prepared using HPMCAS (HF) alone, and combination with sodium alginate in different proportions (Table 2).

TABLE 2: COMPOSITION OF COMPRESSION COATED TABLETS

 Compression of Coats on Core tablets of Mesalazine: Two  coats  (upper and lower) were compressed onto the core tablets of Mesalazine using varying quantities of coating composition i.e. 100mg each for lower and  upper coat; 150mg each for lower and upper coat.

Evaluation of Coated tablets of Mesalazine: The coated tablets were evaluated for the various physical and performance characteristics similar to the core tablets of Mesalazine.

• In vitro release of Mesalazine from Press Coated Tablets: The test was conducted using three tablets of each type of formulation using USP (23) dissolution apparatus (Apparatus I) ⁸.

Procedure:  The tablets of each type of formulations were kept in baskets which were placed successively in above mentioned dissolution media. The dissolution apparatus was run maintaining above stated test conditions (Table 3).

TABLE 3: THE EXPERIMENTAL CONDITIONS USED FOR IN VITRO RELEASE OF MESALAZINE FROM PRESS COATED TABLETS

• In the phase I, the test was performed using 0.1N HCL.10 ml aliquots were withdrawn at time intervals of 30 minutes carefully over a period of 120 minutes. Every time the equal volume of fresh dissolution medium, (maintained at same temperature) was added to the bulk to maintain sink conditions. Samples were filtered through Whatman filter paper (No. 41) and their absorbances were recorded at λ_max 303.5nm.

In the phase II i.e. buffer stage-1, 900 ml of phosphate buffer (pH 6) was transferred into each of the dissolution vessels. Apparatus was run maintaining test conditions as mentioned for buffer stage-1. Aliquots (10ml) were removed after 30 minutes carefully over a period of 60 minutes and were filtered and absorbances were recorded at λ_max 330.0nm. Equal volume of   phosphate buffer (pH 6) was added into the vessels after each withdrawal.

• In the phase III i.e. buffer stage-2, 900 ml of phosphate buffer (pH 7.2) was transferred into each of the dissolution vessels. Apparatus was run again maintaining test conditions as mentioned for buffer stage 2. Aliquots (10 ml) were withdrawn at time intervals of 30 minute carefully over a period of 90 minutes. Every time the equal volume of fresh dissolution medium, (maintained at same temperature) was added to the bulk. These samples were filtered through Whatman filter paper (No. 41) and their absorbances were recorded at λ_max 331.0 nm.

RESULT AND DISCUSSION:

Characterization of Lubricated granules of Mesalazine used for Core Tablets: The values for loose bulk density, tapped bulk density, compressibility index and angle of repose of granules of Mesalazine prepared with PVP K-30 as binder for core tablets indicated good flow properties (Table 4).

Values of loose bulk density and tapped bulk density for Mesalazine granules ranged between 0.21±0.02- 0.24±0.05 and 0.25±0.02- 0.29±0.01 g/ml. Similarly values of Carr’s index ranged between 15.38±0.42- 16.00±0.40. Angle of repose values ranged between 24.22-25.40 suggesting good flow properties of granules (table 5).

TABLE 4: FLOW PROPERTIES OF GRANULES OF MESALAZINE

All values are expressed as mean± SD, n=3

TABLE 5: CHARACTERIZATION OF CORE TABLETS OF MESALAZINE

The core tablets possessed acceptable values for tablet characteristics.

• Effect of varying concentrations of superdisintegrant on in vitro release of Mesalazine from Core tablets: In vitro dissolution data of Mesalazine from the control tablets i.e. tablets prepared without addition of superdisintegrant indicated complete release of the drug within 65 minutes in the buffer stage 2 while the core tablets containing increasing concentrations of superdisintegrant released the contents in shorter span of time period. Thus, the tablets containing highest % (3%w/w of tablet weight) amounts of Ac-di-Sol released Mesalazine within 40 minutes in the buffer stage 2 (Table 6; Fig. 1).

FIG. 1: IN VITRO RELEASE OF MESALAZINE FROM CORE TABLETS.

  TABLE 6:  DISSOLUTION DATA MESALAZINE FROM THE CORE TABLETS

 Characterization of Coated tablets of Mesalazine:

TABLE 7: TABLET CHARACTERISTICS OF COATED TABLETS OF MESALAZINE WITH VARYING AMOUNTS OF COATING FORMULAE

T he pharmacopoeial specifications for deviation in weight from average weight for tablets weighing more than 250 mg are ±5%. The percentage deviation in the weight of prepared tablets (weighing 600 mg except CHA1 weighing 500 mg) was within the specified limits for all the formulations and hence they complied with the test for weight variation

• There was obvious increase in diameter, thickness and hardness of the coated tablets as compared with core tablets.
• The friability of all the coated formulations was lower than the core tablets and complied with the specified limits.
• In vitro release of Mesalazine from prepared compression coated tablets: The Mesalazine tablets coated by compressing 100 mg of HPMCAS each as upper and lower coat did not maintain integrity of the coats and released almost 100% of drug within 3 hrs. This performance is not useful to qualify these tablets as colon targeted formulations (Table 8).

• The tablets coated by compressing 150 mg of HPMCAS on the core tablets maintained good integrity during the dissolution test and prevented escape of Mesalazine totally in acid stage and buffer sage 1. However, the release of Mesalazine in subsequent buffer stage 2 was also affected (Table 8; Fig. 2).

FIG. 2: IN VITRO DISSOLUTION PROFILES OF MESALAZINE FROM EXPERIMENTAL COATED TABLETS

TABLE 8: IN VITRO RELEASE DATA OF MESALAZINE FROM EXPERIMENTAL COATED TABLETS WITH HPMCAS

In vitro release data of Mesalazine from tablets coated with combinations of HPMCAS and Sodium alginate: In vitro dissolution data of Mesalazine from core tablets, from press coated tablets with combination of HPMCAS and Sodium alginate at different proportions viz CHS1 (1:1), CHS2 (1:2) and CHS3 (2:1) (total coat weight 300mg) is presented in Table 9 and Fig. 3.

TABLE 9: DISSOLUTION DATA OF PRESS COATED TABLETS OF MESALAZINE WITH COMBINATION OF HPMC-AS AND SODIUM ALGINATE.

FIG. 3: IN VITRO DISSOLUTION PROFILES OF TABLETS OF MESALAZINE PRESS COATED WITH COMBINATION OF HPMC AS (HF) AND SODIUM ALGINATE

Mesalazine tablets coated with 1:1 blends of HPMCAS and sodium alginate could maintain good mechanical strength in acid stage and buffer stage 1 and released 81.65 % of drug within 5 hrs. While the tablets with higher proportion of Sodium alginate in coat although possessed good mechanical strength indicated slower release of drug.

The amount of Mesalazine released from the tablets coated with higher proportion of HPMCAS alone was comparable to that released from the tablets coated with equal proportions of two pH sensitive polymers.

Comparative evaluation of drug release profiles of Mesalazine from press coated tablets with marketed formulation (Asacol): In vitro dissolution data of Mesalazine from marketed formulation and from press coated tablets with combination of HPMCAS and Sodium alginate at different proportions viz CHS1 (1:1), CHS2 (1:2) and CHS3 (2:1) (total coat weight 300mg).is presented in Table 10 and Fig. 4.

TABLE 10: DISSOLUTION DATA OF PRESS COATED TABLETS OF MESALAZINE WITH COMBINATION OF HPMC-AS AND SODIUM ALGINATE.

FIG. 4: COMPARATIVE EVALUATION OF MARKETED FORMULATION WITH PRESS COATED TABLETS

The comparative results indicated the usefulness of press coated tablets with desirable functions for colon targeting formulation.

CONCLUSION: The applicability of press-coated tablets for colon targeting delivery systems, which suppress drug release totally in acid stage and buffer sage 1, was studied using hydroxypropylmethyl cellulose acetate succinate ( HPMCAS) an enteric polymer alone and its combination with sodium alginate in various proportions in outer shell. The Mesalazine tablets coated by compressing 100 mg of HPMCAS each as upper and lower coat did not maintain integrity of the coats and released almost 100% of drug within 3 hrs. This performance is not useful for qualifying colon targeting drug delivery. The tablets coated by compressing 150 mg of HPMCAS on the core tablets maintained good integrity during the dissolution test and prevented escape of Mesalazine totally in acid stage and buffer sage 1.

The combination of HPMCAS with sodium alginate showed interesting effects on dissolution profile. The result indicate that these systems suppressed drug release completely in acidic stage 1 and the lag time could be controlled by adjusting mixing ratio of HPMCAS with sodium alginate. Comparative study of press coated tablets with marketed formulation (Asacol) indicated the usefulness of it for colon targeted delivery.

ACKNOWLEDGEMENT: The authors are thankful to Sarex Overseas Mumbai, India for providing sample of Mesalazine, Signet Chemical Corporation, Mumbai for sample of HPMCAS and Alembic Pharmaceuticals Ltd. Baroda for sample of Sodium alginate free of cost. Signet Chemical Corporation, Mumbai Authors wish to thank JSPM’s Rajarshi Shahu college of Pharmacy and Research, Pune for providing necessary facilities to carry out the work.

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    How to cite this article:

    Lone KD and Dhole JA: An in vitro investigation of suitability of Press-coated tablets with Hydroxypropylmethylcellulose acetate succinate (HPMCAS) and Sodium alginate in outer shell for Colon Targeting.Int J Pharm Sci Res 2013; 4(6); 2244-2251. doi: 10.13040/IJPSR.0975-8232.4(6).2244-51

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