chapter 8 - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/9712/14/14_appendices.pdf · this...

CHAPTER 8

APPENDICES

Formulation Optimization of Colonic Drug Delivery SyFormulation Optimization of Colonic Drug Delivery SyFormulation Optimization of Colonic Drug Delivery SyFormulation Optimization of Colonic Drug Delivery Systems stems stems stems Chapter 7Chapter 7Chapter 7Chapter 7

Nitesh N. Shah Ph.D. Thesis

123

APPENDIX I

LIST OF INSTRUMENTS



124

List of Instruments

UV/VIS Double beam

Spectrophotometer

Shimadzu, Model: UV-2450, Japan

pH meter EI products, Model: 111, India

Tablet dissolution tester USP Electrolab, Model: TDT-06 T, India

Tablet disintegration tester USP Electrolab, Model: ED – 2L, India

Rotary tablet machine Karnavati Engineering Pvt. Ltd., Model: Rimek mini

press –I, India

HPLC Perkin Elmer, USA

Digital weighing balance Mettler Toledo, Model: XS 205, USA

Hardness tester Erweka hardness tester, Model: TBH225, Germany

Friability tester Electrolab, Model: EF-2, India

Magnetic stirrer Remi equipment Pvt. Ltd., India

Hot air oven USICO, India

Halogen moisture analyzer Mettler Toledo, Switzerland

Granule flow tester Electrolab, Model:GT, India

Tap density tester Electrolab, Model: ETD-1020, India

Sieve shaker Erweka, Model: EMS-8, Germany

FTIR Jasco, Model: FTIR 6100 Type A, Japan

XRD Philips X’Pert MPD, Netherlands

DSC Seiko Instruments, Model:6100, Japan

Coater Neocota, Model: Minimax, India

Stability Chamber Newtronic, USA

Bin Blender Tapasya Engineering, India



125

APPENDIX II

ANIMAL ETHICS COMMITTEE APPROVAL

LETTER

Formulation Optimization of Colonic Drug DelivFormulation Optimization of Colonic Drug DelivFormulation Optimization of Colonic Drug DelivFormulation Optimization of Colonic Drug Delivery Syery Syery Syery Systems stems stems stems Chapter 8Chapter 8Chapter 8Chapter 8


126

APPENDIX III

LIST OF PUBLICATIONS & PRESENTATIONS

Formulation Optimization of Colonic Drug DelivFormulation Optimization of Colonic Drug DelivFormulation Optimization of Colonic Drug DelivFormulation Optimization of Colonic Drug Delivery Syery Syery Syery Systems stems stems stems Chapter 8Chapter 8Chapter 8Chapter 8


127

List of Publications

1. Shah N, Shah T, Amin A. In-vitro evaluation of pectin as a compression

coating material for colon targeted drug delivery. International Journal of

Pharma and Bio Sciences.2011 April-June;2(2):P-410-8.

2. Shah N, Shah T, Amin A. Polysaccharides: a targeting strategy for colonic

drug delivery. Expert Opinion on Drug Delivery.2011 June;8(6): 779-96.

3. Shah N, Shah T, Amin A. Design and development of enteric and compression

coated colonic tablets: an in vitro evaluation. Acta Pharmaceutica

Sciencia.2011;53(2):____ (Page number yet to be published)

List of Presentations

1. Shah NN, Amin AF. Design and Development of Enteric Coated Time

Dependent Compression Coated Tablets of metronidazole. Poster presented at

state level paper presentation competition organized by GUJCOST (Gujarat

council on science & technology) held at Shree Sarvajanik Pharmacy College,

Mehsana, Gujarat on 9th-10

th January 2009.- Secured 1

st position for the

same.

2. Shah NN, Amin AF. Design and development of compression coated colon

targeted mini-tablets. Poster presented at the 10th CRSIC International

Symposium held in Mumbai on 17th-18

th February 2010.

This article can be downloaded from www.ijpbs.net

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RESEARCH ARTICLE

ARTICALTICLE

International Journal of Pharma and Bio Sciences

IN-VITRO EVALUATION OF PECTIN AS A COMPRESSION COATING

MATERIAL FOR COLON TARGETED DRUG DELIVERY

NITESH SHAH*, TEJAL SHAH AND AVANI AMIN

Department of Pharmaceutics and Pharmaceutical Technology, Institute of Pharmacy, Nirma

University, Ahmedabad-382481, Gujarat, India.

NOVEL DRUG DELIVERY SYSTEM

NITESH SHAH

Department of Pharmaceutics and Pharmaceutical Technology, Institute of Pharmacy,

Nirma University, Ahmedabad-382481, Gujarat, India

ABSTRACT Colon targeted delivery of satranidazole (STZ), which immediately releases the drug as soon as the drug delivery system reaches the colon was formulated. Different grades of pectin were used as a compression coat and the effect of degree of esterification (DE) of pectin on swelling and drug release property was evaluated. STZ is a sparingly soluble drug, so to obtain maximum effect of drug at the site of action the solubility enhancement was carried out using Hydroxypropyl-β-cyclodextrin (HP-β-CD). Pectin as a compression coat was unable to direct STZ containing core tablets to the colon, so HPMC was added to increase the tensile strength of the coat. STZ core tablets compression coated with High DE pectin: HPMC in 1:1 ratio imparted the lag time of 5 h and burst release in colon.


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KEYWORDS

Crohn’s Disease, Degree of esterification, HP-β-CD, HPMC, swelling study.

INTRODUCTION Drug delivery systems to the colon are being extensively investigated in order to treat local colonic diseases like irritable bowel syndrome, crohn’s disease and ulcerative colitis 1. Satranidazole (STZ) is a novel 5-nitroimidazole possessing superior activity against anaerobes as compared to metronidazole, tinidazole and ornidazole. STZ can be used as an ideal therapy for crohn’s disease 2. Colon specific drug delivery of STZ will not only increase the availability of the drug at the target site, but also may reduce the dose requirement and the side effects. Amongst different methods developed for targeting drugs to the colon, polysaccharide-based delivery systems rely upon the enzymatic degradation of the carrier in the colon, thereby resulting in drug release 3. The enzyme trigger mechanism in such delivery systems makes them site specific 4, 5. Of all the different polysaccharides, pectin is one of the most extensively investigated for its suitability for targeting drugs to the colon. Pectin is normally classified according to its degree of esterification. Pectin in which less than 50% of the carboxyl acid units occur as the methyl ester is normally referred to as low ester or low DE pectin, whereas pectin with 50% or more carboxyl acid units as the methyl ester is referred to as high DE pectin. Some of the carboxyl groups may be converted to carboxamide groups, when ammonia is used in the process of de-esterification, producing amidated pectin 6. Many researchers have explored usefulness of pectin for directing drug to the colon. Pectin is used alone 7 or in combination chitosan 8 as a compression coat, and as a film coat in combination with ethyl cellulose 9 and Eudragit RS/NE 10. The aim of the present work is to formulate colon-targeted tablets of STZ. STZ is very sparingly soluble in water (0.01mg/ml). Since the aim is to treat the local pathologies of colon, it is essential for drug to be in soluble

form at the site of action to provide maximum effect. Thus, the study was divided in two parts, a) To increase the solubility of STZ, and b) To formulate pectin based colon targeted drug delivery system for satranidazole. Previously, STZ solubility has been increased by complexation with β-cyclodextrin 11. In the present study Hydroxypropyl-β-cyclodextrin (HP-β-CD) was tried to increase the solubility of STZ.

MATERIALS AND METHODS Pectin Classic CU 201 (Non Amidated High methoxy pectin, Degree of esterification (DE): 71, High DE Pectin), Pectin Classic CU 701 (Non Amidated Low methoxy pectin, DE: 38, Low DE Pectin), and Pectin Amid CU 020 (Amidated Low methoxy pectin, DE: 30, Degree of amidation: 19, Amidated Low DE Pectin) were a kind gift from Herbstreith and Fox (Neuenburg, Germany). Pectinex Ultra SP-L® (pectinolytic enzymes, extracted from Aspergillus niger and having an activity of 26,000 PG/ml at pH 3.5) was kindly supplied by Novo Nordisk Ferment Ltd. (Dittingen, Switzerland). STZ was obtained from Alkem Laboratories (Mumbai, India). Colorcon (Mumbai, India) kindly provided HPMC K4M (Methocel® K4M). HP-β-CD was a generous gift from Roquette (France). Flowcel® 301 and Cross Carmellose Sodium were supplied generously from Gujarat Microwax Ltd. (Ahmedabad, India). Double distilled water was used throughout the study. All other materials used were of analytical reagent grade. (i) Solubility enhancement of STZ

STZ was triturated with HP-β-CD in molar ratio of 1:0.1, 1:0.2 and 1:0.3, using water-methanol (1:2 v/v) in a quantity sufficient to form thick paste. The kneading time for


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mixture was optimized to 60 min. The kneaded mass was dried at 45 ºC till the moisture content of sample comes between 4-5 %. The dried mass was sifted through 40 # sieve. (ii) X-Ray Diffraction (XRD) study The powder XRD patterns of STZ and STZ- HP-β-CD complex (STZ-CD) were recorded by using automated Philips Holland –PW 1710 scanner with filter Cu radiation over the interval 5-60°/2θ. The operation data were as follows: voltage 35 kV, current 20 mA, filter Cu and scanning speed 1° / min. The XRD study was carried out to check the conversion of reduction in crystallinity of STZ after kneading it with HP-β-CD. (iii) Preparation of core and compression coated tablets Initially, Flowcel® 301 (diluent), PVP K30 (binder, 8%), Croscarmellose Sodium (disintegrant, 5%) and Talc (glidant, 2%) were sifted through 20 # sieve and was blended with, whereas Magnesium stearate (lubricant, 1%) was sifted through 40 # sieve. Thereafter, STZ-CD equivalent to 300 mg of STZ/tablet was blended with Flowcel®, PVP, Cross

Carmellose Sodium and Talc for 15 min. in a bin blender (Inweka Multi-Purpose instrument, Gujarat, India). This mixture was blended with Magnesium Stearate for 5 min and then compressed into 700 mg tablets using 10 station Rotary tablet machine (Minipress-II, Karnavati Engineering Limited, Gujarat, India), equipped with 13 mm concave punches. The core tablets were tested for hardness, thickness, content uniformity, friability, and disintegration. The compression coat material was prepared using either pectin or a combination of HPMC K4M: Pectin in ratios of 1:3, 1:1 and 3:1 at 200 mg compression coat weight. Core tablets were compression coated with different compression coating mixtures as shown in Table 1. For compression coating, exactly 50% of the coat powder was first placed in the die cavity of the compression machine. Then, the core tablet was carefully positioned at the center of the die cavity, which was filled with the

remainder of the coat powder. The coating material was compressed around the core tablet at an applied force of 5000 kg using 15 mm round concave punches using a 10 station Rotary tablet machine.

Table 1

Compression coat combinations

Pectin type Batch code

HPMC (mg)

Pectin (mg)

P2 - 200

HP231 150 50

HP211 100 100

Pectin Classic CU 201

HP213 50 150

P7 - 200

HP731 150 50

HP711 100 100

Pectin Classic CU 701

HP713 50 150

P0 - 200

HP031 150 50

HP011 100 100 Pectin Amid CU 020

HP013 50 150

(iv) In Vitro Drug Release Studies In-vitro drug release studies were carried out using USP XXIII dissolution test apparatus Type II, paddle apparatus (100 rpm/min, 37 ±

0.5 0C). Compression coated colonic tablets were evaluated by exposing them to 900 ml 0.1 N HCl (simulated gastric fluid, SGF) for 2 h, which was then replaced with 900 ml pH


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7.4 phosphate buffer solution (simulated intestinal fluid, SIF) wherein it was kept for 3 h and lastly SIF was replaced with 900 ml pH 6.8 phosphate buffer solution (simulated colonic fluid, SCF), and tested for release for the rest of the dissolution run. The drug release at different time intervals was analyzed by UV double beam spectrophotometer (Shimadzu UV 2450, Japan) at 319 nm. Each test was performed in triplicate. (v) Swelling studies The compression coated pectin/ pectin-HPMC tablets were accurately weighed (W0) and placed in the USP paddle apparatus (Electrolab, India) in a manner similar to method described under in-vitro drug release studies for compression coated tablets. The changes in weight and swelling were recorded on hourly basis from the beginning and continued until one time point before (n-1) the erosion of the tablet. The n-1 time point was selected on the basis of in-vitro drug release

study carried out in presence of pectinolytic enzymes. After each time point tablets were withdrawn from the medium and lightly blotted with tissue paper to remove excess test liquid and then reweighed (W1). The experiment was performed in triplicate. The percentage increase in weight due to absorbed medium was estimated at each time point from the following equation: % weight gain = W1-W0/W0 x 100………...(1)

RESULTS AND DISCUSSION (i) Solubility enhancement of STZ Aim of the present investigation was deliver STZ to colon for treatment of local pathologies of colon. For the local treatment drug needs to be in soluble form so as to attain its maximum therapeutic effect. STZ shows pH dependent solubility with HP-β-CD complex (Figure 1). 100% drug release was obtained in phosphate buffer pH 7.4 within 25 min. at 1:0.2 ratio of STZ: HP-β-CD.

0

20

40

60

80

100

0 5 10 15 20 25 30

Time (min)

Cumulative percentage drug

released

DH102H DH102B DH102BB

Figure 1 Effect of pH on solubility of STZ (data shown as mean ± SD, n=3)

(ii) X-Ray Diffraction (X-RD) study Crystallinity was determined by comparing peak heights in the diffraction patterns of the STZ-CD (Sample B) with those of a STZ (Sample A). The powder XRD patterns for the STZ and STZ-CD are presented in Figure 2. Characteristic diffraction peaks of STZ and STZ-CD between at 0° and 40° (2θ) were used for conformation studies. The STZ-CD complex showed all

characteristics peaks corresponding to the drug, but with lower intensity. The possible reduction in crystallinity may be due to complex formation. The relationship used for the calculation of crystallinity was relative degree of crystallinity (RDC) RDC= Hsam / Href…………………………..(2)


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Where, Hsam = the peak heights of the sample investigated and Href = the peak heights of STZ with the highest intensity at 2θ values of 15, 21, 25.

The RDC values of corresponding STZ-CD were 2.66, 2.37 and 3.17 at 2θ values of 15, 21 and 25 respectively. RDC values higher than 1 indicate reduction in crystallinity of the STZ-CD.

Figure 2

XRD pattern of STZ (Sample A) and STZ-β-cyclodextrin complex (Sample B) (iii) Core tablets The hardness of the core tablets was found to be in the range of 4.2–5.5 kp. These tablets were found to comply with the friability test since the weight loss was found to be 0.13%. Due to the presence of cross-carmellose sodium in the core tablets, the disintegration time of the core tablets was found to be 2 min ±10 sec. The matrix tablets contained 97.8% to 102.9 % of STZ in each batch. (iv) Effect of different grades of pectin on release property in different media Core tablets compression coated with Pectin 701 and 020 showed 100% drug release within 1 h

and 0.5 h respectively, in both SGF and SIF (Figure 3a and 3b). On the contrary, Pectin 201, a High DE Pectin, delayed the drug release to 3 h in acidic medium as compared to 2 h in basic medium (refer Figure 3a and 3b). This finding is probably due to the lack of gel formation of High DE pectin in phosphate buffer. High DE pectin requires a relative low pH for gel formation, while Low DE pectin requires the presence of divalent cations 12.

Higher the pectin hydration-gel forming ability, the lesser the drug was released.

Figure 3a Release in 0.1 N HCl (data shown as mean ± SD, n=3)

0

20

40

60

80

100

0 0.5 1 2 2.5 3

Time (h)

Cumulative percentage drug relased

P2H P7H P0H


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0

20

40

60

80

100

0 0.5 1 2

Time (h)Cumulative percentage

drug released

P2B P7B P0B

Figure 3b Release in Phosphate buffer pH 7.4 (data shown as mean ± SD, n=3)

(v) Effect of addition of HPMC to the compression coat

From the above results it was clear that pectin alone as a compression coat was unable to prepare colon targeted formulation since it showed premature drug release. To provide sufficient lag time to the system to reach colon, HPMC was added to the compression coat containing pectin. The lag time for a formulation to reach colon was taken as 5 h.

Compression coats containing HPMC:Pectin in the ratio of 1:3 were not able to reach colon. Pectin 201 delayed drug release to the higher extent compared to other grades of pectin used. Batch HP211 containing HPMC:Pectin 201 in the ratio of 1:1 delayed drug release to 7.5 h whereas batch HP231 containing HPMC:Pectin 201 in the ratio of 3:1 delayed drug release to 10 h (Figure 4).

-20

0

20

40

60

80

100

0 0.5 1 2 2.5 3 4 5 5.5 6 6.5 7 7.5 8 9 10

Time (min)

Cumulative

percentage drug released

HP231 HP231P HP731 HP731P HP031 HP031P

Figure 4 Effect of HPMC: Pectin ratio (data shown as mean ± SD, n=3)

Delay in drug release by HP211 is attributable to, (a) strong gel formation of Pectin 201 in SGF, and (b) high swelling capacity. Batch HP211 showed highest weight gain of 135%

(Figure 5) at n-1 time point. This study acted as a proof of concept for proving high DE pectins have the highest swelling and water uptake capacity.


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0

20

40

60

80

100

120

140

160

0 1 2 3 4 5

Time (h)

Percentage weight gain

HP211 HP711 HP011

Figure 5 Water uptake study (data shown as mean ± SD, n=3)

(vi) Effect of the Presence of Pectinolytic Enzymes With the aim of evaluating the influence of the pectin biodegradation process on the drug release profile, we performed a series of experiments by adding in the SCF a commercially available mixture of specific enzymes (Pectinex Ultra SP-L), whose pectinolytic activity showed to be closely correlated with that of the Bacteroides ovatus, the main producer of pectinolytic enzymes in colon 6. The drug release curves obtained from experiments in the presence of pectinolytic enzymes were clearly different from those previously obtained from the same tablets in the absence of enzymes (see Figure 6a and 6b), thus confirming the actual potential of pectins in colon specific delivery. This result is probably attributable to the different degradation rates of the various pectin types, which, in this case, were directly related to their hydration and gel forming properties. Amongst different grades of pectin tried, High DE pectins, the pectin with the highest viscosity among those examined, was the most sensitive to the action of pectinolytic enzymes,

showing the greatest improvement in drug release rate in comparison with the results obtained without enzymes. It is supposable that High DE pectin, being the pectin with the highest swelling hydration power, allows a faster penetration of colonic enzymes which, consequently, leads to a faster degradation of the pectin barrier. The percent of drug release from High DE pectin containing tablets changed from 11% after 6 h (Batch HP211), in the absence of enzymes, to 100% (Batch HP211P) in the presence of enzymes. As expected, it was also observed that effect of enzyme addition was more pronounced in batches containing higher amount of pectin. In presence of enzymes, comparing drug release profile of batch HP211P with HP231P it was observed that batch HP211P containing HPMC:Pectin 201 in the ratio of 1:1 shows 100% drug release in colon within 1 h after the system reaches the colon, whereas batch HP231P containing containing HPMC:Pectin 201 in the ratio of 3:1 takes 3 h for the same. The delay in drug release indicates that higher the amount of HPMC in compression coat lesser is the effect of enzyme on degradation of compression coat.


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0

20

40

60

80

100

0 0.5 1 2 2.5 3 4 5 5.5 6 6.5 7 7.5

Time (h)

Cumulative


HP211 HP211P HP711 HP711P

Figure 6a Effect of Pectinolytic enzymes at 1:1 ratio HPMC: Pectin (data shown as mean ± SD, n=3) In-vitro dissolution study carried (a) in absence of pectinolytic enzymes (HP211, HP711) and (b) in presence of

pectinolytic enzymes (HP211P, HP711P).

0

20

40

60

80

100

0 0.5 1 2 2.5 3 4 5 5.5 6 6.5 7 7.5 8 9 10

Time (min)

Cumulative


HP231 HP231P HP731 HP731P HP031 HP031P

Figure 6b

Effect of Pectinolytic enzymes at 3:1 ratio HPMC: Pectin (data shown as mean ± SD, n=3) In-vitro dissolution study carried (a) in absence of pectinolytic enzymes (HP231, HP731 and HP031) and (b) in

presence of pectinolytic enzymes (HP231P, HP731P and HP031P). (vii) Selection of best batch

The aim of this study was to develop CTDDS for STZ with an intent to have <10% release at the end of 5 h (which is considered as lag time for the system to reach colon) and 100% release within 1 after the system reaches the colon. Moreover to make the system more colon specific it was desirable to choose those batches which are more prone to pectinolytic enzyme degradation. Core STZ tablet compression coated with HPMC:Pectin in the ratio of 1:3 showed premature drug release, whereas core tablets compression coated with HPMC:Pectin in ratio 3:1 showed colon targeting ability but with a disadvantage of

delayed drug release. Only batch HP211P compression coated with HPMC:Pectin in ratio 1:1 met the desired criteria. Thus, batch HP211P was considered as best batch.

CONCLUSION Complexation of STZ with HP-β-CD reduces the crystallinity of STZ and thus increases the solubility. STZ solubility increases with the increase in pH. Pectin alone as a compression coat cannot direct STZ to the colon. Addition of HPMC increases the tensile strength of the compression coat and helps in achieving desired lag time for the formulation


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to reach colon. The results of this study enable us to state that DE plays an important role in swelling mechanism of the pectin. High DE pectins show higher swelling capacity when exposed to the acidic medium. The presence of the pectinolytic enzymes in the dissolution

media results in the increase of the STZ release rate from the compression coated systems. Systems compression coated with high DE pectins are more susceptible to pectinolytic enzymes since than the low DE pectins.

REFERENCES 1. Sinha VR, Kumria R. Microbially triggered

drug delivery to the colon. Eur J Pharm Sci 2003;18:3–18.

2. Gowrishankar R, Phadke RP, Oza SD, Tulwalker S. Satranidazole: experimental evaluation of activity against anaerobic bacteria in vitro and in animal models of anaerobic infection. J Antimicrob Chemoth 1985;15:463–470.

3. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems. Crit Rev Ther Drug Carrier Syst 2007;24:147–202.

4. Ravi V, Siddaramaiah, Pramod Kumar TM. Influence of natural polymer coating on novel colon targeting drug delivery system. J Mater Sci: Mater Med 2008;19:2131–2136.

5. Alias J, Goni I, Gurruchaga M. Enzymatic and anaerobic degradation of amylose based acrylic copolymers, for use as matrices for drug release. Polym Degrad Stabil 2007;92:658–666.

6. Liu L, Fishman M, Kost J, Hicks KB. Pectin-based systems for colon-specific drug delivery via oral route. Biomaterials 2003;24:3333–3343.

7. Wakerly Z, Fell JT, Attwood D, Parkins DA. In vitro evaluation of pectin-based colonic drug delivery systems. Int J Pharm 1996;129:73–77.

8. Fernandez-Hervas MJ, Fell JT. Pectin:chitosan mixtures as coatings for colon-specific drug delivery: an in vitro evaluation. Int J Pharm 1998;169:115–119.

9. He W, Du Q, Cao DY, Xiang B, Fan LF. Study on colon specific pectin/ethylcellulose film-coated 5-fluorouracil pellets in rats. Int J Pharm 348 2008;348:35–45.

10. Semde R, Amighi K, Devleeschouwer MJ, Moes AJ. Studies of pectin HM:Eudragit® RL:Eudragit® NE film-coating formulations intended for colonic drug delivery. Int J Pharm 2000;197:181–192.

11. Derle D, Boddu SHS, Magar M. Studies on the Preparation, Characterization and Solubility of beta-Cyclodextrin - Satranidazole Inclusion Complexes. Indian J Pharm Educ Res 2006; 40:232–236.

12. Sungthongjeen S, Sriamornsak P, Pitaksuteepong T, Somsiri A, Puttipipatkhachorn S. Effect of Degree of Esterification of Pectin and Calcium Amount on Drug Release from Pectin-Based Matrix Tablets. AAPS PharmSciTech 2004;5:1–8.

1. Introduction

2. Polysaccharides: characteristics

and properties

3. Approaches for

colon-targeted drug delivery

4. Conclusion

5. Expert opinion

Review

Polysaccharides: a targetingstrategy for colonic drug deliveryNitesh Shah†, Tejal Shah & Avani AminNirma University, Institute of Pharmacy, Department of Pharmaceutics and Pharmaceutical

Technology, Ahmedabad, Gujarat, India

Introduction: Colon targeting has gained increasing importance for the

topical treatment of diseases of the colon, such as Crohn’s disease, ulcerative

colitis, colorectal cancer and amebiasis. Various strategies used for targeting

drugs to the colon include formation of a prodrug, coating with time or

pH-dependent polymers, use of colon-specific biodegradable polymers,

osmotic systems and pressure-controlled drug delivery systems. Among the

different approaches used, polysaccharides that are precisely activated by

the physiological conditions of the colon hold great promise, as they provide

improved site specificity and meet the desired therapeutic needs.

Areas covered: This review aims to summarize the natural and modified

properties of polysaccharides that are responsible for their colon targeting

abilities. Emphasis is placed on describing formulation approaches that use

polysaccharides as a strategy for targeting drugs to the colon.

Expert opinion: Polysaccharide-based colon-targeted drug delivery systems are

effective when they are precisely activated by the physiological conditions of

the colon. Absence of enzymes during colonic disorders might hinder the acti-

vation of the delivery system. To guarantee delivery of the drug to the colon, it

is preferable to combine polysaccharides with enteric or cellulose polymers.

Keywords: compression coated, hydrogel, physiological conditions, polysaccharides, transit time

Expert Opin. Drug Deliv. [Early Online]

1. Introduction

The oral route of administration is considered to be the most convenient and com-monly used method for drug delivery. Conventional oral dosage forms have tradi-tionally been designed to dissolve drug in the upper part of gastrointestinal tract(GIT) and for it to be absorbed from these regions, depending on the physicochem-ical properties of the drug. Problems arise when local targeting is desired to the dis-tal part of GIT such as the colon or in conditions where a drug needs to be protectedfrom the acidic environment of the stomach [1]. Targeting of drugs to the colon is ofincreasing importance for local treatment of inflammatory bowel diseases (IBD) ofthe colon, such as ulcerative colitis and Crohn’s disease [2,3]. The prevalence of ulcer-ative colitis and Crohn’s disease ranges from 10 to 70 per 100,000 people, butrecent studies in Manitoba, Canada and Rochester, MN, have shown the prevalenceto be as high as 200 per 100,000 people [4,5].

The colon presents less hostile conditions for drug delivery because it is lessdiverse and has a lower intensity of enzymatic activity and a near neutral pH [6].The major function of the colon is to absorb water and electrolytes (each day upto 2000 ml of fluid enters the colon through the ileocecal valve). The absorptioncapacity of the human colon is lower than that of the small intestine, but theresidence time of the formulations is as high as 2 -- 3 days, which may vary indiseased condition such as IBD. This long residence time provides a significantopportunity for the absorption of drugs [7-9]. Most of the previous colon targetingsystems focused on one of the following three approaches: pH-dependent release,

10.1517/17425247.2011.574121 © 2011 Informa UK, Ltd. ISSN 1742-5247 1All rights reserved: reproduction in whole or in part not permitted

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time-dependent release, or bacterial degradation in the distalileum/colon with limited in vivo evaluation. Colonic deliverysystems based solely on time or pH dependency of release arenot reliable because of the inherent variability of pH and tran-sit times through the upper GIT [10,11]. Use of polymers thatrelease the drug at higher pH values (> 7) may fail to releasethe drug in a reliable way in the colon because pH drops to6.4 ± 0.6 on entering the colon [6]. With respect to transittimes, the small intestinal transit time is fairly constant at3 -- 4 h in most individuals, but gastric emptying is highlydependent on whether the dosage form is ingested in the fedor fasted state, on concomitant fluid intake and, in the fastedstate, the extent of the phase of the motility cycle at the timeof ingestion. Therefore, site-specific release in the colon can-not be guaranteed by dosage forms that are designed to releasethe drug a prespecified number of hours after ingestion [12].Of these three approaches, microflora-activated systemsappear to be more promising, as the abrupt increase of thebacterial population and associated enzymatic activity in thecolon represent a non-continuous event, independent of theGI transit time [13,14]. The number of microorganismsincreases gradually on descending along the small intestine,but it rises by several orders of magnitude beyond the ileocecalvalve. This is due to a retardation of movement of the con-tents within the gastrointestinal tract resulting from wideningof the intestinal lumen as the contents move from the ileum tothe cecum and to the ascending colon. These facts and thebag-shaped nature of the cecum make this site the favoriteregion for microbial settlement. Intestinal microflora count:103 CFU/ml; colonic microflora count: 1012 CFU/ml.About 400 bacterial species such as Bifidobacteria,

Eubacteria, Bacteroides, Clostridia, and so on, have beenfound in the colon, which liberate > 500 different types ofenzyme [15]. The occurrence of some common bacteria inthe GIT is listed in Table 1. The energy requirement ofcolonic bacterial flora for maintaining the cellular functionis derived from the fermentation of various substrates thatare left indigested in the small intestine. These substrates

include di- and trisaccharides, such as raffinose, stachyose,cellobiose and lactulose, and residues of partially digestedpolysaccharides, such as starch and polysaccharides fromendogenous sources such as mucopolysaccharides [16,17]. Inaddition to polysaccharides, other substrates for fermentationare dietary fibers, which include all the non-a-glucan poly-mers that originate in the plant cell wall cellulose, hemi-cellulose and pectin substances [18]. Several enzymes, such asb-D-glucosidase, b-D-galactosidase, b-xylosidase, b-arabinosi-dase, azoreductase, deaminase, urea hydroxylase and nitro-reductase, are produced by colonic microflora to carryout fermentation of these substrates (polysaccharides anddietary fibers) [19,20]. These enzymes, which are derived frommicrobes, degrade coatings/matrices as well as break bondsbetween an inert carrier and an active agent, that is, releasedrug from the polymeric prodrugs.

Ideal candidates for colonic drug delivery are drugs thatshow poor absorption from the stomach or intestine, andthe drugs used in the treatment of IBD, diarrhea and coloncancer. The colon is considered to be the preferred absorptionsite for oral administration of proteins and peptide drugsowing to relatively low proteolytic enzyme activities in thecolon compared with the upper gastrointestinal tract. Poten-tial protein and peptide drug candidates for oral colon-specific drug delivery systems are listed in Table 2. Differentdrugs under research for colonic disorders are mentionedelsewhere [21].

The use of naturally occurring polysaccharides is attract-ing a lot of attention for targeting drugs to the colon, as thesepolymers of monosaccharide are found in abundance and areinexpensive. Synthetic polymers are associated with toxiceffects and thus extensive research is being carried out toexplore the use of natural polymers derived from plants andanimals. Natural polymers used for colon-targeted deliveryare based on the fact that anaerobic bacteria in the colon areable to recognize the various substrates and degrade themwith the enzymes. The natural polymers that are stable inthe gastric environment of the upper GIT are preferred forcolon-targeted delivery. The basic intention of this review isto focus on the properties of polysaccharide that are responsi-ble for its application as a colon-targeting tool. The reviewalso focuses on current approaches to targeting drug to thecolon, using natural polysaccharides as carriers for theactive drug.

2. Polysaccharides: characteristics andproperties

Major polysaccharides used for targeting drugs to the colonare pectin, guar gum, chitosan, amylose, inulin, locust beangum, chondroitin sulfate, dextran and alginate. These poly-saccharides when used orally are specifically degraded in thecolon. To understand the characteristic properties responsiblefor their colonic degradation is of particular importance whenusing them as carriers for colon-targeted drug delivery.

Article highlights.

. The residence time of formulations in the colon is2 -- 3 days, which provides a significant opportunity forthe absorption of drugs.

. Polysaccharides, when used orally, are specificallydegraded in the colon owing to the presence of avariety of bacterial species.

. To impart more specificity to the polysaccharide-baseddrug delivery system, extra protection is provided by theaddition of some more release-controlling excipients tothe system.

. The use of naturally occurring dietary polysaccharides asa drug carrier for colonic delivery simplifies the issues ofsafety, toxicity and availability.

This box summarizes key points contained in the article.

Polysaccharides: a targeting strategy for colonic drug delivery

2 Expert Opin. Drug Deliv. [Early Online]

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Chemistry and natural sources of different polysaccharides arelisted in Table 3. Characteristic properties and polysaccharide-specific modified properties of different polysaccharides arediscussed below.

2.1 Pectin2.1.1 Natural characteristicsPectins are polymers of galacturonic acid linked by a(1--4)bonds, where the carboxyl groups are methylated to varyingdegrees. However, pectins also contain neutral sugars such asgalactose, rhamnose or arabinose, either as part of the polymerbackbone (e.g., rhamnose) or as side chains (e.g., arabinose).Neutral sugar side chains tend to be concentrated into

particular areas of the pectin molecule described as ‘hairyregions’, with the sugar-free areas termed ‘smooth regions’.In human digestion, pectin more or less passes intact throughthe small intestine and is degraded by microorganisms presentin the colon; but if the number of hairy regions increases thecolon-targeting property of the pectins may be hindered, as atlow pH (< 2) the hairy regions are less stable compared withsmooth regions [22-24].

2.1.2 Modified characteristics2.1.2.1 Addition of calciumPectin is a soluble dietary fiber, so it led to the development ofderivatives of pectin that were less water soluble but weredegradable by the colonic microflora [25]. Calcium salts ofpectin give a better shielding effect by forming an ‘egg-box’configuration, which reduces the solubility of pectin. Theamount of calcium present in the formulation should begreatly controlled to provide optimum drug delivery [26].

2.1.2.2 Degree of esterification and amidationThe degree of esterification greatly influences the propertiesof pectin, especially its solubility and its requirements forgelation, which are directly derived from the solubility. Innature, ~ 80% of carboxyl groups of galacturonic acid areesterified with methanol. This proportion is decreased moreor less during pectin extraction. The ratio of esterified to non-esterified galacturonic acid determines the behavior of pectinin drug delivery applications. This is why pectins are classifiedas high-ester pectins (HE) and low-ester pectins (LE). Thedegree of esterification (DE) varies depending on the sourceof the pectin and enzymatic activity in the process of ripeningand maturation, and the conditions under which the isolationis conducted. Some of the carboxyl groups may be convertedto carboxamide groups when ammonia is used in the processof de-esterification, producing amidated pectin. Pectins inwhich 50% or more of galacturonic acid are esterified aretermed HE pectins. The non-esterified galacturonic acid unitscan be either free acid or salts with sodium, potassium orcalcium. The efficiency of a pectin-based colonic system

Table 1. Gastrointestinal bacterial count in humans.

Stomach Ileum Jejunum Colon

Aerobic or facultative bacteriaStaphylococci 0 -- 102 0 -- 103 102 -- 105 104 -- 107

Enterobacteria 0 -- 102 0 -- 103 102 -- 106 104 -- 1010

Lactobacilli 0 -- 103 0 -- 104 102 -- 105 106 -- 1010

Streptococci 0 -- 103 0 -- 104 102 -- 106 105 -- 1010

Anaerobic bacteriaEubacteria Uncommon Uncommon Uncommon 109 -- 1012

Clostridia Uncommon Uncommon 102 -- 104 106 -- 1011

Bacteriodes Uncommon 0 -- 102 103 -- 107 1010 -- 1012

Bifidobactrium Uncommon 0 -- 103 103 -- 105 108 -- 1012

Gram-positive cocci Uncommon 0 -- 103 102 -- 105 108 -- 1011

Table 2. Potential protein and peptide drug candidates

for oral colon-specific drug delivery system.

Agent Therapeutic use

Insulin Type I diabetesInterferons Prophylaxis of hepatitis, malignancyLeuprolide Infertility, prostrate carcinomaCiclosporin ImmunosuppressantEpoeitin Anemia associated with chronic

renal failureAmylin Diabetes and nutrition regulationCalcitonin Paget’s disease of bone,

hypercalcemiaAntisenseoligonucleotides

Cancer and AIDS

Filgrastim NeutropeniaGonadorelins Endometriosis, infertilityGlucagon Chronic intractable hypoglycemiaDesmopressin Pituitary diabetes insipidusVasopressin Pituitary diabetes insipidusSomatropin Turner’s syndrome, dwarfismSalcatonin Paget’s disease of bone,

hypercalcemiaUrofollitin InfertilityOctreotide Pancreatitis and acromegalySermorelin Endometriosis and infertilityEtanercept Rheumatoid arthritis

Shah, Shah & Amin

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Table

3.Polysaccharidech

emistryandnaturalso

urce.

Typeofpolysaccharide

Structure

Structuralunit

Naturalso

urce

Pectin

O

OO

H

CO

OH

HO

H

OH

HH

O

HCO

OC

H3

OH

OH

n

a-(1--4

)-linked

D-galacturonic

acid

Cellwallofhigher

terrestrialplants,

fruitsandvegetables

Guargum

O

O

H

CH

2OH

CH

2

OH

HO

OH

HO

O

O

HO

H

CH

2OH

OH

OH

H

H

O

O

n

Linearchainsofmannose

with1b!

4linkagesto

whichgalactose

unitsare

attachedwith

1a!

6linkages

Endosperm

ofthe

seedsofCyamopsis

tetragonolobus

Chitosan

O

O

CH

2OH

CH

2OH

H2N

H2N

OH

OH

HO

OH

O

O

CH

2OH

H2N

OH

O

n

Copolymerofglucosamine

andN-acetylated

glucosamine

Shellofmarine

invertebrates

Amylose

O

O

H

H

HH

HH

CH

2OH

CH

2OH

OH

OH

OH

OH

O

O

n

Linearpolymerof

glucose

linked

mainly

bya(1--4

)bonds

Storagepolysaccharide

inplants



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Table

3.Polysaccharidech

emistryandnaturalso

urce(continued).


Structure

Structuralunit

Naturalso

urce

Inulin

O

O

H

H H

H

CH

2OH

CH

2

OH

H

HO

OH

n

O

OH

HO H

H

H CH

2OH

CH

2O

OO

H

HO H

H

H CH

2OH

HO

CH

2O

OO

H

HO H

H

H CH

2OH

Severalsimple

sugars

linkedtogether

Manytypesofplant

Locust

beangum

HO

OH

OH

HO

O

O

OO

OO

O

HO

OH

OH

O

OH

HO

OH

OH

O

OH

OH

OH

OH

OH

HO

OH

OH

b-1,4-D-galactomannan

Derivedfrom

carob

(Ceratonia

siliqua)

seeds

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Table

3.Polysaccharidech

emistryandnaturalso

urce(continued).


Structure

Structuralunit

Naturalso

urce

Chondroitin

sulfate

OO

CO

OH

H2C

OH

SO

3HO

CH

3

OO

H

OH

O

O

O

HN

D-G

lucuronic

acidand

N-acetyl-D-galactosamine

Cartilaginoustissues

ofmanyinvertebrates

Dextran

OO

H

OH

HO

HO

HO HO

OH

OH

OH

HO

OO

O OO

O

OO

HO

HO

n

a-1,6-D-glucose

Bacterialculturesof

Leuconostoc

mesenteroides

Alginates

OH

H

CO

OH

OH

HO

OH

CO

OH

OH

HO

O

OO

H

H

CO

OH

OH

HO

OH

CO

OH

OH

HO

O

H

O

H

Homopolymericblocks

of(1--4

)-linked

b-D-m

annuronate

anda-

L-guluronate

residues

Seaweed



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depends on the type of pectin used (HE, LE or amidated). Low-ester pectins form more rigid gels with calcium as comparedwith HE pectins, whereas amidated pectins are tolerant to pHvariations and calcium levels, which make amidated pectins anobvious choice for colonic delivery systems [27,28].

2.1.2.3 Crosslinking of pectin with aldehydesGlutraldehyde crosslinked calcium pectinate beads success-fully delivered resveratrol to the colon. A minimum glutralde-hyde concentration and crosslinking time are essential toproduce sufficiently strong beads that can prevent drug releasein the upper GI tract [29].

2.2 Guar gum2.2.1 Natural characteristicsGuar gum is used as for delivering drugs to the colon becauseit retards drug release in the large intestine and is also specif-ically degraded in the presence of colonic microflora [30]. Guargum hydrates and swells in cold water, forming viscous colloi-dal dispersions or sols, which retard drug release from thedrug delivery system [31].

2.2.2 Modified characteristicsOwing to rapid swelling of guar gum, there are chances of thedrug being released before it reaches the colon. To stop pre-mature drug release, low swelling guar gum was manufacturedby crosslinking it with trisodium trimetaphosphate, whichwas capable of delivering drug to the colon [32].

2.3 Chitosan2.3.1 Natural characteristicsChitosan, a linear amino polysaccharide composed ofrandomly distributed (1--4)-linked d-glucosamine andN-acetyl-D-glucosamine units, is obtained by the deacetyla-tion of chitin, a widespread natural polysaccharide foundin the exoskeleton of crustaceans such as crab and shrimp.The degree of deacetylation has a significant effect on thesolubility and rheological properties of the chitosan. Chito-sans with a low degree of deacetylation (£ 40%) are solubleup to a pH of 9, whereas highly deacetylated chitosans(‡ 85%) are soluble only up to a pH of 6.5. Chitosan is aweak base with a pKa value in the range 6.2 -- 7.0, dependingon the source of the polymer [33]. At low pH, the polymer issoluble, with the sol-gel transition occurring at ~ pH 7.Chitosan-based delivery systems can protect therapeuticagents from the hostile conditions of the upper gastrointesti-nal tract and release the entrapped agents specifically at thecolon through degradation of the glycosidic linkages ofchitosan by colonic microflora.

2.3.2 Modified characteristics2.3.2.1 Crosslinking of chitosan solution with aldehydesChitosan has often been limited in colonic targeting of drugsbecause of its high solubility in gastric fluids, sometimesresulting in burst release of the drug at the stomach. Chitosan

can be insoluble at acidic fluids through chemical crosslinkingwith aldehydes [34].

2.3.2.2 Effect of H-bond formationOn granulation of chitosan with poly(vinyl pyrrolidone)(PVP) binders, the solubility of chitosan in the acidic mediumdecreases. Granulation also enhances the cohesiveness andcompressibility of the blended mixture. It enables the forma-tion of an H-bond between PVP and chitosan, leading toincreased water absorbability and rapid formation of a gellayer [35]. Yassin et al. [36] showed that high coat thicknesswith granulated chitosan resulted in complete protectionagainst both acidic and alkaline media.

2.4 Amylose2.4.1 Natural characteristicsThis naturally occurring polysaccharide possesses the ability toform films. These films are water swellable and are potentiallyresistant to pancreatic a-amylase but are degraded by colonicbacterial enzymes [37].

2.4.2 Modified characteristicsOne form of starch, amylose, can be made resistant to pancre-atic enzymes through the formation of an amorphous struc-ture (amorphous amylose), and can be degraded by colonicbacteria [38]. In its glassy amorphous form, amylose is metab-olized by bacterial amylase enzymes of colonic origin. There-fore, on passage through the gastrointestinal tract, glassyamylose will remain intact in the upper gut and then befermented in the colon.

2.5 Inulin

2.5.1 Natural characteristicsInulin is indigestible by the human enzymes ptyalin and amylase,which are adapted to digesting starch. As a result, inulin passesthrough much of the digestive system intact. It is only in thecolon that bacteria metabolize inulin. Inulin also stimulates thegrowth of bacteria in the gut [39]. Major bacteria responsible forfermentation of inulin in colon are bifidobacteria [40].

2.5.2 Modified characteristicsThe introduction of vinyl groups in this sugar polymer by freeradical polymerization formed hydrogels resistant to the upperGIT. Thus, these modified hydrogels can be successfully usedas a carrier for drug delivery to the colon [41].

2.6 Locust bean gum

2.6.1 Natural characteristicsLocust bean gum is soluble in water. The hydration capacityof this polymer is lower in cold water, thus it requires heatfor full hydration and maximum viscosity [42].

2.6.2 Modified characteristicsCrosslinked galactomannan led to water-insoluble film-formingproduct-showing degradation in colonic microflora [43].

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2.7 Chondroitin sulfate

2.7.1 Natural characteristicsChondroitin sulfate is degraded by the anaerobic bacteriaof the large intestine mainly by Bacteroides thetaiotaomicronand B. ovatus [44]. Owing to its specificity for degrada-tion towards colonic enzymes, it can be used as a carrierfor drug delivery to the colon. However, the high watersolubility of chondroitin sulfate is disadvantageous. Theuse of chondroitin sulfate as a carrier for delivery of indo-methacin proved unsuccessful as 100% of the drug releasedin 1 h [45].

2.7.2 Modified characteristicsTo prolong the release it is necessary to use crosslinkedchondroitin sulfate, which could prolong drug delivery.Chondroitin sulfate was crosslinked with 1,12-diaminodo-decane. This crosslinked chondroitin sulfate was used toprepare matrix tablets with indomethacin. The degree ofcrosslinking chondroitin sulfate affected drug release fromits matrices. Higher crosslinking decreased the release,whereas crosslinking in a lower proportion increased releasefrom the matrices [46].

2.8 Dextran2.8.1 Natural characteristics2.8.1.1 Hydrolysis of glycosidic bondsThe glycosidic linkages are hydrolyzed by molds, bacteria andalso by mammalian cells. Dextranases are the enzymes respon-sible for hydrolysis of these glycosidic linkages. Dextranaseactivity of the colon is shown by anaerobic Gram-negativeintestinal bacteria, especially the Bacteroides [47].

2.8.1.2 High-molecular-mass dextransDextrans are polysaccharides that are suitable for colon drugdelivery, especially the high-molecular-mass types, which areless soluble in aqueous media. Tablet formulation of solid dis-persions of budesonide with dextran in the ratio 1:7 and usingmolecular mass of 10,000 of dextran represented an effectivetool for the treatment of colonic inflammatory boweldisease [48].

2.8.2 Modified characteristicsTo impart colon specificity, low-molecular-mass naturaldextrans can be converted to high-molecular-mass dextransby synthetic modifications. Bauer and Kesselhut [49] synthe-sized dextran fatty acid ester and concluded that lauroyldextran esters with molecular mass of ~ 250,000 and degreeof substitution ranging from 0.11 to 0.3 were suitable forcolon drug delivery as film coatings. For theophylline asdrug, Hirsch and co-workers [50,51] demonstrated that forlauroyl dextran esters having degree of substitution between0.12 and 0.40, the release rate (in vitro) was inversely pro-portional to coat thickness. The addition of dextranase tothe dissolution medium increased the degradation rateof dextran.

2.9 Alginates

2.9.1 Natural characteristicsSodium alginate is a linear copolymer consisting of b-(14)mannuronic acid and a-(14) l-guluronic acid residues. In gen-eral, gel formation of polysaccharides in the gastric mediumprevents drug release from the core. Alginates do not gelbecause they have rigid poly(l-guluronic acids), which gel inthe presence of Ca2+ ions [52]. Thus, alginates without thepresence of Ca2+ ions cannot be used as a colonic carrier.

2.9.2 Modified characteristicsAlginate gelation takes place when divalent cations (usuallyCa2+) interact ionically with blocks of guluronic acid residues,resulting in the formation of a three-dimensional networkthat is usually described by an ‘egg-box’ model [53]. It is theion exchange process between Na+ and Ca2+ ions that is sup-posed to be responsible for the swelling and subsequent degra-dation of sodium alginate in the colon. The mechanical andswelling properties of swelled alginate, produced by ioniccrosslinking with cations, depend on several factors, such asvalency of ions, size of ions, and so on. For example, monova-lent cations and Mg2+ ions do not induce gelation [54],whereas Ba2+ ions produce stronger beads than Ca2+ [55].Modifying the release properties by calcium addition ispossible only in pectin and alginate-based systems.

3. Approaches for colon-targeted drugdelivery

All polysaccharides discussed in this review show colon-specific degradation, but to impart more specificity to thedelivery system an extra protection is provided by the additionof some more release-controlling excipients to the system. Thecolonic system can be prepared by either the combination ofdifferent polysaccharides or the combination of natural poly-saccharide with synthetic polymers. Some commonly usedapproaches based on this fundamental are discussed below.

3.1 Prodrug-based formulationsA colon-targeted prodrug is a pharmacologically inert form ofan active drug that must undergo transformation to the parentcompound in the colon by either a chemical or an enzymaticreaction to exert its therapeutic effect. Site-specific drug deliv-ery through site-specific prodrug activation may be accom-plished by some specific property at the target site, such asaltered pH or high activity of certain enzymes relative to thenon-target tissues for the prodrug--drug conversion. The pro-drug approach has been explored for pectin-, inulin- anddextran-based systems.

3.1.1 Pectin-based prodrugsKetoprofen was directed to the colon by preparing a pectin-ketoprofen complex that acted as a prodrug. In vivo studiesin rats demonstrated that ketoprofen was distributed mainlyin the cecum and the colon [56].



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3.1.2 Inulin-based prodrugsMethacrylated inulin hydrogels were successful at targetingproteins to the colon. The feed composition and degree ofsubstitution of inulin seemed to be crucial in controlling theextent and rate of drug release [57]. Colon-targeted inulinhydrogel was prepared by combining methacrylated inulin(MA-IN), aromatic azo agent bis(methacryloylamino)azoben-zene (BMAAB) and 2-hydroxyethyl methacrylate (HEMA) ormethacrylic acid (MA). Uptake of water in the gels wasinversely proportional to the MA-IN feed concentration, thedegree of substitution of the inulin backbone, and the concen-tration of BMAAB. On using prednisolone as a model drug itwas found that on increasing HEMA or MA, drug releasegreatly increased, and on decreasing HEMA or MA, drugrelease decreased [58].

3.1.3 Dextran-based prodrugsThe first attempt to prepare dextran-based prodrug was madeby Harboe and co-workers [59,60], who conjugated naproxen todextran by ester linkage. When ketoprofen and naproxen werelinked with dextran they showed specific release in the colonof pigs. The release of naproxen was up to 17 times higherin homogenates of cecum and colon as compared with controlmedium or homogenates of the small intestine. Glucocorti-coids such as methyl prednisolone and dexamethasone arean effective therapy for colitis. As these glucocorticoids donot have a functional group for attachment to dextrans, theywere attached to dextrans using a spacer molecule. It wasfound that dextran conjugates showed little hydrolysis in theupper GIT contents, but were degraded rapidly in the cecaland colonic contents [61]. Budesonide-dextran conjugateswere effective at improving signs of inflammation in anexperimental model of colitis [62].

3.2 Drug in capsule approachFilling a capsule with the drug is the easiest way of administer-ing drug to the colon. Two different approaches have beentried for these systems: i) filling the drug in polysaccharidecapsules with an extra enteric coating, if required; andii) filling the drug in gelatin/hydroxypropyl methylcellulose(HPMC) capsules with an extra polysaccharide coating toprovide colon specificity.

3.2.1 Chitosan capsulesUsing male Wistar rats as an animal model, Tozaki et al. [63]compared the healing effect of chitosan capsules containinga new thromboxane synthase inhibitor (R68070) on ulcerativecolitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS)with that of a carboxymethylcellulose (CMC) suspension ofR68070. Chitosan capsules provided higher concentrationsof R68070 in the large intestine than the CMC suspension.In another similar study by the same group [64], the authorsused the same animal model to investigate the healingeffect of chitosan capsules containing 5-aminosalicylic acid(5-ASA) on TNBS-induced ulcerative colitis. Chitosan

capsules loaded with 5-ASA provided higher therapeutic effectthan the 5-ASA-CMC suspension.

Hydroxypropyl methylcellulose phthalate, an enteric-coating material, was used to coat chitosan capsules loadedwith insulin. Using male Wistar rats, insulin-containing chi-tosan capsules were administered orally with a total dose of20 IU into the stomach with polyethylene tubing. The hypo-glycemic effect started 6 h after administration, when thecapsules were in the colon, and lasted for 24 h [65].

3.2.2 Dextran capsulesHydrocortisone containing glutaraldehyde crosslinked dex-tran capsules were prepared by Brondsted et al. [66]. In vitrorelease studies carried out in pH 5.4 in the absence of enzymesshowed only 10% release in the first hour and 35% up to24 h. Addition of dextranases to dissolution medium after24 h resulted in fast degradation of capsules, resulting inalmost complete release of hydrocortisone [66].

3.2.3 Polysaccharide-coated HPMC capsulesHPMC capsules coated with a mixture of amylose and ethyl-cellulose were used to deliver 4-aminosalicylic to the colon.In vivo studies revealed that amylose coatings can successfullydeliver 4-aminosalicylic acid to the colon for treatment ofinflammatory bowel disease [67].

3.3 Matrix tabletsPolysaccharide-based matrix tablets are the simplest and mostversatile mode of achieving colon specificity. Almost all thepolysaccharides have been explored for their use as matrix sys-tems. The basic drawback of this system is that they need anextra barrier coat in the form of a compression coat or anenteric coat to prevent premature drug release. A few colonicmatrix systems explored are listed below.

Indomethacin matrix tablets were prepared using guar gumas a carrier. These tablets retained their integrity for a total of5 h, which included 2 h exposure in 0.1 M HCl and 3 h expo-sure in Sorensen’s phosphate buffer (pH 7.4). The total drugreleased after 5 h was 21%, which is a high amount of drugbeing released before the tablet reaches colon [68]. Guargum-based colon-targeted matrix tablets of rofecoxib wereprepared using 40, 50, 60 and 70% guar gum. In vivo evalu-ation in human volunteers showed delayed Tmax, prolongedabsorption time (ta), decreased Cmax and decreased absorptionrate constant (ka) as guar gum concentration increased from40 to 70% [69]. Matrix tablets were also prepared for celecoxiband mebendazole using guar gum as a carrier. In vitro studiesreveal that matrix tablets containing either 20 or 30% of guargum are most likely to target both the drugs for local action inthe colon [70,71].

Colon-specific drug delivery systems for mesalazine wereprepared using locust bean gum and chitosan in the ratios2:3, 3:2 and 4:1. In vivo studies carried out in nine healthymale human volunteers for various formulations revealedthat drug release was initiated only after 5 h, which is the

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transit time of the small intestine. The formulation containinglocust bean gum and chitosan in the ratio 4:1 held a betterdissolution profile and higher bioavailability [72].

3.4 Mixed film coatingsFilms made from polysaccharide lack the strength required tokeep them intact for 5 -- 6 h in the GIT (considered as the lagtime required for reaching the colon). Thus, addition ofanother coating polymer in the same coat would provide ten-sile strength sufficient to obtain the desired lag time. Theextra coating polymer may consist of another polysaccharide,or a hydrophilic or hydrophobic polymer.

3.4.1 Ethylcellulose-based filmsAddition of a hydrophobic polymer such as ethylcellulose ishighly recommended to increase the tensile strength of thefilms and restrict the entry of water and the consequentswelling of the polymer to alter the solubility of the polymer.

3.4.1.1 Pectin-ethylcellulose filmsFirst, pectin-ethylcellulose films were successfully developedon paracetamol cores. The study concluded that drug releasefrom the core was dependent on the pectin-ethylcellulose ratioand coating level [73]. Pectin and ethylcellulose were used in asingle film coat to target 5-fluorouracil pellets to the colon. At1:2 ratio of pectin:ethylcellulose almost 80% drug releasewas found in the colon [74]. The pectin/Kollicoat� (BASF,Germany) SR30D mixed films were susceptible to rat colonicbacterial enzymes and were completely degraded in the colitis-induced rats. The extent of digestion correlated with theamount of pectin present within the film [75].

3.4.1.2 Guar gum-ethylcellulose filmsTo prevent premature release in the small intestine acombination of guar gum and ethylcellulose was used tocoat 5-fluorouracil pellets. In vitro release studies indicatedthat addition of hydrolase enzyme to dissolution medium(pH 6.5 phosphate buffer) accelerated release of drug fromthe formulation. It was concluded that a mixed coating ofguar gum and ethylcellulose prevents drug release in the stom-ach and allows enzymatic breakdown of the coat to releasedrug in the colon [76].

3.4.1.3 Amylose-ethylcellulose filmsAddition of ethylcellulose to an amylose coating solutionincreased the tensile strength of the amylose films [77]. Whenamylose and ethylcellulose were tried as a film coat for formu-lating colonic tablets of mesalazine, it was found that the rateand extent of drug release were inversely proportional to theamount of ethylcellulose in the film coat and the thicknessof the coat. Drug release increased in the presence of cecalcontent, indicating susceptibility of amylose to colonicmicroflora [78]. In another study, 5-ASA pellets were coatedwith aqueous dispersion of amylose and Ethocel� (Colorcon,USA). The optimum coating formulation consisted of

amylose:Ethocel in 1:4 w/w ratio. At this ratio the drug releasewas suppressed for 12 h in simulated gastric and intestinal flu-ids. On introduction of these coated pellets in simulatedcolonic fluids the coat fermented and released the drug within4 h [79]. This study was extended further where glucose wasused as a model drug. Here also a 1:4 w/w ratio of amylose:Ethocel was found to be optimum [80].

3.4.2 Miscellaneous mixed filmsTo provide mechanical strength to polysaccharide films, poly-saccharides can be mixed with insoluble grades of Eudragit�

(Evonik, Germany) such as Eudragit�RL/RS. Study of the-ophylline release from pellets coated with pectin HM:Eudra-git�RL:Eudragit�NE ternary mixtures has shown that thepresence of pectinolytic enzymes in the dissolution mediaresults in an increase of the drug release rate when the pectinHM content of the coatings ranges between 10.0 and 15.0%w/w (related to that of Eudragit RL) [81].

Mechanical strength can also be increased by incorporatingHPMC in the film coat. Radiolabeled (99mTc) tablets coatedwith a 3:1:1::pectin:chitosan:HPMC films were administeredorally to human volunteers. Gamma-scintigraphic studiesindicated that the tablets remained intact through the stom-ach and small intestine. In the colon, the bacteria degradedthe coat and thus the tablets disintegrated [82].

3.5 Double-coated systemsCoating core tablets with a polysaccharide film followed by anenteric coat is another means by which drug release to thecolon can be guaranteed. The enteric coat protects the systemfrom harsh gastric conditions, and as the system reaches thesmall intestine the enteric coat starts dissolving and exposespolysaccharide coat to the small intestine. Polysaccharidefilms degrade only when they reach the colon. Thus, thesesystems have gained high acceptability. A general method ofpreparation and mechanism of drug release from thesesystems is shown in Figure 1.

Tominaga et al. [83] prepared a colon-targeted formulationby using a double-coating system. The core, composed ofacetaminophen, was coated with an inner coating layermade of chitosan and an outer coating layer made of phytin,a gastric acid-resistant material.

3.6 Compression-coated systemCompression-coated systems are the most popular tool to tar-get drug to the colon in recent times. Although these systemsrequire a special compression machine and personnel skills,the major advantage of this system is its versatility to delivera wide variety of drugs. A general method of preparationand mechanism of drug release from these systems is shownin Figure 2.

3.6.1 Pectin as a compression coating materialPectin as a compression coat was evaluated for its capability totarget drug to the colon. This technique was compared with



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Enteric coat

Supercoating withenteric polymer

Entry in stomach

Film coating withpolysaccharide

Core tablet

Entry in colon

Rupturing ofpolysaccharide film coat with

complete release of drugIntact in stomachRupturing of enteric coat

Entry in small intestine

Polysaccharide film coat

Figure 1. Colon-targeted double-coated systems.

Enteric coat

Supercoating withenteric polymer

Entry in stomach

Compression coatingwith polysaccharide

Core tablet

Entry in colon

Erosion of compression coatwith complete release of drug

Intact in stomachRupturing of enteric coat andswelling of compression coat

Entry in small intestine

Polysaccharide

Figure 2. Colon-targeted compression-coated systems.

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plain matrix tablets. Calcium pectinate-indomethacin tabletsprepared by both the approaches showed no release at pH1.5 for 2 h. At pH 7.4 plain matrix tablets showed drugleak but compression-coated tablets remained unaffected.Addition of pectinolytic enzymes increased the drug releasein both cases, but compression-coated tablets released lessdrug (57.6 ± 2.5%) compared with matrix tablets (74.2 ±4%) after 12 h. Thus, the compression coating techniquewas useful for delivery of drug to the colon [84]. Pectin-Compritol� ATO 888 was used successfully as a compressioncoating mixture to direct mesalamine to the colon [85].

3.6.2 Guar gum as a compression coating materialThe compression coating approach was used by Krishnaiahand co-workers to direct tinidazole, ornidazole and 5-fluoro-uracil to the colon. In vitro studies revealed that tinidazoletablets compression coated with 55 or 65% guar gum, ornida-zole tablets compression coated with either 65 or 75% guargum, and 5-fluorouracil tablets compression coated with80% of guar gum coat showed minimum release in the first5 h, targeting maximum drug to the colon [86-88].

3.6.3 Chitosan as a compression coating materialThe compression coat of mixture of spray dried chitosan ace-tate and HPMC in the ratio 60:40 was capable of retardingthe release of 5-ASA until the dosage forms reached thecolon [89]. 5-Flurouracil tablets compression coated with gran-ulated chitosan successfully directed drug to the colon. X-raystudies confirmed localization of the system to the colon [90].

3.7 Enteric-coated hydrogels and microspheresMost of the polysaccharide-based colon-targeted drug deliverysystems developed recently use enteric coating to provide pro-tection to the system from the acidic conditions of the stom-ach. Enteric-coated multi-unit systems provide the advantageof longer residence time in the colon. Multi-unit systemsexplored by the researchers consist mainly of hydrogel beadsand microspheres. General methods for the preparation ofhydrogel beads and microspheres are shown in Figures 3

and 4, respectively.

3.7.1 Pectin-based hydrogel beadsCalcium pectinate gel beads containing 5-fluorouracil pre-pared by an ionotropic gelation method were enteric coatedwith Eudragit�S100. In vivo data showed that EudragitS100-coated calcium pectinate beads delivered most of theirdrug load (93.2 ± 3.67%) to the colon after 9 h [91].

3.7.2 Pectin-based microspheresEudragit S100-coated colon-targeted microspheres of5-fluorouracil were prepared by an emulsion dehydrationmethod. From the organ distribution study in albino rats, itwas concluded that Eudragit-coated pectin microspheres canbe efficiently used to target 5-fluorouracil to the colon [92].Eudragit-coated pectin microspheres prepared using the

solvent evaporation method showed no drug release at gastricpH, however continuous release of drug was observed fromthe formulation at colonic pH. Drug release was found tobe higher in the presence of rat cecal content [93].

3.7.3 Chitosan-based hydrogel beadsEudragit S100-coated chitosan beads offered a high degree ofprotection in the upper GIT and delivered the maximumamount of satranidazole to the colon [94].

3.7.4 Chitosan-based microspheresChitosan microspheres microencapsulated with Eudargit�L100and S100 protected the formulation in acidic pH, but when itreached intestinal pH the coat started dissolving and in colonicfluid chitosan degraded in the presence of cecal matter, releasinga higher amount of drug in colon [95]. Chitosan microspheresprepared by emulsion crosslinking and coated with EudragitS100 by the solvent evaporation technique successfully directedondansetron to the colon [96].

3.8 New approaches

3.8.1 Osmotic technologyMicrobially triggered colon-targeted osmotic pumps (MTCT-OP) were used to target budesonide to colon using chitosanas a carrier. Chitosan has a gel-forming property at acidic con-ditions, which was used to formulate drug suspension andproduce osmotic pressure, whereas the colonic degradationproperty was explored to form in situ delivery pores forcolon-specific drug release. The effects of different formulationvariables, including the level of pH-regulating excipient (citricacid) and the amount of chitosan in the core, the weight gainof semipermeable membrane (cellulose acetate) and entericcoating membrane, and the level of pore former (chitosan) inthe semipermeable membrane, were studied. The study con-cluded that osmotic technology when used in combinationwith the microbial degradation property of the colon couldbe used for developing colon-specific drug delivery [97].

3.8.2 UV-irradiated hydrogelsNew biocompatible and biodegradable hydrogels were pre-pared by UV irradiation of aqueous solutions contain-ing methacrylated dextran (DEX-MA) and methacrylateda,b-poly(N-2-hydroxyethyl)-dl-aspartamide (PHM). In vitrostudies showed that DEX-MA/PHM hydrogels undergo neg-ligible hydrolysis in simulated gastric and intestinal fluid inthe absence of dextranase. On the contrary, when dextranasesare present in the external medium, partial degradationoccurs. The enzymatic biodegradability is due to the combina-tion of DEX-MA with PHM, as crosslinked DEX-MA alone(with degree of substitution 20 mol%) does not undergo degra-dation by dextranase. The potential use of a DEX-MA/PHM-based hydrogel for the treatment of inflammatory boweldiseases was evaluated by loading it with beclomethasonedipropionate and evaluating the effect of dextranases on itsrelease [98].



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Dispersion of API in polysaccharide solution

Washing of hydrogel beads with distilled water

Drying of hydrogel beads

Drop-wise addition of polysaccharide solution into the CaCI2 or BaCI2 solution

Allow the curing of hydrogel beads in the above solution for some time

Figure 3. Method of preparation of colon-targeted hydrogel beads.API: Active pharmaceutical ingredient.

Disperse API in polysaccharide solution

Disperse core microspheres in enteric coating solution

Emulsification in external phase

Washing of microspheres

Emulsification in external phase

Washing of microspheres

Encapsulated microspheres obtained

Formation of microspheres

Figure 4. Method of preparation of colon-targeted microspheres.API: Active pharmaceutical ingredient.

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4. Conclusion

Various polysaccharide-based drug delivery systems alongwith their basic properties and method of preparation havebeen summarized in this article. The use of naturally occur-ring dietary polysaccharides as drug carriers for colonic deliv-ery simplifies the issues of safety, toxicity and availability.Researchers may adopt any of the listed methods to targetdrugs to the colon, but special care in method selection isrequired if the process is to be scaled up. Future investigationsmay concentrate on the development of such polysaccharide-based systems, which have fewer processing steps and are easyto manufacture.

5. Expert opinion

There has been tremendous interest in developing colon-targeted drug delivery systems over the last decade, but onlyenteric-coated colonic tablets have been able to hit the marketso far. The vagaries in pH of different organs of the GIT poseproblems for those systems that take into consideration spe-cific values of pH for their activation. Microflora-activatedsystems appear to be more promising because the abruptincrease of the bacteria population and associated enzymeactivity in the colon represent a non-continuous eventindependent of gastrointestinal transit time.On comparing the colon-specific drug delivery systems

reported previously, the recently used approaches detailedin this review show the advantages and applications of usingpolysaccharide-based pharmaceutical excipients for site spec-ificity of drug release. For any polysaccharide-based colon-specific drug delivery, the rate-limiting step for activationof the system is the ability of polysaccharides to hydrateand swell. The resultant swelling creates a diffusion barrierat the surface of the solid dosage form during its passagethrough the GIT. These hydrated layers of polymers allowthe penetration of colonic enzymes/bacteria, which leads todegradation of the polysaccharide barrier, hence releasingthe drug at the target site. For those systems where polysac-charide fails to swell, its subsequent degradation is stalled,which in turn hinders drug release at the target site. This

can be considered a major setback for using purepolysaccharide-based systems.

In this review different combinations of polysaccharideswith different synthetic polymers have been classified exhaus-tively. The three best approaches that can guarantee drugdelivery to the colon are: mixed film coatings; double-coated systems; and compression-coated systems. In allthese approaches, synthetic polymers such as ethylcellulose,HPMC or an enteric polymer are either added to a poly-saccharide coat or applied as a separate barrier coat. Research-ers have shown promising results using these approaches. Theonly challenge ahead is to scale-up the process at thecommercial level.

A big area of concern is to develop multiple unit colon-targeted systems. So far, a large amount of work has focusedon developing single unit systems for acute therapy of colonicdisorders. As colonic disorders such as ulcerative colitis andCrohn’s disease require chronic therapy, multiple unitsystem such as minitablets, hydrogel beads, microspheresand nanoparticles can be explored more frequently to providecontrolled-release colon-specific drug delivery systems.

The challenges in the future will be to find a polysaccharidefrom which one might be able to obtain a non-permeablefilm or coating that also possess a high colon-specificdegradability. Probably, polysaccharides with a large numberof derivatizable groups, a wide range of molecular mass, vary-ing chemical composition and above all that are stable, safeand biodegradable, may offer a correct solution.

To develop a successful market product for colonic drugdelivery, the formulator needs to address the followingissues before taking these systems to clinical phase trials. Isthe replacement of old technologies and old drugs withcomplicated developments justifiable medically and eco-nomically? Is it pharmacologically not possible to cure theailment with systemic administration of drug? Is thisprocess/technology scalable.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.



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Shah, Shah & Amin


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AffiliationNitesh Shah† MPharm,

Tejal Shah MPharm PhD &

Avani Amin MPharm PhD†Author for correspondence

Nirma University,

Institute of Pharmacy,

Department of Pharmaceutics

and Pharmaceutical Technology,

Ahmedabad -- 382481,

Gujarat, India

Tel: +91 9702635717; Fax: +91 2717 241916;

E-mail: [email protected]



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Acta Pharmaceutica Sciencia

53: ???-??? (2011)

Design and development of enteric and compression coated colonic

tablets: an in vitro evaluation

Nitesh Shah*, Tejal Shah and Avani Amin

Department of Pharmaceutics and Pharmaceutical Technology, Institute of Pharmacy, Nirma University,

Ahmedabad-382481, Gujarat, India.

Abstract

Colon targeted delivery of metronidazole, which immediately releases the drug as soon as the drug

delivery system reaches the colon was formulated for treatment of Crohn’s Disease. To prepare colonic

tablets the core tablets of metronidazole were first compression coated with time dependent polymer,

PEO/ HPMC, and then with pH dependent polymer, Eudragit®

S100. Swelling study concluded that PEO

showed higher swelling capacity compared to HPMC. Metronidazole core tablets compression coated with

250 mg PEO (Polyox®

1105) and enteric coated with 6% w/w of Eudragit®

S100 showed 100% drug

release within 1 h after the delivery system reaches the colon.

Keywords: Crohn’s Disease, PEO, HPMC, swelling study

Introduction

During the last decade there has been interest in developing site-specific formulations for

targeting drug to the colon. The colon is a site where both local and systemic drug delivery can

take place (Bussemer et al. 2001). A local means of drug delivery could allow topical treatment

of inflammatory bowel disease, e.g. ulcerative colitis or Crohn’s disease. Treatment might be

more effective if the drug substances are targeted directly to the site of action in the colon.

Lower doses might be adequate and, if so, systemic side effects might be reduced. A number of

other serious diseases of the colon, e.g. colorectal cancer, might also be capable of being treated

more effectively if drugs were targeted on the colon (Yang et al. 2002).

Colon as a site offers distinct advantages on account of a near neutral pH, a much longer transit

time, reduced digestive enzymatic activity, much greater response to absorption enhancers, and

the presence of large amounts of enzymes (e.g., b-D-glucosidase, b-D-galactosidase, amylase,

pectinase, xylase, dextranase, etc.) for polysaccharides, which are secreted by a large number

and variety of colonic bacteria (Sinha and Kumria 2001). Various systems have been developed

for colon-specific drug delivery. These include covalent linkage of a drug with a carrier, coating

with pH-sensitive polymers, time dependent release systems, and enzymatically controlled

delivery systems (Patel et al. 2007). Enteric coated systems are the most commonly used for

*Corresponding author: [email protected]

mailto:[email protected]

colonic drug delivery, but the disadvantage of this system is that the pH difference between

small intestine and colon is not being very definite. Thus, these delivery systems do not allow

reproducible drug release. The limitation of time dependent release system is that it is not able to

sense any variation in the upper gastro-intestinal tract transit time, any variation in gastric

emptying time may lead to drug release in small intestine before arrival to colon. The microflora

of the colon can split polymers. However, such enzymatic degradation is usually excessively

slow. The bioavailabilities of drugs from such formulations can be low. In addition, little is

known about the safety of the polymers and few have been accepted for use in relation to

medicines. Apparently, the most convenient approach for site-specific drug delivery to colon is

combining time and pH dependent system.

Compression-coating methodology has been used by some researchers for directing drugs to the

colon (Sinha et al. 2004, Nunthanid et al. 2008). Compression-coated core tablet formulations

are simple formulations to manufacture, and were used in this study.

The primary objective of the present study was to design Enteric and compression coated

colonic tablets (ECCCT) consisting of both time and pH release system for oral colonic

targeting. The ECCCT system used in this study composed of three components; a drug-

containing core tablet (rapid release function), the compression-coated layer (timed-release

function) and an enteric coating layer (acid resistance function). The ECCCT system was

fabricated in such a fashion that it provides maximum drug release in colon as soon as the

system reaches colon. Timed release function in ECCCT was imparted by using hydrophilic

polymers like hydroxypropyl methylcellusose (HPMC) or polyethylene oxide (PEO) of different

viscosity and molecular weight. Acid resistance function was provided by Eudragit® S 100. The

pictorial representation of the ECCCT system is shown in Fig. 1.

Figure 1. Design of metronidazole ECCCT

Hydrophilic polymers such as PEO and HPMC are dominant matrix excipients for most

modified release tablet preparations (Kim 1998, Razaghi and Schwartz 2002, Choi et al. 2003).

Once in contact with a liquid, these polymers would hydrate and swell, forming a hydrogel layer

that regulates further penetration of the liquid into tablet and dissolution of the drug from within

(Colombo et al. 2000). As contact time of a polymer with the liquid increases, it would take

more time for drug to diffuse out of the core, since the diffusion path is lengthened by polymer

swelling.

In matrix systems either swelling or dissolution can be the predominant factor for a specific type

of polymer (Sujja-areevath et al. 1998), in most cases drug release kinetics is a result of a

combination of these two mechanisms (Efentakis and Buckton 2002). But in case of

compression-coated systems consisting of hydrophilic polymer we expected polymer swelling

and erosion can be the main mechanism for drug release. The second objective of the study was

to compare the erosion and swelling behavior of two different hydrophilic polymers

hydroxypropyl methylcellusose (HPMC) and polyethylene oxide (PEO) of different viscosity

and molecular weight.

The ECCCT does not release the drug in the stomach due to the acid resistance of the outer

enteric coating layer. After gastric emptying, the enteric coating layer rapidly dissolves, and the

intestinal fluid begins to slowly swell the compression-coated hydrophilic polymer layer, and

when the erosion front reaches the core tablet, rapid drug release occurs. The duration of lag

phase can be controlled either by the weight or composition of the hydrophilic polymer layer.

Therefore, the intestinal transit time of dosage forms after gastric emptying is rather constant,

such systems can deliver drugs to the desired site in the colon. Lag time of the system to reach

colon is basically controlled by swelling and erosion property of compression-coated hydrophilic

polymer layer. In the present study, lag time to reach small intestine was taken as 2 h and lag

time to reach colon was taken as 5 h.

Materials and Methods

Materials

Metronidazole was obtained as a gift sample from J. B. Chemicals, India. Eudragit® S100 was generously

gifted by Rohm Pharma, Germany). Polyvinyl Pyrollidone K90 (PVP K90) was gifted from Anshul

Agencies, India. Methocel® (HPMC) and Polyox® (PEO) were kindly gifted by Colorcon, India.

Crosscarmellose Sodium was obtained as a gift sample from Gujarat Microwax Pvt. Ltd., India. Polyvinyl

pyrrollidone K30 (PVP K30) and lactose were purchased from S.D. Fine-Chem Ltd., India and CDH,

India, respectively. Double distilled water was used throughout the study and all other chemicals used

were of analytical reagent grade.

Preparation of core tablets of metronidazole

Weighed quantity of metronidazole (200 mg/tablet), lactose (diluent) and Cross-carmellose sodium (5%)

were passed through 30# sieve. Both the ingredients were mixed for 15 min in bin blender (Tapasya

Engineering, India). Binder solution consisting of equal quantities of PVP K30 and PVP K90 (5%) in

isopropyl alcohol (IPA) was prepared on a magnetic stirrer. Binding solution was added to the above

blend to prepare a dough mass. The dough mass was forced though 16# sieve and the granules so obtained

were dried at 40 ± 5°C in a tray dryer (USICO, India) till LOD reaches between 3 to 4. The dried granules

were passed though 24# sieve. Talc (2%) and magnesium stearate (1%) were sifted through 40# sieve. The

dried granules were lubricated with talc and magnesium stearate for 5 min. The lubricated granules were

compressed into tablets weighing 400 mg using rotary tablet machine (Rimek, Karnavati Engineering Pvt.

Ltd., India) using 11 mm concave punch. The core tablets were tested for hardness, thickness, content

uniformity, friability, and disintegration.

Preparation of compression-coated tablets

After confirming compliance with the above mentioned tests, the core tablets were compression coated

with different coat powders of HPMC and PEO. Exactly 50% of the coat powder was first placed in the

die cavity of the compression machine. Then, the core tablet was carefully positioned at the center of the

die cavity, which was filled with the remainder of the coat powder. It was then compressed around the

core tablets by using 13-mm concave punches. Two different grades of HPMC (Methocel® E15,

Methocel® K4M) were tried individually and in combination (Table 1) for compression coating.

Table 1. HPMC used as a compression coat

Batch No. HPMC K4M (mg) HPMC E15 (mg)

K1 150 -

K2 200 -

K3 250 -

E1 - 200

E2 - 300

HE1 100 100

HE2 75 125

HE3 50 150

HE4 25 175

HE5 12 187.5

Five different grades of PEO (Polyox® WSR N-80, WSR N-750, WSR 1105, WSR 301, WSR 303) of

different molecular weights were tried at different weights as shown in Table 2. The compression-coated

metronidazole tablets were then evaluated for drug content, hardness, friability, thickness, and drug

release.

Table 2. Different types of Polyox® (PEO) used as a compression coat

Sr. No. Polyox®

Grade Molecular Weight

(Daltons) Batch No.

Compression

coat weight (mg)

1 WSR N-80 2,00,000

PN1 200

PN2 250

PN3 300

2 WSR N-750 3,00,000 PN4 200

PN5 250

3 WSR 1105 9,00,000

PN6 200

PN7 225

PN8 250

4 WSR 301 40,00,000 PN9 200

5 WSR 303 70,00,000 PN10 200

Preparation of coating solution and coating of core tablets

The coating solution was prepared by dissolving Eudragit® S100 (10%w/v) in Acetone:Isopropyl alcohol

(IPA) using a magnetic stirrer at 50 rpm. After complete solubilization of polymer, 4% w/v of dibutyl

phthalate (plasticizer) was added to the coating solution. The solution was stirred for 15 min. Talc (25%

w/w of polymer content) was added to the coating process. Coating was carried out in pan coater (Neocota

Minimax, India). The tablets were loaded in the pan and warmed to achieve product temperature of 38°C.

20 tablets were sampled and their average weight was taken. Coating process was set with inlet

temperature of 45°C, Exhaust at 35°C, Spray rate at 9 g/min and pan rpm of 20. Spraying was continued

till desired weight gain was obtained. Weight gain was calculated on dry average tablet weight basis.

Preparation of enteric coated time dependent compression-coated tablets

Enteric coated time dependent compression-coated tablets (ECCCT) were prepared by first applying

compression-coating on core tablets with either HPMC or PEO. Above this coat an enteric coat of

Eudragit® S coating was applied. Eudragit® S was tried at different coating levels. Coating level was

calculated in terms of % weight gain on core tablet weight basis.

Table 3. ECCCT Batches

Batch No. Compression coat Batch Enteric Coat (% w/w) KE6 HE5 5.0

KE7 HE5 7.5

KE8 HE5 10.0

KE9 HE5 12.5

KE10 HE5 15.0

KE11 HE4 5.0

PS1 PN6 10.0

PS2 PN7 10.0

PS3 PN8 6.0

PS4 PN8 7.5

In vitro drug release studies

In vitro drug release studies were carried out using USP XXIII dissolution test apparatus Type II, paddle

apparatus (100 rpm/min, 37 ± 0.5°C). The time dependent compression-coated tablets were evaluated by

exposing them to 900 mL pH 7.4 phosphate buffer solution (simulated intestinal fluid, SIF) for 3 h, which

was later replaced by 900 mL pH 6.8 phosphate buffer solution (simulated colonic fluid, SCF), and tested

for release for the rest of the dissolution run.

ECCCT were evaluated by keeping them in 900 mL 0.1 N HCl (simulated gastric fluid, SGF) for 2 h,

which was then replaced with 900 mL SIF wherein it was kept for 3 h and lastly SIF was replaced with

900 mL SCF for the rest of the dissolution run. The drug release at different time intervals was analyzed

by UV double beam spectrophotometer (Shimadzu UV 1601, Japan) at 276.5 nm in SGF, 319.4 nm in SIF

and 320.4 nm in SCF. Each test was performed in triplicate.

Swelling study

Swelling studies were performed using a modification of a previously described method (Ebube et al.

1997). Briefly, initial diameter and height of individual matrices were measured and were placed in a

dissolution medium (phosphate buffer pH 6.8) at 37 ± 0.5°C in the manner similar to in vitro drug release

study. Swollen/hydrated tablets were withdrawn from the medium at the end of the dissolution run, extra

buffer present on the matrix surface was gently wiped with the soft tissue, and individual diameter and

height were measured at the end of the study. Percent of the radial (diameter) and axial (height) swelling

of tablet was calculated according to the following formula:

Radial swelling (%) = swollen diameter − original diameter × 100

original diameter

Axial swelling (%) = swollen thickness − original thickness × 100

original thickness

Swollen thickness and diameter in this work reflects the entirely free axial and radial swelling of the

matrix without any constraint imposed on the swelling. This approach is entirely novel and different to the

visually observed swelling reported by some authors where thin discs of pure polymers are sandwiched

between two Plexiglas plates and radial expansion of the constrained discs are investigated (Colombo et

al. 1999, Bettini et al. 2001).

Stability Study

Optimized formulations of metronidazole were packed in 75 mL HDPE bottles. The packed formulations

were placed in a controlled temperature cabinet maintained at 40 ± 2°C and 75 ± 5 %RH for 3 months in

order to perform the accelerated stability test. The samples were withdrawn at the end of each month and

evaluated for changes in physical appearance, drug content, hardness and in vitro drug release studies.

Results and Discussion

Core Tablets

The aim of the present investigation was to release the drug as soon as it reaches colon. Thus,

core tablets of metronidazole were prepared with the aim of having disintegration time (D.T.)

lower than 5 min. The optimized batch containing 5% cross carmellose sodium showed D.T. of

4 min with 100% drug being released in 12 min. The tablets hardness was found between 4.2 to

6.4 kp, and the friability of these tablets was 0.12%. The assay was found between 97.2 to

103.7%.

Compression-Coated Tablets

Compression coating was performed using two different polymers HPMC and PEO. Two

different viscosity grades of HPMC were tried, HPMC K4M having higher viscosity (4000 cp)

and HPMC E15 having lower viscosity (15 cp). HPMC K4M even when used at lower

compression coat weight of 150 mg (Batch K1) showed only 12.94% release after 480 min,

whereas HPMC E15 even when used at compression coat weight as high as of 300 mg (Batch

E2), showed 100% drug release within 180 min (Fig. 2).

HPMC based compression coated systems

0

20

40

60

80

100

120

0 60 120 150 180 240 300 330 360 420 480

Time (min)

Cu

mu

lati

ve %

Dru

g R

ele

as

ed

K1 E2 HE1 HE2 HE3 HE4 HE5

Figure 2. HPMC based compression coated systems (data shown as mean ± SD, n=3)

Thus, combination of HPMC K4M and E15 was tried in order to achieve desired lag time and

drug release profile. Different combinations of HPMC K4M:E15 tried at 200 mg compression

coat weight are given in Table 1. Of the different combinations, only Batch HE1 and HE2

consisting of HPMC K4M:E15 in the ratio of 100:100 mg and 75:125 mg respectively, cannot

be used for further studies since only about 25 and 77% drug released at the end of 480 min.

From the Fig. 2, it can be concluded that in the combination of two HPMC, as the proportion of

HPMC K4M decreases drug releases faster. For HPMC based system Batch HE4 and HE5 were

used for preparation of ECCCT.

In order to increase the sustainability of the compression coated tablet other hydrophilic polymer

PEO was tried. Different grades of Polyox® (PEO) having different molecular weights were

tried at different compression coating weight (Table 2). From the preliminary trials it was found

that as the compression coat weight increases drug release delayed. Polyox® WSR 301 and 303

at compression coat weights of 150 mg exhibited extensive drug delay, where less than 5% drug

released even after 18 h. Moreover, the tablets adhered to the dissolution vessel and thus it was

not used for further studies. Batch PN3 and PN5 in which core tablets were compression coated

with Polyox® N-80 and N-750 at 300 and 250 mg respectively, showed premature drug release.

Fig. 3 compares the release profile of different grades of Polyox® (WSR N-80, WSR N-750,

WSR 1105).

PEO (Polyox) based compression coated systems

0

20

40

60

80

100

120

0 30 60 120 180 240 300 360

Time (min)

Cu

mu

lati

ve %

Dru

g R

ele

ased

PN3 PN5 PN6 PN7 PN8

Figure 3. PEO (Polyox®) based compression coated systems (data shown as mean ± SD, n=3)

As expected, it was found that as the molecular weight of Polyox® increases drug release delay

increases (refer Fig. 3). Of the different grades tried, for surprise it was found that Polyox® 1105

gave burst release after specific lag times. For batch PN8 it was found that only 27.37% drug

released till 300 min and at 360 min 100% drug released. It was found that till 300 min gel was

intact whereas after 360 min gel completely ruptured after swelling. This indicates that as the

molecular weight of Polyox® (PEO) increases, its swelling capacity increases which finally

results in erosion of the layer and complete release of the drug. For PEO based system Batch

PN6, PN7 and PN8 were considered for further preparation of ECCCT.

In general it can be said that the lag time imparted to the compression coat system is dependent

on both polymer viscosity and compression coat weight.

Colonic tablets

In order to direct drug to the colon there was a need to provide some additional coat on

compression coated tablets since compression coated tablets alone were unable to meet the

desired criteria of preventing drug release till 5 h, which is lag time to reach colon, and provide

100% drug release as the system reaches the colon. Additional coat of Eudragit® S100 was

provided on compression tablets prepared using HPMC and Polyox®.

From the earlier results it was concluded that HPMC K4M and HPMC E15 cannot be used alone

since HPMC K4M delays the release excessively, whereas HPMC E15 causes premature release

of the drug. In addition, combination of HPMC K4M and E15 favorable ratios are HPMC

K4M:E15, 25:175 mg (HE4) and 12.5:187.5 mg (HE5). Eudragit® S 100 was coated at different

coating levels varying from 5 to 15% w/w. Initial trials indicated that even 5% coating level on

batch HE4 delayed drug release to more than 8 h and thus did not fit our criteria, since our aim

was to have immediate release of drug as soon as the system reaches the colon. Batch KE6

containing HPMC K4M:E15 in the ratio of 12.5:187.5 mg (Batch HE5) as a compression coat

and supercoated with Eudragit® at 5% coating level exhibited 100% drug release within 5 h,

thus showed premature release. From the different batches shown in Figure 4, Batch KE8

compression coated using HPMC K4M:E15::12.5:187.5 mg and supercoated at 10% Eudragit®

S coating level met the criteria of delaying drug release till the drug reaches colon (8.2% at the

end of 300 min) and releasing almost 100% drug within 1 h after it reaches the colon. Thus,

Batch KE8 can be considered as best batch prepared using HPMC and Eudragit® S100.

HPMC and Eudragit S based colonic systems

0

20

40

60

80

100

120

0 60 120 150 180 240 300 330 360 420 480

Time (min)

Cu

mu

lati

ve %

Dru

g R

ele

ased

KE6 KE7 KE8 KE9 KE10

Figure 4. HPMC and Eudragit® S based colonic systems (data shown as mean ± SD, n=3)

From the compression coating study using Polyox® it was found that only Polyox® WSR 1105

was found to be suitable for providing time dependent release. Different combinations were tried

with Polyox® 1105 as inner compression coat and Eudragit® S 100 as outer enteric coat. Batch

PS1 and PS2 containing batch PN6 (200 mg) and PN7 (225 mg) as compression coated tablet,

when coated at 10% coating level of Eudragit® S show delayed release after the system reaches

colon. For both PS1 and PS2, after 300 min when the system enters colon it takes another 3 h to

achieve 100% release, whereas batch PS3 containing 250 mg Polyox® 1105 and 6% Eudragit®

S showed only 5.57% release till 300 min and 100% release in 360 min, indicating 100% drug

release in colon within 1 h after system reaches colon (Fig. 5). Thus, Batch PS3 meets the

desired criteria.

It can be concluded that Eudragit® S is responsible for delayed release of drug since higher

coating levels of Eudragit® will require more time to dissolve and rupture in intestine. Also at

higher coating levels of Eudragit® S, amount of fluid penetrating the compression coated system

will be less in initial phase after the system reaches the intestine.

Polyox 1105 and Eudragit S based colonic systems

0

20

40

60

80

100

120

0 60 120 150 180 240 300 330 360 420 480

Time (min)Cu

mu

lati

ve %

Dru

g R

ele

ased

PS1 PS2 PS3 PS4

Figure 5. Polyox® 1105 and Eudragit® S based colonic systems (data shown as mean ± SD, n=3)

Swelling study

Swelling study was performed for both, only compression coated tablets and ECCCT.

Measurement of swelling/hydration rates of different tablets were carried out to gain insight into

the observed phenomena of drug release from the tablets. Results of axial and radial expansion

for batch K1, E2 and HE5 and PN8 are enumerated in Table 4 and the photographs at different

time intervals are presented in Fig. 6(A).

Table 4. % Axial and radial swelling

Batch Code % Axial Swelling % Radial Swelling

K1 29.26 50.00

E2 23.07 23.84

HE5 26.66 46.15

PN8 37.50 61.50

PS3 31.70 56.06

From Table 4 it is clear that % axial and radial swelling of Polyox® (PN8) was higher, 37.5 and

61.5% respectively, compared to HPMC (HE5), 26.66 and 46.15% respectively, which reflects

faster erosion property of Polyox®. Swelling study results characteristically complement in vitro

release study data. On comparing Batch K3 and PN5 both of which are having nearly similar

viscosities and compression coated at similar coating levels of 250 mg each, it was observed that

Batch PN5 showed 100% drug release within 3 h whereas Batch K3 showed only 8% drug

release after 8 h. Thus, it was concluded that PEO swell and erode faster whereas HPMC have a

slower swelling property. In general, it can be said that PEO has a lower gel strength compared

to HPMC. PEO does not retain the gel structure formed after swelling, for a longer time, as long

as HPMC does.

Compared to batch E2, batch K1 showed higher swelling since batch K1 contains HPMC K4M

having higher viscosity compared to HPMC E15 having lower viscosity. Thus, it can be

concluded that as the viscosity of the polymer increases gel strength increases and thus erosion is

prolonged.

In the swelling study, it was found that terminal radial/axial swelling was less steep because the

diffusion path length and distance to be traveled for dissolution media to reach the dry core

increases with time. Fig. 6(B) depicts photographs at different time interval for PS3. From the

Fig. 6(B) it can be concluded that after the system reaches intestine the outer coat of Eudragit®

S starts dissolving. The compression coat system made from hydrophilic polymer swells and

forms a hydrogel layer when they are placed in an aqueous medium. With the diffusion of

medium into the polymer a hydrogel layer forms. As soon as the compression coat comes in

contact with the dissolution fluid, the system starts swelling and the drug is released from the

system after it completely ruptures. Thus, it can be concluded that swelling and erosion are

dominant release mechanism compared to diffusion.

Stability Study

Physical appearance of the all the stability Batches of PS3 was similar to the fresh batch.

Hardness of the batch varied from 13.65 to 17.8 kp. Drug content varied from 97.9 to 102.3%.

Stability Study of Batch PS3

0

20

40

60

80

100

120

0 60 120 150 180 240 300 330 360

Time (min)

Cu

mu

lati

ve %

Dru

g R

ele

ased

Initial 1 month 2 month 3 month

Figure 7. Stability study of batch PS3 (data shown as mean ± SD, n=3)

There was no substantial change in in vitro drug release profile between all the stability batches

(Fig. 7). Thus, Batch PS3 was considered as the best batch prepared by ECCCT.

Conclusion

Colonic drug delivery systems prepared using ECCCT technique can be successfully used to

deliver drug to the colon. Both HPMC and PEO can be used as a compression coat. However,

for HPMC based system, selection of appropriate viscosity grade will play an important role

since in present study combination of two different viscosity grades, HPMC K4M (4000cp) and

E15 (15cp) was used to fabricate ECCCT. From the formulation aspect at larger scale it will be

preferable to have a single polymer having desired viscosity.

Whereas, PEO showed efficient release profile using Polyox® WSR 1105. Erosion behavior is

faster for Polyox®, compared to HPMC. Thus, colonic tablets prepared using PEO show faster

release after the system reaches colon. Thus, ECCCT prepared using PEO as a compression coat

and Eudragit® S100 as an enteric coat can be used in acute treatment of Crohn’s disease.

References

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Int. J. Pharm. 235:1–15.

Received: 15.11.2010

Accepted: 17.02.2011

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