Colonic Delivery Of Drugs Biology Essay


Biresh C Sarkar et al. conducted study on colonic delivery of drugs used in treatment of IBD and UC. As prednisolone in conventional form largely absorbed from upper GIT causing more systemic side effects, site specific drug delivery is desirable, for that polysaccharides shows potential in colon specific drug delivery. In the current study guar gum microspheres were prepared by emulsification cross linking technique, and coated with pH sensitive polymer and were evaluated as per method of Jain et al. the prepared Microspheres were spherical in shape in the size range of 29 to 48 μm, the encapsulation efficiency was in range of 69-74 % depending upon the concentration of guar gum. The drug release was about 7-11% in first four hours of study gradually rises in 5th hour and 80% drug release occurs in 8-10 hr thus showing desirable drug release in the colonic simulated environment.20

Krishniah Y.S.R., P.R.Basker Reddy .et al.: Developed oral colon targeted drug delivery system of metronidazole in the treatment of amoebiasis. They developed multilayered & compress coated tablets with various concentrations of guar gum.21

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P.Ravi, et al. prepared guar gum microspheres using gluteraldehyde as a cross linking agent and also studied affect of several factors on the guar gum microspheres. In vitro release was investigated in gastro intestinal medium of different pH and phosphate buffer saline with and without rat ceacal contents, which was found to be affected by changing the concentration of guar gum and glutaraldehyde. In this study it is confirmed that the maximum drug release occur upon enzymatic action of drug in in vitro study.22

Krishniah Y.S.R, et al. carried out the invitro drug release studies on guar gum based colon targeted oral drug delivery systems of 5-fluorouracil. The broad objective of the study was to develop novel tablet formulations for site-specific delivery of 5-fluorouracil to the colon.23

Jae HP et al., developed biodegradable polymers for microencapsulation of drugs. The majority of biodegradable polymers have been used in the form of micro particles, from which the incorporated drug is released to the environment in a controlled manner. The factors responsible for controlling the drug release rate are physicochemical properties of drugs, degradation rate of polymers, and the morphology and size of micro particles.24

Zahirul Khan, et al. formulated pH dependent colon targeted oral drug delivery system using methacrylic acid polymers. Drug release was manipulated using Eudragit L 100-55 and Eudragit S 100 combinations. The coated tablets were tested invitro for their suitability for pH dependent colon targeted oral drug delivery.25

Aviral jain et al, Matrix tablets containing various proportions of guar gum were prepared by wet granulation using starch paste as a binder. Guar gum matrix tablets released 8-15% of the mebendazole in the physiological environment of the stomach and small intestine depending upon the proportion of guar gum used in the formulation. The results of the study showed that matrix tablets containing either 20% or 30% of guar gum are most likely to provide targeting of mebendazole for local action in the colon. Matrix tablets containing either 20%-30% of guar gum showed no change in physical appearance, drug content and dissolution pattern after storage at 45 oc/ 75% humidity for 3 months. Differential scanning calorimetry indicated no possibility of interaction between mebendazole and guar gum.26

H. Rajpurohit, et al, review article covers different types of polymers which can be used in formulation of colon targeted drug delivery systems. It also described the various types of biodegradable polysaccharides that have already been used in the initial approaches for colon specific drug delivery.27

Upendra Nagaich, et al. prepared colon specific sustained release matrix tablets of an anti filarial drug, and delivered to colon for its effective actions. Dosage form prepared by wet granulation technique using different percentage of guar gum as matrix carrier and coated with Eudragit L-100. The novelty in this study was to incorporate guar gum as carrier to retard the drug release in the region of stomach and small intestine. The dissolution study of DEC matrix tablet was in simulated colonic fluids (phosphate buffer pH 6.8) was 94% and in simulated colonic fluids (rat caecal content medium) was 98% at the end of the 24 h study. Studies showed that colon targeted matrix tablet containing 45% of guar gum was most likely to provide targeting of DEC for local action in the colon. The colon targeted matrix tablet of DEC showed no change either in physical appearance, drug content or in dissolution pattern after storage at 30±20 c / 65 ± 5% RH for 2 month.28

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Sunil al, studied the effect of formulation parameters on entrapment efficiency, size, and drug release by conducting experiment on cephalexin loaded guar gum beads. The % entrapment efficiency was the lowest for beads prepared in pH 5 media, whereas the highest % entrapment efficiency was observed for the beads produced in pH 9 media. This difference in the % entrapment efficiency may be attributed to the degree of ionization of carboxyl groups of GG in different pH media. Swelling studies of the formulations are important to assess the hydrogelation of the beads formed. Dynamic swelling experiments were carried out gravimetrically in 0.1 N HCl or pH 7.4 phosphate buffer. Since no significant difference (P < 0.01) was observed in the sorption of beads between both the media studied, In vitro drug release studies were performed in 0.1 N HCl or pH 7.4 phosphate buffer for 6 h. The release rates were slower for formulations containing lower amount of the drug, while the release rate increased with increasing amount of drug in the beads. The release rate can be correlated with the diffusion coefficient which indicates that as the diffusion coefficient increases for the formulations which have greater % of drug, the release rate also has increased.29

Graeme S. Macleod et al., A study has been carried out to assess the potential of pectin: chitosan: hydroxypropyl methylcellulose (HPMC) (P: C: H) films for colonic drug delivery. Radiolabelled (99mTc) tablets were coated with a 3:1:1, P: C: H film and administered to human volunteers. The gastro-intestinal transit of the tablets was assessed by gamma scintigraphy. The results showed that in all cases (n_4), the tablets were able to pass through the stomach and small intestine intact. Breakup of the tablets commenced once they were in the colon, due to degradation of the coat by colonic bacteria. The labeled tablets were tested for release of the marker using a Caleva ® dissolution apparatus following the BP 1998 Apparatus II (Paddle apparatus) method at 50 rpm and 37°C. Simulation of GIT transit was achieved by using different dissolution media. 0.1 M HCl was used for the first 2 h, pH 7.4 Sorensen's phosphate buffer for 3 h and finally, pH 5.0 Sorensen's phosphate buffer with pectinolytic enzyme (Pectinex Ultra SP-L 2 ml l_1) was used to mimic the colon. The pH of 5.0 was chosen as a compromise between pH values of around 7.0 found in the colon (Evans et al., 1988) and the optimal pH for enzyme activity of 3.5. A sodium iodide crystal scintillation counter was used to measure the radioactivity (counts per 20 s) in each of the tablets prior to the dissolution experiment. The tablet with the lowest number of counts was assigned the reference tablet. The radioactivity (counts per minute) of each of the samples removed during the dissolution experiment together with that of the reference tablet were measured using a gamma counter (Cobra II, Auto-gamma, Packard, Canberra) at the end of the experiment. This allowed the percentage release (counts per minute) to be calculated for each tablet.30

Kishor Sahebrao Salunkhe and Mohan Vinayak Kulkarni, Develop colon targeted drug delivery system by using dextrin (polysaccharide) as a carrier for ibuprofen. Drug release profile was evaluated in simulated gastric, intestinal fluid and simulated colonic fluid. The matrix tablet containing dextrin as a carrier and ethyl cellulose as binder was found to be suitable for targeting ibuprofen for local action in the colon as compare to other matrix tablets containing different binders because of fewer amounts (8-11%) of drug release in the simulated gastric and intestinal fluid. Matrix tablets containing dextrin released 95-98% of ibuprofen in simulated colonic fluid with 4% human fecal matter solution.31

Anil K. Philip, Betty Philip, this review, mainly compares the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules, CODESTM, and osmotic controlled drug delivery which are unique in terms of achieving in vivo site specificity, and feasibility of manufacturing process. Treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects.32

Shailendra Shukla et al, this review discuss the important chemistry and general properties of pectin, its gel formation mechanism properties and its uses in novel drug delivery to the colon.33

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Anil K. Philip et al., reviewed to say that colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review, mainly compares the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules, CODESTM, and osmotic controlled drug delivery which are unique in terms of achieving in vivo site specificity, and feasibility of manufacturing process.34

A.Dashora, C.P.Jain., carried their work to obtain a novel micro particulate formulation of prednisolone, which was adequate for the treatment of ulcerative colitis. They have prepared two types of pectin microspheres by an emulsion dehydration technique and o/o solvent evaporation method. Various process variables and formulation variables were optimized to get small uniform and spherical microspheres. Invitro drug release studies were performed in SGF, SGF-SIF, and SIF respectively, in the presence or absence of rat caecal contents. The cumulative percent drug release of prednisolone from pectin microspheres in SGF and SIF after 4hrs was varied from 30-45% and from eudragit coated microspheres after 4 hrs it varied from 6.25 to 8.95% respectively. Further, the release of drug was observed higher in the presence of rat caecal contents, indicating the susceptibility of pectin to colonic enzymes released from rat caecal content.35

K.L.Shantha et al., developed azo polymeric hydrogels for colon specific targeting. Methacryloyloxy azobenzene was synthesized and hydrogels were prepared by copolymerizing with hydroxyethyl methacrylate. The prepared hydrogels were characterized and subjected to swelling studies. The In vitro release profiles of the drug were obtained in the presence of azoreductase in the culture of intestinal flora. The release was faster and almost followed a zero order pattern. This can be attributed to the cleavage of the azo crosslink's in the hydrogel by the azoreductase and the release of the entrapped drug at the site of targeting.36

P.M.Dandagi et al., formulated mebeverine loaded microspheres using natural polysaccharide as a carrier. Mebeverine is known to suffer from extensive first pass effect. In an attempt to improve its oral bioavailability and possibility to restrict its absorption only to colon, mebeverine microspheres were prepared by emulsion solvent evaporation method. The prepared formulations were subjected to various evaluation parameters. Practical yield of microspheres was up to 89.59% with encapsulation efficiency up to 79.4%. SEM studies confirmed that the microspheres structures were smooth, spherical, and discrete and the particles were range 200-300μm. In vitro release of the drug showed biphasic release pattern with non-fickian diffusion release in 12hrs.37

Mohini Chaurasia et al, prepared guar gum microspheres by incorporating anticancer drug and the prepared spheres were characterized for local release of drug in the colon which is a prerequisite for the effective treatment of colorectal cancer. Guar gum microspheres were prepared by emulsification method using gluteraldehyde as a cross linking agent. Particle size, shape and surface morphology were significantly affected by guar gum concentration, gluteraldehyde concentration, emulsifier concentration, stirring rate, stirring time, the entrapment efficiency was found to be 75.7%. the invitro drug release carried in different media i.e. phosphate buffer saline, gastrointestinal fluid of different pH, and rat caecal content release medium which was found to be affected by a change to the guar gum concentration and gluteraldehyde concentration. The drug release in PBS and simulated gastric fluids followed a similar pattern and had a similar release rate, while a significant increase in percent cumulative drug release was observed in the medium containing rat caecal content. In the in vivo studies microspheres delivered most of the drug loaded to colon.

3.1. Drug and excipient profiles:

3.1.1. Drug profile:

Drug name: Mebeverine HCl

Chemical structure

Therapeutic indication: For the symptomatic relief of irritable bowel syndrome.

Mebeverine is effectively used to treat the symptoms of this, abdominal pain and cramps persistent, nonspecific diarrhea (with or without alternating constipation) and bloated feeling.

Solubility: very soluble in water, freely soluble in ethanol, and practically insoluble in ether.

Description: a white or almost white color amorphous powder.

Melting point: 85-87oc

pH 4.5-6.5 determined in a 2%w/v solution.

Administration Should be taken on an empty stomach. (Take 20 min before meals.

Retard cap: May be taken w/ or w/o meals. Swallow whole, do not chew/crush.)

Pharmacology:  Mebeverine is a musculotropic, antispasmodic with a direct action on the smooth muscle of the gastrointestinal tract, relieving spasm without affecting normal gut motility. Since this action is not mediated by the autonomic nervous system, the usual anticholinergic side effects are absent. Mebeverine is suitable for patients with prostatic hypertrophy and glaucoma.


Absorption: Mebeverine is rapidly and completely absorbed after oral administration of tablets. The modified release formulation permits

a twice daily dosing scheme.

Distribution: No significant accumulation occurs after multiple doses.

Biotransformation: MebeverineHCl is mainly metabolized by esterases, initially splitting the ester bonds into veratric acid and mebeverine alcohol. The main metabolite in plasma is DMAC (Demethylated carboxylic acid). The steady state elimination half-life of DMAC is 5.77h. During multiple dosing (200 mg b.i.d.) the Cmax of DMAC is 804ng/ml and tmax is about 3 hrs. The relative bioavailability of the modified release capsule appears to be optimal with a mean ratio of 97%.

Elimination: Mebeverine is not excreted as such, but metabolized completely; the metabolites are excreted nearly completely. Veratric acid is excreted into the urine; mebeverine alcohol is also excreted into the urine, partly as the corresponding carboxylic acid (MAC) and partly as the demethylated carboxylic acid (DMAC).

Plasma protein binding: 75%

Half life 2.5 hours

pKa 8.1

tmax 1hour.


FORMULATIONS Colofac MR - Abbott Healthcare Products



Adults (including the elderly):


DOSE: 135mg of dose should be taken thrice daily 20 minutes before meals.

MODIFIED RELEASE: The capsules should be swallowed with a sufficient amount of water (at least 100 ml water).They should not be chewed because the coating is intended to ensure a prolonged release mechanism

One capsule of 200 mg twice daily, to be given one in the morning and one in the evening.

Paediatric Population Mebeverine 200 mg modified release capsules are not recommended for use in children and adolescents below 18, due to insufficient data on safety and efficacy.

Duration of use is not limited.

If one or more doses are missed, the patient should continue with the next dose as prescribed; the missed dose(s) should not be taken in addition to the regular dose.

Special Population No posology studies in elderly, renal and/or hepatic impaired patients have been performed. No specific risk for elderly, renal and/or hepatic impaired patients could be identified from available post- marketing data. No dosage adjustment is deemed necessary in elderly, renal and/or hepatic impaired patients.

Over dose: Theoretically CNS excitability may occur in cases of overdose. In cases where Mebeverine was taken in overdose, symptoms were either absent or mild and usually rapidly reversible. Observed symptoms of overdose were of a neurological and cardiovascular nature.

No specific antidote is known and symptomatic treatment is recommended.

Storage Store in a cool, dry place. Stored temperature not below 0°C and preferably not above30°C.

3.1.2. Guar gum

Synonyms: Guar flour, jaguar gum

Chemical name: Galactomannan polysaccharide.

Chemical structure

Functional category: suspending agent, viscosity increasing agent, tablet binder,

Tablet disintegrant.

Description: Guar gum occurs as an odorless or nearly odorless, white to yellowish

white Powder with a bland taste.

Solubility: Practically insoluble in organic solvents. In cold or hot water guar gum

disperses and swells almost immediately to form a highly viscous,

thixotropic sol.

pH 5-7.

Storage: should be stored in a well-closed container in a cool, dry place

Stability: Aqueous guar gum dispersions have a buffering action and are stable at

pH 4.0-10.5.

Incompatibilities : Guar gum is compatible with most other plant hydrocolloids such as

tragacanth. It is incompatible with acetone, ethanol (95%), tannins,

strong acids and alkalis.

Safety: it is generally regarded as a nontoxic and nonirritant material. Excessive

consumption may cause gastrointestinal disturbances such as flatulence,

diarrhea or nausea.

3.1.3. Glutaraldehyde:

Synonym Pentane dial, Glutaric dialdehyde

Chemical name 1, 5-pentanedial

Chemical formula C5 H8 O2

Chemical structure

Storage Store in light-resistant container. Keep containers

tightly closed in a cool, well ventilated area.

Appearance Liquid

Odour Pungent and like rotten apples

Color Colorless or light yellow

Boiling point 101 0 c

Melting point -6 0 c

Specific gravity 1.062 - 1.124

Vapour pressure 0 kpa (at 20 0c)

Solubility Easily soluble in cold water

Action and use Used in treatment of warts.