INTRODUCTION:

In colon targeted drug delivery system, the drug is targeted to the colon without being absorbed in stomach and small intestine. Colon targeted drug delivery have gained attention in recent years due to its potential to improve the treatment of disease affecting the colon and minimizing systemic side effects.

The goal of targeted drug delivery is to deliver the drugs to the colon via gastrointestinal tract; it requires the protection of drug from being released in stomach and small intestine. It can be achieved by the use of drug delivery system that can protect the drug during its passage to colon and the drug must be released in the colon from the drug delivery. Drugs, which are destroyed by the stomach acid and metabolized by pancreatic enzymes, are protected.

Phytoconstituents like Curcumin, Sennosides, Andrographolides, Boswellic acid, Taxol, Triphala, Quercetin, Ginger extract, Rhubarb, Gallic acid etc., possesses therapeutic effect on various colonic disease.

ADVANTAGES:

1. Prolonged residence time, thus the drug is allowed prolonged contact with the absorbing surface

2. Relatively low enzyme secretion and low brush border enzyme activity, which makes it particularly attractive site for the absorption of enzymatically labile drugs

3. Drugs absorbed from the proximal colon are delivered directly into the systemic circulation, avoiding hepatic first-pass effect

4. Lesser amount of dose required

5. Improved drug utilization

6. Improved patient compliance and convenience

7. Increased safety margin

8. Protection of mucosa from irritating drugs

9. Increase the absorption of poorly absorbed drug molecules.

DISADVANTAGES:

1. Multiple manufacturing steps

2. Low dose loading

3. Required high need of excipients

4. Lack of efficacy and manufacturing reproducibility

5. Large number of process variables

6. Required skilled person.[1-4]

FACTORS AFFECTING ORAL BIOAVALABILITY OF DRUGS:

PHYSIOLOGICAL FACTORS:

a. GI motility

b. pH of the GIT

c. Metabolism

d. Presence of food

e. Drug stability

FORMULATION FACTORS:

a. Drug pKa

b. Lipid solubility and partition co-efficient

c. Drug solubility

d. Particle size

e. Drug carrier

PATIENT REALTED FACTORS:

a. Transit time

b. Gastric time

c. Colonic micro flora

d. Disease associated with colon

PHYSIOLOGICAL FACTORS:

GI MOTILITY:

Gastrointestinal motility is an essential function of the digestive and absorptive process of the gut. It propels intestinal contents, mixes them with digestive juices, and prepares unabsorbed particles for excretion.

The length of time a drug moiety is in contact with the absorbing tissue will obviously influence the extent of drug absorption. Intestinal motility moves materials in the stomach or small intestine distally towards the large intestine and it has been estimated that in some cases residence of drug moiety in the small intestine can be in the order of minutes, thereby severely limiting the effective contact time.

pH OF THE GIT:

Drug release based upon the pH of the GIT.

Table No.1: pH of the GIT

Region of GIT	pH
Stomach Fasted condition Fed condition	1.5-2.0 3.0-5.0
Small intestine	5.0-6.5
Large intestine	6.4-7.6

METABOLISM:

Drug metabolism may occur at various sites along the GI tract, including:

a. In the gut fluid.

b. Within the microvilli of enterocytes.

c. Within the enterocytes, either within the cell cytoplasm or within cellular lysosomes.

d. By colonic microflora, in the lower end of the tract.

PRESENCE OF FOOD:

Drug absorption is generally less efficient when food is present in the GIT. Food may reduce rate of absorption by No. of mechanisms:

a. By slowing down gastric emptying rate.

b. Food provides a viscous environment, which may retard drug dissolution as well as drug diffusion to the absorptive surface.

c. Drugs may bind to food constituents forming a non absorbable complex.

d. Food constituents may compete with drug for carrier mediator absorption mechanisms.

DRUG STABILITY:

Oral dosage form destabilize either during its shelf life or GIT. Two major stability problems resulting in poor bioavailability of an orally administered drug are:

a. Degradation of drug into inactive form.

b. Interaction with one or more different components either of the dosage form or those present in the GIT to form complex which is poorly soluble or is un absorbable.[5]

FORMULATION FACTORS:

DRUG pKa:

Majority of drugs are either weak acids or weak bases. Therefore, they are ionized to a certain extent, determined by either pKa or pH of the biological fluid in which they are dissolved. The extent of ionization can be quantified by the Henderson-Hasselbalch equation.

Acidic drugs are best absorbed at pH < pKa (i.e.in the stomach), while basic drugs are best absorbed at pH > pKa (i.e.in the intestine).

For eg., Quinine (obtained from cinchona tree), a weakly basic drug, is absorbed approximately four times higher at pH 7, than at pH 4.

LIPID SOLUBILITY AND PARTITION COEFFICIENT:

The oil/water partition coefficient is an index of the probability of partitioning of a drug into the phospholipid bilayers that comprise biological membranes. Generally, the larger the partition coefficient, the more lipophilic is a compound, and the more readily would it partition into biological membranes.

DRUG SOLUBILITY:

As drugs must generally be in aqueous solution for them to be absorbed, drugs with limited solubility often exhibit poor absorption and large inter and intra subset variation in blood levels following oral administration.

The ionized form of a drug displays a higher dissolution rate and greater solubility than the non ionized form. Therefore, drug solubility is critically depends on the pKa of the drug moiety and the prevailing pH of the GIT.

PARTICLE SIZE:

Particle size is a key factors that influences drug dissolution rate. The smaller the particle size, the greater is the surface area for dissolution. The Noyes- Whitney equation describes the influence of surface and other factors on the dissolution rate.

Dc/dt= ks(c_s-c_t)

a. Smaller particle size à increase surface area à increase dissolution rate à increase rate of absorption à increase oral bioavailability.

b. Larger particle size à less surface area à decrease dissolution rate à decrease rate of absorption à decrease oral bioavailability.

DRUG CARRIER:

Selection of drug depends upon the physiochemical nature of the drug as well as the disease for which the system is to be used. The factors such as chemical nature, stability, partition coefficient of drugs and the type of absorption influences the carrier’s selection.[6]

PATIENT RELATED PARAMETERS:

TRANSIT TIME:

The arrival of an oral dosage form at the colon is determined by the rate of gastric emptying & the small intestinal transit time. The transit time of dosage form in GIT is as follows

Table No 2: Transit time of GIT

Organ	Transit time
Stomach	<1 (fasting), >3 (fed)
Small intestine	3-4
Large intestine	20-30

GASTRIC EMPTYING:

Once the dosage form enters the stomach, the primary concern is how long it will remain there before being discharged into the duodenum. Emptying generally completes in 5-10 minutes up to 2 hours depending on the phase of the stomach at the time of drug administration. It is preferable for a colonic delivery system to spend little time in the stomach. Such system may release the drug at a distant locus from the colon.

COLONIC MICROFLORA:

Drug release depends on enzymes that are derived from micro flora present in colon. These enzymes are used to degrade coating/ matrices as well as to break bonds between inert carrier and an active agent resulting in the drug release from the formulation.

Important metabolic reactions carried out by intestinal bacteria: hydrolysis, reduction, dehydroxylation, decarboxylation, dehalogenation, deamination, acetylation and esterification.

DISEASE ASSOCIATED WITH COLON:

Gastrointestinal disease may affect the release and absorption of drug from colon specific drug delivery system.

Inflammatory bowel syndrome:

Crohn’s disease and ulcerative colitis are two inflammatory bowel diseases that cause chronic inflammation in the GIT.[7]

Herbs used in inflammatory bowel disease:

Coriolus versicolor, Bacopa monnieri, Inonotus obliquus, Cordyceps sinensis, Prunus mume, Gardenia jasminoides, Chrysanthemum indicum, Zingiber officinalis and Withania somnifera.[8]

Colorectal cancer:

Colorectal cancer starts in the colon or in the rectum. Colorectal cancer also referred as the colon cancer or rectal cancer, depending on where they start.

Herbs used in colon cancer:

Curcuma longa (Turmeric), Allium sativum (Garlic), Zingiber officinalis (Ginger), Piper nigrum (Black pepper), cumin, and caraway.

Table No 3: Phytoconstituents used in colon diseases

COLONIC DISEASE	HERBAL DRUGS
Inflammatory bowel syndrome	Curcumin, Bowsellic acid and Quercetin.
Chronic pancreatitis, Pancreatactomy, and Cystic fibrosis.	Berberine, Gallic acid and Curcumin.
Constipation	Sennosides and Triphala.
Cancer	Andrographolide and Curcumin
Helminthiasis	Gallic acid

APPROACH FOR COLON TARGETED DRUG DELIVERY SYSTEM:

1. pH sensitive polymer coated approach.

2. Time dependent approach

3. Pressure dependent drug delivery approach

4. Microbially triggered approach

a. Pro drug approach

b. Polysaccharide based approach

5. Novel approach

a. Hydrogel based approach

b. CODES^TM approach

c. Pulsatile colon targetd delivery approach

d. Nanoparticle based approach

e. Microspheres based approach.

pH SENSITIVE POLYMER COATED SYSTEM:

a. This system is based on solubility of different polymers at different pH range, as the pH various at different parts of GIT.

b. Polymers are insoluble at lower pH and get solubilized as the pH increase i.e., colon

c. So, formulation can be protected in stomach and to some extent in small intestine.[11]

pH sensitive polymer + drug core colonic pH Release of drug on colon.

Table No 4: pH sensitive polymers

POLYMER	THRESHOLD LEVEL
Eudragit * L 100	6.0
Eudragit *S 100	7.0
Eudragit *L-30D	5.6
Eudragit *FS- 30D	6.8
Eudragit *L-100-55	5.5
Shellac	7.0

Table No 5: Various polymers & their ratio used in colon targeted formulation

Drugs used	Polymer used	Polymer Ratio
Gallic acid	Eudragit *L 100 & ethyl cellulose	1:1
Andrographolide	Eudragit* S 100 with diethyl phthalate	3:1
Sennosides	Pectin & HPMC	8:2
Rhubarb	Pectin & HPMC	1:1

Scheme 1: Preparation of tablets. [12]

TIME DEPENDENT BASED APPROACH:

a. This approach is based on the principle of delaying the release of the drug until it enters into the colon.

b. The strategy in designing limited released systems is to resist the acidic environment of the stomach and to undergo a lag time of predetermined span of time, after which release of drug take place.

c. They are generally nonspecific with respect to pH solubility characteristics and the employment of these polymers as carrier matrices for colonic delivery often utilize a time dependent mechanism.

d. These provide an initial lag phase of low or no release during transit through the upper GIT.

e. The lag time in this case is the time required to transit from the mouth to colon.

f. Non biodegradable polymers are used.

g. Drug release from these systems is not pH dependent.

h. Various polymers used are: polyacrylate, methycellulose, HPMC and CMC etc.[13]

PRESSURE CONTROLLED DRUG DELIVERY APPROACH:

Pressure controlled drug delivery system can be developed in such a way that withstands the pressure in intestine and ruptures in response to raised pressure in colon due to peristaltic movement.

Scheme 2: Colon targeted Curcumin pellets. [14]

MICROBIALLY TRIGGERED SYSTEM:

a. The micro flora of the colon is in the range of 1011-1012 CFU/ ml, consisting mainly of anaerobic bacteria, e.g. Bacteroides, Bifidobacteria, Eubacteria, Enterobacteia and Ruminococcus etc.,

b. Micro flora produces a vast numbers of enzymes like glucoronidase, xylosidase, arabinosidase, azareducatase, deaminase and urea dehydroxylase.

c. Presence of the biodegradable enzymes only in the colon, the use of biodegradable polymers for colon specific drug delivery.

d. These polymers shield the drug from the environment of stomach and small intestine, and are able to deliver the drug to colon.

a) PRODRUG APPROACH:

a. Prodrug is a pharmacologically inactive derivative of a parent molecule that requires some form of transformation in-vivo to release the active drug at the target site.

b. This approach involves covalent linkage between the drug and its carrier.

c. Biotransformation is carried out by a variety of enzyme, mainly of bacteria origin, present in the colon.

d. The enzymes that are mainly targeted for colon drug delivery include azoreductase, galactosidase and nitroreductase.

e. For colonic delivery, prodrug is designed to undergo minimal hydrolysis in upper GIT and undergo enzymatic hydrolysis in colon there by releasing the active drug moiety from drug molecule.

Scheme 3: Prodrug approach. [15]

b) POLYSACCHARIDE BASED APPROACH:

a. The colonic micro flora secretes a number of enzymes that are capable of hydrolytic cleavage of glycosidic bonds.

b. Enzymes include Beta-D- glucosidase, amylase, pectinase, xylanase and dextranases.

c. Natural polysaccharides like pectin & inulin are not digested in stomach and small intestine but are degraded in colon by resident bacteria.

d. These polysaccharides thus have the potential as nontoxic carriers for colon specific drug delivery.[16]

Table No 6: Different bacterial species acting on polysaccharides in colon.

POLYSACCHARIDES	BACTERIAL SPECIES
Amylase	Bacteriodes
Chitosan	Bifidobacteriom
Dextran	Bacteriodes
Cyclodextrin	Bacteriodes
Guar gum	Ruminococcus

E.g. Preparation of Calcium Sennoside matrix tablets by using polysaccharide based approach.

Scheme 4: Preparation of calcium sennosides matrix tablets

NOVEL APPROACH:

HYDROGELS BASED APPROACH:

a. Hydrogels are three dimensional polymer networks which are hydrophilic in nature. So, it is swellable in water and body fluids.

b. Drug carriers made up of natural and modified polysaccharide hydrogels tend to swell following their hydration. The degree of swelling is an important property of the hydrogels.

c. Initially, the swollen hydrated polymer creates a diffusional barrier on the surface and eventually, allows the penetration of colonic enzymes, which cause the degradation of polymer.

d. The swelling property therefore, limits the use of hydrogels for poorly water soluble drugs and incase of highly water soluble drugs; an addition of compressed polymer layer is designed to delay the diffusion of drug for longer time.[18,19]

CODES^TMAPPROACH:

a. CODES^TM is a combined approach of pH dependent + microbially triggered colon drug delivery system.

b. CODES^TM is a unique colon drug delivery system technology that was designed to avoid the inherent problems associated with pH or time dependent systems.

c. This system consists of a core tablet coated with 3 layers of polymer coating.

I. Outer coating: Enteric coating which protects the tablet in stomach.

II. Middle coating: Acid soluble coating which protects the tablet in intestine.

III. Inner coating: Polysaccharides layer, which gets degraded by microbes upon reaching the colon.[20]

PULSATILE COLON TARGETED DRUG APPROACH:

a. It consists of enteric coated capsules containing water soluble cap and water insoluble body.

b. The body is loaded with hydrogel plug and drug layer.

c. When capsules contact with the dissolution fluid. The hydrogel plug absorbs water and swells & release drug at predetermined lag time of 4 hours.

d. Polymers used for designing of the hydrogel plug were various grades of HPMC, polymethylmethacrylates, polyvinyl acetate and polyethylene oxide.[20]

E.g. working principle of colon specific pulsatile capsule with tablet of Curcumin loaded self micro emulsifying drug delivery system (SMEDDS) filled in an impermeable capsules.

Scheme 5: Colon specific Curcumin pulsatile

NANOPARTICLES:

a. Nanaoparticle are colloidal carriers composed of natural or synthetic polymers used for colonic drug delivery.

b. Orally administrated nanoparticles serve as carriers for different types of drugs and have been shown to enhance their solubility, permeability and bioavalability.

c. For colonic pathologies, it was shown that nanoparticles tend to accumulate at the site of inflammation in Intestinal bowel syndrome.[22]

E.g. Colon targeting nanoparticles derived from Edible ginger

Scheme 6: Ginger nanoparticles for colon delivery

MICROSPHERES:

a. Microspheres are used for the delivery of proteins and peptides to the colonic region.

b. They provide stability to the acid labile drugs.

c. The drug matrixes to form microspheres have shown increased stability, reduced toxicity and also targeted delivery to the site of action.

d. The microspheres also improve drug absorption from paracelluar route.

e. The mechanism of drug release from microspheres can be diffusion, degradation, hydrolysis or erosion.

E.g. Preparation of colon targeting microspheres of Curcumin

Scheme 6: Curcumin microspheres for colon targeting

CONCLUSION:

Plant based medicines have been widely used by physicians and patients all over the word for their better therapeutic value and fewer side effects in comparison to modern medicines. The therapeutic value of herbal drugs can be increased by use of different scientific approaches making it more targets specific that helps to reduce potential side effects. The therapeutic potential of herbal drugs used in colonic diseases depends on its ability to reach the site of action. Therefore by using various colon targeting drug delivery systems, it is possible to use the herbal medicines in more effective manner for colonic diseases.

REFERENCES:

1. Anya M. Hillery, Andrew W. Lioyd, James Swarbrick. The Textbook of Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists. Special Indian Edition., New Delhi; CRC press: 2010.

2. Sardarmal Yadav, Ashish Kumar Pareek, Dr. Shiv Garg, Manoj Kumar and Pradeep Kumar. Recent Advances In Colon Specific Drug Delivery System. World Journal of Pharmaceutical Sciences 2015; 4(6): 1380-1394.

3. Nishant Singh and Dr. R.. C. Khanna. Colon Targeted Drug Delivery Systems- A Potential Approach Pharmaceutical Research. The Pharma Inoovation 2012; 1(2): 3120-3132.

4. Bhushan Prabhakar Kolte, Kalyani V. Tele, Vinayak S. Mundhe, Sandeep S. Lahoti. Colon Targeted Drug Delivery System- A Novel Perspective. Asian Journal of Biomedical and Pharmacutical Sciences 2012.

5. Kushaldhir, Harminderpal Singh Kahlon and Sukhbirkaur. Recent Approaches For Colon Targeted Drug Delivery System. International Journal of Pharmaceutical, Chemical and Biological Sciences 2013; 3(2): 360-371.

6. Surender Verma, Vipin Kumar, D. N. Mishra and S. K. Singh. Colon Targeted Drug Delivery: Current And Novel Perspectives. International Journal of Pharmaceutical Sciences and Research 2012; 3(5): 1274-1284.

7. Pawar Dhanashree G, Darekar Avinash B, Saudagar Ravindra B. Colon Targeted Drug Delivery System: Pharmaceutical Approaches With Current Trends. World Journal of Pharmacy and Pharmaceutical Sciences 2013; 2(6): 6589-6612.

8. Trishna Debnath, Da Hye Kim and Beong Ou Lim. Natural Products as a Source of Antiinflammatory Agents Associated with Inflammatory Bowel Disease. Molecules 2013; 18: 7253-7270.

9. Subapriya Rajamanickam and Rajesh Agarwal. Natural Products and Colon Cancer: Currrent Status and Future Prospects. NIH Public Access 2008; 69(7): 460-471.

10. Pratik Terse and Rashmi Mallya. Importance of Colon Targeted Drug Delivery System in Herbal Medicines. International Journal of Pharmaceutical Sciences and Research 2017; 8(11): 4513-4524.

11. Jasvir Kaurl. Geeta Aggarwal, Anu Maharajan and Satvinder Kaur. Colon Targeted Drug Delivery System To Treat Colorectal cancer. World Journal of Pharmacy and Pharmaceutical Science 2015; 5(01): 407-420.

12. Anil Bhandari, Imran Khan Pathan, Peeyush K. Sharma, Rakesh K. Patel, Suresh Purohit. Development and Optimization of Colon Taregeted Drug Delivery System of Ayurvedic Churna Formulation Using Eudragit L100 and Ethly Cellulose As Coating Material. International Journal of Pharmacological and Pharmaceutical Sciences 2013.

13. Mundhe Vinayak S, Dodiya Shamsundar S. Review Article: Novel Approach for Colon Targeted Drug Delivery. Indo American Journal of Pharmaceutical Research 2011: 3: 158-173.

14. Suresh kumar R, Ganesh GN, Jawahar N, Nagasamy Venkatesh D, Senthil V, Raju l and Samantha M. Formulation and Evaluation of pectin-hydroxy propyl methyl cellulose coated curcumin pellets for colon delivery. Asian Journal of Pharmaceutics 2009; 3(2): 138.

15. Danda Sreelatha and Chandan Kumar Brahma. Colon Targeted Delivery – A review on Primary and Novel Approaches. Journal of Global Trends in Pharmaceutical Science 2013; 4(3): 1174-1183.

16. Ravi Kumar, M. B. Patil, Sachin R. Patil, Mahesh S. Paschapur. Polysaccharides Based Colon Specific Drug Delivery: A Review. International Journal of Pharm Tech Research 2009; 1(2): 334-346.

17. Ahuja Naresh and Bhandari Anil, Devendra Yadav, Atul Garg and Sanjay Khanna. Formulation and Development of Controlled Release Multiparticulate Tabltes Using Blends of Various Natural Gum. International Journal of Research in Pharmacy and Chemistry 2012; 2(3): 2231-2781.

18. S. P. Vyas. Theory and Practice in Novel Drug Delivery System. First Edition, India binding house; Noida: 2009.

19. Nitin B. Charbe, Paul A. McCarron, Majella E. Lane, Murtaza M. Tambuwala. Application of Three-Dimensional Printing For Colon Targeted Drug Delivery Systems. International Journal of Pharmaceutical Investigation 2017; 7: 47-59.

20. Vinay K Gupta, G.Gnanarajan, Preeti Kothiyal. A Review Article on Colonic Targeted Drug Delivery System. The Pharma Innovation 2012; 1(7): 2277-7695.

21. Huang Y, Tian R, Hu W, Jia Y, Zhang J, Jiang H and Zhang L: A Novel Plug-Controlled Colon-Specific Pulsatile Capsule With Tablet of Curcumin-Loaded SMEDDS. Carbohydrate Polymers 2013; 92(2): 2218-23.

22. R.B. Desi Reddy, K. Malleswari, G. Prasad and G. Pavani. Colon Targeted Drug Delivery System: A Review. International Journal of Pharmaceutical Sciences and Research 2012; 4(1): 42-54.

23. Hang M, Viennois E, Prasad M, Zhang Y, Wang L, Zhang Z, Han MK, Xiao B, Xu C, Srinivasan S and Merlin D. Edible Ginger-Derived Nanoparticles: A Novel Therapeutic Approach For The Prevention and Treatment of Inflammatory Bowel Disease and Colitis-Associated Cancer. Biomaterials 2016; 1(01): 321-400.

24. Ankit Vajpayee, Suresh Fartyal, Alok Pratap Singh, Sajal Kumar Jha. Formulation and Evaluation of Colon Targeted and Opnion 2011; 1(4): 108-112.

25. Madhavi M, Madhavi K and Jithan AV: Preparation and in vitro/in vivo Characterization of Curcumin Microspheres Intended to Treat Colon Cancer. Journal of Pharmacy and Bioallied Science 2012; 4(2): 164.

Received on 08.01.2019 Modified on 12.02.2019

Research J. Pharm. and Tech. 2019; 12(7):3144-3150.

DOI: 10.5958/0974-360X.2019.00530.4