13874-38949-1-pb

8/11/2019 13874-38949-1-PB

http://slidepdf.com/reader/full/13874-38949-1-pb 1/4

Singh et al., Novel Science International Journal of Pharmaceutical Science (2012), 1(6):395-398

395

A recent review on pH sensitive and biodegradable polymeric microspheres: as colon targeted drug

delivery systemSingh Nipendra *, Sharma D.K and Ahmad Shamim

Translam Institute of Pharmaceutical Education & Research, Mawana Road, Meerut, (U.P.) India. Received 25 July 2012; Accepted 13 August 2012

Abstract

Inflammatory bowel disease is a known idiopathic inflammatory disorder of the colon, which involve mucosa and sub mucosa.Among various forms of inflammatory bowel disease in human being, Crohn’s disease and ulcerative colitis are most common ones.For the treatment of these diseases colon targeted drug delivery system has been used to transport the drug in adequate concentrationwithout loss before reaching into the proximal part of the colon for getting optimum therapeutic efficacy. This delivery system is alsoused for the systemic administration of the drug for the reduction in the adverse effect on the upper gastrointestinal tract. For targetingthe drugs to the colonic region microspheres are used. There are various methods for the preparation of microspheres like Oil/oilemulsification, single emulsion technique,double emulsion technique, and oil/water emulsification - solvent extraction. For the

preparation of microspheres and for targeting the drug to the colonic region pH sensitive polymer and biodegradable polymers areused. There are various systems are present. These systems are pH sensitive system, microbially triggered system, pressure controlledsystem. Now a day’s researchers are working on colon targeting formulations for giving the sustain release effect and also fordecreasing the side effects associated with the conventional dosage forms.Keywords: Ulcerative colitis, Crohn’s disease,Microspheres, pH sensitive system, microbially triggered system, and pressurecontrolled system.

IntroductionInflammatory bowel disease (IBD) is an idiopathic

inflammatory disorder of the colon in which mucosa and submucosa are involved. Among various forms of (IBD) occurs inhumans just like Crohn’s disease and ulcerative colitis 1.

Corresponding author: Nipendra SinghPresent address: Translam Institute of Pharmaceutical Education & Research,Mawana Road, Meerut, (U.P.) IndiaE mail: [email protected]

NaGenerally high dose of anti-inflammatory drugs induceremission of the active diseases was the general treatment ofinflammatory bowel diseases (IBD). For avoiding the

absorption of the drugs from the small intestine, variousstrategies have been followed:

Prodrugs are developed for drug delivery to the large bowel after cleaving the active part from thehydrophilic carrier by bacterial enzymes in the colon2–5 .

Under the influence of the physiologicalenvironment, drug should be released in the colononly 6-8 .

Targeted drug delivery to the colon has been widely used totransport the drug in adequate concentration without loss

before reaching into the proximal part of the colon for gettingoptimum therapeutic efficacy 9. This delivery system is also

used for the systemic administration of the drug for thereduction in the adverse effect on the upper gastrointestinal

tract. The use of pH-dependent systems is one of the leadingformulation approaches for the site-specific colon delivery ofdrugs in the oral treatment of IBD. The residence time ofcurrently existing colon delivery devices like enteric coatedtablets, pellets, and granules is less due to diarrhoea which is thecommon symptom of the IBD 6,7 . Another problem associated with

pH dependent polymer is that if the drug release in the smallintestine is earlier then therapeutic efficacy decreases due tovariability of gut pH 9. Therefore, a pressing needs for thedevelopment of a drug delivery system that is able to targetselectively the inflamed tissue of the colon as well as haveenhanced residence time. This type of system could maximize thetherapeutic efficacy and reduce the systemic side-effects

associated with the anti-inflammatory drugs. The pH-sensitive polymers e.g.: Eudragit dissolve in aqueous medium at specific pH, equivalent to drug release to the distal ileum. If we considerthe case of ulcerative colitis which mainly affects the distal partsof the colon, an early drug loss with non flamed tissue of theupper colon may reduce the adverse effects (11-13) .

Benefits of colon targeting:• Colonic drug delivery has importance not only for the

delivery of the drugs for the treatment of local diseasesassociated with the colon but also for its potential for thedelivery of proteins and therapeutic peptides.

• Colon targeting can be very helpful for many pharmaco-therapies, including the treatment of inflammatory bowel

diseases, such as Crohn’s Disease (CD) and UlcerativeColitis

Available online at http: //www.novelscience.info ISSN 2278 – 0033

Novel ScienceNovel ScienceNovel ScienceNovel ScienceInternationaInternationaInternationaInternational Journal of l Journal ofl Journal ofl Journal of

PharmaceuticalPharmaceuticalPharmaceuticalPharmaceutical Scie ScieScieScience ncencence

www.novelsciencepharmacy.info

8/11/2019 13874-38949-1-PB



396

• Drug is directly available at the targeted site.• Reduction of toxicity due to site specific drug delivery.• High intracolonic drug concentration.• Dose reduction.• Improved efficacy.

Drawbacks of colon targeting:• Dose absorption • Residence time is less due to Diarrhoea(common

symptom of IBD) • Targeting of drug in the colon region of GIT is very

difficult. Approaches to colon targeting1. Prodrug approachBacteria present in colon produce various enzymes which maydegrade compounds containing azo, nitro, oxo, aldehyde,ketones, alcohol etc. Thus such types of prodrug can be

prepared by using these groups which do not degrade byhuman stomach enzyme releases drug in colon only after

degradation by colonic bacterial enzyme. For examplesulfasalazine in which 5-Aminosalicylic acid andsulfapyridine bonded by azo bond releases both drug in colonafter degradation in colon used in IBD treatment 14.2. Delayed release productTablets or formulation coated by material which release drugafter a long time. Two types of materials generally used forthis purpose either pH sensitive polymer which dissolve atcolonic pH and exposes drug to colonic region or combinationof hydrophilic material and enteric coating material entericcoting material exposes drug to intestinal environment thanhydrophilic polymer swell to form a gel layer to release

product, this process generally time taking thus drug achievesufficient time to reach colonic region. For example

pulsincap ® is gelatin like product used for coting offormulation for colonic delivery 14. However use of pH sensitive polymer is most common andeasy approach. Different delivery system can be prepared byusing these polymers like microspheres, spheroids etc.MicrosphereSpherical particles diameter ranging from 1 µm to 1000 µmcontaining hollow space inside is known as microspheres 15.Various varieties of drugs with effective protection can bedelivered by these microspheres. Microspheres are suitablecandidate for colonic drug delivery due to effective protectionof drug and wide variety of material used for preparation.Method of preparation of polymeric microspheres:Microspheres can be prepared by various methods but theoil/oil emulsification is the standard one.

Oil/oil emulsification Single emulsion technique Double emulsion technique Oil/water emulsification - solvent extraction

Oil/oil emulsification method:In this technique the polymer and the drug is dissolved in thedifferent ratio of the solvent and then a solution is formed.This solution is poured into oil (liquid paraffin) by whichoil/oil emulsion formed by continuous stirring with the help ofthree blade propeller at specific R.P.M. That emulsion should

be kept under vacuum till solvent removed. Then the

microspheres are collected by filteration colon8.

Figure 1: Microspheres preparedby Oil/oil emulsification method.Single emulsion technique:Basically the microspheres with natural polymers containingcarbohydrates and proteins were prepared by single emulsiontechnique. In this technique natural polymers are dispersed inaqueous medium followed by the dispersion in the non aqueousmedium e.g., oil. After that cross-linking of the dispersed globuleis occur. This cross linking can be achieved by heating or bychemical cross linking agents e.g., formaldehyde, glutaraldehydeetc. Cross-linking by heat can be affected by adding the dispersionto previously heated oil 15.Double emulsion techniques:This technique is suitable for the water soluble drugs, peptides,

proteins and vaccines. In this technique formation of multiple ordouble emulsion of type w/o/w occur. The aqueous proteinsolution is dispersed in the lipophilic organic phase. This proteincontains the active constituents. The primary emulsion is thenfacing the homogenization or sonication before adding the polyvinyl alcohol (PVA) aqueous solution. By this the formation ofdouble emulsion occurs. This emulsion is then incorporated tosolvent removal by solvent evaporation or extraction process. Forthe organic phase diffusion emulsion requires the addition of largequantity of water (with or without surfactant). After that solidmicrospheres are obtained by filtration and washing 15.Oil water emulsification –solvent extraction:Solvent extraction technique is one of the most suitabletechniques for the preparation of microspheres. It involves theremoval of the organic phase by extraction of the organic solvent.

Figure 2: Microspheres prepared by solvent extractionmethod.Organic phase is removed by extraction with water. This processdecreases the hardening time for the microspheres. The rate ofremoval of solvent by extraction method depends on thetemperature of water, ratio of the emulsion value of the water andthe solubility profile of the polymer 15.Need for colon targeting:• Targeted drug delivery to the colon it is necessary for the

treatment of disease with fewer side effects.• It allows the oral administration of peptides and protein,

specific formulation of colon is also used for the drugdelivery prolongation.

• The colon is a site for the treatment of ulcerative colitis orCrohn’s disease, treated with glucocorticoids andsulphasalazine.

• If drugs were targeted to the colon then other serious diseasesof the colon are also being treated more effectively e.g.colorectal cancer.

8/11/2019 13874-38949-1-PB



397

pH sensitive systemIt is the leading formulation approaches for the site-specificcolon delivery of drugs in the oral treatment of IBD. Forcurrently existing colon delivery devices like enteric coated

tablets, pellets, and granules the residence time is less due todiarrhoea a common symptom of the IBD. 11-13 If the drug release in the small intestine is earlier then

therapeutic efficacy decreases due to variability of gut pH 16

this is the another problem associated with pH dependent polymer. Therefore, for enhancing residence time andtargeting of the drug to the inflamed tissue of the colon a

pressing needs for the development of a drug delivery system.By this system we can maximize the therapeutic efficacy andreduce the systemic side-effects associated with the anti-inflammatory drugs. The pH-sensitive polymers e.g.: EudragitS- 100, L- 100 etc. are used as a pH sensitive polymer. The

basic principle of pH sensitive polymer is to coat the dosageform for targeting to the specific site of the colonic region. 17-19

Mechanism of action of a pH dependent system fortargeted drug delivery to the colon

Need of biodegradable polymers: Basically biodegradable polymers are the polymers which aredegraded by the colonic bacteria. So these polymers can also beused for the targeted delivery to the colonic region. Biodegradable

polymers are coated on the microspheres which contain drug.

When these microspheres are administered inside the body then itwill reaches to the colonic region without any degradation byenzymes or any other body fluids. The given dosage form is onlyaffected by the colonic bacteria which is present in the colonicregion. When colonic bacteria act on the microspheres then thecoating of the biodegradable polymer is dissolved and the drug issustainly released out. So by using biodegradable polymers wecan deliver the most of the amount of drug to the colonic region,as we know that the most of the drugs are absorbed from theupper git tract and least of the amount of drug reaches to thecolonic region. So for the distraction of these problems of drugdelivery system we can use targeted drug delivery system for thecolonic region.Mechanism of action of Biodegradable polymeric system fortargeted drug delivery to colon:

Some examples of pH sensitive and biodegradablepolymers:List of pH sensitive polymer:

Biodegradable polymers:ChitosonPectin

Guar gum

DextranAlmond gumLocust bean gumCyclodextrinsInulinAmylose

Microbially triggered systemMicrobially triggered system is based on the enzymaticactivity of the micro flora (enterobacteria) which is present inthe colonic region. There are various enzymes secreated forthe metabolism of carbohydrates and proteins by colonic

bacteria which is anaerobic in nature. This metabolism by

colonic bacteria escapes the digestion in the upper GI tract.6-8

There are various types of enzymes species are present such asBitidobacterium, Bacteroides, Eubacterium etc. Those play asignificant role in the metabolism process of the colonicregion via hydrolysis and reduction process. Basically the

bacterial count is very high in the colonic regionapproximately 10 11- 10 12 CFU/ ml with 400 different specieswhich are aerobic in nature. Basically this vast presence of the

biodegradable enzymes in the colon increases the use of biodegradable for colonic specific drug delivery and this is themost rational approach for site specification as compared toothers.Time controlled systemTime dependent system is related to the circadian rhythms.This system is used as the preselected time for the

synchronous drug delivery; it means patient should take the drugwhen the drug is needed. Delayed release formulation and timerelease formulation both are same for colonic delivery in whichdelay in drug delivery is based upon the time. Individualdifferences in gastric emptying time, pH of the stomach and smallintestine or presence of anaerobic bacteria in the colon should notaffect the site of drug delivery; this is the important parameterwhich should remember during the designing of the formulation.

When a dosage form is orally administered it takes approximately3 hrs for travelling to colon via small intestine 20. Small intestinaltransit time is relatively consistent comparing with gastricemptying rate. In this system drug release occurs after

predetermination of lag phase. For colonic drug delivery timecontrolled formulation also include pH dependent (enteric coat)components because the gastric emptying time is largely affectsthe transit of a formulation in the GI tract. For the prevention ofrapid swelling and disintegration in the upper GI tract entericcoating is used while other components are based on swelling(gelling) and osmosis or the combination of both. Ueda et al.developed the time dependent system for colon delivery in firstattempt 21.

Pressure controlled systemPressure controlled system is based on the centrality activity and peristaltic movement of the digestive process in the GI tract forintestinal contents propulsions. From the ascending colon totransverse colon by peristaltic movement the contents are movedfrom one part to another in the large intestine. Peristalticmovement occur only 3 – 4 times in a day that’s why increment inthe luminal pressure within the colon is the basis of pressurecontrolled system.From peristaltic movement the luminal pressure is higher than the

pressure in the small intestine which is due to the difference in theviscosity of the luminal contents. In stomach viscosity is less dueto fluidic contents while in the colon viscosity is increased due toreabsorption of water from the lumen and formation of feces 22.

8/11/2019 13874-38949-1-PB



398

Future aspectsColorectal cancer is the third most commonly diagnosedcancer in the world, but it is more common in developedcountries. GLOBOCAN estimated that, in 2008, 1.23 millionnew cases of colorectal cancer were clinically diagnosed, and

this type of cancer killed more than 600,000 people23

. It isinteresting fact that half of the people die in developingcountries from colorectal cancer thus colon targeting therapymay provide new horizon in pharmaceuticals and medicaltherapy. A number of others serious diseases of the colon, e.g.colorectal cancer, might also be capable of being treated moreeffectively if drugs were targeted to the colon. There arevarious research is going on for the development of differenttypes of the formulations which is advantageous upon theconventional dosage forms. These formulations are basedupon the pH sensitive system, microbially triggered systemand pressure controlled system. Now a day’s researchers aretrying to develop the formulations which having the sustainrelease effect with less side effects. The developingformulations are Microspheres, Nanospheres, Nanorods etc.ConclusionBy this study we can conclude that pH sensitive and

biodegradable polymeric microspheres have the ability toreach the colonic region without the loss of drug. So these

biodegradable and polymeric microspheres can be used fortargeting the drug to the specific site and also for the sustainrelease effect of the drug.AcknowledgementThe author thanks his seniors and respected faculty ofPharmaceutical Department, Meerut Institute of Engineeringand Technology, Meerut, who have contributed in thediscussion and editing of the paper.

References:1. Abdallah M., Yuichi T., Hirofumi T. pH-Sensitive nanospheres

for colon-specific drug delivery in experimentally inducedcolitis rat model, Eur J Pharm Biopharm, 2009; 72:1–8.

2. Lamprecht M., Yamamoto H., Takeuchi H., Kawashima Y.Design of pH-sensitive microspheres for the colonic delivery ofthe immunosuppressive drug tacrolimus, Eur J PharmaBiopharma, 2004; 58:37–43.

3. Friend D.R., Colon-specific drug delivery, Adv. Drug Deliv.Rev., 1991; 7:149–199.

4. McLeod A., Friend D.R., Tozer T.N. Glucocorticoid–dextranconjugates as potential prodrugs colon-specific delivery:hydrolysisin rat gastrointestinal tract contents, J Pharm Sci,1994: 83:1284–1288.

5. Fedorak R., Haeberlin B., Empey L.R., Cui N., Nolen H. III, JewellL.D., Friend D.R. Colonic delivery of dexamethasone from aprodrugaccelerates healing of colitis in rats without adrenalsuppression,Gastroenterology, 1995; 108:1688–1699.

6. Rubinstein A. Approaches and opportunities in colon-specific drugdelivery, Crit. Rev. Ther. Drug Carrier Syst., 1995; 12:101–149.

7. Watts P.J., Illum L. Colonic drug delivery, Drug Dev. Ind.Pharmcol., 1997; 23:893–913.

8. Kinget R., Kalala W., Vervoort L., Van den Mooter G., Colonicdrug targeting, J Drug Target., 1998; 6:129–149.

9. Lamprecht A. Multiparticulate systems in the treatment ofinflammatory bowel disease, Curr. Drug Targets Inflamm. Allergy,2003; 2:137–144.

10. Hamman J.H. Drug Tar. Insi, 2007, 80.11. Makhlof, A., Tozuka, Y., Takeuchi, H. pH-sensitive Nanospheres

For Colon-Specific Drug Delivery In Experimentally InducedColitis Rat Model, Eur. J Pharm Biopharm, 2009; 72:1-8

12. Watts, P.J. The Transit Rate Of Different-Sized Model DosageForms Through The Human Colon And The Effects Of A Lactulose-Induced Catharsis, Int. J Pharm, 1992; 87 : 215–221

13. Meissner, Y., Pellequer, Y., Lamprecht, A. Nanoparticles inInflammatory Bowel Disease: Particle Targeting Versus Ph-Sensitive Delivery, Int. J Pharm, 2006; 316: 138–143

14. Sarasija, J., Hota, A. Colon-specific drug delivery systems, Indian JPharma Sci, 2000; 62 (1); 1-8

15. Sahil, K., Akansha, M., Premjeet, S., Bilandi, A., Kapoor, B.Microsphere: A Review, Inter. J. Res. Phar. Chem. 2011; 1 (4)

16. Yang L., Chu J.S., Fix A. Colon-Specific Drug Delivery: NewApproaches And In Vitro/In Vivo Evaluation, Int J Pharm, 2002;235:1–15

17. Rudolph M., Klein M., Beckert T.E., Petereit H.U., Dressman, J. B.A New 5 Aminosalicylic Acid Multi-Unit Dosage Form for theTherapy of Ulcerative Colitis, Eur J Pharm Biopharm, 2001;51:183–190

18. Jeong Y.I. Application Of Eudragit P-4135F For The Delivery OfEllagic Acid To The Rat Lower Small Intestine, J Pharm Pharmaco,2001; 53:1079–1085

19. Hu Z. Characterization of Norfloxacine Release from Tablet CoatedWith A New Ph-Sensitive Polymer- P-4135F, J Drug Tar, 1999;7:223–232

20. Hu Z., Shimokawa T., Ohno T., Kimura G., Mawatari S.S.,Kamitsuna M., Yoshikawa Y., Masuda S., Takada K.Characterization of Norfloxacine Release From Tablet Coated WithA New pH-Sensitive Polymer, P-4135F, J Drug Tar, 1999; 7:223–232

21. Sarasija S. and Hota A. Colon-Specific Drug Delivery Systems,Indian J. Pharm. Sci, 2000; 62 (1):1- 8

22. Martindale, the Extra Pharmacopoeia, 1993; 30: 890-89123. Astin M., Griffin T., Neal R.D., Rose P., Hamilton W. The

diagnostic value of symptoms for colorectal cancer in primary care:

a systemic review, British J gen prac: the journal of the royal collageof general practitioners, 61 (586): 231-243

13874-38949-1-pb

Documents