“FORMULATION, OPTIMIZATION AND EVAULATION OF …



DEVELOPMENT OF MESALAZINE MICROSPHERES FOR COLON TARGETING

SYNOPSIS FOR

M.PHARM DISSERTATION

SUBMITTED

TO

[pic]

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA.

BY

Mr. KATTA RAJESH

Ι M.PHARM (2012-2013)

DEPARTMENT OF PHARMACEUTICS

M.S.RAMAIAH COLLEGE OF PHARMACY

BANGALORE- 560 054

KARNATAKA

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR P.G. DISSERTATION

| | | |

|1. |NAME OF THE CANDIDATE AND ADDRESS(IN BLOCK LETTERS) |Mr. KATTA RAJESH |

| | |s/o HEMAPRASAD K, |

| | |D.NO 63-3-44B, JAWAHARNAGAR, SRIHARIPURAM, VISAKHAPATNAM-530011, ANDHRA |

| | |PRADESH. |

| | | |

|2. |NAME OF THE INSTITUTION |M.S.RAMAIAH COLLEGE OF PHARMACY |

| | |M.S.R.NAGAR |

| | |M.S.R.I.T POST |

| | |BANGALORE-560 054. |

| | | |

|3. |COURSE OF STUDY AND SUBJECT |MASTER OF PHARMACY |

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| | |PHARMACEUTICS |

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|4. |DATE OF THE ADMISSION |28th MARCH 2012 |

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| |TITLE OF THE TOPIC: |

|5. | |

| | |

| |DEVELOPMENT OF MESALAZINE MICROSPHERES FOR |

| |COLON TARGETING |

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| |BRIEF RESUME OF THE INTENDED WORK |

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| |6.1 NEED FOR THE STUDY |

| |Colon is such a place which is concerned with a number of disease like IBD, colon carcinoma etc. The term inflammatory bowel disease (IBD) covers a |

| |group of disorders in which the intestines become inflamed (red and swollen). Two major types of IBD are described: ulcerative colitis and Crohn’s |

| |disease. These two diseases are mainly associated with colon as their target tissue. When there is a severe inflammation, the disease is considered to|

|6. |be in active stage, and the person experiences a flare-up of the condition1. |

| |Ulcerative collitis is a form of inflammatory bowel disease (IBD). Ulcerative colitis is a form of colitis, a disease of the colon (large intestine) |

| |that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual |

| |onset. IBD is often confused with irritable bowel syndrome (IBS), a troublesome, but much less serious, condition. |

| |Ulcerative colitis is treated as an autoimmune disease. Treatment is with anti-inflammatory drugs, immune-suppression and biological therapy targeting|

| |specific components of the immune response. Colectomy (partial or total removal of the large bowel through surgery) is occasionally necessary if the |

| |disease is severe, doesn't respond to treatment or if significant complications develop. A total proctocolectomy (removal of the entirety of the large|

| |bowel) can be curative, but it may be associated with complications. |

| |Crohn's disease, also known as Crohn’s syndrome and regional enteritis, is a type of inflammatory bowel disease that may affect any part of the |

| |gastrointestinal tract from mouth to anus, causing a wide variety of symptoms. It primarily causes abdominal pain, diarrhea (which may be bloody if |

| |inflammation is at its worst), vomiting (can be continuous), or weight loss, but may also cause complications outside the gastrointestinal tract such |

| |as skin rashes, arthritis and inflammation of the eye, tiredness, and lack of concentration. Crohn's disease is caused by interactions between |

| |environmental, immunological and bacterial factors in genetically susceptible individuals. This result in a chronic inflammatory disorder, in which |

| |the body's immune system attacks the gastrointestinal tract possibly directed at microbial antigens.2 |

| |Mesalazine also known as mesalamine or 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug used to treat inflammatory bowel disease, such |

| |as ulcerative colitis and mild-to-moderate Crohn's disease. Mesalazine is a bowel-specific amino-salicylate drug that acts locally in the gut and has |

| |its predominant actions there, thereby having few systemic side effects. As a derivative of salicylic acid, mesalazine is also thought to be |

| |an antioxidant that traps free radicals, which are potentially damaging by-products of metabolism. Mesalazine is considered the |

| |active moiety of sulfasalazine, which is metabolized to sulfapyridine and mesalazine. |

| |The effective usage of most of the current mesalazine formulation requires multiple daily dosing with upto 12 tablets or capsules. Reduced patient |

| |compliance and disease control are the results of this inconvenience of frequent daily dosing and the number of tablets or capsules required per day. |

| |Accordingly, in order to overcome these problems in formulating mesalazine in a successful delivery system, it is tremendously important to minimize |

| |mesalazine release in the upper gastrointestinal tract and to localize its release in the colon in a sustained-release manner. Single unit dosage |

| |forms (tablets and capsules) for modified release colonic delivery suffer from problems such as unpredictable gastric emptying, GI transit variations |

| |resulting from intersubject variability in transit patterns, and incomplete drug delivery in the GI tract due to the risk of not dissolving the |

| |polymer coat on the large, low surface area coated tablets. |

| |On the other hand, multi-particulate drug delivery system for colonic delivery shows several advantages over single unit dosage forms. Being of |

| |smaller size, it is expected to provide less inter and intra individual variability, more rapid and uniform gastric emptying, more uniform dispersion |

| |and reproducible transit through GI tract. In multi-particulate delivery systems, it is challenging to develop a colon-targeted sustained release |

| |dosage form. It suffers from the risk of early dissolution and release of the drug before reaching to the colon due to its large surface area. This is|

| |more difficult in the case of mesalazine due to its physico-chemical properties. Mesalazine exhibits amphoteric property. Its solubility is increased |

| |at acidic pH in the stomach and at more alkaline values in the lower part of small intestine. Hence the present study was envisaged. |

| | |

| |The aim of the present study is to investigate the feasibility of development of colon-targeted, sustained release mesalazine microspheres by |

| |solvent-evaporation method employing pH dependent polymers. The prepared microspheres will further be evaluated for particle size, shape, production |

| |yield, encapsulation efficiency and in-vitro drug release profile. |

| |REVIEW OF LITERATURE |

| |Sirisha VNL et al. had developed sustained release matrix tablets of mesalamine using hydrophilic and hydrophobic polymers which was targeted to |

| |colon. The tablets were prepared by direct compression method using different concentrations of HPMC and ethyl cellulose (EC). Prepared formulations |

| |were subjected to various studies like hardness, friability, thickness, % drug content and weight variation. Tablets were subjected to in-vitro drug |

| |release studies using pH 1.2, 4.5 and 6.8 buffers. The test batch comparison analysis was confirmed that the combination of both hydrophilic and |

| |hydrophobic polymers successfully employed for formulating the sustained release colon targeted matrix tablets of mesalamine.3 |

| |Ahmed Abd El-Bary et al. has mainly focused to understand the influence of different formulation variables on the optimization of pH dependant, colon |

| |targeted, sustained release mesalamine microspheres prepared by O/O emulsion- solvent evaporation method, employing pH-dependant eudragit S 100 and |

| |hydrophobic pH-independent ethyl cellulose. Formulation variables included concentration of eudragit S in the internal phase and the ratios between |

| |internal to external phase, drug to eudragit S and eudragit S to ethyl cellulose to mesalamine. Prepared microspheres were evaluated by carrying out |

| |in-vitro release studies and determination of particle size, production yield and encapsulation efficiency.4 |

| |Krishnaiah YSR et al. have developed oral colon targeted drug delivery systems for metronidazole using guar gum as a carrier. Matrix, multilayer and |

| |compression coated tablets of metronidazole containing various proportions of guar gum were prepared. The results of the study showed that coated |

| |metronidazole tablets with guar gum of metronidazole for local action in the colon was more effective.5 |

| |Rahman Ziyaur et al. have developed core microspheres of alginate with 5-fluorouracil by modified emulsification method in liquid paraffin followed by|

| |cross linking with calcium chloride. These core microspheres were coated with eudragit S-100 by solvent evaporation technique. Drug release was |

| |sustained for up to 20 hours in formulations with core microspheres to eudragit coat ratio of 1:7 and no change in size, shape and drug content were |

| |observed.6 |

| |Amol Paharia et al. has aimed at preparation and evaluation of eudragit-coated pectin microspheres for colon targeting of 5-Fluorouracil (FU). Pectin |

| |microspheres were prepared by emulsion dehydration method using different ratios of FU and pectin, stirring speeds, and emulsifier concentration. The |

| |formed microspheres were evaluated for surface morphology, particle size and size distribution, swell ability, percentage drug entrapment and in-vitro|

| |drug release in simulated gastrointestinal fluids.7 |

| |Shivakumar HN et al. have designed and evaluated a pH sensitive multiparticulate system for chronotherapeutic delivery of diltiazem hydrochloride. A |

| |pH sensitive multiparticulate system intended to approximate the chronobiology of angina pectoris is suggested for colon targeting. Core pellets was |

| |coated with microcrystalline cellulose and further coating of pellets using eudragit S -100. In-vitro dissolution studies of the coated pellets were |

| |performed following pH progression method. The drug release from the coated pellets depends on the coat weights and pH of the dissolution media.8 |

| |Fatemeh Atyabi et al. have prepared ethyl cellulose coated gelatin microspheres as a multiparticulate colonic delivery system for 5-aminosalicilic |

| |acid by solvent evaporation method. The prepared microspheres were then coated with ethyl cellulose by coacervation-phase separation technique. It was|

| |shown that this system could provide a suitable drug release pattern for colonic delivery of active agents.9 |

| |Mohini Chaurasia et al. have aimed at preparing guar gum microspheres containing methotrexate and targeting them for local release of drug in colon |

| |region. Guar gum microspheres were prepared by emulsification method using glutaraldehyde as a cross-linking agent. Surface morphological |

| |characteristics were investigated using scanning electron microscopy. Particle size, shape, and surface morphology were significantly affected by guar|

| |gum concentration, emulsifier concentration, stirring rate, and operation temperature.10 |

| |Abdul A Hindustan et al. have worked on the fabrication of gastro-retentive high density microspheres with both synthetic and natural polymers for the|

| |sustained release of famotidine to treat gastric ulcers. The microspheres were prepared by coacervation phase separation technique. Famotidine was |

| |checked for its compatibility with natural polymers using FTIR. The surface morphology was studied by scanning electron microscopy. The product was |

| |further tested for percentage yield, surface associated drug content, drug entrapment efficiency and in-vitro dissolution studies and dissolution data|

| |was treated with mathematical kinetic models.11 |

| |Vidhi Jain et al. have worked on preparation and evaluation of colon specific microspheres of mesalazine for the treatment of irritable bowel disease.|

| |The work involves the preparation of chitosan microspheres by emulsification method in liquid paraffin and by cross-linking with glutaraldehyde. The |

| |core microspheres were coated with eudragit S-100 by solvent evaporation technique and to prevent the drug release in the stomach and small intestine |

| |region. The microspheres were characterized for shape, size, surface morphology, size distribution, incorporation efficiency and in-vitro drug release|

| |studies.12 |

| |Deveswaran R et al. have worked on the formulation of sustained release microspheres of aceclofenac using egg albumin as release retarding agent. The |

| |prepared albumin microspheres released the drug completely within 10 hours at lower drug to polymer ratio. At ratio of more than 1:2, the drug release|

| |was sustained over a period of 12 hours. The prepared microspheres were evaluated for drug polymer interaction by FT-IR studies. It was also evaluated|

| |for percentage drug entrapment efficiency, DSC studies and accelerated stability studies.13 |

| |Deshmukh VN et al have prepared controlled release microspheres using a mixture of hydrophilic polymers like locust bean gum and xanthan gum in |

| |different concentration ratios so as to release the drug in a controlled manner. The microspheres were prepared by ionic cross-linking method. The |

| |prepared microspheres were evaluated for percentage drug entrapment, assay DSC and SEM studies. The prepared microspheres were also subjected for |

| |accelerated stability studies.14 |

| |Jose S et al. have worked on the development of multiparticulate system containing system containing chitosan microspheres for colon targeted delivery|

| |of ondansetron for the treatment of inflammatory bowel disease. They have worked on the parameter of pH dependent solubility of eudragit S-100 polymer|

| |and microbial degradability of prepared chitosan microspheres. The microspheres were prepared by emulsion cross-linking method. They have further |

| |studied the effect of various parameters involved in the preparation of microspheres like drug-polymer ratio, chitosan concentration, emulsifier |

| |concentration and stirring speeds. They even performed the various evaluation tests for microspheres like assay, particle size, in-vitro studies, |

| |percentage drug release and in-vivo studies.15 |

| |Rana Muzumder et al. have worked on the preparation and evaluation of natural polymers based metronidazole microspheres. They have first prepared the |

| |microspheres by ionotropic gelation method. The prepared microspheres contained metronidazole and the drug entrapment efficiency was further enhanced |

| |by addition of glutaraldehyde. The prepared microspheres were characterized for entrapment efficiency, particle size, micromeritic properties, |

| |in-vitro release behavior, scanning electron microscopy and FT-IR.16 |

| |Ramana G et al. have worked on the preparation and evaluation of the colon specific pectin alginate microspheres of 5-fluorouracil. They have prepared|

| |calcium alginate beads by extruding 5-FU and alginate, alginate and calcium chloride. The prepared core beads were coated with ethyl cellulose to |

| |prevent the drug release in the stomach and to felicitate the maximum drug release in the colon region. The formed microspheres were evaluated for DSC|

| |and FT-IR studies. The kinetics of drug release was elaborately studied.17 |

| |Keshavarao KP et al have worked on the formulation and evaluation aspects of sustained release indomethacin microspheres prepared by using different |

| |ratios of drug and polymer eudragit S-100 and eudragit L-100. The microspheres were initially prepared by solvent evaporation method. The prepared |

| |microspheres were characterized for various physic-chemical parameters such as particle size, percentage yield, incorporation efficiency, drug-polymer|

| |compatibility studies (FT-IR studies) scanning electron microscopy and percentage in-vitro drug release.18 |

| |Swapna A et al. have worked on the preparation and evaluation of mesalamine microspheres for colon targeting. They have prepared microspheres by |

| |emulsion solvent evaporation method using different ratios of mesalamine, HPMC and ethyl cellulose. They have tested different formulation parameters |

| |like stirring speeds, emulsifier concentration studies. They have even worked on the physical characterization of microspheres like surface |

| |morphology, particle size analysis, percentage drug entrapment efficiency, percentage yield and in-vitro drug release studies.19 |

| |Girish Kumar T et al. have worked on the modification of chitosan to obtain alkyl succinate and phthalyl derivatives and to synthesize metronidazole |

| |microspheres using these modified chitosan derivatives and to evaluated for efficiency of pH sensitive polymers for colon targeted drug release. They |

| |have prepared the chitosan derivative microspheres by solvent evaporation method. The formed microspheres were further characterized for particle |

| |size, morphology, percentage drug entrapment efficiency, percentage drug content and in-vitro drug dissolution profiles. The two polymers were |

| |compared for the physical characterization of microspheres and for their muco-adhesive strength.20 |

| |6.3 OBJECTIVES OF THE STUDY |

| |Formulation of mesalazine microspheres for colon targeting using polymers such as xanthan gum, guar gum, eudragit S100 and ethyl cellulose. |

| |To carry out compatibility studies of drug and polymer by FTIR & DSC studies. |

| |To evaluate the formulations for in-vitro drug release profiles. |

| |To carry out the characterization of the prepared microspheres |

| |To predict the drug release mechanism of the prepared microspheres. |

| |To carry out stability studies as per ICH guidelines. |

| |To subject the generated data for statistical analysis. |

| | |

| |MATERIALS AND METHOD |

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| |7.1 SOURCE OF DATA |

| |Library of M.S. Ramaiah College of Pharmacy. |

| |E-library of M.S. Ramaiah College of Pharmacy. |

| |Official books such as IP, BP, USP. |

| |Internet source. |

| |HELINET, RGUHS Library, Bangalore. |

| |Micromedex® Health Care Series, Drug Information Centre: M.S.Ramaiah College of Pharmacy. |

| |International and National Pharmaceutical Journals. |

| |Lab based studies. |

| | |

| |7.2 MATERIALS |

| |Drug: Mesalazine. |

| |Polymers: Eudragit S-100, Xanthan gum, Guar gum, Ethylcellulose and Magnesium stearate. |

| |Solvents/Chemicals: Liquid paraffin, iso-propyl alcohol, petroleum ether, n-hexane, acetone, sodium hydroxide, potassium dihydrogen phosphate |

| | |

| |7.3 METHODS OF DATA COLLECTION |

| |Data will be collected from experimental studies carried out in different stages; |

| | |

| |Preformulation studies |

| |Drug-polymer compatibility studies using FTIR and DSC techniques. |

| |Construction of the calibration curve for mesalazine by spectrophotometric method to estimate the drug loading efficiency and analysis of in-vitro |

| |dissolution samples. |

| |Preparation of microspheres |

| |Solvent evaporation method. (or) Emulsion solvent diffusion method. |

| |Evaluation of microspheres |

| |Sphericity and surface morphology of microspheres by SEM. |

| |Percentage yield, particle size and distribution and drug entrapment. |

| |FT-IR, DSC and XRD studies of the prepared microspheres |

| |In-vitro drug release studies using simulated pH conditions. |

| |Statistical analysis of all the generated data. |

| |Stability studies of best formulations as per ICH guidelines. |

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| |7.4 Does the study require any investigation or intervention to be conducted on patients or other human or animals? |

| |-NO- |

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| |7.5 Has ethical clearance been obtained from your institute? |

| | |

| |-NOT APPLICABLE- |

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| |8. REFERENCES |

| |Madhu EN, Shanker Panaganti, Prabakaran L, Jayveera KN. Novel colon specific Drug Delivery System: A Review. Int J Pharm Sci Res. 2011; |

| |2(10):2545-2561. |

| | (Assessed on 2nd January 2013). |

| |Sirisha VNL, Vamsi Krishna N, Vinay Kumar TVS. Formulation and evaluation of colon targeted mesalamine matrix tablets. Int J Pharm Edu Res. 2012; |

| |4(6):177-185. |

| |Ahmed AE, Ahmed AA, Ibrahim M, Sharabi A. Influence of some formulation variables on the optimization of pH dependent, colon targeted, sustained |

| |release mesalamine microspheres. AAPS PharmSciTech. 2012; 13(1):75-84. |

| |Krishnaiah YSR, Bhaskar Reddy PR, Satyanarayana RS, Karthikeyan. Studies on the development of oral colon targeted drug delivery systems for |

| |metronidazole in the treatment of amoebiasis. Int J Pharm. 2002; 23(6):43-55. |

| |Ziyaur R, Kohli K, Roop K, Ali Mushir, Naseem A. Characterization of 5-fluorouracil microspheres for colon delivery. AAPS PharmaSciTech. 2006; |

| |7(2):113-121. |

| |Amol P, Awesh KY, Gopal Rai, Sunil KJ, Shyam SP. Eudragit coated pectin microspheres of 5-fluorouracil for colon targeting. AAPS PharmaSciTech. 2007; |

| |8(1):87-93. |

| |Shivakumar HN, Suresh Sarasija, Desai B.G. Design and evaluation of pH sensitive multi-particulate system for chrono-therapeutic delivery of diltiazem|

| |hydrochloride. Ind J Pharm Sci. 2006; 68(6):781-787. |

| |Fatemeh A, Rudabeh V, Dinarvand R. Preparation of ethyl cellulose coated gelatin microspheres as a multi-particulate colonic delivery system for |

| |5-aminosalicilic acid. Iran J Pharm Res. 2004; 2:81-86. |

| |Mohini Chaurasia, Manish Chaurasia, Nitin K Jain, Aviral Jain, Vandana Soni. Cross-linked guar gum microspheres: a viable approach for improved |

| |delivery of anticancer drugs for the treatment of colorectal cancer. AAPS PharmaSciTech. 2006; 7(3):143-151. |

| |Abdul AH, Sreenivasulu R, Rani ME. Preparation and evaluation of famotidine high density gastro-retentive microspheres with synthetic and natural |

| |polymers. J Pharm Edu Res. 2011; 2(1):54-60. |

| |Vidhi Jain, Shailesh Gupta, Pandey GK, Dubey BK. Design and characterization of eudragit coated microspheres of mesalazine for irritable bowel |

| |disease. Int J Drug Dis Herb Res. 2012; 2(1):301-307. |

| |Deveswaran R, Manavalan R, Madhavan V, Bharath S. Formulation and evaluation of albumin microspheres containing aceclofenac. Int J Pharm Sci Rev & |

| |Res. 2010; 4(1):112-117. |

| |Deshmukh VN, Jadhav JK, Masirkar, Sakarkar DM. Formulation, optimization and evaluation of controlled release alginate microspheres using synergy gum |

| |blends. Res J Pharm Tech. 2009; 2(2):324-327. |

| |Jose S, Dhanya K, Chinu TA, Aleykutty A. Multi-particulate system for colon targeted delivery of ondansetron. Ind J Pharm Sci. 2010; 72(1):58-64. |

| |Rana Mazumder, Lila KN, Anwarul Haque, Tarasankar Maity, Prasanta KC, Bhupendra Shrestha, Manas Chakraborty, Rabindra NP. Formulation and in-vitro |

| |evaluation of natural polymers based microspheres for colonic drug delivery. Int J Pharm Pharm Sci. 2010; 2(1): 211-219. |

| |Ramana G, Krishna Chaitanya A. Preparation and in-vitro characterization of ethyl cellulose coated pectin alginate microspheres of 5-fluorouracil for |

| |colon targeting. J App Pharm Sci. 2011; 01(08):170-176. |

| |Keshavarao PK, Dixit M, Selvam P, Rudra Singh D. Formulation and evaluation of indomethacin microspheres for colon drug delivery system. Int Res J |

| |Pharm. 2011; 2(8):181-184. |

| |Swapna A, Abdul BM, Vinay W, Swathimutyam P. Formulation and evaluation of mesalamine microspheres for colon targeted drug delivery system. J Pharm |

| |Res. 2011; 4(6):1670-1672. |

| |Girish Kumar T, Satyawan Singh, Shrishti S, Archana Singh, Ravi Kant D. Synthesis & design of chitosan derivative pH stimuli sensitive microparticles |

| |for colon targeted metronidazole delivery. J Chem Pharm Res. 2012; 4(5):2656-2665. |

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|9 |SIGNATURE OF THE CANDIDATE | |

| 10 | | |

| |REMARKS OF THE GUIDE |Recommended for Registration |

| 11| | |

| |NAME AND DESIGNATION OF | |

| | | |

| |11.1 GUIDE |Dr.R. DEVESWARAN, M.Pharm., Ph.D |

| | |Asst. Professor, |

| | |Dept. of Pharmaceutics, |

| | |M.S.Ramaiah College of Pharmacy, |

| | |Bangalore-560054. |

| | | |

| |11.2 SIGNATURE | |

| | | |

| |11.3 CO-GUIDE |Not applicable |

| | | |

| |11.4 SIGNATURE |Not applicable |

| | | |

| |11.5 HEAD OF THE DEPT. |Dr. S.BHARATH, M.Pharm., Ph.D., ACCR |

| | |Professor and Head, |

| | |Dept. of Pharmaceutics |

| | |M.S.Ramaiah College of Pharmacy, |

| | |Bangalore-560 054. |

| | | |

| |11.6 SIGNATURE | |

| | | |

|12 |REMARKS OF THE PRINCIPAL |Forwarded for Registration |

| | | |

| |12.1 SIGNATURE | |

| | | |

| | | |

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