“FORMULATION AND EVALUATION OF MUCOADHESIVE DRUG DELIVERY SYSTEM CONTAINING AN
ANTIDIABETIC DRUG”
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA
BY
RAGA PRIYA KANAKALAPATI
I M.PHARM
UNDER THE GUIDANCE OF
Dr. S. J. SHANKAR
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
PES COLLEGE OF PHARMACY
BANGALORE-560050
(2011-12)
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1 /Name of the candidate and address
/ TEMPORARY ADDRESS :PES COLLEGE OF PHARMACY
50 FEET ROAD,HANUMANTH NAGAR,
BANGALORE-560050.
PERMANENT ADDRESS :
K. RAGA PRIYA
C/O K.HARINARAYANA,
DR NO. NNB3-401,
SHRIRAM SPANDANA APPTS., CHALLAGATTA,
NEAR EMBASSY GOLF LINK,
BANGALORE-560037.
E MAIL ID :
2 /
Name of the institution
/P.E.S. COLLEGE OF PHARMACY
50 FEET ROAD,HANUMANTH NAGAR,
BANGALORE-560050.
3 /
Course of study and subject
/MASTER OF PHARMACY IN PHARMACEUTICS
4 /Date of the admission
/ 11th JULY 20115 /
Title of the topic:
“ FORMULATION AND EVALUATION OF MUCOADHESIVE DRUG DELIVERY SYSTEM CONTAINING ANANTIDIABETIC DRUG ”
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6 / Brief resume of the intended work:6.1 Need for the study:
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, glycosuria, hyperlipaemia, negative nitrogen balance and sometimes ketonaemia. A widespread pathological change is thickening of capillary basement membrane, increase in vessel matrix and cellular proliferation resulting in vascular complications like lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency.
Two types of Diabetes mellitus:
Ø Type I: Insulin dependent diabetes mellitus (IDDM).
Ø Type II: NonInsulin - dependent diabetes mellitus (NIDDM).
The different classes of oral anti-diabetic drugs are: Sulfonyl ureas, Biguanides, Phenyl alanine analogues, Thiazolidinediones and α-Glucosidase inhibitors.1
The drugs like Glipizide, Metformin, Repaglinide, Netaglinide, Rosiglitazone, Miglitol has short half-life and low bioavailability, which needs frequent dosing to maintain therapeutic blood levels.1,2
The present study is an attempt to develop a Mucoadhesive formulation capable of delivering the selected anti-diabetic drug in the desired therapeutic concentration for prolong period.
Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. The mucoadhesive ability of a dosage form is dependent upon various factors, including the nature of the mucosal tissue and physicochemical property of the polymeric form. Over the past few decades, mucosal drug delivery has received a great deal of attention.3
Advantages of this formulation are:-
Ø Prolongs the residence time of the dosage form at the site of absorption.
Ø Due to an increased residence time it enhances absorption and hence the therapeutic efficacy of the drug.
Ø Excellent accessibility.
Ø Rapid absorption because of enormous blood supply and good blood flow rates.
Ø Increase in drug bioavailability due to first pass metabolism avoidance.
Ø Drug is protected from degradation in the acidic environment in the GIT.
Ø Improved patient compliance ease of drug administration.
Ø Faster onset of action is achieved due to mucosal surface.4
6.2 Review of the literature
· Deshpande MC et al., Designed and Evaluated Oral Bioadhesive Controlled Release formulations of Miglitol using Polymers like Ethyl Cellulose, HPMC and Eudragit. Four controlled release formulations (CR1, CR2, CR3 and CR4) of miglitol comprising of multilayered pellets were designed successfully. The CR4 formulation containing 30% of 20 cps of ethyl cellulose have showed slowest release of miglitol in vitro in comparison to other formulations. The ex vivo bioadhesion experiment revealed that a total of 95.46% of the pellets used in the experiment were found to be adhering to different parts of the intestine. Two of the controlled release formulations CR1and CR4 were evaluated in vivo in dogs. Both the formulations displayed significantly higher and more prolonged levels of GLP-1 and they even displayed a significantly better control of postprandial glucose in comparison to either the placebo or the immediate release formulations. A comparison study between the two controlled release formulations (CR1 and CR4) revealed that the plasma GLP-1 (AUC by CR1 = 63.1±1.32 and CR4 = 66.2±0.82) and postprandial glucose values due to both the formulations were rather similar despite their differences in in vitro release as well as pharmacokinetic profiles (plasma miglitol AUC of CR1 = 16.17±4.11 and CR4 = 27.17±4.33).5
· Krishna SS et al., Formulated and Evaluated the Mucoadhesive Dosage Form Containing Rosiglitazone maleate using different Polymers like Carbopol 934, Ethyl Cellulose and Cellulose Acetate Phthalate. The tablets are prepared by direct compression method using simplex lattice design, followed by optimization of the evaluation parameters was employed to get final optimized formulation. This optimized formulation is with the composition of 10% rosiglitazone maleate, 80% carbopol 934, 1.92% ethylcellulose, and 8.08% cellulose acetate phthalate and this showed a mucoadhesive strength >40 gm-f, and a mucoadhesion time >12 hours with release profile closer to the target release profile and followed Non-Fickian diffusion mediated release of rosiglitazone maleate.6
· Adikwu MU et al., recorded Pharmacodynamic–Pharmacokinetic profiles of Metformin Hcl from a Mucoadhesive Formulation of a Polysaccharide with Antidiabetic property in Streptozotocin-Induced Diabetic Rat Models. The antidiabetic property of a formulation containing metformin Hcl and detarium gum has been evaluated in streptozotocin model of experimental rats. The pharmacokinetics of metformin from the mucoadhesive dosage forms indicated that for metformin alone, the area under curve (AUC) values were 125.6 and 135.6 mgh/ml at 200 and 400 mg/kg BW, respectively. For the mucoadhesive products using the same dose levels, the AUCs were modified to 102.4 and 150.2 in detarium gum and 59.9 and 80.4 in sodium carboxy methyl cellulose (NaCMC). The results indicate that detarium gum is a good excipient for the formulation of metformin mucoadhesive delivery systems when compared with NaCMC.7
· Prakya V et al., Developed Site-Specific Oral Controlled Release Metformin Tablets and in vitro, ex vivo and in vivo evaluations are carried out. Various batches of mucoadhesive core tablets from F-1 to F-4 were developed by both wet granulation and direct compression by using various grades of HPMCs. As the formulation F-4 showed maximum ex vivo bioadhesion strength and in vitro longer duration of drug release, this was chosen for coating. Three batches of coating formulations CF-1 to CF-3 were developed. The standardized formulation CF-1 satisfied the physicochemical parameters, in vitro and in vivo drug release profile requirements for a site specific oral controlled release dosage form of metformin.8
· Patel JK et al., Formulated and Evaluated Glipizide Floating-Bioadhesive Tablets using Polymers such as Carbopol 934P, Polymethacrylic acid (PMA), Chitosan, and HPMC. Tablets with 5% effervescent base had longer lag time than 10%. The type of polymer had no significant effect on the floating lag time. From in vitro studies, all tablets floated atop the medium for 23-24 hr. Increasing carbopol 934P caused higher bioadhesion than chitosan (p < 0.05). All formulations showed a Higuchi, Non-Fickian release mechanism. Tablets with 10% effervescent base, 80% CH/20% HPMC, or 80% CP/20% PMA seemed desirable.9
· Shaikh AC et al., Formulated and Optimized Hydrodynamically Balanced Oral Controlled Release Bioadhesive Tablets of Tramadol Hcl using different Polymers like Carbopol 971P and HPMC by direct compression method. In vitro drug release profile, floatational characteristics and ex vivo bioadhesive strength using texture analyzer was determined and systematically optimized using a 32 central composite design (CCD). The studies indicated successful formulation of gastroretentive compressed matrices with excellent controlled release, mucoadhesion and hydrodynamic balance.10
· Chavanpatil MD et al., Developed Novel Sustained Release, Swellable and Bioadhesive Drug Delivery System of Ofloxacin using Polymers like Psyllium husk, HPMC K100M and a swelling agent, Crosspovidone. Formulations were evaluated for in vitro drug release profile, swelling characteristics and in vitro bioadhesion property. The in vitro drug release followed Higuchi kinetics and the drug release mechanism was found to be of anomalous or Non-Fickian type. For the developed formulation, the value of n was found to be 0.5766 while for the marketed formulation the value was 0.5718 indicating the anomalous transport. The similarity factor f 2 was found to be 91.12 for the developed formulation indicating the release was similar to that of the marketed formulation. The swelling properties were increased with increasing crosspovidone concentration. The bioadhesive property of the developed formulation was found to be significant (P < 0.005) in combination as compared to HPMC K100M and psyllium husk alone.11
· Alladi KK et al., Formulated and Characterised Clarithromycin Controlled Release Bioadhesive Tablets using Polymers namely Carbopol 974P, HPMC K15M and HPMC K4M. Different formulations (F1-F12) were developed and among these formulations, F9 and F12 showed prolonged release of drug over the period of 12 hrs. The cumulative percent of drug release of formulation F9 and F12 were 93.16 and 96.82 respectively. In vitro releases of F1 to F12 were found to be diffusion controlled and followed zero order kinetics. Formulation of F9 and F12 which were formulated by using polymers HPMC K4M, HPMC K15M and carbopol 974P were established to be the optimum formulation with optimum bioadhesive force, swelling index and desired in vitro drug release.12
· Singh B et al., Formulated and Optimized Controlled Release Mucoadhesive Tablets of Atenolol using Response Surface Methodology. Carbopol 934P and NaCMC were used as polymers. Tablets were prepared by direct compression and evaluated for bioadhesive strength and in vitro dissolution parameters. A central composite design for 2 factors at 3 levels each was employed to systematically optimize drug release profile and bioadhesive strength. Response surface plots and contour plots were drawn, and optimum formulations were selected by feasibility and grid searches. Compressed matrices exhibited Non-Fickian drug release kinetics approaching zero-order, as the value of release rate exponent (n) varied between 0.6672 and 0.8646, resulting in regulated and complete release until 24 hours. Both the polymers had significant effect on the bioadhesive strength of the tablets, measured as force of detachment against porcine gastric mucosa (P < .001). Polynomial mathematical models, generated for various response variables using multiple linear regression analysis, were found to be statistically significant (P < .01).13
· Chandrakala VV et al., Formulated and Evaluated Bioadhesive Cyproheptadine Tablet using Polymers namely, HPMC, NaCMC and Carbopol 934P and 974P. Screening of these polymers in solution were carried out by shear stress and detachment force measurement, based on Taguchi model, in order to determine their bioadhesion properties. Central composite design (CCD) was applied to optimize the combined effects of the polymers on release rate constant (K), diffusion coefficient (n), regression coefficient (R2) and detachment force of a sustained release tablet formulation of cyproheptadine Hcl. The results showed that shear stress of 3 % solution of HPMC was greater than that of an equivalent concentration of carbopol 934P. The values of K, n, R2 and detachment force for the optimized formulation were 0.269, 0.696, 0.964 and 0.066 Newton (N), respectively, and showed good correlation with the predicted values, thus confirming the practicability and validity of the model.14
6.3 Main objectives of the study:
The objectives of the present study are as follows:
1. To carry out the preformulation studies of the selected drug and polymers.
2. To formulate different formulations of mucoadhesive tablet containing an antidiabetic drug using various polymers alone and in different ratios.
3. To carry out the pre-compression and post-compression evaluations of the prepared formulation.
4. To evaluate in vitro drug release profile of the prepared formulation.
5. To optimize the formulation based on the results of the different evaluation tests.
6. To carry out the ex vivo bioadhesion studies of the optimized formulation.
7. To carry out the stability studies of the optimized formulation as per ICH guidelines.
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/ Materials and methods:
7.1 Source of data:
· The data will be obtained from the literature survey and internet source.
· The data will be obtained from the experimental work, which includes formulation of Mucoadhesive tablets by using different polymers, evaluation of drug content and stability studies.
7.2 Method of collection of data (including sampling procedures if any):
The data will be collected from prepared formulations subjected to different evaluation techniques, estimation of drug content, in vitro drug release profile, ex vivo bioadhesion strength and stability studies.
7.3 Does the study require any investigation or interventions to be
Conducted on patients or other humans or animals?
- YES, ex vivo bioadhesive studies.
7.4 Has ethical clearance been obtained from your institution in case of
7.3?
- YES – Letter enclosed
8. List of References:
1. Tripathi KD. Essentials of Medical Pharmacology.6 ed. New Delhi: Jaypee Brothers Medical Publishers (P) LTD; 2008.2. Yadav VK, Kumar B, Prajapathi SK, Shafaat K. Design and Evaluation of Mucoadhesive Microspheres of Repaglinide for Oral Controlled Release. Int J Drug Delivery. 2011;3:357-70.
3. Shaikh R, Singh TRR, Garland MJ, Woolfson DA, Donnelly RF. Mucoadhesive Drug Delivery Systems. J Pharm Bioallied Sci. 2011;3(1):89-100.
4. Tangri P, Madhav NVS. Recent Advances in Oral Mucodhesive Drug Delivary Systems: A Review. IJPRD. 2011;3(2):151-62.
5. Deshpande MC, Venkateswarlu V, Babu RK, Trivedi RK. Design and Evaluation of Oral Bioadhesive Controlled Release Formulations of Miglitol, Intended for Prolonged Inhibition of Intestinal α-glucosidases and Enhancement of Plasma Glucagon like Peptide-1 Levels. Int J Pharm. 2009;380:16-24.
6. Krishna SS, Ray S, Thakur RS. Formulation and Evaluation of Mucoadhesive Dosage Form Containing Rosiglitazone Maleate. Pak. J. Pharm. Sci., 2006;19(3):208-13.
7. Adikwu MU, Yoshikawa Y, Takada K. Pharmacodynamic–Pharmacokinetic Profiles of Metformin hydrochloride from a Mucoadhesive Formulation of a Polysaccharide with Antidiabetic Property in Streptozotocin-Induced Diabetic Rat Models. Biomaterials. 2004;25:3041-8.
8. Prakya V, Vemula KD, Devi K, Sonti S. Site-Specific Oral Controlled Release Metformin Tablets - Development, in vitro, ex vivo, and in vivo Evaluation. The Internet J Pharmacol. 2010;8.
9. Patel JK, Chavda JR. Formulation and Evaluation of Glipizide Floating-Bioadhesive Tablets. Braz Arch Biol Tech. 2010;53:1073-85.
10. Shaikh AC, Quazi A, Nazim S, Majaz Q, Siraj S, Khan T, et al. Formulation Optimization of Hydrodynamically Balanced Oral Controlled Release Bioadhesive Tablets of Tramadol hydrochloride. Asian J Pharm Clin Res. 2011;4(3):61-70.
11. Chavanpatil MD, Jain P, Chaudhari S, Shear R, Vavia PR. Novel Sustained Release, Swellable and Bioadhesive Gastroretentive Drug Delivery System for Ofloxacin. Int J Pharm. 2006;316:86-92.
12. Alladi KK, Suram R, Bela M, Kiran S, Ramaesh V, Narendra Y. Formulation and Characterisation of Clarithromycin Controlled Released Bioadhesive Tablets. J. Chem. Pharm. Res. 2011;3(2):684-90.
13. Singh B, Chakkal SK, Ahuja N. Formulation and Optimization of Controlled Release Mucoadhesive Tablets of Atenolol Using Response Surface Methodology. AAPS PharmSciTech. 2006;7(1):E1-10.
14. Chandrakala VV, Srinath MS, Mary SA, Utpal KS. Formulation and Evaluation of Bioadhesive Cyproheptadine Tablets. Trop J Pharm Res. 2011;10(4):365-73.
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12. /
Signature of the candidate:
(RAGA PRIYA KANAKALAPATI)
Remarks of the guide:
Forwarded for Approval
Name And Designation of:
11.1 Guide Dr. S. J. SHANKAR
Assistant Professor
Department of Pharmaceutics,
P.E.S. College of Pharmacy,
Bangalore-560050.
11.2 Signature
11.3 Co-Guide
NOT APPLICABLE
11.4 Signature11.5 Head of the department DR. SATISH C.S.
Professor & Head,
Department of Pharmaceutics,
P.E.S. College of Pharmacy,
Bangalore -560050.
11.6 Signature
12.1 Remarks of the Chairman and Principal:
FORWARDED FOR APPROVAL
Prof. Dr. S. Mohan,
Principal,
P.E.S. College of Pharmacy,
Bangalore-50050.
12.2 Signature
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