“FORMULATION AND IN VITRO EVALUATION OF FLOATING MICROSPHERES OF AN ANTIDIABETIC DRUG”
SYNOPSIS FOR REGISTRATION
OF
M.PHARM DISSERTATION
Submitted to
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA
By
SRAVANI .A
I M.PHARM
Department Of Pharmaceutics
DAYANANDA SAGAR COLLEGE OF PHARMACY
2008
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidateand Address / Sravani.A
#26,Pragathi layout, 14 th Cross, Bhuvaneshwarinagar, Dasarahalli, Hebbal, Bangalore 560024
2. / Name of the Institution / Dayananda Sagar College of Pharmacy,
Kumaraswamy layout, Bangalore – 560 078
3. / Course of Study and
Subject / M. Pharm
Pharmaceutics
4. / Date of Admission / 30 th May -08
5. Title of the Topic:
“FORMULATION AND IN VITRO EVALUATION OF FLOATING MICROSPHERES OF AN ANTIDIABETIC DRUG”
6.0 / Brief resume of the intended work:
6.1 – Need for the study:
Conventional oral dosage forms offer no control over drug delivery, leading to fluctuations in plasma drug level. Various approaches have been worked out to improve the retention of oral dosage form in the stomach, e.g. floating systems, swelling and expanding systems, bioadhesive systems, high density systems. One such approach is Floating Microspheres (Hollow Microspheres). Gastro-retentive floating microspheres are low-density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period. The drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration. Floating microspheres improves the patient compliance by decreasing dosing frequency, increase the therapeutic effect of short half-life drugs and enhance absorption of drugs which solubilise only in stomach by increasing gastric retention time due to buoyancy.
Type 2 diabetes is one of the most prevalent diseases in the modern world. Diabetes is currently the fourth leading cause of death by disease in the United States. Type 2 diabetes represents 98% of all diabetes among patients older than 45 years of age. There are two widely accepted hypotheses about origin of type 2 diabetes. First one is related to insufficient insulin secretion from beta cells. The second hypothesis is related to insulin resistance in the peripheral tissues. The beta cells initially compensate the normal glucose metabolism by increasing insulin secretion. However, when the demand for insulin exceeds the ability of beta cells to compensate, it leads to pancreatic exhaustion.
If the patients fail to achieve near target blood glucose levels from non pharmacological treatment, then pharmacotherapy is added to diet and exercise plan. Pharmacotherapy includes oral anti diabetic drugs. . The sulphonylureas and biguanides are the most commonly prescribed categories of medications for oral anti diabetic therapy. They are safe, have better tolerability and superior pharmacodynamic effects.
Among the various Antidiabetic drugs used, metformin hydrochloride (biguanides), Glipizide, Glimepride, Glibenclamide, (sulphonyl urea), Repaglinide (non sulphonyl urea) and Rosiglitazone maleate (thiazolidinedione) are very widely accepted drugs.
The absorption of sulphonyl ureas is erractic in diabetic patients due to the impaired gastric emptying. To overcome these drawbacks the present study is focused on the formulation of floating microspheres with prolonged gastric retentive behaviour.
6.2 Review of literature
Hollow microspheres of cellulose acetate butyrate (CAB)[1] and poly ethylene oxide (PEO) were prepared by emulsion-solvent evaporation method. Repaglinide was successfully encapsulated into floating microspheres. Various formulations were prepared by varying the ratio of CAB and PEO, drug loading and concentration of poly vinyl alcohol (PVA) solution. Encapsulation of the drug upto 95% was achieved. The microspheres tend to float over the simulated gastric media for more than 10 hrs.
The use of floating drug-delivery systems[2] was one method that is used to achieve prolonged gastric residence times. A novel, multiple-unit, floating drug-delivery system of microspheres with micro balloons inside from xanthan gum (XG) and gelatin (GA) were developed by a water-in-oil method. With Theophylline as the model drug, four formulations (FI-FIV) with different ratios of the two polymers were prepared. The size distribution, drug-encapsulation efficiency, floating behavior, release characteristics, and morphological properties were investigated. The ratio of the two polymers influenced the size distribution, encapsulation efficiency, and drug release appreciably.
Floating microspheres of Verapamil hydrochloride[3] were prepared for improving the drug bioavailability by prolongation of gastric residence time. Cellulose acetate, acrycoat S100 and eudragit S100 microspheres loaded with verapamil hydrochloride were prepared by solvent diffusion evaporation method. The prepared microspheres exhibited prolonged drug release and remained buoyant for more than 12 hrs.
The floating microspheres were prepared with Cimetidine[4] as model drug for prolongation of gastric residence time by the solvent evaporation method using polymers hydroxypropylmethyl cellulose and ethyl cellulose. The prepared microspheres exhibited prolonged drug release (8 hrs) and remained buoyant for > 10 hrs. The floating microspheres have been utilized to obtain prolonged and uniform release in the stomach for the development of formulation once daily.
Floating microspheres of Metformin hydrochloride[5] were prepared by non-aqueous emulsification solvent evaporation technique using ethylcellulose as the rate controlling polymer containing 250 mg of metformin hydrochloride. Its in vitro performance was evaluated by the usual pharmacopoeial standards and other tests such as drug polymer compatibility (FTIR scan), yield (%), particle size analysis, drug entrapment efficiency, surfacetopography and in vitro floatation and release studies. The developed floating microspheres of metformin hydrochloride may be used in clinic for prolonged drug release in stomach for at least 8 hrs, thereby improving the bioavailability and patient compliance. Optimization of floatation and drug release pattern to match target release profile was investigated.
A bilayer floating tablet was prepared for Tizanidine hydrochloride[6] using direct compression technology. HPMC, sodium bicarbonate and starch 1500 formed the floating layer. The release layer contained tizanidine hydrochloride and various polymers. Because of sodium bicarbonate added to the floating layer, when immersed in 0.1N HCl the tablet expands and rises to the surface, the drug is gradually released. In vivo gastro retentive study of tablets gave successful results by floating in gastric content over period of 6 hrs.
Floating tablets of Carbamazepine[7] were developed using melt granulation technique. Bees wax was used as a hydrophobic meltable material. Hydroxypropylmethylcellulose, sodium bicarbonate and ethyl cellulose were used as matrixing agent, gas-generating agent and floating enhancer, respectively.
A gastro retentive floating controlled drug delivery system containing Glipizide [8] was prepared in the form of tablet. Ten formulations containing retardant materials such as HPMC4K and eudrajit RS100, alkanising agent sodium bicarbonate and other release promoters such as sodium lauryl sulphate and polyvinyl pyrrolidone were used. Tablets remained buoyant over 8 hrs in the release medium.
Sustained release floating systems for Verapamil hydrochloride[9] were prepared by using different hydrocolloid polymers including hydroxypropylmethylcellulose(HPMC), hydroxypropylcellulose (HPC), ethyl cellulose (EC) and Carbopol (CP). Floating was achieved by adding an effervescent mixture of sodium bicarbonate and anhydrous citric acid. Tableting of granules containing various verapamil: HPMC-4000 ratio showed excellent buoyancy and slow release prome. Results also revealed that floatation was able to delay the gastric emptying of verapamil tablet in beagle dogs for more than four hours compared to almost one hour for a control tablet devoid of the gel forming polymer and the gas generating mixture.
A study was conducted in optimization and evaluation of the floating tablets of Atenolol[10] that prolongs the gastric residence time. Semisynthetic polymers, HPMC K4M, HPMC K100M and natural polymer, Xanthan gum were used as release retarding agents. Sodium bicarbonate was used as a gas-generating agent. Dicalcium phosphate was used as a channeling agent. The floating matrix tablets of Atenolol were prepared by direct compression method. The concentration of polymers and a gas-generating agent was optimized to get the controlled release of atenolol for 8hrs.The prepared tablets were evaluated for their physicochemical parameters and found to be within the range.
A study described the development of an intragastric drug-delivery system[11] for Cefuroxime axetil. The factorial design was employed to evaluate contribution of hydroxypropyl methyl cellulose (HPMC) K4M/HPMC K100 LV ratio (polymer blend) and sodium lauryl sulfate (SLS) on drug release from HPMC matrices. Tablets were prepared using direct compression technique. Formulations were evaluated for in vitro buoyancy and drug release study using United States Pharmacopeia (USP) 24 paddle-type dissolution apparatus using 0.1N HCl as a dissolution medium. Multiple regression analysis was performed for factorial design batches to evaluate the response. All formulations had floating lag times below 2 minutes and
constantly floated on dissolution medium for more than 8 hrs.
Floating tablets of Famotidine[12] were prepared employing two different grades of methocel K100 and methocel K15M by effervescent technique; these grades of methocel were evaluated for their gel forming properties. Sodium bicarbonate was incorporated as a gas-generating agent. The floating tablets were evaluated for uniformity of weight, hardness, friability, drug content, in vitro buoyancy and dissolution studies. The effect of citric acid on drug release profile and floating properties was investigated. The prepared tablets exhibited satisfactory physicochemical characteristics. All the prepared batches showed good in vitro buoyancy. The tablet swelled radially and axially during in vitro buoyancy studies. It was observed that the tablet remained buoyant for 6-10 hrs.
Metformin microspheres[13] with sodium alginate alone and in combination with gellan were prepared using an emulsion-cross linking method. The effect of various formulation variables like polymer concentration (sodium alginate; and proportion of gellan in microspheres prepared by a combination of sodium alginate and gellan), drug loading, cross linking agent concentration and cross-linking time on the in vitro dissolution of the prepared microspheres were evaluated. The results showed that both the particle size and the incorporation efficiency were proportional to the polymer concentration. In case of microspheres containing both sodium alginate and gellan, the mean diameter and the incorporation efficiency were higher than the corresponding microspheres containing only alginate, both increasing with an increase in proportion of gellan. The prepared microspheres were found to be discrete and spherical in shape and were successful in sustaining the drug release for 8 hrs.
6.3 Objective of the study:
Ø Improves patient compliance by decreasing dosing frequency.
Ø Gastric retention time is increased because of buoyancy.
Ø Enhanced absorption of drugs which solubilise only in stomach
Ø Drug releases in controlled manner for prolonged period.
Ø Site-specific drug delivery to stomach can be achieved.
7.0 / Materials and methods
7.1 Source of data:
Official Pharmacopoeia, Standard books, International journal of Pharmaceutical sciences, Journal of applied polymer science, Brazilian Journal of Pharmaceutical Sciences, Indian journal of Pharmaceutical sciences, IJPER, Current drug delivery system, Pharmaceutical database and internet.
7.2 Method of collection of the data
Experimental data will be collected from the evaluation of designed formulation and then subjecting to different studies such as preformulation, physico-chemical characteristics of microspheres like particle size, morphology using SEM, incorporation efficiency and in vitro drug release studies, etc
1. Preformulation studies standard to development of floating microspheres.
2. Selection of excipients and rate control polymer of the formulations and fixing their ranges to be used.
3. Development of formulation based on studies in step1 and step 2.
4. Optimization of the formulations.
7.3 - Does the study require any investigations or interventions to be conducted on
patients or other humans or animals? If so, Please describe briefly.
No
7.4 – Has ethical clearance been obtained from your Institution in case of 7.3?
Not applicable.
8. / List of References:
1. Rokhade Ajit P, Patil Sangamesh A, Belhekar Anaga A, Halligudi Shivraj B, Aminabhavi Tejraj M, Preparation and evaluation of cellulose acetate butyrate and poly (ethylene oxide) blend microspheres for gastroretentive floating delivery of repaglinide. Journal of Applied Polymer Science. 2007; 105:2764-2771.
2. Zhenqiu Yang , Baozhen Song, Qiaoxia Li, Honglei Fan, Fan Ouyang, Preparation of microspheres with microballoons inside for floating drug-delivery systems. Journal of Applied Polymer Science. 2004; 94:1,197-202.
3. Yuveraj Singh Tanwar, Pushpendra Singh Naruka, Garima Rani Ojha, Development and evaluation of floating microspheres of verapamil hydrochloride. Brazilian Journal of Pharmaceutical Sciences. 2007; 4: 529-534.
4. Anand Kumar Srivastava, Devendra Narayanarao, Ridhukar Saurabh Wadhwa, Floating microspheres of cimetidine: Formulation, characterization and in vitro evaluation. Acta Pharm. 2005; 55: 277-285.
5. Asha patel, Subhabrata ray, Ram sharnagat thakur , Invitro evaluation and optimization of controlled release floating drug delivery system of metformin hydrochloride. DARU volume. 14, 2006; 2, 57-64.
6. Chaudhari pravin, Chaudhari shilpa, Barhate nilesh, Mistry chetan and Kolsure pramod, Design and evaluation of bilayer floating tablets of tizanidine hydro chloride. Indian J.Pharm.Educ.Res. 2008; 42 (1):36-47.
7. Patel DM, Patel NM, Pandya NN, Jogani PD, Formulation and optimization of carbamazepine floating tablets. Indian J.Pharm Sci. 2007; 69:763-7.
8. Prabhakara Prabhu, Harish Nayari M. Gulzar Ahmed M, Brijesh Yadav, Narayana Charyulu R, SatyanarayanaD, and Subramanayam E.V.S, Formulation and invitro evaluation of gastric oral floating tablets of glipizide. Indian J.Pharm.Educ.Res. 2008; 42 (2):174-183.
9. Seham A. Elkheshen, Alaa Eldeen B. Yassin, SaIeh Alsuwayeh, and Fayza A. AlkhaIed, Invitro and invivo evalution of floating controlled release dosage forms of verapamil hydrochloride. Pharm.Ind. 2004; 66:1364-1372.
10. Vijay Daulatrao Havaldar, Ajit Shankarrao Kulkarni, Remeth Jacky Dias, Kailas Krishnat Mali, Optimization and invitro evaluation of floating tablets of atenolol. Journal of Pharmacy Research. 2008; 1:73-78.
11.Viral F Patel, Natavarlal M Patel, Intragastric floating drug delivery system of cefuroxime axetil: in vitro evaluation. AAPS Pharm Sci Tech. 2006; 7 (1) E1.
12. Jaimini M, Rana A.C and Tanwar Y.S, Formulation and evaluation of famotidine floating tablets. Current Drug Delivery. 2007; 4: 51-55.
13. Balasubramaniam J, Vinay U Rao, Vasudha M, Jeevan Babu, Rajinikanth P S, Sodium Alginate microspheres of Metformin HCl: Formulation and In Vitro evaluation. Curr.Drug.Deliv. 2007; 4(3):249-56
9 / Signature of the candidate: /
(Sravani.A)
10 / Remarks of the Guide: / Requested for clearance and approval
11 / Name and Designation of:
11.1 Guide:
11.2 Signature: / J.Josephine Leno Jenita,
Asst.Professor,
Dept of Pharmaceutics,
Dayananda Sagar College of Pharmacy,
Kumaraswamy layout,
Bangalore – 560 078.
11.3 Co – guide if any
11.4 Signature / Not applicable
11.5 Head of the Department:
11.6 Signature / Dr. Arshia Shariff
Professor and HOD
Dept of Pharmaceutics
Dayananda Sagar College of Pharmacy,
Kumaraswamy layout, Bangalore – 560 078.
12 / 12.1 Remarks of the Principal
12.2 Signature
/ Dr. V. Murugan
Professor and principal
Dept of Pharmaceutical Chemistry
Dayananda Sagar College of Pharmacy,
Kumaraswamy layout, Bangalore – 560 078.
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