DESIGN AND INVITRO EVALUATION OF GASTRO RETENTIVE DRUG DELIVERY SYSTEMS
M.PHARM DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIVGANDHIUNIVERSITY OF HEALTHSCIENCES,
BANGALORE, KARNATAKA.
By
G.PRAVEEN
Under the guidance of
M.V.RAMPURE
M.Pharm. (Ph.D)
DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s COLLEGE OF PHARMACY
GULBARGA-585105
2010-11
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCE, KARNATAKA
BANGALORE
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the candidate(In block letters) / G.PRAVEEN
Permanent address / G.PRAVEEN,
S/O GOGU LIMBAIH,
H-NO: 1-110, POST-KONDOOR,
MANDAL-SIRIKONDA, DIST-NIZAMABAD,
ANDHRA PRADESH-503165.
2. / Name of the institution / H.K.E.SOCIETY’s COLLEGE OF PHARMACY
SEDAM ROAD,
GULBARGA-585105.
3. / Course of study and subjects / M.PHARM
(PHARMACEUTICAL TECHNOLOGY)
4. / Date of admission to the course / 26-09-2010
5. / Title of the topic / “DESIGN AND INVITRO EVALUATION OF GASTRO RETENTIVE DRUG DELIVERY SYSTEMS”
6. / Brief resume of the intended work
6.1 / Need for the study:
During the last decade, many studies have been performed concerning the sustained release dosage forms of drugs, which have aimed at the prolongation of gastric retentive time (GRT). The GRT has been reported to be from 2 to 6 hours, in humans in the fed state.1Retention of drug delivery systems in the stomach prolongs overall gastrointestinal transit time, thereby resulting in improved bioavailability. Drugs that required to be formulated into gastro retentive dosage forms include: (a) drugs acting locally and primarily absorbed in the stomach, (b) drugs that are poorly soluble at an alkaline pH, (c) those with a narrow window of absorption, (d) drugs absorbed rapidly from GI tract and (e) drugs that degrade in colon.2Scintigraphic studies determining gastric emptying rates revealed that orally administered controlled release dosage forms are subjected to basically two complications; that of short gastric residence time and unpredictable gastric emptying rate.
6.2 / Various approaches have been worked out to improve the retention of oral dosage forms: (i) swelling and expanding systems3, (ii) alter density dosage forms4, (iii) low density or floating drug delivery systems; (iv) bio adhesive systems5 (v) high density non-floating drug delivery system; and (vi) modified shaped systems6. Depending on the mechanism of buoyancy, two distinctly different methods viz., effervescent and non-effervescent systems have been used in the development of floating drug delivery systems (FDDS).7Effervescent drug delivery systems utilize matrices prepared with swellable polymers such as methocelor polysaccharides and effervescent components e.g., sodium bicarbonate and citric acid or tartaric acid.8
Ciprofloxacin hydrochloride is a broad spectrum anti-biotic drug. It is used as antifungal drug, in systemic infections, in treatment of leprosy, tuberculosis and other infections.Its oral bioavailability is 70% with a plasma half life is 3.5-4.5 hrs. It is rapidly and well absorbed from the gastrointestinal tract. Hence enhanced gastro retention time of ciprofloxacin hydrochloride controlled release dosage form will increase its absorption.9Hence ciprofloxacin hydrochloride is considered as a suitable candidate for the design of gastric floating drug delivery system with a view to improve its oral bioavailability.
The objective of present work is to develop and optimize GRDDS of ciprofloxacin hydrochloride, employing HPMC of different viscosity grades, carbopol and other polymers.
Review of Literature
Literature survey was carried out on the proposed research work by referring various scientific research journals, Helinet facilities and science direct.
Dave BS, Amin AF, Patel MM have formulated and evaluated gastroretentive system of Rantidine HCL using gel forming polymers like HPMC and gas generating agent like sodium bicarbonate and achieved in vitro buoyancy. Addition of citric acid and stearic acid in the formulation has achieved buoyancy under elevated pH of stomach and reduce drug dissolution due to hydrophobic nature. 10
Strubing S, Metz H, Mader K have characterized of poly vinyl acetate based floating matrix tablets, using direct compression technique. The drug release from the formulation was delayed efficiently by kolloidon SR as matrix forming excipient. All the formulations showed an increased floating strength with a higher drug/polymer ratio.11
Barhate SD, Patel MM, Deshmukh RV, Nimase PK have prepared controlled release Metronidazole loaded floating alginate beads using sodium alginate, chitosan, k-carrageenan and HPMC E5. A 33 full factorial design was used to optimize and prepare systemic model formulations.12
Sauzet C, Bruno MC, Nicolas M, Kister J, Piccerelle P, Prinderre P have developed an innovative gastro retentive floating dosage form. The technology induces a low density dosage form containing high active pharmaceutical ingredient concentration using a hydrophobic dusty powder excipient. The incorporation of hygroscopic dusty powder using a wet granulation technique represents a new alternative for the sustained release dosage form. It represents an innovative formulation for a gastro retentive platform.13
Vani M, Meena A, Savio F G, Priya M, Nancyhave prepared Ranitidine HCL floating beads by extrusion congealing technique using different percentage of gas forming agent and polymers like HPMC and sodium alginate.14
Dalavi VV, Patil JS have prepared and optimized gastro retentive system of Antiretroviral drug using a 32 factorial design. In this study the mixture of sodium bicarbonate, citric acid used as gas generating agents along with HPMC K15M as a polymer.15
Arunachalam A, Rathinraj BS, Rajveer Ch, Kumaraswamy D, Umarunnisha AM have prepared Levofloxacin hemihydrate floating tablets by using HPMC K4M, Ethyl cellulose, Sodium bicarbonate as gas generating agent. This formulation has improved in vitro bioavailability.16
Salunke P, Rane B, Bakliwal S, Pawar S have prepared floating microcarriers of Metformin HCL. The microcarriers were prepared by ionotropic gelation method by dispersing Metformin HCL with calcium carbonate and sodium bicarbonate in to a mixture of both anionic and cationic polymers containing into a solution of calcium chloride containing acetic acid.17
Sangeetha S, Sakthisaravanan V, Komala M, Harish G,Sivakumar Vhave prepared gastro retentive beads of theophylline by ionotropic gelation technique.The formulation were prepared different combinations of polymers such as sodium alginate along with guar gum, sodium alginate with hydroxyl ethyl cellulose(HEC) and gas forming agents like calcium carbonate were also added in four different concentrations.18
Nimase PK, Gali V, Ghaule PJ have prepared and evaluated multiple unit floating drug delivery system of clarithromycin. The release rate, entrapment efficiency, drug loading and buoyancy was greater with formulation containing 2% sodium alginate solution and 5% calcium chloride along with 5ml sunflower oil.19
Ranga RK, siva P, Sajeeth CI, Abdul bari MD, Santhi K have prepared gastro retentive of glipizide in the form of floating and bioadhasive tablet by direct compression method using HPMC K4M,HPMC K15M, HPMC K100M as hydrophilic polymers and carbopol 974P has bioadhesive polymer wich has prolonged retention of tablet in stomach as compared to conventional stomach specific dosage form.20
6.3 / Objectives of the study:
In the present work, studies will be carried out on the design and evaluation of gastric floating drug delivery systems of ciprofloxacin with a view to improve its oral bioavailability and increased patient compliance. The prepared formulations will be evaluated for hardness, friability, weight variation, drug content, buoyancy time, drug release profile, stability studies and drug excipient interaction
(IR spectroscopy).
7. / Materials and Methods :
7.1 / Source of Data:
Internet
Helinet facility of our affiliating university RGUHS Bangalore
International pharmaceutical journals
National pharmaceutical journals
7.2 / Drug: Ciprofloxacin hydrochloride
Viscolyzing agent: Guar gum, hydroxyl propyl methyl cellulose
Swelling agent:cross -linked polyvinyl pyrrolidine or cross-linked sodium carboxy methylcellulose.
Gas generating agent: carbonates like calcium carbonate, sodium bicarbonate or potassium hydrogen carbonate or sodium hydrogen carbonate.
Other polymers: Carbopol, chitosan,fenugreek.
Other excipients:lactose, mannitol, dextrose, sorbitol and water soluble diluents such as microcrystalline powdered cellulose or lubricants such as talc, citric acid, tartaric acid or ascorbic acid, magnesium stearate.
Equipments:
UV-visible spectrophotometer (Shimadzu 1700)
Digital cover head stirrer electronic balance
USP XXIII tablet dissolution test apparatus II
Punching machine
- pH-meter (systronic 335)
Methods:
The gastric floating matrix tablets of ciprofloxacin hydrochloride will be designed using HPMC of different viscosity grades, carbopol, sodium alginate, sodium CMC, guar gum either alone or in combination with sodium bicarbonate as gas generating agent. The prepared drug formulations will be evaluated for the hardness, friability, weight variation, drug content, buoyancy time, drug release profile, stability studies and drug excipient interactions.
a)Estimation of drug content: The drug contents of formulation will be determined spectrophotometrically.
b) Drug release study:The in vitro dissolution study will be carried out in USPXXIII tablet dissolution test apparatus employing rotating paddle and using 0.1N HCL as dissolution medium at 37±0.50C over a period of 12 hours.
c) In-vitro floating studies:Floating time and floating lag time will be determined by using USP XXIII dissolution test apparatus at 50 rpm using 900 ml of 0.1N HCL and temperature will be maintained at 37±0.50C throughout the study. The duration of floating (floating time) is the time formulation floats in medium and floating lag time is a time required for the dosage form to float to the surface of the medium.
d)Accelerated stability studies:The drug formulation will be stored at a temperature of 40±20C with 75±5% RH, 50±20C with 75±5% RH for 3 months and evaluated for drug content; the drug release profile as per ICH guidelines and drug excipient interactions [IR spectroscopy].
7.3 / Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so please describe briefly
…………………. Not under the plan of work…………………..
7.4 / Has ethical clearance have been obtained from your institution in case of 8.4?
………………….. Not applicable…………………….
8. / List of references :
1. Tayade P.Gastroretentive drugs: A review. Express Pharma Pulse 2003; 14:1-4.
2. Jose GR, Omidian H, Shah K. Progess in Gastroretentive Drug Delivery
Systems, Pharma Tech 2003;13: 152-60.
3. Vyas SP, Khar RK. Gastro Retentive Systems in: controlled drug delivery:
Concepts and Advances. 1st edn, CBS Publication, New delhi 2002; 196-
217.
4. Deshpande AA, ShahNH, Rhodes CT and Malik AW. Controlled Release Drug
Delivery Systems for Prolonged gastric residence: An overview. Pharma Res
1996; 22(6): 531-9.
5. Chickering. DE, Jacob.JS and Mathowitz E.Bio adhesive microspheres 2:
Characterisation of bio adhesion involving hard, bio erodible polymers and soft
tissues,Reactive polymers 1995; 25: 189-206.
6. Garg S, Sharma S. Review: Gastro retentive drug delivery systems. Pharma
Tech 2003; 13: 160-6.
7. Hiton AK, Desay PB. In vitro and in vivo evaluation of oral sustained release
Floating dosage form of amoxicillin trihydrate. Int J Pharm 1992; 86: 79-88.
8. Rubinatein A, Friend DR. Specific delivery to the gastrointestinaltract.
Polymeric site specific pharmacotherapy. Wiley Chichester 1992: 282-3.
9. Sweetman SC. The editor Martindale: The Complete Drug Reference.
Martindale 35th edn, Pharmaceutical Press. London2007; 218-22.
10. Dave BS, Amin AF, Patel MM. Gastroretentive drug delivery of Rantidine HCL:
Formulation and in vitro evaluation.AAPS Pharm Sci Tech 2004; 5(2): 1-9.
11. Strubing S, Metz H, Mader K. Characterization of poly(vinylacetate) based
Floating matrix tablets. J controlled Release2008; 126: 149-55.
12. Barhate SD, Dr Patel MM, Deshmukh RV, Nimase PK. Formulation and
evaluation of control release metronidazole loaded floating alginate beads
using natural polymers. J Pharm Res 2009; 2(3): 524-7.
13. Sauzet C, Clayes Bruno, Nicolas M, Kister J, Piccerelle P, Prinderre P.
An innovative floating gastroretentive dosage system: Formulation and
Invitro evaluation. Int J Pharm2009; 378: 23-9.
14. Vani M, Meena A, Savio FG, Priya M, Nancy. Design and evaluation of
gastroretentive beads of ranitidine hydrochloride. Int J Pharm Biomed Sci
2010; 1(1): 1-4.
15. Dalavi V.V, Patil J.S. Statistical optimization and development of Gastro
Retentive System of an Antiretroviral drug using a 32 factorial design. Indian J
Pharm Educ Res 2010;44(3):236-9.
16. Arunachalam A, Rathinraj BS, Rajveer Ch. Design and evaluation of
Levofloxacin hemihydrates floating tablets. Int J App Bio Pharma Tech 2010;
1(2): 260-8.
17. Salunke Poonam, Rane Bhushan, Bakliwal Sunil, Pawar Sunil. Floating
Microcarriers of an Antidiabetic drug: preparation and Its in vitro evaluation.
J Pharm Sci Tech 2010; 2(6): 230-40.
18. Sangeetha S, Shaktisaravanan V, Komala M, Harish G, Sivakumar V.
Design and evaluation of gastroretentive beads of Theophylline by Ionotropic
Gelation. Int J Pharm Phama Sci 2010; 2(3): 99-101.
19. Nimase PK, Gali V, Ghule PJ. Preparation and evaluation of multiple-unit
Floating drug delivery system of clarithromycin. Int J Pharm Res Dev2010;
2(9): 139-45.
20. Ranga RK, siva P, Sajeeth CI, Abdul bariMD, Santhi K. Formulation and
evaluation of gastroretentive floating bioadhesive tablets of glipizide. Int J Res
Pharm Sci 2011; 2(2): 252-60.
9. / Signatures of candidate / [G.PRAVEEN]
10. / Remarks of Guide / Formulation of gastro retentive drug delivery system will definitely improve the oral bioavailability of the drug. It helps in reducing the dosing frequency with improved patient compliance.
11. / Name and designation of
(in block letters)
11.1 Guide / M.V.RAMPUREM. Pharm. (Ph.D)
ASST. PROFESSOR
DEPT.OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’sCOLLEGE OF PHARMACY
GULBARGA-585105
11.2 Signature
11.3 Co-guide / S.B.SHIRSAND M. Pharm. (Ph.D)
ASST. PROFESSOR
DEPT.OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’s COLLEGE OF PHARMACY GULBARGA-585105
11.4 Signature
11.5 Head of the Department / Dr. P.V SWAMYM. pharm. Ph.D
PROFESSOR
DEPT.OF PHARMACEUTICAL TECHNOLOGY
H.K.E.S’sCOLLEGE OF PHARMACY
GULBARGA-585105
11.6 Signature
12. / 12.1 Remarks of chairman and Principal
12.2 Signature
1