Formulation and Invitro Evaluation of Captopril Floating Matrix Tablets

FORMULATION AND EVALUATION OF GASTRORETENTIVE DRUG DELIVERY SYSTEM OF LANSOPRAZOLE

M.PHARM DISSERTATION PROTOCOL

Submitted to

RajivGandhiUniversity of Health Sciences,

Bangalore, Karnataka.

Mr. Ajaya Patil

B. Pharm.

Under the Guidance

Prof. Hariprasanna R.C.

M. Pharm. (Ph. D).

DEPARTMENT OF PHARMACEUTICS

R.M.E.S’s COLLEGE OF PHARMACY,

GULBARGA-585102

2013-2014

RajivGandhiUniversity of Health Sciences, Bangalore, Karnataka.

Curriculum Development Cell

Conformation for Registration of Subject

for Dissertation

Registration No.:

Name of the Candidate: Mr.Ajaya Patil

Name of the Institution: R.M.E.S’s College of Pharmacy

Gulbarga, Karnataka.

Course of Study and Subject: M. Pharm. in Pharmaceutics

Date of Admission to the Course: 2nd August 2013

Title of the Topic : Formulation and evaluation of gastroretentive

drug delivery system of Lansoprazole

Brief resume of the intended work: Enclosed

Signature of the student:

Guide Name: Prof. Hariprasanna R.C. M.Pharm.(Ph.D)

Remarks of the Guide: Recommended for approval

Signature of the Guide:

Co-Guide Name: Prof. Basawaraj S. Patil. M.Pharm. Ph.D.

Signature of the Co-Guide:

HOD Name: Prof.M. Najmuddin. M.Pharm. Ph.D.

Signature of the HOD:

Director/Principal Name: Prof. Kishoresingh K. C. M.Pharm. Ph.D

Mobile : +919880200905

Director/Principal E-mail ID:

Remarks of Director/Principal: Recommended for approval

Director/Principal Signature:

RajivGandhiUniversity of Health Sciences, Bangalore, Karnataka

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. / Name and Address of the candidate / MR. AJAYA PATIL
Plot No. 38, Ram Nagar, Behind TV Station
Humnabad Road, Gulbarga.
Pin- 585 104
2. / Name of the Institution / R.M.E.S’s College of Pharmacy, Gulbarga, Karnataka- 585102
3. / Course of study and subject / Master of Pharmacy in Pharmaceutics
4. / Date of admission to course / 2nd August 2013
5. / Title of the topic / Formulation and evaluation of gastroretentive drug delivery system of Lansoprazole
6. / Brief resume of the intended work
6.1 Need of the study
Floating drug delivery systems were first described by Davis in 1968.1,2 It is possible to prolong the gastric residence time of drugs using these systems. Several techniques are used to design gastro retentive dosage forms. These include, floating drug delivery systems (FDDS), high-density DDS, mucoadhesive systems, swelling and expanding DDS, modified shape systems, and other delayed gastric devices.3-5
Floating drug delivery systems, also called as hydrodynamically balanced system, is an effective technology to prolong the gastric residence time in order to improve the bioavailability of the drug.6 This technology is suitable for drugs with an absorption window in the stomach or in the upper part of small intestine,7 drugs acting locally in the stomach8 and for the drugs that are poorly soluble or unstable in the intestinal fluid.9 Floating drug delivery systems have a bulk density lower than the gastric fluid and thus remain buoyant in the stomach, without affecting gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly.4 Based on the mechanism of buoyancy, two distinctly different technologies, that is non effervescent and effervescent systems, have been utilized in the development of floating drug delivery systems. The effervescent floating drug delivery systems utilize matrices prepared with swellable polymers and effervescent components eg: sodium bicarbonate and citric acid or stearic acid. The matrices are fabricated such that in the stomach carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the gellified hydrocolloid. This produces an upward motion of dosage form and maintains its buoyancy. In non-effervescent floating drug delivery systems, the drug is mixed with gel forming hydrocolloid, which swells on contact with the gastric fluid after oral administration and maintains relative integrity of shape and bulk density of less than unity within and outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms.4,10
Lansoprazole it is more potent than Omeprazole, but similar in properties. Inhibition of H+ , K+, ATPase by Lansoprazole is partly reversible. It has higher oral bioavailability, faster onset of action. Lansoprazole an proton pump inhibitor similar to omeprozole ,is used as anti-ulcer agent and enzyme inhibitor. Lansoprazole is widely used for the treatment and maintenance of healing of duodenal or gastric ulcers, erosive and reflux esophagitis, NSAID-induced ulcer,& Zollinger- Ellison syndrome .Lansoprazole is active against Helicobacter pylori . The absorption of Lansoprazole is rapid ,with Cmax occupying approximately 1.7 hours after oral dosing ,and relatively complete with absolute bioavailability over 80%.The stability of Lansoprazole is pHdependent and the rate of degradation increases with decreasing pH.The acidic environment of the stomach causes significant degradation of Lansoprazole leading to reduced bioavailability and clinical effect11.
Lansoprazole is a good candidate for gastroretentive drug delivery system. The aimed delivery system provides the prolonged release of a single dose, thereby minimizing the frequent administration and hence total dose required to elicit pharmacological activity, thereby reducing the side effects.
6.2Review of Literature:
1)BasakSC, et al.(2004).12Prepared oral floating matrix tablets of Ciprofloxacin using gas generating agent sodium bicarbonate and hydrophilic polymer hydroxy propyl methyl cellulose (HPMC). In vitro drug release study of tablets indicated controlled sustained release for Ciprofloxacin and 80-89% release at the end of 8 hours.
2)Ziyaur Rahman, et al. (2006).13Formulatedbilayer floating tablets (BFT) for captopril using different compression technology. HPMC, K-grade and effervescentmixture of citric acid and sodium bicarbonate formedthe floating layer. The release layer contained captopriland various polymers such as HPMC-K15M, PVP-K30and Carbopol 934p, alone or in combination with the drug. The floatinglag time was 10 min and the tablet remained floatablethroughout all studies.
3)Patel VF, et al. (2007).14 Prepared Monolithic floating matrix tablets of Dipyridamole by using hydrophilic polymer, polyethylene oxide and ratio of lactose to starch 1500. All formulations had total floating time of more than 12 hours. As content of polymer increased the release rate declined with increase in value of diffusion exponent giving anamolous drug release to zero order drug release (p<0.05). Lactose gave higher drug release with release mechanism towards zero order compare to starch 1500 which gave slower release with release mechanism towards diffusion based.
4)Jaimini M, et al. (2007).15 Prepared Famotidine floating tablets employing two different grades of methocel K100 and methocel K15M by effervescenttechnique; these grades of methocel were evaluated for their gel forming properties. All the prepared batchesshowed good in vitro buoyancy. The tablet swelled radially and axially during in vitro buoyancy studies. It was observedthat the tablet remained buoyant for 6-10 hours. Decrease in the citric acid level increased the floating lag time but tabletsfloated for longer duration. A combination of sodium bicarbonate (130mg) and citric acid (10mg) was found to achieveoptimum in vitro buoyancy. The tablets with methocel K100 were found to float for longer duration as compared withformulations containing methocel K15M. The drug release from the tablets was sufficiently sustained and non-Fickiantransport of the drug from tablets was confirmed.
5)Patel DM, et al. (2007).16 Prepared Carbamazepine floating tablets using melt granulation technique. Bees wax was used as hydrophobic meltable material. Hydroxy propyl methyl cellulose, sodium bicarbonate and ethyl cellulose were used as matrixing agent, gas generating agent and floating enhancer, respectively. The tablets were evaluated for in vitro buoyancy and dissolution studies. Formulation S3 was selected as a promising formulation and was fond stable at 400and 75% relative humidity for three months.
6)Thakkar VT, et al. (2008).17 Prepared Levofloxacin hemihydrate floating tablets by direct compression method using Gelucire 43/01 (hydrophobic)and hydroxypropylmethylcellulose (hydrophilic) polymer in different ratios. In vitro release study reveals that increasing the proportion of Gelucire 43/01, 5 to 40%, decreased the release rate of drug. The release rate of levofloxacin hemihydrates from matrices was mainlycontrolled by the hydrophilic and hydrophobic polymer ratio. Matrix tablet containing 25% HPMC K4M and 15% Gelucire 43/01 (F4 batch) showed a release as target profile. Optimal batch (F4) was selected byregression analysis which followed Higuchi kinetic.
7)Shweta Sharma, et al. (2009).18 Prepared Captopril floating matrix tablets with various grades of HPMC in varying ratios to formulate the floating tablets. Lactose was used as a diluent in the preparation of the tablets. Sodium bicarbonate was incorporated into the tablets to aid buoyancy of the tablets. it was concluded that the formulation F1 is the best formulations as the extent of drug release was found to be around 85 %.
8)Prajapati ST, et al. (2009).19 Floating matrix tablet of Domperidone were prepared by wet granulation technique, using polymers such as hydroxy propyl methyl cellulose K4M, carbopol 934P, and sodium alginate, either one or in combination, and other standard excipients. In vitro release mechanism was evaluated by linear regression analysis. Floating matrix tablets based on combination of three polymers namely; hydroxyl propyl methyl cellulose K4M, carbopol 934P and sodium alginate exhibited desired floating and prolonged drug release for 24 hours. Carbopol loading showed negative effect on floating properties but were found helpful to control the release rate of drug.
9)Havaldar VD, et al. (2009).20 Prepared floating matrix tablets of Atenolol by direct compression method. All the formulations, except F2, F3 and F6 showed Korsemeyer-Peppas model as the best fit model. Formulation F2 and F3 showed first order model while F6 showed zero order model. Diffusion exponent (n) value was found in the rage of 0.52-0.99 indicating diffusion as a release mechanism.
10)Danki Lingaraj S, et al. (2010).21 Prepared Hydrodynamically Balanced Systems (HBS) of Alfuzosin hydrochloride tablet using Hydroxy propyl methyl cellulose (HPMC) of different viscosity grades at three different drugs to polymer ratios, different diluents and gas generating agents by direct compression technique. The rate of drug release decreased with increased polymer concentration. It was found that HPMC viscosity had significant impact on the drug release from the prepared HBS.
11)Zawar Laxmikant R, et al. (2010).22 Prepared floating mucoadhesive tablets of Clarithromycin by directcompression using directly compressible polymers such as HPMC K4M, HPMC K15M and carbopol 974P andwere evaluated for drug - excipient compatibility, density, buoyancy test, mucoadhesion force, swelling study,drug content and in-vitro release profile. Sodium bicarbonate and citric acid were used for producingeffervescent base for buoyancy of tablets. Analysis of drug release from tablet indicates drug release by zeroorder rate kinetics.
12)Akash Yadav, et al. (2010).23 Prepared gastro retentive floating microballoons of Metformin by the emulsion solvent diffusion technique using acrylic polymers (i.e. Eudragit RS-100 and Eudragit S-100) with drug (metformin) in a mixture of ethanol, dichloromethane and propanol. The drug encapsulation efficiency was high. Incorporation of Eudragit RS-100 and Eudragit S-100 in the microballoons proved to be an effective method to achieve the desired release behavior and buoyancy.
13)Ritesh Kumar, et al. (2010).24 Formulated sustained release floating matrix tablets of Metformin hydrochloride using gas generating agent (potassium bicarbonate) and hydrophilic gelling polymer hydroxyl propyl methyl cellulose (hypromellose) by wet granulation technique. The prepared formulations were evaluated for floating time and in vitro drug release characteristics using modified dissolution method. All formulations possessed good floating properties with total floating time more than 12 hours. Formulations with high amount of hypromellose were found to float for longer duration and provide more sustained release of drug. The formulated drug delivery system was found to be independent of pH. Release kinetics of formulations followed Higuchi model with anomalous non-fickian diffusion.
14)Sudhir Kumar Yadav, et al. (2010).25 Prepared floating tablets of Ranitidine hydrochloride by direct compression method using natural and synthetic polymers. The drug release kinetic was fitted in three different mathematical models like- Zero order,Higuchi and Korsmeyer-Peppas model. The results indicate that the drug release mechanismwas found fickian diffusion type in most of the formulations.
15)Anilkumar Shinde J, et al. (2010).26 Sustained release of floating tablets of Cephalexin were formulated employing the hydrophilic polymer hydroxy propyl methyl cellulose (HPMC), gas generating agentsodium bicarbonate and citric acid. The tabletscontaining CFL released 72.28 to 99.461 % of drug at the end of 12 hrs by in vitro release study. The drug release from the tablets was sufficientlysustained followed the Korsmeyer and Peppas model controlled mechanism of cephalexin tablet.
16)Gupta SK, et al. (2010).27 Prepared floating tablets of Acyclovir containing polyvinylpyrrolidon (PVP), polyvinyl alcohol (PVA) and hydroxy propyl methyl cellulose (HPMC) as the polymers and sodium bicarbonate as a gasgenerating agent, to reduce floating lag time and tablets were prepared by wet granulation method. On the basis of evaluation parameter formulation AV4 selected as developedformulation.
17)Lakshmi Narasaiah V, et al. (2010).28 Formulated Sumatriptan Succinate floating tablets by wet granulation method using hydroxy propyl methyl cellulose (HPMC) as gel forming agent and sodium bicarbonate and citric acid were incorporated as gas generating agents. The drug release for all the formulations were followed by zero order kinetics andPeppas modeling. The diffusion exponent of formulations was found (n<0.89) to be nonfickian(Anomalous) diffusion mechanism.
6.3 Objectives of the study
The present research investigation is planed with the following objectives.
1)To formulate gastroretentive drug delivery system of Lansoprazole using different polymers.
2)To evaluate the formulations with respect to various physical parameters.
3)To evaluate the formulations with respect to content uniformity, floating capacity, water uptake study, in-vitro dissolution study etc.
4)The release data will fit into different kinetic models.
5)To characterize the formulation by instrumental methods like FTIR and DSC.
6)To perform the stability studies on promised formulation as per ICH guidelines
7. / Materials and Methods:
Materials
Drug:Lansoprazole.
Excipients:

Hydroxy propyl methyl cellulose (HPMC K4 M).
Methyl cellulose.
Chitosan.
Guar gum.
Xanthan gum.
Citric acid.
Sodium bicarbonate.
Lactose.
Talc.
Magnesium stearate.
Ethyl cellulose.
Polypropylene foam powder etc.

Equipments:

Dissolution test apparatus
Disintegration test apparatus
UV spectrophotometer
Monsanto hardness tester
Roche friabilator
Electronic balance
Single pan digital balance
Tablet punching machine
Sieves
FTIR spectrophotometer & DSC.

Methods:
Lansoprazolegastroretentive drug delivery system will be prepared by one of the following method.

Direct compression method: In this method drug, polymers and other additives were weighed accurately and mixed well to get uniform mixture and thus obtained blend is compressed by using 10 station rotary tablet punching machine. (Clit Ahmedabad).

Hot melt extrusion method: In this method, a mixture of drug, polymers, thermal lubricants, sodium bicarbonate and/or MCC was first blended. The blended powder was placed in the hopper of single- screw extruder and extruded at different temperatures. After melt processing, the extrudates were cool at room temperature for 48 hours and then manually cut into tablets.

Effervescent technique: In this method, a drug mixed with polymer, gas generating agent and other excipients. Isopropyl alcohol was added drop wise then wet mass was passed through sieve 40#. Dry the granules at room temperature for 1 hour and then blended with talc and magnesium stearate and compressed in rotary tablet compression machine.

7.3Evaluation parameters: (pre and post compression)29,30.

Bulk density and tap densities: Exactly 50 gm of powder blend will weigh on chemical balance and transferred into a 100 ml measuring cylinder. The cylinder was dropped on a wooden platform from a height of 2.5 cm three times at 2 seconds interval. The volume occupied by the granules will record as the bulk volume. The cylinder will then tap on the wooden platform until the volume occupied by the powder blend remained constant. This will repeat three times for granules. The data generated will use in calculating the Carr’s compressibility index and Hausner’s ratio.

Angle of repose: 50 gm of the powder blend will placed in a plugged glass funnel which had a distance of 10 cm from the flat surface. The granules will then allow to flow through the 8 mm funnel orifice by removing the cotton plug from the funnel orifice. The height of the heap (h) formed as well as the radius of the heap (r) will be noted.

Tablet thickness: The thickness of 10 tablets each selected at random from the formulated tablets will determine using a vernier caliper and the mean of these readings will taken as the mean tablets thickness.

Tablet weight uniformity: Twenty tablets will weighindividually using a digital balance with the precision of 0.05 mg and readability of 0.1 mg, from which the mean will calculate and percentage deviations determine.

Hardness (Crushing strength): The crushing strengths of tablets will determine individually with the Monsanto hardness tester, following 10 tablets will use and the mean crushing strength will calculate.

Friability: The friability of 10 tablets will determine using Roche friabilator (Electrolab, Mumbai). This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets will place in the friabilator and will subject to 100 revolutions. Tablets will dedust using a soft muslin cloth and reweigh.
Disintegration test: The disintegration time of tablets will determine according to the method described in the British Pharmacopoeia 1998. Six tablets will place in each compartment of the disintegration apparatus, with water thermostatedat 37 ± 10 C as the medium. The tablets will consider to have passed the test after the 6 tablets passed through the mesh of the apparatus.

Drug content uniformity: The drug content of the matrices will determine in triplicate by equilibrating an accurately weigh quantity of the Lansoprazole in appropriate dissolution medium. The samples will filter, suitably diluted and assayed spectrophotometrically.

In-vitro dissolution studies: Release of drug, from the tablet will determine by usingUSP paddle method. The dissolution rate will study using 900 ml appropriate dissolution medium and scanned in the UV-Visible spectrophotometer.

Drug polymer interaction study: The drug and different polymers will be used in this research work. There will be a chance of interaction between drug and polymer. To know any interaction between drug and polymer we planned to check it by FTIR and DSC studies.

Swelling index: The individual tablets were weighed accurately and kept in 50 ml of double distilled water. Tablets were taken out carefully after 60 minutes, blotted with filter paper to remove the water present on the surface and weighed accurately. Percentage swelling index (SI) was calculated by using the formula SI = (Wet weight – Dry weight / Dry weight) X 100.31

Buoyancy determination: Floating time was determined by using USP dissolution apparatus at 100 rpm using 900 ml of 0.1N HCL and temperature was maintained at 37 ± 0.50 C throughout the study. The duration of floating (floating time) is the time the tablet floats in the dissolution medium (including buoyancy lag time).

Stability studies: On selected fabricated tablets will strip pack and kept at 450 C with 75% RH. Samples will withdraw at 0, 15, 30 and 45 days for evaluation of appearance, drug content and in- vitro drug release.