FORMULATION AND EVALUATION OF MUCOADHESIVE IN SITU GEL CONTAINING H2 RECEPTOR ANTAGONIST FOR STOMACH SPECIFIC ULCER THERAPY
M.pharm dissertation protocol submitted to
Rajiv Gandhi University of Health Science
Karnataka, Bangalore – 560041
By
Mr. LALAKIA KEYUR H. B.Pharm
Under the Guidance of
Dr. B. PRAKASH RAO M. Pharm, Ph.D
Professor and HOD
Dept. of Industrial Pharmacy
Department of Industrial Pharmacy
Acharya & B.M.Reddy College of Pharmacy
Soldevanahalli,
Hesaraghatta main road,
Chikkabanavara (Post), Bangalore – 560 090
2009 – 2010
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1 / Name and address of candidate / Mr. LALAKIA KEYUR H.“Shiv-Dhara I” appartment, Block no.-201,
Mayani chowk,
Behind Backbone shopping centre,
Mahadev wadi main road,
Rajkot(Gujarat).
Pin- 360 004.
2 / Name of institution / ACHARYA & B.M. REDDY COLLEGE OF
PHARMACY.
Soldevanahalli, Hesaraghatta Main Road,
Chikkabanavara Post.
Bangalore-560090
3 / Course of study and subject / M. Pharm
(Industrial Pharmacy)
4 / Date of admission /
2nd May-2009
5 / Title of the project / FORMULATION AND EVALUATION OF MUCOADHESIVE IN SITU GEL CONTAINING H2 RECEPTOR ANTAGONIST FOR STOMACH SPECIFIC ULCER THERAPY6
6.1 / BRIEF RESUME OF INTENDED WORK
NEED FOR THE STUDY:
In situ gel forming drug delivery systems are in principle capable of releasing drug molecule in a sustained manner affording relatively constant plasma profiles. These hydrogels are liquid at room temperature but undergo gelation when in contact with body fluids or change in pH. These have a characteristic property of temperature dependent, pH dependent and cation induced gelation. Compared to conventional controlled release formulations, in situ forming drug delivery systems possess potential advantages like simple manufacturing processes and ease of administration.
Intimate contact of a delivery system at the absorbing site maximizes not only drug absorption, but also influences the rate of drug absorption. These in situ gel preparations can be easily formulated in bulk and these formulations give homogeneity of drug distribution when compared to other conventional suspensions. These in situ gels also have good mucoadhesion property, which helps in coating of the ulcer lining once the solution comes in contact with the gastric pH.
The H2-receptor antagonists (H2RA, often shortened to H2 antagonist) are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. Famotidine, ranitidine, cimetidine, nizatidine, roxatidine are some examples of H2RA. H2 antagonists are clinically used in the treatment of acid-related gastrointestinal conditions like peptic ulcer diseases (PUD), dyspepsia, gastro esophageal reflux disease (GERD) and stress induced ulcer. Some patients with reflux oesophagitis who are being treated with proton pump inhibitor may continue to produce acid in the night (nocturnal acid breakthrough) and could be benefited by taking a sustained release formulation of H2 receptor antagonist.
It is also reported that oral treatment of gastric disorders with an H2-antagonist like ranitidine or famotidine used in combination with antacids promotes local delivery of these drugs, also increases stomach wall receptor site bioavailability and increases the efficacy of drugs to reduced acid secretion. Several approaches are currently used to prolong gastric retention time. Among them the principle of bioadhesive preparations offers a simple and practical approach to achieve increased gastric residence time for the dosage form and sustained drug release.
In the present study, an attempt was made to prepare a formulation and its evaluation of in situ gel forming drug delivery system containing H2 receptor antagonist for oral delivery by using different polymers.
6.2
6.2.1
/ REVIEW OF LITERATURE:-
Review of work done on in situ gelling system
Ø Oral administration of aqueous solutions of either gellan gum (1.0 %, w/v) or sodium alginate (1.5 %, w/v) containing calcium ions in complexed form resulted in the formation of gel depots in rabbit and rat stomachs as a consequence of the release of the calcium ions in the acidic environment. In vitro release studies showed diffusion controlled release and also the bioavailability was found to be similar like that of a commercial marketed suspension.1
Ø Insitu gelling system for paracetamol was prepared to enhance its bioavailability. According to the study the potential of xyloglucan formulation with in situ gelling properties for oral sustained delivery of paracetamol was evaluated. Gelation of dilute aqueous solutions in rabbits and rats stomach was seen after in vitro release studies and also bioavailability was similar to that of a commercially available suspension.2
Ø Dilute aqueous solutions (1 % & 2 % w/v) of low methoxy pectin formulation was evaluated for its potential to form in situ gels of paracetamol for sustained delivery in the presence of complexed calcium ions. Diffusion controlled release was seen for a period of six hours after the in vitro release studies. In situ gels formed in rat stomach showed 96 % bioavailability of paracetamol with appreciably lower peak plasma levels.3
Ø Theophylline insitu gel was prepared and its release kinetics was determined by in vitro release study. After administration of 1 % (w/v) aqueous solutions of gellan gum to rats and rabbits in situ gel was formed in presence of complexed calcium ions. In vitro release studies of theophylline from the gellan gels followed root time kinetics for a period of six hours. Bioavailability was increased from four to five fold in the in situ gels formed in rats and rabbits stomach compared to that of a commercial oral formulation.4
Ø Novel chitosan-glyceryl monooleate (GMO) in situ gel system for sustained drug delivery & targeting was developed. The delivery system consisted of 3 % (w/v) chitosan & 3 % (w/v) glyceryl monooleatein 0.33M citric acid. In situ gel was formed at a biological pH & in vitro release studies were conducted in Sorensen’s phosphate buffer (pH 7.4). Characterization of the gel included the
effect of cross-linker, determination of diffusion coefficient and water uptake by thermo gravimetric analysis (TGA). Incorporation of a cross-linker (glutaraldehyde) retarded the rate and extent of drug release. Drug release from the gel followed a matrix diffusion controlled mechanism.5
Ø Here, three different liquid formulations containing cimetidine were used like (a) enzyme-degraded xyloglucan, (b) gellan gum and; (c) sodium alginate has been assessed for their potential for the in situ gelling properties of oral delivery of cimetidine. The in vitro release of cimetidine from gels followed root-time kinetics over a period of six hours. Plasma levels of cimetidine of each of the formulations were compared with those resulting from administration of a commercial cimetidine/alginate suspension with an identical drug loading.6
Ø Here, pectin was used as gel forming agent. Gels formed in situ following oral administration of dilute aqueous solutions of pectin (1.0 and 1.5 %, w/v) containing calcium ions in complexed form to rats was evaluated as vehicles for the sustained release of the expectorant drug ambroxol hydrochloride. A bioavailability of approximately 64 % of that of a commercially available formulation was achieved from gels containing an identical dose of ambroxol formed in situ in the stomachs of rats, with appreciably lower peak plasma levels, diffusion controlled and sustained release of drug over a period of at least six hours.7
Ø In-vitro and in vivo release of paracetamol and ambroxol by the influence of different polyhydric alcohols like xylitol, mannitol and sorbitol in different concentration of in situ gelling pectin formulations was examined. 2 % (w/v) pectin gels containing 10 % (w/v) sorbitol showed a sustained release of paracetamol and bioavailability of approximately 90 % was seen. Sustained release of ambroxol with pectin concentrations of 1.5 and 1 % (w/v) and a sorbitol concentration of 10 % (w/v) was seen.8
Ø Insitu gelling alginates formulations as an alternative to incorporation of various excipients N4- alkoxy carbonyl cytosine derivatives possessing various physicochemical properties and cytosine regeneration rates was being examined to modify release rate and kinetics. Release rate constants and square root of solubility showed a linear relationship for suspension. A zero order release of parent cytosine was observed from in situ gelling suspension and diffusion co-efficient calculated was observed to be similar for suspension and solution.9
Ø Comparison of the gelation and drug release characteristics of formulations of pectin with high (31%) and low (9%) degrees of methoxylation over a wide pH range (pH 1.2-5.0) was done in this work. Gelation of formulations of pectin with a degree of esterification of 9% (DE9) was observed over the pH range 2.5-5.0 in the presence of 1.6mM Ca (++), but was incomplete in formulations of pectin with a degree of esterification of 31% (DE31). A sustained release of ambroxol was observed following oral administration of pectin DE9 formulations to gastric-acidity controlled rabbits at pH 5.5-5.7 and visual observation of the stomach contents of these rabbits confirmed in situ gelation of these formulations.10
Ø The influence of a variation of gastric pH & addition of a taste masking agent on gelation of pectin solutions & on in vitro/in vivo release of acetaminophen from gels was studied. Increase of pH above 2.5 & addition of 10% (w/v) D-sorbitol significantly affected ability of 1.5% (w/v) pectin solutions to form coherent gels in vitro. Gelation of sorbitol-free formulations was observed at pH 1.2 & in vitro release of acetaminophen from gel followed diffusion-controlled kinetics; in vitro gelation was incomplete at pH 3.0 resulting in poor sustained release characteristics. While D-sorbitol inhibited in vitro gelation & noted poor sustained release properties.11
Ø A thermo sensitive in situ gelling and mucoadhesive ophthalmic drug delivery system containing puerarin based on poloxamer analogs (21% (w/v) poloxamer 407/5% (w/v) poloxamer 188) and carbopol (0.1% (w/v) or 0.2% (w/v) carbopol 1342P NF) was developed. The combined solutions would convert to firm gels under physiological condition and attach to the ocular mucosal surface for a relative long time. In vitro release studies demonstrated diffusion-controlled release of puerarin from the combined solutions over a period of 8h. In vivo evaluation indicated the combined solutions had better ability to retain drug than poloxamer analogs or carbopol alone.12
Ø Biodegradable glucose-sensitive in situ gelling system based on chitosan for pulsatile delivery of insulin was developed. The sols/gels were thoroughly characterized for swelling properties, rheology, texture analysis and water content. Insulin load onto the gels was optimized and was found to affect the rheological behavior of these gels, the final preparation used for in vitro contained 1IU/200mul of the sol. These gels released the entrapped insulin in a pulsatile manner in response to the glucose concentration in vitro. The formulations also evaluated for their in vivo efficacy in streptozotocin induced diabetic rats at a dose of 3IU/kg.13
Ø Here, insitu gel was developed by using Pluronic F-127 and PF-127. The use of high viscosity hydromiscible vehicles such as hydrophilic gels, is one of various approaches for controlled drug delivery, and represents an important area of pharmaceutical research and development. Of these systems, PF-127 provides the pharmacist with an excellent drug delivery system for a number of routes of administration and is compatible with many different substances. Gels containing penetration enhancers have proven to be especially popular for administering anti-inflammatory medications since they are relatively easy to prepare & very efficacious.14
Ø The gelation behavior of concentrated micellar solutions of mixtures of a block copolymer of ethylene oxide and styrene oxide (E(137)S(18)E(137)) with one of ethylene oxide and propylene oxide (E(62)P(39)E(62)) have been investigated . Over a wide range of compositions, up to 90 wt.% E(137)S(18)E(137) in the mixture, gelation resembled that of solutions of E(62)P(39)E(62) alone, i.e. they gelled on heating from ambient to body temperature. In related experiments, using the aromatic drug griseofulvin as a comparative standard, it was demonstrated that solubilisation efficiency of dilute micellar solutions of the mixtures with 80 wt.% or more E(137)S(18)E(137) approached that of solutions of E(137)S(18)E(137) alone.15
Ø An ophthalmic delivery system of an anti-inflammatory drug, indomethacin for the treatment of uveitis based on the concept of pH induced in situ gelation was formulated and evaluated. The carbopol solutions which are acidic and less viscous, transform into stiff gels upon increase in pH of eye was used as the gelling agents and its combination with hydroxypropylmethylcellulose-K under 15 M, a well known ocular viscosity enhancing agent. The enhanced therapeutic efficacy and sustained release of indomethacin over 8 hour period make them an excellent candidate for in situ gelling ocular delivery systems.16
6.2.2 / Review of work done on H2 receptor antagonist
Ø A novel w/o/w emulsion-spray drying method was developed to prepare chitosan microspheres with a sustained drug release pattern. Release of the model drugs cimetidine and famotidine, from the microspheres prepared by the emulsion-spray drying methods, was greatly retarded with release lasting for several hours, compared with drug loaded microspheres prepared by conventional-spray drying or emulsion methods where drug release was almost instant. The slow release of drug was partly due to the poor wetting ability of the microspheres which floated on the surface of the dissolution medium.17
Ø In this formulation, gastro retentive drug delivery system of famotidine was prepared. Floating tablets of famotidine 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. Floating tablets were evaluated for uniformity of weight, hardness, friability, drug content, in vitro buoyancy and dissolution studies. Effect of citric acid on drug release profile & floating properties was investigated.18
Ø In the present work, a gastro-retentive in situ gelling liquid formulation for controlled delivery of ranitidine was formulated using sodium alginate, calcium carbonate and ranitidine. Prapared formulations were evaluated for buoyancy lag time, viscosity, drug content and drug release. Analysis of the release pattern showed that the drug release from the in situ gel follows a diffusion mechanism.19
Ø The purpose of present research work was to prepare calcium alginate beads containing water-soluble drug famotidine to prolong gastric residence time, target peptic ulcer and increase drug bioavailability. The floating bead formulations were prepared by dispersing famotidine together with calcium carbonate into a mixture of sodium alginate and hydroxy propyl methyl cellulose solution and then dripping the dispersion into a solution of calcium chloride. Calcium alginate beads were formed, as alginate undergoes ionotropic gelation by calcium ions and carbon dioxide develops from the reaction of carbonate salts with acid.20