DESIGN AND CHARACTERISATION OF SUSTAINED RELEASE MUCOADHESIVE MICROSPHERES OF H2 ANTAGONIST
M.Pharm dissertation protocol submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560041
By
Miss. BHARANI KOMARRAJUB.Pharm
Under the Guidance of
Mrs. A.GEETHA LAKSHMIM.Pharm, (Ph.D)
Asst.Professor
Department of Industrial Pharmacy
Acharya & B.M.Reddy College of Pharmacy
Soldevanahalli,Chikkabanavara (Post),
Hesaraghatta main road, Bangalore – 560 090.
2010– 2012
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1 / Name and address of candidate / Miss.Bharani KomarrajuFlat no.-402, Plot no.-56,
Poojitha Apartments,
Rajiv nagar, Yousufguda,
Hyderabad-500045,
Andhra pradesh.
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 /
18-09-2010
5 / Title of the project / DESIGN AND CHARACTERISATION OF SUSTAINED RELEASE MUCOADHESIVE MICROSPHERES OFH2 ANTAGONIST
6
6.1 / BRIEF RESUME OF INTENDED WORK
NEED FOR THE STUDY:
H2 antagonists are a class of drugs that competitively inhibit H2 receptors on the parietal cells that are responsible for the gastric acid secretion and thus block the actions of histamine.H2 antagonists are clinically used in the treatment ofacid-related gastrointestinal conditions like peptic ulcer diseases (PUD), dyspepsia, gastro esophageal reflux disease (GERD) and stress induced ulcer. The various medications for the treatment includes antacids, H2 antagonists, PPI’s and antibiotics in case of H.pylori associated1.
The clinical therapy for the G.E.R.D by H2 antagonists is the worldwide accepted therapy and hence there is a continued effort to improve the pharmaceutical formulations of H2 receptor antagonists in order to achieve an optimized therapy. The current medication for the G.E.R.D includes the conventional solid dosage forms i.e., tablets, capsules and rarely injections2.
The H2 antagonists competitively inhibit the H2 receptors on the parietal cells and suppress the basal and food stimulated acid secretion which is not only induced by histamine, cholinergic stimulation and food but also promote healing of duodenal and gastric ulcers. The rank order of potency of H2 antagonists is nizatidine> famotidine> ranitidine> cimetidine1.
Among all routes of drug administration, the oral route constitutes the most convenient and preferred means of drug delivery to the systemic circulation of the body. The popularity of the oral route is attributed to patient acceptance, ease of administration, accurate dosing, cost-effective manufacturing methods and generally improved shelf-life of the product.
Mucoadhesive drug delivery systems are the principal drug delivery system that have attained a prominent importance in the present days and are capable of releasing the drug substance in a sustained manner and affords to maintain the constant plasma profiles. Mucoadhesion process in the recent days has attained a much more prominent role in the design of gastroretentive drug delivery systems where in the drug actions can be improvedAs the gastric layer contains an underlying mucosal layer, supply of drugs as mucoadhesive drug delivery systems would be much beneficial.
Among the mucoadhesive drug delivery systems, mucoadhesive microspheres, one of
the multiparticulate drug delivery systems that prolong the residence time at the site of application or absorption and facilitates an intimate contact with the underlying absorption surface and improves the therapeutic performance of the drug, by enhancing the bioavailability of the drug and drug release for an extended period of time thereby reduces the frequency of dosing. The absorption of the drug from
the site is rapid because of the enormous blood supply and good blood flow rates. The dose of the drug can also be decreased and hence, the toxicity when compared to conventional therapy3,4.
The criteria for a particular drug to be formulated as gastro retentive mucoadhesive drug delivery system are listed as follows:
Drugs that are primarily absorbed in the stomach
Drugs with narrow window of absorption
Drugs that act locally in the stomach and
Also those drugs that get degraded in the colon.
In the present study, an attempt will be made to design and characterise the muco adhesive drug delivery system containing H2 receptor antagonist for its sustained drug delivery.
6.2 / REVIEW OF LITERATURE:-
1) Venkateswaramurthy Net al., worked on formulation and evaluation of in vitro performances of mucoadhesive furazolidone microspheres for the potential use of treating gastric and duodenal ulcers associated withH.pylori. Microspheres were prepared by simple emulsification phase separation technique using eudragit RS100 as matrix and carbapol 974P and HPMC K4M as mucoadhesive polymers. The drug release from the microspheres was sustained upto a period of about 12 hours5.
2) Radi Hejazi et al., examined the effect of chemical crosslinking of chitosan microspheres on gastric residence time and local tetracycline concentrations following oral administration in fasting gerbils .Stomach tetracycline concentrations were determined using tritiated tetracycline loaded cross linked microspheres. It was observed that tetracycline concentration profile in the stomach from the cross linked microspheres formulation was higher than that of the aqueous solution and the non- cross linked microsphere formulation. The AUCs for tetracycline solution, non- cross linked chitosan microspheres and chitosan cross linked microspheres were compared and was found to be greater for the cross linked microspheres. The results concluded that those microspheres prepared by the chemical cross linking provide a longer residence time than either tetracycline solution or those prepared by ionic precipitation6.
3) Cuna Met al., carried out a work on mucoadhesive microparticles containing amoxycillin-resin complexes to increase the efficacy of amoxycillin in the treatment of peptic ulcers, by ion-exchange resin encapsulation using muco-adhesive polymers like polycarbophil and carbopol 934 for achieving targeted drug delivery in the gastric mucosa and prolonged drug release. A modified oil-in-oil solvent evaporation technique was employed in the preparation of the microspheres and the prepared microspheres were evaluated for various parameters. The gastrointestinal transit was investigatedin rats by flourescence microscopy and was found that the gastric residence time was longer and the distribution of particles on mucosa was apparently better without any polymer coating. Much of the prominent differences in the gastric residence time as a regard of the quantity of the polymer administered7.
4) Yuanfen Liu et al., studied the gastroretentive drug delivery of glyceryl mono oleate coated hollow bioadhesive microspheres to lengthen the drug retention time in the stomach. Ethyl cellulose was used as matrix and eudragit EPO was employed to modulate the release rate and glyceryl mono
oleate as the bioadhesive polymer. The in vitro release test showed that the release rate of the drug from microspheres was pH dependent and was not influenced by the glyceryl monooleate coating film, but it showed strong muco adhesive properties. Since the half-life time of the bioadhesive microspheres was prolonged and elimination rate was decreased, the conclusions were drawn that this type of the mucoadhesive drug delivery system might beadvantageous in the treatment of the stomach diseases8.
5) Sinha VR et al., reviewed on chitosan microspheres as a potential carrier for various drugs and observed that chitosan as a biodegradable natural polymer with great potential for pharmaceutical applications due to its biocompatibility, high charge density, non-toxicity and mucoadhesion. It not only improves the dissolution of poorly soluble drugs but also exerts a significant effect on fat metabolism. The gellingproperty of chitosan allows a wide range of applications such as coating of many pharmaceuticals and microencapsulation of various drugs9.
6) Maria Palmira DGet al., reviewed the importance of mucoadhesive drug delivery systems in the development of new pharmaceuticals. Mucoadhesive systems are those that remain in close contact with the absorption tissue, the mucous membrane, releasing the drug at the action site leading to a bioavailability increase and both local and systemic effects.The phenomena of mucoadhesion can be explained using electronic, adsorption, wettability, diffusion, fracture and mechanical. The various polymers used in the mucoadhesive drug delivery systems are chitosan, HPMC. HEC etc., are used10.
7) Rajeshwar Kamal KAet al., studied the preparation and characterization of mucoadhesive microspheres with famotidine as the model drug. The microspheres were prepared by w/o emulsification solvent evaporation method using mucoadhesive polymers Sod. CMC and a release controlling polymer sodium alginate. The prepared microspheres exhibited prolonged drug release for more than 8 hours and it was also found that as theconcentration of Sod. CMC was increased, mucoadhesion also increased and the drug release rate decreased at higher concentrations of sodium alginate11.
8) Govender S et al., employed a Box-Behnken experimental design to statistically optimise the formulation parameters of a tetracycline microsphere preparation for maximum bioadhesivity and
controlled drug release. A formulation comprising of 3% (w/w) chitosan, 10% (w/w) tetracycline HCl
and 9% (w/v) tripolyphosphate was identified for maximising bioadhesivity and obtaining controlled drug release.Kinetic models revealed that drug release followed Fickian diffusion while textural analysis showed minimal hydration over the test period. Thermal analyses showed a possible interaction between the drug and polymer. Scanning electron microscopy confirmed the integrity of the microspheres and identified the morphological changes following drug release12.
9) Ji-Shan Quan et al., aimed a study using eudragit–cysteine conjugate to coat on chitosan microspheres (CMs) fordeveloping an oral protein drug delivery system, having mucoadhesive and pH-sensitive property. Bovineserum albumin (BSA) as a protein model drug was loaded in thiolated eudragit-coated CMs (TECMs) tostudy the release character of the delivery system. After thiolated eudragit coating, it was found that therelease rate of BSA from BSA-loaded TECMs was observably suppressed at pH 2.0 PBS solution, whileat pH 7.4 PBS solution the BSA can be sustainingly released for several hours. The mucoadhesive property ofTECMswas evaluated and compared with CMs and eudragit-coated chitosan microspheres (ECMs). Itwasconfirmed that after coating thiolated Eudragit, the percentage of TECMs remained on the isolated porcineintestinal mucosa surface was significantly higher than those of CMs and ECMs. This study also suggested thatTECMs had comparatively stronger mucoadhesive characters13.
10) Shiva Kumar Yet al., designed and characterized amoxicillin trihydrate muco adhesive microspheres for prolonged gastric retention for the treatment of H.pylori induced peptic and duodenal ulcers with ethyl cellulose as a matrix and carbapol 934P as a mucoadhesive polymer. The microspheres were prepared by emulsification/ evaporation method. The formulation with less amount of ethyl cellulose showed more mucoadhesive property and high cumulative amount of the drug release of about 91.12% and the drug release was also maintained for longer time14.
11) Bhabani NSet al., developed a new sustained release microencapsulated drug delivery system employing sustained release mucoadhesive polymers to enhance the gastro retentive drug delivery. The microcapsules of famotidine were formulated by orifice ionic gelation technique and were evaluated for various parameters including the drug release study and the wash off study for mucoadhesive study. Formulation containing drug:polymer combination of 1:3 with polymer combination of Sod.CMC and carbapol934 was found to be the best formulation with a slow release
of famotidine over 9 h. This showed that combination of polymers instead of single polymer may be
an effective strategy in the design and development of famotidine mucoadhesive microcapsules15.
12) Patil PBet al., prepared and evaluated mucoadhesive microspheres of atenolol and propranolol by an interpolymer complexation of poly (acrylic acid) PAA with PVP to increase the gastric residence time by solvent evaporation method. The release rate of atenolol from the PAA/PVP complex microspheres was significantly slower than the PVP microspheres at pH 2 and 6.8. This suggests that the PVP/PAA microspheres can be used as a drug delivery system for the treatment of the gastric diseases16.
13) Ping He et al., studied the mucoadhesive properties of chitosan and chitosan microspheres and were evaluated by studying the interactionbetween mucin and chitosan in aqueous solution by turbidimetric measurements. It was found that the extent of mucusadsorption was proportional to the absolute values of the positive zeta potential of chitosan microspheres andnegative ‘zeta potential’ of mucus glycoprotein. Factors leading to a reduction or a reversal of these absolute values(e.g. different crosslinking levels of chitosan microspheres, different types of mucin, different pH, or ionic strength ofthe medium used) led to a reduction in the amount adsorbed17.
14) Raffin RP et al.,carried out a work on preparation, characterisation, and in vivoanti-ulcer evaluation of pantoprazole which is an important drug in the treatment of acid-related disorders. The gastro-resistant pantoprazole-loaded microparticles were prepared using an O/O emulsification/solvent evaporation technique using eudragit S100.The in vivoactivity of the pantoprazole-loaded eudragit S100 microparticles was carried out in rats and the studies showed that the microparticles were able to protect rat stomachs against ulcer formation, which was not the case with the drug aqueoussolution. Drug dissolution profiles from tablets demonstrated slower release than untabletted microparticles. Weibull equation was found to be the best model for the drug release profiles for both microparticles and tablets18.
6.3 / OBJECTIVES OF THE STUDY:
The objectives of the present study are following:-
To design and formulate sustained release mucoadhesive microspheres of H2 antagonist drug.
To characterize the formulated sustained release mucoadhesive microspheres for various parameters.
To carry out the stability studies on the optimized formulation as per the ICH guidelines.
To carry out in vivo studies with the optimized formulation and to compare this with the conventional dosage forms in the market.
7.0
7.1
7.2 / MATERIALS AND METHODS:
SOURCE OF DATA:
1) Review of literature from:
a. Journals – such as
- International Journal of Pharmaceutics
- International Journal of Pharmacy and Pharmaceutical sciences
- European Journal of Pharmaceutics and biopharmaceutics.
- Journal of controlled release
- International Journal of Pharmaceutical sciences and Drug Research etc.
- Essentials of medical pharmacology, 6th edition- K D Tripathi.
- Targeted & Controlled Drug Delivery- Novel Carrier Systems, S P Vyas & R K Khar
- J-Gate@Helinet
DRUG: H2 receptor antagonist.
POLYMERS: Biodegradable polymers like chitosan, eudragit; non biodegradable polymers
like HPMC, Sod.CMC, ethyl cellulose, carbopol, etc.
EXCIPIENTS: excipients as required.
METHOD OF COLLECTION OF DATA:
Selection of the drug and other excipients.
Authentification of the drug and excipients.
Characterisation of drug and excipients for intended formulations and to carry out the compatability studies for selected drugs and polymers by FTIR.
To carry out the pre-formulation parameters like angle of repose, bulk density, etc.
Formulation of sustained release mucoadhesive microspheres using suitable methodology which may include any one of the following methods like-
Emulsification-solvent diffusion technique or solvent evaporation technique or Ionic-precipitation and chemical cross linking technique orInterpolymer complexation and solvent diffusion method orWet phase inversion method orSpray drying method or any other standard method as suitable.
The evaluation parameters include
Micromeritic properties- particle size analysis, determination of shape and surface morphology by Scanning Electron Microscopy.
Entrapment efficacy
Drug content estimation
In vitro evaluation of mucoadhesiveness
Drug release studies and kinetics and any other as required.
Analysis of in vitro drug release data by pharmacokinetic models such as Higuche, Peppas, first-order, zero order, etc.
To carry out in vivo studies on the optimised formulation
Stability studies on the optimized formulation as per ICH guidelines at 30±2°C (65±5% RH) and 40±2°C (75±5% RH).
7.3
7.4 / DOES THE STUDY REQUIRE ANY INVESTIGATION TO BE CONDUCTED ON PATIENT OR OTHER HUMANS OR ANIMALS?
“ YES”
Has ethical clearance been obtained from your institution in case of 7.3?
“ OBTAINED”
8 / LIST OF REFERENCES:-
1)Sharma HL, Sharma KK. Histamine, Serotonin, Bradykinin and their antagonists, Treatment of gastric acidity, peptic ulcer and gastroesophageal reflux disease. In: Principles of Pharmacology. Hyderabad:Paras Medical Publisher;2007. P.346, 386-93.
2)Shaji S, Pasha ST, Srinivasan S, Ray S. Design and optimization of a multiparticulate gastroretentive dosage form for better control of gastric acidity. J Pharm Sci.Tech 2009; 1(1):40-7.
3)Harshad Parmar, Sunil Bakliwal, Nayan Gujarathi, Bhushan Rane, Sunil Pawar. Different methods of formulation and evaluation of mucoadhesive microspheres. IJABPT 2010; 1(3):1157-67.
4)Gavin Andrews P, Thomas Laverty P, David Jones S. Mucoadhesive polymeric platforms for controlled drug delivery. Eur J Pharmaceut Biopharmaceut. 2009; 71:505-18.
5)Venkateswaramurthy N, Sambathkumar R, Vijayabaskaran M, Preumal P. Formulation and in vitro evaluation of Furazolidone mucoadhesive microspheres. IJPPS 2010; 2(3): 104-6.
6)Radi Hejazi, Mansoor Anjil. Stomach specific anti H.pylori therapy, part III: Effect of chitosan microspheres cross linking on the gastric residence and local tetracycline concentrations in fasted Gerbils. Int J Pharm 2004; 272: 99-108.
7)Cuna M, Alonso MJ, Torres D. Preparation and in vitro evaluation of muco adhesive microparticles containing amoxycillin-resin complexes for drug delivery to the gastric mucosa. Eur J Pharmaceut Biopharmaceut. 2001; 51: 199-205.
8)Yuanfen Liu, Jianjun Zhang, Yuan Gao, Jiahi Zhu. Preparation and evaluation of Glycerylmonooleate coated hollow bioadhesive microspheres for gastroretentive drug delivery. Int J Pharm 2011.
9)Sinha VR et al., Chitosan microspheres as a potential carrier for drugs. Int J Pharm. 2004; 274: 1-33.
10) Flavia Chiva Carvalho, Marcos Luciano Bruschi, Raul Cesar Evangelista, Maria Palmira Daflon Gremiao. Mucoadhesive drug delivery system review. BJPS 2010; 46(1): 1-17.
11) Kamal Kant Arya, Ripudam Singh, Vijay Juyal. Mucoadhesive microspheres of Famotidine: preparation and characterisation and in vitro evaluation. IJEST 2010; 2(6): 1575-80.
12) Govender S, .Pillay V, Chetty DJ, Essack SY, Dangor CM, Govender T. Optimisation and characterisation of bioadhesive controlled release Tetracycline microspheres. Int J Phar 2006;
306:24-40.
13) Ji-Shan Quan et al., pH-sensitive and mucoadhesive thiolated eudragit-coated chitosan microspheres. Int J Pharm 2008; 359:205-10.
14) Shiva Kumar Yellanki, Jeet Singh, Jawad Ali Syed, Raj Kamal Bigala, Sharada Goranti, Naveen Kumar Nerella. Design and characterisation of Amoxicillin trihydrate microspheres for prolonged gastric retention. IJPSDR 2010; 2(2): 112-4.
15) Bhabani Nayak S, Sunil Ghosh K, Tripati K, Patro K. Preparation and characterisation of Famotidine microcapsule employing mucoadhesive polymers in combination to enhance gastroretention for oral delivery, IJPPS 2009; 1(2):112-20.
16) Patil PB, Gawali VU, Patil HN, Hardikar SR, Bhosale AV. Preparation and evaluation of muco adhesive microspheres of Atenolol and Propranolol. Int J PharmTech Res 2009; 1(3):639-43.
17) Ping He, Stanley Davis S, Lisbeth Illum. In vitro evaluation of the muco adhesive properties of chitosan microspheres. Int J Pharm 1998; 166: 75-88.
18) Raffin RP, Colome LM, Pohlmann AR, Guterres SS. Preparation, characterisation, and in vivo anti-ulcer evaluation of pantoprazole-loaded microparticles. Eur J Pharmaceut Biopharmaceut 2006; 63:198-204.
9 / Signature of the candidate:
10 / Remarks of the Guide:
11 / Name and Designation of:
11.1 Institutional Guide: / Mrs.A.Geetha Lakshmi
Asst.Professor
11.2 Signature:
11.3 Co-Guide:
11.4 Signature:
11.5 Head of the Department: /
Mr. Anup Kumar Roy
Asst. Professor & HODDept. of Industrial Pharmacy
11.6 Signature
12 / 12.1 Remarks of the Principal
12.2 Signature /
Dr. Divakar Goli
Principal
ACHARYA & B.M.REDDY COLLEGE OF PHARMACY,SOLDEVANAHALLI,
HESARAGHATTA MAIN ROAD,
BANGALORE-90.
1