REGISTRATION OF SUBJECT FOR DISSERTATION
A PROTOCOL FOR THE PROJECT WORK ENTITLED
“DESIGN AND EVALUATION OF MUCOADHESIVE MICROSPHERES
OF TIZANIDINE HYDROCHLORIDE FOR NASAL DELIVERY”.
By,
SOWMYA
M Pharm, Part I
Department of Pharmaceutics
N G S M Institute of Pharmaceutical Sciences
Paneer, Deralakatte
Mangalore – 574 160.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE,
KARNATAKA
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATE AND ADDRESS / SOWMYAN.G.S.M. INSTITUTE OF
PHARMACEUTICAL SCIENCES,
PANEER, DERALAKATTE,
MANGALORE – 574 160.
2. / NAME OF THE INSTITUTION / N.G.S.M. INSTITUTE OF
PHARMACEUTICAL SCIENCES,
PANEER, DERALAKATTE,
MANGALORE – 574 160.
3. / COURSE OF STUDY AND SUBJECT / MASTER OF PHARMACY IN PHARMACEUTICS
(INDUSTRIAL PHARMACY)
4. / DATE OF ADMISSION OF COURSE / JUNE 2007
5. / TITLE OF THE TOPIC:
“DESIGN AND EVALUATION OF MUCOADHESIVE MICROSPHERES OF TIZANIDINE HYDROCHLORIDE FOR NASAL DELIVERY”.
6. / BRIEF RESUME OF THE INTENDED WORK
6.1 Need for the study:
Nasal drug delivery has received intensive interest since ancient times and is considered to be an alternative to oral route for systemic drug delivery. In recent years many drugs have shown to achieve better systemic bioavailability by self medication through the nasal route than by oral administration. This has been attributed to the rich vasculature and a highly permeable structure of the nasal mucosa coupled with avoidance of hepatic first-pass elimination, gut wall metabolism, destruction of the drugs and gastro intestinal side effects. The nasal route is readily accessible and therefore convenient1.
Nasal formulation consists of nasal drops, nasal sprays, gels and powders. Since these preparations would encounter rapid mucociliary clearance, alternative formulations and novel drug delivery systems have been developed in recent times to prolong nasal residence of the drug. One such drug delivery system is microspheres prepared from mucoadhesive polymers such as carbopols, hydroxy propyl methyl cellulose (HPMC) etc 2 .
Mucoadhesive microspheres have advantages such as efficient absorption and enhanced bioavailability of the drugs owing to high surface to volume ratio, a much more intimate contact with the mucus layer, longer residence time of the dosage form at the site of application and specific targeting of the drugs to the absorption site. Thus mucoadhesive microspheres offer not only unique carrier system but also for controlled release, enhancing bioavailability, reduction in frequency of administration and can highly improve patient compliance3. These microspheres with good bioadhesive characteristics swell easily when in contact with nasal mucosa, with the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions1.
Tizanidine hydrochloride is a new centrally acting skeletal muscle relaxant. It is an α2 adrenergic agonist used in the management of spasticity associated with multiple sclerosis or spinal chord disorders, also has central analgesic effect and gastro protective effect. Tizanidine hydrochloride undergoes extensive hepatic first pass metabolism in the liver, is incompletely absorbed from the gastro intestinal tract with 30-40% oral bioavailability. It has a half life of 2.1 to 4.2 hours, given at the dose of 24 mg-36 mg daily. Peak plasma concentrations occurred 2 hours after administration by mouth4. Hence this drug will benefit from formulation into mucoadhesive microspheres by avoidance of first pass effect, reduced mucociliary clearance and therefore improvement in bioavailability. As a result of controlled release, patient compliance can be improved by reduction in dosage frequency.
6.2 Review of literature:
1. El-Hameed MDA and Kellaway IW (1997)5 prepared and evaluated mucoadhesive microspheres of FITC-dextran for intra nasal delivery. Microspheres of hydrophilic polymers were prepared by w/o emulsification solvent evaporation process having optimum particle size for nasal administration, reproducible drug loading efficiency and release profiles. The in vitro mucoadhesive study demonstrated that carbopol 934P adhered to the mucus to a greater extent than the chitosan, hydroxyl propyl methyl cellulose (HPMC) and poly vinyl alcohol (PVA).The drug release from carbopol 934P, HPMC and PVA microspheres were higher than chitosan due to more rapid hydration rate observed by microscopy.
2. Gavini E et al., (2005)6 prepared micro particulate drug delivery systems for nasal administration of an antiemetic drug, metoclopramide hydrochloride. Microspheres composed of sodium alginate, chitosan, hydrochloride or both obtained using spray drying method had a mean diameter in the range of 3-10 micron and showed good in-vitro mucoadhesive properties. The in vitro release profiles and swelling behavior depended on their composition: the drug release occurred in 1-3 hours. Ex vivo studies showed that drug permeation through the mucosa from the microparticles based on chitosan was higher than from those consisting of alginate alone. Microscopy observation of microspheres during the permeation revealed that microspheres swelled and gelled, maintaining their shape. Thus the preliminary studies showed that alginate/chitosan spray dried microspheres had promising properties for use as mucoadhesive nasal carriers of an antiemetic drug.
3. Harikarnpakdee S et al., (2006)7 prepared spray-dried mucoadhesive microspheres for nasal delivery. Microspheres composed of hydroxypropyl methyl cellulose, chitosan, carbopol 934P, and various combinations of these mucoadhesive polymers, and maltodextrin, colloidal silicon dioxide, and propylene glycol as filler and shaper, were prepared by spray-drying technique. Using propranolol hydrochloride microspheres were prepared at loadings exceeding 80% and yields between 24% and 74%. Adhesion time of mucoadhesive microspheres on the isolated pig intestine was ranked, chitosan > carbopol 934P: HPMC > carbopol 934P > HPMC. The permeation of the drug through nasal cell monolayer corresponded to their release profiles.
4. Gavini E et al.,(2006)8 prepared chitosan microspheres of carbamazepine for nasal administration using spray drying technique and characterized in terms of morphology, drug content, particle size and thermal behavior. In vitro and in vivo tests were carried out for microspheres containing chitosan glutamate and the results were compared to the blank microspheres. For evaluation of in vivo data statistical analysis was carried out using unpaired t-test. The results showed that microspheres containing chitosan glutamate increased the drug concentration in the serum when compared to the nasal administration of pure drug.
5. Dandagi PM et al., (2007)9 prepared and evaluated mucoadhesive microspheres of propranolol hydrochloride using gelatin A as polymer. The mean size ranges of microspheres were estimated between 1-50 mm which were suitable for intranasal administration and were spherical in shape, and also observed that increase in the concentration of the drug enhances the entrapment efficiency. The in vitro release pattern shows the slow release of the drug with the negligible burst effect. The slow release was due to the medium being diffused into the polymer matrix and the drug diffusing out of the microspheres. The stability studies showed that there was no change in the appearance of the microspheres and was stable at all conditions exposed.
6. Patil SB and Murthy RSR (2006)10 prepared and evaluated mucoadhesive chitosan microspheres of amlodipine besylate for the mucoadhesive properties using sheep nasal mucosa. It was found that as the amount of polymer increased, the percentage in vitro mucoadhesion also increased due to the fact that amino groups available for binding with the sialic acid residues in mucus layer also increase in the in vitro mucoadhesion of microspheres.
7. Chowdary KPR and Rao YS (2003)11 prepared and evaluated indomethacin microcapsules with a coat consisting of alginate and mucoadhesive polymer such as sodium carboxy methyl cellulose (sodium CMC) and methyl cellulose. The resulting microcapsules were discrete, large, spherical and free flowing. Microencapsulation efficiency was 41-70% and exhibited good mucoadhesive property in the in vitro wash off test. Drug release was diffusion controlled and followed first order kinetics. The in vitro release studies showed that the drug release from alginate methyl cellulose and alginate sodium carboxy methyl cellulose was slow and extended for a period of 12 hours.
8. Patel JK et al., (2004)12 prepared and optimized mucoadhesive microspheres of metclopromide. The study demonstrated the preparation of mucoadhesive microspheres of metoclopromide using chitosan as polymer. Glutaraldehyde was used as a cross linking agent. The volume of cross linking agent, polymer to drug ratio and stirring speed had a significant effect on the microsphere characteristics. The microspheres also showed good mucoadhesive properties. Chitosan microspheres were able to give extended drug release.
9. Lee DW et al., (2002)13 prepared and evaluated the release of felodipine from polymer coated and blended alginate microspheres. Extended release of drug was shown with polymer coated or blended alginate microspheres when compared to the fast release of the drug from plain alginate micro spheres. Chitosan coated micro spheres showed a smooth and round surface and HPMC blended microspheres exhibited a linear release profile. In vitro release studies showed that as amount of polymer in sodium alginate or coating solution increase, the drug release generally decreased and hence were used for drug delivery systems.
10. .Patel JK et al., (2005)14 formulated and evaluated mucoadhesive microspheres of glipizide. Glipizide microspheres containing chitosan were prepared by emulsification phase separation technique using glutaraldehyde as cross linking agent. Microspheres obtained were discrete, spherical, free flowing and the drug was estimated by UV/visible spectrophotometric method at 276 nm. The drug entrapment efficiency being calculated using the formula practical drug content/ theoretical drug content X 100. In vitro studies showed that drug release was sustained for more than 12 hours.
11. Nagori BP and Dahiya R (2007)15 developed a spectrophotometric method of estimation for quantitative determination of Tizanidine hydrochloride using factorial design for optimization of reaction parameters. Tizanidine hydrochloride was made to react with p-dimethyl amino benzaldehyde reagent in strongly acidic media to give products including sciff bases that were oxidized by ferric ions to give yellow colored species. Regression analysis of beer’s plots showed good correlation in the concentration range of 5-50 mcg/ml and method was validated according to ICH guidelines.
6.3 Objectives of the study:
The purpose of the present study is to:
1. Formulate physically and chemically stable mucoadhesive microspheres of Tizanidine hydrochloride for nasal administration using polymers such as HPMC, carbopol 934P, sodium CMC, chitosan.etc and methods such as solvent evaporation, heat rigidization, and simple emulsification cross linking method.
2. Evaluation of study of the prepared microspheres for-
a. Particle size analysis.
b. Drug content and drug entrapment efficiency.
c. Mucoadhesive strength.
d. Drug release using a suitable in vitro model.
3. To perform stability studies of the formulation.
7. / MATERIALS & METHODS:
7.1 Source of Data
(a) Journals and publications
(b) Internet
§ www.google.com
§ www.pubmed.com
§ www.sciencedirect.com
(c) Textbooks and reference books.
7.2 Method of collection of data (including sampling procedure, if any)
1. From the available literature
2. The formulations formulated will be subjected to different studies such as
a) Microspheres size, shape and analysis.
b) Swelling index.
c) Drug content determination.
d) Microencapsulation efficiency.
e) In vitro wash off test for mucoadhesion.
f) In vitro drug release studies using USP dissolution apparatus and nasal diffusion cell with sheep nasal mucosa.
g) Stability studies for one month at refrigeration temperature of 4 degree Celsius, room temperature of 28-30 degree Celsius, and oven temperature of 40-45 degree Celsius.
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 REFERNCES
1. Chein YW, Chang SF. Treatise on controlled drug delivery.2nd ed., New York: Marcel Dekker, Inc. 2007:229-266.
2. Suresh S, Bhaskaran S. Nasal drug delivery: An Overview. Indian J Pharm Sci 2005 Feb;67(1):19-25.
3. Chowdary KPR, Narayana TV, Rao SY. Mucoadhesive microspheres. The Indian Pharmacist 2004;27(11):1717-1724.
4. Martindale KP. The complete drug reference. 32nd ed., London: London pharmaceutical press, 1999:1641-1642.
5. El-Hameed MDA, Kellaway IW. Preparation and in vitro characterization of mucoadhesive polymeric microspheres as intra-nasal delivery systems. Eur J Pharm and Biopharm 1997 Apr; 44(1):53-60.
6. Gavini E, Rassu G, Sanna V, Cossu M, Guinchedi P. Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopromide: in vivo/ex vivo studies. J Pharm Pharmacol.2005 Mar;57(3):287-94.
7. Harikarnpakdee S, Lipipun V, Sutanavibul N, Ritthidej GC. Spray dried mucoadhesive microspheres: preparation and transport through nasal cell monolayer. AAPS PharmSciTech. 2006 Nov; 7(1):701-12.
8. Gavini E, Hegge AB, Rassu V, Sanna V, Testa C, Pirisino G, Karlsen J, Giunchedi P. Nasal administration of carbamazepine using chitosan microspheres: in vitro/in vivo studies. Int J Pharm 2006 Jan; 307(1):9-15.
9. Dandagi PM, Mastiholimath VS, Gadad AP, Iliger SR. Mucoadhesive microspheres
of propranolol hydrochloride for nasal delivery. Indian J Pharm Sci 2007 May;
69(3):402-407.
10. Patil SB, Murthy RSR. Preparation and in vitro evaluation of mucoadhesive chitosan microspheres of amlodipine besylate for nasal administration. Indian J Pharm Sci 2006 Feb; 68(1):64-67.
11. Chowdary KPR, Rao SY. Preparation and evaluation of mucoadhesive microcapsules of indomethacin. Indian J Pharm Sci 2003 Nov; 65(1):46-52.
12. Patel JK, Bodar MS, Amin AF, Patel MM. Formulation and optimization of mucoadhesive microspheres of metclopromide. Indian J Pharm Sci 2004 Apr; 66(3):300-305.
13. Lee DW, Hwang SJ, Park JB, Park HJ. Preparation and release characteristics of polymer coated and blended alginate microspheres. J Microencapsul 2003 Mar; 20(2):179-192.
14. Patel JK, Patel RP, Amin AF, Patel MM. Formulation and evaluation of mucoadhesive Glipizide microspheres. AAPS PharmSciTech.2005 Nov; 6(1); 49-55.
15. Nagori BP, Dahiya R. spectrophotometric method for tizanidine hydrochloride and its application of factorial design. Indian drugs 2007 Aug; 44(8):597-601.
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