RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA
M. PHARM SYNOPSIS
YEAR OF ADMISSION-JUNE 2010
TITLE OF THE SYNOPSIS
Preparation and in vitro evaluation of microparticles loaded with Anti-Alzheimer’s drug.
BY
RAHUL.R
M. PHARM., PART-I
DEPARTMENT OF PHARMACEUTICS
UNDER THE GUIDANCE OF
Dr. K. MANJUNATH, M. PHARM., Ph. D. Professor DEPARTMENT OF PHARMACEUTICS
INSTITUTION
SREE SIDDAGANGA COLLEGE OF PHARMACY
B. H. ROAD, TUMKUR-572 102
KARNATAKA
CORRECTIONS AS PER COMMENTS
NAME OF STUDENT / NAME OF GUIDE / REMARKS HAVE BEN CORRECTEDRAHUL R / DR. K. MANJUNATH / 1) THE REFERNES AND JOURNAL NAMES AS PER VANCOUVER STYLE.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BANGALORE, KARNATAKA
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATEAND ADDRESS / RAHUL R.
NO.29, 8TH CROSS, VISHVESHWARAIAH LAYOUT,
SIDEDHAHALLI MAIN ROAD, NAGASANDRA (PO).
DIST. - BANGALORE
PIN - 560073
STATE - KARNATAKA
2. / NAME OF THE INSTITUTION / SREE SIDDAGANGA COLLEGE OF PHARMACY
B. H. ROAD, TUMKUR- 572 102
KARNATAKA
3. / COURSE OF STUDY AND SUBJECT / MASTER OF PHARMACY IN PHARMACEUTICS
4. / DATE OF ADMISSION OF COURSE / JUNE 2010
5. TITLE OF THE TOPIC
“Preparation and in vitro evaluation of microparticles loaded with Anti-Alzheimer’s drug”
6. / BRIEF REVIEW OF THE INTENDED WORK
6.1 - Need for the study
Alzheimer’s Disease (AD) is common form of dementia occurring in old individuals. It seriously affects the person’s ability to carry out daily activities. Alzheimer’s disease is a neurodegenerative condition – nerve cells and their connections are destroyed. It is caused due to formation of abnormal clumps called amyloid plaques and tangled bundle of fibers called neurofibrillary tangles. It affects the brain which control thought, memory and language. The persons affected will have trouble in speaking, reading or writing. It is a slowly progressive disease of brain occurring in old age which is characterized by impairment of memory and eventually causing disturbances in reasoning, planning, language and perception. The size of the elderly population in the world is increasing, and the number of patients suffering from Alzheimer’s disease will increase. Hence there is a need to provide better treatment of the disease which is lacking with existing dosage forms of anti-Alzheimer’s drugs.
Rivastigmine is used in the treatment of Alzheimer’s disease and it acts by mechanism of reversible cholinesterase inhibitor. Following oral administration, it is well absorbed with bioavailability of about 40%. It is rapidly and extensively metabolized, primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. CYP-450 is minimally involved. Rivastigmine plasma concentrations declined rapidly with an elimination half-life approximately 1.5 hours exhibiting short duration of action. Frequent administration is required to prolong the action which doesn’t have patient compliance. Rivastigmine being used in Alzheimer’s disease needs to be developed into sustained release dosage form, for maintaining therapeutic levels for prolonged time periods and thereby to improve patient compliance.
Rivastigmine has an excellent safety and shown to improve patients’ performance in three major domains: cognitive function, global function and
behavior. This indicates it is suitable candidate to be developed into sustained release dosage form.
Slow release of the drugs could be achieved with the help of microparticles. Polymeric or lipid microparticles prepared by following different methodologies proved slow release of the drug. Methods to prepare microparticles includes such as phase separation emulsification technique1,2,3 emulsion solvent evaporation technique,4,5 solvent diffusion technique,6,7 water-in-oil-in-water emulsification technique8 etc. Microparticles have been exploited for their potential as a controlled drug delivery system. Mechanisms involved in control release of drugs from microparticles is typically achieved by either drug diffusion through the matrix or erosion of the material.8 both hydrophillic and lipophyllic drugs can be encapsulated within the polymer by selecting suitable matrices and appropriate techniques. Log P value of rivastigmine is 2.3 indicates lipophillic nature. Hence devalopment of rivastigmine lipid microparticles is proposed in this study.
.
6.2 - Review of Literature
1. Marja Savolainen et al., studied on controlled-release polar lipid microparticles of poorly-soluble drug, felodipine, and various erodable lipophilic excipients. They formulated the drug and the excipients into solid dispersion microparticles using spray chilling technique, which were then compressed. The microparticles were characterised by Fourier transform infrared spectroscopy, hot-stage microscopy, scanning electron microscopy, and image analysis. surprisingly, the degree of crystallinity in felodipine and the ease of tablet disintegration played a more significant role on the felodipine dissolution rate than the matrix lipophilicity. Felodipine release rate was slowest from the least lipophilic tablets.9
2. Long Chunxia et al., studied on preparation and crystal modification of ibuprofen-loaded solid lipid microparticles. An emulsion-congealing technique is used to prepare solid lipid microparticles (SLM) containing ibuprofen with glyceryl behenate, tripalmitin and beewax as excipients. Both the solubility parameter analysis and the experimental results showed that glyceryl behenate is the best among the three excipients. Glycerides exhibit marked polymorphism and their rapid rates of crystallization accelerate the formation of metastable crystal modification. Increasing the content of lipophilic drug in a lipid matrix facilitates the transformation of excipients to more stable polymorphic forms.10
3. Vanna Sanna et al., studied on preparation and in vivo toxicity study of solid lipid microparticles as carrier for pulmonary administration Compritol (5.0% wt/wt) SLM dispersions were prepared by rotor-stator homogenization, at different surfactant concentrations and emulsification times. The SLM were characterized, in terms of morphology and size, after lyophilization and sterilization by autoclaving process. In vivo assessment was carried out in rats by intra-tracheal instillation of either placebo or SLM dispersion, and by bronchoalveolar lavage for cytological analysis. Mean particle size of 4 to 5 μm was achieved using 0.3% and 0.4% (wt/wt) of emulsifier (Poloxamer 188) and emulsification times of 2 and 5 minutes. These results suggest that a single intratracheal
administration of the SLMs does not induce a significant inflammatory airway response in rats and that the SLMs might be a potential carrier for encapsulated drug via the pulmonary route.11
4. SM Wong et al., tried to improve the dissolution rate, oral absorption and bioavailability of a poorly watersoluble drug by formation of surfactant-containing microparticles. Microparticles containing the drug were produced by spray drying in the absence/presence of a hydrophilic surfactant. A hydrophilic surfactant improves the particle wetting and hence the dissolution rate. The spray dried particles were characterized and in vitro dissolution studies and in vivo absorption studies were carried out. The results obtained showed that the dissolution rate and absolute oral bioavailability of the spray dried drug/surfactant particles were significantly increased compared to the control. Therefore, it is believed that the better wetting characteristics conferred by the hydrophilic surfactant was responsible for the enhanced dissolution rate and absolute oral bioavailability of the model drug.12
5. Izabela Galeska et al., studied on the controlled release of dexamethasone from PLGA microspheres embedded within polyacid-containing poly(vinyl alcohol) hydrogels. Here they described a delivery system based on physically cross-linked poly (PVA) microgels (cross-linked via repetitive freeze/thaw cycling) containing entrapped dexamethasone-loaded poly(lacticco-glycolic acid) (PLGA) microspheres for controlled delivery. On the basis of a comprehensive evaluation of the structure-property relationships of these hydrogel/microsphere composites, in conjunction with their in vitro release performance, it was concluded that these polyacids segregate on the PLGA microsphere surfaces and thereby result in localized acidity. These surface-associated polyacids appear to cause acid-assisted hydrolysis to occur from the surface inwards. Such systems show potential for a variety of localized controlled drug delivery applications such as coatings for implantable devices.13
6. Rassoul Dinarvand et al., studied on the preparation of biodegradable
microspheres and matrix devices containing naltrexone using solvent evaporation technique. Poly(L-lactide) (PLA) microspheres containing naltraxone was prepared and compressed at temperature above Tg of the polymer. The effect of different process parameters, such as drug/polymer ratio and stirring rate during preparation of micro-spheres, on the morphology, size distribution, and in vitro drug release of microspheres was studied. The drug release rate from smaller microspheres was faster than from larger microspheres and also showed the drug release from matrix devices prepared by compression of naltrexone microspheres is much slower than that of microspheres. Applying higher compression force, when compressing microspheres to produce tablets, resulted in lower drug release from matrix devices. The results suggest that by regulating different variables, desired release profiles of naltrexone can be achieved using a PLA microparticulate system or matrix devices.14
7. Sunit Kumar Sahoo et al., studied on the formulation and in vitro evaluation of eudragit microspheres of stavudine by solvent evaporation method using an acetone / liquid paraffin system and magnesium stearate was used as the droplet stabilizer and n-hexane was added to harden the microspheres. The in vitro release studies were performed and drug-loaded microspheres showed 67-91% of entrapment and release was extended upto 6 to 8 h. The release was found to be diffusion controlled.15
8. Shrinidh A Joshi et al., studied on the Rivastigmine-loaded PLGA and PBCA nanoparticles and carried out the preparation, optimization, characterization, in- vitro and pharmacodynamic studies. The pharmacodynamic performances of the nanoparticles (NPs) were evaluated for brain targeting and memory improvement. PLGA NPs were prepared by nanoprecipitation technique, while PBCA NPs were prepared by emulsion polymerization technique. FTIR and GPC characterization confirmed complete polymerization of n-butyl cyanoacrylate (nBCA) monomer into PBCA. Pharmacodynamic study demonstrated faster
regain of memory loss in amnesic mice with both PLGA and PBCA NPs. This
indicates rapid and higher extent of transport of RT into the mice brain and thus
shows the suitability of both NPs as potential carriers for providing sustained brain delivery of Rivastigmine Tartrate.16
9. Barnabas Wilson et al., studied on the Poly(n-butylcyanoacrylate) nanoparticles coated with polsorbate 80 for the targeted delivery of Rivastigmine into the brain to treat Alzheimer’s disease which is a progressive and fatal neurodegenerative disorder manifested by cognitive and memory deterioration, progressive impairment of activities of daily living, and a variety of neuropsychiatric symptoms and behavioral disturbances. Rivastigmine is a reversible cholinesterase inhibitor used for the treatment of Alzheimer's disease. They made an attempt to target the anti-Alzheimer's drug Rivastigmine in the brain by using poly(n-butylcyanoacrylate) nanoparticles.Which showed a significant increase in Rivastigmine uptake in the brain. In conclusion that the study demonstrates that the brain concentration of intravenously injected Rivastigmine can be enhanced over 3.82 fold by binding to poly(n-butylcyanoacrylate) nanoparticles coated with polysorbate 80.17
6.3 - Objective of the Study
Following are the objectives of the present study :-
· Development of Rivastigmine lipid microparticles using different lipids.
· Characterization of Rivastigmine lipid microparticles including in vitro drug release evaluation.
7. / MATERIALS AND METHODS
Materials:
Drugs : Rivastigmine
Lipids such as stearic acid, tristearin, trimyristin etc.,
Stabilizers such as tweens and spans.
Methods:
Hot homogenization of melted lipid in a hot aqueous surfactant method or any suitable method shall be utilized.
7.1 - Source of Data
Review of Literature from
a) Journals such as,
1) Indian Journal of Pharmaceutical Sciences
2) European Journal of Pharmaceutical Sciences
3) International Journal of Pharmaceuticals
4) Drug Development & Industrial Pharmacy
5) Tropical Journal of Pharmaceutical Research
6) Chinese Journal of Chemical Engineering
7) AAPS PharmSciTech
8) Journal of Nuclear Medicine
9) Brain Research
b) Web sites such as
1) DrugBank (www.drugbank.ca)
2) Pubmed (www.ncbi.nlm.nih.gov/pubmed)
3) Rx List (www.rxlist.com)
7.2 - Method of collection of data
a) Analytical method for the estimation of Rivastigmine will be developed in simulated gastric fluid and/or simulated intestinal fluid.
b) Preparation of Rivastigmine lipid microparticles using different lipids such as stearic acid, tristearin, trimyristin etc.
Microparticles of rivastigmine shall be prepared by hot homogenization technique. Drug, lipid and oil soluble surfactant shall be dissolved in a mixture of chloroform and ethanol. Organic solvents shall be completely removed by using rotoevaporator. Lipid layer is melted by heating at 5ºC above melting point of the lipid. An aqueous phase is prepared by dissolving water soluble surfactant in double distilled water and heated to same temperature of the molten lipid phase. Hot aqueous phase is added to molten lipid phase and homogenization shall be carried out (temperature maintained at 5ºC above the melting point of lipid ) with the help of homogenizer. Microparticles shall be obtained by allowing hot coarse emulsion to cool to room temperature.
c) Characterization of Rivastigmine lipid microparticles for particle size, entrapment efficiency, assay, stability, state of drug and lipid, surface morphology, etc.
Particle size of the prepared drug loaded microspheres shall be carried out using optical microscope as well as particle size analyzer. Entrapment efficiency is carried out by estimating the amount of drug present in aqueous phase after suitably separated. State of the drug and lipid in the final formulation shall be carried out by DSC. Particle size and surface characteristics shall be done by SEM.
d) In vitro evaluation of Rivastigmine lipid microparticles for the release characteristics.
In vitro release studies shall be performed using diffusion cells using
dialysis membrane having pore size 2.4 nm, molecular weight cutoff between
12000-14000. Buffer pH 7.2 shall be used as media. Microparticle dispersion
shall be placed inside the dialysis cell ( donor compartment ) by taking buffer as media in receptor compartment. At fixed time intervals, 2 ml of the sample shall be withdrawn from the receiver compartment and same amount of 7.2 pH buffer shall be replaced. The drug contents shall be analyzed by UV spectrophotometer.
e) Statistical analysis of data obtained from the results.
/ 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.
“ NOT APPLICABLE ”
7.4 - Has ethical clearance been obtained from your institution in case of 7.3?
“ NOT APPLICABLE ”
8.0 / REFERENCES
1. Subaraya AR, Narayanacharya R. Design and evaluation of chitosan microspheres of metaprolol tartrate for sustained release. Ind J Pharm Sci 2003; 65(3):250-2.
2. Patel JK, Bodar MS, Amin AF, Patel MM. Formulation and optimization of mucohedisive microspheres of metaclopramide. Ind J Pharm Sci 2004; 66(3):300-5.
3. Scheffel U, Rhodes BA, Natarajan TK, Wager HN. Albumin microspheres for study of the reticuloendothelial system. J Nucl Med 1972;13(7):489-503.
4. Gohel MC, Avani FA. Studies in the preparation of diclofenac sodium microspheres by emulsion solvent evaporation technique using response surface analysis. Ind J Pharm Sci 1999;61(1):48-53.
5. Sandra K, Gareth DR, Simon AY, John T, John DS. In-situ evaluation of drug-loded microspheres on a mucosal surface under dynamic conditions. Int J Pharm 2004;276:51-8.
6. Gowthamarajan K, Giriraj KT, Senthil RD, Suresh B. Microspheres as oral delivery system for insulin. Ind J Pharm Sci 2003;65(2):176-9.
7. Latha S, Selvamani P, Pal TK. Preparation and in vitro evaluation of ranitidine HCl magnetic microspheres by emulsion-solvent evaporation method. Ind Drugs 2004; 41(6):371-3.
8. Donald LW. Hand book of pharmaceutical controlled release technology. New York. Basal: Marcel Dekker Inc; 2005.
9. Marja S, Cynthia K, Hakan G, Carina D, Anne MJ. Evaluation of controlled-release polar lipid microparticles. Int J Pharm 2002;244:151-61.
10. Long C, Zhang L, Qian Y. Preparation and crystal modification of ibuprofen-loaded solid lipid microparticles. Chinese J Chem Eng 2006;14(4):518-25.
11. Vanna S, Nathalie K, Pascal G, Elisabetta G, Isabelle R, Luc D, Evrard. Preparation and in vivo toxicity study of solid lipid microparticles as carrier for pulmonary administration. AAPS PharmSciTech 2004;5(2):Article 27.
12. Wong SM, Kellaway IW, Murdan S. Enhancement of the dissolution rate and oral absorption of a poorly water soluble drug by formation of surfactant-containing microparticles. Int J Pharm 2006;317:61-8.
13. Izabela G, Tae-Kyoung K, Siddhesh DP, Upkar B, Debjit C, Fotios P, Diane JB. Controlled release of dexamethasone from PLGA microspheres embedded within polyacid-containing PVA hydrogels. AAPS J 2005;7(1):Article 22.
14. Rassoul D, Shadi HM, Leyla MF, Fatemeh A. Preparation of biodegradable microspheres and matrix devices containing naltrexone. AAPS PharmSciTech 2003;4(3):Article 34.
15. Sunit KS, Abdul AM, Barik BB, Prakash CS. Formulation and in vitro evaluation of eudragit microspheres of stavudine. Trop J Pharm Res, 2005;4(1):369-75.
16. Shrinidh AJ, Sandeep SC, Krutika KS. Rivastigmine-loaded PLGA and PBCA nanoparticles: preparation, optimization, characterization, in vitro and pharmacodynamic studies. Eur J Pharm Biopharm 2010;76:189-99.
17. Barnabas W, Malay KS, Kumaraswamy S, Kokilampal P, Sampath K, Nallupillai P, Bhojraj S. Poly (n-butylcyanoacrylate) nanoparticles coated with polsorbate 80 for the targeted delivery of rivastigmine into the brain to treat Alzheimer’s disease. Brain Res 2008;1200:159-68.
9. / SIGNATURE OF THE CANDIDATE
10 / REMARKS OF THE GUIDE / Recommended
11 / NAME AND DESIGNATION OF
11.1 Guide / Dr. K. MANJUNATH, M. PHARM., Ph. D.
Professor Department of Pharmaceutics
11.2 Signature
11.3 Co-Guide ( If any)
11.4 Signature
11.5 Head of the Department / Dr. SURESH KULAKARNI, M. Pharm., Ph. D
Professor & Head
Department of Pharmaceutics
11.6 Signature
12 / 12.1 Remarks of the Chairman and Principal / Forwarded to the University for approval
12.2 Signature
/ Principal
Sree Siddaganga College of Pharmacy
B. H. Road, Tumkur-572 102.
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