FORMULATION AND VALIDATION OF IBUPROFEN NANOPARTICLES GEL
M. PHARM DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES, KARNATAKA,
BANGALORE.
BY
JAGADISH
B.Pharm
UNDER THE GUIDANCE OF
Dr.R.NAGENDRA RAO
M.Pharm, Ph.D.
PROFESSOR HEAD
P. G. DEPARTMENT OF QUALITY ASSURANCE
S. C. S. COLLEGE OF PHARMACY,
HARAPANAHALLI-583131
2010-11
RajivGandhiUniversity of Health Sciences, Karnataka, Bangalore
Annexure – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
01 / Name and Address of the Candidate / JAGADISHS/OASHOK PASARGI
“AASHIRWAD NILAYA” INSIDE PAPNASH GATE, SHIVNAGAR
BIDAR-585401
KARNATAKA
02 / Name of the Institution / T. M. A. E. Society’s
S. C. S. College of Pharmacy,
Harapanahalli – 583 131
(Davangere dist.) Karnataka
03 / Course of the Study
Branch / M. Pharm.
Quality Assurance
04 / Date of Admission to course / 07/07/2010
05 / Title of the Topic / FORMULATION AND VALIDATION OF IBUPROFEN NANOPARTICLES GEL
06 /
Brief resume of the intended work
6.1. Need for the Study /Enclosure – I
6.2. Review of the Literature / Enclosure – II6.3. Objective of the Study
/ Enclosure – III07 /
Materials and Methods
7.1. Source of data /Enclosure – IV
7.2. Methods of collection of data
/ Enclosure – V7.3. Does the study require any
Investigations on animals?
If yes give details / -No-
7.4. Has ethical clearance been
obtained from your institution
In case of 7.3. / -NOT APPLICABLE-
08 /
List of References
/ Enclosure – VI09 /
Signature of the candidate
/ (JAGADISH )10 / Remarks of the Guide / The present work is rationally designed and it can be easily carried out in our laboratory.
11 / Name and Designation of
(In Block Letters)
11.1. Guide reference no. of RGUHS
ACA/CDC/PGT-
M.Ph/SCS/02/2005-06/19.01.09
11.2.Signature
11.3.Co-Guide (if any)
11.4.Signature
11.5. Head of the Department
11.6.Signature / Dr.R.NAGENDRA RAO
M.Pharm, Ph.D
PROFFESSOR & HEAD PG DEPT OF QUALITY ASSURANCE,
------
------
Dr.R.NAGENDRA RAO
M.Pharm, Ph.D
PROFFESSOR & HEAD PG DEPT OF QUALITY ASSURANCE,
------
12 / Remarks of the Principal
12.1. Signature / The present study is permitted to perform in the quality assurance laboratory of our institution by above said student.
------
ENCLOSURE-I
06. Brief resume of Intended Work
6.1 Need for the study.
Abnormalities associated with inflammation comprise a large, officially unrelated group of disorders which underlie a vast variety of human diseases.Inflammation is the manifestation of vascular and cellular response of the host tissue to injury. Injury to the tissue may be inflicted by physical or chemical agents, invasion of pathogens, ischemia and excessive (hypersensitivity) or inappropriate (autoimmunity) operation of immune mechanisms. As soon as the injury is recognized, the mechanisms to localize and clear foreign substances and damaged tissues are initiated. Further, the response is amplified by activation of inflammatory cells and production of chemical mediators like acidic lipids e.g. prostaglandins (PGs), thromboxanes, leukotrienes, vasoactive amines, cytokines etc 1.
Various skeletal-muscular diseases like rheumatoid arthritis, oesto-arthritis which are characterized by inflammation of limbs are believed to be the result of auto-immune reactions of body. Even though these conditions are rarely fatal, these conditions result in debilating effect on persons and have socio-economic effect.
Various classes of anti-inflammatory drugs like Non-Steroidal Anti-Inflammatory Drugs(NSAID) are used popularly to treat the inflammatory conditions and various skeletal-musculardiseases. Among these, aryl propionic acid derivatives like ketoprofen, Ibuprofen, naproxen,flurbiprofen etc, are popularly used 2.
Ibuprofen is Non-Steroidal Anti-Inflammatory Drug(NSAID) which shows its action by inhibiting prostaglandin synthesis. It is used in form of tablets or topical preparations.Ibuprofen, a phenylpropionic acid derivative is established as first-lineNSAID for rheumatoid arthritis and chronic arthropathies.The mechanism of action of Ibuprofen involves not onlyinhibition of prostaglandin synthesis but also decreasedproduction of pro-inflammatory cytokines such asinterleukin 1β and tumour necrosis factor α, inhibition ofleucocyte, leucotriene B4, nitric oxideand possibly apositive effect on the production of oxyradicals andsignalling transduction via the NFκB pathway. Due to its major side effect that is GIT irritation, Ibuprofenhas been used in topical application form when it is intended to be used for chronic treatment.
Ibuprofen belongs to class-2 of BCS classification system. Being a class-2 drug, it possess solubility problem for formulation scientists in formulating it into a suitable dosage forms for formulation.Many attempts are made in past in which Ibuprofen has been converted into various novel drug delivery forms to overcome the solubility problem like preparation of its solid dispersions, nanoparticles, microspheres, neosomes etc.In therapeuticuse, Ibuprofen proved to have a favourable risk benefit ratioand predictable adverse effects (Rainsford, 2002). Thus forpatient compliance, improve bioavailability, minimize totaldrug quantity, minimize accumulation on chronic use andreduce fluctuation in drug level sustained release ofIbuprofen is desirable3.
Nanoparticles are form of novel drug delivery systems having the capability to release the drug at an optimumrate with lesser dose.The size range of the nanoparticles is 1 to 1000nm. Nanoparticular formulations can be prepared by using wide range of polymers like synthetic, natural, biodegradable and non biodegradable polymers. Thestability of this formulation is anotherattraction for the pharmaceutical scientists, while most other novel drug delivery systems like liposomes and neosomes suffer with stability problem. Literature reports suggest nanoparticles can be successfully used for delivery of various BCS class-II drugs4.
Process validation is an integral part of development of novel formulations. Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality.Process validation is carried out in every step of development of novel formulation to ensure the quality of finished product. In the present work also, the concept of process validation will be utilized for selecting an ideal formulation5.
In the present work, similar attempt will be made forformulation of Ibuprofen nanoparticles and further they will be converted into topical gels. Further, thus prepared gels will be validated by using various physicochemical parameters in view of getting a suitable formulation which is devoid of solubility problem. Hence the present study is needed and justifiable.
ENCLOSURE-II
6.2 Review of Literature
Ibuprofen is one of the most widely used NSAID which belongs to BCS Class-II.So overcome the solubility problem and then to improve its bioavaibility, various attempts are made to increase its solubility by using different methods. The data from the literature suggests various methods which are mentioned below.
1) In this study the Ibuprofen beads were prepared by using alginate as the polymer. For this purpose, different cross- linking agents including Ca2+, Ba2+, Mn2+, Co2+, Sn2+ and Pb2+ were used for bead preparation.Results showed that only Ca+2 ion is suitable for the formation of Ibuprofen beads.A good swelling profile for beads in phosphate buffer (pH=7.4) and the lack of swelling in hydrochloric acid (pH= 1.2) show the suitable nature of the beads. In addition, formulation of sodium-alginate (2%) and calcium-chloride (2%) beads resulted in an encapsulation efficacy of around 90% and it has also shown rapid and complete drug release from the beads6.
2)Methacrylic acid copolymer nanoparticles containing Ibuprofen were prepared by emulsion polymerisation technique in continuous aqueous phase. The drug content and drug recovery of the nanoparticles were studied and it was possible to increase the drug loading capacity by increasing the concentration of the polymer. The invitro release studies carried out across the artificial membrane indicated that the release of the drug from nanoparticles followed zero order kinetics. The study of anti inflammatory activity on albino rats revealed that nanoparticles ofIbuprofen can produce better therapeutic efficacy when compared with the aqueous solution of the drug7.
3) In this method, Ibuprofen was formulated as microspheres by using ethyl cellulose as carrier. These ethylcellulose microspheres were prepared by solvent evaporation methodand subjected to various invitro releases studies . It has been noted that highest percentage of loading was obtained by increasing the amount of Ibuprofen with respect to polymer8.
4)Studywas carried out to formulate the Ibuprofen micro spheres by using co-acervation phase separation technique to improve the bioavailability of drug using Ibuprofen as a model drug.Ibuprofenmicro spheres were formulated by using different polymers likegelatine and carbopol in 6 batches was F1, F2, F3, F4, F5 & F6. Ibuprofen Micro spheres were subjected to various evaluation tests and investigated by in-vitro dissolution studies using phosphate buffer (PH 7.4) to know the drug release. The study shown improved drug release and bioavilability9.
5)In a study it was shown that the rate of dissolution of Ibuprofen was increased by preparing its solid dispersions.Then dissolution of drug was carried out by solvent evaporation method.In this the drug was taken with mannitol in the proportions of (1:1, 1:2and 1:3) and by this method there has been increase in rate of dissolution of drug was found with the proportion of (1:3) when compared to the other formulations. As well as in melt dispersion method rate of dissolution of Ibuprofen was increased with the (1:3) proportionwhen compared to the other formulations10.
6)Study was carried out to develop solid dispersion self emulsification pellets (SDSEP). This is a recent technique for poorly watersoluble drugs, where it increase water solubility and enhances the bioavailability. The method involves the study with different polymers like MCC: lactoseand croscarmellose sodiumwere taken as an independent variables. Then it was evaluated by conducting the study of cumulative percentage drugrelease , disintegration time and friability. The differential scanning calorimetry and x-raydiffraction studies demonstrated that enhanced dissolutions of Ibuprofen from SDSEP might be due to a decrease in the crystallinityof drug has been noted. In conclusion, dissolution enhancement of Ibuprofen was obtained by preparing a solid dispersion self emulsion using melttechnique. The use of a factorial design approach helped in identifying the critical factors in the preparation and formulation of SDSE11.
ENCLOSURE -III
6.3 Objectives of the study:
In the present work,by using suitable literature methods and factorial design frame work,Ibuprofen nanoparticles will be prepared. Thus prepared nanoparticles will be characterized by suitable analytical techniques like SEM, DSC.Pharmacokinetic properties of thus prepared nanoparticles will be evaluated by using various parameters. The steps which are intended to be carried out are as follows.
Step-1:Selection of various polymers and factorial design for preparation of
Ibuprofen Nanoparticles.
Step-2: Preparation of Ibuprofen Nanoparticles.
Step-3:Characterization of Ibuprofen Nanoparticles.
Step-3: Validation of preparation methods employed for formation of Ibuprofen
nanoparticles.
Step-4: Formulation of Ibuprofen Nanoparticles into gel using suitable factorialdesign.
Step-5: Validation of prepared formulation by using various physicochemical
Parameters12-14.
ENCLOSURE– IV
7. Material & methods:
7.1 Source of data:
The primary data required for designing the work will be collected from
- Various national and international journals available in college library.
- From various open access journals available in internet.
- From helinet service of RGUHS, Bangalore.
- From various reference books available in college library.
- By referring various journals from libraries of Indian Institute of Science, Bangalore, Libraries of various Universities likeKuvempuUniversity, Shankargatta, KarnatakaUniversity, Dharwad.
- For validation of preparation methods for Nanoparticles, the data collected from various analytical techniques like DSC,SEM, etc.
- For validation of formulation, various data collected from evaluation of prepared formulations like % drug loading, % encapsulation efficiency, particle size distribution, SEM, in-vitro dissolution studies, etc.
ENCLOSURE – V
7.2 Method of collection of data:
1. By using suitable literature methods, Nanoparticles of Ibuprofen will be
prepared.
2. Nanoparticles of Ibuprofen thus prepared will be characterized by various
analytical techniques like SEM, DSC, etc.
3. Based on data obtained from analytical methods, if required validation of the
preparation method employed for preparing Nanoparticles will be carried out.
4. Thus prepared Ibuprofen Nanoparticles will be formulated into gels by
using various factorial designs.
5. Thus prepared formulations will be evaluated for
a. Percentage drug loading by Ultraviolet spectroscopy.
b. Percentage encapsulation efficiency by Ultraviolet spectroscopy.
c. Particle size distribution by Scanning Electron Microscopy.
d. Compatibility studies between various ingredients by using DSC.
e. In-vitro dissolution and diffusion study by USP method.
6. Validation for identification of a suitable factorial design formula byusing
the data obtained from the above methods (Step-5).
ENCLOSURE – VI
8.0 List of references:
1)Ahuja Munish, Dhake Avinash S,Sharma Surendra K, Dipak
Majumdar K.Topical Ocular Delivery of NSAIDs.The American Association of Pharmaceutical Scientists(AAPS)Journal.
2008; 10(2):23-25.
2) Tripathi KD.Essential of Medical Pharmacology. Sixth edition 2008; p193-
94.
3)BrahmankarDM,Jaiswal Sunil B. Biopharmaceutics and Pharmacokinetics.2009; p335-45.
4)KumarSS, RajkumarS, RuchmaniK.Formulation and evaluation of
Ibuprofen loaded nanoparticles for improved anti inflammatory activity. Acata Pharmaceutica Turica.2003; 45: 125-30.
5)Jams Agallow, Frederic Carleton. Validation of Pharmaceutical Processes, Thirdedition. p1-10.
6)Payam Khazaeli, Abbas Pardakhty, Fereshteh Hassanzadeh.Formulation ofIbuprofen Beads by Ionotropic Gelation.Iranian Journal of Pharmaceutical
Research. 2008; 7(3): 163-70.
7)KumarSS, RajkumarS, RuchmaniK.Formulation and evaluation of
Ibuprofen loaded nanoparticles for improved anti inflammatory activity. Acata Pharmaceutica Turica. 2003; 45: 125-30.
8 )SudhamaniT, Noveenkumar reddy K,Ravi Kumar VR, Revathi R, Ganesh
V.Preparation and evaluation of ethyl cellulose microspheres of Ibuprofen for
sustained drug delivery.International Journal of PharmaResearch and
Development.2010; 2(8): 119-22.
9)Surendiran NS, Yuvaraj TV.Preparation and evaluation of Ibuprofenmicro
spheres by using Co-acervation phase separation technique. International
Journal of ChemTech Research.2010;2(2): 1214-19.
10)Siva Ramakrishna G , Keshireddy, AnjiReddy, Jalachandra Reddy B ,Dinakar
P, Ramatherdana Rao P, Pamula Reddy Bhavanam.Enhanced dissolution
rate of Ibuprofen by solid dispersion method.Journal of Innovative Trends in
Pharmaceutical Sciences. 2010; 1(4):170-173.
11) Jessy Shaji, Digambar Jadhav. Statistical development and optimization of
solid dispersion self emulsifying pellets.International Journal of
Pharmaceutical Sciences Review and Research. 2010; 4(3): 157-67.
12) Selvakumar Kalimuthu, Yadav AV.Formulation and evaluation of Carvedilol
loaded Eudragit 100 Nanoparticles. International Journal of Pharm Tech
Research.2009; 1(2): 179-83.
13)ShahDivyen, Londhe Vaishali, Parikh Rima.Formula optimization of
levamisole loaded chitosan nanoparticles by 23 factorial designs.
14)Daniel D, Frey AE, Clive L, Dym. Validation of design methods: lessons
frommedicine.Research in Engineering Design, 2006; 17:45–57.