“SYNTHESIS AND CHARACTERIZATION OF GUAR GUM DERIVATIVE’S; FORMULATION AND EVALUATION OF TRANSDERMAL PATCHES OF ACECLOFENAC”
M. PHARM DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIVGANDHIUNIVERSITY OF HEALTH
SCIENCES, KARNATAKA, BANGALORE
BY
SHYANUBHOGARA BASAVARAJ
B.Pharm.
UNDER THE GUIDANCE OF
Mr. G.M.SREENIVASA,
M.Pharm.
ASST. PROFESSOR
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 / SHYANUBHOGARA BASAVARAJS/O S. MALLIKARJUNAPPA
KANCHIKERI-583125
HARAPANAHALLI (TQ)
DAVANGERE (DIST)
KARNATAKA (STATE)
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 / 7th JULY 2010
05 / Title of the Topic / “SYNTHESIS AND CHARACTERIZATION OF GUAR GUM DERIVATIVE’S ; FORMULATION AND EVALUATION OF TRANSDERMAL PATCHES OF ACECLOFENAC”
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 / Enclosure – VI
7.4. Has ethical clearance been
obtained from your institution
In case of 7.3. / Yes,Registration No:157/1999/CPCSEA
(Copy enclosed)
08 /
List of References
/ Enclosure – VII09 /
Signature of the candidate
/ (SHYANUBHOGARA BASAVARAJ)10 / Remarks of the Guide / The above mentioned title will be carried out in our college, in the Dept. of Quality Assurance under the supervision of
Sri. G.M.Sreenivasa
11 / Name and Designation of
(In Block Letters)
11.1. Guide
Guide reference no. of RGUHS
ACA/CDC/PGT-
M.Ph/SCS/02/2005-06/19.01.09
11.2.Signature
11.3.Co-Guide
Co-Guide reference no of
RGUHS
ACA-2/RP-TEA/01/97-98/3-6-
98
11.4.Signature
11.5. Head of the Department
11.6.Signature / Mr. G. M.SREENIVASA
M.Pharm,
ASST.PROFESSOR
P.G.DEPTOF QUALITY ASSURANCE
S.C.SCOLLEGE OF PHARMACY
HARAPANAHALLI-583131.
DAVANAGERE (DIST)
Dr. E. JAYACHANDRAN
PROFESSOR & HEAD
P.G. DEPT OF PHARMACEUTICAL
CHEMISTRY
Dr.R.NAGENDRA RAO
M.Pharm, Ph.D
PROFFESSOR & HEAD
P.G. 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.
Pharmaceutical excipients are substances other than the API which have been appropriately evaluated for safety and are intentionally included in a drug delivery system. Traditionally, excipients were included in drug formulations as inert vehicles that provided the necessary weight, consistency and volume for the correct administration of the active ingredient and performance of technological functions that ensure ease of manufacture. The specific application of natural polysaccharides polymers in pharmaceutical formulations include to aid in the processing of the drug delivery system during its manufacture, protect, support or enhance stability, bioavailability or patient acceptability, assist in product identification, or enhance any other attribute of the overall safety, effectiveness or delivery of the drug during storage or use1.
Developments of several drug delivery systems are based on natural polymers that do not change their chemical structure but these materials degrade within the body as a result of natural biological processes, eliminating the need to remove a drug delivery system after release of the active agent has been completed. Moreover these modify, drug release to achieve the dosage forms to release the drug in a constant manner and maintain steady state plasma concentration for the entire period of treatment to reduce the dose related adverse effects. The recent rediscovery of polysaccharide based materials is also attributable to new synthetic routes for their chemical modification, with the aim of promoting new biological activities and/or to modify the final properties of the biomaterials for specific purposes2.
Polymers have been successfully employed in the formulation of solid, liquid and semi-solid dosage forms and are specifically useful in the design of modified release drug delivery systems. Both synthetic and natural polymers have been investigated extensively for this purpose3 but the use of natural polymers for pharmaceutical applications is attractive because they are economical, readily available, non-toxic, and capable of chemical modifications, potentially biodegradable and with few exceptions, also biocompatible. Because of their wide diversity in structure and physical properties natural polysaccharides have found a wide range of applications in the food, pharmaceutical and other industries4.
Guar gum is a naturally occurring galactomannan polysaccharide, consists of chiefly high molecular weight hydrocolloidal polysaccharide, composed of galactan and mannan units combined through glycosidic linkages and shows degradation in the large intestine due to the presence of microbial enzymes. It contains about 80% galactomannan, 12% water, 5% protein, 2% acid soluble ash, and 0.7% fat. Guar gum has a molecular weight of approximately 1 million, giving it a high viscosity in solution. The high viscosity of guar gum results from its high molecular weight and long chain structure.
Guar gumand its derivatives are most commonly used at concentration below 1% w/v. High viscosity products form thick dispersions and form gels at 3% w/v. Guar and guar derivatives are available in lower viscosity grades for special applications. Guar gum has been used in various pharmaceutical applications, however, its pharmaceutical application limits its use because of uncontrolled rate of hydration, drop in viscosity on storage, poor interaction coefficient and susceptibility to microbial contamination. Moreover, guar imparts colour when used in extemporaneous preparations and produces translucent or turbid solution in liquid dosage form. Keeping this in view, an attempt is made to over come such limitations by suitably derivatizing the guar gum to sodium carboxy methyl hydroxy propyl guar5-6.
Transdermal drug delivery is one of the most promising methods for drug application. Increasing numbers of drugs are being added to the list of therapeutic agents that can be delivered to the systemic circulation viaskin. The transdermal route offers several advantages over conventional dosage forms such as tablets and injections, including avoidance of first-pass metabolism by the liver, minimization of pain, reduction of side effects, extended duration of activity, reduction in the fluctuations of drug concentrations in the blood and possible sustained drug release7.
The transdermal route of drug delivery is becoming increasingly popular with the demonstration of the percutaneous absorption of a large number of drugs. In view of its excellent film forming property, sodium carboxymethyl guar (sodium CMG) has been chosen and studied for its usefulness as a monolithic polymeric matrix in the development of transdermal patches8.
Aceclofenac is a Non-steroidal anti-inflammatory drug (NSAID) used for relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.Aceclofenac is a phenylaceticacid derivative and it is a inhibitor of prostaglandins synthesis. Aceclofenac is readily absorbed from the gastrointestinal tract, peak plasma concentration occur about 4hour after a dose, 99% bound to plasma protein. Unfortunately, the systemic administration of this drug, similar to other NSAIDs, presents gastrointestinal side effects that could be avoided by using a topical application9-12 .
In view of the shorter plasma half life, aceclofenac is chosen as a candidate for exploring its application as transdermal drug delivery system.
ENCLOSURE-II
6.2 Review of Literature
1) Paranjyothy KLK, Thampi PP13. Studies were carried out by synthesizing and
characterization of sodium carboxy methyl guar and studied the rheological
properties of the derivative. Sodium carboxy methyl guar was found to be stable and
less prone to the microbial contamination then guar gum. The solution showed
pseudo plastic flow pattern and to be a promising derivative for exploring its utility
in pharmaceutical application.
2) Misra AN, Baweja JM14. Evaluated modified guar gum for its use in
development of controlled release tablets using phenylpropanolamine as a model
drug. The prepared products were compared with the products made with guar gum
and HPMC as the matrices.
3) Paranjyothy KLK15. Synthesized various derivative of guar gum such as guar
acetate, guar phthalate, guar succinate and guar benzoate and studied their physical
characterization like viscosity solubility and pharmaceutical application.
4) Roy Whistler AM16. Industrial gum; Gave information on the effect of time,
temperature, ionic strength, and pH on the viscosity of guar gum solution. The
guar gum dispersion was subjected to various pH ranges, temperature etc and it was
observed, and all these factors affected the viscosity of the guar gum dispersion.
5) Lawrence AA17. Edible gums gave information regarding synthesis of guar gum
derivatives for its utility in food supplements. Different derivatives were
synthesized and there utility in the food supplements were studied.
6) Li-Ming Zhang18. Study the two important guar gum derivatives,hydroxypropyl
substituted guar (HPG) and carboxy methyl hydroxyl propyl substituted guar
(CMHPG), were studied at different mixing ratios,shear rates and temperatures.
Values are higher than the calculated viscosity values determined by the additivity
rule for ideal two-component solution mixture, showing an interesting synergistic
viscosity property. This viscosity synergism may be attributed to the formation of
interpolymer complex between the mixed CMHPG and HPG components, as
confirmed by UV spectroscopy measurements and its degree depends on the
compositions of the mixed polysaccharide solutions and the shear rates. At same
temperature, the zero-shear viscosity of the mixed solution is larger than that of
any component solution. For aqueous CMHPG, HPG component solutions with
same concentrations of 1.0% (w/v) and their mixed solution with a 0.50 weight
fraction of HPG, the activation energies of the apparent viscosity were
determined to be 30.1, 27.9 and 14.0 kJ/mol, respectively. In contrast, the mixed
CMHPG/HPG solution showed improved temperature tolerance with respect to the
viscosity.
7) Narasimha Murthy S19. Carboxy methyl guar (CMG), an anionic semisynthetic guar
gum derivatives was evaluated for its suitability of use in transdermal drug
delivery systems. Terbutaline sulfate (TS) was used as a model drug. The
diffusion of terbutaline sulfate from CMGS solution was relatively slower at pH 5
than atpH 10.It is most likely that the interaction between CMGS and terbutaline
sulphate at pH 5 is physical at involving static interaction. The ability of such
interactions in modifying the release kinetics of drug from the CMGStransdermal
films was studied. The release was exponential from pH 5 formulations whereas
the release rate followed zero or higuchian from pH 10 formulations. However,
the diffusion kinetics of both pH 5 and pH 10 formulations followed zero order
across human cadaver epidermis. Such an interaction was also found to alter the
pharmacokinetic parameters of the drug.
8) Brij Raj Sharma20. Carbamoylethylation of guar gum was carried out with
acryl amide in presence of sodium hydroxide under different reaction conditions.
Variables studied were concentration of sodium hydroxide, acrylamide, guar gum
as well as reaction temperature and time. The nitrogen content, carboxyl content
and total ether content were determined. Rheological properties of carbamoylethyl
guar gum solutions showed non-Newtonianpseudo plasticbehaviour regardless of
the %N. At a constant rate of shear, the apparent viscosity of carbamoylethyl guar
gum solutions decreases with the increase in %N of the product.
ENCLOSURE -III
6.3 Objectives of the study:
Guar gum is a galactomannan polysaccharide with high swellability, reduced toxicity and cost effective. However its pharmaceutical application limits because of its uncontrolled rate of hydration, fall in viscosity on storage and susceptibility to microbial contamination.An attempt is made to overcome the above stated limitation by derivatizing guar gum to sodium carboxy methyl hydroxy propyl guar.
For derivitization trial and error, method was adopted, by varying the amount of guar gum, propylene oxide sodium monochloroaceteate and sodium hydroxide at different temperature to obtained sodium carboxy methyl hydroxy propyl derivative of guar.
The best method will be selected based on yield of derivative and reproducibility of the results.
To characterize the derivative based on physical, chemical, and spectral data.
Study of stability and compatibility of the derivative with other excipient used in formulation.
To develop transdermal patches of aceclofanac using sodium carboxy methyl hydroxy propyl derivative of guar as a film forming agent and to carry out comparative evaluation with patch prepared using various polymers.
To study the release pattern of the drug from transdermal patches prepared using sodium carboxy methyl hydroxypropyl guar derivative and other polymer patches.
To study the drug release and release rate kinetics from the formulations.
To carry out stability study of the selected formulation.
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.
- From various search engines like google.com, ask.com etc.,
- By referring various journals from libraries of Indian Institute of Science,
Bangalore.,
- Libraries of various Universities like KuvempuUniversity, Shankargatta,
KarnatakaUniversity, Dharwad.
- Various data collected for evaluation of prepared formulations like
Thickness.
Tensile strength and percentage elongation.
Moisture content determination.
Weight variation.
Folding endurance.
Drug content and content uniformity.
In-vitro drug release pattern by using static dissolution test apparatus.
Stability studies.
ENCLOSURE – V
7.2 Method of collection of data:
Synthesis of sodium carboxy methyl hydroxy propyl guarby alkali slurry method (NaCMHPG).
Carry out physical characterization such as effect of temperature, pH, and electrolyte, compare with that of guar gum.
Carry out rheological studies and rate of hydration of NaCMHPG and compare with that of guar gum.
Carry out chemical characterization such as sodium content, determination of degree of substitution, chemical tests etc.
Carry out spectral characterization such as I.R technique to identify the introduction of sodium carboxy methyl group and hydroxy propyl group in the guar structure.
Study the compatibility of NaCMHPG with drug and other excipient used in formulation.
Standard graph of drug aceclofenac.
To develop transdermal patches of aceclofenac using sodium carboxy methyl hydroxy propyl derivative of guar as a film forming agent and to carry out comparative evaluation with patch prepared using various polymers.
To study the release pattern of the drug from transdermal patches prepared using sodium carboxy methyl hydroxy propyl guar derivative and other polymer pathches.
To study the drug release and release rate kinetics from the formulations.
To carry out stability studied of the selected formulation.
ENCLOSURE – VI
7.3DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTION. TO BE CONDUCTED ON PATIENTS OR OTHER HUMANS /ANIMALS? IF SO PLEASE DESCRIBED BRIEFLY.
Yes, the above study requires investigation to be done on the Albino rats for the
in vitro release study of prepared patches.Experiments are to be conducted on
anaesthetized rats.
7.4Has ethical clearance been obtained from your institution in case of 7.3?
The present study is approved from Institutional Animal Ethics Committee (IAEC certificate enclosed.)
ENCLOSURE – VII
8.0 List of references:
1)Manjanna KM, Prmod kumar TM,Shivakumar B.Natural polysaccharide
hydrogels as novelexcipients formodified drug delivery systems.
International Journal of Chem Tec Research. 2010;2 (1): 509-25.
2)Tommasina coviello, Pietro matricardi.Polysaccharide hydogels for modified
releaseformulations. J.control release. 2007;119:5-24.
3) Guo JS, Kinner GW, Harcum WW, BarnumPE. Pharmaceutical application of
naturally occurring water-soluble polymers.PSTT. 1998;1:254-61.
4)Varshosaz J, Tavakoli N, Eram SA.Use of natural gums and cellulose
derivatives in production of sustained release metoprolol tabletsdrug
deliv.2006;13:13-19.
5) Robert L, Davidson. Hand book of edible gums. New York: Academic press;
1980;22-43.
6)Whisler RL. Industrial gums. 2nd edition.McGraw-Hill Book Company; 1973;
315-39.
7)Prausnitz MR, Mitragotri S, Langer.Current status and future potential
oftransdermal drug delivery.Nature Reviews, Drug Discovery. 2004;3:
115-24.
8) Paranjyothy KLK.Thesis titled “Synthesis of derivatives of guar gum
and study of their pharmaceutical application. 1992.
9)Gowda DV, Girish B, Shivakumar HG, Afrasin Moin. Preparation and
evaluation of carnaubawax microspheres loaded with aceclofenac for
controlled release.Ind.J. Pharm. Edu&Res.2008;42:329 -36.
10)Burkhard Heinz, Thomas Rau, Daniel Werner. Aceclofenac spares
cyclooxygenase-1as a result of limited but sustained biotransformation to
diclofenac.Clin PharmacolTher. 2003;74: 22-27.
11) Jaehwi Lee, Yoonjin Lee, Jongseok Kim, Mikyeong, Young Wook Choi.
Formulations of micro emulsion systems for transdermal delivery of
aceclofenac.ArchPharm Res.2005;28: 197 -02.
12)Srinivas Mutalik. Enhancement of dissolution rate and bioavailability of
aceclofenac: A chitosanbased solvent change approach. Int. J.Pharm.2008;
350:279 -90.
13)Paranjyothy KLK, Thampi PP. Synthesis of Sodium carboxy methyl guar
andits characterization. Indian drugs. 1992;29 (9): 404-07.
14)MisraAN, Baweja JM. Modified guar gum as hydrophilic matrix for
controlled release tablets. Indian drugs.1997;215-23.
15)Paranjyothy KLK. Synthesis of guar derivatives.Indian drugs. 1991;29 (2):
84-87.
16) Whisler RL. Industrial gums. 2nd edition. McGraw-Hill Book Company; 1973;
315-39.
17) Lawerence AA. Edible gums and related substances. Noyes Data Corporation.
1973; 1-32.
18) Li-Ming Zhang. Synergistic viscosity characteristics of aqueous mixed
solutions of hydroxypropyl and carboxymethyl hydroxypropyl-substituted
guar gums.Colloids and Surfaces A, Physicochem. Eng.Aspects.2006;
279: 34–39.
19) Narasimha Murthy S, Shobha Rani R, Hiremath, Paranjothy KLK.
Evaluation of carboxymethyl guar films for the formulation of transdermal
therapeutic systems. International Journal of Pharmaceutics. 2004; 272:
11–18.
20) Brij Raj Sharma, Vineet Kumar, Soni PL. Carbamoylethylation of guar
gum.Carbohydrate Polymers. 2004; 58:449–453.