FORMULATION AND EVALUATION OF TOPICAL NSAIDMICROEMULSION

M.PHARM DISSERTATION

SUBMITTED TO

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES

KARNATAKA

BY

G.JEEVAN REDDY

I M.PHARM

UNDER THE GUIDANCE OF

Dr.K.RAMESH

PROFESSOR

DEPARTMENT OF PHARMACEUTICS

KARNATAKACOLLEGE OF PHARMACY

BENGALURU-560064

(2012-2013)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.

ANEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 / Name of the Candidate and Address / G.JEEVAN REDDY
Karnataka College of Pharmacy
#33/2, Thirumenahalli
Hegde Nagar Main Road
Bengaluru-560 064
PERMANENT ADDRESS
s/o G.Nageswara Reddy
Maddur (vil),
Pamulapadu (md),
Kurnool (dt),
Andhra Pradesh-518 533
.
2 / Name of the Institute / KarnatakaCollege of Pharmacy
#33/2, Thirumenahalli
Hegde Nagar Main Road
Bangalore-560064
3 / Course of the Study & Subject / MASTER OF PHARMACY
in
PHARMACEUTICS
4 / Date of the Admission to the Course / May21st 2012
5 / Title of the topic:
FORMULATION AND EVALUATION OF TOPICAL NSAIDMICROEMULSION
6 / BRIEF RESUME OF THE INTENDED WORK:-TIVIT
6.1
6.2 / Need forStudy:
Topical medications are applied directly to the skin. The different classes of topical drug delivery systems (TDDS) are as follows: lotion, ointment, cream, gel, emulsions etc., . Among these, microemulsions as skin drug delivery systems has gained interest recently. Microemulsions are thermodynamically stable transparent, single optically isotropic liquid systems of water, oil and surfactants.
Transdermal drug delivery (TDDS) has high drug loading capacity they can provide higher concentration gradient, thus increasing driving force across the skin. Microemulsion has low interfacial tension and will allow excellent contact with skin surface, with the vehicle filling even wrinkles and microscopic gaps. This enhances the vehicle skin drug transfer.
Microemulsionsare used to improve the bioavailability of various poorly soluble drugs including Non-steroidal anti-inflammatory drugs (NSAID). Their size generally range from 10-200nm. They can be classified as oil-in-water (o/w), water-in-oil (w/o) or bi-continuous systems depending on their structure and are characterized by ultra low interfacial tension between oil and water phases1.
Topical NSAID represent an attractive alternative to systemically administered drugs.In topical formulations they have been proved to increase the cutaneous absorption of both lipophilic and hydrophilic active pharmaceutical ingredient (API). In this type of applications the micro emulsions attribute to the performance to generally a higher solubility of the API of micro emulsions, generating increased concentration gradient towards skin.
Topical application of NSAIDon the inflamed site can offer the advantage of delivering a drug directly to the disease site and producing its local effect.NSAIDhave been widely used in the treatment of rheumatoid arthritis and other related conditions.
The present dissertation work is to focus on developing an NSAIDmicroemulsion adaptable transdermal delivery systems which provides protection against oxidation, fastabsorption, thereby balances bioavailability, prolonged release and enables reduction in dose. So the current research work is strong potential to formulate and evaluate the microemulsions using an ideal topical drug candidate of NSAID by suitable method with its release and stability studies as per ICH guidelines.
Review of Literature:-
  • The study deals with the preparation of topical microemulsion gels of Nimsulide a poorly water-soluble non-steroidal anti-inflammatory drug, with an aim to increase its penetration capacity and there by its efficiency. The area of the microemulsion region increased with increasing ratios of surfactant/cosurfactant. The sizes of the systems formed were 87± 2 and 61± 4 nm. For the final study four formulations were chosen out of which two are microemulsions gels and the rest were microemulsion-based gels. The results showed that release of drug from F4 was found to be 91.33% as compared to 64.19% from marketed and microemulsion based gels2.
  • Microemulsions, which are clear, stable, isotropic mixtures of oil, water and surfactant, frequently in combination with a co surfactant. The system is currently of interest to the pharmaceutical scientist because of their considerable potential to act as drug delivery vehicles by incorporating a wide range of drug molecules. The use of micro emulsions and closely related micro emulsions-based systems as drug delivery vehicles is reviewed, with particular emphasis being placed on recent developments and future directions3.
  • Glipizide based micro emulsion is developed and its usefulness as topical drug carrier system for the non-insulin dependent diabetes mellitus (NIDDM) was investigated. The results indicates that the developed micro emulsion systems may be promising vehicles for the transdermal delivery of glipizide. Microemulsion system provides viscous consistency for the topical application, which delivered the drug in sustained or controlled manner and prolonged delivery as compared to conventional dosage form4.
  • Investigation on photo degradation of some tretinoin cream formulations is evaluated. Several oils are selected to prepare the cream formulations: olive oil, maize oil, castor oil, isopropyl myristate and miglyol 812. The photo stability of tretinoin in oils is comparable with the photo stability of a tretinoin lotion (ethanol/propylene glycol 50/50), castor oil and olive oil giving slightly better results than the other oils. Tretinoin is far more stable in the cream formulations than in the respective oils; however it is not clear whether this is due to the formulation or due to a different irradiation technique5.
  • The purpose of the study is to improve the solubility and enhance bioavailability of poorly water-soluble cyclosporine-A loaded in o/w microemulsion systems.Droplet size of microemulsion without cyclosporine-A is decreased with the increase of cremophor EL content. The droplet size increased on increasing the incorporation of. The enhanced bioavailability of cyclosporine-A loaded in this microemulsion system might be due to the reduced droplet size of microemulsion systems6.
  • Investigated metaprolol tartarate as a transdermal drug delivery system for controlledrelease of drug for extended period of time. Eudragit RL and hydroxy propyl methylcellulose were used for fabrication of the formulation. These systems were characterized for their thickness, tensile strength and drug content. Then this is evaluated in vitro releasekinetics and skin permeation studies and compared its drug plasma profile with metaprolol tartarate7.
  • In vitro release rate of diclofenac sodium from microemulsion vehicles containing soybean oil, non-ionic surfactants, and different alcohols as co-surfactant. The optimum surfactant: co-surfactant weight ratios and microemulsion areas are detected by the aid of phase diagrams. Three microemulsion formulations are selected, and their physicochemical properties are examined for the pH, viscosity, and conductivity. Moreover, viscosity measurements were examined as a function of shear rate, and Newtonian fluid characterization was observed for each micro emulsion system8.
  • The potential application of highly biocompatible o/w microemulsions as topical drug carrier systems for the percutaneous delivery of anti-inflammatory drugs are investigated. Microemulsions were made up of triglycerides as oil phase, a mixture of lecithin and n-butanol as a surfactant/co-surfactant system and an aqueous solution as the external phase. No significant percutaneous enhancer effect is observed for ketoprofen-loaded oleic acid–lecithin micro emulsion. The human skin tolerability of various micro emulsion formulations was evaluated on human volunteers. Micro emulsions showed good human skin tolerability9.
  • The purpose of thestudy is to improve the solubility of ibuprofen, a poorly water-soluble drug, ina microemulsion system that is suitable for oral administration.The optimal formulation consists of 17% Labrafil M 1944CS, 28% Cremophor RH40/Transcutol P (3:1, w/w), and 55% water, with a maximum solubility of ibuprofen up to 60.3 mg/ml. The meandroplet size of microemulsion was 57 nm. The pharmacokinetic study of microemulsion is performed inrats and compared with granule formulation. The microemulsion has significantly increased the Cmax andarea under the curve (AUC) compared to that of the granule (p < 0.05)10.
  • Methoxsalen has been used for the treatment of psoriasis. In order to develop alternative formulations for the topical administration of methoxsalen, chitosan coated microemulsion are evaluated as delivery vehicle. Microemulsions were prepared using water, soya bean oil. The ability of the system to deliver into the skin was evaluated using dialysis membrane and human cadaver skin. These in vitro studies clearly show that methoxsalen loaded chitosan-coated micro emulsion provides control release of methoxsalen with retention on the skin11.
  • Topical microemulsions of nimusulide, a poorly water-soluble non-steroidal anti-inflammatory drug, using olive oil as oil phase and tween 80/iso-octanol as surfactant/co-surfactant are formulated. In vitro permeation study of the gel is carried out through excised hairless rat skin and it is compared with a marketed preparation. The drug release after 24 h from the prepared microemulsion gel and marketed formulation was found to be 72% and 81% respectively. Microemulsion-based gel of poorly water-soluble nimesulide was successfully developed with in vitro release rates comparable to that of the marketed gel formulation12.

6.3 / Objective of the study:-
The objective of the study is as follows:
  • To develop microemulsions as drug carrier system
  • To formulate a suitable method for microemulsions
  • Evaluation of formulated micro emulsions
  • Characterization of selected formulation of microemulsions
  • Stability studies for the selected formulations as per ICH guidelines

7 / Material & Methods
7.1 / Source of Data
  1. The data will be obtained from the literature survey and internet source.
  2. The data will be obtained from the experimental work, which includes formulation of self micro emulsion, evaluation and stability studies.

7.2 / Method of Collection of Data
  • Data on drug and excipients are collected from the drug information centre, patents, reference books, text books, catalogs etc.
  • Data will be collected from the prepared formulations, in-vitro dissolution studies and stability studies. In- vitro dissolution studies will be used as criteria for assessing the enhancement of oral bioavailability of poorly aqueous soluble drug.

7.3 / Materials:
Drug
The Non-steroidal anti-inflammatory drugs will be procured or obtained from suitable pharma grade manufacturer.
Excipients The natural, synthetic, biodegradable polymers, oils, surfactant, co-surfactant will be procured from pharma grade manufacturer.All other chemicals will be used of analytical grade.
7.4 / Methods
1) Preformulation Studies
a) Thermal analysis
b)Incompatibilitystudies
2)Formulation Studies
  • Microemulsion method
  • Self-emulsification
  • Particle sizing
  • Droplet method
3) Evaluation of Microemulsions
  • Drug loading efficacy
  • Content uniformity
  • Assay
  • Particle size determination
  • Viscosity
  • Transmission test
  • Droplet size measurement
  • Zeta potential measurement
4) Characterisation of Microemulsions
  1. Surface morphology
  2. Particle size analysis
5) Stability Studies as per ICH guidelines
7.5 / 7.3 Method of Screening:
Does the study require any investigations or interventions to be conducted
On patients or other human or animals? If so please describe briefly
-NOT APPLICABLE-
7.6 / Has the Ethical Clearance been obtained from your Institution in case of 7.5?
-NOT APPLICABLE-
8 / LIST OF REFERENCES:
  1. Sushama T, Adnan A, Farhan JA, Roop KK, Shadab AP, Zeenat IK.Microemulsions: A novel approach to enhanced drug delivery. Bentham Sci Publishers Ltd 2008; 2:238-257.
  2. Ashish Y. Pawar et al.Formulation, Development and evaluation of topical microemulsion gels for nimsulide. J Pharm Research 2011;4(4):1004-1006.
  3. Lawrence MJ, Gareth D. Microemulsion-based media as novel drug delivery systems. Adv Drug Delivery Rev 2000; 45: 89–121.
  4. Suman R, Manish K,Vikas C, Vandana G. Formulation development and characterization of micro emulsion for topical delivery of glipizide. Der Pharmacia Lettre 2010; 2(3): 33-42.
  5. Brisaert M, Plaizier JA, Vercammen. Investigation on the photo stability of tretinoin in creams.Int J Pharm 2007; 334: 56-61.
  6. Chong KK, Zhong GG, Han-G C, Hee Jong S, Kyung MP, Soo Jeong. Physicochemical characterization and evaluation of a micro emulsion system for oral delivery of cyclosporine A. Int J Pharm 1998; 161: 75–86.
  7. Sedigeh D, Behzad S, Makhmal Z, Rahim F. Preparation and evaluation of the self emulsifying drug delivery system containing loratadine.Int J Adv Pharm Sci2010; 239-248.
  8. Sevgi A, Gulten K, Ozguney I, Yesim K. Comparison of different Water/Oil micro emulsions containing diclofenac sodium preparation, characterization, release rate, and skin irritation studies. AAPS Pharm SciTech 2007; 8 (4): 91.
  9. Donentella P, Cinzia AV, Steven N, Giovanni P, Massimo F. Lecithin Micro emulsions for the topical administration of ketoprofen; percutaneous adsorption through human skin and in vivo human skin tolerability. Int J Pharm 2002; 44: 21–31.
  10. Huabing Chen A et al,Microemulsion-based hydrogel formulation of ibuprofen for topical delivery. Int J Pharm 2006;315:52–58.
  11. Jitendra B, Raj K.K, Arvind Y. Methoxsalen loaded chitosan coated micro emulsion for effective treatment of psoriasis. Int J Drug Del 2010; 2: 159-67.
  12. Derle DV, Sagar BSH, Pimpale S. Microemulsion as a vehicle for transdermal permeation of nimesulide. Ind J Pharm Sci 2006; 68(05): 622-5.

9 / Signature of the Candidate / (G.JEEVAN REDDY)
10 / Remarks of the Guide
The topic selected for dissertation is satisfactory. Adequate equipment & chemicals are available to carry out the project work.
11 / Name & Designation (in BLOCK LETTERS)
11.1 / Guide / Dr.K.RAMESH
PROFESSOR & DIRECTOR
DEPARTMENT OF PHARMACEUTICS
KARNATAKA COLLEGE OF PHARMACY
BANGALORE-560064.
11.2 / Signature of Guide / ( Dr.K.RAMESH)
11.3 / Co-Guide / NOT APPLICABLE
11.4 / Signature of Co-Guide / NOT APPLICABLE
11.5 / Head of the Department / Dr.K.RAMESH
PROFESSOR AND HEAD OF THE DEPARTMENT OF PHARMACEUTICS
11.6 / Signature of HOD /
( Dr.K.RAMESH)
12 / Remark of the Principal
All the required facilities will be provided to carry out dissertation work under the supervision of the guide.
12.1 / Principal / DR.K.RAMESH.
PRINCIPAL
KARNATAKACOLLEGE OF PHARMACY
BANGALORE-560064
12.2 / Signature of the Principal / ( K.RAMESH )