Formulation and Evaluation of Diclofenac Sodium Microsponge Gel for Topical Drug Delivery

“FORMULATION AND EVALUATION OF DICLOFENAC SODIUM MICROSPONGE GEL FOR TOPICAL DRUG DELIVERY”

MASTER OF PHARMACY DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE.

Miss. RESHMY VASAVAN

M.PHARM – I

Under The Guidance of

Dr. A.R. SHABARAYAM.Pharm, Ph.D.

DEPARTMENT OF PHARMACEUTICS.

SRINIVAS COLLEGE OF PHARMACY, VALACHIL MANGALORE – 574143.

2012-2014

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE AND ADDRESS: / MISS. RESHMY VASAVAN
1st YEARM.PHARM,
DEPT. OFPHARMACEUTICS,
SRINIVAS COLLEGE OF PHARMACY
VALACHIL, MANGALORE-574143.
2. / NAME OF THE INSTITUTION: / SRINIVAS COLLEGE OF PHARMACY
VALACHIL, FARANGIPETE POST, MANGALORE-574143.
3. / COURSE OF STUDY AND SUBJECT: / MASTER OF PHARMACY (PHARMACEUTICS)
4. / DATE OF ADMISSION: / 25 JUNE 2012
5. / TITLE OF THE PROJECT:
“FORMULATION AND EVALUATION OF DICLOFENAC SODIUM MICROSPONGE GEL FOR TOPICAL DRUG DELIVERY”
6.
7.
8. / Brief Resume of the intended work:
6.1 Need of the study:
A Microsponge Delivery System (MDS) is patented, highly cross-linked, porous, polymeric microspheres that can entrap wide range of actives and then release them onto the skin over a time and in response to trigger. This system was employed for the improvement of performance of topically applied drugs.1
Microsponges can be defined as polymeric delivery systems consisting of porous microspheres that can entrap ingredients such as fragrances, sunscreens, essential oils, emollients, anti-fungal, anti-infective and anti-inflammatory agents. Like a true sponge, each microspheres consists of myriad of interconnecting voids within a non-collapsible structure with a large porous surface.2
MDS is a unique technology for the controlled release of topical agents and consists of microporous beads, typically 10-25 microns in diameter, loaded with an active agent. When this is applied to the skin, the release of drug can be controlled through diffusion or other variety of triggers, including rubbing, moisture, pH, friction, or ambient skin temperature.
Microsponges offers, enhanced product performance; extended release; reduced irritation and hence improved patient compliance; improved product elegancy; oil control: It can absorb oil up to 6 times its weight without drying; improved formulation flexibility; improved thermal, physical, and chemical stability; flexibility to develop novel product forms; These are also non-irritating, non-mutagenic, non-allergenic and non-toxic.1
The MDS has advantages over other technologies like microencapsulation and liposomes. Microcapsules usually control release of the actives. Liposomes suffer from lower payload, difficult formulation, limited chemical stability and microbial instability. Similarly ointments are often aesthetically unappealing, greasy, sticky etc. They also require high concentration of the active ingredient for effective therapy. 3
Characteristics of Microsponges

These formulations are stable over a range of pH 1 to11
These are stable at the temperature up to 130˚C
These are compatible with most vehicles and ingredients.
These are self sterilising as their average pore size is 0.25µm where bacteria cannot penetrate
These have higher payload (50% to 60%), still free flowing and can be cost effective.4

Diclofenac is a non steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic. It is used to treat pain, inflammatory disorders and dysmenorrhoea. It is primarily available as sodium salt. The anti-inflammatory effects of diclofenac are believed to be due to both inhibition of leukocyte migration and the enzyme cyclooxygenase (COX 1 and COX 2), leading to the peripheral inhibition of prostaglandin synthesis. As these prostaglandins sensitize pain receptors, inhibition of their synthesis is responsible for the analgesic effect of diclofenac. Antipyretic effects may be due to action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat dissipation. Diclofenac is the drug having short biological half life (2 hours).5
In present study, attempt is made to design and evaluate microsponge gel containing Diclofenac sodium for external application.
6.2 – Review of literature:
Maiti S, Kaity S, Ray S, Sa B (2011) prepared and evaluated Microsponges by double emulsification technique and subsequently dispersed in a carbopol gel base for controlled delivery of Diclofenac sodium to the skin. SEM revealed the porous, spherical nature of the microsponges. Increase in the drug/polymer ratio increased their yield, drug entrapment efficiency and mean particle diameter. FTIR spectroscopy and DSC analyses indicated the chemically stable, amorphous nature of the drug in these microsponges. The microsponge system obtained at the lowest drug/polymer ratio could be useful for the controlled release of Diclofenac sodium to the skin.6
Mahajan AG, Jaytap LS, Chaudhari AL Swami SP, Mali PR (2011) prepared
Indomethacin microsponges by using Eudragit RS 100 PVA. Microsponges
were prepared by Quassi emulsion solvent diffusion method by changing the drug polymer ratio and the process was optimised. In-vitro dissolution study indicated that the release of indomethacin varied according to the concentration of the matrix forming polymer. Indomethacin microsponge prepared in this study were found to be more useful than the conventional forms.7
Mehta M, Panchal A, Shah VH, Upadhyay U (2012) prepared and evaluated controlled release microsponge gel for topical delivery of Clotrimazole. So, encapsulation into microsponge would modify the release rate and also reduce the side effects. The formulation was made by emulsion solvent diffusion technique. The drug release data of optimised batch was fitted into different kinetic models. Optimised gel formulation was compared with the marketed formulation and the pure drug for anti-fungal activity, which shows that the prepared formulation is having comparative anti fungal activity with marketed formulation.8
Nokhodchi A, Jelvehgarim M, Reza, Siahi Reza, Mozafari (2005) Benzoyl peroxide (BPO) is used in treatment of acne vulgaris. Skin irritation is a common side effect, and it has been shown that controlled release of BPO from a delivery system to the skin could reduce the side effects while reducing percutaneous absorption. Benzoyl peroxide micro particles were prepared using quasi emulsion solvent diffusion method. The release data showed that the highest release rate was obtained from lotions containing BPO micro particles and the lowest was obtained from cream formulations.9
Saravanan M, Bhaskar K, Maharajan G, Pillai KS (2011) developed gelatine microspheres loaded with Diclofenac sodium for intra-articular administration. This was formulated to overcome complications in the administration of magnetic microspheres and achieve higher targeting efficiency. This was prepared by emulsification/cross linking method and characterised by Scanning Electron Microscopy (SEM), drug loading, FTIR, DSC etc. The formulated microspheres could prolong the drug release upto 30 days in vitro, revealing good targeting efficiency.10
Shahin M, Hady SA, Hammad M (2011) Jojoba oil-based emulgel formulations were prepared using different concentrations of various gelling agents, such as hydroxypropylmethylcellulose (HPMC) and Carbopol 934 P and combination of both. The drug release from the commercial preparation was lower than some of the prepared emulgel formulae.11
Rizkalla C, Aziz R, Soliman I (2011) evaluated by in-vitro and in-vivo, Hydroxyzine hydrochloride microsponges for topical delivery. The side effects associated with the usage of his drug was reduced and so was percutaneous absorption.themicrosponges were prepared by oil in oil emulsion solvent diffusion method using acetone as the dispersing solvent and liquid paraffin as the continuous medium. It was found that microsponges of 98% encapsulation efficiency and 60%to 70% porosity were produced.12
John ID, Harinath N (2008) prepared microsponge containing Flucinoloneacetonide(FA) by optimised quassi emulsion solvent diffusion method. FTIR and DSC studied compatibility of drug with reaction adjuncts. Production yield, loading efficiency, particle size analysis and surface morphology of microsponges were performed. Microsponges were spherical in shape between 31.34µm and 82.26µm in diameter. Drug release was observed controlled.13
Jain V, Singh R (2010) formulated microsponge containing paracetamol loaded Eudragit based microsponges using quassi emulsion solvent diffusion method. The compatibility of the drug with various formulation components were established. In vitro and in vivo studies were carried out. In the first hour, release of the drug from the microsponge was found to be between 17-30%. The release kinetics showed that it followed Higuchis model and the main mechanism of drug release was diffusion.14
Comoglu T, Gomul N, Baykara T(2002) prepared ketoprofen microsponges by quassi emulsion solvent diffusion method with Eudragit RS100 and then tablets were made by direct compression method. Results obtained showed that microsponge compressibility was much improved over the physical mixture of the drug and the polymer.15
6.3 – Objectives of the study:

Selection of suitable drug moiety (Diclofenac sodium) for the formulation of Microsponge for topical drug delivery
Screening of polymers and excipients required for the formulation.
Conducting preformulation studies for drug and the polymer with FTIR.
Formulation of microsponge gel.
Evaluation studies8

1)Compatibility studies
2)Evaluation test for microsponge.

Particle size and shape
Production yield
Loading efficiency
In-vitro drug release study

3)Evaluation of microsponge gel

Viscosity
pH
Clarity
Drug content
In-vitro permeation study
Skin irritancy studies6
Stability studies as per ICH guidelines

6.4 - Materials and Methods:
Materials:
a)Drug : Diclofenac sodium
b)Polymers :Ethyl cellulose, HPMCK4M, Carbopol 934, Eudragit RS100, Eudragit
S100, Eudragit RL100 etc.
c)Methods: Anyone of the following methodsLiquid – Liquid Suspension
Polymerisation, Quassi - Emulsion Solvent Diffusion.
d)Equipments:FTIR Spectrometer
USP dissolution test apparatus
pH meter
Franz diffusion cells.
7.1 Source of data:
Review of literature from
a) Journals such as

International Journal of Pharmaceutical Sciences and Research
Global Journal of Pharmaceutical Research.
International Journal of Advanced Pharmaceutics.
International Research Journal of Pharmacy.
Acta Pharm.
Indian Journal of Drug Discovery and Medical Research.
International Journal of Pharmaceutical Sciences Review and Research
Journal of Pharmacy Research
International Journal of Pharmacy and Pharmaceutical Sciences
International Journal of Comprehensive Pharmacy
International Journal of Pharmaceutical Research and development.
International Journal of Research in Pharmacy and Chemistry.
International Journal of Pharma and Bio Sciences

b)Internet Browsing.
c)Laboratory based studies.
7.2 – Method of Collection of Data:
a)An Overview of Microsponges.
b) Formulation of microsponges.
b)Evaluation of formulated Microsponges, as follows:
1) Compatibility studies
2) Evaluation test for microsponge.8

Particle size and shape
Production yield
Loading efficiency
In-vitro drug release study

3)Evaluation of microsponge gel

Viscosity
pH
Clarity
Drug content
In-vitro permeation study
Skin irritancy studies6
Stability studies as per ICH guidelines
Drug and excipients interaction:

By F.T.I.R Spectroscopy.

In vitro drug release study

 USPdissolution by apparatus.
7.3Does the study require any investigations or interventions to beconducted on patients or other humans or animals? If so, please describe briefly.
-Yes, study requires investigation on Orytolagguscunniculus white rabbit.
7.4Has ethical clearance been obtained from your institution in case of 7.3?
-Yes, Ethical clearance has been obtained. (Copy enclosed)
Ref: SCP/CPCSEA/P14/F150/2012
List of references:

Mandava SS, Thava V. Novel Approach: Microsponge Drug Delivery System. Int J Pharm Sci and Res 2012;3(4):967-80.

Pal G. An overview on Microsponge delivery system. Int J Drug Discovery and Medical Res 2012;1(2):1-3

Pradhan SK. Microsponges as the versatile tool for Drug Delivery System. Int J Res Pharm and Chem 2011; 1(2):212-8.

Shelke OS, Sable KS, Gadhava MV, Gaikwad DD. Microsponge Drug Delivery System: An emerging tool for topical drug delivery. The Global J Pharm Res 2012; 1(4):805-18.

URL:

Maiti S, Kaity S, Ray S, Sa B. Development and Evaluation of Xanthum gum-facilitated ethyl cellulose microsponges for controlled percutaneous delivery of diclofenac sodium. Acta Pharm; 61(2011):257-70.

Mahajan AG, Jaytap LS, Chaudhari AL, Swami SP, Mali PR. Formulation and Evaluation of Microsponge Drug Delivery using Indomethacin. Int Res J Pharm 2011; 2(10):64-9.

Mehta M, Panchal A, Shah VH, Upadhyay U. Formulation and in-vitro Evaluation of controlled release microsponge gel for topical delivery of Clotrimoazole. Int J Adv pharm 2012; 2(2):93-101.

Nokhodchi A, Jelvehgari M, Reza, Siahi Reza, Mozafari M. Factors affecting the morphology of benzoyl peroxide microsponges. Micron 2007; 38:834-40.

Saravanam M, Bhaskar K, Maharajan G, Pillai KS. Development of gelatine microspheres loaded with diclofenac sodium for intra-articular administration. J Drug Targeting 2011; 19(2):96-103.

Shahin M, Hady SA, Hammad M. Novel jojoba oil-based emulsion gel formulation for clotrimazole delivery. AAPS Pharm Sci Tech. March 2011; 12(1):239-46.

Rizkalla C, Aziz R, Soliman I.Invitro and Invivoevaluation of hydroxyzine hydrochloride microsponges for topical delivery. AAPS Pharm Sci Tech 2011; 12(3):989-1001.

John I D’souza, Harinath N. Topical Anti-inflammatory Gels of Fluocinolone Acetonide entrapped in Eudragit based microsponge delivery system. Res J Pharm Tech 2008; 1(4):502-6.

Jain V, Singh R. Development and Characterisation of Eudragit RS100 loaded microsponges and its colonic delivery using natural polysaccharides. Actapoloniae pharm drug res 2010; 67(4):407-15.

Comogluy T, Gomul N, Baykara T. The effects of pressure and direct compression on tabeltting of microsponges. Int J Pharm 2002; 242:191-95.

9. / Signature of the candidate / (RESHMY VASAVAN)
10. / Remarks of the Guide / The work, which is assigned to
RESHMY VASAVAN is under my guidance.
11. / 11.1 Name and Designation of the
Guide / Dr.A.R. SHABARAYA M.Pharm., Ph.D.
Principal and Director,
Srinivas College of Pharmacy
Valachil, Mangalore- 574143
11.2 Signature / (Dr. A. R. SHABARAYA)
11.3 Head of the Department / Dr. A. R. SHABARAYA M.Pharm., Ph.D.
HOD and Principal
Srinivas College of Pharmacy,
Valachil, Mangalore- 574143
11.4 Signature / (Dr. A. R. SHABARAYA)
12. / 12.1 Remarks of the Principal / Recommended and forwarded for favourable consideration.
12.2 Signature / Dr. A. R. SHABARAYAM.Pharm., Ph.D.
HOD and Principal
Srinivas College of Pharmacy,
Valachil, Mangalore- 574143