Download formulation and evaluation of - Rajiv Gandhi University of Health

DESIGN, OPTIMIZATION AND EVALUATION OF OPTHALMIC IN-SITU GEL
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA
BY
CHITLURI KALYANI
I M.PHARM
UNDER THE GUIDENCE OF
MR.S.RAJARAJAN
ASSISTANT PROFFESOR
DEPARTMENT OF PHARMACEUTICS
KARNATAKA COLLEGE OF PHARMACY
BENGALURU-560064
(2011-2013)
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BENGALURU.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1
Name of the Candidate and Address
CH.KALYANI
# 33/2, Thirumenahalli,
Hegde Nagar Main Road,
Bengaluru-560064.
PERMANENT ADDRESS
D/O:Chitluri.NageswaraRao,
H.NO:5-6, ASN Street,
MNDL: Sathupalli,
DIST: Khammam,
STATE: Andhra pradesh-507303.
Name of the Institution
KARNATAKA COLLEGE OF PHARMACY
2
# 33/2, Thirumenahalli,
Hegde Nagar Main Road,
Bengaluru-560064.
3
Course of the Study and Subject
4
Date of Admission
5
TITLE OF THE PROJECT:DESIGN, OPTIMIZATION AND EVALUATION OPTHALMIC
IN- SITU GEL
MASTER OF PHARMACY IN
PHARMACEUTICS
23- SEP-2011
1
6
BRIEF RESUME OF INTENDED WORK:-
6.1
NEED FOR THE STUDY:Today, topical opthalmic application is considered the preferred way to achieve therapeutic levels of
active medicament used to treat ocular diseases. Solutions, suspensions, and semisolids like ointments
and gels are conventionally available as ophthalmic delivery systems.
From a biopharmaceutical standard point, their use has met some criticism over their efficiency as drug
delivery systems. Bioavailability, particularly for ocular solutions, ranges from 1% to 10% of the total
administered dose. This could be due to the rapid pre-corneal kinetics resulting from reflex tearing and
blinking.
The basic disadvantage associated with the use of ocular formulation is rapid loss of both solutions and
suspended solid. Opthalmic ointments give blurred vision, leading to poor patient acceptance.
These problems can be overcome by using in situ gelling opthalmic drug delivery systems prepared
from polymers that exhibit sol-to-gel phase transitions because of a change in a specific
physicochemical parameter in their environment. In fact, such a system is liquid at room temperature
suitable to be instilled into the eye which, upon exposure to physiological changes to the gel phase,
thus increasing the pre-corneal residence time and enhancing ocular bioavailability of topically dosed
opthalmic drugs. In situ gel–forming systems can be classified as pH-triggered systems, temperaturedependent system and ion-activated systems.
Opthalmic use of Non-steroidal anti-inflammatory drugs (NSAIDs) offer several benefits after
intraocular and refractive surgery. NSAIDs also can reduce patients intra- and postoperative pain, help
maintain pupillary dilation, control inflammation after surgery.
In our present work, study was focused to develop a ideal opthalmic in situ gelling system using a
potent and effective non-steroidal anti-inflammatory drug (NSAID) as a model drug, various polymers
and by simple method. The study includes the pre-formulation studies and the formulations will be
subjected for its physicochemical and release studies. Stability studies as per ICH Guidelines.
2
6.2 REVIEW OF LITERATURE:

Pluronic F127-based thermoresponsive diclofenac sodium ophthalmic in situ gels (DS in-situ
gel). They were prepared by cold method and investigated their physicochemical properties
i.e., pH, flowability, sol–gel transition temperature, gelling capacity and rheological properties.
In-vivo opthalmic absorptions was studied in rabbits1.

A thermo sensitive in situ gelling vehicle was prepared to increase the pre-corneal resident
time and the bioavailability of methazolamide (MTA). Poloxamer analogue were used as the
gelling agents, and the in situ gel was obtained by using a cold method. The gelation
temperature, rheological properties, in vitro release as well as in vivo evaluation of the
optimized formulations were investigated2 .

Based on the concept of pH-triggered in situ gelation. Polyacrylic acid (Carbopol® 934)was
used as the gelling agent in combination with hydroxyl propyl methylcellulose (Methocel
K4M) which acted as a viscosity enhancing agent was formulated and evaluated an ophthalmic
delivery system for a non-steroidal anti inflammatory drug, ketorolac tromethamine3.

A thermo sensitive and mucoadhesive in situ gelling ophthalmic system of azithromycin
(ATM). Poloxamer 407 (P407) and poloxamer 188 (P188) were used as gelling agents.
Addition of Carbopol 974P (CP 974P) to the gelling systems could increase the solubility of
ATM by salt effect In vitro and in vivo indicated that this droppable gel performed better than
ATM eye drop did4.

Poor bioavailability and therapeutic response exhibited by the conventional opthalmic
solutions due to pre- corneal elimination of the drug by the use of in-situ gel forming system.
The purpose of this work was to develop an opthalmic delivery system of the NSAIDS
indomethacin, based on the concept of ion-activated in-situ gelation. Gelrite gellan gum, a
novel opthalmic vehicle, was used as the gelling agent5.

Polyacrylic
acid
(Carbopol®980NF)as
a
phase
transition
polymer,
hydroxypropyl
methylcellulose (Methocel® K100LV) as a release retardant was used for the in-situ gelling
system, and ion exchange resin as a complexing agent. Ciprofloxacin hydrochloride was
complexed with ion exchange resin to avoid incompatibility between drug and polyacrylicacid6.
3

Pluronic-g-poly(acrylic acid) copolymers were studied as a temperature-responsive in situ
gelling vehicle for an ophthalmic drug delivery system. The rheological properties and in vitro
drug release of Pluronic-g-PAA copolymer gels, as well as the in vivo resident properties of
such in situ gel ophthalmic formulations, were investigated7.

The potential of a chitosan solution as well as an in situ gel- forming system comprised of
poloxamer/chitosan as vehicles for enhanced corneal permeation and sustained release of
fluconazole (FLU). Microdialysis was employed in a rabbit model to evaluate the in vivo
performance of the formulations. The in vitro release studies showed the sustained release of
FLU from the poloxamer/chitosan formulation8.

The Pluronic F127 (PF127) based formulations of timolol maleate (TM) were developed with
the aim. Which is enhancing ocular bioavailability? The effect of isotonicity agents and PF127
concentrations on the rheological properties of the prepared formulations was examined. In an
attempt to reduce the concentration of PF127 without compromising the in situ gelling
capabilities, various viscosity enhancing agents were added to PF127 solution containing 0.5%
TM. The viscosity and the ability of PF127 gels to deliver TM. In vivo study showed that the
ocular bioavailability of TM, measured in albino rabbits9.

Controlled release in situ gel consisting of carbopol and cellulose derivatives showed increased
in viscosity, gelling capacity. Hydroxypropyl methyl cellulose combined with carbopol to
reduce the concentration of the incorporated carbopol. Study was designed control release
opthalmic systems for ciprofloxacin based on polymeric carriers that undergo sol-to-gel
transition upon change in pH and to prolong the effect of cirofloxicin10.

The concentration of S(−)-satropane in dialysates was measured by using liquid
chromatography/tandem mass spectrometry (LC–MS/MS). Unlike the common solution
prepared in normal saline, in which the level of S(−)-satropane in aqueous humour increased
rapidly after instillation and reached the maximal level within 1 h, S(−)-satropane exhibited 3.2fold greater in the in situ forming gel11.
4

A novel copolymer, poly(N-isopropylacrylamide)–chitosan (PNIPAAm–CS), was investigated
for its thermosensitive in situ gel-forming properties and potential utilization for ocular drug
delivery. The thermal sensitivity and low critical solution temperature (LCST) were determined
by the cloud point method. The in vivo ocular pharmacokinetics of timolol maleate in
PNIPAAm–CS solution were evaluated and compared to that in conventional eye drop solution
by using rabbits according to the micro dialysis method12.

The rheological measurements and a small in vivo study of ocular residence times in humans
were used to evaluate poloxamer as an ocular vehicle. An increasing concentration of
poloxamer resulted in a slightly increasing elasticity of the gels and a decreasing sol–gel
transition temperature. The contact time increased with increasing concentration of poloxamer.
In the present study rheological measurements were performed13.
5
6.3 OBJECTIVE OF THE STUDY:- The main objective of the current study is as follows:

Pre-formulation studies.
i. The current study is to develop an ideal opthalmic in-situ polymeric drug
delivery system by using factorial design (Design expert software).
ii. Formulation of opthalmic in-situ gel by suitable method.
iii. The opthalmic in-situ gel is design for to retain in the eye for extended period of
time.
iv. Evaluation of opthalmic in-situ gel for their physicochemical studies (Viscosity,
Clarity, Gel Strength, Gelling capacity, Gelation PH and temperature, In-vitro
studies)
v. Stability studies for selected formulations.
7
MATERIALS & METHODS:-
7.1 SOURCE OF DATA:•
Review of literature from:
Journals such as:
•
Indian Journal of Pharmaceutical Sciences
•
International Journal of drug delivery
•
International Journal of Pharmaceutical research
•
International Journal of Pharma. Research and development
•
Asian Journal of Pharmaceutics
•
European journal of pharmaceutics and biopharmaceutics
Web sites :
• World Wide Web.
• J-Gate@Helinet
• Science Direct
• Khup.com
• Informa healthcare
6
7.2 MATERIALS
Non steroidal anti inflammatory drug and polymers will be procured from Pharma grade suitable
manufacturer. Other reagents will be of Analytical grade.
7.3 METHODS
1) Preparation of oral in-situ gel by simple mixing method.
2) Evaluation
a) Clarity
b) Solution-gel transition température and gelling time
c) Gel- strength
d) Viscosity
e) pH
f) In-vitro drug release studies
g) Microbial studies.
3) Stability studies as per ICH guidelines
7.4
Method of collection of data (including sampling procedures if any):
The data will be collected from prepared formulations subjected to different evaluation techniques,
scale-up techniques and stability studies obtained from ICH guidelines.
Does the study require any investigation or interventions to be conducted on
7.5 patients or other humans or animals?
\
-NOT APPLICABLE-
7.6 Has ethical clearance been obtained from your institution in case of 7.5?
-NOT APPLICABLE-
7
8
LIST OF REFERENCES :1. Rathapon A, Suthira T, Asira F. Optimization and evaluation of thermo -responsive diclofenac
sodium ophthalmic in situ gels. Int J Pharm 2011Apr;411:128-35.
2. Yong Q, Fengzhen W, Preparation and evaluation of in situ gelling ophthalmic drug delivery
system for methazolamide. Drug Develop Ind Pham 2010Mar;36(11):1340–7.
3. Basavaraj K, Manjappa AS, Murthy RSR, Pol YD. A Novel pH-triggered in-situ Gel for
Sustained
ophthalmic
delivery
of
ketorolac
tromethamine.
Asian
J
Pharm
Sci
2009Mar;4(3):189-99.
4. Feng Cao, Xiaolin Z, and Qineng P. New method for ophthalmic delivery of azithromycin by
poloxamer/carbopol-based in situ gelling system. Drug Deliv 2010Mar;17(7):500–7.
5. Jagdish B, Shrikanth, Jayanta KP. In vitro and in vivo evaluation of the gelrite gellan gumbased ocular delivery system for indomethacin. Acta Pharm 2003Oct;53:251-61.
6. Satish KP, et al. In Situ ophthalmic gel of ciprofloxacin hydrochloride for once a day sustained
delivery. Drug Develop Ind Pharm 2008;34:445–52.
7. Wen-di Ma, Hui Xu, Shu-FN, and Wei-SP. Temperature-responsive, pluronic-g-poly(acrylic
acid) copolymers in situ gels for ophthalmic drug Delivery: rheology, in vitro drug release, and
in vivo resident property. Drug Develop Ind Pharm 2008;34:258–66.
8. Taís G, Guilherme M G , Osvaldo DF, Eduardo M R, Renata F.V. Lopez. Enhancing and
sustaining the topical ocular delivery of fluconazole using chitosan solution and
poloxamer/chitosan in situ forming gel. Eur J Pharm Biopharm 2011May;1-44.
9. El-Kamel AH. In vitro and in vivo evaluation of pluronic F127-based ocular delivery system
for timolol maleate. Int J Pharm (2002);247:47–55.
10. Raida S, AI-Kassas, Mona M, EI-Khatib. Opthalmic controlled release in situ gelling systems
for ciprofloxacin based on polymeric carriers. Drug Deliv 2008Dec;16(3):145-52.
8
11. Jun Fu, et al. Study of ocular pharmacokinetics of in situ gel system for S(−)-satropane
evaluated by microdialysis. J pharm Biomed Anal 2008Jun;48:840-43.
12. Yanxia Cao, et al. Poly(N-isopropylacrylamide)–chitosan as thermosensitive in situ gelforming system for ocular drug delivery. J Control Release 2007May;120:186-94.
13. Katarina E, Johan C, Roger P. Rheological evaluation of poloxamer as an in situ gel for
ophthalmic use. Eur J Pharm 1998;6:105-12.
9
9
Signature of the Candidate
(CH.KALYANI)
10
Remarks of the Guide:
11
Name And Designation
11.1
Guide
11.2
Signature of the Guide
The topic selected for dissertation is satisfactory. Adequate
equipments and chemicals are available to carry out the
project work
MR.S.RAJARAJAN
DEPARTMENT OF PHARMACEUTICS
KARNATAKA COLLEGE OF PHARMACY
#33/2, THIRUMENHALLI
HEGDE NAGAR MAIN ROAD
BENGALURU-64
( S.RAJARAJAN )
11.3
Co- Guide
11.4
Signature of the Co- Guide
11.5
Head of the Department
-NOT APPLICABLE-
-NOT APPLICABLE-
DR.K. RAMESH
HEAD OF THE DEPARTMENT OF
PHARMACEUTICS
KARNATAKA COLLEGE OF PHARMACY
#33/2, THIRUMENHALLI
HEGDE NAGAR MAIN ROAD
BENGALURU-64
10
11.6
Signature of the HOD
(DR.K.RAMESH)
12
12.1
Remarks of the Principal
Principal/DIRECTOR
12.2
12.3
All the required facilities will be provided to carry out
dissertation work under the supervision of the Guide.
DR.K. RAMESH.
DIRECTOR
KARNATAKA COLLEGE OF PHARMACY
#33/2, THIRUMENHALLI
HEGDE NAGAR MAIN ROAD
BENGALURU-64.
Signature of the
Principal/DIRECTOR
(DR.K.RAMESH)
11