Download Formulation and evaluation of ketorolac tromethamine as an anti

Formulation and evaluation of ketorolac tromethamine as an
anti-inflammatory drug for topical application
‫صياغة وتقييم الكيتوروالك تروميثامين كعقار مضاد اللتهابات لالستخدام الظاهرى‬
Raafat El Sayed Aabd El-Raheem
‫رأفت السيد عبدالرحيم‬
Fawzia S.Habib, Maha Ahmed Hassan, Amal El-Sayeh Fadl
‫ آمال السايح فضل‬،‫ مها أحمد حسن‬،‫فوزية سيد حبيب‬
Abstract:
Rheumatoid disorders are chronic auto-immune inflammatory diseases characterized by
progressive damage of the involved tissues. Rheumatoid arthritis affects about 0.3 to 1.5 % of
the population worldwide . Its incidence is (2-3) times greater in women than in men. The
non-steroidal anti-inflammatory drugs (NSAIDs) are used as a classical treatment for several
rheumatic disorders such as arthritis and rheumatoid arthritis .
Ketorolac tromethamine (KT) is considered as a member of NSAIDs
that used in treatment of musculoskeletal and joint disorders such as rheumatoid arthritis ,
ankylosing spondilitis and acute gouty arthritis . Because KT appears to be associated with a
higher incidence of adverse effects mainly irritation to the stomach , change in kidney and liver
functions , its use is restricted for the treatment of patients for whom other NSAIDs have been
ineffective .
The main problems associated with the frequent administration of
KT could be overcomed by alternative routes of administration . This could be achieved by
avoiding the contact between the drug and the stomach through formulating the drug in topical
formulations and this was the aim of the thesis.
This study was classified into three parts .
Part 1 : Formulation and characterization study of KT in some topical formulations.
Part 2 : Biological evalution of the anti-inflammatory activity of KT topical formulations.
Part 3 : Comparative assessment of the effectiveness and tolerability of KT gel and piroxicam
gel in osteoarthritis patients .
Part I
Formulation and characterization study of KT in some topical formulations .
In this part, KT was formulated in different topical formulations such
as (gel, emulgel and cream bases) and characterization of theses formulations (compatibility
with polymers , drug content , pH , viscosity , in-vitro release , kinetic analysis, in-situ skin
permeation and stability during storage ) were studied.
1-Formulation of (0.5% w/w )KT in some topical formulations.
● Gel bases :
Different concentrations of methyl cellulose (MC), sodium carboxy methyl cellulose (NaCMC),
hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), sodium alginate
(Na.alg) , carbopol 934 , carbopol 940 , pluronic F127 (P F127) and pluronic F68 (P F68)
polymers were used in gel formulations .
● Emulgel bases :
All emulgel bases which were formulated were O/W type , different in type of oil or polymer
which was used .
● Cream bases :
Four cream bases were formulated , two of them were O/W bases and other two were W/O
bases .
2- Characterization study of KT formulations.
●Compatibility between KT and polymers.
This study was done using Differential Scanning Calorimeter (DSC) and Infra-Red (IR)
spectroscopy .
A- DSC study indicated that, no drug : polymer interaction occurred as the endothermic peak of
KT melting point is still identified in both KT and mixture thermograms except in case of HPMC
and carbopol 934 , the first showed weakness to endothermic peak of KT melting point while
the second showed also weakness to endothermic peak of KT melting point and shifting to low
temperature.
B- IR spectroscopy also indicated that, no drug : polymer interaction occurred as there is no
remarkable shifting in characteristic peaks of KT in both KT and mixture IR spectra.
● Drug content determination :
KT content of the prepared formulations was determined and was between 94.6 % and 99.6 % of
claimed amount of KT.
● pH measurement :
The results revealed that, the pH of KT formulations was between 6.10 -7.28 , i.e. all of them
were approximately neutral . Also the results showed that, the pH of KT formulations was
slightly less than these of placebo and this can be explained by the weak acidity of KT.
● Viscosity measurement :
The results obtained from viscosity measurement indicated that , Na.alg gels had the lowest
viscosity compared to other gels, while poloxamer gels had the highest viscosity. These
differences in viscosity due to the different polymeric structures. Also the results indicated
that, the viscosity of gel bases was higher than that of emulgel bases and lower than that of
cream bases.
● In-vitro release of KT from topical formulations .
1-Gels bases .
It,s found that, as the polymer concentration increase , the release of KT decrease that may be
due to the increase of the viscosity of polymer by increase its concentration .
a- Cellulose derivatives :
It was clearly obvious that, NaCMC gel bases exhibited the highest release, this may be to the
high affinity of the drug to the polymer which is actually highly water soluble ,then followed by
HPMC, HPC and the lowest release rate was from the MC gel bases , the observed differences in
drug release may be due to the differences in the structure and the viscosity of the polymer.
b- Sodium alginate :
The obtained data proved that , the release of KT from Na.alg gel bases is similar to these
obtained from cellulose derivatives bases.
c-Carbomers :
The obtained results revealed that, the release of KT from carbopol 934 is greater than that
from carbopol 940. This may be due to the difference in cross-linking density , increasing the
cross-linking density of polymer increases the tortuosity of the matrix through which the drug
has to diffuse and thus decreasing the drug release