al Studies Towards Improving Certain Performance Qualities of Naproxen Gel
.‫درا سات ص يدالن يه ل تح س ين خ صائ ص ادان يه مع ي نه ل ص ياغات هالم ال ناب روك س ين‬
Mai Sayed Ismael
‫مى س يد إ سماع يل‬
El-Sayed Ali Ibrahim, Mona Mostfa El-Mahdy
‫ م نى م صط فى ال مهدى‬،‫ال س يد ع لى إب راه يم‬
e to the drug involved in a suitable formulation. Non steroidal anti-inflammatory drugs (NSAIDs) are the m
ommonly associated with the oral route of administration of NSAIDs such as gastrointestinal complicati
d be used for a long term therapy. Naproxen is NSAIDs that produces analgesic and antipyretic effects a
fects. Because of the pharmaceutical advantages of topically applied dosage form, it is worthy to study
ing poor aqueous solubility (27 mg /l) and thus could show minimal percutaneous absorption. In addition
lubility to facilitate its formulation into proper topical dosage forms. So the present thesis comprises the
naproxen in the selected formulations. Chapter One Solubility Studies of Naproxen ● Assessment of th
pH 7.4 and 5.8 was investigated by equilibrium solubility technique at 37 ºC over 24 hrs at predetermine
attained after two hours and the equilibrium solubility of naproxen in acetate buffer was 207.78 ± 0.26 m
mcg /ml. ●Assessment of the Solubility of Naproxen in Presence of Co-solvents: The effect of different
MF, DMSO, DMA, ethanol and isopropanol. The results showed that the solubility of naproxen was impro
ns (w/v) or (v/v) as DMA >DMF >PEG 600 >PEG 400 > PEG 200 > Isopropyl alcohol > DMSO > ethyl a
c surfactants; Tween 20, Tween 40 and Tween 80 on the solubility of naproxen in water at 37 ºC was de
s a marked improvement in the solubility of the drug in the presence of tested surfactants, and this impro
howed the lowest solubilizing effect 1880.54 ± 7.59 mcg/ml. Chapter Two Preparation and Evaluation o
ation of a transparent aqueous gel taken in consideration the low aqueous solubility of NPX. These trial
he drug in the gel. 2. Evaluation of Naproxen Gels: 2.1. Physicochemical Evaluation of Different Prepare
howed good homogeneity except two non-aqueous emulgel formulations which were excluded from fur
range of 4.61 - 4.75, those of non aqueous emulgels were in the range of 5.02 - 5.24 and carbopol gels
of the tested formulations were in the range of 2500± 500 cps to 37500 ± 500 cps. Viscosity is an import
ould cause a more rigid structure with a consequent decrease of the rate of drug permeation. 2.2. Perm
pared and the permeation of naproxen from these formulations was evaluated. The data revealed that th
a control gel base. 2.2.1. Effect of Different Enhancers on the Permeation Pattern of Naproxen from the
ude the following:- 2.2.1.1. DimethylSulfoxide (DMSO): We preferred to study the effect of low concentra
ults revealed that as the concentration of DMSO increased, the release of naproxen was found to be de
ristate (IPM): It was studied at concentration levels of 3%, 5% and 10% (w/w). The results showed a low
the isopropoyl myristate concentrations and the cumulative amount of NPX permeated. 2.2.1.3. Terpen
ected for our studies because it is also considered as fragrant agent that induces a strong cooling sensa
d at two concentrations 3% and 5% (w/w) and for comparative purposes we choose thymol at the same
portional to the menthol concentrations. This may be due to the increase in the viscosity value between
at the presence of thymol at varying concentrations did not facilitate the permeation of NPX from carbap
enhanced during the presence of the oily terpenes and this in turn retarded the NPX flux with respect to
as studied. Sorbitan monolaurate (Span 20) and polysorbate 20 (Tween 20) was selected in this study b
zed by having a more hyDROPhilic group than Span 20. Tween 20 and Span 20 were used at 1%, 3% a
dition the cumulative amount of NPX permeated from the selected gel formulations was directly proporti
increased. It was evident that the permeation profiles from gel formulations containing different concent
he permeation of NPX from the tested formulations could be explained on the basis that a part of NPX w
the other hand, the micellar core of Span 20 is hyDROPhilic in nature and a small fraction of NPX, lipop
aproxen from Carbapol 940 Hydroalcoholic Gels through Cellophane Membrane: The in -vitro permeatio
he best permeation profile was attained from the formulation containing ethyl alcohol and water. The diff
rmulations. The molecular weight of ethyl alcohol is (46.07) and that of isopropyl alcohol is (60.1). The la
Emulgels through Cellophane Membrane: Different formulations were prepared using glycerol, instead
5 and 7.5 % were studied. Also, different concentrations of mixture of Span 20 and Tween 20 at 2%, 4%
ned on the basis that, the concentration of the drug in the external aqueous phase of the emulgel is inve
Cellophane Membrane: The permeation data of the drug from different gel formulations were subjected
NPX from various formulations follows to a great extent zero order model as the highest regression coef
m the Control Gel Base Containing 5:3 PG and PEG 600: The solubility of the drugs in the glycols is the
nd therefore, PG could be involved in transcellular diffusion enhancement. 2.4.1.1. Effect of Different En
y of naproxen from carbapol gels containing 1% ,5% and 10% DMSO., The results revealed that the ge
h ) . On the other hand, formulations containing DMSO at 1% and 5% did not enhance the flux of NPX f
permeation enhancement activity was concentration dependant. 2.4.1.1.2. Isopropyl Myristate (IPM): The
te has a significant influence on increasing NPX flux at all the tested concentrations (3%, 5% and 10%
unt of NPX permeated after 4 hr. Isopropyl myristate appears to affect the fluidity of the lipid component
Moreover IPM is able to dissolve considerable amounts of cholesterol, which act as a membrane stabiliz
compared to the control gel base. It was observed that the amount of NPX permeated per unit surface a
269 ±0.67 mcg /Cm2 and from formulation containing 3% menthol was 174.103 ± 0.23 mcg /Cm2 . This
nt, which in turn improved the skin permeation of drugs by increasing drug diffusivity in the skin through
he presence of thymol produce a dose proportional increase on NPX flux and permeability coefficient ( P
0.32 mcg /Cm2 ) with higher diffusion coefficient and higher permeability than that obtained from the fo
g effect on the permeation of the naproxen from gels containing thymol compared with the control gel b
could be explained as the efficacy of terpenes on the percutaneous absorption of different drugs is not s
nto which they are formulated. 2.4.1.1.4. Effect of Surfactant: The Permeation profiles of NPX from F21
F21 (289.33 ± 0.639 mcg /Cm2 ) and from F22 (468.72 ± 0.93mcg /Cm2 ) which are significantly higher
umulative amount of naproxen permeated indicated a synergetic effect between PG and Span 20 for en
Span 20 on the intercellular lipids by making them more fluid and thus enhancing the diffusivity of NPX.
ophilic pathway). Regarding to the permeation profiles of NPX from carbapol gel formulations (F24, F25
rate of NPX as compared with the other tested concentrations F24 and F26. 2.4.2. Permeation Study o
l formulations containing 70% ethanol with compared to the control gel base, containing 5:3 PG and PE
he PG alone as an enhancer didn’t affect the lipid structure of the skin like ethanol did. 2.4.3. Permeation
queous emulgels (F5 and F 6) containing the same concentration of NPX ( 2%) was performed to evalu
observed in F6 containing 5% olive oil and there was an increase in the diffusion coefficient and enhanc
udy of naproxen from cellophane membrane while enhanced the permeation through the skin. 2.5. Kinet
meation from all investigated formulations followed the Higuchi diffusion model, as confirmed from the go
olved drug through the different skin layers to the external medium 3. In-vivo Evaluation of the Efficacy o
hich may be useful in modulating drug action in terms of anti-inflammatory effect, skin irritation tests and
aluate the anti-inflammatory efficacy of naproxen formulated in F15 (5% IPM), F22 (3% Span 20) and co
e to their enhanced absorption rates of the drug from F15. It was found that the nature of topical vehicle
om carbopol gels containing 5% IPM and PG which provided good enhancement effects over the other t
t-inflammatory effect was obtained. 4. In-vivo Evaluation of the Safety of Naproxen in The Selected Gel
gher flux of naproxen (F15 and F22). It was concluded that neither naproxen nor its excipients caused a
of The Skin Treated with The Formulations:- Histological changes in hairless rat’s skin were examined
he first three days three rats of each group were killed and samples of the applied skin area were taken
ing histological stains were used: (1) Hematoxylin- eosin stains for general histological examination. (2)
g diffusion and penetration. On the other hand, there were no great harmful effects of the two formulatio
dered safe and suitable for the delivery of NPX. The effect of NPX on the collagen fibers will need furthe