This action might not be possible to undo. Are you sure you want to continue?
29 (3): 354-61 (2010)
Original Article Received: July 22, 2009 Accepted: September 30, 2009
Formulation and Evaluation of Thermoreversible Mucoadhesive Nasal Gels of Metoclopramide Hydrochloride
Remeth J. DIAS 1*, Kailas K. MALI 1, Jitendra V. SHINDE 1, Vijay D. HAVALDAR 1 & Rahul K. MALI 2 Department of Pharmaceutics, Satara College of Pharmacy, Plot no. 1539, New Additional M.I.D.C., behind Spicer India Ltd. Degaon, Satara-415004, India 2 Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Sector 8, C.B.D., Navi Mumbai 400614 India.
SUMMARY. The prolonged residence of drug formulation in the nasal cavity is of utmost importance for intranasal drug delivery. The objective of the present investigation was to develop a mucoadhesive in situ gel with reduced nasal mucocilliary clearance in order to improve the bioavailability of the antiemetic drug, metoclopramide hydrochloride. The in situ gelation upon contact with nasal mucosa was conferred via the use of the thermogelling Pluronic flake 127 (18%). Mucoadhesion was modulated via the use of hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (Na CMC) and sodium alginate (Na-alginate) whereas drug release was modified by varying concentrations of polyethylene glycol 6000 (PEG 6000). The results revealed that the different mucoadhesives increased the gel viscosity but reduced its sol gel transition temperatures. The increase in viscosity was highest in formulations with Na-alginate and lowest in formulations with HPMC. PEG 6000 significantly decreased mucoadhesive strength of formula containing 0.3% HPMC (776.6 ± 19.55 to 713.6 ± 5.03), 0.2% Na CMC (656 ± 11.13 to 575 ± 9.07) and 0.2% Na-alginate (659 ± 11.13 to 618.3 ± 9.45) whereas the gelation temperature increased by 3 to 40C. 100% of drug diffusion was found at four hours for formulation F5, F9, and F12. Formulation F5 showed maximum permeability (0.00949 ± 0.00021 mg.cm/min) than other formulation containing PEG6000. This study concluded the potential use of mucoadhesive in situ nasal gel in terms of ease of administration, accuracy of dosing, prolonged nasal residence and improved nasal bioavailability.
INTRODUCTION Metoclopramide hydrochloride (MTCH) is a potent antiemetic, effective in the treatment of nausea and vomiting associated with cancer therapy, pregnancy, and migraine 1. The interest was renewed in this drug with its in vitro and in vivo radio- and chemosensetizing properties. However the oral bioavailability of MTCH is highly variable showing values between 32 and 98% due to extensive presystemic metabolism 1. Oral forms of MTCH often get vomited before systemic absorption compelling parenteral or rectal administration where both methods result in low patient compliance. In these conditions, the intranasal delivery seems to be an attractive alternative. However, low residence time of drug in nasal cavity is limitation of this route, which may affect absorption and in turn bioavailability of drug. Hence the design of nasal dosage forms has to consider the anatomic and physiologic characteristics of nasal mucosa and more partic-
ularly the rapid mucocilliary clearance (MCC) that limits the time available for drug absorption from the applied dosage form 2,3. So the possible strategy to decrease rapid MCC is by the use of gel/mucoadhesive formulations to prolong the residence time at the nasal absorption site and thereby facilitate the uptake of the drug. Ordinary gels are difficult to administer and an accurate drug dose cannot be measured while mucoadhesive powders are not highly favored products. They can cause irritation on the nasal mucosa and give a gritty feel to the tissues 4. A nasal mucoadhesive in situ gel appears very attractive since it is fluid like prior to nasal administration and can thus easily be administered as a drop allowing accurate drug dosing. Pluronic flake127 (PF127) has excellent thermosensitive gelling properties 5, low toxicity and irritation 6, excellent water solubility, good drug release characteristics and compatibility with other chemicals 7. It is an ABA triblock copolymer consisting of the hydrophilic
KEY WORDS: Metoclopramide hydrochloride, Mucoadhesive, Nasal drug delivery, Pluronic F 127, PEG 6000.
* Author to whom correspondence should be addressed. E-mail: email@example.com
4 0.. Ltd.5 0. sodium carboxy methyl cellulose (Na CMC) and polyethylene glycol 6000 (PEG 6000) were purchased from Loba Chemie Pvt.1 to 0. Composition of various thermoreversible mucoadhesive nasal gel formulations is given in Table 1. PF127 was added slowly with agitation. 10 18 … 0. Ltd.29 (3) . The PF127 was added slowly with continuous stirring. After cooling the solution to 4 °C.2 … 0.33 Purified Water q. 8. Preparation of mucoadhesive thermoreversible nasal gels MTCH along with mucoadhesive polymer (HPMC or Na CMC or Na alginate).3 0. The temperature-induced gelation of PF127 has been explained on the basis that the polymer exists as a mobile viscous liquid at reduced temperatures but forms a rigid semisolid gel network with an increase in temperature 6.s.2 … 1 0. The dispersions were then stored in a refrigerator until clear solution was obtained and finally volume was adjusted. clear ++. *All concentrations in 355 .33 q. 10 18 … … 0. Also. Finally volume was adjusted by using cold distilled water. very clear (glassy): +++. mucoadhesive force.3 … … 0. Pune. Mumbai.3 … … … 0. optimized concentration of PF127 was used to study the effect of PEG 6000 on gelation temperature in the concentration range of 0.s.75 0. 10 18 0. India.33 q.33 q.33 q.33 q.s. diffusion through nasal mucosa and viscosity of formulation.33 q.2 … 0. 10 18 0. Optimization of plain and drug loaded PF127 gels were done by varying concentration of Composition F1 F2 F3 F4 F5 Metoclopramide HCl 10 PF127 18 HPMC … Na CMC … Na-Alginate … PEG 6000 … Methyl Paraben 0. Ltd. and /or PEG 6000 and methyl paraben was dissolved in double distilled water by agitation at room temperature.s.2 … 0. Optimized concentration of PF127 was used for further studies of effect of mucoadhesive polymers on gelation temperature and mucoadhesive strength. PF127 and evaluating them for gelation temperature..33 q.4 0. Chandigarh.3 … … 0.2 0. 10 18 … … 0.2010 polyethyleneoxide (PEO) and the hydrophobic polypropyleneoxide (PPO). (Systronics µ pH System 362).33 q.s. 10 18 … 0.s.5 0. Evaluation of formulations Clarity The clarity of various formulations was determined by visual inspection under black and white background and it was graded as follows.33 q.5 0. Composition of various thermoreversible mucoadhesive nasal gel formulations. Sodium alginate (Na alginate).3-1%. 10 18 … … 0. The resulting dispersion was then kept overnight at 4 °C until clear and viscous transparent solution was formed.s.2 0. India.. 10 18 … … 0.s.s. Table 1.3 … … 0. content uniformity. Evaluation of final formulations was done with respect to clarity. pH of resulting solution was determined by using pH meter. Pluronic flake (PF127) was purchased from Hi Media Lab Pvt.2 … … 0. pH of formulation One ml of each formulation was transferred to the 10ml volumetric flask and diluted by using distilled water to make 10ml.Latin American Journal of Pharmacy .33 q. For drug loaded PF127 gels. The objective of the present study was to develop a MTCH mucoadhesive in situ nasal gel with a modulated phase transition temperature which would enhance nasal residence time and absorption of drug across nasal mucosal membrane.33 q. respectively. pH.2 0. 10% of drug was stirred with sufficient quantity of double distilled water while for plain PF127 gels only sufficient quantity of double distilled water without drug was kept overnight at 4 °C in refrigerator.5%. 10 18 … 0. percentage. 10 18 … 0. 10 18 0. turbid: +.33 q.s.s.s. Satara India and Panacea Biotech. F6 F7 F8 F9 F10 F11 F12 F13 MATERIALS AND METHODS Materials Metoclopramide hydrochloride and hydroxy propyl methyl cellulose (HPMC K4M) were kindly gifted by Medi-Orals Pvt.s.6 0. India. Preparation and optimization of thermoreversible PF127 gels The plain and drug loaded PF127 gels were prepared by cold method described by Schmolka et al. gelation temperature. 10 18 0. The concentration of mucoadhesive polymers were screened in the range of 0.
added 50 ml of distilled water with gentle shaking and final volume was adjusted to 100 ml. The bioadhesive force. Japan). After the removal of blood and bony cartilage from the mucosal membrane it becomes ready for use. E: Nasal Mucosa. for a period of 4 h. Then the height of second vial was adjusted so that mucosal surfaces of both vials come in intimate contact.. MALI K. Analysis of drug release data To understand the release mechanisms of various nasal in situ gelling formulations of MTCH. A: Modified balance. Measurements were repeated six times for each of the gel preparations. In-vitro permeation studies Fresh nasal mucosa was carefully removed from the nasal cavity of sheep obtained from the local slaughterhouse. The temperature within the chamber was maintained at 34 °C by circulating hot water. Content uniformity Required quantity (1 ml) of formulation was taken in 100ml volumetric flask. In vitro drug permeation was carried out in triplicate. 1 ml quantity from this solution was transferred into the 100 ml volumetric flask and final volume was made to 100 ml by using distilled water to get 10 µg/ml.DIAS R. The nasal mucosa was changed for each measurement. Detachment stress (dyne/cm2) = m x g /A  where m =Weight required for detachment of two vials in grams. B: Weights. Then weight was kept rising in the pan until vials get detached. 10 ml volume of solution was transferred to 20 ml transparent vial containing a magnetic stirrer bar (1x5/16 inch octagonal). Then next vial with a section of mucosa was connected to the balance in inverted position while first vial was placed on a height adjustable pan.K. The samples withdrawn were diluted to 10 ml by SNES. 9. expressed as the detachment stress in dyne/cm2.. In brief. HAVALDAR V.. The vial was heated at an increasing rate of 1 °C/min with constant stirring at 100 rpm. 100ml of simulated nasal electrolyte solution 12 (SNES) pH 5. Mucoadhesive force The mucoadhesive potential of each formulation was determined by measuring the force required to detach the formulation from sheep nasal mucosal tissue by using a modified chemical balance (Fig. C: Glass Vial. At predetermined time intervals. The temperature at which rotation of bar stopped was taken as the gelation temperature. g = Acceleration due to gravity [980 cm/s2] and A = Area of tissue exposed.5 after each sampling. A section of nasal mucosa was cut from the sheep’s nasal cavity and instantly fixed with mucosal side out onto each glass vial using a rubber band. Fixed amount of sample of each formulation were placed onto the nasal mucosa of first vial. & MALI R. The amount of permeated drug was determined using UV-visible spectrophotometer (λmax = 309 nm). 1). Gelation temperature The gelation temperature of aqueous solution of PF127 was measured by using procedures reported by Choi et al. Finally the absorbance of prepared solution was measured at 309 nm by using UV visible spectrophotometer (Shimadzu UV 1700. Modified balance for mucoadhesion study. was determined from the minimal weights that detached the tissues from the surface of each formulation using the equation  10.J. 1 ml of sample was withdrawn from the acceptor compartment and replaced the sample volume with SNES pH 5.K. 356 . The mucosa was stored in normal saline with few drops of gentamycin sulphate injection to avoid bacterial growth. formulation equivalent to 10 mg of MTCH was placed in donor chamber. we attempted to describe the rate of release using the semi-empirical model of Korsmeyer et al. filtered and used for analysis. Modified nasal diffusion cell 11 was used to study in vitro drug diffusion profile.5 at 34 °C was added to the acceptor chamber. The vials with nasal mucosa were stored at 37 °C for 5 min. D: Poloxamer Gel. After a preincubation time of 20 min.D. F: Height adjustable Pan. and more precisely the equation  proposed by Peppas 13: Figure 1. Two minutes contact time was given to ensure intimate contact between tissues and the sample. SHINDE J.V.
it was found that gelation temperature of formulations increased significantly (P<0.06 ± 0. If n is 0. n=6.57. Mucoadhesive polymers reduced the gelation temperature while PEG 6000 increased the Tsol-gel of the corresponding mucoadhesive nasal insitu gelling formulations in a concentration dependent manner as described earlier (Table 5).00 ± 0. RESULTS Optimization of concentration of PF127 Gelation temperatures for plain PF127 gels were observed for the concentration range of 16-20% w/v of PF127 and it was found that the gelation temperature of plane PF127 gels decreased with increasing concentration of PF127. The percentage drug content of formulations from same batch was found to be uniform (Table 5). The kinetic parameters (n and k) were calculated from the plot of log (Mt /M∞) versus log (t). Statistical treatment Values are expressed as mean ± SD.45-0.57-0.42 24. indicative of the drug release mechanism. MTCH–metoclopramide hydrochloride. From Table 3 it was found that 0. From Table 2 it was found that only 18% of PF127 gel with drug showed ability to form gel in the range of 25 to 32 °C. 357 . PF127. As concentrations of mucoadhesive polymers increased. Effect of PEG on gelation temperature of PF127 Effects of PEG 6000 in the concentration range of 0. Gelation temperature Various excipients like mucoadhesive polymers as well as PEG 6000 had shown to have effect on the gelation temperature.3 to 1% are shown in Table 4. Viscosity measurement The viscosities of various formulations were measured with increase in temperature by using Cone and Plate viscometer (Brookfield viscometer Model Cap 2000 +2). The percentage drug content of all prepared nasal formulations were checked and found to be in the range of 93-104%. Permeability coefficient was calculated at steady-state condition by using the formula . Statistical analysis of data was performed using paired t-test or one-way ANOVA followed by Dunnett’s multiple comparison test. and 0.48 where (Mt /M∞)is the fraction of released drug at time (t).0068 Table 2. NA CMC and Na alginate was done by considering optimum gelation temperature and mucoadhesive force.5. where Jss = slope of linear portion of graph of amount of drug permeated per unit area Vs time and Cv = Initial donor concentration. there was significant (P<0. When 10% of MTCH was added into PF127 gels.pluronic flake 127.0001 0. pH of all the formulations was found to be in the range of 4.05).05). Gelation temperature of PF127 solutions.25 24.5-6. the drug is released from polymer with a non Fickian (anomalous) release. When n is 0.25 ± 0. Formulation studies Clarity. Permeability Coefficient: Jss / Cv  0.2010 Mt /M∞ = k tn or the logarithmic form of this equation  log (Mt /M∞) = log(k) + n log(t)  Composition Gelation Temperature P value* (°C) Mean ± S. In the final formulations concentration of PEG 6000 was varied so as to maintain.3% of HPMC K4M with 18% w/v of PF127 showed optimum results in term of mucoadhesion. * p < 0.05 considered statistically significant. So. the drug is released from polymer with Fickian diffusion mechanism. A P value < 0. Analysis of permeation coefficient The permeability coefficient was calculated for each set of formulation.  PF127 16% PF127 16% + 10% MTCH PF127 18% PF127 18% + 10% MTCH PF127 20% PF127 20% + 10% MTCH 42.2% of Na CMC and Na-alginate. Values are expressed as mean ± SD. As the concentration of PEG 6000 increased gelation temperature was found to be increased significantly (P<0.Latin American Journal of Pharmacy .D.30 44.23 ± 0. 18% w/v concentration of PF127 was used for further studies. pH and content uniformity All the prepared sets of formulations were found to be clear. gelation temperature in the range of 29 to 32 °C.23 29.05) decrease in gelation temperature while increase in mucoadhesive strength of formulations.62 25. (k) a characteristic constant of the dosage form and (n) the release exponent.05 was considered significant. Hence these concentrations of mucoadhesive polymers were selected for final formulations.70 ± 0.30 0.58 ± 0.84.29 (3) . Optimization of mucoadhesive polymers with 18 % w/v of PF127 The optimization of mucoadhesive polymers HPMC K4M.
polyethylene glycol 6000.23 0.12* 0. Effect of PEG on Gelation Temperature of PF127.V.93 28.3 %HPMC + 0.12* 0.11* 486 544 696 768 554 560 600 636 656 693 709 571 659 701 732 756 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 20 45* 23* 18* 75* 55* 18* 19* 92* 11* 27* 30* 20* 46* 32* 25* Table 3.26 28.3 % Na alginate + 0. PF127.1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.0 % PEG 6000 6000 6000 6000 6000 6000 6000 6000 25.D. In vitro drug diffusion studies Diffusion of drug from various formulations was studied by using sheep nasal mucosa.D.01* 0.1* 0.62 27.12* 0.05 considered statistically significant.1* 0.15* Drug permeation studies Amount of drug permeated per unit area for various nasal insitu gelling formulations are shown in Figure 2. From viscosity studies all formulations are in a liquid state at room temperature for ease of administration and accurate measurement of dose and would be converted into gel with increased residence time at the lower limit Table 4.08* 0.D. & MALI R.Pluronic Flake 127. SHINDE J.62 24.9 % PEG %+1. Sharp rise in viscosity was observed at the point of Tsol-gel transition.1 0. formulations containing PEG 6000 permeate more quantity of drug per unit area and per unit time than the formulations without PEG 6000 except in case of Na CMC containing formulations.05 considered statistically significant. PEG 6000.57* 0. Values are expressed as mean ± S.sodium carboxy methyl cellulose. Composition Gelation Temperature °C Mean ± S.4 %Na CMC + 0.16* 0.23 0.52 27.. HPMC.87 25.92 24. Values are expressed as mean ± S. n = 6.2 % Na alginate + 0.4 % PEG %+0.4 % Na alginate + 0.10* 0.55 24.7 % PEG %+0. Mucoadhesive force Preformulation studies have shown that mucoadhesive strength of formulations increases with increase in concentration of mucoadhesive polymers.4 27.5 % Na alginate 25.88 25.12* 0.2 %HPMC + 0.65 26..5 %Na CMC + 0.15* 0.97 26.. 100 % of drug diffusion was obtained at 240 min for formulations F5.3 %Na CMC + 0.3 % PEG %+0. DISCUSSION The physiological range of the nasal mucosal temperature lies between 32-34 °C 15. Na alginate.52 23. PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 % % % % % % % % % % % % % % % % (control) + 0. From Table 5 it was found that as the concentration of PEG 6000 was increased there was significant (P<0. Composition Gelation Temperature (°C) Mean ± S.05 27.48 28.93 23.06* 0. Figure revealed that. Na CMC. MALI K. PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 PF127 18 18 18 18 18 18 18 18 18 % (control) %+0.05) decrease in mucoadhesive strength.D. From viscosity studies it was found that all formulations were in liquid state at room temperature and were converted into gel at nasal physiological temperature.93 24.12* 0.K.K.2 %Na CMC + 0..hydroxyl propyl methyl cellulose.7 ± ± ± ± ± ± ± ± ± 0.4 %HPMC + 0.5 % PEG %+0. Gelation temperature and mucoadhesive strength of formulations containing various mucoadhesive polymers.J..47 24.6 % PEG %+0. There was no considerable change in viscosity upto the point of gelation temperature. Viscosity studies The plots of viscosity versus temperature for various nasal insitu gelling formulations are shown in Figure 3.23 25.sodium alginate.12* 0.8 % PEG %+0.1* 0.5 %HPMC + 0. 358 .11* 0. F9 and F12 (Table 6). HAVALDAR V.1 % Na alginate + 0.1 %HPMC + 0.DIAS R. * p < 0.58 26.D.53 23. * p < 0.17 26.15* 0. Mucoadhesive Strength (dyne/cm2) Mean ± S. n = 6.1 %Na CMC + 0.12* 0. So the thermoreversible nasal gels were prepared with the phase transition temperature in the range of 29-32 °C.D.12 0.58 25.
49* 618.3 ± 10. F6 control.6 ± 12.8 5.1 5 4. gelation temperature and mucoadhesive strength of various mucoadhe- sive nasal insitu gelling formulations.. c) containing 0.Latin American Journal of Pharmacy .15 446 ± 8. of the nasal physiological temperature range.2% Na CMC.12 93. Values are expressed as mean ± S. n=6 Mucoadhesive Strength (dyne/cm2) Mean ± S.13 629 ± 11.17 31.5 5.F10-F13.5* 713.3 ± 10.76 ± 0.2% Na CMC.2 ± 0.D. For mucoadhesive strength: Group I formulations containing HPMC .9 ± 0.55 732.66* 633 ± 12. F10 control.7 5. The loading of MTCH in the different formulations was kept at 10%w/v such that 100 µl gel (the optimum volume for nasal administration) would contain 10 mg.01* 575 ± 9.9 5.15 30.6 ± 5.87 776.11 94.05 considered statistically significant.71 99. pH.31 99.62 97.86 ± 0.11 30.53 ± 0.7 5.21 31.07* 659 ± 11.06 ± 0.29 (3) .42 29. c) containing 0.04* 715.96 ± 0.15 29.16 99.3 4.46 ± 0.56 ± 0.3 % HPMC.2010 Formulation Clarity pH Content Uniformity n=3 Gelation Temperature (ºC) Mean ± S.D.1 5 4. n=6 F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 5.2 5.D.84 101.06 28. Figure 2.23 ± 0.9 5.96 ± 0. * p < 0.15 31.53* 533. a) containing 0. 359 . Group III formulations containing Na alginate.2% Na alginate.13 649.F6-F9. Clarity.1 29. Viscosity against temperature plot for the formulations.1 ± 0.96 ± 0. Group II formulations containing Na CMC . Figure 3.23 102.47 94.9 104.31 29. a) containing 0.45* Table 5.21 31.F2-F5.26 30.7 93.3 ± 9. which is the adult dose 16.03* 656 ± 11.2% Na alginate. F2 control.33 ± 5. content uniformity.11 32.65 98. b) containing 0. Amount of drug permeated per unit area against time for the formulations.3% HPMC. b) containing 0.6 ± 19.79 98.
67 8.30 12.0087238 0.. Incorporation of MTCH into insitu nasal gels increases the gelation temperature. MTCH being a weakly basic drug having pKa value of 9. Formulation % Drug diffused at 240 min Mean ± SD ‘n’ Value ‘k’ Value Permeability Coefficient (mg.00814 0.37 2.70 90.551 81.63 1.D.00021* 0.13 100. The decrease in the gelation temperature with increase in PF127 concentration may be attributed to the higher number and volume occupied by micelles at low temperature.24. Increase in concentration of mucoadhesive polymers decreases the distance traveled by in situ nasal gels. So its further addition was stopped when Tsol-gel of the in situ nasal gels approaches to 32 °C.5786 2.7771 0.0096010 0.00715 0.92 1. HAVALDAR V. As the concentration of PF127 increases.71 68. above which mucoadhesive strength decreases 20.00029 0.J. The increase in Tsol-gel observed upon addition of PEG 6000 could be attributed to its interference with the process of micellar association of PF127 chains 19.24 1.86 0.5333 0. is found to be in ionic form at low pH. it was evident upto 0. this might be related to the decrease in viscosity caused by PEG 6000.24 101.0083042 ± ± ± ± ± ± ± ± ± ± ± ± ± 0.6 7.21 82.00062* Non Fickian Non Fickian Non Fickian Non Fickian Non Fickian Fickian Fickian Fickian Fickian Fickian Fickian Fickian Fickian Table 6.6706 0. Mucoadhesive strength increases with increasing concentration of mucoadhesive polymers.K.53 1.97 0.93 6.0094942 0.00042* 0.2959 5.4737 0. n = 3.4788 0.63 2. But in case of HPMC containing formulations. the mucoadhesive strength increases in concentration dependent manner. the gel structure becomes more closely packed with the arrangement in the lattice pattern. Also the molecular interactions between MTCH and mucoadhesive polymers appeared to be involved in the release retarding effect of the mucoadhesive polymers 22.3541 6.5-6. In case of Na-alginate and Na CMC.55 101. This may be due to water soluble nature of metoclopramide hydrochloride which may cause modification of the process of micellar association of PF127 gels thereby increasing their Tsol-gel 17. The addition of PEG 6000 to the formulations decreases the mucoadhesive strength in concentration dependent manner.3178 7.37 88.00033 0.00019 0..44 91. slow release of MTCH from gels can be attributed to the formation of ion-pair of “MTCH and anionic polymer” 23.V. It is therefore advisable to keep the pH of formulation in the range of 4. Values are mean ± S.00087 0.0781 1. Further.00791 0.00069* 0.DIAS R.0084746 0.8372 0. Under alkaline pH lysozyme is inactive and nasal tissue is susceptible to microbial infection.5.2645 7.45 0.87 1.0080107 0.6113 0.00050 0.5641 0. SNES used to simulate vivo conditions. Tsol-gel lowering effect of mucoadhesive polymers could be explained by their ability to bind to PEO chains present in the PF127 molecules promoting dehydration and causing an increase in entanglement of adjacent molecules with more extensive intermolecular hydrogen bonding 18.3%. contained polyelectrolytes may also affect drug release from gels. SHINDE J.44 77.3368 7. The concentration of PEG 6000 was adjusted in such a manner that formulations may form gel at nasal physiological temperature.4618 2.K.4527 0.6 82.83 98.006562 0.05 considered statistically significant.0073764 0.0012 0. The mechanism of mucoadhesion may be related to hydrogen bonding between gel formulation and mucosal membrane via carboxyl groups in case of Na-alginate and Na CMC while hydroxyl groups are involved in case of HPMC containing formulations 20.21.00038 0.D.0078005 0.67 ± ± ± ± ± ± ± ± ± ± ± ± ± 2.0531 6..8 0. since mucoadhesive polymers increase the viscosity of in situ nasal gels.000006* 0.4789 0. MALI K.cm/min)(Mean ± SD) Release Mechanism F1(control) F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 77.8084 3. Hence.3349 0. The retardation of MTCH release with the mucoadhesive polymers could be explained by their ability to increase the overall gel product viscosity 21.639 2.6275 0. Release data of Metoclopramide HCl mucoadhesive nasal in situ gels.00013* 0. This may be associated to the diffusion of Cl– 360 .5254 0.0075215 0. Lysozyme is formed in the nasal secretions. * p < 0. which is responsible for destroying certain microbes at acidic pH. & MALI R..
K. J.J.. Sileno. 2. mucoadhesive strength. Manzo.K. and permeability coefficient. G. U. Churchill Livingstone. Lim.K. 165: 3344.S. Also the release enhancing effect of PEG 6000 might be due to its higher water solubility and its viscosity lowering effect 21. (1998) Adv.J.. 18.45-0. Oh & C.K. J. Jimenez-Kairuz A. 23.. Ryu. Guyot & P. Sci. Pharm. S.B. N. 6: 571-82.H. N. Verbeke.A. Khar.D. Millet (2004) Int. 59: 163-72. Rel. Rev.. C. Llabot. The non Fickian (anomalous) release kinetics.E. pp. M.V. 23: 2709-27. 19. Savaser. Gourishankar Education Society.P. 14. Pharm. Johnston. J. Res.. Blanchard (1998) J. Mygind N. Res.. Koffi. Allemandi & R. 21. 9: 425-34. Pisal. D. Y. C.. R. 5.A. New York. Taha (2003) Saudi.). Schmolka. On one hand Cl– may affect the diffusion of MTCH by acting as a counterion and on the other hand. Pharm. K. Ugwoke. Manzo. M. Mahadik. M132-6. P. Pharm. 9.57) and drug was released by diffusion mechanism (Table 6). Jung. Lee... PEG 6000 increased the drug diffusion and permeability while mucoadhesive strength gets decreased. Pharm. Permeability coefficient increases with increasing concentration of the PEG 6000 except Na CMC containing formulations. J. Punjabi. Tech. Chaumeil (2006) Pharm. Sci. Rev. A. Hussein. M. R. Acknowledgements. Choi.. Sci.G. London. S. 85: 73-81.K. L. Satara for providing laboratory facilities. (2005) Int. 8. Vanbilloen. M. Fawaz. (1998) Eur.A.U.K. DeMeireles. 6: 102-12. (1992) Pharm. 1999. Drug Del. & J.Latin American Journal of Pharmacy . F. 4. Carlfors & R.S. ed. Dahl (1998) Adv. Chung. Pharm.K. A. J. 29: 89-116.K. On the other hand in case of formulations containing Na CMC and Na alginate Fickian release kinetics was observed (n value between 0. Drug Del. (1999) J.. H. Y. Preformulation studies showed that drug and PEG 6000 increases the gelation temperature while mucoadhesive polymers were found to decrease the gelation temperature of PF127.. (1998) Int. N.. Pharm. Pharm. which proves its release enhancing effect. mucoadhesive polymers and PEG 6000 on gelation temperature of PF127 were studied. Ltd. 29: 3949. Mucoadhesive strength increases with increase in concentration of mucoadhesive polymers. (2006) Int. REFERENCES 1. Ozkan. might indicate that the release of drug followed coupled erosion diffusion mechanism in case of HPMC containing formulations 13.M. Baetens (2000) J. J. Choi.. R. 361 . Rhee. S. Mortada. K. (2002) J. Agnely & J. and C. Jagtap.F.57-0. K.R. for providing gift sample of metoclopramide hydrochloride and hydroxypropyl methylcellulose respectively. R. Kadam. W. Biopharm. Authors are also thankful to Prof. (2004) AAPS Pharm.I. & J. C.F.. J. 2nd ed.H. J. 288: 8799. Mater. in vitro drug diffusion. R. Yoon. C. pp..F. T. C. J. M.2010 and Na+ from the receptor compartment to the gel (donor compartment).H. Chandigarh. Control Rel. Shim. 24. Tasdemir & H. G.Z. Kim & S. Awad. J. Drug Del. S. Manzo. J. & V.K. Hinchcliffe. 79: 243-9.D.K. PF127 gel formulation with 0. Parson. Allemandi & R. Pimplaskar. Petersson. Agu.. Desai. Shelke. Jain. J. 20.84. Abd Elhady. C.J. Dollary.. J. Ozkan.. J. Quan. 17. D. J. A. Y. Pharm. Control Rel..A. Ali (1997) “Mucoadhesive Drug Delivery” in “Controlled and novel drug delivery” (N. Su & S.P. Zhang. J. 68: 207-14. Q.S. Control Rel. A. 353-81. H. N. 5: 1-9. Navarre & U.A. S. Kim. Sci. V. Grosslord. 87: 226-30. F. Nankervis & A.H. H. Y. (2001) Int. Hotchkiss. M. 10.29 (3) . Altunay (2006) Eur. Chang ( 1999) Nasal Systemic drug delivery. Pharm. (1998) Adv. 11. 29: 3-12. 11: 159-71. Tas. the ionic exchange between Na+ and MTCH may also affect drug release from the polyanion 25.3% HPMC was found to be optimum formulation in terms of gelation temperature.J. J. Cheng. 280:151-62. effects of drug. Res. (1972) J. 15.C. 250: 129-36. 13. (2003) Int. D. Ahuja & J. 16.F. Romeo. M.D. Behl. CONCLUSION In the present study. 22. New Delhi.A. Kompella. Pharm. 12. Kim & C. (1999) Therapeutic Drugs. J. 3. 322: 36-43 25. Carlfors & R.M. Yong. Rev. Peterson (1998) Eur. & R. Kinget. (2002) J. Chairman. Biomed. 39-78. Marcel Dekker Inc. 226: 195-205. Allemandi & R.L. Watts..M. 7. Edsman. C. & S. From the results of formulation studies it can be concluded that. I..S. Control.L. Edsman. D. J. 64: 246-54. S. CBS Publishers and distributors. A. Authors are very much thankful to Medi-orals Pvt. revealed by (n) values between 0. Zaki & R. J. Jimenez-Kairuz A. Ryu. 6: 105-12. Dumortier. Ramyrez Rigo M. Chien. 6.. pp. C.S. Faraj.H. Satara and Panacea Biotech.
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue listening from where you left off, or restart the preview.