Formulation and Evaluation of Floating Drug Delivery System of Cefpodoxime Proxetil
Pathan DN1*, Shaikh NH1, Thube RT1, Bhise KS1 and Polshettiwar SA2
1Allana College of Pharmacy, Azam Campus, Camp, Pune, India.411001.
2MAEER’S Maharashtra Institute of Pharmacy, Kothrud, Pune, 411038
*Corresponding Author E-mail: dilnawazpathan@gmail.com
ABSTRACT
The objective of the present study was to develop floating drug delivery system of Cefpodoxime proxetil to increase its residence time in stomach as high solubility, chemical and enzymatic stability and absorption profile was observed in acidic pH value. The floating tablets of Cefpodoxime proxetil were prepared by direct compression method using sodium bicarbonate as floating agent and HPMC as rate retarding polymer. A 32 full factorial design was constructed to study the effect of the amount of HPMC and sodium bicarbonate on the drug release profile from the formulations. The formulations were evaluated for floating lag time, floating duration time and in vitro drug release studies. The optimized formulation showed sufficiently sustained drug release and remained buoyant on the surface of medium for more than 10 hours. It was observed that the increase of floating agent concentration displayed a common phenomenon that the drug release rate and extent were increased in all cases. As the concentration of HPMC increases in the formulation the release rate was found to be decreased. Accelerated stability studies were performed as per ICH guidelines at temperature of 40 ± 2 şC and humidity 75 ± 5 %RH for a period of 3 months. The results indicated that these formulations remained stable. It can be concluded that floating drug delivery system of Cefpodoxime proxetil can be successfully formulated as an approach to increase gastric residence time and thereby improve its bioavailability.
KEYWORDS: Cefpodoxime proxetil, floating, gastro retentive, HPMC.
INTRODUCTION:
Gastro retentive Floating drug delivery system is meant for drugs with local action in the proximal gastrointestinal tract (GIT), which are unstable in lower part of GIT or are poorly absorbed in the intestine or the drugs which are specially soluble in acidic pH of stomach.
The challenge to develop efficient gastroretentive dosage for began about 25 years ago, following the discovery of Helicobacter pylori by, Warren and Marshall1. Dosage forms that that can be retained in the stomach are called gastroretentive drug delivery systems (GRDDS)2. GRDDS can improve the controlled delivery of drugs that have an absorption window by continuously releasing the drug for a prolonged period of time before it reaches its absorption site thus ensuring its optimal bioavailability3. Various attempts have been made to develop gastro retentive delivery system. For example, floating, swelling, mucoadhesive, and high density systems have been develop to increase gastric retention time of the dosage form.
Floating system can be of effervescent or non effervescent in nature. In the former ones gas generating excipients eg. Bicarbonate salts were used that can form CO2 in presence of gastric acid4. Matrix tablets containing hydroxy propyl methyl cellulose (HPMC), drugs, and gas generating agents have shown duration of floating over 8 hrs and in vitro lag time before the unit floats is less than 1min5.
Hydroxy propyl methyl cellulose (HPMC), which is commonly used in hydrophilic matrix drug delivery systems because of broad US FDA acceptance. The solubility of HPMC is pH independent6.
Cefpodoxime proxetil, a prodrug ester of cefpodoxime7, is a third generation broad spectrum β- lactam cephalosporin class of antibiotic administered orally which on absorption is esterified to its active metabolite cefpodoxime. It exhibits its antibiotic action by binding to penicillin-binding protein, thereby causing abnormal bacterial cell wall synthesis and lysis. It is categorized as a Class IV drug according to the biopharmaceutical classification of drugs, having poor solubility and poor absorbability.
Traditional oral sustained release formulations releases most of the drug at the colon, thus the drug should have absorption window either in the colon or throughout the gastrointestinal tract8. Cefpodoxime proxetil is absorbed only in the initial part of the small intestine and has 50% absolute bioavailability. Further, its solubility is reported to be highly pH dependent, with favored solubility in acidic media. The metabolism of Cefpodoxime proxetil is arrested in acidic pH of stomach. The short biological half life of drug (2.5 to 3 hrs) also favors development of a gastroretentive formulation.
The high solubility, chemical and enzymatic stability and absorption profile of Cefpodoxime proxetil in acidic pH value (stomach) points to the potential of a Gastro retentive dosage form in altering the absorption profile of Cefpodoxime proxetil. Hence, attempts were taken to formulate into gastro retentive dosage form using Sodium bicarbonate as floating agent and HPMC as rate retarding polymer.
MATERIALS AND METHODS:
Cefpodoxime proxetil was received as a gift sample from Ranbaxy Research Laboratories, Gurgaon, (India).HPMC K4 was procured from Colorcon Asia Pvt. Ltd, Goa (India). Sodium bicarbonate was obtained from Loba Cheme, Mumbai,(India).
Table1: Variable levels used in factorial design.
|
Batch Code |
X1 |
X2 |
|
F1 |
-1 |
-1 |
|
F2 |
-1 |
0 |
|
F3 |
-1 |
1 |
|
F4 |
0 |
-1 |
|
F5 |
0 |
0 |
|
F6 |
0 |
1 |
|
F7 |
1 |
-1 |
|
F8 |
1 |
0 |
|
F9 |
1 |
1 |
Where; X1 = HPMC K4, X2 = NaHCO3
Table2: Coded values and actual values used in factorial design.
|
Coded Values |
Actual values X1 |
Actual values X2 |
|
-1 |
15 |
20 |
|
0 |
20 |
25 |
|
1 |
25 |
30 |
Preparation of Cefpodoxime proxetil floating tablets:
The tablets were prepared by direct compression method. All the ingredients listed in the composition table3 were blended in a polybag using geometric dilution principle. The blend was compressed using 8 station tablet punching machine-Karnavati-Minipress-D-II Link, Mumbai. All the tablets were punched by using 8mm flat punch. The compressed tablets were then evaluated for tablet characteristics such as diameter, thickness, weight variation, friability and hardness.
Full factorial design:
A 32 full factorial design was used in this study. In this factorial design 2 factors were evaluated, each at 3 levels and experimental trials were performed at all 9 possible combinations. The amount of HPMC(X1) and NaHCO3(X2) were selected as independent variable while all other quantities remained constant. Percent cumulative drug release and floating lag time were selected as dependent variables.
Variable levels which used in factorial design were depicted in table1 and code values were depicted in table 2.
The formulations prepared by factorial design were depicted in table 3.
Tablet density:
Tablet density is an important parameter for floating tablets. The tablet will float only if its density is than that of gastric fluid (1.004). Density (d) was determined using the relationship d = m/v where v = πr2h.
In Vitro Buoyancy Studies:
The time taken for tablet to emerge on the surface of medium is called as the floating lag time (FLT) or buoyancy lag time and the duration of time the dosage form constantly remained on surface of medium is called the total floating time (TFT).
The in vitro buoyancy was determined by floating lag time, per the method determined by Rosa et al9. The tablets were placed in a 100-mL beaker containing 0.1N HCl (pH1.2).
Fig.1.In vitro drug release profile of optimized formulations.
In Vitro Dissolution Studies:
The release rate of Cefpodoxime proxetil from floating tablets (n=3) was determined using USP dissolution testing apparatus II (Basket type).The dissolution test was performed using 900ml 0.1N HCl(pH1.2). The basket rotation speed was kept at 100rpm and temp of 37± 0.5 °C was maintained. At predetermined time interval of 1, 2, 3…10h sample was withdrawn from the dissolution apparatus and the volume of dissolution medium was adjusted with the fresh dissolution medium. The samples were passed through Whatman filter paper and the absorbance of these solutions was measured at 262nm. The cumulative percentage release was calculated using ‘PCP Disso v3’ software (Poona College of Pharmacy, Pune, India).
Table3: Tablet Formulation.
|
Ingredients |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
|
Drug(*) |
145 |
145 |
145 |
145 |
145 |
145 |
145 |
145 |
145 |
|
HPMC K4 |
15 |
15 |
15 |
20 |
20 |
20 |
25 |
25 |
25 |
|
NaHCO3 |
20 |
25 |
30 |
20 |
25 |
30 |
20 |
25 |
30 |
|
Mag.stearate |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
Total weight |
182 |
187 |
192 |
187 |
192 |
197 |
192 |
197 |
202 |
|
FLT(sec) |
38 |
34 |
32 |
40 |
37 |
35 |
42 |
38 |
36 |
|
% drug release** |
83.95 |
86.14 |
88.60 |
75.52 |
77.86 |
80.20 |
73.39 |
74.87 |
76.76 |
|
TFT(hrs) |
8. |
8.6 |
>10 |
8.3 |
8.5 |
>10 |
8.2 |
9 |
>10 |
(*All batches containing 145mg of cefpodoxime proxetil equivalent to 100mg of cefpodoxime,) (** After 10hrs.)
Table 4. In vitro Drug release of optimized formulations.
|
Time(h) |
F3 |
F6 |
F9 |
|
0 |
0 |
0 |
0 |
|
1 |
29.18 |
25.34 |
18.85 |
|
2 |
37.73 |
29.92 |
25.44 |
|
3 |
43.34 |
34.48 |
32.47 |
|
4 |
49.96 |
42.36 |
38.38 |
|
5 |
56.71 |
48.69 |
45.43 |
|
6 |
62.96 |
55.24 |
52.53 |
|
7 |
70.21 |
61.31 |
58 |
|
8 |
75.23 |
68.79 |
64.4 |
|
9 |
81.59 |
74.13 |
71.41 |
|
10 |
88.6 |
80.2 |
76.76 |
Accelerated stability studies:
The stability studies were carried out according to the ICH and WHO guidelines to assess the drug and formulation stability10. The optimized formulations were sealed in aluminum packaging material. Samples were kept in a humidity chamber (Thermolab) maintained at 45 şC and 75 % RH for 3 months. At the end of the study period, samples were analyzed for drug content, buoyancy lag time buoyancy time and drug release.
RESULT AND DISCUSSION:
The tablets were prepared by direct compression method following extensive preformulation studies to select the appropriate formulation components and processing factors. A 32 factorial design was constructed to study the effect of amount of HPMC (X1) and sodium bicarbonate (X2) on the drug release from the formulations.
Tablet Hardness:
The hardness of all the formulations was found to be 5 – 6 kg/cm2.
Tablet Density:
The tablet density was found to be uniform among different batches ranged from 0.92 to 0.97 g/cm2.
The tablet density is less than gastric fluid so the tablet float on the surface of the gastric fluid for as long as 10-12 h.
Buoyancy Test:
The tablet floating lag time was found to be less than 50s and total floating time more than 8h.
The floating lag time may be explained as a result of the time required for dissolution medium to penetrate tablet matrix and develop the swollen layer for entrapment of CO2 generated in situ. The tablet mass decreased progressively due to liberation of CO2 and release of drug from the matrix. On the other hand, as the solvent front penetrated the glossy polymer layer, the swelling of HPMC caused an increase in the volume of tablet. The combined effect is a net reduction in density of tablets, which prolong the duration of floatation beyond 8h.
In vitro dissolution studies:
The release data were evaluated by model-dependent method using “PCP Disso v3” software. The release rates kinetic for optimized formulations with varying quantity of polymer were shown in the Table 4. Formulations F3, F6, F9, exhibited a release of 88.60, 80.20, 76.76 % respectively, in 10h. It was observed that the increase of floating agent concentration displayed a common phenomenon that the drug release rate and extent were increased in all cases. As the concentration of HPMC increases in the formulation the release rate was found to be decreased.
Accelerated Stability studies:
The stability studies were carried out on the optimized formulations as per ICH guidelines. The results indicated that these formulations remained stable for a period of 3 months.
CONCLUSION:
From the data obtained it can be concluded that floating drug delivery system of Cefpodoxime proxetil can be successfully formulated as an approach to increase gastric residence time and thereby improve its bioavailability. Formulated tablets gave satisfactory results for various physicochemical evaluations for tablets like hardness, tablet density, floating lag time and in vitro drug release.
Thus the objective of formulating a floating drug delivery system of Cefpodoxime proxetil using sodium bicarbonate as floating agent and HPMC as rate retarding polymer has been achieved successfully.
ACKNOWLEDGEMENTS:
The authors are very grateful to Ranbaxy Research Laboratories, Gurgaon, for generously providing gift sample of Cefpodoxime proxetil. Authors acknowledge Colorcon Asia Pvt Ltd, Goa, supplying HPMC K4.
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Received on 11.06.2009 Modified on 13.08.2009
Accepted on 10.09.2009 © RJPT All right reserved
Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 812-815