Studies on Oral Sustain Delivery of Cefixime from Floating Matrix Tablets Formulation and In Vitro Evaluation  

 

R. Divya, S. Sivaneswari*, N. Preethi, B. Mounika, G. Hemalatha B. Naveen Kumar, J. Jayasree,  S. Vasudeva Murthy

 

ABSTRACT:

The objective of the present study was to develop Cefixime  gastroretentive floating  matrix  tablets for prolonged  gastric retention time and thereby increased drug bioavailability. Cefixime is a third generation Cephalosporins antibiotic which is slowly and incompletely absorbed from the GIT, which resulting into the poor bioavailability 40-50%.The floating tablets were prepared by direct compression method, using polymers like SCMC, Carbopol 934P, and HPMC K100M in an effervescent system and polypropylene foam powder (Accurel) in low density system.The powder blends was subjected for pre-compression parameters and were within prescribed limits and indicated free flowing property.The prepared tablets were evaluated for post- compression parameters such as weight variation, thickness, friability, hardness, drug content, in vitro buoyancy studies and in vitro release studies in 0.1N HCl (pH1.2) for 12 h. Among all the formulations (F1 to F12), formulation (F8) which showed the buoyancy lag time 52 Sec, remained buoyant for 12h and release of Cefixime sustained over 12h when compared to other formulations. The in vitro data is fitted into different Kinetics models. The optimized formulation F8 followed Zero order kinetics and best fitted Korsmeyer - Peppas model followed by non-fickian diffusion (n=0. 753).  FTIR studies revealed that, there was no incompatibility of the drug with excipients used. The stability studies conducted as per the ICH guidelines at 40 ± 2^oC and 75 ±5% RH for 1 month and the optimized formulation (F8) showed no significant change in physical appearance, drug content, total buoyancy time  and  in vitro dissolution study after storage. From this study, it was concluded that, the formulation (F8) can be retained for a longer period of time in the stomach and provided prolong release of the drug, hence it may increase the therapeutic efficacy of the drug by increasing the bioavailability.

 

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1. INTRODUCTION:

Oral sustained release dosage forms (SRDFs) have been developed in the past three decades due to their considerable therapeutic advantages. However, this approach has not been suitable for a variety of important drugs, characterized by a narrow absorption window in the upper part of the gastrointestinal tract (GIT), i.e. stomach and small intestine due to the relatively short transit time of the SRDFs in these anatomical segments. Thus, after only a short period (< 6 h), the SRDF lefts the upper GIT and the drug is released in nonabsorbing distal segments of the GIT. This results in a short absorption phase that is often accompanied by lesser bioavailability.

 

It was suggested that compounding narrow absorption window drugs in a unique pharmaceutical dosage form with gastroretentive properties would enable an extended absorption phase of these drugs. After oral administration, such a dosage form would be retained in the stomach and release the drug there in a sustained manner, so that the drug could be supplied continuously to its absorption sites in the upper GIT. This mode of administration would best achieve the known pharmacokinetic and pharmacodynamic advantages of SRDFs for these drugs¹. Various gastroretentive techniques were used, including floating, swelling, high density, and bioadhesive system, has been explored to increase the gastroretention of dosage forms. Floating systems having low density that has sufficient buoyancy to float over the gastric contents and remain in the stomach without affecting the gastric emptying rate for a prolonged period. While the system floats over the gastric contents, the drug is released slowly at the desired rate, which results in increased gastric retentive time and reduces fluctuation in plasma drug concentration, Such retention systems are important for those drug that are degraded in the intestine like antacids or certain antibiotics, enzymes that act locally in the stomach².Cefixime is a third generation cephalosporin antibiotic which is  used in the treatment of uncomplicated UTI, otitis media, pharyngitis, acute bronchitis and acute exacerbation of chronic bronchitis, uncomplicated gonorrhea. Cefixime  is slowly and incompletely absorbed from the gastrointestinal tract after its oral administration because of poor solubility, which resulting into the decreased  bioavailability around 40-50 %. Cefixime with pKa value of 2.5 a weak acid, which will remain unionized at acidic pH, thus increases absorption in the stomach region. It is primarily absorbed from the stomach and upper part of intestine^3-6. Based on this absorption characteristic and short half life (3 - 4 hrs), an attempt was made in the current investigation to prolong the gastric residence time through formulating Cefixime  floating matrix tablets  by efferevescent system and low density system using different hydrophilic polymers like SCMC, Carbopol 934 P, HPMC K 100 and low density polypropylene foam powder (Accurel). 

 

2. MATERIALS AND METHODS:

2.1. Materials:

Cefixime was obtained as a gift sample from Hetero Drugs, Hyderabad. SCMC, Carbopol 934 P, HPMC K 100 and Accurel were procured from Sigma Aldrich PVT Limited, Hyderabad. All other exipients and chemicals were procured S.D.Fine Chemicals, Mumbai.

 

2.2. Formulation of floating tablets of Cefixime:

Floating tablets of Cefixime were prepared by direct compression method employing sodium bicarbonate as gas-generating agent. SCMC, Carbopol 934P and HPMC K100 were used as a rate controlling polymers in formulation F1 - F9. Accurel is used in formulating F10 - F12 along with HPMC K100.  The concentrations of the above ingredients were optimized as shown in Table 1 on the basis of trial preparation of the tablets. All the ingredients were weighed accurately. The drug was mixed with the release rate retarding polymers and other excipients, except magnesium stearate, in geometric proportion. The powder mix was blended for 20 min to have uniform distribution of drug in the formulation. Then, magnesium stearate was added and mixed for not more than 1 min (to ensure good lubrication). The powder blend was evaluated for pre-compression parameters such as Bulk density, Tapped density, Angle of Repose, Carr’s index and Hausner’s ratio. The results were shown in Table: 2. Then the powder blend was compressed using 19 X 9 mm modified tablet punches in rotary tablet punching machine (Pankaj Industries, Maharashtra, India).  

 

2.3. Characterization of Cefixime Floating Matrix Tablets:

2.3.1. Evaluation of tablet properties:

The prepared cefixme floating tablets were evaluated for weight variation, thickness, hardness and friability⁷. To study weight variation, 20 tablets of each formulation were weighed using an electronic balance, and the test was performed according to the official method. The thickness of the tablets was measured using Vernier calipers. The hardness of the tablet was determined by the Monsanto hardness tester. The friability of the tablets was determined using Roche friabilator. 20 tablets were initially weighed and transferred into the friabilator. The friabilator was operated at 25 rpm for 4 min. After four minutes the tablets were weighed again. The % friability was then calculated using the formula,

 

Friability [%] = (Initial weight - Final weight)/ Initial weight x 100

The results were shown in Table: 3.

 

2.3.2. Swelling property:

Swelling characteristics were expressed in terms of percentage water uptake shows the relationship between swelling index and time⁸. One tablet from each formulation was weighed and kept in a petri dish containing 50 ml of 0.1N HCl solution. At the end of specified time intervals tablets were withdrawn from the petri dish and excess liquid blotted with tissue paper and re-weighed.  The % of weight gained by the tablet was calculated by using the following formula:

 

Swelling index (%) = (M_t – M₀) /M₀  x 100

 

Where, M_t – weight of tablets at time t’,  M₀ – weight of tablets at time ‘0’. The results were shown in Table 4 and Fig 1

 

 

 

Table.1: Composition of  Cefixime  Floating Matrix Tablets

 

 

2.3.3. In vitro buoyancy studies:

The in-vitro buoyancy was determined by the floating lag time⁹. The tablets were placed in a 100 ml beaker containing 0.1N HCl (pH 1.2). The time required for the tablet to rise to the surface for floating was determined at the floating lag time and further floating duration of all tablets was determined by visual observation. The results were shown in Table: 4.

 

2.3.4. Drug content uniformity:

Accurately weighed quantity of the powdered tablet equivalent to 200 mg of the drug was transferred to 100 ml volumetric flask. 10 ml of methanol was added. Mixture shaken for 10 min, and then the volume was made up to 100 ml with 0.1N HCl (pH 1.2) and filtered through the membrane filter disc with an average pore diameter not greater than 0.45μm. the above solution were suitably diluted  and analyzed spectrophotometrically  (U.V Spectrophotometer 1800 Shimadzu, Kyoto, Japan) at 288nm ¹⁰. The results were shown in Table: 4.

 

2.3.5. In vitro dissolution study:

The Dissolution study was carried out using dissolution test apparatus USP type II. 900 ml of 0.1N HCl (pH 1.2) was used as a dissolution medium at 37±0.5º C. The paddle speed was kept at 50 rpm throughout the study. An aliquot of 5 ml was withdrawn at predetermined time interval and equivalent amount of fresh medium was replaced to maintain a constant volume. After each sampling and suitably diluted with buffer, solutions were analyzed spectrophotometrically at 288nm against blank using UV-visible spectrophotometer (1800, Shimadzu, Kyoto, Japan). The drug release profiles were shown in Fig. 2, 3, 4and5.

 

2.3.6. Drug-Excipient compatability study:

IR spectra of drugs and optimized tablets were recorded at scanning range 4000cm^-1 to 400cm^-1 by KBr pellet technique in FT-IR spectrophotometer. The IR spectra were shown in Fig. 6 and 7.

 

2.3.7. Kinetic modeling of drug release:                                                                                       

The results of in vitro release profile obtained for all the formulations were fitted to zero order, first order, Higuchi and Korsmeyer-Peppas equation to assess the kinetic modeling of drug release^11-14.

 A Zero order release would be predicted by the following equation,

 

A_t = A₀ – K₀t

 

Where, A_t - Drug release at Time ‘t’, A₀ - Initial drug concentration, K₀ - Zero-order rate constant (hr^-1).

First - order release would be predicted by the following equation:-

 

Log C = log C₀ – K_t / 2.303

 

where,C -Amount of drug remained at time‘t’, C₀ - Initial amount of drug, K = First order rate constant (hr^-1).

Drug release from the matrix devices by diffusion has been described by followingHiguchi’s classical diffusion equation.

 

Q = [Dε / τ (2 A - εCs) Cst] ^½

 

Where, Q - Amount of drug released at time ‘t’, D- Diffusion coefficient of the drug in the matrix, A  - Total amount of drug in unit volume of matrix, Cs - the solubility of the drug in the matrix.

 

ε - Porosity of the matrix, τ - Tortuosity, t - Time (hrs) at which ‘q’ amount of the drug is released.

Above equation may be simplified if one assumes that ‘D’, ‘Cs’, and ‘A’, are constant. Then the equation becomes,

 

Q = Kt^1/2

 

To study the mechanism of drug release from the sustained release matrix tablets of Cefixime, the release data were also fitted to the well-known exponential Korsmeyer equation  Peppa’s law equation, which is often used to describe the drug release behavior of polymeric systems.

 

M_t / M_α = Ktⁿ

 

Where, M_t / Mα - the fraction of drug released at time ‘t’.

K - Constant incorporating the structural and geometrical characteristics of the drug / polymer system.

n- Diffusion exponent related to the mechanism of the release.

 

The above equation can be simplified by applying the log of both sides, and we get:

 

Log M_t / M_α = Log K + n Log t

 

For Fickian release ‘n’ = 0.5 while for anomalous (non – Fickian) transport ‘n’ ranges between 0.5 and 1.0.

 

The regression coefficient values were shown in Table:5 and the graphs were shown in Fig 8,9,10 and 11.

 

2.3.8. Accelerated stability studies:

Accelerated stability studies were performed at a temperature of 40 ± 2^oC and 75 ± 5% RH over a period of  one month  for  optimized formulation F8. Sufficient number of  tablets   were  packed  in  amber  colored  screw capped bottles and kept in a modified  stability chamber. At the end of one month period, physical appearance and post- compression parameters such as weight variation, hardness, friability,   drug content, in vitro buoyancy studies and in vitro release studies were performed to determine the drug release profiles.

 

3. RESULTS AND DISCUSSION:

Cefixime floating matrix tablets were prepared by direct compression technique using different hydrophilic polymers HPMC K100, Carbopol 934 P and SCMC by incorporating gas generating agent sodium bicarbonate in formulation (F1-F9).  In the formulation (F10 – F12), low density poly propelene foam powder (Accurel) was incorporated with HPMC K100 to study floating ability of tablets, as shown in Table 1.

 

3.1. Pre- compression parameters of powder blends:

Initially the mixed powder blend was subjected to evaluate the flow property and compression characteristics such as bulk density, tapped density, angle of repose, Carr’s index and Hausner’s ratio. The results were found to be satisfactory and in acceptable limits indicate that all batches are having the good flow ability and compression characteristics which were shown in Table 2. 

 

3.2. Characterization of Cefixime floating matrix tablets:

Cefixime floating matrix tablets were prepared by direct compression method. All the tablets were white in color and round with smooth surfaces. The tablets were evaluated for weight variation, thickness, hardness, friability, swelling index, floating lag time(FLT), floating duration, drug content and in vitro drug release study. All the formulations passed the evaluation tests and showed comparable satisfactory results. The weight variation, thickness, hardness, friability and drug content of all formulations(F1-F12) was found to be in the range of 695±3.15-708±3.99 mg, 5.18±0.19 - 5.25±0.80 mm, 7.0±0.30– 9.0±0.31 kg/cm² 0.30±0.17–0.72±0.21 and 97.70±0.38 to 99.94±0.21 % respectively. The results of the above physiochemical evaluation were found to be in the acceptable range, as shown in Table 3 and4.

 

Swelling index was found to range from 30.32% to 38.48% within two hours time period, which indicates that the formulations swell to a certain degree after coming in contact with the simulated gastric medium. Swelling index of tablets containing SCMC showed lower % swelling index than that of the tablets with carbopol 934P and HPMC because carbopol 934P and HPMC K100M were more viscous in nature. The results of formulations containing carbopol 934P   showed more swelling than tablet containing SCMC and HPMC K100M. 

 

The floating lag time of formulations made of HPMC K100M and 20% of gas evolving agent were found to be satisfactory  because  hydrophilicity and swells fast when it comes in contact with 0.1 N HCl (pH 1.2). But the tablets made of SCMC and carbopol 934P showed lesser FLTs as its viscosity is less and that the polymer took even lesser time to form a matrix that could accommodate the evolved gas. And also the entrapped gas bubbles during compression are more in matrices of HPMCK100M,  the gas released by the bicarbonate could facilitate the floating of the tablets and at the later stage of the drug dissolution, which is evident in the tablets showing a floating duration up to 12 h. The results were shown in Table 3and4. 

 

 

 

 

Table 2:Pre-Compression parameters for  formulation (F1-F12)

Formulation code	Bulk density(g/cc)*	Tapped density(g/cc)*	Carr’s Index(%)*	Hausner Ratio *	Angle of repose(θ) *	Flow property
F1	0.45±0.045	0.52±0.09	15.60±0.2	1.15±0.02	28.06±0.31	Good
F2	0.45±0.045	0.50±0.07	12.23±0.6	1.11±0.04	27.58±0.15	Good
F3	0.44±0.044	0.53±0.09	12.58±0.8	1.13±0.08	28.44±0.11	Good
F4	0.45±0.045	0.52±0.04	15.19±0.1	1.15±0.06	28.36±0.13	Good
F5	0.44±0.044	0.52±0.01	15.48±0.6	1.18±0.08	28.52±0.19	Good
F6	0.45±0.045	0.51±0.04	13.48±0.8	1.13±0.09	29.32±0.19	Good
F7	0.51±0.045	0.59±0.04	14.48±0.8	1.15±0.09	29.69±0.19	Good
F8	0.45±0.045	0.50±0.07	12.23±0.6	1.11±0.04	27.58±0.15	Good
F9	0.45±0.045	0.52±0.04	15.19±0.1	1.15±0.06	28.36±0.13	Good
F10	0.51±0.045	0.59±0.04	14.48±0.8	1.15±0.09	29.69±0.19	Good
F11	0.45±0.045	0.52±0.04	15.19±0.1	1.15±0.06	28.36±0.13	Good
F12	0.45±0.045	0.50±0.07	12.23±0.6	1.11±0.04	27.58±0.15	Good

*All the values are expressed as mean ±SD(n=3)

 

Table 3: Post compression parameters of   formulations (F1-F12)

Formulation	Weight Variation* (mg)a	Thickness *(mm)b	Hardness* (kg/cm2)b	Friability* (%)a
F1	700±4.36	5.20±0.20	7.2±0.54	0.72±0.21
F2	702±4.02	5.22±0.22	7.5±0.75	0.37±0.42
F3	695±3.89	5.18±0.17	7.6±0.45	0.40±0.38
F4	708±3.99	5.25±0.05	7.9±0.25	0.46±0.36
F5	706±3.49	5.19±0.17	8.5 ±0.44	0.32±0.25
F6	703±2.99	5.20±0.25	9.0±0.31	0.30±0.17
F7	700±2.89	5.25±0.80	7.8±0.40	0.36±0.20
F8	702±2.88	5.19±0.20	8.2±0.55	0.31±0.25
F9	695±3.15	5.22±0.66	8.9±0.57	0.34±0.36
F10	697±1.36	5.20±0.25	7.0±0.30	0.35±0.31
F11	699±2.42	5.18±0.19	7.5±0.31	0.30±0.17
F12	700±2.78	5.21±0.17	7.4±0.25	0.46±0.36

a= 20 Tablets; b=6 Tablets. *All the values are expressed as mean ±SD (n=3)

 

 

 

Table 4: Post compression parameters of  formulations (F1-F12)

Formu lation	Drug content a(%)*	Floating lag time b(min)	Swelling indexb(%)	Floating durationb (hrs)
F1	98.78±0.24	1	30.32	5.5
F2	97.70±0.38	1.5	31.36	7
F3	99.51±0.32	1.3	32.75	8
F4	99.94±0.21	1.2	34.85	10
F5	98.42±0.28	1.8	37.75	12
F6	98.91±0.23	1.5	38.48	>12
F7	98.58±0.24	1.1	33.23	8
F8	99.26±0.44	52sec	36.32	12
F9	99.12±0.32	54sec	37.66	>12
F10	98.78±0.32	Immediate	34.25	6
F11	98.60±0.23	Immediate	35.36	7
F12	98.91±0.33	Immediate	38.21	7

a= 6 Tablets; b=3 Tablets, *All the values are expressed as mean ±SD (n=3)

 

Fig. 1: Swelling Index Graph for formulation (F1-F12)

 

3.3. In vitro dissolution study:

The in vitro dissolution of formulations (F1 –F12) was carried out in USP Type 2 paddle apparatus using 0.1N HCl (pH 1.2).   In formulations, (F1-F9 ) SCMC, Carbopol 934 P and HPMC K100 were used individually in the range of drug to polymer ratio 1:0.5, 1:0.75 and 1:1 respectively.   The formulations F1, F2, F3, F4, F7,  F10, F11,and  F12  have not sustained up to the time  period of 12 h. Formulations F5, F6, F9 have sustained release upto 12 h. Formulation F8 was found to have good integrity throughout the entire dissolution and has sustained release up to 12 h. In all formulation polymers concentration increases drug release sustained. In formulation F10 – F12,  Accurel was used as  low density polymer used along with HPMC K100  for floating, even though it floats immediately the drug release  sustained  up to  6 -8 h only. Based on floating time and integrity maintained upto 12hr, formulation F8 was optimized as best formulation. The drug release profiles were shown in Fig. 2, 3, 4and5.

 

3.4. Drug - excipient compatibility:

By correlating the functional group of pure Cefixime  and  optimized formulation (F8), there was no difference in absorption bands, hence providing the evidence that the  drug is compatible with other excipients present in the formulation. The FT-IR spectra were shown in Fig. 6and7.

 

Fig.2 : In vitro drug release profile  for formulations (F1 – F3)

 

Fig.3: In vitro drug release  profile for formulations (F4-F6)

 

Fig.4:  In vitro  drug release profile for formulations  (F7-F9)

 

Fig.5: In vitro drug release  profile for formulations (F10-F12)

 

Fig. 6 FT-IR Spectra of pure Cefixime 

 

Fig. 6 FT-IR Spectra of optimized formulation (F8)

 

3.5. Kinetic modeling of drug release

The release kinetic data for the formulation (F8) is shown in Table 5. As shown in Fig.8,9,10and11, the optimized formulation (F8) followed zero order kinetics(r² = 0.9511) indicating that the rate of drug release is independent of concentration, best fitted with Korsmeyer-Peppas model (R² =0.9648) and followed by non-fickian diffusion (n=0.753).

 

Fig. 8: Zero order plot for optimized  formulation (F8)

 

Fig.9: First order plot for optimized  formulation (F8)

 

Fig. 10:  Higuchi plot for optimized  formulation (F8)

               

Table 5: Regression Coefficients of different  release kinetic models for Cefixime floating tablets.

Formulation	Zero order(R2)	First order(R2)	Higuchi Model(R2)	Korsmeyer-Peppas model
				(R2)	(n)
F1	0.9244	0.7673	0.9938	0.9869	0.4955
F2	0.9041	0.9481	0.9834	0.9792	0.5327
F3	0.9372	0.9323	0.9915	0.9857	0.6305
F4	0.9383	0.9353	0.9834	0.9782	0.6959
F5	0.9422	0.9920	0.9899	0.9763	0.6856
F6	0.9522	0.9915	0.9890	0.9718	0.7738
F7	0.9123	0.9428	0.9854	0.9793	0.5747
F8	0.9511	0.9245	0.9622	0.9648	0.753
F9	0.9345	0.9869	0.9838	0.9722	0.6830
F10	0.9471	0.8641	0.9837	0.9774	0.6534
F11	0.9603	0.8778	0.9913	0.9820	0.7445
F12	0.9248	0.9861	0.9779	0.9582	0.7382

Fig.11:  Korsmeyer -Peppas plot for optimized  formulation (F8)

 

3.6. Accelerated stability studies:

The stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic, and toxicological specifications. Floating tablets of F8 were kept in accelerated stability study at 40 + 2^oC and 75 + 5% RH for 1 month in the modified stability chamber.  After a period of one month,  It was observed that surface was devoid of any change in color or appearance.  It was also noted that surface was free of any kind of microbial or fungal growth or bad odor.  No changes in the smoothness of the tablets were noted.  The drug content was found to be 98.92% indicates the no significant changes. The same drug release pattern was achieved after one month period indicates the stability of the formulation.  The in vitro release profiles were shown in Fig. 12.

 

 

Table. 6: Stability study data of formulation (F8)   on initial day and after  one month

Parameters	Tablets on initial  day	Tablets after one month
Physical appearance	Off white, smooth, flat faced	Off white, smooth, flat faced
Weight variation(mg)	702±2.88	701±2.97
Hardness(kg/cm2)	8.2±0.55	8.1±0.28
Friability(%)	0.31±0.25	0.3±0.22
Drug content(%)	99.26±0.44	98.92±0.41
Buoyancy lag time(sec)	52 sec	51 sec
Total floating time(hr)	12hr	12hr
Buoyancy an disturbing	Float	Float

 

 

 

 

 

 

 

 

 

 

 

4. CONCLUSION:

From this present study of Cefixime floating matrix tablets, it was concluded that efferevescent based floating drug delivery might be a promising approach to prolong gastric retention of cefxime where absorption pattern is good. Thereby able to maintain the steady state plasma concentration which will result in increasing bioavailability and also decreases the dosing frequency improves the patient compliance.

 

Fig. 12: In vitro release of Cefixime of formulation (F8) on initial day and after one month

 

5. ACKNOWLEDGEMENT:

The authors wish to thank the management of Jayamukhi Educational Society for providing necessary research facilities.

 

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Received on 28.03.2014          Modified on 25.04.2014

Accepted on 01.06.2014          © RJPT All right reserved