INTRODUCTION:

Conventional oral drug delivery systems have posed certain disadvantages like drug with short half life requires frequent administration of dose leading to patient non-compliance. The fluctuating plasma drug level may lead to precipitation of adverse effects especially of drugs with narrow therapeutic index. The research and development of new drugs was required so many time and high cost and now a time very few drugs are coming out of research studies. Sustained release is providing promising way to decrease side effect of drug by preventing the fluctuation of drug plasma in the body, to extend the duration of action, to reduce the frequency of dosing and it is required for better patient compliance.¹

In sustained release drug delivery system is continuous release of drug have been achieved for an extended period of time after administration of a single dose and it achieve prolong therapeutic effect and maintain constant plasma drug level.^{2, 5} Sustained release of drug can be obtained by formulating drugs in matrix controlled release system using various polymers. Matrix devices may employ hydrophilic polymer (e.g. hydroxypropyl methyl cellulose) or hydrophobic materials (e.g. polymethacrylates).^2,6,8The advantage of matrix system was utilized to develop sustained release formulation of drugs. Hydroxyl propyl methylcellulose (HPMC) is the hydrophilic polymer which has advantage of release drug from matrix irrespective of pH and hence constant release rate throughout the gastrointestinal tract can be expected from HPMC based matrix tablets.⁹

Cephalexin is a first generation cephalosporin antimicrobial agent with activity against Gram negative microorganisms. Oral therapy with cephalexin results in peak concentration in plasma of 18 mcg/mL after a dose of 500mg. The usual oral or parenteral antibiotic regimen results in high peak levels that fall well below therapeutic concentration before administration of next dose.²² The commonly accepted optimum approach to administration of many beta lactam antibiotics including cephalexin, involves frequent dosing in quantities that will maintain plasma concentration above MIC for duration of dosing interval (for cephalexin the plasma concentration above 1.0 mcg/mL is above the MIC in vitro for most of the susceptible microorganisms).³ These characteristics coupled with the short biological half life (1 hour) of cephalexin suggest that it is a rational candidate for a SR (sustained release) dosage form. On the other hand the recommended dosage regimen for conventional formulations requires 1-4gm/day in four divided doses.^{22, 23} This regimen results in unnecessarily high peak plasma concentration and undesirable low (usually sub therapeutic) plasma concentrations during laterportion of dosing interval.^12-16 Thus to reduce the frequency of dosing and consequently improve patient compliance, formulating cephalexin in sustained release dosage form is desirable.

Preparation of sustained release formulations by matrix technique is a commonly employed method because of its ease, flexibility and cost efficiency and is recommended by the regulatory bodies.^2,4,7The judicious selection of polymers is required based on physicochemical properties of drug candidate. In the present study,hypromellose polymers (Methocel 100LV, K4M, K15M and K100M), Acrylic acid polymers (Carbomer 974P and 971P) and Methacrylate polymers (Eudragit L100, RL100 and RS100) are used for sustaining the drug release from the matrix formulation.^18,21,55,56Hence it was envisaged to develop sustained release tablets of cephalexin by using combination of hydrophilic and hydrophobic polymers.

MATERIALS AND METHODS:

Materials

Cephalexin monohydrate was obtained as gift sample from Sun Pharmaceuticals Ltd., Ahmadabad (India). Methocel (HPMC) K15M, K4M, K100M, K100LV was obtained as gift samples from Colorcon Ltd., Goa (India). Eudragit RS100, RL100, L100 were obtained as gift samples from Degussa India Pvt Ltd., Mumbai (India).Other materials used were of analytical reagent grade and were purchased from S.D. Fine chemicals, Mumbai (India).

Determination of cephalexin dose for extended release ^{26, 66-83}

The dose of cephalexin required for initial and sustained delivery is calculated by considering pharmacokinetic parameters of cephalexin.

Biological half life (t_1/2) = 1hour

First order elimination rate constant (K _el) = 0.693/t_1/2

Time to reach peak plasma concentration (T_p) = 1hour

Volume of distribution (V_d) = 15L

Desired therapeutic concentration (DTC) for 125 mg dose = 4.5 mg/L

Time for which drug is to be released from extended dose (T) = 6hours

Desired constant release rate K ^o_r (zero order release)

K ^o_r = K _el´V_d´DTC

K ^o_{r =}0.693/1 ´ 15 ´ 4.5 = 46.7 mg/h

DT = DI* + DS

Where, DT is total dose, DI* is corrected initial dose, DS is

Sustained dose

DS = K ^o_r´T

DS = 46.7 ´ 6 =280.7 mg

Amount of drug released from maintenance dose during release of initial dose (Till peak plasma concentration achieved)

= K ^o_r´Tp

= 46.7 ´ 1 = 46.7 mg/h

DI* = DI - 46.7

DI* = 125 - 46.7 = 78.3 mg

DT = DI* + DS

DT = 78.3 + 280.7 = 359 mg

Total dose for extended release formulation = 359 mg (Adjusted to 375 mg.)

Briefly; the tablet should release 78.3 mg of cephalexin initially within first 1 h and 46.7 mg of cephalexin per hour for next 5 h from 375 mg of calculated total dose in order to maintain plasma cephalexin concentration of 4.5 mg/L.

Analysis of drug candidate cephalexin monohydrate^57-65

v Organoleptic properties: The drug sample was studied for odor, color and appearance.

v Solubility: The drug was added to fixed amount of solvent till saturation. After 24 hours the supernatant was filtered, appropriately diluted and analyzed by UV at 261 nm.

v UV Spectroscopy: A stock solution of cephalexin 100 µg/mL was prepared in water. The UV spectrum was recorded in the range of 200-400 nm. The wavelength of maximum absorption (λ max) was determined.

Preparation of matrix tablets of Cephalexin

The tablets were prepared by wet granulation technique. Various ingredients and their quantities used were as shown in the Table 1, 2 and 3. Cephalexin, lactose and polymer were mixed by passing through 60# sieve and granulated using PVP K-30 in isopropyl alcohol as granulating aid, the wet mass was then passed through 16# sieve. Granules thus obtained were air dried for one hour. Dried granules were lubricated with magnesium stearate. Desired quantity of granules were weighed and fed manually into the die of rotary tablet machine (Kilburn Manesty Single Punch Machine) to produce tablets using flat-faced lower punch and upper punch with central break line (diameter 12 mm).^22-31

Table 1 Matrix systems containing HPMC and ethyl cellulose

Formulation code.Þ Ingredients (mg)ß	K1	K2	K3	K4	K5	K6	K7	K8	K9	K10
Cephalexin monohydrate	395^*	395^*	395^*	395^*	395^*	395^*	395^*	395^*	395^*	395^*
Lactose	40	40	40	40	40	40	40	40	40	40
PVP K30	7	7	7	7	7	7	7	7	7	7
Magnesium stearate	3	3	3	3	3	3	3	3	3	3
Ethyl cellulose	5	5	5	5	5	5	5	5	5	5
HPMC K4M	-	-	-	-	35		-		-	-
HPMC K15M	-	-	-	-		35	32	-	-	-
HPMC K100M	70	53	44	28	-	-	-	-	-	-
HPMC K100 LV	-	-	-	-	-	-	-	35	45	100
Tablet Weight (mg)	520	503	494	478	485	485	482	485	495	550

* Equivalent to375mg of anhydrous cephalexin

Table 2 Matrix systems containing carbomer

Formulation code.Þ Ingredients (mg)ß	C1	C2	C3	C4	C5	C6	C7
Cephalexin monohydrate	395*	395*	395*	395*	395*	395*	395*
Lactose	40	40	40	40	40	40	40
PVP K30	7	7	7	7	7	7	7
Magnesium stearate	3	3	3	3	3	3	3
Carbopol 971P	50	20	30	35	-	-	-
Carbopol 974P	-	-	-	-	45	30	35
Tablet Weight (mg)	495	465	475	480	490	475	480

Table 3 Matrix systems containing Eudragit

Formulation code.Þ Ingredients (mg) ß	E1	E2	E3	E4	E5	E6	E7
Cephalexin monohydrate	395*	975*	395*	395*	395*	395*	395*
Lactose	40	40	40	40	40	40	40
PVP K30	7	7	7	7	7	7	7
Magnesium stearate	3	3	3	3	3	3	3
Eudragit RS100	-	-	-	45	15	-	-
Eudragit RL 100	-	-	-	-	-	45	20
Eudragit L100	45	80	100	-	-	-
Tablet Weight (mg)	490	525	545	490	460	490	465

Comparisons of optimized formulation batches with marketed formulations

It is required to compare the optimized formulation batches with marketed formulation by utilising the parameters like difference factor (f₁), similarity factor (f₂), t_50%,t_70%and t_90%..The difference factor measures the percent error between two release profile curves over all time points. The percent error is zero when the test and the reference profiles are identical and increases proportionally with increasing dissimilarity between the two dissolution profiles. The similarity factor measures similarity between two release profile curves.According to FDA,f₁values lower than 15 (0-15) and f₂values higher than 50 (50-100) indicate similarity of dissolution profiles

Table 5 Comparison of in vitro dissolution profiles of formulations with that of marketed formulation using similarity factor (f2) and difference factor (f1)

Formulation code	Similarity factor (f2)	Difference factor (f1)
K4	68.28	4.4
K5	66.73	5.23
K7	57.46	8.51
K10	53.74	8.78
C4	57.81	7.96
C7	48.85	12.39
E3	31.01	18.80
E5	51.81	10.47
E7	50.53	10.67

Table 6 Comparisons of t_50%, t_70%, t_90% and Mean dissolution time (MDT)

Formulation code	t _50% (h)	t _7o% (h)	t _90% (h)	MDT (h)
K4	1.48	2.82	4.18	1.46
K5	1.64	3.03	4.56	1.54
K7	2.05	3.30	4.56	1.93
K10	1.07	2.53	4.00	1.34
C4	1.60	2.93	4.26	1.60
C7	1.94	3.31	4.67	1.94
E3	2.81	3.93	5.04	2.78
E5	2.03	3.33	4.63	1.94
E7	1.24	2.79	4.34	1.50
M1	1.67	2.98	4.30	1.61

Stability studies

Stability studies of optimized formulation batches were performed as per ICH guidelines. Optimised batches were kept for stability studies at 40 ⁰C/75 %RH for two months. From results of stability studies it was observed that there was no significant change (1 to 3%) in drug content and in vitro dissolution profiles.

Discussion

A sustained release matrix tablet should release drug in predetermined rate to maintain the controlled and effective plasma drug concentration. In order to achieve the tablet that releases drug in predetermined rate, we formulate drug with hydrophilic polymers (e.g. HPMC, carbopol, and eudragit) in matrix device to obtain sustained release. In present study we were developed the formulation of cephalexin monohydrate using different concentration and various grades of polymers having different viscosities to achieve the sustained release of the drug up to 6hours.

Effect of polymers on release pattern of cephalexin

A] Effect of HPMC

An ideal extended release tablet should release required quantity of drug in order to maintain effective constant plasma drug concentration. Formulation batches K1 to K10 were formulated using various types and proportion of HPMC as per the formula given in table 1. Figure 1 and 2 reveal the effect of HPMC on release of cephalexin from tablet matrix. It was observed that the release rate was slower with higher quantities and higher viscosities of HPMC i.e. (HPMC K100LV < K4M < K15M < K100M). The tablet compositions containing 26.66% of K100LV, 9.3% of K4M, 8.5% of K15M, 7.4 % of K100M with respect to anhydrous drug provided sustained release for 6 hours as shown in Figure 5. The mechanism of release of drug from HPMC based matrix was observed as when HPMC comes under the presence of drug releasing medium, it was swelled to form a thick gel and hence may decrease thickness of pores through which diffusion of drug towards dissolution medium occurs.

B] Effect of carbopol

Formulation batches C1 to C7 were formulated using different proportions of carbopol 971P and 974P. With the increase in proportion of carbopol, release of cephalexin was found to be decreased. Carbopol 971P and 974P in proportion of 9.3% with respect to anhydrous drug produced sustained effect for 6 hours as shown in figure 6. Although two carbopols sustained the drug release, rate of drug release was slower in case of carbopol 974P, which may be attributed to its viscosity, which is greater than that of carbopol 971P.

C] Effect of eudragit

In order to study effect of eudragits on release of cephalexin, eudragit L100 (pH dependent) and eudragits RL100 and RS100 (pH independent) were employed. Batches E1 to E7 were formulated as shown in table 3. Figure 4 shows the effect of eudragits on release of cephalexin from the tablet matrices. An inverse relation is observed between release of cephalexin and quantity of eudragit. Eudragit L100 being pH dependent, solubilises at pH above 6. It shows retardant effect in acidic pH for initial two hours and faster release in alkaline pH.

Eudragit L100, RL100 and RS100 in proportion of 21.33%, 5.3%, and 4% respectively with respect to anhydrous drug provided sustained effect for desired time as shown in figure7. Release rate with Eudragit RS100 was slower as compared to Eudragit RL100, which might be due to lower permeability of Eudragit RS100 as compared to Eudragit RL100.

D] Release kinetic treatment

For Zero order treatment the R²values ranged from 0.804-0.90, which indicates that, the formulations do not follow zero order kinetics.The R²values of first order treatment ranges from 0.820-0.997. Mainly the formulations containing HPMC and carbopol has shown fair linearity in release of drug from the matrices as R² values were 0.996, 0.997, 0.974, 0.994, and 0.962 for the formulations K4, K5, K7, K10 and C4 respectively.

When the data was subjected to Higuchi treatment, R²values ranged from 0.88-0.97. The formulations containing HPMC as well as eudragit produced fair linearity; R²values ranging from 0.914-0.987 further strengthens the statement. The data was also given Hixson-Crowell treatment where in R²values ranged from 0.857-0.986.

In order to predict the release mechanism, the data was subjected to Korsmeyer-peppas treatment. The release exponent (n) values were determined and play an important role in determining release mechanism. For the formulations containing HPMC i.e. K4, K5, K7and K10 the values ranged from 0.5 –0.67 indicating that the dominant mechanism for drug release through HPMC basedmatrix systems may be anomalous (non-fickian) transport. For formulations containing carbopol namely C3 and C7, exponent values were 0.56 and 0.60 respectively indicating that drug may be released by anomalous transport. On the other hand Eudragit L100 containing formulation (E3) has exponent value equal to 1.02.indicating that Super case II transport may be the release mechanism from this matrix system. For formulation E5 and E7 the (n) values were found to be 0.73 and 0.34, which denote anomalous transport. The marketed preparation shows exponent value of 0.50 indicating fickian diffusion as release mechanism.

E]Comparison of release profiles using Similarity factor (f2) and Difference factor (f1)

Similarity factor and difference factor were calculated for all optimized formulations (showing sustained effect for 6 hours) considering marketed formulation as the reference standard. The values for the same are shown in table 5. It can be seen that formulations C7 and E3 have lowest values of f2 i.e. 48.85 and 31.01 respectively and higher values of f1 i.e. 12.39 and18.80 suggesting that these formulations show greatest deviation from marketed formulation as compared to other formulated products. Other formulations show f2 values between 50-100 and f1 values between 0-15 indicating similarities of dissolution profiles with that of marketed formulation.

Comparisons of t_50%, t_70%, t_90% and mean dissolution time (MDT) between optimized formulations and marketed formulation

The parameters t_50%, t_70%, t_90% (as shown in Table 6) was used for the comparison of formulated products with that of marketed preparation. The values for t_50%, t_70%and t_90% of formulation C4 was found to be 1.59 hours, 2.92hours and 4.26hours respectively. The values for t_50%, t_70%and t_90%of formulation K5 was found to be 1.63hours, 3.03hours and 4.44hours respectively. The marketed formulation has shown the value of t_50%, t_70%and t_90%as 1.6hours, 2.98hours and 4.30hours respectively. This suggests that formulations C4 (carbopol 971P) and K5 (HPMC K4M) show release profiles comparable with that of marketed preparation.

MDT is another parameter, which can be used for comparison of release profiles. MDT of formulation E3 was found to be highest (2.78hours) which show higher retarding effect, on other hand formulation K4 has shown lower value of MDT (1.46hours). The MDT value of C4 (1.6hours) and marketed formulation (1.61hours) were same. This further confirms that C4 (carbopol 971P) and marketed formulation have similar release profiles.

Stability studies

From results of stability studies it was observed that there was no significant change (1 to 3%) in drug content and in vitro dissolution profile at 40⁰C/75%RH for two months.

Sustained release matrix tablets of cephalexin were prepared using Hypromellose (HPMC), Carbomers and Polymethacrylates (Eudragit) as release retarding polymers. In case of formulations containing Carbopol and HPMC, viscosity was a major factor affecting the drug release. An inverse relationship existed between polymer viscosity and drug release; thus higher the polymer viscosity, lower was the drug release.Thus Carbopol, Eudragit and HPMC were found to be suitable as bases for preparing tablet matrices containing Cephalexin but only Carbopol 971P and HPMC K4M were able to produce release profile similar to that of marketed preparation.

SUMMARY AND CONCLUSION:

Sustained release matrix tablets of Cephalexin were prepared using HPMC, Carbomers and Polymethacrylates as release retarding polymers. Kinetic treatment of drug release data revealed that formulations containing K4, K5, K7, K10, E5 and C4 followed First order release kinetics. Formulation E3 showed zero order release kinetics where as marketed preparation and formulation E7 followed Higuchi’s release kinetics.

Similarity factor and difference factor values indicated that formulations K4, K5, K7, K10, C4, E5 and E7 showed similarity of dissolution profiles. Formulations C4 and K5 showed drug release pattern which were similar to marketed preparation (Nufex SR) manufactured by RPG Life sciences Limited, Mumbai. This was further supported by similarity factor, difference factor, MDT, t_50%, t_70%and t_90% values. In case of formulations containing Carbopol and HPMC, viscosity was a major factor affecting the drug release. An inverse relationship existed between polymer viscosity and drug release; thus higher the polymer viscosity lower was the drug release.

ACKNOWLEDGEMENT:

The authors would like to thank University Grant Commission (UGC), New Delhi for the financial assistance and authors would also like to thank, Head of the Department of Pharmaceutical Sciences, R.T.M Nagpur University, Nagpur, India for constant encouragement and support for the work.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 20.03.2016 Modified on 24.04.2016

Research J. Pharm. and Tech. 9(4): April, 2016; Page 474-478

DOI: 10.5958/0974-360X.2016.00088.3

Formulation Code	(R²) values
Formulation Code	Zero order	First order	Higuchis model	Hixson-Crowell model
K4	0.8115	0.9964	0.9344	0.9860
K5	0.8044	0.9969	0.9490	0.9680
K7	0.8745	0.9745	0.9869	0.9510
K10	0.9001	0.9940	0.9744	0.9770
C4	0.7887	0.9626	0.8890	0.8570
C7	0.8209	0.8279	0.8810	0.9020
E3	0.9747	0.9162	0.9523	-0.8390
E5	0.8419	0.9310	0.9159	0.9140
E7	0.7362	0.8199	0.9141	0.9060
M1	0.8636	0.9643	0.9747	0.9630

Amount of drug released from maintenance dose during release of initial dose (Till peak plasma concentration achieved)

K1

K2

K3

K4

K5

K6

K7

K8

K9

K10

C1

C2

C3

C4

C5

C6

C7

E1

E2

E3

E4

E5

E6

E7

Evaluation of tablets

Formulated matrix tablets and marketed tablets were evaluated for thickness, weight variation, hardness (Monsanto hardness tester), and friability (friability test apparatus, Veego Ltd.).