Formulation and Evaluation of Floating Drug Delivery System of Antidiabetic Drug

 

Rekha Hondadakatti*, S. R. Iliger, Manjula Lagali

Department of Pharmaceutics, S.E.T’s College of Pharmacy, Dharwad-580 002 India.

 

ABSTRACT:

Repaglinide is an anti-diabetic, oral blood-glucose lowering drug of the meglitinide class used in the management of type-II diabetes mellitus. The present investigation was concerned with the development of the floating matrix tablets, which after oral administration are designed to prolong the gastric residence time and thus, improve the bioavailability of the drug as well as its half life. Repaglinide showed maximum absorption at wavelength 244 nm in 0.5N HCl. Drug-polymer compatibility studies by FT-IR gave confirmation about their purity and showed no interaction between drug and selected polymers. Various formulations were developed by using release rate controlling and gel forming polymers like HPMC (K-4M, K-15M & K-100M) by direct compression method with the incorporation of sodium bicarbonate as gas generating agent. All the formulations had floating lag time below 47.5 seconds and constantly exhibited floating on dissolution medium for more than 24 h. swelling studies indicated significant water uptake and contributed in drug release. The formulation with HPMC K4M (F1, F2 & F3) showed drug release rate between 96 to 99%. The use of HPMC K15M (F4, F5 & F6) have shown drug release rate from 89.3 to 98.2% and formulations with HPMC K100M (F7, F8 & F9) have shown drug release rate between 72 to 84%. From among all the developed formulations, as formulation F5-99% released the drug for longer period of time and it had slightly less floating lag time as compared to other formulations. So, it was selected as the best formulation. It was concluded that the drug release followed zero order kinetic, as the correlation coefficient (R2 value) was higher for zero order release.

 

 

 

 

INTRODUCTION:

Floating drug delivery systems are type of gastro retentive systems that are formulated to remain in the stomach region for several hours for effective delivery of certain acidic drugs that are absorbable in stomach region. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients. Furthermore drugs which are readily absorbed exhibit improved bioavailability and hence are considered as ideal candidates for sustained release in gastro intestinal track. Many methods are available for increasing retention time of formulation in the stomach such as low density based, bioadhesive type, swelling and expanding drug delivery systems.¹

 

MATERIAL AND METHODS:

Repaglinide was received as gift from Sun Pharmaceuticals Ltd Mumbai. Hydroxy propyl methyl cellulose (K4M, K15M, K100M) was procured from Ozone Pharmaceuticals, Mumbai. Sodium bicarbonate was purchased from S D fine-chem limited. Lactose, Carbopol 940, Magnesium stearate and Talc from HiMedia Laboratories Pvt Ltd. All other ingredients and chemicals used were of analytical grade.

 

Preformulation study:

The drug was physically characterized according to following methods

 

Color of the drug sample:

The drug sample was viewed visually for the determination of its color using the black and white backgrounds.

 

Melting point of the drug sample:

The melting point is one of the important methods for the identification of the drug sample. The melting point of the given drug sample was carried out by using Liquid paraffin as a bath liquid.

 

Solubility:

Preformulation study is one of the important prerequisite in development of any drug delivery system. Thus, a preformulation study was carried out to check the compatibility between drug and selected polymers and development of analytical method of drug.

 

Drug polymer compatibility studies:

Drug polymer compatibility studies were carried out using FTIR.

 

Infrared spectrum of pure drug was seen in between 1215.39 to 3307.99 cm-1.

 

Method of preparation:

Repaglinide, selected polymer (Hydroxypropyl methyl cellulose), Sodium bicarbonate and Lactose, Carbopol 940 were taken in required quantities. In dry state, drug was mixed with other ingredients for the period of 10 min in mortar to get uniform mixture. Powder was lubricated with magnesium stearate and talc. Lubricated powder was compressed to tablets in 7.5 mm die cavity of tablet punching machine.5-7 Table 1.

 

 

Table 1 Formulation of repaglinide

Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Repaglinide	8	8	8	8	8	8	8	8	8
HPMC K4M	24	32	40	-	-	-	-	-	-
HPMC K15M	-	-	-	24	32	40	-	-	-
HPMCK100M	-	-	-	-	-	-	24	32	40
Carbopol 940	10	10	10	10	10	10	10	10	10
Lactose	53	50	42	53	50	42	53	50	42
NaHCO3	50	45	45	50	45	45	50	45	45
Talc	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
Magnesium Stearate	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
Total weight	150	150	150	150	150	150	150	150	150

 

 

RESULTS AND DISCUSSION:

Preformulation studies:

The preformulation study like qualitative analysis of raw materials and drug which includes physical characterization and analytical methodologies and evaluation of tablet blend including determination of bulk density, tapped density, compressibility index, Hausner ratio and angle of repose were performed.

 

Physical characterization of drug sample:

a.     Description: The received sample of repaglinide was found to show the following characteristics.

b.     Nature: amorphous powder.

c.     Color: White to off white powder.

d.     Melting Point: 130-1310 C

The description of the drug was found to be identical with the reference sample of Repaglinide

e.     Solubility:

The solubility of the received sample of Repaglinide in methanol and acidic buffer (pH1.2).

 

Drug polymer compatibility studies:

Drug polymer compatibility studies were carried out using FTIR.Infrared spectrum of pure drug was seen in between 1215.39 to 3307.99 cm-1. The study was carried out on individual pure drug and its physical mixture with the selected polymers under study.

 

 

Fig 1: FTIR of Drug and polymer

 

Evaluation of preformulation parameters:

 

Table2: Micromeritics data of Repaglinide floating matrix tablets

 

Angle of Repose:

The angle of repose value for formulation F1–F9 ranged from 25.69±0.213 to 28.94±0.866 which indicate the passable flow properties of powder.

 

Bulk density and tapped density:

The value of bulk density and tapped density for formulation F1–F9 ranged from 0.31 ± 0.0009 to 0.38 ± 0.0018 g/ml and 0.36 ± 0.0006 to 0.44 ±0.0024 g/ml respectively.

 

Compressibility index:

The Compressibility index values for formulation F1–F9 ranged from 10.57.± 0.17 to 13.76±0.79 %. These values indicate that the powder mixture of all batches exhibited good to fair characters and hence, they were suitable for direct compression.

 

Evaluation of physicochemical parameters of developed floating matrix tablets:

Table 3: Physicochemical parameters of floating matrix tablet of Repaglinide.

Formulation Code	Hardness (kg/cm2)	Friability (% loss)	Weight Variation (mgs)	Thickness (mm)	Drug Content (%)	Floating Lag Time (sec)	Floatig Time (h)
F-1	5.6 ± 0.56	0.54	149.88 ±0.61	2.69 ±0. 048	99.56±0.82	43.50±1.10	> 12
F-2	5.0 ± 0.18	0.458	150.22±1.85	2.68± 0.02	100.65±0.53	46.43±0.60	> 12
F-3	5.2±0.78	0.355	150.11±1.9	2.715±0.034	99.12±0.82	35.33±0.31	> 12
F-4	5.2±0.61	0.387	150.89±2.26	2.703±0.045	97.14±0.82	37.67±0.41	> 12
F-5	5.6±0.39	0.34	150.33±2.07	2.758±0.062	96.92±0.82	36.10±0.36	> 12
F-6	6.8±0.7	0.444	150.607±18	2.753±0.028	99.12±0.82	33.67±0.31	> 12
F-7	5.6±0.78	0.45	149.00±1.69	2.68± 0.03	98.02±0.53	40.90±0.79	> 12
F-8	4.8±0.47	0.378	149.88±2.37	2.698±0.103	98.68±0.53	47.5±0.44	>1 2
F-9	6.2±0.41	0.331	150.13±2.47	2.737± 0.11	99.34±0.53	35.26±0.31	> 12

 

Post compression formulation studies:

Hardness:

Hardness of the developed formulations F1 to F-9 varied from 4.8±0.47 kg/cm2 to 6.8±0.7 kg/cm2 indicating enough hardness for tablet to remain intact up to 12 h.

 

Friability:

Friability of the developed formulations varied from 0.331 to 0.54 % loss which was less than 1% as per official requirement of IP.

 

Weight variation:

The average weight of 20 tablets was calculated for formulation F1 – F9 and it varies from 149.88 ± 0.61 to 150.89± 2.26 % which complied with the official limit of the IP.

 

Thickness:

The thickness values for formulation F1 – F9 ranged from of 2.68± 0.03 mm to 2.758± 0.062 mm. Each sample was analyzed in triplicate (n=3).

Uniformity of drug content:

The drug content varied from 96.92± 0.82% to 100.65± 0.53 % which was within the required limits.

 

Floating lag time:

The floating lag time for formulation F1 – F9 ranged from 33.67±0.31 to 47.5±0.44 sec.

 

Total floating time:

The total floating time for formulation F1 – F9 was found to be more than 12h.

 

 

Table 4: Swelling Characteristics of Floating Matrix Tablets of Repaglinide

Formulation	Swelling Index (%)
	Time (h)
	1	4	8	12
F1	35.19 ±0.87	50 ±0.66	81.11 ±1.01	111.77 ±1.01
F2	39.33 ±0.54	56.22 ±0.83	90 ±0.54	118 ±0.54
F3	45.11 ±0.83	59.33 ±0.54	95.33 ±0.54	124.66 ±0.54
F4	47.33 ±0.54	64 ±0.54	90.88 ±0.83	132.66 ±0.54
F5	51.11 ±0.83	76.88 ±0.62	96.44 ±0.83	133.55 ±0.83
F6	62.22 ±0.83	80.44 ±0.83	102.44 ±0.83	141.55 ±0.83
F7	49.77 ±0.62	75.77 ±0.31	97.11 ±0.83	135.33 ±0.54
F8	62 ±0.54	82.88 ±0.83	98.66 ±0.54	136.88 ±0.83
F9	75.33 ±0.54	88.22 ±0.54	111.33 ±0.54	148.66 ±0.54

 

 

Swelling characteristics:

The swelling characteristics for formulation F1 – F9 ranged from 35.19± 0.87 to 148.66± 0.54 % up to 12 h. The percentage water uptake was found to be improved by increasing the concentration of HPMC in formulations. Formulation F9 had maximum swelling index of 131.6 ± 3.302%. The highest degree of hydration was achieved by HPMC K100M based formulations.

The swelling index of HPMC K4M based formulations F1 to F3 was low compared to that of HPMC K15M and HPMC K100M based tablets. The swelling index of HPMC K15M based formulations F4 to F6 was low compared to that of HPMC K100M tablets and it was high compared to that of HPMC K4M tablets. The swelling index of HPMC K100M based formulations F7 to F9 was high compared to that of HPMC K4M and HPMC K15M based tablets.

The swelling index of the selected polymers is in the following order:

HPMC K100M > HPMC K15M > HPMC K4M

 

In-vitro dissolution studies:

The release rate of repaglinide from floating matrix tablets were determined using USP dissolution testing apparatus II (paddle type). The dissolution test was performed using 900 ml of simulated gastric fluid (0.1 N HCl) at 37 ± 0.5 °C at 50 rpm. Aliquots were withdrawn at hourly internals for 12h and the volume withdrawn was replaced with fresh dissolution medium. The After filtration, the amount of drug release was determined from the standard calibration curve of pure drug.

 

Table 5: Cumulative % drug release

Abs.	%CDR F1	%CDR F2	%CDR F3	%CDR F4	%CDR F5	%CDR F6	%CDR F7	%CDR F8	%CDR F9
0.001	12.00	9.00	6.00	12.00	9.00	6.00	9.00	6.00	3.00
0.003	21.01	15.00	12.00	18.00	15.00	12.00	15.00	12.00	9.00
0.005	33.01	21.01	21.01	27.01	24.01	18.00	21.01	18.00	15.00
0.007	45.02	27.01	27.01	33.01	30.01	24.01	27.01	24.01	21.01
0.008	54.02	36.01	33.01	42.02	36.01	30.01	30.01	27.01	24.01
0.010	63.03	45.02	39.02	54.02	45.02	36.01	33.01	33.01	30.01
0.011	72.03	57.03	45.02	60.03	54.02	39.02	39.02	36.01	33.01
0.013	78.04	66.03	54.02	69.03	63.03	45.02	45.02	42.02	39.02
0.015	81.04	75.04	63.03	75.04	72.03	54.02	54.02	48.02	45.02
0.017	99.05	84.04	72.03	81.04	81.04	63.03	63.03	57.03	51.02
0.021	----	96.05	87.04	99.05	87.04	75.04	75.04	69.03	63.03
0.024	----	----	96.05	----	99.05	87.04	84.04	78.04	72.03

 

Fig 2: Dissolutions of F1to F9

 

 

In vitro drug release studies:

The release of Repaglinide from floating tablets varied according to the types and proportion of matrix forming polymers.The progressive decrease in the amount of drug release from formulations F1 to F3 attributed to gradual increase in HPMC K4M content. It has been concluded that increase in the proportion of matrix forming polymer HPMC K4M, increases the viscosity of gel and retards the drug release which leads to better control of polymers on the release of folic acid. The duration of drug release of formulation F3 was slower among the formulations F1 to F3. Same condition was found in case of HPMC K15M and HPMC K100M. In case of HPMC K15M drug release of formulation F6 was slower among the formulations F4 to F6. In case of HPMC K100M, drug release of formulation F9 was slower among the formulations F7 to F9.

 

Among the three grades of HPMC used, the tablets prepared with lower viscosity grade i.e. HPMC K4M have shown drug release rate higher than the tablets prepared with HPMC K15M and HPMC K100M. Among all F1 to F9 formulation F5 was found to be best release profile 99.05% in 12 h.The order of drug release from the selected polymers were found to decrease in the following order

 

HPMC K-100M > HPMC K-15M > HPMC K-4M

 

Table 5: Kinetic release study of Zero order, First order, Highchi’s, Peppas.

Formulation	Kinetics Modeling
	Zero order	First order	Higuchi	Korsmeyer- Peppas
F1	0.988	0.838	0.946	0.773	1.400
F2	0.991	0.784	0.877	0.847	1.395
F3	0.984	0.748	0.868	0.893	1.400
F4	0.993	0.630	0.914	0.792	1.328
F5	0.996	0.676	0.902	0.846	1.346
F6	0.977	0.824	0.862	0.885	1.341
F7	0.973	0.849	0.869	0.818	1.233
F8	0.977	0.876	0.870	0.874	1.292
F9	0.980	0.900	0.866	0.938	1.407

 

Kinetics modeling of drug dissolution profiles:

The in vitro drug release data obtained were fitted in to various kinetic models (Zero order, First order, Higuchi, Korsmeyer-Peppas). Correlation coefficients of formulation F1 to F9 batch showed higher correlation with zero order plots than higuchi and first order. Hence the mechanism of drug release is by controlled release.

Then (release exponent) value of formulation F1 to F9 in Korsmeyer-Peppas model is more than 0.89. So, the diffusion mechanism was Super case-II transport. Case-II relaxation release is the drug transport mechanism associated with stresses and state-transition in hydrophilic glassy polymers which swell in water or biological fluids. This term also includes polymer disentanglement and Erosion. Values of the exponent and indicate that the drug release is by diffusion controlled mechanism.

 

CONCLUSION:

In the present investigation, it can be concluded that the development of oral gastro- retentive floating tablets of Repaglinide can be an innovative and promising approach for the delivery system in the treatment of diabetes mellitus.

 

Developed floating matrix tablets were evaluated for physicochemical parameters such as hardness, friability, weight variation, drug content, swelling index and floating properties. All the developed floating matrix tablets floated up to 12 and 24 h.

 

Swelling studies indicated significant water uptake and contributed in drug release and gastro-retention. From among all the developed formulations, formulation F5 showed the drug release of 98.20% up to 12h. F5 produced sufficient swelling index to remain intact up to 12 h and released the drug slowly up to 12 h. So, it was selected as the best formulation.

 

This study is encouraging because a longer gastric residence time is an important condition for higher bioavailability of the drugs included in the prolonged or controlled release dosage form.

 

ACKNOWLEDGEMENT:

The authors are grateful to the S.E.T’s College of Pharmacy, Dharwad for the facilities.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 06.03.2021          Modified on 12.03.2021

Accepted on 20.03.2021       ©A&V Publications All right reserved